Robbins Essential Pathology [1 ed.] 9780323640251

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2015v1.0

RO B B I N S

ES S ENTIA L

PAT H O LO GY

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page

intentionally

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blank

RO B B I N S

ES S ENTIA L

PAT H O LO GY Vinay

A lice

Kumar,

Hogge

a nd

Depa r t ment

Biolog ic

of

Prit zker

The

Universit y

Chicago,

Abul

K.

Universit y

C.

Professor

Brig ha m

Boston,

of

Med ici ne

Chicago

Emeritus

Pat holog y

Ca lifornia

Sa n

Fra ncisco

Ca lifornia

Aster,

of

MBBS

Cha irma n

of

of

MD,

PhD

Pat holog y

a nd

Women’s

Med ica l

Hospita l

School

Massachuset ts

Andrea

A ssociate

T.

Deyrup,

of

Pat holog y

Universit y

Durha m,

MD,

Professor

Depa r t ment

Du ke

of

Abbas,

Fra ncisco,

Ha r va rd

FRCPath

Dist i ng uished

Div ision

School

a nd

Depa r t ment

Jon

MD,

Baer

Il li nois

Professor

Sa n

A.

Pat holog y

Science

The

MBBS ,

A r t hur

Nor t h

Med ica l

Ca roli na

Center

PhD

Ser v ice

Professor

1600

Ste

John

F.

Kennedy

Blvd.

1600

Phladelpha,

PA

19103-2899

ROBBINS

ESSENTIAL

Copyright

©

No

part

of

ths

mechancal,

permsson

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by

PATHOLOGY

Elsevier,

publcaton

ncludng

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wrtng

the

and

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as

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may

from

the

ISBN:

All

noted

rights

and

or

recordng,

publsher.

our

transmtted

or

Detals

any

on

contrbutons

can

be

to

seek

wth

found

contaned

n

any

nformaton

how

arrangements

Agency,

978-0-323-64025-1

reserved.

reproduced

Lcensng

ndvdual

be

be

polces

Copyrght

may

Inc.

photocopyng,

permssons

and

book

(other

2021

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at

form

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storage

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Content

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Manager:

Direction:

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Strategist:

Jm

Development:

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Kate

Catherne

Grulow

Jackson

Mannx

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Canada

s

the

prnt

number:

9

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of

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by

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heren.

dagnoses

products,

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descrbed

assumed

heren.

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experence

vericaton

responsblty

persons

operaton

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law,

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methods,

978-0 -323-64025-1

Executive

Last

and

nformaton,

and

Elsever,

of

drug

products

or

evaluatng

of

rapd

dosages

authors,

nstructons,

n

Because

edtors

lablty,

deas

and

advances

should

or

be

contrb-

neglgence

contaned

n

or

the

P R E F A C E

We

are

neced

In

pleased

o

e

Cnca

e

e

and

ded

n

a

n

ow

ogca,

e

new

ese

o

s

concse,

member

edon

n

new

empass

educaon,

s

wo

aug

scools,

e

o

o

e

Robbns

Textbook

1957),

book:

readabe

on

me-onored

dscplne

medcal

rs

(publsed

consderabe

medcal

e

mos

o

prncples

Wle

a

amly

con-

 •

 More than 600 USMLE-style, multiple-choice questions are avail-

able

Appcatons

wt

cne. ”

presen

preace

gudng

sented

o

roos.

Sanley

“te

fason,

reatng

major

devod

basc

and

matter

of

ow

ave

ave

to

to

ad

an

learn

scences

are

on

aug

n

n

an

An

all-elecronc

suden

efec,

a

a

o

apply

ese

me

clncal

neracvy

me

devoed

decreased.

o

ss

oday’s

and

graed

 •

Robbns

medcal

o

s

(and

Essenta

sudens

and

paolog y

new

oer

addon

e

o

s

dsllng

provdng

o

basc

Patoog y

by

early

scences)

nended

basc

clncal

Robbns

o

amly

o

o

dsease.

e

progressvely

sasy

conceps

o

exposure,

as

vgnees

undersandng

e

clncal

e

needs

paogene-

glg

To

consss

o

mee

e

ese

ree

ne-

componens:

concse,

maeral

suden,

s

readabe

dslled

w

an

o

fason,

e

empass

devod

normaon

on

of

dstractng

essenal

mecansms

o

or

detas. ”

ever y

Core

medcal

dsease.

daon

evance

ave

s

o

o

to

e

core

cnca

medcne. ”

pracce

paogenc

always

exensve

poo

been

e

plosopy

o

Cases

medcne

mecansms.

sreng

s

woven

o

glg

and

e

underscore

scenc

e

Clncal-paologc

e

no

Robbns’

e

abrc

amly

o

oun-

clncal

rel-

correlaons

o

books,

Robbns

and

o

We

crcal

orma

n

place

o

brngs

s

as

n

ope

e

a

capers

e

normaon

enables

o

been

a

er

an

possble

lbrar y

e

wa

uorals

collecon

mages

and

organ

cases

and

sysem-based

necessar y

or

negraed

neracve

negraon

o

ex,

only

mages

n

rom

sudens

coosng.

exper

aclaes

learned

allow

o

elecronc

(Supplemenal

vsual

ex

and

learn

Ho-spong

paologs

an

o

e

o

gross

orma.

syles

classwork.

er

In

rom

and

own

and

suden’s

eFgures)

learnng

a

so-

sde.

Suc

addon,

e

In

pace

an

Robbns

augmens

e

key

ex.

Althoughthetextisavailableinprintform,thecases,questions,and

expanded

orm.

We

mage

We

collecon

srongly

ope

o

Essenta

a

are

encourage

we

ofered

e

only

readers

n

o

e

ake

neracve

advanage

elecronc

o

e

ree

Patoog y.

ave

succeeded

n

provdng

a

book

a

as

adaped o e modern eacng o paolog y. We welcome, and ndeed

apprecae,

ors.

 E ach chapter is associated with ve to six clinical cases that relate

“patoog y

eaures

componens

 Nineteen text chapters in which the subject matter is presented in

“ogca,

 •

paolog y

morpolog y

relevance

goals,

o

o

are

and

w

because

conceps

casesandquestionstopromoteactivelearning.ecaseschallengethe

logc

Second,

mporan

preparaon.

assmlaon

negraed, organ sysem-based currculum a blends basc prncples

relevance.

board

currcula.

med-

Frs,

renorce

n

organc

deta

embed-

o

ad

cases, linked to both the text and the questions, will facilitate an

pre-

mpac

.

o

down

be

cnca

remaned

sudens

clncal

lad

s

dstractng

patoog y

canges

and

Patoog y–Wt

Robbns

subject

undamenals

now

of

commens

Parnersp

lence

n

and

beween

eedback

auors

rom

and

e

sudens

readers

s

and

er

essenal

nsruc-

or

excel-

educaon.

Vnay

Abul

Jon

Andrea

Kumar

K.

T.

Abbas

C.

Aster

Deyrup

Essenta

Patoog y.

v

A C K N O W L E D G M E N T S

Wrng a new book s a sgncan efor. We ave underaken s ask

n

response

orened

Several

ey

are

em

are

negraed

wo

currcula

asked

n

or

wc

a

sor,

clncally

paolog y

s

no

a

Dr.

provded

numerous

Raga

our

e

e

people

on

o

us

menon

Ramacandran,

edor

lg

o

e

a

e

mpeus

UCSF ,

Elsever,

o

ndvdually

and

Dr.

camponed

develop

bu

s

prncpal

Sco

s

book.

Senor

Senor

Lovc,

book

so

BWH.

a



day.

(lver),

ndvduals

and

a

Dr.

Mara

Duke

Margea,

Unversy

UCSF

Scool

o

(ner vous

Medcne

advsed n e developmen o e clncal cases. ey nclude Dr. Anna

Lsa Crowley (cardac), Dr. E. Wayne Massey (neurolog y), and Dr. Jon

Robers

rom

er

mages

Some

Robbns

ws

vi

o

(kdney).

Many

collecons.

ave

o

been

e

Revew

as

worked

Specal

we

wroe

relessly

menon



rom

and

conen

paenly

sould

be

w

made

o

o

desgn.

us

on

e

Execuve

Several

produc-

Conen

used

o

ese

n

e

our

gems

Patoog y

acknowledge.

colleagues

ave

been

provded

us

w

acknowledged

mages

were

e

book.

mulple-coce

of

Projec

by

bu

no

Ebooks

leas,

Kumar,

er

Kae

and

we

Ann

Mannx;

Clncal

owe

a

Abbas,

unwaverng

deep

Paul

deb

Ern

suppor,

Desgner

Key

o

graude

Malone,

we

could

Bran

Salsbury ;

were

Kumar

orgnally

and

Ed

publsed

Kla,

wom

n

we

and

Dever.

and

no

o

Tony

ave

our

amles:

Wllamson.

added

wses

lae

eac

Dr

oer

o

acknowledge

Tony

or

Monag

e

endurng

(1954–2018).

complemenng

and

menorsp

Fnally,

ndeed

we

ws

and

o

one

more

enancng

suppor

o

acknowledge

our

ndvdual

conrbuons.

Vnay

Abul

Kumar

K.

Jon

Andrea

quesons

Vnay

Manager

book o e several w wc we are already nvolved. Andrea T. Dey-

e

K.

ex.

Manager

Wou

rup

UCSF

Several

s

Las

Dr.

sysem).

developed

Elsever

Ramnder

capers. ey nclude Dr. Tony Cang, Unversy o Ccago (kdney),

Gll,

o

among

We are graeul o ose wo advsed us on e conen o ndvdual

Ryan

book

a

Sraegs Jm Merr; Drecor, Conen Developmen Rebecca Grulow ;

ndvduals

oo

see

or

colleagues

course

Merr,

could

numerous

exbook

sandalone

Jm

o

T.

Abbas

C.

Aster

Deyrup

To

our

sudens,

wo

connually

nspre

and

callenge

us.

C O N T E N T S

1

Cell

Injury

and

2

Inflammation

3

Hemodynamic

4

Diseases

5

Neoplasia,

6

Genetic

7

Diseases

8

Heart,

9

Hematopoietic

of

Cell

and

the

Immune

Diseases,

of

Blood

14

Thromboembolism,

System,

and

41

88

Vessels,

105

118

and

and

11

Kidney,

12

Gastrointestinal

13

Liver,

Biliary

14

Male

Genital

15

Female

16

Endocrine

17

Disorders

18

Musculoskeletal

19

Environmental

viii

1

63

Lung

327

Repair,

Disorders,

10

Index,

Death,

Upper

Lymphoid

Respiratory

Systems,

Tract,

137

163

186

System,

System,

Tract,

Genital

of

the

and

Pancreas,

Prostate,

Tract

System,

205

and

and

Breast,

222

Bladder,

250

264

Nervous

System

Disease,

System,

and

314

280

Skin,

296

240

Shock,

30

1

Cell

Injury

and

Cell

Death

O U T L I N E

Overview

of

Causes

Reversible

Cell

Cell

of

Cell

Death,

oer

sck

a

on

Cell

Injury

dseases

advances

e

cell

er

aler

e

Death,

and

s

n

e

cells

o

cells

sck.

bolog y

rs

o

s

“evl

unconal

all

One

medcne

un

sare

e

“masma, ”

o

was

o

dseases:

srucure.

an

umors, ”

causes.

and

dseases

and

medcne

s

and

All

8

Injury,

Reticulum

9

(ER)

Stress,

9

9

Aging,

9

Pathologic Accumulations in Cells, 12

underle

uncon

and

eme

n

7

unprovable

srucural

Cell

Cellular Adaptations to Stress, 11

arbued

and

uman

are

cellular

6

Death,

were

nebulous

paoog y

njured,

Cell

abnormales

ey

o

of

7

Ischemia,

Damage,

Cellular

mes,

because

Stress,

and

Toxin-Mediated

3

equally

a

and

1

DNA

of

undamenal

sms

Injury,

Pathways

medeval

zaon

Hypoxia

3

Mechanisms

and

Oxidative

1

Endoplasmic

Apoptosis,

In

1

Injury,

2

Necrosis,

Other

Injury,

Cell

e

e

lvng

ereore,

undersandng

o

e

aso

real-

organ-

Indvduals

common

bo

mos

bud

ces

are

o

oxygen

and,

nurens

and

n

e

oxc

case

o

scema,

meaboes

are

ces

are

aowed

o

up

 Toxns, wc abound n e envronmen, as we as some terapeu-

 •

 Envronmenta nsuts, suc as pysca rauma, radaon exposure,

 •

 Genetc abnormates, ncudng muaons a mpar e uncon

tc

ounda-

ow

ssues

essena

 •

are

eaure

deprve

dened

drugs

and

caper.

o

nurona

varous

mbaances

essena

accumuaon

o

proens

damaged

and

DNA

oer

or

muaons

abnorma,

a

ead

msoded

o

e

proens,

bo o wc cause ce dea  ey canno be repared or correced

OVERVIEW

OF

CELL

INJURY  •

In

response

and

recover,

Ces

beng

Ces

are

 •

to

stress,

or

may

normay

consany

dea

w

grouped

cells

be

manan

ree

adapt,

irreversibly

exposed

exerna

no

may

a

o

or

seady

be

damaged

sae,

couness

nerna

broad

may

injured

and

caed

sresses

by

or

njur y,

die.

omeostass,

poenay

Immunoogc

eases)

reversibly

despe

damagng

undergong

 •

reactons

agans

envronmena

oten

by

se

angens

rggerng

angens

(as

n

(as

n

auommune

aerges),

wc

ds-

cause

ce

nlammaon

 Agng, a orm o sow, progressve ce njur y

agens.

canges

a

caegores.

REVERSIBLE

CELL

INJURY

 Adaptatons are aeraons a enabe ces o cope w sresses w-

Reversible ou

damage,

suc

as

ncreased

musce

mass

n

response

o

changes workoad.

e

major

ceuar

adapaons

and

er

pysoogc

sgncance

are

summarzed

a

e

end

o

e

in

cells

is

that

characterized

are

not

by

functional

and

structural

permanent.

and

e paoogc

injury

ncreased

eares

canges

assocaed

w

ce

njur y

mosy

afec

cyo-

caper.

pasmc srucures bu do no damage nuce (nucear damage s usuay

 •

 Reversbe njury reers o srucura and uncona abnormaes a

rreversbe)

and

ncude

e

oowng:

can be correced  e njurous agen s removed. I e njury s per-

 • ssen

or

severe,



can

become

rreversbe

and

ead

o

ce

dea.

 Sweng of ce s as a resu  o n ux o waer. Ts s usu a  y c aus e d

In +

by many

cases,

ces

de

wou

raversng

a

deecabe

reversbe

a ure

o

 e

adenos  ne

 r pospae

( ATP) -d ep enden

Na

pase. +

K

 •

 Ce

deat

wo

major

s

e

end

resu

o

njur y.

As

we

dscuss

aer,

ere

p asma

membrane

pump

due

o

d e cre as e d

genera on

o

are +

ATP paways

o

ce

dea,

necross

and

apoposs,

and

or

p asma

membrane

d amage.

Te

 oss

o

n rac e u  ar

K

ey +

occur

Causes

Diverse

of

Cell

erng

responses

 •

cause

e

 Hypoxa

suppy),

nsus

crca

a

a

varey

o

njurous

injury

or

death

and

result

in

(reduced

are

osmo c

dr  a

disease.

wc

njure

ces

uncons,

neced

and

og c

ces

n

by

or

e

producng

by

oxns,

smuang

course

o

r yng

and

ner-

mmune

o

 •

eads

oxygen

caused

suppy)

by

and

bockage

scema

o

areres

(reduced

or

oss

o

bood

bood;

 •

 e

o

Na

ver,

o

n

are

o

o

In

sub e,

br ngs

oxc

waer

e

p asma

re c u um

bu

a

organs

o

are

njur y

accumuaon

n

mcrov   

compresson

organs

ear),

rapd

resu   ng

oss

endop as m c

(due

cange.

 Eosnopa.

(red

b a  ance,

bebbng ,

canges

p a e

 Fatty

(e.g.,

erad-

necon

wc

 an

 n  ux

w  



o

man-

agens.

ncude:

ceuar

damage

comp ens aor y

ncudng

cell

patogens,

w

o

Injury

njurous

 Infectous

cae

exposure

insults

ese

 •

upon

and

o

cyopasm

and

membrane

swe ng

(E R)

may

(Fg .

app e ar

o

1.1).

m o con -

Te

g rossy

so -

swo en

c ap   ar  es ) .

acvey

dsrups

nvoved

meaboc

rgycerde-ed

emaoxyn-and-eosn

a er a ons ,

o

njured

[H&E]

ces

n

pd

appears

sans)

meabosm

paways

and

vacuoes.

eosnopc

because

o

oss

o

1

2

CHAPTER

Cell

1

Injury

and

Cell

Death

NORMAL

CELL

Reversible Recovery injury

Swelling

Condensation

of

of

endoplasmic

reticulum

chromatin

and

mitochondria

Membrane

blebs

Myelin

figure Membrane

blebs

Progressive

Breakdown

plasma

injury

of

membrane, Cellular

organelles,

and fragmentation

nucleus;

of

leakage

contents

Inflammation

APOPTOSIS Apoptotic

body

Phagocytosis

of

Phagocyte

apoptotic

and

cells

fragments

NECROSIS

Fig.

1.1

injury

Reversible

that

layers

released

amorphous

RNA,

wc

becomes

 •

bnds

more

e

cell

culminate

from

bue

injury,

visible

emaoxyn

w

necrosis,

necrosis

damaged

densities

pronounced

in

or

plasma

by

apoptosis.

e

oward

Myelin

membranes.

electron

san.

progresson

and

apoptosis.

In

microscopy,

eosnopa

necross.

The

figure

figures

cells

of

are

illustrates

undergoing

unknown

or g na 

njur y ;

brane

cromatn

n

 •

 e mtocondra may swe.

 •

 e

ER

may

become

e

daed,

cyoso.

w

deacmen

o

rbosomes

and

o

poysomes,

ang

proen

Nucear

 •

 ese aeraons become more severe  e njur y progresses o e

rreversbe

brane

W 

p ass

a

nebu ous

o

nomena:

 ere

o

and

p erssen

A  oug 

re aes

pase

negry

may

necross,

or

no

r re versb  y,

 e

nabty

o

no

d e  n ve



to

s

o

e

reur n”

oss

o

pasma

and

mem-

njure d

u ndergo

or

ce 

by

f unc ton

ce s

de a  .

bo cem c a 

carac er z e d

mtocondr a

causes,

mitochondria

in

cell

concentric

often

contain

and

AT P

atered

ntraceuar

str uc tura

genera on )

str uc ture

and

membranes;

e ven

a er

f unc ton

and

of

DNA

res ou on

te

pa sma

damage

and

o

 e

mem-

oss

of

nteg r ty

  re e

cor-

pe-

(oxd a ve

and

apoptosis,

mechanisms,

the

and

two

main

functional

forms

of

cell

death,

differ

in

consequences.

Necross and apoposs are usuay dsnc orms o ce dea, w d-

eren

exp osures ,

mor poog c

conssen y

restore

n

nuceus.

noxous

in

DEATH

Necrosis

cumnang

excessve

“p o n

are

cump.

breakdown

events

syness.

 •

cromatn

of

and

CELL dssocaon

sequence

phospholipids

necrosis,

pospor y  a on

ceuar

appear

of

significance.

 “Myen gures” composed o pospopds derved rom damaged

membranes

the

collections

morpoogc

Necross

may

be

canges

oug

and

o

as

oer

dsngusng

“accdena”

ce

eaures

dea,

(T abe

relecng

1.1).

severe

njury a rreparaby damages so many ceuar componens a e ces

smpy

ory

ss

“a

apar” .

response

s

a

“reguaed”

Wen

cears

ce

ces

e

dea,

de

scene

by

o

because

necross,

e



s

ere

“accden. ”

medaed

s

a

By

by

oca

nlamma-

conras,

dened

apopo-

moecuar

CHAPTER

Table

1.1

Features

of

Necrosis

and

Necrosis

Cell

size

Enlarged

Pyknosis

Plasma

membrane

Disrupted

Cellular

contents

Enzymatic

inflammation

or

(swelling)

→

Reduced

karyorrhexis

digestion;

→

may

karyolysis

role

leak

out

of

cell

Intact;

altered

Intact;

may

pathologic

cell

(culmination

of

Often

injury)

a

are

acvaed

under

specc

crcumsances

and

k

damage.

In

precson,

some

wou

suaons,

ce

nlammaon

dea

may

3

or

sow

nucleosome-sized

be

released

especially

in

fragments

orientation

apoptotic

of

lipids

bodies

may

e

assocaed

eaures

o

be

means

of

pathologic

especially

DNA

eliminating

after

and

some

protein

unwanted

forms

of

cell

damage

ces ces

surgca

into

structure,

physiologic

cells;

injury,

w

Death

No

Invariably

irreversible

paways

Cell

(shrinkage)

Fragmentation

Frequent

pathologic

and

Apoptosis

Nucleus

Physiologic

Injury

Apoptosis

Feature

Adjacent

Cell

1

are

dead

(Fg.

1.3).

s

orm

o

necross

s

caracersc

coaera

bo

o

ypoxa-nduced

o

bood

ce

dea,

caused

mos

commony

by

a

oss

necross suppy

(scema).

e

resuan

necross,

caed

nfarc-

and apoposs, or may sar w apoposs and progress o necross, so e ton,

s

seen

n

mos

sod

organs,

suc

as

e

ear

and

kdneys.

dsncons may no be as absoue as once oug. Nevereess,  s use-

 •

u

o

consder

e

wo

orms

as

argey

nonoverappng

paways

o

 In

quefactve

because

er

prncpa

mecansms

and

uncona

e

dead

ces

are

dgesed

by

reeased

ce enzymes

dea

necross,

(Fg.

1.4).

s

s

seen

n

necross

resung

rom

bac-

consequences era

and

unga

necons

and

n

scemc

narcs

o

e

bran

are usuay dferen. (even

 •



sere).

 Gangrenous necross s a cnca erm used or e dea o sot s-

Necrosis sue

Necrosis

is

the

result

of

severe

injury

and

is

a

pathologic

process

and

s

oten

apped

o

a

mb

a

as

os

s

bood

suppy

and

in as undergone coaguave necross nvovng mupe ssue ayers.

which

cells

spill

their

contents

into

the

extracellular

milieu,

causI resus rom scema (e.g., rom dabec vascuar dsease, afec-

ing

local

inammation. ng

e

amarks

o

necross

e

ower

remans

 •

 Dssouton

of

ceuar

mbs)

and

s

caed

dry

gangrene



e

dead

ssue

are:

membranes,

ncudng

e

pasma

nac

or

wet

gangrene



e

ssue

quees,

as

s

common

membrane oowng supermposed bacera necon.

and

ysosoma

membranes,

because

o

damage

o

membrane

pds

 •

and

acvy

o

 Caseous

necross

necons

 •

suc

caracersc

as

o

sopasmoss.

ubercuoss

e

dead

and

ssue

some

unga

breaks

down,

 Leakage of ysosoma enzymes a dges e ce creang

 •

s

pospopases

 L oca

nlammaton

n

response

o

e

reeased

conens

o

a

ceesy

S ome

specc

componens

o

ese

conens

ave

been

moecuar

paerns

(DAMPs).

ese

ncude

ATP

(rom

damaged

mocondra),

examnaon

(Fg.

e

necroc

ocus

s

a

coecon

o

1.5).

ragmened

ysed

ces

w

an

amorpous

granuar

pnk

(eosnopc)

reeased appearance.

acors

gross

caed or

damage-assocaed

on

dead Mcroscopcay,

ces.

conssency

urc

acd

Ceuar

ounes

canno

be

dscerned,

and

ere

s

(a oten a perpera coecon o macropages ormng a granuoma.

breakdown

produc

o

DNA),

and

numerous

oer

moecues

a

 •

are

normay

conaned

wn

eay

ces

and

wose

 Fat

necross

resung

ndcaes

severe

ce

njur y.

ese

moecues

are

recognzed

rom

expressed

by

macropages

and

mos

oer

ce

rgger

pagoc yoss

o

e

debrs,

as

we

as

e

o

c yoknes

acue

a

nduce

nlammaon

(see

Caper

2).

produce

more

proeoyc

enzymes

a

o

w

exacerbae

and

e

subsequen

reacon,

un

e

e

o

a

desrucon,

pancreac

ypcay

pases

pancreas

and

e

peronea

cavy.

no

s

e

occurs

(Caper

cacum

o

13).

produce

Fay

acds

grossy

are

vsbe

reeased

caky

and

we

(a

saponcaon),

necroc

ssue

o

deny

wc

e

enabe

esons

e

surgeon

(Suppemena

eFg.

and

e

1.1).

On

as examnaon,

e

oc

o

necross

conan

sadowy

ceared.

man

causes

o

necross

ncude

scema,

exposure

o

oxns,

burns

and

oer

orms

o

cemca

and

pysca

ounes

o

necroc

deposs

and

an

a

ces

surrounded

nlammaor y

by

basopc

cacum

reacon

mcro-

 • ba

areas

acvaed

e

soogc

been

e

pancreas

paoogs

damage

o

Inlammaareas

ces

oca

producon combne

or y

o

reease

ypes, n

and

e

by subsance

recepors

reers

reease

njury,

 Fbrnod

necross

s

a

caracersc

mcroscopc

ndng

seen

and

mos

commony

n

mmune

reacons

n

wc

compexes

o

unusua suaons n wc enzymes eak ou o ces and njure adjacen

angens

and

anbodes

and

exravasaed

pasma

proens

are

ssues (as n pancreas). A ese nang rggers ead o rreparabe

deposed damage

o

numerous

ceuar

componens,

wc

cumnae

n

pnk, brane

damage,

e

Morphology.

bass

or

Necroc

e

ces

subsequen

sow

more

seps

n

dfuse

noss)

o

sequena

canges,

ragmenaon

dssouon

o

rom

cyopasmc

condensaon

nuce

o

(karyorrexs)

croman

o

er

rom

e

eosno-

(pyk-

compee

was

o

bood

appearance

vesses,

were

remnscen

o

ey

brn

ave

a

(Fg.

brg

1.6).

aboraory

ncrease

necroc

n

serum

ces

dagnoss

eves

because

o

o

o

necross

nraceuar

membrane

may

be

proens,

damage.

s

made

by

wc

s

e

deecng

eak

bass

ou

o

o

an

e

measur-

ng serum roponn or dagnoss o myocarda narcon, ransamnases

or ver dsease, and pancreac enzymes suc as amyase or pancreas.

(karyoyss).

Necross

e

amorpous

necross.

pa compared w a seen n reversbe njur y (Fg. 1.2). Nuce

undergo

n

mem-

dferen

causes

s

manesed

by

dferen

mor-

Apoptosis pooges, and recognon o ese paerns s epu or deermn-

ng

 •

e

 In

underyng

coaguatve

preser ved,

a

Apoptosis

eoog y :

necross,

eas

or

e

some

underyng

me,

even

ssue

oug

arcecure

e

s

consuen

no

a

longer

is

a

form

needed

potentially

of

or

cellular

are

harmful

suicide

damaged

that

beyond

inammatory

eliminates

repair,

response.

cells

without

that

are

eliciting

CHAPTER

Supplemental

deposits

eFig.

represent

1.1

foci

of

Fat

fat

necrosis.

necrosis

The

with

areas

of

calcium

white

soap

chalky

formation

(saponification) at sites of lipid breakdown in the mesentery. (Courtesy of

Dr.

James

cine

at

Crawford,

Department

Hofstra/Northwell.)

of

Pathology,

Zucker

School

of

Medi-

1

Cell

Injury

and

Cell

Death

3.e1

4

CHAPTER

Cell

1

Injury

and

A

Cell

Death

B

Fig.

1.2

with

of

Morphologic

viable

epithelial

cytoplasm,

of

nuclei

and

katachalam,

and

changes

cells.

(B)

swelling

of

fragmentation

University

of

in

reversible

Early

occasional

of

cells

Texas

and

(reversible)

and

Health

irreversible

ischemic

cells.

(C)

leakage

of

Sciences

cell

injury

Necrotic

contents.

Center,

San

injury

(necrosis).

showing

surface

(irreversible)

(Courtesy

injury

of

Drs.

(A)

Normal

blebs,

of

epithelial

Neal

kidney

increased

cells,

Pinckard

tubules

eosinophilia

and

with

M.A.

loss

Ven-

Antonio.)

I

N

A

B

Fig.

of

1.3

the

outlines

is

In

s

dsmane

paway

e

o

ce

nuceus

Causes

Apoptosis

nae

poenay

uness

(Tabe

damaged,

ens;

rapdy

occurs

n

us,

e

many

I

especay

rreparaby



•



•

o

o

ces

o

o endng

•

by

A

and

wedge-shaped

(N)

an

and

necrotic

inflammatory

kidney

cells

infiltrate

in

infarct

the

(dark

(yellow).

infarct

nuclei

(I).

(B)

The

Microscopic

necrotic

interspersed

cells

between

view

of

show

the

edge

preserved

necrotic

tubules)

and

e

and

suaons

ces

as

a

a

by

specc

ragmens

afecs

ce

s

sgnas

a

are

are

even

e

o

repaced

( neu rop s

 mmune

ser ves

ouved

ce’s

o

em-

er

wen

DNA

use-

ces

or

are

pro-

emnaed.

deveopmen

a

and

ave

paoogc

damage

ssues

acvaed

generang

pagocyes.

damaged

eu ko c yes

n  ammaor y



e

durng

prmorda

 D e a 

(A)

kidney

nuclei,

enzymes

occurs

wen

 Pysoogc apoptoss

ces

of

pysoogc

ces

aso

 •

 D ea

necrosis.

normal

cyopasm,

ceared

armu

1.2).

loss

dea,

and

and

of

with

with

present.

recognzed

Apoposs

Coagulative

infarct,

and

organsms,

by

maure

suc

y mpo c yes )

resp ons es

ave

as

ssues

a er

em nae d

agens

 E mnaon

o

dysuncona

or

auoreacve

ympocyes

or

ympocye precursors, parcuary n e bone marrow and e

ymus

Fig.

tion

1.4

of

Liquefactive

the

tissue.

necrosis.

An

infarct

in

the

brain

showing

dissolu-

CHAPTER

Table

Cell

1

1.2

Injury

Physiologic

Associated

With

and

and

Cell

Death

Pathologic

5

Conditions

Apoptosis

Condition

Mechanism

of

apoptosis

Physiologic

During

embryogenesis

Loss

of

growth

(presumed

Turnover

sues

of

proliferative

(e.g.,

bone

marrow

Involution

of

tis-

lymphocytes

and

Absence

in

survival

of

signaling

signals

death-inducing

or

acti-

signals

thymus)

hormone-

dependent

of

vation

factor

mechanism)

tissues

Decreased

(e.g.,

hormone

reduced

survival

levels

lead

to

signals

endometrium)

Decline

of

leukocyte

numbers

immune

at

the

and

Loss

end

of

for

inflammatory

of

survival

leukocyte

signals

as

activation

stimulus

is

elim-

inated

responses

Elimination

harmful

Fig.

1.5

Caseous

caseous

necrosis

necrosis.

Tuberculosis

containing

of

yellow-white

the

lung,

(cheesy)

with

a

large

area

of

of

potentially

Strong

self-reactive

recognition

induces

lymphocytes

mitochondrial

debris.

of

apoptosis

and

self

by

antigens

both

death

the

receptor

pathways

Pathologic

DNA

damage

Accumulation

of

misfolded

Activation

of

proapoptotic

proteins

Activation

of

proapoptotic

proteins,

proteins

possibly

direct

activation

of

caspases

Infections,

viral

especially

certain

Activation

infections

of

pathway

Killing

T

of

the

by

mitochondrial

viral

infected

proteins

cells

lymphocytes,

by

which

cytotoxic

activate

caspases

proens

dea

 •

s

e

ater

e

sensors

1.6

Fibrinoid

necrosis

in

an

artery

in

a

patient

with

n

The

wall

of

the

artery

shows

a

circumferential

bright

pink

necrosis

with

protein

deposition

and

e

(ntrnsc)

end

by

patway

pysoogc

cyopasm

e

bodes

and

deec

resu

seems

o

paoogc

e

o

apopoc

ce

pagocyes.

ack

o

be

responsbe

suaons.

sur vva

or

Moecuar

or

e

accumuaon

o

msoded

proens.

sgnas,

ese

DNA

acvaed

area

sensors of

mos

resdues.

apopoc

polyarteritis

damage, nodosa.

n

acd

o

mtocondra

apoposs

Fig.

asparc

cearance

nduce

e

dmerzaon

o

wo

proens

(caed

BAX

and

inflammation.

BAK)

a

nser

no

e

mocondra

membrane

and

orm

can-

nes, eadng o ncreased mocondra permeaby. e cannes

aow proapopoc acors (.e., cyocrome c and oer proens) o



•

 Ce oss a aernaes w ce proeraon n ormone-responeak

no

e

cyoso,

were

ey

acvae

e

enzyme

caspase-9.

A

sve ssues suc as e endomerum cascade



•

 •

 Patoogc apoptoss o

•

addona

caspases

s

acvaed,

cumnang

n

e

enzy-

 Emnaon o ympocyes a recognze se angens mac



o

breakdown

nuce

and

o

oer

nuce

and

organees

cyopasmc

suc

as

srucures.

mocondra

Fragmens

are

exruded

 S evere DNA damage, ater exposure o radaon or cyooxc drugs no



•

 Accumuaon o msoded proens, gvng rse o ER sress



•

 C eran

ragmens

pagocyosed.

necous

agens,

parcuary

some

vruses

suc

B

and

C,

wc

rgger

mmune

responses

a

Because

apopoc

ceuar

bodes)

membranes

a

are

reman

subsequeny

nac,

enzymes

as and

epas

(caed

oer

ce

conens

do

no

eak

ou

(as

ey

do

n

necross),

and

desroy ere s no nlammaon. e dmerzaon o e efecor moecues

neced

ces. BAX

o

Mechanisms

of

sic)

are

two

pathway

differ

in

e

dea-

pathways

and

their

the

and

of

apoptosis,

death

initiation

bocemca

enzymes

receptor

and

caspases.

the

(or

molecular

paways

sur vva-nducng

caed

BAK

BCL

s

normay

amy,

noaby

prevened

BCL-2

by

and

anapopoc

BCL-x.

ese

moecues

are

acvaed

Apoptosis by

There

and

e

o

extrinsic)

signals

apoposs

sgnas

Caspases

mitochondrial

and

are

pathway,

(Fig.

conro

umaey

cysene

(or

intrin-

ce

which

o

1.7).

e

e

baance

a

o

o

ceave

 •

acors,

sur vva

BCL-2

sands

acvaon

proeases

grow

or

by

B

and

dscovered

 e

deat

one

as

an

way

aberraons

oncogene

(extrnsc)

membrane

a

grow

proeraon.

ympoma-2,

receptor

pasma

s

subsequen

genec

ce

was

are

wc

so

s

seen

(see

o

Consuve

umors;

or

Caper

patway

recepors

n

named

e

of

acors

e

n

promoe

acvaon

ac,

umor

n

BCL-2

wc



5).

apoptoss.

umor

Dea

necross

recepors

acor

(TNF)

6

CHAPTER

Cell

1

MITOCHONDRIAL

Injury

and

Cell

Death

(INTRINSIC)

DEATH

RECEPTOR

P ATHWA Y

(EXTRINSIC)

P ATHWA Y

Receptor-ligand

Cell

•

injury

•

FAS

•

TNF

interactions

receptor

Mitochondria

Growth

factor Adaptor

proteins

withdrawal

•

DNA

damage

Phagocyte (by

radiation,

Cytochrome BCL-2

toxins,

and effectors

(BAX,

activation

proapoptotic

Protein

proteins

misfolding

(ER

Caspase

other

BAK)

radicals)

•

c

family

free

Regulators

BH3

stress)

(BCL-2,

BCL-x

) L

sensors

Endonuclease

Breakdown

activation

of

cytoskeleton

Nuclear

fragmentation

Ligands

for

phagocytic

cell

Apoptotic

Fig.

and

1.7

Mechanisms

both

related

culminate

to

members

BH3-only

proteins

ciency

BCL-2

and

of

various

induce

from

the

complex,”

recepor

ser ved

amy

ound

cyopasmc

activation

the

activate

and

as

of

two

pathways

caspases.

sense

molecules

that

receptors

in

cell

lead

caspases,

to

and

that

c,

the

lack

a

e

ype

I

membrane

Wen

cues

ese

are

dea

urn,

TNF

enter

and

on

many

ces.

doman”

T

recognze

doman.

kng

o

n

and

expressed

acvaes

nvoved

recepor

proen

cross-nked

ese

by

ese

a

en

e

recepors

medaes

by

and

o

on

ave

a

neracon

FAS

and

of

survival

the

is

ey

by

of

begn

recepors

ragmens

undergo

cyoss

e

o

express

on

apopoc

a

pyknoc,

rom

o

appearng

ces,

ces

race,

T

s

and

e

o

In

Wen

o

oten

FAS

recepor

the

protein

In

caspases.

into

concert

which

with

a

reticulum;

defi-

leaky

caspases

pathway,

“death-inducing

Endoplasmic

are

These

become

Activated

receptor

a

regulation,

damage.

mitochondria

death

proteins

and

proteins,

signals

signaling

TNF,

tumor

ces are removed so qucky and eiceny a ey are oten no den-

w

ed

va

e

wc,

and

a

n

n

dyng

so

wn

eicen

o

a

s

o

n

s

e

Other

dea,

er

bu

 •

express

Pathways

severa

dead

ces

vruay

ces

s

1.8).

ces

nuce

and



 •

e

and

ces

are

apopoc

e

n

ssues

n

wc

many

ces

are

consdered

e

s

a

oca

are

by

o

ead

o

o

ave

orm

ce

by

ce

o

and

o

s

n

response

produced

rrans.

njur y,

moecues,

ce

eaures.

knases

wc

o

receny.

nvesgaon,

unque

oer

membrane

paways

descrbed

opc

specc

as

ke

n

as

Sgnas

necross,

apoposs,

so

bo.

nduced

cyoknes,

and

a

and

(TNF),

specc

dea

reeases

nlammaon

o

mcrobes

pasma

been

remans

acor

eaures

o

bes-dened

aso

names

acvaon

reguaed

o

er

necross

response

s

e

ave

dseases

aware

umor

dyng

Death

apoposs

uman

be

knases

process

 P yroptoss

Cell

nduced

os

ese

nduce

 •

appear

o

e

s

s

cyokne

wc

dsappear

absen.

However,

bu

pago-

dsncve

e

croman,

e

e

even

mecansms

n

soud

 Necroptoss

e

of

and

oer

mporance

rom

e

necross

sudens

o

apoposs,

desroy

specmens,

apoposs.

Aoug

recognzed

beore

conens.

secons,

(Fg.

are

and

mnues,

apopoc

vacuoes

undergo

a

nges

er

nlammaon

H&E-saned

n

ces

soogc

by

s

moe-

paway

ympocyes

moecues

reease

condensaon

e

or

permeability.

the

ER,

induction

BH3-only

DNA

activate

In

body

their

con-

(FASL)

proens

ympocyes

Pagocyes

and

appearance

necross.

because

srunken,

number

damage

apopoc

eavng

morpoogc

dferen

fragments.

a

pagocyes.

membrane

o

wou

apoptotc

o

and

same.

par

 Cearance

or

permeability,

adaptor

the

FASL

 •

mitochondrial

cytosol

of

in

pathway,

signals

fragmentation.

result

ympocyes.

caspase-8,

dea

se-reacve

cyooxc

T

arges,

adapor

acvae

e

gand

acvaed

bnd

caspases.

some

(CD95).

FAS-expressng

recru

emnaon

ces

FAS

many

FASL

downsream

arge

mitochondrial

assembly

end

differ

factor.

“dea

ces

apoptosis

increase

oer proens nvoved n ce dea. e prooypc dea recepors

are

the

of

mitochondrial

death

the

In

a

maintain

cytochrome

culminate

activates

The

family,

proteins

such

that

membrane

BCL-2

effector

other

substances,

which

apoptosis.

the

of

changes

plasma

necrosis

in

of

receptors

ever

by

suc

(ence

bacera

as

oxns

nereukn-1,

pyro

n

e

n

a

name).

 Autopagy s a orm o “se-eang” (Greek, paga = o ea) n wc

ces

sar ved

maera

o

o

nurens

provde

and

porons

use

w

o

dges

energy

e

ysosomes,

or

cyoso

and

e

er

own

sur vva.

are

organees

In

encosed

conens

are

s

and

process,

wn

recyce

vacuoes,

desroyed

by

e

organees

wc

ysosoma

CHAPTER

aer)

Cell

1

and

Injury

decreased

moecues,

suc

as

ATP

and

Cell

producon.

cyocrome

c,

Death

7

Mocondra

wose

reease

no

aso

e

sequeser

cyoso

s

an

ndcaor o damage and, as descrbed earer, a rgger or apoposs.

 •

 C euar

and

and

organees

suc

as

lud

branes,

dges

by

resu

by

(some

indicated

shown.

(The

apoptosis

cells

in

in

this

chromatin

by

arrows)

preparative

epithelial

normal

and

the

in

a

crypt

regimen

cells,

tissue.)

which

Note

shrunken

for

the

cell

in

the

cells.

colonic

colonoscopy

explains

the

fragmented

bodies,

some

Apoptotic

abundance

nuclei

with

with

pieces

dead

condensed

falling

off

ron

n

(Courtesy

of

Dr.

Sanjay

Kakar,

Department

of

Pathology,

ecues

rom

of

California

San

as

e

ces

o

 ROS

to

of

type

of

OF

injury

the

o

necross.

ceuar

genec

mem-

enzymes

Damage

consuens,

maera.

ceuar

proeraon.

ncude

e

ER

processng)

to

a

are

o

be

a

o

e

Nucear

uncons

Irreparabe

(one

and

e

end

damage

(.e.,

damage

proen

o

DNA

e

se

o

proen

cyoskeeon

syness

(e

sruc-

ces).

damaged

rom

durng

cellular

group

gy

orb.

proens,

ree

e

ousde,

nlammaor y

abnormalities

of

molecules

reacve

ey

reac

pds,

or

exampe,

reacons.

that

called

and

moecues

w

a

nucec

converng

radcas

produced

connues

because

e

nuren

decency

are

free

induced

by

radicals.

em

w

an

norganc

acds)

no

and

ree

unpared

and

eec-

organc

remove

radcas.

mo-

eecrons

Boogcay

ncude

ROS

normay

n

and

sma

nrc

oxde

amounts

n

(Fg.

a

1.10).

ces

respraon

CELL

INJURY

AND

from

any

offending

injurious

agent,

its

and

reactons

energ y

a

generaon.

occur

durng

In

s

durng

te

mocon-

process,

moecuar

a

addon

sma

are

o

our

amouns

eecrons.

o

generaed

gy

wen

s

reacon

reacve

oxygen

bu

s

s

mperec,

sor-ved

ony

paray

owever,

oxc

nerme-

reduced.

ese

DEATH

stimulus

severity,

(redox)

oxygen s reduced n mocondra o generae waer by e sequen-

s

nermedaes

degree

ce

may

moecues,

are

daes

the

ce’s

eukocyes

refers

belong

ouer

(e.g.,

and

on

ysosoma

of

no correced,  can rgger apoposs by e mocondra paway.

The

o

o

o

reease

ces

Francisco.)

process

MECHANISMS

oss

o

o

uncons

Stress

stress

oer

dra

I

e

“moor”

reducton–oxdaton

enzymes.

amark

n

ranspor

Damage

eads

proen

Univer-

 • sity

o

agens

and

radcas

an

mporan

them.

we

producs

which

Free

are

induces

of

resus

crca

conan

srucure

cells

epithelium

frequently

as

srucures,

e

ROS, apoptotic

mos

scafod

Oxidative

of

e

and

e

apoposs.

Oxidative

appearance

ce,

agens,

pds

 In addon o ce njur y resung rom mparmen o ese nrn-

sc

Morphologic

omeosass.

oer

pos-ransaon

ura

1.8

numerous

ranscrpon-dependen

njurous

and

Fig.

o

manan

 Oter ceuar components a sufer damage upon exposure o var-

ous

 •

ey

necross.

syness),

rggers

composed

ser ve

on

or

njured

sore

dsrups

 •

and

membrane

o

 Nuce

are

moecues.

and

ROS

e

pasma

 •

membranes

carboydrae

varies

and

its

gen peroxde (H

depending

duration,

ncude

2

superoxde

as

O

2

superoxde

O

,

2

wc

s

convered

o

ydro-

) sponaneousy and by e acon o e enzyme

dsmuase.

H

2

O

s

2

more

sabe

an

O

and

2

can

cross

2+

well

as

the

Sma

adaptive

amouns

ability

o

a

and

oxn

genetic

or

bre

makeup

perods

o

of

the

target

scema

boogc

cell.

may

s

cause

3

cause

ours,

ater

may

n

20

One

wereas

o

aso

genes

rae

o

o

necross.

30

Sraed

cardac

mnues

deermne

encodng

meabosm

e

goas

ndvduas

w

o

o

musce

musce,

reacon

members

o

many

precson

reac

o

o

e

w

scema.

e

n

e

o

e

s

survves

ger

genec

medcne

ypes

s

o

o

meaboc

agens.

cyocrome

and

scema

makeup

njurous

cemcas

dferen

eg

P450

ence

use

e

o

2

needs,

e

o

des

afec

efecs

o

o

e

injury

results

from

abnormalities

in

 •

or

 ROS

are

durng

ow

owng

more

components,

mainly

mitochondria,

membranes,

and

urn

(Fig.

reacve

o

ree

o

meas,

ydroxy

radcas

s

suc

radca

ncreased

as

Fe

by

by

,

e

H

2

O

2

Fenon

exposure

o

mpar

ROS

mocondra

producon

uncons.

because

o

Oxygen

ncompee

deprvaon

reducon

o

produced

o

n

pagocytc

desroy

nlammaon.

ngeson

e

o

a

In

e

o

O

2

,

a

many

mcrobes

“respraor y”

mcrobe,

generaon

eukocytes,

ngesed

and

or

s

burs,

membrane

convered

o

H

2

and

subsances

“oxdave”

pagosome

wc

neutrops

oer

O

2

o-

enzyme

convered

o

a

gy

reacve

compound,

.

H

2

O

ypocore

2

s

(e

the major

nucleus

presence

essential n

cellular

o

macropages,

smu.

one

gy

generaon

may

eads

caayzes

Cell

e

e

e

oxygen.

oxns.

predc

wc

aso

ndvdua

amy

o

In

UV g, radaon and oxns, and durng norma ceuar agng, a

o

Poymorpsms

genecs

njurous

or

convered

reacon.

reversbe njury bu arger doses o e oxn or more proonged scema

may

membranes.

componen

o

ouseod

beac),

by

e

enzyme

myeoper-

1.9). oxdase,

wc

s

presen

n

eukocye

granues.

s

s

one

reason

e consequences o mparmen o eac o ese ceuar organees wy

are

dsnc

bu

nlammaon

o

k

necous

paogens

s

oten

overappng. assocaed

 •

nended

w

njur y

o

norma

ssues.

 Mtocondra are e ses were ATP , e prmary carrer o energy n  •

 Ntrc

oxde

s

anoer

reacve

ree

radca

produced

n

macro-

ces, s produced by oxdave posporyaon. Injury due o ypoxa, pages

scema,

radaon,

or

oer

nsus

mpars

oxdave

and

eadng

o

e

ormaon

o

reacve

oxygen

eukocyes

durng

nlammaor y

reacons.

I

can

posporyacombne

on,

oer

speces

(ROS)

w

O

2

o

orm

a

gy

reacve

(see re,

wc

aso

parcpaes

n

ce

njur y.

compound,

peroxyn-

8

CHAPTER

Cell

1

Injury

and

Cell

Death

Hypoxia/ischemia

Radiation

Radiation

Other

injurious

ROS

agents

Other

MITOCHONDRIA

ATP

injurious

CELLULAR

Damage

ROS

to

Mutations

agents

MEMBRANES

lysosomal

Damage

membranes

Damage

Energy-

NUCLEUS

to

plasma

membrane

to DNA

lipids,

dependent

proteins,

nucleic

functions

Leakage

acids

of

Impaired

enzymes

Leakage

transport

of

damage

functions

cellular

contents

Reduced

Activation

protein Cell

of

caspases

injury synthesis

NECROSIS

Fig.

1.9

branes,

NECROSIS

Principal

or

triphosphate;

ROS

can

damage

cross-nkng),

dues),

s

and

us

conroed

ase,

ree

wc

and

by

afec

a

down

durng

(by

(by

enzymes

break

radcas

pds

DNA

cellular

nuclear

DNA.

ROS,

reactive

ceuar

as

ydrogen

paoogc

breaks

stimuli.

structures

(many

er

injurious

progress

Increased

by

res-

accumuaon

peroxdase

over wems

Most

may

and

caa-

generaon

ese

Hypoxa

bood

Oxygen

eres

w

reduced

of

leads

energy-dependent

reduced

cellular

generation

systems

(Fig.

of

ATP

e

apoptosis.

cellular

ATP,

coronar y

or

cerebra

n

bood

and

failure

1.11).

low,

arer y

arer y

probems

s

may

and

s

on

mem-

Adenosine

n

o

esmaed

e

major

ese

ces

are

o

a

o

n

arera

o

o

some

n

oxygen

s

pds,

o

seen

suaons

(wc

emogobn).

cause

cause

mocondra

and

o

s

posonng

Iscema,

obsrucon

myocarda

sroke)

o

e

or

a

mos

o

ner-

or

(as

narcon,

severe

drop

requen

and

medcne.

pospae

proens

a

capacy

major

reducon

g-energ y

syness

oxygen)

monoxde

consequence

e

cnca

e

a

e

(sock).

produced

depends

be

dsease,

n

o

carbon

dsease,

pressure

a

avaaby

and

oxygen-carr yng

bood

n

ATP

to

anema,

o

Ischemia

deciency

mitochondria,

or

(reduced

oss,

serous

and

affect

necrosis

scavengng

mecansms.

Hypoxia

stimuli

to

species.

deoxyymdne

componens.

peroxde.

injurious

these

proens

a

guaone

njur y

of

to

oxygen

peroxdaon),

creang

suc

targets

Injury

APOPTOSIS

an

requred

and

eay

eecrocemca

(oxdave

or

urnover

ndvdua

membrane

o

reacon

pospor yaon)

ranspor,

pospopds.

burn

50

o

75

kg

I

o

s

ATP

Ischemia

ever y

ATP

day.

ereore,

damages

many

oxygen

ceuar

deprvaon

and

componens,

as

e

resung

depeon

+

 •

 Reduced

acvy

o

e

pasma

o

oows:

membrane

ATP-dependen

Na

+

-K

+

pump

resus

eadng

e

o

n

ce

eares

e

nlux

sweng

o

and

manesaons

Na

and

daon

o

ce

o

njur y

waer,

e

as

ER,

(see

dscussed

wc

Fg.

are

earer,

some

o

1.1).

Mitochondrion

 •

 Anaerobc

absence

Oxidative

decreased

phosphorylation

many

gycoyss

o

oxygen,

ncreases

resung

nraceuar

nraceuar

pH,

n

n

an

aemp

ncreased

and,

o

generae

producon

consequeny,

ATP

o

n

acc

reduced

e

acd,

acvy

o

enzymes.

 •

 Rbosomes deac rom e ER, eadng o reduced proen syness.

 •

 Hypoxa

ATP

may

damagng

+

Na

pump

Anaerobic

glycolysis

Detachment

of

 •

ribosomes

of

e

generaon

o

ROS,

wc

ave

many

 Umaey, ysosoma and mocondra membranes are damaged,

ysosoma

begns

2+

Influx

ncrease

efecs.

o

acd

dges

ydroases

se,

are

acvaed

cumnang

n

by

ow

pH,

and

e

ce

necross.

Ca

+

H

O,

2

and

Na

Glycogen

Lactic

pH

Protein

acid

synthesis

Ischemia–Reperfusion

Injury

+

Efflux

of

K

Restoration

ER

swelling

Cellular

Loss

doxically

of

of

blood

exacerbates

ow

to

tissue

an

ischemic

tissue

sometimes

para

injury.

e ce njur y a may oow reperuson s key due o ncreased

swelling

microvilli

producon

o

ROS

by

njured

ces

w

damaged

mocondra

and

Blebs

by

Fig.

1.10

The

functional

and

morphologic

consequences

of

hypoxia

eukocyes,

ATP,

Adenosine

triphosphate.

ER,

endoplasmic

are

recrued

o

ge

rd

o

e

necroc

ces.

and

ese ischemia.

wc

nlammaor y

ces

may

reease

enzymes

a

cause

ye

more

s-

ener

e

reticulum.

sue

damage

(see

Caper

2).

Compemen

proens,

wc

CHAPTER

Cell

1

Injury

Pathologic

and

Cell

Death

9

effects

Radiation

Toxins

Production

of

ROS:

Lipid

peroxidation

Membrane

damage

Reperfusion

O

H

O

2

2

Superoxide

OH

2

Hydrogen

Hydroxyl

peroxide

radical

Protein

DNA

Conversion

to

H

by

O

2

Decomposition

H

2

1.11

ROS

is

The

radicals

in

maor y

ssue,

may

aso

free

by

to

removal,

and

injurious

may

role

of

stimuli.

Excessive

damage

lipids

reactive

These

production

(by

oxygen

free

or

by

directly

cytochrome

A

cassc,

njury

s

ver

conrbue

moecue

s

njury,

e

ER

and

in

o

used

e

njur y,

convered

many

e

n

by

membrane

toxins

conversion

as

n

oer

nlam-

sae;

dry

exampe

naaon

ceanng

ver

no

membrane

causes

reactive

cellular

com-

metabolites,

often

a

o

o

carbon

ndusry

a

ree

n

bu

radca

pospopd

decne

oxn-medaed

e

eracorde,

now

a

banned.

s

e

cause

peroxdaon.

syness

o

o

ansm

o

acon.

enzymes,

serous

and

ver

I

e

s

acue

anagesc

meabozed

overdose

damage

n

e

o

aceamnopen

o

a

s

Uned

ree

drug

Saes

radca

s

e

and

as

by

smar

and

mec-

cyocrome

mos

oer

a

requen

deveoped

Reticulum

(ER)

as

Tabe

accumulation

of

misfolded

mechanisms

and

trigger

n

Wen

mpropery

proecve

oded

proen

ransaon

s

a

manan

mechanisms

s

ncreased

(Fg.

(see

of

injury.

free

SOD,

proen-secreng

mupe

and

myeoma.

ceuar

Caper

ypoxa,

Dseases

Damage

P450

cause

o

counres.

o

erapeuc

Damaged

ce

age,

abnormay

17).

by

n

Deprvaon

aso

caused

ces,

may

parcuary

Proen

o

ncrease

msoded

msodng

severa

neu-

gucose

e

and

burden

proens

are

o

sed

o

poena

o

e

n

p53

apoposs

I

a

be

p53,

ese

upon

and

corrected

o

exposure

ROS

wc

and

arress

be

an

e

nerere

a

w

s

w

n

and

o

by

DNA

e

aby

o

o

G1

aso

correc

repair

pase

e

a

ce.

arres

cancers

o

ce

e

DNA

DNA

us,

DNA

e

cemo-

muaons.

acvaes

paway.

o

numerous

radaon,

resu

abnorma

ransormaon

w

o

a

ces

mocondra

survve

assocaed

as

repared

mecansms

by

magnan

are

to

occurs

damage

raer

nduce

great

drugs,

apoposs

de

o

muaons

DNA

acvaes

aow

rggers

“cooses”

too

apoptosis.

nucear

mecansms.

p53

is

to

(ancancer)

DNA

cyce

repar

that

leads

in

the

ER

can

stress

dam-

e

ce

as

e

Predcaby,

cycng

or

(see Caper

o

5).

Aging

adapage

because

of

accumulation

of

mutations,

progressively

apoptosis.

caed

accumuae

e

unfoded

n

e

ER,

proten

ey

reduced

and

e

producon

newy

syneszed

proens

n

1.12).

I

e

oad

o

msoded

and

defective

protein

homeostasis.

rs

response,

o

replication,

age

because

er

ces

age.

Aoug

muc

o

e

pubc’s

n on

agng

s

ocused

on

s

cosmec

and

pysca

conse-

caperones

er

e

greaes

danger

o

ceuar

agng

s

a



promoes

e

proper deveopmen

sape)

o

as

undamena

scema

Damage

quences, (moecues

suc

dseases

damage

aenon wc

cell

by

Stress

proteins

proens

reacon

e

DNA

Peope a

in

of

and

accumulation

neopasms

proens.

decreased

acvae

be

DNA

Cells tive

production

decay

1.3

Cellular The

to

resulting

neopasms

o

msoded

nduce

Endoplasmic

ceran

ce

oug

Damage

enzymes

deec resus n e accumuaon o pds n epaocyes and oer ces

aer).

The

a

s

orm compexes w rgycerdes, acang rgycerde secreon; s

see

leads

DNA,

injury.

spontaneous

ce

pasma proens, as we as apoproens, wc are ranspor proens a

(seaoss;

and

oxygen,

n

sorca,

e

to

damage

cells.

oowng

n

and

cell

by

removal

rodegenerave

microbial

liver

many

in

dismutase.

Injury

after

damage

once

o

or

P450

now

cemca

ce

Cell

(ROS)

removed

proteins,

pasma

environmental

ponents

are

inadequate

s

Many

species

radicals

peroxidation),

reacons.

Toxin-Mediated

Mutations

catalase

systems.

which

damage

radicals

many

enzymatic

misfolding

glutathione

generation,

cells,

superoxide

reperused

of

increased

specialized

by

peroxidase,

SOD

Removal

Fig.

O

2

Breakdown,

modifications

proens

s

o

many

degenerave,

meaboc,

and

neopasc

dsor-

oo ders. Numerous nrnsc moecuar abnormaes are beeved o cause

grea,

e

ce

des

by

e

mocondra

paway

o

apoposs;

n

s e

way,

ces

a

can

no

onger

uncon

are

 • Inraceuar

accumuaon

o

agng

msoded

proens

may

be

abnormaes

reduce

e

a

aby

ncrease

o

e

emnae

producon

em.

o

ese

msoded

may

resu

be

suc

as

ose

responsbe

or

c ysc

bross,

producon

w

o

a

proens

a

decreased

canno

capacy

o

od

propery :

correc

a

agng,

msodng;

 D ecreased

ead

vra

necons,

wen

arge

amouns

o

syneszed

wn

ces,

exceedng

e

mcroba

ce’s

wc

ncreased

nsun-ressan

demand

saes;

or

secreor y

canges

n

e

proens

wc

occurs

nauray

and

muagens.

repcaton

eomerase,

of

ces

wc

because

manans

o

progressve

e

norma

oss

o

e

eng

o

eomeres.

ese

sor

DNA

sequences

a

e

e

ends

o

cro-

proec

w

e

ever y

ends

rom

repcaon

uson

bu

can

and

be

degradaon.

mananed

by

Teomeres

e

acvy

proens e

enzyme

eomerase.

Because

mos

ces

(excep

germ

ces)

proen-odng

suc

as

nraceuar

pH

e

or

no

eomerase,

eomere

sorenng

s

nevabe

nsun n

n

DNA,

envronmena

s

conan capacy ;

n

and

necons,

o are

ROS

o

soren especay

by

gene

mosomes assocaed

1.13).

mutatons

proens

rom

enzyme e

o

enanced

enzyme muaons,

(Fg.

caused

 • or

ces

 Accumuaon

may by

o

emnaed.

and

redox

dvdng

ces.

W

compee

oss

o

eomeres

durng

ceuar

10

CHAPTER

Cell

1

Injury

Mild

Misfolded

ER

lumen

ER

membrane

ER

and

Cell

Death

Stress

Severe

ER

Stress

proteins

P

P

P

P

P P P

P

Sensor

of

P

P

misfolded

Signaling

proteins

Signaling

Cytosol Increased

Reduced

Increased

protein

protein

Activation synthesis

of

BH3 chaperones

synthesis

Reduced

load

of

Fig.

1.12

proteins

trigger

the

an

1.3

Diseases

ER

adaptive

pathway

unfolded

unfolded

the

misfolded

drial

Table

The

in

is

misfolded

Caused

by

Mutant

by

Proteins

hypercholesterolemia

Tay-Sachs

and

sensors

in

amount

and

of

endoplasmic

ER

which

reticulum

membrane

can

misfolded

the

disease

protect

proteins

irreparably

Retinitis

by

stress.

the

is

cell

too

damaged

from

great

cell

The

proteins,

the

to

dies;

this

presence

also

misfolded

earlier)

that

consequences

corrected,

is

of

mentioned

harmful

be

PROTEIN

APOPTOSIS

the

called

of

mitochon-

the

terminal

Proteins

protein

That

are

Pathogenesis

Degraded,

Leading

to

Their

Misfolded

Loss

of

CFTR

LDL

Loss

of

LDL

Lack

of

the

receptor

Proteins

pigmentosa

Deficiency

CFTR

Hexosaminidase

Caused

(er)

(BH3-only

α

subunit

sides

Diseases

UNFOLDED

RESPONSE:

the

response,

induced

Misfolded

fibrosis

Familial

response

by

the

Affected

Diseases

TERMINAL

response.

Disease

Cystic

is

of

caspases

proteins

RESPONSE

protein

When

apoptosis

protein

Caused

protein

unfolded

proteins.

of

PROTEIN

detected

Activation

degradation

ADAPTIVE

UNFOLDED

of

proteins

That

Result

in

ER

in

Stress–Induced

Rhodopsin

Abnormal

death,

leads

to

receptor

defects

leads

lysosomal

to

in

chloride

transport

hypercholesterolemia

enzyme

leads

to

storage

of

GM

2

ganglio-

neurons

Cell

Loss

folding

of

resulting

rhodopsin

in

causes

photoreceptor

loss

and

cell

blindness

sc

Creutzfeldt-Jakob

disease

Prions

Abnormal

folding

and

folding

of

aggregation

of

PrP

causes

neuronal

cell

death

Alzheimer

disease

Aβ

peptide

Abnormal

rons

Diseases

the

Caused

by

Misfolded

Proteins

That

Result

From

Both

ER

and

peptide

causes

aggregation

within

neu-

Stress–Induced

Cell

Loss

and

Functional

Deficiency

of

Protein

Alpha-1-antitrypsin

deficiency

α-1

antitrypsin

Storage

of

absence

elastic

Selected

CFTR,

Aβ

apoptosis

illustrative

Cystic

examples

fibrosis

of

diseases

transmembrane

are

shown

conductance

in

which

regulator;

protein

LDL,

misfolding

low-density

is

thought

lipoprotein.

to

be

the

nonfunctional

of

enzymatic

tissue,

major

giving

protein

activity

rise

mechanism

of

to

in

in

hepatocytes

lungs

causes

causes

apoptosis;

destruction

of

emphysema

functional

derangement

or

cell

or

tissue

injury.

CHAPTER

Environmental

metabolic

and

Telomere

insults

Cell

1

Injury

and

Abnormal

shortening

protein

Cell

Death

11

Calorie

homeostasis

restriction

ROS?

Insulin/IGF

Accumulation

mutations

in

of

Cellular

DNA

TOR

Proteins,

replication

signaling

misfolded

proteins

Defective

Altered DNA

repair

transcription

DECREASED

CELL

CELL

DECREASED

FUNCTIONS,

CELL

LOSS

CELL

LOSS

FUNCTIONS

DNA

CELLULAR

repair

AGING

Protein COUNTERACTS

Fig.

1.13

proteins

calorie

Mechanisms

are

restriction,

Insulin-like

agng,

e

response,

 •

“naked”

causng

 D efectve

muaon

 •

 Atered

ors.

par

ere

nang

ewer

 In

as

e

One

DNA

a

o

o

o

mechanisms

by

activating

reactive

acvae

e

ncreased

oxygen

DNA

repcave

proens,

damage,

of

replicative

cellular

various

species;

TOR,

damage

urnover

w

possby

afec

n

denng

obser vaon

s

grow

a

caore

acor,

nrnsc

responses

so

o

ese

a

caore

cyce

ess



and

dyng

e

bo

and

some

ypes

o

as

aerosceross,

ype

2

such

factors.

no

reeved.

scema

as

IGF,

For

due

exampe,

o

dabees,

cancer.

a

an

Grow

survvng

ces

are

e

can

be

reave

cardac

ack

exampe

due

o

are

dea

ess-dferenaed

by

o

capabe

and

a

s

o

yper-

oxygen

o

varey

responsbe

remova

repcaon

oten

ncreased

n

or

paoogc

by

ce

ypes.

o

e

e

and,

n

and

Posparum

o

ducuar

nduced

smuang

may

o

ormones

proeraon

some

occurs

and

response

yperpasa

or

o

o

progenor

Hyperpasa

smuaed

pysoogc

or

ces.

pysoogc

proeraon

produced

acors

o

yperropy

breas

ater

eer

dferenaed

popuaons

w

ceuar

o

s

ce

Hyperpasa

acors

mones.

suc

s

nsances,

conans

enargemen

dsposes

dseases,

sress

proeraon,

suaons,

epeum

many

transcription

myocarda

some

smu.

ces nduce ow-eve nlammaton, and cronc nlammaon pre-

o

e

concurreny

grow

damaged

n

ssue

same

errors.

abnormaes,



cause

ncreased

or,

occur

sg-

sufer

and

misfolded

stresses,

 Hyperpasa s an ncrease n e number o ces n an organ a sems

ces

n

and

homeostasis

and

rapamycin.

njury

can

decreased

devery, and evenuay gve rse o cardac aure.

 •

resrcon

reduces

of

and

environmental

pathways

ropy

ac-

paways,

resrcon

ces

grow

Some

target

organ

and

accu-

aging.

signaling

senescence.

ogeer

senescence,

rom

neres

nrgung

ese

ROS,

sae

due

may

repcaon–reaed

addon

a

aging

DNA

proens.

grea

nsun-ke

ends

ener

aging.

best-described

factor;

nraceuar

patways

been

o

e.

by

o

msoded

because

proongs

 •

o

o

omeostass,

syness

sgnang

growth

ces

the

cellular

counteract

cromosome

e

proten

decreased

among

of

AGING

by

or-

proeraon

ces

n

an

o

organ

(e.g., grow o resdua ver oowng para epaecomy, caed com-

pensatory

CELLULAR

ADAPTATIONS

TO

yperpasa).

napproprae

Adaptations

metabolic

their

are reversible changes in

activity,

or

functions

of

the

cells

number,

in

size,

response

phenotype,

to

changes

progeserone

environment.

o

be

paoogc.

androgens

ces

o

medaors

uerus

e

norma

(e.g.,

durng

case

o

Pysoogc

smuaon

e

by

and

or

o

musces).

usuay

ormones

ormone-nduced

pregnancy),

bones

adaptatons

e

or

represen

enargemen

demands

Patoogc

o

o

e

mecanca

adaptatons

are

njur y,

bu

paopysoogc

 •

 Hypertropy

men

s

o

e

caused

a

e

expense

adapaons

s

an

organ

eer

ncrease

(Fg.

by

an

o

can

n

1.14).

norma

ake

e

I

sze

can

ncreased

uncon.

severa

be

o

dsnc

sress

ces

uncona

or

demand

or

n

by

e

o

and

organ

o

enarge-

py

oowng

sress.

an

weg

Cardac

exampe

o

tng

yperropy

paoogc

s

n

an

e

esrogen

adapaon

yperenson

yperropy

eves.

workoad

ormona

o

or

Musce

ncreased

aorc

resung

rom

dsuse

yperro-

mecanca

vave

dsease

ncreased

s

work

and

resu

grow

o

ac-

Bengn

cause

prosac

obsrucon

o

yperpasa

e

low

o

s

nduced

urne

and

by

preds-

suc

sgnas

as

a

abae.

In

afecng

some

e

cases,

perssen

endomerum,

ses

paoogc

e

sage

or

I

s

caused

acvy)

by

and

decreased

ncreased

proen

proen

syness

(due

breakdown

o

med-

aed by e ubqun–proeasome paway. Causes ncude a decreased

and

(as

n

aropy),

ces

ncreased

grow

srnk.

ormone

by

can

meaboc

pregnancy

caused

ypcay

 Atropy s a decrease n e number o ces and, ence, may cause an

smuaon. For exampe, pysoogc enargemen o e uerus durng

s

s

ormones

muaons and oncogenc ransormaon.

 •

reduced

paoogc

by

e deveopmen o cancer because proerang ces are suscepbe o

orms.

resung

pysoogc

baance.

and

yperpasa,

(n

responses

Pysoogc

wen

and

sress a aow ces o moduae er srucure and uncon and us

escape

yperpasa

smuaon

sa rom neopasa: Unke neopasc grows, yperpasa s reversbe

cemca

breas

excessve

pose o urnary rac necons. I s mporan o dsngus yperpa-

responses

endogenous

and

ors, as n endomera yperpasa resung rom a dsurbed esrogen–

in

Ceuar adapaons may be par o pysoogc ceuar responses or

may

Paoogc

STRESS

mmobzaon

progressve

smuaon

undergo

aropy

(as

or

denervaon

scema,

n

raer

reduced

menopause).

an

dea

as

o

Faced

an

musce,

nuron,

w

eadng

and

o

reduced

manuron,

adapaon

o

reduced

energy suppy. I s oten assocaed w ncreased auopagy.

 •

 Metapasa

response

o

s

a

cange

sress

n

o

one

wc

a

adu

ce

ce

a

s

ype

o

sensve

anoer.

o

a

I

s

sress

a

s

oad. In a orms, ormones and mecanca sensors acvae sgnang

repaced by anoer ce ype a s beer abe o sur vve e adverse

paways a ead o ncreased proen syness and assemby o more

envronmen.

organees,

ssue

o

sress,

and

us

enargemen

yperropy

can

o

progress

e

o

ce.

Aoug

unconay

an

adapaon

sgncan

ce

or

sem

e

ces

mecansm

o

s

dferenae

oug

aong

a

o

be

new

reprogrammng

paway.

o

Exampes

ncude squamous meapasa o e bronca coumnar epeum

12

CHAPTER

Cell

1

Injury

and

A

Cell

Death

C

B

Adapted Adaptation: Normal

myocyte response

to

myocyte

(hypertrophy) increased

load

D

E

Fig.

1.14

nancy.

partum

plump,

tion.)

1

n

cronc

squamous

1.15).

er

broncus

e

ar ways

smu,

and

ng

upper

n

rom

e

as

n

uncon;

n

o

bronc

o

Barre

w

o

e

uterus

cells

a

o

e

sur vve,

ce

smooth

gravid

with

left

oten

epeum

o

a

Physiologic

and

a

uterus;

severe

com-

n

acon,

a

o

proec

rggerng

neopasc

carcnoma

o

rans-

e

wall

e

e

is

 •

ces

man

Some

ACCUMULATIONS

IN

exampes

may

which

accumulate

may

mediastinal

degrees

of

be

abnormal

harmless

lymph

injury.

nodes

(e.g.,

of

amounts

carbon

city

and

uterus.

C,

preg-

for

(C)

post-

Large,

same

magnifica-

myocardium

(thickness

cm.

be

or

ocaed

n

may

e

be

o

and

are

during

removed

n

e

produced

abnorma

deposon

descrbed

n

and



may

wn

be

organees

syneszed

by

esewere.

nraceuar

degradaon

or

cyopasm,

nuceus,

or

o

an

e

accumuaons

excessve

producon

abnorma

exogenous

are

o

an

mae-

oowng.

eFg.

1.2),

mos

ay

and

w

or

ver

n

n

obese

dsease

coeser y

pd

oten

(see

esers.

e

ver

oowng

ndvduas

Caper

as

proonged

componen

o

13).

Pagocyc

(rgycerdes,

a

ces

coesero,

may

and

become

coeser y

CELLS

of

various

particles

dwellers)

(B

consumpon

 Coestero

esers)

Cells

may

subsance,

overoaded

PATHOLOGIC

2

paways

nonacooc

 •

(B).



uterus

was

 Fatty cange (steatoss). Seaoss s e accumuaon o pds (Sup-

acoo

esopagus).

the

non-gravid

than

or

of

that

Normal

remova

pemena

ars-

(D)

ysosomes),

endogenous

ra.

a

with

subsance

afeced

e

(left)

from

thicker

nadequae

ung)

adenocarcnoma

cells

compare

(ypcay

e

wo

hypertrophy

uterus

hypertension.

ventricular

(Fg.

gravid

muscle

esopagea

car y

perssence

(esopagea

The

relux



epeum

se

from

(A-C)

(right)

uterine

patient

gasrc

provde

e

be

in

hypertrophy.

squamous

(squamous

rac

muscle

cronc

ces

hypertrophy.

normal

spindle-shaped

meapasa

and

can

a

hypertrophy

bronca

Aso,

epeum

of

smooth

nsance,

mucus

norma

gasronesna

seng

Small

w

aows

or

pathologic

Myocardial

coumnar

necon.

e

(E)

paens

produce

meapasc

ormaon,

cm).

and

uncons

(B)

Myocardial

meapasa

canno

mporan

E)

and

appearance

hypertrophied

1.5

smokers

Gross

bleeding.

(D,

epeum

Aoug

promses

to

Physiologic

(A)

or

in

may

substances,

the

lungs

cause

and

varying

1.3),

n

severa

mosy

osm

o

Caper

pds.

8).

dferen

paoogc

caracerzed

O

ese,

by

processes

ncreased

aerosceross

nake

s

e

(Suppemena

or

decreased

mos

eFg.

caab-

mporan

(see

CHAPTER

Cell

1

mmunogobuns

some

oc

 •

pasma

yane”

(see

browns,

a

a

s

Squamous

membrane

columnar

metaplasia

n

o

eFg.

aropc

by

and

ssues.

Death

accumuae

anges

ypes

Is

so

may

maera

ree

1.5).

njur y,

Cell

n

n

13

e

roug

neurons;

and

ER

o

“aco-

13).

severa

granuar

produced

radca–medaed

msod

Caper

fuscn

s

and

neurobrar y

Pgmens

(Suppemena

Normal

a

ces;

 Pgments.

ens

Basement

Injury

accumuae

composed

radca–medaed

accumuaon



s

oten

Hemosdern

s

seen

a

n

n

o

n

pd

ces

oder

ces.

pds

s

Lpo-

and

pro-

peroxdaon

a

sgn

o

ree

ndvduas

emogobn-derved

and

brown

epithelium

A

pgmen

 •

(Suppemena

and

oer

ces

ron

overoad

n

eFg.

1.6)

condons

(see

Caper

o

a

accumuaes

ncreased

red

ce

n

pagocyes

breakdown

or

9).

 Gycogen. Excessve nraceuar deposs o gycogen are assocaed

w

abnormaes

n

e

meabosm

o

eer

gucose

or

gycogen.

Gycogen may accumuae n poory conroed dabees or n gyco-

gen

 •

sorage

dseases

(see

Caper

13).

 Cacum. Cacum sa deposs are seen n a varey o dsease saes.

Dystropc

cum

n

and

areas

ropc

caccaton

s

o

e

caseous

necross

caccaon

cc

senoss

due

o

o

occurs

deposon

e

can

aorc

n

o

e

seng

cacum

and

ave

n

sas

advanced

uncona

vave

o

n

causng

norma

njured

serum

(e.g.,

aerosceross).

Dys-

consequences,

et

ca-

ssue

venrcuar

as

n

ca-

yperropy

B

Fig.

1.15

(right)

in

Metaplasia

a

bronchus,

of

normal

shown

columnar

(left)

schematically

(A)

to

squamous

and

histologically

pressure

ccaton

epithelium

(B).

saes

o

occurs

 Protens.

Morpoogcay

common

an

up

are

or

synesze

vsbe

excessve

n

11)

bodes,

proen

accumuaons;

excessve

rena

amouns

gomeruar

er

pd

vsbe

ubuar

o

damage

For

epea

ces

eadng

eosnopc

may

amouns.

proens

(Suppemena

ey

eFg.

o

rom

e

1.4).

ncusons

e

accumuaons

exampe,

wen

urne,

neproc

Oer

occur

ces

ake

wc

newy

resorb

occurs

(see

ncude

on

w

Cap-

Russe

syneszed

occurs

nersa

mucosa.

dropets

ubues

syndrome

o

ess

proten

e

exampes

comprsed

wen

are

 •

ar

o

a

reaed

o

n

e

(Suppemena

seng

cancers

usuay

Amyod

brar

ssues,

organs

as

wdey

ssues

I

 Amyod.

assume

n

yperparayrodsm

desrucon,

 •

overoad

were

o

e

does

e

e

no

cause

o

may

processes

o

are

1.8).

s

or

s

ncreased

Measac

ungs,

ca-

seen

n

bone

cacca-

afecs

and

e

gasrc

dysuncon.

many

and

Metastatc

wc

prncpay

kdneys,

nerere

and

bu

cnca

one

eFg.

1.7).

16),

bone.

body

vascuaure,

conormaon

ey

Caper

nvovng

consss

eFg.

ypercacema,

(see

rougou

(Suppemena

mmune

o

dferen

deposed

w

e

Amyod

dscussed

proens

n

norma

uncons

deposon

n

a

exraceu-

Caper

4

s

oten

CHAPTER

1

Supplemental

tubular

of

the

the

liver.

James

at

In

displaced

most

rim

Crawford,

1.2

Fatty

cells,

of

the

liver.

High-power

well-preserved

cytoplasm

Department

of

about

the

nucleus

fat

Pathology,

detail

of

is

vacuole.

Zucker

fatty

change

squeezed

(Courtesy

School

of

into

Dr.

Medicine

Hofstra/Northwell.)

Supplemental

phages

by

eFig.

(foam

eFig.

cells,

cholesterolosis.

ogy,

University

of

1.3

arrow)

Cholesterolosis.

in

(Courtesy

the

Dr.

Washington,

lamina

Matthew

Seattle.)

Cholesterol-laden

propria

Y eh,

of

gallbladder

Department

macro-

affected

of

Pathol-

Injury

eFig.

1.4

epithelium

Rennke,

Supplemental

Cell

Boston.)

in

Department

a

Protein

patient

of

and

Cell

reabsorption

with

Pathology,

13.e1

Death

albuminuria.

Brigham

droplets

in

(Courtesy

and

the

Dr.

Women‘s

renal

Helmut

Hospital,

13.e2

CHAPTER

Cell

1

Injury

and

Cell

Death

A

B

Supplemental

indicated

by

eFig.

arrow)

1.5

and

Lipofuscin

(B)

electron

granules

in

microscopy

a

cardiac

(note

the

myocyte

shown

perinuclear,

by

(A)

light

intralysosomal

microscopy

(deposit

location).

B

A

Supplemental

golden-brown,

sian

blue

eFig.

finely

1.6

Hemosiderin

granular

granules

pigment.

(B)

Iron

in

liver

cells.

deposits

(A)

shown

Hematoxylin-eosin–stained

by

a

special

staining

section

process

called

showing

the

Prus-

reaction.

Supplemental

eFig.

1.7

Dystrophic

aortic

heart

with

calcific

valve

thickened

in

and

a

fibrotic,

and

calcification

aortic

behind

each

stenosis.

cusp

are

of

It

is

the

aortic

markedly

irregular

valve.

View

narrowed

masses

of

looking

down

(stenosis).

piled-up

The

dystrophic

onto

the

semilunar

unopened

cusps

calcification.

are

CHAPTER

A

Cell

1

Injury

and

Cell

Death

B

C

Supplemental

deposits

of

the

of

deposits

almost

Hinton,

eFig.

amyloid

totally

in

when

1.8

walls

of

observed

obliterated

Department

Amyloidosis.

the

of

by

the

blood

by

a

(A)

section

polarizing

massive

Pathology,

A

vessels

and

of

of

Texas

of

liver

stained

sinusoids.

microscope.

accumulation

University

the

along

(C)

In

amyloid.

(B)

the

(B,

Southwestern

with

Note

kidney,

red

reveals

yellow-green

the

Courtesy

Medical

Congo

the

glomerular

Dr.

Trace

School,

architecture

Worrell

Dallas.)

pink-red

birefringence

and

is

Sandy

13.e3

2

Inflammation

and

Repair

O U T L I N E

Overview of Inflammation, 14

Causes

of

Sequence

Features

Cells

Acute

of

Inflammation,

of

of

Events

Acute

in

and

Vascular

Chronic

Cellular

Reactions,

Resolution

of

OF

Inammation

is

Outcomes

Inflammation,

15

Chronic

15

to

brings

Clinicopathologic

Tissue

17

Repair,

20

consequences

e

anbodes,

n

e

o

e

were

In

as

and

bood,

ssues,

sue

such

bu

ey

be

ces

nvoved

n

ey

uncon

on

s



nlammaor y

se

be

as

(e.g.,

response

s

ts

 •

(e.g.,

noe

crca

ater

an

aso

or

on

pan,

a

par

o

organ

e

the

Some

ssues,

reas.

s

and

response

uncona

appropraey

denoes

ea

regu-

and

s-

nlammaon

menngs).

[as

n

(e.g.,

26

Chronic

Inflammation,

Features

of

Chronic

Features

of

Tissue

26

Inflammation,

27

Repair,

28

be

 e

n  amma on.

n  ammaor y

or

no

a a ,

o

v ra ,

mos

D   eren

resp ons es ,

 as ng

p aras c)

and

m d

o

cron c

and

me d c a  y

n e c  ous

 rom

d amage,

proonge d

 u nga ,

common

p a ogens

ac ue

s e vere

e  c 

n   am ma on

s ysem c

re ac   ons

m crob a 

mp or  an

 a

a

range

 a

re ac  ons

c aus e

ox -

c aus es

o

c aus es

 a

exens ve

c an

 ssue

njur y.

Immune

em

reactons occur wen e normay proecve mmune sys-

damages

gens

ndvdua’s

ese

n

Caper

assocaed

o

end

w

Necross

oss

s

4).

be

cronc

rom

bood

necroc

o

any

a

ssues

reacng

major

and

eer

o

aergc

by

o

ssue

smu

or

dseases

and

aackng

envronmena

cause

e

perssen

njur y

e

canno

dcu

o

se

an-

subsances

n

ese

nlammaor y

be

cure

emnaed,

and

are

oten

nlammaon.

cause,

suppy,

or

Because

auommune

reacons

own

dseases)

Inlammaon

(see

responses

by

e

(auommune

dseases

n

Inlammaon

(b ac er  a ,

among

even

ecs

sere

njur y

nlammaon

as

due

n

o

narcon

moecues

caused

reeased

ces.

or

normay

armess

commensa

envronmena

mcrobes,

or

agans

se

dseases])

and

even

some

nlammaon

as

n

gou



and

endogenous

arge

substances

amouns

coesero

are

smuae

deposed

cr ysas

n

n

poenay

ssues

(e.g.,

armu

urae

cr ys-

aerosceross).

 he smuus s persstent and canno ready be emnaed (e.g., e

Too

e

a

causes

nlammaon,

Sequence

ubercuoss)

wc

s

ypcay

manesed

by

ncreased

suscepby o necons, s aso probemac and s mos oten caused

quanave

rom

or

repacemen

eukocyes

by

quaave

o

cancer

e

deecs

marrow

erapes,

or

by

use

n

eukocyes,

cancers,

o

wc

desrucon

may

o

mmunosuppressve

nlammaor y

resores

ssue

reacon

ses

n

moon

e

process

o

drugs.

repar,

The

wc

negry.

he

Events

hese

reactions

major

remova,

seps

a

Recog nton

or

and

seps

are

in

n

o

e

and

be

 e

nl amma on.

consists

recruitment

by

(e

e

descrbed

noxous

he

of

of

response

repar

medaed

w

Inflammation

response

reguaon,

medaors

1.

of

inammatory

vascular

resu

norma

Ater e noxous smu and e damage ey cause are emnaed,

e

23

Foregn bodes (e.g., spners, dr, suures) may ec nlammaon,

agans

aerges]

auommune

mycobacerum

by

are

(aerges).

useu

norma

o

norma

body.

n

ns

 e

ces),

crcuae

o

resde

ever,

an

bood

normay

n

needed

and

tissues).

damage

se

ookou

empass

o

and

ese

are

toxins)

(we

preven

any

they

or

damage

rom

msdrected

n

a

o

o

tissue

:

 I

[as

o

conjuncvs,

 •

ssues

e

e

cells

responses

consequences

 I s nadequatey controed

s

on

mporan

 •

subsances

Mos

recrued

o

where

eukocyes

sequesered

muc

sux

sites

and

microbes

necrotic

proens.

are

appendcs,

damagng

(e.g.,

sennes

s

he

the

(e.g.,

nlammaor y

armu

bu

of

Inflammation,

25

28

Clinicopathologic

infections

ncude

rapdy

medcne,

manenance.

can

injury

to

to

injury

compemen

ey

cnca

of

deense

can

been

a

o

were

mparmens),

aed

of

response

molecules

cause

medaors

Acute

Inflammation,

27

Angiogenesis,

Inflammation,

host

and

the

Acute

20

of

INFLAMMATION

a

cells

eliminate

of

Features

Reactions

Infec tons

that

Inflammation,

Inflammation,

Cellular

16

Acute

OVERVIEW

14

16

Reactions,

of

Clinicopathologic

Inflammation,

Inflammation,

Inflammation,

Mediators

14

sequential

are

5

events

involving

leukocytes.

Rs),

recognon,

descrbed

coordnaed

recrumen,

nex

acons

(Fg.

o

2.1).

cemca

aer.

agen

ce s

 a

 a

s

 r g ger

 e

n  a ng

s mu us

nl amma on

( ssue-

resden s en ne ce s, pago c yes, and o ers, des cr b e d  aer) are

Causes

of

e qupp e d

Inflammation

w  

subs ances The

major

causes

of

inammation

are

infections,

14

tissue

necrosis,

and

environmental

 a

 rom

re cog nze

d amage d

mcrob a 

ce s.

pro duc s

C e u  ar

re cepors

and

or

immunologic

mcrob es reactions,

re cepors

ree as e d

substances.

c an

be

o c ae d

n

p asma

membranes

(or

ex race u  ar

CHAPTER

and

STIMULUS

(microbes,

necrotic

tissue)

BY

TISSUE

compemen

(ops onze d)

2.

RECOGNITION

or

Inflammation

2

w  

Recr utment

CELLS

B e c aus e

o

proens,

an b o des

eu ko c yes

bo o d

p er  us es

and

w c

and

and

re cog nze

15

mcrob es

co ae d

compemen.

p as ma

e ver y

Repair

proens

 ssue,

no

 eu ko c y es

 e

and

 ssues .

proens

(”sentinels”)

suc

o

PRODUCTION

OF

as

compemen

mcrob a 

be

d evere d

Wen

o

any

p a ogen c

vas c u  ar z e d

mcrob es

se

nvad e

 e

MEDIATORS

 ssues,

 aer,

or

 ssue

ce s

mono c yes

rapd y

Blood

c an

nvas on .

d  e,

and

re cr ue d

eu ko c yes

( rs ,

y mpo c y es)

 rom

 e

and

crc u  a on

man y

neu rop  s;

p as ma

o

 e

proe ns

are

ex ravas c u  ar

se

vessel

w ere

 e

p asma

bo o d

Exudation

and

of

plasma

vess es

de a 

fluid

proteins

3.

o endng

proens

agen

 rom

and

 e

s

o c ae d.

bo o d

Te

re qures

s e cre on

o

exo dus

o

co ord nae d

me d aors ,

c e s

and

canges

d es c r b e d

n

n

more

 aer.

Remova o e smuus or nlammaon s accompsed many by

pagocyc

DILATION;

ces,

wc

nges

and

desroy

mcrobes

and

dead

ces.

Pagocyoss, descrbed aer, nvoves ree sequena seps: (1) rec-

INCREASED

ognon and aacmen o e parce o be ngesed by e eukocye; PERMEABILITY

(2) engumen, w subsequen ormaon o a pagocyc vacuoe;

and

4.

(3)

desrucon

Reg uaton

o

 e

o

e

ngesed

resp ons e

s

maera.

mp or  an

or

er mna ng

 e

re ac -

 on w en  as accompse d s pur p os e. In  arge p ar , er m na -

 on

s

a er

b e c aus e

 e

o

 e

s mu us

s

d e c ay

o

me d aors

e mnae d.

I

s

and

 key

d e a 

 a,

o

n

eu ko c yes

conc er 

w  

LEUKOCYTE

 e ADHESION

n  ammaor y

resp ons e,

ac  ve

regu  aor y

me can sms

a s o

TO

are

 r g gere d

 a

s er ve

o

ur n

o 

 e

resp ons e.

ENDOTHELIUM

5.

Repar

eas

Features

The

two

differ

of

e

damage,

Acute

principal

in

kinetics

and

and

dscussed

Chronic

patterns

and

s

many

of

a

e

o

e

caper.

Inflammation

inammation,

other

end

acute

and

chronic,

features

LEUKOCYTE

Acute

nammaton

s

a

rapd,

oten

se-med,

response

o

nec-

or

ours

TRANSMIGRATION

ons

and

and

s

zed

o

by

ssue

sor

e

emgraon

LEUKOCYTE

ACTIVATION

ELIMNINATION

OF

AND

ng

2.1

Sequence

tory

reactions,

of

events

recognition

of

in

inflammation.

an

smuus

offending

In

agent

most

(the

inflamma-

stimulus

repared.

reacon

leads

to

the

production

of

chemical

mediators,

Bu

the

vascular

and

cellular

o

lud

deveops

ours

and

o

e

a

reacon

wn

ew

pasma

predomnany

emnaed,

reactions

that

serve

to



e

progresses

mnues

days).

proens

I

caracer-

(edema)

neurops.

subsdes

s

and

I

and

e

e

ofend-

o

na

a

response

proraced

as

ype

o

o

cear

resdua

e

njur y

smuus,

nlammaon

a

s

e

caed

nlammaon.

which

Chronc elicit

(severa

eukocyes,

s

ypcay

for

cronc

inflammation)

duraon

exudaon

o

I

STIMULUS

s

Fig.

damage

eliminate

nammaton

may

oow

acue

nlammaon

or

arse

the

de

novo

(and

acue

nlammaon

may

be

supermposed

on

a

back-

offenders.

ground

o

duraon

p a ogens),

(or

 e

ce 

c yos o

njur y

re cepors

 ke

a

by

k nes,

o

w os e

L eu ko c yes

re cepors,

and

o

o

a

pro duc s

 aer.

e ver-nducng

re cepors

 e

 a

c yos o

pres en

resu 

e y

are

c a  e d

 e

A

c a  e d

and

are

p a ogen-

(PAMPs

e ads

c yo-

subs e

o

o

c yos oc

c a  e d

 e

c yok ne

nereu k n-1

or

p or  on

Fc

To -

re cepors

compex

o

o

 e

pron-

(IL-1).

an b o des

s

ympoc yes

and

 rom

ncudng

pro duc  on

 e

n

es e

ncudng

p aer ns

nl amma on,

mu  proen

 e

are

re cog nze

moe c u  ar

des cr b e d

s mu  aes

express

o ers.

 e y

o

or

bre a kdow n).

am es,

Engagemen

ac  vaes

w c

and

a s o

are

DNA

and

ce 

d amage

moe c u es

o

b e c aus e

de ad

me d aors

 unc  ons

mcrob es),

ce 

moe c u  ar

d amage-ass o c ae d

re cepors

l ammaor y

pro duc 

re cepors

resp e c  vey).

nammas ome,

o

re cog nze

a

s e vera 

mcrob a 

pro duc  on

NOD- ke

ngese d

S ens ors

e y

acd,

NOD- ke

and

DAMPs,

 e

ce s:

ur c

b eong

ass o c ae d

(or

agens).

re cog n on

ac  vae d

o

o

(e.g .,

re cepors,

p aer n

and

endos omes

n race u  ar

cronc

and

was

know

s

as

and

w

Cronc

more

macropages,

ssue

e

nlammaon

desrucon,

proeraon

o

s

o

e

onger

presence

bood

vesses,

ibross.

Aoug

on

nlammaon).

assocaed

a

e

ey

response

many

dsncon

s

a

based

dfer

o

n

and

response

bacera

and

beween

on

e

severa

ofendng

bacera

necon

some

e

orgnay

vra

o

oer

acue

duraon

ways

agens

(Tabe

a

necons

agens

a

paogens,

are

Acue

dead

as

we

emnaed,

and

suc

cronc

eradcae,

and

now

nlammaon

ces,

o

se

nlamma-

reacon,

ready

dcu

we

cronc

e

2.1).

and

are

as

and

o

suc

as

envronmena

angens.

Cells

The

of

cells)

in

he

a

Inflammation

principal

the

major

deec

cells

of

circulation

ces

o

paogenc

inammation

and

are

leukocytes

(white

blood

tissues.

nlammaon

mcrobes,

are

oxns,

(1)

and

ssue-resden

producs

o

ce

sennes

damage,

16

CHAPTER

Table

2.1

Acute

and

Inflammation

2

Chronic

and

Repair

Inflammation

Acute

Inflammation

Chronic

Onset

Rapid:

minutes

Slower:

Duration

Typically

Cellular

Mainly

infiltrate

brief

to

hours

(days)

Inflammation

days

Prolonged

neutrophils

Macrophages

(derived

from

blood

monocytes),

lymphocytes

Tissue

injury

Usually

self-limited

Scarring

Uncommon

Major

Histamine,

mediators

prostaglandins

cytokines,

Local

and

Common

systemic

signs

complement

and

leukotrienes,

Pyogenic

death

Immune

reactions

Trauma

(e.g.,

necrosis

Antibody

deposition

fungi,

some

Intracellular

sis),

tissues

in

burns,

Not

tissues

(in

autoimmune

immediate

dis-

T

human

deposition

Infections,

acute

ces

many

a

o

e

emnae

 he major sentne ces are:



•

 D endrtc

ces,

so

medaors

e

 •

Sometimes,

in

tissues

(e.g.,

named

noxous

syndrome

because

o

nlammaon,

and

(2)



•

recognze

dspay

proen

mcrobes

angens

and

o

o

T

dead

er

ces,

o

ces

w

dendre-ke

and

nae

aso

 Mast ces are ocaed adjacen o bood vesses.



•

 Tssue-resdent

macropages

are

presen

n

a

(e.g.,

Kuper

sysem,

mos

ces

aveoar

n

e

ver,

macrophages

macropages

are

mcroga

n

e

derved

n

ung).

responses.

rom

connecve

e

bood

Acute

cenra

rom

emaopoec

sem

ces

nervous

nlammaon,

cells,

Acue

ssues

monocyes,

n

e

bone

progenors

deveopmen

and

are

n

e

yok

sac

and

ea

ver

eary

durng

dever

were

bood

eukocyes,

no

e

monocyes

or

se

PMNs)

o

monocytes,

nlammaon.

maure

no

are

Foowng

macropages.

recrued

er

rom

enry

Neurops

The

e

respond

macropages

ved.

more

become

Aoug

pagocyoss,

ey

rapdy

n

cemoacc

progressvey

bo

dfer

o

ce

e

ypes

are

span

and

medaors,

domnan

sare

e

because

common

specazed

no

bu

ey

moe

 •

acves

o

(T abe

 Oer ces pay dverse roes n varous nlammaor y reacons:

•

 Lymphocytes, especay T ymphocytes, are promnen wen e

adapve

mmune

response.

hs

s

oten e case w vra necons and auommune and aergc

reacons.

aso

Anbody-producng

be

promnen

n

B

ymphocytes

reacons

o

and

parcuar

atherosclerosis,

asthma,

fibrosis

seen

n

aergc

reacons

and

necons

parases.

is

a

rapid

antibody

and

and

tissue

response

to

microbes,

toxins,

deposition.

consss

pasma

o

vascuar

proens

proens

ge

and

rom

rd

o

e

e

ceuar

bood

noxous

reacons

no

e

a

ssues,

subsances

a

pasma

smu.

ces

changes

in

blood

increased

o

ces

aeraons

and

n

vessels

during

acute

inammation

are

permeability.

pasma

bood

proens

vesses.

he

rom

e

na

bood

canges

no

are

ssues

daon

e

ex

o

 Vasodaton

eukocyes.

s

nduced

by

e

acon

o

severa

medaors,

noaby

samne, on vascuar smoo musce. I irs nvoves e areroes

and

en

eads

o

e

openng

o

new

capar y

beds

n

e

area.

he

resu s ncreased bood low, wc s e cause o ea and redness

are

uncon



an

exposure

and ncreased permeaby o e vesses, oowed by canges a pro-

w

 •

ecs

radiation

beryllium)

Reactions

ex

 •

(er yema)

a

 Increase

vascuar

n

conracon

racon

agen

ces

and

requres

more

2.2).

ofendng

silica,

response.

major

dilation

abundan eary n e reacon because ey are more numerous n e

and

low-dose

(e.g.,

arthritis,

oten

nlammaon

ese

he

and

and

eukocyes

eced

ong-ved.

he wo major casses o crcuang pagocyes, neutrophs (poymor-

may

repeated

wc

 Phagocytes are ces specazed or eang and kng ofendng agens.

ponucear

diseases

marrow.

Many o e ssue-resden macropages are derved rom ema-

opoec

cause

inflammatory

INFLAMMATION

Vascular orgnae

are

emnc

inammation

necrotic

Durng

tuberculo-

fungi

and

and mos organs. hey are gven speca names n dferen organs

onger

inflam-

projec-

capure

mmune

•

me

acute

Mycobacterium

hepatitis),

underlying

particles

Rheumatoid

 Eosnophs

subsances.



bood

in

gout)

distress

ACUTE ons,

ssues,

involved

hypersensitivity

radiation

respiratory

(e.g.,

(e.g.,

frequent

pulmonary

produce

pagocyc

a

bacteria

viruses

cell–mediated

diseases

e

mediators

milder

Inhaled

Crystal

of

of

IgE-mediated

injury,

staphylococci),

toxins

Others

Examples

(e.g.,

influenza).

Ischemic

Physical

Environmental

 •

other

mation

Usually

bacteria

eases),

aso

extensive

Cytokines,

proteins

Prominent

viruses

and

be

causes:

Infections

Cell

May

Prominent

o

s

e

s

eced

ca

mos

o

sows,

o

common

by

o

e

nlammaon.

permeabty

endoea

a

e

w

cause

openng

o

(wn

e

eakage.

eukorenes,

o

a

ssue.

wo

30

njur y.

and

medae

hs

and

occurs

mnues).

Drec

mecansms:

nerendoea

vascuar

15

by

endoea

o

vasodaon,

proens

no

occur

drec

bradyknn,

medaor

pasma

can

and

mecansm

aso

vesses

ces

ces

samne,

aowng

roug

se

endoea

medaors

exposure

e

os

response

oer

cem-

rapdy

he

bood

deense

endoea

Con-

spaces

o

njur y

ater

low

pass

s

e

CHAPTER

Table

2.2

Origin

HSCs

in

bone

marrow

HSCs

in

Many

tissue-resident

in

tissues

1–2

days

bone

liver

marrow

(early

Inflammatory

Responses

to

activat-

Rapid,

stimuli

Reactive

oxygen

Rapidly

species

Nitric

short-lived,

mostly

degranulation

and

enzymatic

More

activity

induced

(respiratory

oxide

Low

levels

Degranulation

Major

Cytokine

Low

or

by

assembly

of

phagocyte

oxidase

Less

inflammatory

17

reactions)

stem

cells

in

yolk

sac

or

development)

days

macrophages:

prolonged,

gene

in

(in

macrophages:

macrophages:

Tissue-resident

ing

Repair

Macrophages

fetal

span

and

Phagocytes

Neutrophils

Life

Inflammation

2

slower,

or

weeks

years

often

dependent

on

new

transcription

prominent

burst)

none

response;

Induced

induced

by

cytoskeletal

rearrange-

Not

following

transcriptional

activation

of

iNOS

prominent

ment

production

levels

or

none

Major

functional

activation

NET

formation

Secretion

somal

This

table

many

(the

of

lists

the

features,

of

e

canges

ng

red

e

n

resu

a

nvoved

n

er

o

o

o

As

o

nitric

proens

of

nuclear

contents

Less

bood

ermed

sass

ou

aso

low,

o

stass,

as

synthase;

venues,

njur y

o

e

e

e

(e.g.,

ssue

oss

o

NET,

reactions

into

and

o

vesses

wc

bood

vascuar

n

s

and

resus

ncreased

concenraon

e

w

seen

bood.

sowy

mov-

soogcay

redness

(er y tema)

eukoc yes,

o

hese

prncpay

endoeum,

e

and

and

ender

irs

nlammaor y

ses

o

reacons

acue

and

nlamma-

(ympadens).

Te

p a s e s ,

a

other

inammation

 e

and

thelium

into

the

and

o

 e

stimulate

tissue.

e

text.

a

Note

typical

orgna

that

blood

n

smuus

end

recru

and

neurops

o

the

two

cell

neutrophil

and

nay

ympocyes,

some

cases

predomnae

apoposs

a d  e s  on

 ea 

o

(n

24

a ge n .

o

a

types

and

aergc

durng

48

e

share

monocyte

duraon

recru

mxed

e

reacons

irs

o

o

e

neurops,

nirae.

ours),

a   ow  ng

an d

o

2.3).

m ove m e n

 nvo ve s

e x pre s s e d

o

 a c 

pr  n c p a 

s e  e c   ns

Te

c an

6

o

be

be

 e u ko c y  e s

 r ans m  g r a  on

sep

 a e r

Te

o

  n a  y

 e u ko c y  e s

pro e  ns ,

Tab e

 en

an d

 e

e m  g r a  on

a d  e s  on

E ac

v a s c u  au re .

 am    e s

2.2

o

wa  ,

m o e c u  e s ,

ce s,

 e

 e u ko c y  e

 rs

 n   am m a  on ,

ve s s e 

o e n d  ng

activate

endothelial

cells

at

the

In

24

ave

acue

ours,

repaced

by

seps

s ou b e

on

on

o

n

 e

 e

 e u ko c y  e s

ce s

an d

m o e c u  e s

 e u ko c y  e

 ow ard

m e d  a or s

e n d o  e   a 

 n e g r  ns ,

 n o

e n d o  e  u m

 e u ko c y  e s

a d  e s  on

an d

o

o

d v  d e d

o

an d

an d

endo-

ce s

an d

b e  ong

 er

re c r u  m e n

o

  g an d s

are

 e

 L eukoc y te

the

binding

migration

of

of

leukocytes

cells

through

marg naton .

As

 e

bo o d

 ow

sow s,

eu ko c ye s ,

site

to

endo-

the

endo-

 arger

 e

 eum. the

the

o  ow  ng :

mediators

subsequent

o

necons

undergo

s  e

ne ar thelium

in

show

necons

eosnops,

pro c e s s

b eng of

naure

c ons  s   ng

  rou g 

 • and

vra

en

(Fg.

Reactions

Cytokines

images

monocyes.

as

o

e

nlammaon,

 wo

swoen

described

The

Bacera

ncreased

ymp

are

are

trap.

on

wereas

 e

dranng

above

chemotaxis.

he ype o eukocye a emgraes no a se o necon or njur y

depends

 e ave

nodes

and

extracellular

capares,

vesses.

Vesses

summarized

tissues,

neutrophil

burns)

(exudate)

lud

ncreased

vscosy

ocazed

parcpae

exudae.

oxide

escape

sma

deveops,

o

The

vessels

response.

ncreased

exernay

adere

blood

oxns.

he

and

macrophages.

through

on are oten engorged and congesed (ympangs), and e dranng

Cellular

transcriptional

reactions).

necrozng

no

sower

and

migrate

inflammatory

escapes

and

vesses

e

and

severe

a

to

inducible

engorgemen

mgraon

remove

in

neutrophils

ability

nlammaon.

condon

ssue.

Lympac

ep

lud

e

begn

o

mcroba

vesses,

congeston

neurops,

sep

ead

n

the

iNOS,

ces

cases

se

sma

ces,

vascuar

e

a

cells;

wc

n

some

dameer

ces

extrusion

requires

genes

Less

between

macrophages

proen-rc

edema

vesse

o

differences

phagocytosis,

stem

by

areroes

exposure

red

as

tissue

mecansm

n

by

Prominent

major

such

Hematopoietic

and

induced,

activity,

cytokine

enzymes

precursor

HSC,

Rapidly

lyso-

of

 an

vess e

re d

wa  ,

ce s,

sow

a  ow ng

 e

d ow n

 e

mos

eu ko c yes

o

and

bnd

acc umu  ae

o

 e

end o-

18

CHAPTER

Inflammation

2

and

Repair

ROLLING

INTEGRIN

BY

Selectin

ACTIVATION

CHEMOKINES

ligand

Leukocyte STABLE

ADHESION

Integrin

(low-affinity

state)

MIGRATION

THROUGH

ENDOTHELIUM

Integrin

(high-affinity

state)

P-selectin

E-selectin

PECAM-1 Proteoglycan

(CD31)

Integrin

ligand

(ICAM-1)

Cytokines

(TNF,

Chemokines

IL-1)

Fibrin

Macrophage Microbes with

Fig.

2.2

blood

to

Leukocyte

vessels

the

migrate

toward

roles

different

in

on

adhesion;

1;

2.3

and

Adhesion

Selectin

L-selectin

and

for

then

steps

of

CD31

this

in

platelet

process:

Major

in

in

Cell

tissues.

The

from

The

the

the

in

cell

rolling;

Leukocyte

to

of

process

roll;

injury.

pierce

leukocyte

become

the

Different

the

Intercellular

molecule-1;

of

then

chemokines

increase

ICAM-1,

adhesion

first

endothelium,

source

neutrophils

transmigration.

multistep

leukocytes

across

selectins

the

endothelial

Molecules

Molecule

to

emanating

activating

(PECAM-1)

(CD31),

blood

neutrophils.

transmigrate

chemoattractants

Adhesion

Family

from

here

endothelium)

PECAM-1

Selected

migration

shown

endothelium;

glycans

Table

is

and

fibronectin

(extracellular

microbes

molecules

tumor

molecule

necrosis

adhere

to

integrins

1;

and

predominant

bound

integrins;

through

and

membrane,

play

displayed

of

adhesion

TNF,

basement

(usually

avidity

migration

activated

matrix)

IL-1,

proteo-

in

firm

interleukin

factor.

Migration

Type

Principal

Lymphocytes

Ligands

Sialyl-Lewis

X

on

various

glycoproteins

expressed

on

endo-

X

on

glycoproteins

expressed

on

neutrophils,

glycoproteins

expressed

on

neutrophils,

thelium

E-selectin

Activated

endothelium

Sialyl-Lewis

monocytes,

T

P-selectin

Activated

endothelium

lymphocytes

Sialyl-Lewis

X

monocytes,

Integrin

LFA-1

T

MAC-1

Monocytes,

lymphocytes,

VLA-4

T

lymphocytes

α4β7

T

lymphocytes,

neutrophils

dendritic

cells

of

the

integrins,

ICAM,

integrins

and

their

intercellular

are

expressed

ligands

are

adhesion

also

on

many

named

molecule;

Ig,

leukocytes;

according

to

only

the

immunoglobulin;

CD

the

cell

types

nomenclature,

IL-1,

interleukin-1;

that

but

expressed

on

activated

endothelium

expressed

on

activated

endothelium

expressed

MAdCAM-1;

are

most

their

TNF,

CD

tumor

lymphocytes

ICAM-1

ated

Most

T

ICAM-1

VCAM-1

monocytes

on

necrosis

are

on

a

not

factor;

activated

expressed

lymphoid

dependent

numbers

on

endothelium

endothelium

in

gut

and

gut-associ-

tissues

particular

shown

VCAM,

on

for

integrin

for

adhesion

are

listed.

simplicity.

vascular

cell

adhesion

molecule.

All

the

selectins,

CHAPTER

 •

 Endotea actvaton. Two o e cyoknes secreed n response o

mcrobes

ac

on

ns

and

oer

nearby

and

smu,

endoea

gands

or

umor

ces

negrns.

o

necross

ncrease

Cyoknes

acor

e

aso

(TNF)

and

expresson

conver

e

o

 •

bnd

seec-

endoe-

 •

 L eukoc y te

pro duc s,

rong.

o

bnd

e

a

eukocyes

aong

e

Seecn

seecns

s

on

easy

bnd,

gands

e

on

dsruped

deac,

e

ps

endoeum.

and

by

e

bnd

o

neurop

s

lowng

agan,

s

a

and

mcro-

us

on

and

ro

e

nzed

a

surace

by

The

cange

1.

acvaed

o

e

recepors

ow-any

A

by

e

o

on

endoea

endoeum.

e

rong

conormaon

a

g-any

RECOGNITION

AND

Microbes

phagocyte

o

ces

bnd

hese

and

are

cemoknes

eukocyes,

negrns

o

on

wc

e

by

dspayed

are

 •

rom

e

wc

arres

are

and

nduced

irm

on

endoea

aacmen

o

ces

eukocyes

s mu  ae

cemc a 

Ts

C emok nes

compemen

eu ko c y e

g rad  en).

sp aces,

 roug 

pro cess

noxious

o

substances

through

and

pro duc  s ,

cemo axs

Te

 e

w a  ,

o er

and

o

dead

by

following

bnd

ces,

membranes

o

mcrob a 

movemen

mg rae

 e

ex ravas a on

se

as

b e we en

o

n  am -

b e en

triggered

inammation

intracellular

steps

(Fig.

are

destruction,

cleared

mcrobes

cr ysas,

around

and

and

e

oer

oregn

parces,

parces

maera),

and

(suc

wrap

nernaze

e

as

ragmens

er

pasma

parces

Lysosome

with

enzymes

Fusion

of

phagosome

Microbe

in

with

ingested

lysosome

phagosome

Degradation

2.

by

ENGULFMENT

Phagocyte

zips

membrane

up

in

Phagolysosome

of

lysosomal

microbes

enzymes

phagolysosome

around Phagosome

with

microbe

3. ingested

KILLING

AND

DEGRADATION

microbe

Cytoplasmic Primary oxidase granule

MPO

MPO

+ O

NADPH

Active

Cl

2

oxidase

+

iNOS

NADP

•

O

•

H

2

O

2

OCl

Arginine

2

++

Fe

Membrane

NO oxidase

•

OH

ROS

Membrane

Phagocyte

oxidase O

B

PHAGOCYTIC

Fig.

2.3

rium)

Phagocytosis

involves

vacuoles

with

lysosomal

binding

to

of

the

and

intracellular

receptors

lysosomes.

enzymes

components

and

This

by

is

on

phagocyte

destruction

the

followed

reactive

2

C

VACUOLE

by

oxygen

oxidase

of

leukocyte

microbes.

enzyme

(A)

membrane,

destruction

and

of

nitrogen

assemble

Phagocytosis

engulfment,

ingested

species.

in

the

particles

(B)

In

of

and

within

activated

membrane

of

a

particle

fusion

the

of

(e.g.,

the

bacte-

phagolysosomes

phagocytes,

the

a

phagocytic

by

cytoplasmic

phagosome

to

form

the

– .

active

enzyme,

which

catalyzes

the

conversion

of

oxygen

into

superoxide

(O

2

)

and

H

O

2

.

2

Myeloperoxidase,

. present

in

the

granules

of

neutrophils,

converts

H

O

2

2

to

hypochlorite

(OCl ).

In

the

presence

of

metals

such

. ++

as

Fe

gen

be

,

H

O

2

species

released

NADPH,

2

can

(ROS)

into

also

and

be

converted

nitric

oxide

extracellular

nicotinamide

adenine

to

(NO)

tissues

highly

kill

(not

dinucleotide

reactive

ingested

shown).

hydroxyl

microbes.

iNOS,

phosphate;

pro

2.3)

to

receptors

receptor

c a  e d

which

ATTACHMENT

Phagocytic

o

me d aors,

s ome

(dre c e d

eu ko c yes

vess e

eu ko c ye

that

followed

the

macropages

a

sae.

bind

by

 Recognton, attacment, and engufment. Acvaed neurops and

sgnas

eukocyes

gands,

o

transmg raton .

phagocytosis

ceeds

recog-

dever

19

dapedes s.

endoeum.

aso

a

ma on.

 Integrn actvaton. Cemoknes secreed by senne ces n e s-

sue

er

eu ko r enes ,

endo e a 

hereore,

sowy

as

a ong

ow-any

bood.

Repair

e endoeum.

oxns.

v

o

eadng

suc

neracon

 •

gy

cyoknes,

sae. Loca romboss may preven dssemnaon o mcrobes and

 Leukocyte

and

 Stabe adeson o eukocyes. he acvaed negrns on e eukocyes

IL-1,

a surace rom s norma anromboc sae o a proromboc

 •

Inflammation

2

radicals

During

Inducible

ROS,

).

(C)

Microbicidal

phagocytosis,

NO

reactive

(OH

synthase;

oxygen

granule

MPO,

species.

reactive

contents

oxy-

may

myeloperoxidase;

no

20

CHAPTER

vesces

o

caed

recepors

bnd

e

o

IgG

 •

w

 Kng

and

 e y

 a

(e.g .,

by

as

so

(or

n

C3b



a

varey

a

gycoproens.

e

ave

Fc

use

recepors

wa

and

a

parces

recepors,

recepors

C4b

subs anc es

and

ave

are

suc

on

(wc

e

bnd

 a

( e. g . ,

sp e ces

o

d amag ng

o

g ranu  es ,

gone

and

ved.

a

In

because

o

n

sop

e

lammaory

and

e

medaors

addon,

varey

swc

as

sgnas

ype

o

o

e

a

o

oowng)

deveops,

acvey

aracdonc

eukorenes

beraon

(see

nlammaon

and

e

ermnae

acd

e

meaboe

annlammaory

annlammaory

neurops

process

reacon,

produced,

poxns

cyoknes,

are

se

ncudng

rom

a

pron-

(descrbed

ncudng

sor

rggers

aer),

ransormng

grow acor-β (TGF-β) and IL-10, rom macropages and oer ces.

 e

o er

more

d es r uc  ve

sub-

ma r  x

enzy mes

mye op erox d as e,

w  c

 re e

r ad-

nex) .

ey

by

no

producs

cause

suc

(IFN-γ)

and

as

eukocyes

njur y

o

are

n

ssues.

a

quescen

Ater

acvaon

popoysaccardes,

cemoknes,

and

cyoknes

pagocyc

suc

recepors

of

reactions

duced

or

hese

o

a

e

and

the

at

medaors

may

o

a

described

mediators

the

reacon

se

moecues

ucs

inammation

called

activated

nlammaor y

vaed

Inflammation

of

chemicals,

site

be

or

of

the

are

nlammaon.

by

ces

recrued

hey

are

rom

(Table

a

e

ces.

induced

are

e

se

bood

ony

ncudng

necroc

are

that

pro-

2.4).

resdng

rom

produced

nlammaon,

reeased

previously

inammation,

reaction

produced

a

smuae

subsances

of

o

and

n

response

mcroba

One

e

ac-

prod-

medaor

can

smuae e reease o oer medaors. For nsance, producs o com-

pemen

Crcuang

do

Mediators

The

g ran -

ngese d

ce aves

and

and

ves ces

s e c ond ar y)

d es roy

proe as es)

me can sms

 es e

 yp es

(or

 a

ys os omes,

o

w  ou

 wo

sp e c c

proe as e

o er

w  

con  nes

en zy mes

s er ne

oxy gen

 us e

 e

 ngese d

many

actvaton.

neeron-γ

pagocyes

IgG-specic

Pagos omes

con an

and

re ac  ve

mcroba

ce

o

pr  mar y)

k   ng

a

mannose

ncreased

producs

Repair

Pagocyes

e

Neu rop s

e as as e,

des cr b e d

sae

as

mcroba

bnd

 e

s e ) .

e as n,

 Leukocyte

suc

greay

ac  vae d

g ranu es

ac  vae

c a s,

are

azurop 

conver s

wc

(wc

des roy

pago c ye

proen

or

s

compemen

(w ere

s ances

on

process

destr uc ton .

Tes e

pagosomes.

and

recepors).

enzy mes

u es.

or

mcrobes,

mannose

ags

s e vera 

c a  e d

o

s

and

compemen

 e

 •

o

anbodes

pagocyes)

o

bnd

ermna

ecency

opsonzed

as

endosomes

o

Inflammation

2

TNF

acvaon

acs

on

cyokne,

vaed

us

a

IL-1,

by

smuae

endoea

and

many

enzymes,

sysem

o

or

reease

o

o

oer wse

and

samne,

smuae

cemoknes.

are

cecks

e

ces

baances

e

hey

qucky

scavenged

a

and

e

producon

or

reguaes

cyokne

o

decay,

anoer

are

nbed.

medaor

nac-

here

s

acons.

suc as mannose recepors or recepors or opsonns, e eukocyes

acqure

 •

 he

major

ncude

and



•

e

aby

kng

reacve

ysosoma

process

o

and

neurops

(ROS)

(see

dead

and

Caper

Cell-Derived

ces.

macropages

1),

nrc

oxde,

enzymes.

hese

gens

ese

o

ydrogen

peroxde

or,

superoxde,

under

e

pagocye

wc

acon

can

o

be

con-

neurop

gens

and

Fc

damage

pysca

proens,

by

and

ssues

e

DNA,

ad

n

are

acon

and

e

normay

o

pd

ceanup

membranes

o

debrs

proeced

anoxdan

rom

enzymes

and

rom

us

desroy

necroc

ces.

ROS-medaed

dam-

a

degrade

ROS,

suc

oer

recepors,

acd.

In

many

pospopase

pospopds.

cycooxygenase

scavenge e ree radcas.

renes.

(NO)

s

made

mosy

n

macropages

oowng

ran-

hese

kocyes,

as

scrpona acvaon o e enzyme nducbe nrc oxde synase

cncay

(NOS). NO s convered o ree radcas a ac muc ke ROS.

nb

 Lysosoma enzymes, ncudng easase and oer proeases, gan

 •

access

o

e

 E xtraceuar

ngesed

destructon.

parces

Some

o

and

dges

ese

em.

moecues,

especay

yso-

n

desroy

maon

er

mcrobes

nucear

neurop

s

mes

reeased

Some

ve

os

deveop

se

suc

as

cear

desroyed

e

coaera

responses,

wen

e

or

poen

raps

by

a

ssues.

mes

Neurops

o

(NETs).

aso

sones

and

Mcrobes

are

anmcroba

subsances

exrude

DNA

caed

rapped

a

are

n

aso

NETs.

damage

bu

s

s

s

an

oer

nevabe

usuay

usuay

s

consequence

se-med.

argeed

armess

o

Paoogc

abnormay

(e.g.,

envronmena

proec-

esons

agans

subsances

aergens).

eukocye

wc

n

rops

and

urn

and

e

ces

o

e

reease

Acute

Inflammation

acd

n

Tabe

o

acvy

PGE,

ce

o

I

by

acng

capares

s

sored

acvaon

aergens

o

producs

,

derved

s

PGD

2

en

and

IgE

C5a

n

by

on

o

on

and

mas

pao-

mas

and

2.4.

,

he

C3a,

ce

and

2a

,

on

by

bood

enzyme

membrane

e

enzyme

no

vesses

acon

on

srucura

and

e

mporan

PGF

rom

er

euko-

and

o

eu-

many

aby

o

medaors.

PGG,

ndcaes

aracdonc

e

poxygenase

depends

ese

on

acd

erapeuc

drugs

o

rom

nduce

convered

by

acons

based

mos

smu

aracdonc

PGF ,

wc

he

nvoved

e

gves

e

o

are

dverse

n

recrumen.

o

pao-

casses

PGI

eaures

PGH)

number

and

o

by

subscrp

doube

prosagandns

(prosacycn),

2

coded

a

n

bonds

nlam-

and

TXA

2

).

some

acvaor

4

of

2

seps,

and LTE

Resolution

2

A

 Leukotrenes are

and

beraes

named

2),

PGE

(romboxane

 •

are

1,

major

areroes

ces.

mas

nlammaor y

ave

or

PGD,

(e.g.,

are

bndng

annlammaor y

compound.

mupe

nlammaon

agans

and

dead

ormng

exraceuar

and

no

angens

and

conens,

e

daes

upon

prosagandns

producon

numera

soma enzymes, are reeased no e exraceuar space, were ey

wc

cemcas

(e.g.,

recognze

he

permeaby

endoea

eukotrenes

summarzed

eer

a

ea.

no

 Prostagandns

a

e

compemen

Aracdonc

useu

e

as

e

ypes,

A2,

o

rapdy

suc

o

and

ce

wc deoxies ydrogen peroxde, as we as serum proens a

oxde

and

ces

eukocyes.

a

ncreases

reracon

sgnas,

senne

moecue

and

exposure

rauma

e

recrued

oowng.

reeased

Prostagandns

by

by

sma

ces

and

as superoxde dsmuase, wc degrades superoxde, and caaase,

 Ntrc

a

and

e

causng

granues

myeoperoxdase, o gy reacve ades. A o ese subsances

are

s

by

ROS

e

Hstamne

ce

e

o

medaors

venues

o

assemby

ocay

ces,

ayzes

generaon

rapd

produced

dead

enzyme n e membrane o e pagoysosome. hs enzyme ca-

e

by

are

and

Mediators

musce

age

 •

speces

mcrobes

smoo

Heay

•

mecansms

oxygen

naed

mcrobes



ngesed

oxdase

vered

•

desroy

 ROS are produced many n neurops by e respraory burs,

a



o

irs

o

rse

o

vascuar

he

wc

LTB

4

venuar

ysosoma

smoo

o

generaes

or

macropages,

neurops,

and

syness

LTC

4

and

s

causng

endoeum,

enzymes.

.

a

eukorene

LTB

4

s

LTC

4

poen

s

A

4

nvoves

(LTA

4

by

cemoacc

and

generaon

and

reacons

produced

aggregaon

e

musce

eukorenes

agen

adeson

o

ROS,

meaboes,

),

neu-

o

and

LTD

4

, are produced many n mas ces and cause nense vaso-

consrcon,

broncospasm

(mporan

n

asma),

and

ncreased

Normay, oowng cearance o e ofendng agen, e acue nlamma-

permeaby o venues. In genera, eukorenes are ar more poen

ory

an

response

sponaneousy

subsdes,

because

e

acvang

smuus

s

samne.

CHAPTER

Table

2.4

Mediators

of

Inflammation

2

and

Repair

21

Inflammation

Pharmacologic

Mediator

Production

Cell-Derived

Role

in

Inflammation

Antagonists

Mediators

Histamine

Stored

as

cells

a

preformed

and

ulation

in

trauma,

molecule

basophils;

response

released

to

complement

IgE

in

granules

rapidly

of

upon

cross-linking

mast

Dilation

degran-

of

blood

increased

vessels,

vascular

Antihistamines

permeability

bind

(allergy),

to

receptors

products

itively

for

allergy;

histamine

and

inhibit

compet-

histamine

binding

Arachidonic

acid

PLA

derived

2

production

complement

releases

Produced

and

→

in

prod u c ts ,

cells

cells,

by

in

ma n y

c ell

c y to kines ,

a c id

converted

mast

other

trauma,

indu c e d

arachido n ic

pholipids

Prostaglandins

is

to

fro m

o the r

activ e

→

pho s -

m e diators

endothelial

cyclooxygenase;

products,

by

s t i m ul i

me mb r a ne

leukocytes,

complement

t y pes

activated

cytokines,

cells,

Vasodilation

by

microbial

(PGI

products

Produced

and

Table

or

in

mast

other

cells

cells,

by

leukocytes,

lipoxygenase;

products,

endothelial

activated

cytokines,

by

microbial

cells,

stimulate

pain,

vascular

PGE

(TXA

);

)

(PGD

nonsteroidal

antiinflammatory

platelet

2

fever

Many

inhibit

2

(NSAIDs)

,

inhibit

drugs

cycloo-

xygenase

2

)

muscle

products

,

2

2

Neutrophil

trauma,

increased

(PGD

aggregation;

complement

Cytokines:

)

2

PGE

Leukotrienes

and

permeability

(LTC

,

chemotaxis

(e.g.,

LTD

4

),

4

(LTB

bronchial)

involved

);

4

smooth

Leukotriene

contraction

in

receptor

antagonists

for

asthma

asthma

see

2.5

Platelet-activating

factor

Produced

(PAF)

and

in

mast

platelets

cells,

by

leukocytes,

action

of

PLA

2

endothelial

on

cells,

Vasodilation,

membrane

meability,

phospholipids

platelet

increased

vascular

constriction

aggregation

of

per-

bronchi,

(promotes

thrombosis)

Plasma

Protein–Derived

Complement

proteins

Produced

(see

Chapter

Mediators

tial

at

site

enzymatic

of

complement

(protease)

activation

by

sequen-

C5a,

activity

C3a

cytes

4)

are

chemotactic

(especially

for

leuko-

neutrophils),

Anti-C5

dilate

vessels

C3b

Synthesized

in

the

liver

in

response

to

cytokines

diseases

by

excessive

complement

coats

their

Pentraxins

for

caused

microbes

and

promotes

(in

activation

trials)

phagocytosis

Markers

of

inflammation

(acute-phase

proteins)

C-reactive

protein

(CRP)

CRP:

opsonizes

microbes

for

phago-

cytosis

Serum

Kinins

amyloid

Bradykinin:

cells

by

protein

peptide

the

(SAP)

produced

kinin–kallikrein

SAP:

in

activated

endothelial

unknown

Vasodilation,

system

increased

permeability,

vascular

bronchial

constriction,

pain

 •

 Lpoxns

ase

are

aso

paway,

suppress

bu

generaed

unke

rom

aracdonc

prosagandns

nlammaon

by

nbng

and

e

acd

by

e

eukorenes,

recrumen

poxygen-

e

o

poxns

cysene

cemoaxs,

Cytoknes

kocyes

and

moecues

subse

o

are

cemoknes,

o

e

se

o

o

sgnang

knes.

no

ces

and

uncon

by

oer

paways

cyoknes

major

groups

o

communcaon

ave

e

dsnc

descrbed

accordng

o

e

earer,

or

e

eads

and

2.5).

o

o

o

e

roes

arrangemen

o

known

and

sennes,

acvaon

n

are

e

hes e

n

 e

on.

or

Protein–Derived

o

cyo-

acue

and

cassied

conser ved

medaors

ver

he

oowng

he

eukocyes

secreon

Cemoknes

One

mcrobes

recepors

overappng

aer.

o

eu-

messenger

(Tabe

movemen

syness

among

e

cyoknes,

Recognon

recognon

menoned

nduce

consdered

nlammaon

drec

Eac

group

acs

preerenay

on

neurops,

are

syn eszed

ympocyes.

Mediators

endoeum.

cemoaracan

paern

ces,

as

and

e

s

e

ereore

(cemoaxs).

e

a

nlammaon,

our

o

o

drec

are

mmuny

consss

wose

dead

Varous

cronc

reguae

adeson

a

and

nlammaon

macropages,

o

ces,

cyoknes

as

producs

proens

oer

a

and

resdues.

eosnops,

eukocyes,

Plasma neurop

(C)

monocyes,

are

and

mos

(s ee

are

Tabe

by

o

ssues

mp or  an

compement

acvaed

pro duc s

o er

o

pasma

and

proens

ac vaed

 es e

a

 a

 e

me daors

are

se

o

nlamma-

des cr b ed

n

 e

2.4).

system

mcrobes

consss

and

by

o

severa

anbodes

crcuang

or

pasma

proens

ecns

a

bound

o

mcrobes and oer angenc subsances. Compemen acvaon eads

o

sequena

e

oer

ces

mcrobes.

er

enzymac

deposon

4,

n

or

o

a

pagocyoss;

Compemen

e

modicaon

producs

conex

o

o

varousy

recru

acvaon

s

e

coa

proens,

eukocyes;

descrbed

ypersensvy

cumnang

(opsonze)

n

reacons.

and

mcrobes

yse

more

n

and

n-waed

dea

n

Cap-

22

CHAPTER

Table

2.5

Major

Inflammation

2

Cytokines

of

Acute

and

and

Repair

Chronic

Inflammation

Principal

Functions

and

Role

in

a

Cytokine

Principal

Cytokines

Tumor

in

Acute

necrosis

factor

Cell

Sources

Use

of

Therapeutic

Antagonists

Inflammation

Macrophages,

(TNF)

Inflammation

cells,

T

dendritic

Endothelial

cells

cells:

adhesion

reduced

activation

molecules,

→

expression

secretion

anticoagulant

of

of

Rheumatoid

chemokines,

properties

bowel

arthritis,

disease,

inflammatory

psoriasis

(inflammation,

coagulation)

Neutrophils:

activation

Hypothalamus:

Muscle,

Interleukin-1

(IL-1)

Macrophages,

cells,

lial

dendritic

fibroblasts,

cells,

Endothelial

endothe-

keratinocytes

Macrophages,

cells,

T

dendritic

B

(many)

Virtually

all

cell

types

Th17

cells:

(inflammation,

Rheumatoid

TNF

matory

of

Th17

acute-phase

of

in

Chronic

(IL-2)

T

of

protein

Rheumatoid

antibody-producing

cells

arthritis

(juvenile

and

adult)

from

the

circulation

into

Inflammatory

(in

of

lymphoid

of

T

and

tissue

B

cells

clinical

bowel

disease

trials)

architecture

in

secondary

organs)

Inflammation

cells

T

genetic

proteins

acute-phase

leukocytes

(segregation

Interleukin-2

(rare

differentiation

of

Maintenance

Cytokines

autoinflam-

diseases)

tissues

lymphoid

arthritis,

syndromes

differentiation

proliferation

Recruitment

to

fever

synthesis

cells:

(cachexia)

activation

similar

synthesis

cells:

Liver:

cells

T

Chemokines

cells:

Hypothalamus:

T

(IL-6)

fever

catabolism

coagulation),

Liver:

Interleukin-6

fat:

(mainly

CD4+

helper

T

cells:

cells)

and

proliferation

memory

and

cells;

development,

differentiation

promotes

survival,

and

into

regulatory

effector

Anti-IL-2

T-cell

acute

receptor

organ

used

to

transplant

prevent

rejection

function

+

Interleukin-4

(IL-4)

CD4

T

cells

(Th2),

mast

B

cells

T

cells:

cells:

isotype

Th2

in

to

differentiation,

Macrophages:

Role

switching

alternative

allergic

IgE

Asthma,

atopic

dermatitis

proliferation

activation

inflammation

+

Interleukin-5

(IL-5)

CD4

T

cells

(Th2)

Eosinophils:

Role

Interleukin-12

Macrophages,

dendritic

cells

(IL-12)

T

in

cells:

NK

activation,

allergic

Th1

cells

increased

generation

Asthma

inflammation

differentiation

and

T

cells:

IFN-γ

synthesis

+

Interleukin-17

CD4

T

cells

(Th17)

Epithelial

cells,

increased

GM-CSF

macrophages,

chemokine

and

activation

of

G-CSF

and

and

other

cytokine

production

→

cell

types:

Psoriasis;

production;

recruitment

some

effect

in

multiple

sclerosis

and

neutrophils

+

Interferon-γ

(IFN-γ)

T

cells

NK

(Th1,

CD8

T

cells),

Macrophages:

cells

microbicidal

T

Interleukin-10

Macrophages,

(IL-10)

(mainly

Transforming

growth

T

factor-β

cells,

cell

T

cells

regulatory

cells:

Th1

cells)

Role

macrophages,

other

T

in

cells:

types

inhibition

(increased

Hemophagocytic

syndromes

cells:

inhibition

inflammation

proliferation

inhibition

angiogenic

Fibroblasts:

of

of

differentiation

Macrophages:

of

dendritic

termination

functions;

(TGF-β)

activation

differentiation

Macrophages,

T

classical

functions)

of

of

and

Th17

effector

and

activation;

Treg

stimulation

factors

increased

collagen

synthesis

a

Specific

for

the

Pentraxns

(CRP)

and

popds

cytokine

are

serum

or

its

pasma

amyod

expressed

on

receptor.

proens

proen

bacera

a

(see

ncude

beow).

membranes

C-reacve

ey

(and

proen

recognze

apopoc

pos-

ces)

crcuang

pan

and

1s

e

caor

emnaon

nes

proens

o

ese

ncrease

nlammaor y

mcrobes

durng

reacons,

e

and

dead

ces.

acue-pase

dscussed

aer.

e

pasma

response

Knns

are

a

eves

o

accompa-

produced

rom

e

he

promoe pagocyoss or acvae e compemen sysem, us causng

ese

a

by

precursor

se

our

cenur y

o

major

AD

(warm),

e

acons

uncon,

was

proens

by

eaures

e

tumor

o

and

conrbue

o

vascuar

daon

and

nlammaon.

nlammaon

aer.

(nay

encycopeds

(sweng),

parcuar

added

o

Roman

and

medaors

door

(Tabe

descrbed

Cesus),

(pan),

2.6).

A

rubor

can

be

it

n

e

(redness),

expaned

sgn,

oss

o

CHAPTER

B ecause

a

Tabes

on

2.4

o

wdey

e

o

nb

er

and

2.5).

ndvdua

used

o

syness

o

are

s

as

),

as

aso

that

clinical

typically

e

drugs

An

nlammaor y

pyscan’s

bock

excepon

e

n

are

o

oug

medaors

(see

a

o

are

nb

(by

nbng

c yoknes.

corcoserod-nduced

apoposs,

varous

o

auommune

Features

reactions

associated

manifestations

dsorders

as

of

with

(Table

Acute

show

Inflammation

distinct

different

morphologic

inciting

patterns

conditions

and

Fig.

2.4

skin

blister

Serous

Speca

inflammation.

Low-power

view

of

a

cross

section

of

a

2.7)

collection

Morphology.

23

unc-

mupe

producon

reang

or

corcoserods

wc

acd–derved

as

producon

Repair

drugs

armamenarum

e

s

process,

and

magnances.

inammatory

are

n

e

nlammaon,

sensve

useu

ympoc yc

o

ese

we

Clinicopathologic

Acute

o

medaors.

2

an

we

Mos

roe

par

aracdonc

A

Lympoc yes

a

are

suppress

pospopase

efec

essena

medaors

Inflammation

2

morpoogc

paerns

are

oten

showing

of

pale

the

epidermis

pink-staining

or

separated

clear

from

serous

the

dermis

by

a

focal

effusion.

supermposed

on e genera eaures o acue nlammaon (vasodaon, eukocye Table

2.6

Role

of

Mediators

in

Cardinal

Features

of

recrumen, and edema), dependng on e severy o e reacon, s Acute

specic

ance

cause,

o

and

e

recognzng

parcuar

e

gross

ssue

and

and

se

nvoved.

mcroscopc

he

paerns

s

Inflammation

mpor-

a

ey

Feature

Mechanism

oten provde vauabe cues abou e underyng cause. Redness

 •

 In

serous

nammaton

(Fg.

2.4),

exuded

lud

s

ce

poor

and

(rubor)

Vasodilation

dins)

accumuaes

n

body

caves

suc

as

e

peura

or

(caused

by

histamine,

prostaglan-



percardum

and

stasis

congestion

in

of

blood

(erythema

parenchymal

in

the

skin,

organs)

(ormng an efuson) or under epea suc as e skn (ormng Warmth

bsers

or

vesces).

hs

reacon

s

ypca

o

md

njury

Swelling

erma

burns

o

skn),

necons

a

damage

e

(calor)

Increased

blood

Exudation

of

adjacen

(tumor)

fluid

(suc

as

peurs

accompanyng

pneumona)

or

resorbed

 •

wen

 Fbrnous

necons

e

(suc

as

nlammaon

nammaton,

ke

vra

percards).

he

lud

s

fibrin

subsdes.

serous

sible

nlammaon,

occurs

on

Pain

(dolor)

Action

cuar eaks are arge and ence, e exudae conans arge-moec-

paway

pasma

acors,

proens

wc

suc

become

as

ibrnogen

acvaed

and

and

nsoube

organ

(Fg.

ibrn

2.5),

co.

and

Fbrn

may

s

deposed

eer

be

removed

e

by

can

resouton)

cause

ibrnous

or,



sgnican

exudae

by

exensve,

be

uncona

scar

ssue

s

repaced

o

enzymac

by

mparmen.

 Puruent

(suppuratve)

by

histamine,

deposits

for

in

fibrinogen

and

extravascular

induration

in

chronic

tissue

of

prostaglandins

and

kinins

o

dead

eadng

ssues

sensory

scar

2.7

Patterns

of

Acute

Inflammation

ssue

of

a

Repacemen

Inflammation

Morphology

Serous

Accumulation

Examples

of

Diseases

o

of

cell-poor

Pleuritis,

pericarditis,

caed organzaton.

nammaton

nlammaon

coecon

on

endings

e

s

caracerzed

exudate

mild

burns,

o

and

e

ormaon

neurops.

I

o

s

pus,

a

mos

skin

dis-

by (pemphigus)

qFibrinous

ueied

of

(respon-

inflammatory

eases

desrucve

prostaglan-

formation

yss

fluid

 •

of

ibrnogen

surace

Type

(caed

organ

vascular

coaguaon

conver

on

(caused

leakage

nerve

Table o

affected

increased

reactions)

e

surace o organs suc as e ung or ear, bu n s case e vas-

uar-weg

the

to

reavey dins);

nondesrucve

in

due

spermeability

sue

flow

(e.g.,

Deposition

of

fibrin

Pericarditis,

meningitis,

oten pleuritis

caused

by

necons

by

pyogenc

(pus-producng)

bacera

a

Suppurative

ec

a

neurop

Necrosis

(purulent)

 •

 An

abscess

s

a

with

ocazed

coecon

o

puruen

tion

of

leukocytes

2.6)

w

cenra

necross

and

acue

and

Bacterial

nias,

pneumo-

appendicitis,

nlammaon formation

(Fg.

accumula-

exudae.

nlammaon

of

pus

(con-

abscesses

oten taining

dead

leukocytes

surrounded by nlammaory ces and scar ssue (  s cronc). and

tissue

cells)

Abscesses may orm n any organ as a resu o seedng by bacera Ulcer

or

odgng

o

sepc

embo.

Because

ey

are

poory

Epithelial

defect

underlying

ey

 •

may

ave

o

be

draned

surgcay

or

eang

o

e

as

a

somac

necon

resu

or

and

o

necross

duodenum

exacerbaed

and

(oten

by

oss

o

caused

gasrc

e

by

acd),

epeum,

Hecobacter

or

n

e

as

sores

seen

n

n

dabecs

edery

pressure).

Mos

because

ndvduas

ucers

o

reduced

because

sow

eaures

o

o

bood

acue

and

ulcer,

dia-

betic

ulcer,

venous

chronic

and

arterial

inflammation

(typically

in

ulcers

lower

extremities)

pyor

or

as

mmoby

cronc

Manifestations

bed

and

nlam-

maon. Heang o ucers requres reamen o e underyng con-

don.

Gastric

exremes

suppy,

proonged

and

n

Systemic (oten

acute

occur.

 An ucer (Fg. 2.7) s a ocazed deec n e surace o a ssue,

usuay

with

vascuarzed,

Acute

inammation

festations

diagnostic

that

may

clues

is

(Table

Inlammaon,

cyokne-nduced

usually

cause

even

accompanied

clinical

problems

by

and

systemic

provide

mani

valuable

2.8)



sysemc



s

ocazed,

reacons

a

may

are

be

assocaed

coecvey

w

caed

e

24

CHAPTER

Inflammation

2

and

Repair

F

P

B

A

Fig.

2.5

overlies

Fibrinous

the

pericarditis.

pericardial

surface

(A)

Deposits

of

fibrin

on

the

pericardium.

(B)

A

pink

the

lung

meshwork

of

fibrin

(F)

(P)

A

B

Fig.

2.6

monia.

Purulent

(B)

The

surrounded

intensely

by

inflammation.

abscess

congested

congested

(A)

contains

blood

alveolar

Multiple

bacterial

neutrophils

vessels.

walls

and

and

Alveolar

abscesses

cellular

destruction

intra-alveolar

(arrows)

debris

is

in

resulting

seen

in

the

from

lower

in

a

case

destruction

right

corner.

of

of

bronchopneu-

alveoli,

Above

left

and

is

shows

exudate.

A

B

Fig.

2.7

The

Low-power

in

the

base.

morphology

of

cross-sectional

an

ulcer.

view

of

a

(A)

A

chronic

duodenal

duodenal

ulcer

crater

ulcer

with

seen

an

as

acute

a

defect

and

in

the

chronic

mucosa

(arrow).

inflammatory

(B)

exudate

CHAPTER

Table

2.8

Systemic

Manifestations

of

Cytokines

the

Clinical

(IL-1,

TNF)

stimulate

hypothalamus,

Initially,

TNF

act

on

prostaglandin

body

production

temperature

control

in

In

severe

center

cause

stimulates

release

of

leukocytes

from

the

bone

Marker

marrow.

Later,

by

colony-stimulating

stem

cells

in

neutrophils

Increased

of

plasma

acute-phase

levels

Increased

proteins

factors

macrophages

bone

and

liver

(GM-CSF ,

and

marrow

T

and

cells

G-CSF)

act

stimulate

on

cases,

mental

with

for

clinical

activated

inated

intravascular

coagulation,

alized

of

increased

can

coma

not

by

itself

a

cause

of

production

of

monocytes

synthesis

in

response

to

cytokines

(IL-6,

IL-1,

C-reactive

TNF

and

other

procoagulant

cytokines

activity

of

→

vasodilation,

protein:

endothelium

amyloid

tions

tion

marker

increases

chronic

and

inflammation

may

lead

causes

acute

sedimentation

to

rate

amyloidosis

in

inflammation

complication

other

(burns,

of

erythrocyte

protein:

Life-threatening

gener-

edema,

temperature

and

problems

Fibrinogen:

levels

body

NSAIDs

inflammation;

prolonged,

High

increased

disturbances

produced

TNF)

dissem-

25

hemopoietic

Serum

Hypotension,

Repair

Features

Treated

Leukocytosis

and

Inflammation

Mechanism

Fever

Inflammation

2

of

of

disseminated

severe

acute

infec-

inflamma-

pancreatitis)

organ

failure

G-CSF,

TNF,

Granulocyte

tumor

acue-pase

ncreased

Fever

pon.

or y

s

a

s

(caed

c yoknes

ncrease

acd

suc

presen.

as

IL-1

rese

e

2

,

s

nbng

assocaed

maor y

muaons

mcrobes

n

oten

Cyoknes

o

ours)

margna

e

an

nduced

o

aned

eukoc yoss

n

bone

e

es

and

e

ser ve

o

o

ncrease

ous

o

orgn

promnen

can

reac

Pasma

aed

by

un

e

ces

are

e

a

reease

a

aracdonc

prosagandns,

Nonseroda

asprn,

reduce

producon

resu

o

o

pyrogens)

eve.

aso

amy

s

neuroransmers

ger

caed

o

ever

o

IL-1

reease

days

a

We

n

o

o

gan-o-uncon

o

by

durng

ces

bood

ce

a

acng

sense

In

s

n

a

rom

more

hese

avaabe

are

o

wdey

o

wc,

n

ces

acv-

and

may

as

and

IL-1,

interleukin

1;

NSAID,

nonsteroidal

antiinflammatory

drug;

o

n

o

cyoknes

opsonns

causes

IL-6)

protens

o

rse

ncrease

wen

er

e

ver

syness.

s

o

and

ix

orm

proen

and

(CRP),

SAA

bnd

compemen.

sacks

rae

producon

serum

o

amyod

mcroba

Fbrnogen

(roueaux)

a

ce

bnds

sedmen

A

(SAA)

was

o

red

more

and

ces

rapdy

wose

(ESR)

as

an

s

ndcaor

ncreased

n

o

nlammaon.

e

acue-pase

Anoer

response

s

e ron-reguang pepde epcdn. Croncay eevaed pasma con-

cenraons

e

o

epcdn

be

or

9).

Acue-pase

maon,

n

anema

bu

saes

o

Severe

response

proens

proonged

(see

cassc

cnca

nravascuar

eadng

on

cyoknes,

o

Caper

by

ese

coaguaon,

bances

o

organ

ron

efecs

n

and

are

durng

proens

some

respons-

(see

Caper

acue

nlam-

(especay

cases,

cause

SAA)

secondar y

4).

(see

n

o

nlammaon

ese

can,

3),

s

and

condons

generazed

s

n

e

suc

caused

as

caused

and

by

by

suc

as

severe

he

dssemnaed

meaboc

e

ds-

nammatory

pancreas.

ypoenson,

edema,

a

sepss,

systemc

condons

reacons

dysuncon,

prncpay

seen

n

nonnecous

nlammaor y

rad

o

nlammaon

caused

and

cronc

producon

acue

syndrome,

rauma,

avaaby

beneica

nlammaon

necons

burns,

e

w

ave

Caper

sysemc

semnaed

reduce

assocaed

cronc

amyodoss

Outcomes

Mos

 •

acue

 R esouton.

and

e

cases,

ree

 •

he

massve

dsur-

produc-

TNF .

o

Inflammation

be

n

acve,

ence

e

perssen

to

and

ends

are

e

o

descrbed

chronc

canno

are

srucure

n

B ecause

s

oucomes.

ved

more

and

are

no

mnma

s

may

In

naed

o

need

e

smua-

onger

ssue



ces

presen

desruc-

reaned.

dea

emnaed.

a

mos

nlammaon

nammaton

be

ree

smu

agens

ere

acue

o

e

sor 

ofendng

ssue

ypes

one

emnaed.

Typcay,

norma

Some

ave

because

nlammaon

once

(scarrng),

 Progresson

ces)

subsdes.

 Organzaton.

responses

response

necroc

reacon

on,

 •

Acute

moecues

on

mos

smu-

of

nlammaor y

(mcrobes,

e

so-caed

he

em

CRP

pepde

ibross

acute-pase

(many

C-reacve

sedmenaon

nec-

e

ac

are

ibrnogen.

an ndvdua red ces. hs s e bass or measurng e er yrocye

emnae

severe

(e

e

proens

proen,

reacon).

eves

factor;

sus-

reacon

used

be

nlammaon,

eukemas

s

mnues

progenor

presumed

acue

ose

on

a

eukoc yes.

(n

nlammaor y

are

couns

ces

eukoc yes

produce

producon.

neurops,

approxmang

acvaed

aso

e

a

wc

oer wse.

bood

may

weeks)

bood

eukoc yoss

preormed

and

eukoc ye

de

by

o

man

auonlam-

proens

we

produced

marrow,

numbers

s

e

o



popoysacca-

conver 

Excessve

appearance

ncrease

proved

ncrease

a

crcuang

nlammaon,

numbers

eukemod

o

agen.

dagnose

rapd

(over

e

n

c yoknes

bone

repace

ofendng

cnc

by

marrow

a

ncudng

recepor

as

bu

nlamma-

eukoc yes

endogenous

syndromes,

wc

ncrease

e

e

a

syness.

ever

o

suc

producon

pon

uncear,

se

ces.

enancng

poo

colony-stimulating

and

emperaure

underyng

ypoaamus,

e

se

Nod-ke

s

(caed

e

an

smuae

(NSAIDs),

some

smuae

by

In

eukocyoss,

body

remans

(c ycooxygenases)

perodc

necroc

Leukocy toss

mos

TNF

ever,

e

producs,

prosagandn

and

ever

pyrogens),

drugs

syndromes,

o

aers

Bacera

emperaure

w

a

by

weer

smuae

an-nlammaor y

by

granulocyte-macrophage

proens.

assessng

and

enzymes

PGE

GM-CSF,

manesed

uncon

n

prosagandns.

especay

a

sgn

are

acue-pase

response

exogenous

e

no

o

pysoogc

process

rde

and

eves

c yokne

cnca

factor;

factor.

response

pasma

e

vauabe

colony-stimulating

necrosis

are

repaced

by

aer.

occur

mos



e

smuus

nsances,

s

owever,

26

CHAPTER

Inflammation

2

and

Repair

Antigen+

CD4 presenting Th1

cell

cell

Presents

antigen

IL-17,

T

TNF

to

Granuloma

cells

Epithelioid

Giant

Cytokines

IFN-

Leukocyte

cell

cell

γ (e.g.,

IL-12,

IL-6,

IL-23)

Monocyte

Activated

recruitment,

macrophage

inflammation

Fibroblast

Activated

Blood

Fig.

2.8

that

recruit

Macrophage–lymphocyte

activate

ing

of

Lymphocyte

vessel

macrophages

macrophages

antigens

and

via

(tumor

(interferon

cytokines

interactions

necrosis

gamma

such

as

in

factor

[IFN-γ]).

IL-12.

chronic

[TNF],

inflammation.

interleukin

Activated

Prolonged

17

macrophages

activation

of

Te

oow

pro ducng

acue

in

T

cells

produce

chemokines)

turn

stimulate

macrophages

may

T

and

cells

lead

to

cytokines

others

by

the

that

present-

formation

granulomas.

cronc nlammaon s a dsnc reacon a does no necessary

an

Activated

[IL-17],

macrophage

pase.

macropages

NO,

r y

o

d es roy

ys os oma 

or

en zy mes,

wa  

and

o 

 e

o end ng

c yok  nes

 a

agen

by

re c r u

more

angens,

env-

eu ko c yes.

T

CHRONIC

ympocyes

ronmena

Chronic

in

inammation

which

a

be

coesero

adapve

ces,

oer

o

mmuny,

and

many

e

especay

nlammaon

and

e

seng

ere

acvaon

perssen

summarzed

usually

s

or

a

o

coexist.

nec-

reumaod

o

oxc

agens

endogenous

srong

(e.g.,

componen

o

c yokne-producng

T

promnen

he

n

stimuli

perssen

(e.g.,

exposure

and

macropages.

are

persistent

o

dseases

parces)

cases,

to

scarring

proonged

sca

especay

o

n

reaction

auommune

(e.g.,

In

conrbue

eukoc yes,

cronc

injury,

deveops

sceross),

exogenous

cr ysas).

wc

prolonged

tissue

ubercuoss),

mupe

may

a

nlammaon

(e.g.,

arrs,

is

inammation,

Cronc

ons

mos

Tabe

acvaon

requen

o

ens),

rom

a

Reactions

of

inammatory

Chronic

reactions

e

ces

T

proen

oer

ces.

ese

Subses

o

o

auommune

angens

o

acvaed

T

and

dseases).

T

ces

ces

and

mody

se

pro-

Macropages

respond

produce

many

o

and

sgnas

cyoknes

nlammaon:

 IL-5 acvaes eosnops.

 IL-17 smuaes e producon o cemoknes a recru neuro-

 •

 TNF acvaes endoea ces and promoes recrumen o euko-

ps.

causes

cyes

2.1

(as

Oer

ere

n

ces

are

acue

n

nlammaon).

cronc

nlammaor y

supermposed

epsodes

o

reacons

acue

ncude

pasma

nlammaon,

ces.

neurops

Inflammation

are

reacons

neracons

mmune

Macropages

ac  vae d

dspay

(n

o

 •

dominated

by

inltration

may

be

promnen.

of

deveop

as

a

consequence

o

inammation

beween

macropages,

T

by

are

 e

ces

(Fg.

cen ra 

c yok  nes

at

the

same

is

accompanied

by

tissue

injury

and

repair

time.

pro-

Tssue

are

angens

bnd

cells.

nlammaor y

bdrecona

and

mcroba

 IFN-γ acvaes macropages.

njur y

s

caused

by

e

numerous

medaors

a

macro-

ympo-

pages cyes,

by

somemes

 •

occurring

onged

se

conrbue

Chronic mononuclear

Cronc

acvaed

(wc

 •

aso

Chronic

cemcas

and

dendrc

I

Cellular

are

INFLAMMATION

produce

n

e

aemp

o

emnae

e

ofendng

agen.

Wen

2.8).

ce s

o

pro duce d

cron c

by

T

 n   am ma on .

ce s,

mos y

e

response

age

o

s

srong

and

proonged,

ere

s

oten

consderabe

dam-

Te y

IFN-γ,

oer wse

eay

ssues

a

e

se

o

nlammaon.

and

Repar o njured ssues oten accompanes cronc nlammaon. o er

sg na s

prov d e d

by

T

ce s.

Pers sen

n nae

m mune

s  m-

Proeraon u  a on

by

To - ke

re cepors

and

o er

re c epors

may

a s o

Tes e

macropages

ave

b e en

c a  e d

c ass c a  y

grow

macropages

(n

con ras

o

a er na vey

ac  vae d

w c

are

nvove d

n

 ssu e

rep ar,

and

vesses

(angogeness)

c yoknes,

noaby

and

ibross

vascuar

are

nduced

endoea

d s c uss e d

(VEGF)

and

TGF-β,

produced

by

e

acvaed

grow

macropages.

[M2]

hs macropages,

bood

acors

ac  vae d

acor (M1)

o

con-

by  r bue.

 aer) .

process

s

dscussed

aer

n

e

conex

o

ssue

repar.

CHAPTER

Inflammation

2

and

Repair

27

*

A

B

Fig.

2.9

logic

are

Chronic

features:

replaced

(fibrosis,

tiple

Clinicopathologic

inflammation.

(1)

by

collection

spaces

arrows).

(B)

Langhans-type

Features

of

lined

inflammation

inflammatory

cuboidal

epithelium,

tuberculous

cells,

Chronic

Chronic

chronic

by

Typical

giant

(A)

of

granuloma

epithelioid

cells,

and

in

cells

the

(*),

lung,

(2)

arrowheads),

showing

an

inammation

underlies

many

o

e

mos

vexng

dseases

o

umans,

suc

as

aeroscleroc

renal

caused

a

dsease,

coronar y

leas

advances

n

n

and

varous

arer y

dsease,

par

by

auommune

lver

cronc

mmunoerapy

or

and

crross,

allergc

nlammaon.

In

w

weg

cnca

caenges

some

and

o

major

ese

causes

Despe

dseases,

o

hese

dsorders

are

dscussed

n

capers

connective

surrounded

tissue

by

mul-

severe

appee

and

and

proonged

ncrease

cases,

e

g

eves

caabosm

o

o

TNF

pds,

may

resung

oss

e

(caed

s

aso

cacexa

assocaed

wen

w

severe).

Inrequeny,

deposon

o

amyod

cronc

proen

because

e

precursor

serum

amyod

proen

s

an

n

acue-pase

proen

wose

cases

cronc

producon

ncreases

durng

nlammaon.

In

some

mpressve

ey

morbdy

on

histo-

alveoli

are

o

nlammaon,

suc

as

cronc

vra

epas,

obvous

reman

and

dferen

sgns

are

absen,

and

e

dagnoss

requres

aboraor y

assess-

mormen

ay.

by

necrosis

(normal

end-

dseases,

pysca mporan

replacement

central

characteristic

pumonar y

ssues, sage

three

parenchyma

diseases.

nlammaon ibross,

all

of

lymphocytes.

n Some

(3)

of

ubercuoss.

Inflammation

important

and

area

nerere Chronic

showing

destruction

and

ssue

bopsy.

organ

sysems.

TISSUE

Morphology.

Mos

cronc

nlammaor y

dseases

sow

After cear

ce

(ympoc ye

and

macropage)

niraon

REPAIR

mononu-

w

the

offending

damaged and

ssue

njur y

(Fg.

2.9A).

Under

some

crcumsances,

agent

is

eliminated

and

inammation

subsides,

ibross

suc

tissue

is

repaired

by

two

processes,

regeneration

and

as scarring.

necon

w

uberce

bac,

e

reacon

may

deveop

a

parcuhe

erms

repar,

eang,

and

resouton

are

oten

used

ner-

ar morpoog y reerred o as granuomaous nlammaon. Grancangeaby, uomas

are

crcumscrbed

coecons

o

acvaed

abundan

ave

a

c yopasm,

caed

epteod

ces

because

epeum-ke

sape

Acvaed

may

use

o

orm

munuceae

gant

ces

(Fg.

2.9B).

ormaon

s

a

cassc

exampe

o

a

speca

n

wc

macropages

are

ype

srongy

o

T

mas

ces

are

ence

or

by

seen

as

recognon

n

ony

mporan

a

ew

o

perssen

condons,

erapeuc

oregn

and

acvaed

bodes.

recognzng

mpcaons.

endemc,



may

Fg.

In

be

e

e

mos

wesern

requen

word,

Were

cause

o

granuomas

o

resoraon

o

norma

ssue

arcecure

and

w-

Under

by

dferen

regeneraon

or

condons

scarrng

o

ssue

(descrbed

njur y,

beow

e

and

repar

sown

2.10).

a

B o

are

processes

produced

are

many

rggered

by

by

c yoknes

macropages.

In

and

some

grow

suaons,

macropages

a

nae

repar

beong

o

e

aernavey

ac-

Granuo-

er

vaed

(M2)

knes

(o

subse,

wc

produces

varous

annlammaor y

c yo-

presermnae

nlammaon)

and

grow

acors

(o

promoe

ubercuoss One

secreed

c yokne

a

can

bo

suppress

nlammaon

granuomaous and

nlammaon.

wounds

eer

repar). s

skn

cronc

e by

reers

scarrng.

many

acors nlammaon

o

Grann

uoma

reers

macropages s

aso

generay

ey ou

laened,

eang

macropages resouon

w

aoug

are

more

smuae

ibross

(scarrng)

s

TGF-β

oten Regeneraon s e proeraon o resdua ces o resore e dam-

seen

n

Cron

dsease,

a

ype

o

nlammaor y

bowe

dsease,

n aged

sarcodoss,

a

rare

bu

proean

dsease

o

unknown

eoog y,

or n

some

unga

dseases

suc

as

ssue.

conans

e

scafod

seen

he

n

Manifestations

sysemc

cay

ess

ac,

reacons

severe

an

recurren

o

cronc

ose

ever

and

o

nlammaon

acue

ng

occurs

sem

wen

ces

e

a

njured

can

ssue

dferenae

s

capabe

no

o

proeraon

uncona

ces,

and

sopasmoss. wen

Systemic

I

and

are

nlammaon.

sweas

are

a

smar

Fever

cassc

o

s

bu

yp-

common;

manesaon

o

n

connecve

or

e

epea

o

e

capacy

proeraon

s

o

oer

ces.

proeraon

sroma

arcecura

proerave

and

ssue

skn,

and

smuaed

By

by

and

suceny

resoraon.

nesnes,

conan

conras,

s

regeneraon.

Regeneraon

and

ver,

abundan

grow

cardac

nac

acors

musce

s

wc

ssue

sem

secreed

and

o

by

neurons

provde

mos

ave

a

ces.

a

oten

g

her

macropages

are

ncapabe

28

CHAPTER

Inflammation

2

and

Repair

Platelet

Eschar

Fibroblast

Epithelial

cells

Granulation

Macrophage

Collagen

scar

tissue Neutrophil New

blood

vessels

Capillary

A

B

Fig.

2.10

Tissue

resolution

by

scar

(A)

occurs

Fbrous

scar

srucura

acks

e

ura

Inflammation

as

uncons

e

ropages,

called

a

o

njur y

ibroblass

o

e

s

a

cesses

ssue

ad

ibers

o



n

by

a

and

e

hs

by

and

se

o

newly

o

e

ssue

skn)

organ

are

e

n

s

o

nuron

ssue

e

o

caed

a

arge

by

e

e

during

by

not

the

underlying

connective

wound

vessel

tissue,

healing

growth

and

in

tissue,

repair

the

is

skin.

proliferating

nduced

Separaton

e

o

by

vascuar

percytes

basemen

endoea

rom

membrane

e

o

grow

abumna

aow

acor

surace

ormaon

o

(VEGF)

and

a

breakdown

vesse

sprou

 Mgraton o endothea ces oward e area o ssue njur y

 •

 Proeraton o endothea ces jus bend e eadng ron (p) o

 •

 Remodeng no capar y ubes

 •

 R ecr utment

mgrang

 ar es

and

maure

 •

ces

per e ndothea

mus ce

ce s

ce s

(p er c yes

or

 arger

or

sma  

vess es )

o

c ap  -

or m

 e

vess e

 Suppresson

men

o

smo o 

o

endothea

proeraton

and

deposon

o

e

base-

membrane

Grad-

wc

roug

cross-nkng

Clinicopathologic

The

eads

depos-

bu

amouns

wen

pro-

same.

extent

Wen

on,

pes



s

of

e

gu.

No

Heang

son

o

ay

of

e

njur y

s

by

md,

ce

scar

by

ssue

irst

by

macropages

of

tissue

Tissue

varies

s

e

Repair

according

to

the

nature

e

and

ver

n

so

a

ssue

e

and

capabe

edges

e

are

o

proera-

cosed.

epeum

o

Exam-

e

skn

ormed.

cosed

bood

and

o

ntenton occurs

a

a

s

acue,

regeneraon,

regeneraon

skn

seaed

Features

repaired

injury.

repared

ncude

and

(ver,

underyng

appearance

and

resapng

scar,

the

 •

o

marx,

C oagen

to

but

Vasodaton n response o nrc oxde (NO) and ncreased perme-

o

mac-

Remodeng

coagen.

tissue

aby

 •

syn-

days

scar,

subsequen

 •

depends

marx

e



leads

capllares,

orm

nvoves

e

5

nlammaon.

o

n

damage

specifically

granulation

acors

collagen

o

of

epithelium

with

shown,

scar

produced

3

are

injury

the

scar.

sruc-

macropages,

nal

or

a

ibroblass

undamena

essenay

fibrous

exracellular

abnormay

he

are

ormed

usuay

Formation

the

damages

severe

formation

Grow

provde

and

(B)

more

adequae

exraceuar

process

scar

and

meaoproeases.

ibross.

reacons

on

by

loose

after

which

regenerae

granuaon

we-compaced

(mb,

as

a

nensy

e

marx

ac

injury,

Aoug

(FGF)

ibrobass

n

o

uncon.

and

n

by

provdes

Durng

w

enzymes

parencyma

ese

vessels

srengen

srong

reerred

a

by



but

produce

unabe

produced

amoun

deec

to

proleraon

embedded

e

down

resorpon

n

s

also

mild

formation.

acor

cells,

er

illed

repair

damaged.

ssue

below).

remodeng.

perpera

occurs

ung),

tssue.

modied

caed

para

n

s

s

s

ssue,

grow

blood

in

clot

ssue

oer

(see

and

srucuray

ed

new

and

some

VEGF ,

o

coagen

and



me

process

o

o

Steps

Remodeling

eay

and

area

sze

e

C

Following

regeneration,

rreversby

smulae

ibroblass

coagen

(C)

ibroblas

o

granuaton

e

over

and

ormaon

repar,

uay,

e

C oncomanly,

e



s

manan

ssue

prolerang

on

o

macropages

connecve

o

o

TGF-β

acvaed

ess.

ormed

ramework

negry

suc

s

by

formation.

fibroblasts.

e

repair.

co,

w

n

oowed

ormaon

o

a

cean,

surgca

a

by

e

sma

unneced

suures.

arrva

amoun

he

o

surgca

nc-

s

n-

neurops

and

o

wound

granuaon

s-

Angiogenesis sue a s repaced by a n scar. Concomany, e surace epea

Ang ogeness

exs ng

a s o

n

and

n

o

 e

(Fg .

 e

I

s

pro cess

no

de veopmen

a  ow ng

 er

ne w

s

vess es.

or g na 

vess es

2.11):

o

umors

bo o d

 rom

o

on y

ne w

co  aera 

o

ncre as e

suppy.

exs  ng

bo o d

cr  c a 

ones

n

vess e

e a  ng

crc u  a ons

n

sz e

ses

a

conss s

 e

nvoves

o

o

ses

b e yond

Ang ogenes s

and

d e veopmen

a

 e

 rom

njur y

o

s cem  a

c ons ra n s

sprou ng

o ow ng

ces

bu

o

seps

regenerae

Heang

res

o

evens

e

s

on

a

sss

or

e

a

by

and

skn,

amoun

onger

ibrous

o

scar

e

e

o

perod,

s

e

ncsona

ntenton

wen

denca

e

brdge

second

occurs

edges

one

canno

descrbed

granuaon

and,

cker.

gap.

n

ence,

By

abou

more

be

ssue

o

s

6

weeks,

deep

e

arger

s

ad

e

nju-

sequence

w

muc

coagen

and

he

prevousy,

more

4

severe

cosed.

and

down

skn

o

excep-

per-

and

wound

CHAPTER

Quiescent

Vasodilation

vessel

(VEGF)

Leading

(“tip”)

Inflammation

2

and

Repair

29

cell

(VEGF) Angiogenic

factors

Pericyte

Pericyte

detachment

(angiopoietin)

Basement

membrane Basement

Endothelium

membrane

degradation

(MMPs)

Pericyte

A recruitment

ECM

Elongation

of

Formation

vascular

of

new

stalk

vessel

B

Fig.

2.12

vessels,

Tissue

inflammatory Fig.

2.11

Angiogenesis.

In

tissue

r e p a i r,

angiogenesis

occurs

the

sprouting

of

new

vessels.

The

steps

in

the

process,

and

signals

involved,

are

illustrated.

The

newly

formed

cells.

a

(A)

Granulation

loose

tissue

extracellular

Collagen

is

stained

showing

matrix

blue

numerous

containing

by

the

blood

occasional

mature

collagen

can

be

seen

at

this

point.

trichrome

(B)

Trichrome

stain;

stain

the

of major

and

mainly minimal

by

repair.

edema,

mature

scar,

showing

dense

collagen,

with

only

scattered

vascular

vessel

channels. joins

up

bed.

ECM,

VEGF,

with

vascular

conracs

ssue,

other

vessels

extracellular

endothelial

because

srnkng

o

e

(not

matrix;

e

growth

acon

area

shown)

MMP,

o

o

njur y

to

form

matrix

the

new

vascular

metalloproteinases;

f a c t o r.

myoibroblass

(Fg.

n

e

connecve

cyokne

2.12).

ea

 • Repair

can

be

impaired

by

numerous

producon

normay

and

 Compromsed

by

macropages.

conan

bood

exensve

suppy,

wc

Dabec

skn

granuaon

can

cause

ucers

do

no

ssue.

ucers

n

e

ower

factors. exremes.

ese

ncude: In

 •

ons

 •

 Infecton,

wc

proongs

e

nlammaon

and

causes

ssue

n

wc

o

ese

e

suaons

repar

process

o

deecve

becomes

repar,

excessve.

ere

hs

are

can

cond-

gve

rse

progressve o

yperropc

scars

oowng

njur y,

wc

usuay

regress

sowy,

njur y and

 •

conras

 Mecanca factors suc as excessve movemen or pressure

 Dabetes,

a

underyng

dsease

n

meaboc

wc

eang

abnormay

and

s

rearded

vascuar

because

narrowng,

o

scar

ssue

a

grows

beyond

e

margns

o

e

njur y

and

as

e o

regress,

n

organs

caed

keod

(Suppemena

eFg.

2.1).

Excessve

scarrng

eadng resus

n

uncona

compromse

and

s

e

bass

o

serous

o a reduced bood suppy. Furermore, dabecs are suscepbe o dsorders necons

because

o

decreased

neurop

uncon

and

suc

as

pumonar y

mpared e

ver

(Caper

13).

ibross

(Caper

10)

and

crross

o

CHAPTER

Supplemental

eFig.

scar

Keloid.

a

Atlas

Dermatopathology.

of

raised

2.1

forming

known

as

Excess

keloid.

collagen

(From

Philadelphia,

WB

deposition

Murphy

GF ,

Saunders,

in

the

Herzberg

1996,

p

skin

AJ:

219.)

2

Inflammation

and

Repair

29.e1

3

Hemodynamic

Disorders,

Thromboembolism,

and

Shock

O U T L I N E

Hyperemia,

Edema,

Congestion,

and

Edema,

30

Embolism,

30

Hemostasis and Hemorrhage, 31

Platelets,

Coagulation

Control,

ea

devers

aboc

mens

and

34

Shock,

depends

nurens

producs.

made

Infarction,

n

e

Bood

marrow

on

adequae

and

removes

as

wo

(we

bood

major

ces,

crcuaon,

carbon

doxde

consuens:

red

ces,

and

wc

and

lud

pase

(pasma),

conssng

o

waer,

ceuar

paees)

norganc

sas,

and

Imporan

numerous

pasma

proens,

proens

mos

ncude

o

wc

abumn,

are

e

In

nor ma 

o

waer

n

pasma;

mmunogobuns

and

componens

o

sysem

(dscussed

n

Caper

4);

and

coaguaon

and

n ravas c u  ar

by

no

o er

junc   ons

sma  

n

c ap   ar  es

mo e c u es ,

bu

are

no

p er me abe

o

yd ros a c

pressure

ends

o

pus

proens .

waer

 e

 ssues ,

bu

 s

s

ne ary

b a  anc e d

by

o s mo c

and

pressure,

e s

generae d

by

p as ma

proe ns

and

pu  s

waer

b ack

no

 e

abundan

e

(Fg .

3.1).

Te

sma  

amoun

o

 ud

 a

do es

acc umu  ae

n

compenor ma 

men

end o e a 

s a s

and

vess es proen

 ssues,

and

organc

made

mos

39

ee-

w c ver.

Shock,

Edema

s a s meaboes,

37

37

me-

Hg  a

Emboli,

37

37

38

Septic

ssues

oxygen

wase

33

35

o

Thromboembolism,

Thromboembolism,

Nonthrombotic

Cascade,

e

Systemic

32

Coagulation

Thrombosis,

36

Pulmonary

acors,

 ssues

s

 a ken

up

by

y mpa  c

vess es

and

reur ne d

o

 e

wc crc u  a on

 roug 

 e

 orac c

duc .

upon acvaon caayze a seres o reacons a cause e bood o co. Edema

and

efusons

may

occur

w

ncreased

ydrosac

pres-

Dsorders a dsurb norma lud baances beween e bood and sure, ssues

or

a

compromse

e

negry

or

paency

o

bood

decreased

ver y

common,

and

may

cause

dysuncon

or

necross

o

In

s

caper,

we

w

rs

dscuss

dsorders

o

lud

e

accumuaon

o

excessve

lud

wn

ssues

or

and

e

oss

o

bood,

and

en

urn

o

dsorders

are

sed

or

excessve

cong,

ncudng

paoogc

n

roug

Common

Tabe

3.1.

severa

Noe

drec

a

or

some

ndrec

acors

cause

lud

accu-

efecs.

 Inammaton (dscussed n Caper 2) promoes edema by ncreas-

o

bo

bood

nravascuar

low

and

vascuar

permeaby

o

proens.

he

pro-

nadeen-rc

quae

obsrucon.

body ng

caves

ympac

baance,

 • ncudng

or

afeced muaons

ssues.

pressure,

vesses causes

are

osmoc

lud

o

nlammaon

s

reerred

o

as

an

exudate,

wereas

cong proen-poor

nonnlammaor y

edema

lud

s

reerred

o

as

a

tran-

(romboss) and e seddng o cos no e crcuaon (embosm), sudate. and

er

sock,

a

downsream

dsorder

sysemc

aure

w

o

consequences.

severa

ssue

We

dferen

w

causes

ns

a

by

ave

dscussng

n

common

 •

 Cardac aure, wc akes wo orms:



•

a

 Rght-sded

cardac

e

sysemc

crcuaon,

mcrocrcuaon,

HYPEREMIA,

CONGESTION,

AND

lud

EDEMA

 Swelling

of

tissues

may

stem

from

increased

blood

volume

due

•

n

or congestion,

or from

increased

uid

within

the

a

condition

s

called

dened

generay

due

o

o

e

ncreased

low

o

arera

bood

no

a

areroar

envronmena

skeea

musce,

or

congeson

daon.

caenges

cod

cardac

n

urn

causes

resung

aure

s

a

n

egress

pressure

o

subcuaneous

common

cause

n

n

e

proen-poor

edema.

o

peura

efuson

and

aso

dmnses

pumonar y

e

kdney,

wc

responds

by

ncreasng

bood

renn

sup-

produc-

Renn

I

s

a

norma

n

(e.g.,

exposed

ncreased

skn).

By

adapaon

workoad

conras,

n

acvaes

angoensn,

ereby

ncreasng

ar eroar

smusce

one

and

smuang

e

producon

o

ado-

o by

e

adrena

corex,

wc

promoes

reabsorpon

exercso

ng

venous

ydrosac

edema.

by

serone ceran

wc

nersum,

and

smoo sue,

passve

e

inter

on. Hyperema

causes

rasng

to

py stitium,

e

 L et-sded

edema hyeperemia

aure

peruson.

congeson

sodum

and

waer

by

e

kdney.

he

reenon

o

sodum

s and

waer

ncreases

e

ydrosac

pressure,

oten

worsenng

an abnorma process caused by decreased venous oulow rom a ssue. edema Congesed

on

and

ssues

even

ave

necross.

poor

bood

Edema

dever y

reers

o

an

and

are

prone

abnorma

o

rougou

e

body.

dysunc-

accumuaon

o

Morphology.

Edema

s

easy

recognzed.

Tssues

(parcuary

e

lud n ssues. hroug smar mecansms as ose a cause edema

subcuaneous (descrbed

n

e

oowng),

abnorma

lud

accumuaons

suc

as

caed

ssue,

ungs,

and

bran)

are

swoen

and

eavy.

Sub-

efu-

cuaneous edema s accenuaed n dependen pars o e body (e.g., sons

may

aso

gaer

n

body

caves

e

peura,

percarda,

e and

30

peronea

spaces.

sacrum

n

recumben

paens

and

e

ee

oowng

proonged

CHAPTER

Hemodynamic

3

Disorders,

he sng

or

sandng).

Pumonar y

edema

s

marked

by

eavy

Thromboembolism,

erms

sed

descrbe

and

beeds

Shock

accordng

31

o

er

may

range

sze

and

ungs, appearance:

wc

reease

roy,

bood-nged

lud

wen

cu.

Bran

edema,



 • generazed,

eads

o

e

narrowng

o

suc

because

o

 Hematoma

bruses o

e

swoen

g yr

agans

e

sku.

Anasarca

(generazed

seen

n

panes

(e.g.,

cronc

rena

e

ear

aure

eyeds).

congeson

ear

as

aure,

aure.

somemes

Varous

we

By

as

congeson

e

preerenay

orms

edema.

conras,

o

In

ear

afecs

aure

paens

produces

edema

are

w

necross

o

a

e

aa

a

beed

nracerebra

no

ssues

and

emorrages

(Fg.

 Petecae

are

pnpon,

1-

membranes,

or

serosa

o

2-mm

suraces

beeds

paens

nadequae

(see

Fg.

no

e

3.3),

skn,

usuay

ssues

assocaed

w

paee

uncon.

w

rg-sded

epac

obues Table

3.1

Causes

of

Edema

and

Effusions

(centrlobular necross). he gross appearance s known as numeg

ver

(Fg.

produces

3.2).

In

et-sded

bood-engorged

ear

aure,

capares,

pumonar y

nersa

congeson

edema,

and

Increased

alure

o

emosdern-aden

cells),

e

aer

nraaveoar

semmng

rom

macropages

sma

Hydrostatic

Venous

Congestive

Liver

wdey

Features.

he

dependng

cnca

on

er

efecs

sze

and

o

lud

heart

ocaon.

accumuaons

sgna

an

mporan

underyng

dsorder

Subcuaneous

(e.g.,

ear

and

ance

necons.

o

ay

aso

e



severe

exacerbang

ncreases

bran

e

canno

may

nerere

Pumonar y

underyng

rsk

o

expand

w

edema

wound

mpars

condons

necons.

wn

e

gas

suc

Bran

eang

obstruction

Venous

thrombosis

edema

encosed

ear

may

sku.

extremity

may

compromse

e

bood

suppy

o

e

or

(e.g.,

by

a

mass)

(e.g.,

with

renal

prolonged

failure,

dependency

left-sided

heart

failure)

cear-

Sodium

(poen-

aure)

aa

Increases

bran

inactivity

retention

and

Renal

snce

n

Retention

failure

Left-sided

heart

failure

CNS Arteriolar

pressure

compression

kdney

and

be

or

edema

or

excange

as

(ascites)

Venous

var y

Sodium

aure)

failure

pericarditis

cirrhosis

Lower

may

Return

(heart

beeds.

Constrictive

Clncal

Pressure

e

Impaired

presence

cause

Dilation

er-

Inflammation

naon

a

roug

conro

e

oramen

respraon

(see

magnum,

Caper

njurng

meduar y

ceners

17). Reduced

Osmotic

Protein-losing

HEMOSTASIS

AND

HEMORRHAGE

Liver

Pressure

glomerulopathies

(nephrotic

syndrome)

failure

Malnutrition

Hemorrhage

allowing

is

blood

caused

to

by

injuries

extravasate

into

that

tissues

disrupt

or

blood

outside

of

the

vessels,

body.

Protein-losing

he

ders

failure

negry

a

o

desroy

of

gastroenteropathy

It

Lymphatic represents

Obstruction

hemostasis.

bood

vesse

vesses

was

may

(e.g.,

be

dsruped

vascus,

by

eroson

rauma

by

or

Inflammatory

dsor-

cancers).

Neoplastic

Ds-

Postsurgical

orders

a

mpar

bood

cong

exacerbae

beedng

endences,

even

Postirradiation

n

e

absence

o

obvous

rauma.

LYMPHATICS

To

thoracic

duct

to

left

and

eventually

subclavian

vein

Obstruction

Increased Hydrostatic

interstitial

pressure fluid

pressure

Malnutrition

Liver

Heart

Renal

failure

failure

Nephrotic

failure

syndrome

Inflammation

Sepsis

Plasma

osmotic

Arterial

Fig.

are

3.1

lates

or

Factors

normally

is

cleared

heart

CAPILLARY

influencing

by

failure),

meability

end

balanced,

so

fiuid

there

lymphatic

osmotic

increases

(as

movement

is

little

drainage.

pressures

with

rom

skn

3.3).

fall

net

across

(as

in

or

may

pressure

Venous

capillary

of

result

or

walls.

fluid

into

when

malnutrition,

sepsis),

colloid

BED

movement

Edema

inflammation

mucous

accom-

oose

severe

o

edema)

 • s

descrbes

compresson

liver

Capillary

the

lymphatic

hydrostatic

interstitium.

hydrostatic

failure,

end

or

vessels

pressures

nephrotic

are

and

What

osmotic

little

rise

(as

fluid

in

syndrome),

obstructed.

forces

accumu-

renal

failure

vascular

per-

seen

n

32

CHAPTER

Hemodynamic

3

Disorders,

Thromboembolism,

and

Shock

A

A

B

Fig.

(A)

3.2

In

Liver

this

compared

liver”

(so

with

autopsy

with

chronic

the

called

passive

specimen,

surrounding

because

it

congestion

central

tan

areas

viable

resembles

and

are

hemorrhagic

red

and

slightly

parenchyma,

the

cut

creating

surface

of

a

necrosis.

depressed

“nutmeg

nutmeg).

B

(B)

Fig. Microscopic

preparation

shows

centrilobular

hepatic

necrosis

with

3.3

(A)

Punctate

and

scattered

Hofstra/Northwell

 •

School

of

cells.

Medicine,

(Courtesy

of

Hempstead,

Dr.

James

hemorrhages

thrombocytopenia.

(B)

Fatal

of

the

colonic

intracerebral

mucosa,

a

hemorrhage.

NY .)

are

3-

o

5-mm

 unc  on,

be e ds

 rauma,

 a

vas c u  ar

may

sem

 rom

 n  am ma on ,

d ee c  s

or

n

vas c u  ar

Platelets

 rag   y.

that

 Eccymoses are 1-2 cm n sze and correspond o “bruses”; ey are

lant

usuay

of

Crawford,

Platelets

 P ur pura

p aee

 •

inflammatory

petechial

hemor-

consequence rhage

caused

by

Paee

rauma.

the

essential

life.

clotting

of

blood

following

blood

vessel

trauma,

fragments

primary

that

promotes

uncon

and

plug

secondary

depends

cyoskeeon,

derived

hemostatic

on

surace

cyopasmc

from

and

megakaryocytes

provide

a

procoagu-

hemostasis.

gycoproen

granues

a

recepors,

conan

a

a

con-

number

is o

for

anucleate

the

surface

race Hemostasis,

are

form

procoaguan

undergo

a

subsances.

seres

o

In

sereoypc

e

seng

o

vascuar

njur y,

paees

evens:

Under norma crcumsances, bood cong occurs a ses were e

 • was

o

bood

vesses

ave

been

pyscay

dsruped.

he

na

seps

 Adeson. Paee adeson s medaed argey by neracons w

n vWF ,

co

ormaon

are

wo

muuay

renorcng

processes

(Fg.

gen

 •

 Prmary

emostass

s

naed

by

e

exposure

o

and

von

Webrand

acor

(vWF)

and

wn

njured

hese

 Actvaton.

orm

acors

a

ead

o

paee-rc

e

adeson

and

 S econdary

emostass

s

acvaon

o

e

rggered

by

e

exposure

o

ssue

subendoeum

w

acor

VII

and

ssues.

(descrbed

aer)

Tssue

o

acor

nae

acs

e

as

wc

uses

n

e

paees

coacors

and

cange

e

coacors

growng

subendoea

1b

coa-

(Gp1b).

sape

conens

o

rom

smoo

er

granues,

dscs

o

wc

spky

ncude

(cacum,

a

are

presen

on

e

eads

o

e

deposon

o

brn.

dpospae

acor

(ADP),

V)

and

wc

paee

recru

acvaors

oer

paee

paees

acvaon

exposes

pug.

con-

 Aggregaton.

he

sape

cange

assocaed

w

coaguaon

suraces

carged

Fbrn

pospopds,

wc

are

requred

by

ceran

o coaguaon

acvaed

reease

adenosne

negavey cascade,

exposed

gycoproen

acor

 • juncon

beween

recepor

paees,

o wn

brdge

pug. suc

 •

a

Paees

and

coaguaon wc

as

surace

vesse speres

was.

acs

paee

subendoea

 • coagen

wc

3.4):

acors

(descrbed

aer),

and

aso

aers

e

conorma-

renon o surace gycoproen IIb/IIIa (GpIIb/IIIa), converng GpIIa/

orces

and

sabzes

e

paee

pug,

seang

e

area

o

vascuar IIIb

damage

and

prevenng

urer

o

a

g-ainy

neracons Once

a

co

as

ormed,

s

exen

mus

be

med

o

e

area

hs

s

medaed

by

counerreguaor y

mecansms,

wc

paees

dscuss

aer

n

s

or

GpIIa/IIIb

brnogen.

recepors

Bvaen

and

brdgng

brnogen

o

cump

no

en

aggregaes.

we Decences

w

nvovng

o cause

damage.

recepor

beedng.

o

GpIb,

caper. ma

beedng

(Fg.

3.5).

GpIIa/IIIb,

or

vWF

are

assocaed

w

abnor-

CHAPTER

A.

Hemodynamic

3

Disorders,

Thromboembolism,

VASOCONSTRICTION

and

Shock

33

Deficiency:

Bernard-Soulier Endothelium

Basement

membrane

Arteriole

smooth

muscle syndrome

Deficiency: GpIb Glanzmann Platelet thrombasthenia

Site

of

injury

GpIIb-IIIa Fibrinogen complex

GpIb Endothelium

ADP

Endothelin

causes

release

Reflex

vasoconstriction

ECM

induces

conformational

(collagen)

change

vasoconstriction

von

Willebrand

factor

B.

PLATELET

ACTIVATION

AND

AGGREGATION Deficiency:

von

Subendothelium

Fig.

2

Shape

change

4

3

Granule

Recruitment

3.5

sive

(ADP, Platelet

adhesion

between

and

aggregation.

subendothelial

vWF

collagen

functions

and

the

as

an

adhe-

glycoprotein

Ib

release (GpIb)

1

Platelet

bridge

Willebrand

disease

TXA

adhesion

platelet

receptor.

Platelet

aggregation

is

accomplished

by

fibrin-

)

2

ogen

Aggregation

binding

genital

(hemostatic

to

platelet

deficiencies

in

GpIIb-IIIa

the

receptors

various

on

receptors

different

or

bridging

platelets.

Con-

molecules

lead

vWF plug)

to

the

diseases

indicated

in

the

colored

boxes.

ADP,

Adenosine

diphos-

5

phate.

Endothelium

Basement

reeased

Collagen

by

acvaed

paees

s

romboxane

A

2

,

a

poen

agons

o

membrane

paee

be

C.

ACTIVATION

OF

OF

CLOTTING

FACTORS

AND

A

FORMATION

2

aggregaon.

nbon

Asprn’s

anpaee

o cycooxygenase, an

efecs

enzyme

are

due

requred

o

or

s

rrevers-

romboxane

syness.

FIBRIN

Coagulation

he

nae 2

coaguaon

n

e

cascade

deposon

s

o

a

seres

brn.

o

In

enzymac

e

reacons

aboraor y,

e

a

cascade

cum-

as

wo

e

sec-

Phospholipid

3 complex

Thrombin

naon

activation

Fibrin

ond

polymerization

 • Tissue

pons,

one

nvovng

acor

XII

(conac

acor)

and

expression

4

1

Cascade

factor

Tissue

one

 e

nvovng

ntrnsc

acor

VII

patway

(Fg.

sars

3.6).

w

acor

XII

and

s

naed

n

e

factor

aboraor y

by

e

addon

o

negavey

carged

maera

suc

as

1

gass

beads,

me

un

aong

e

 •

Fibrin

 e

extrnsc

addon

factors

protein

induce

Ib

granule

boxane

A

GpIIb-IIIa

a

transient

(GpIb)

matrix

release.

2

(TxA

)

2

vasoconstriction.

receptors

and

to

are

(B)

Willebrand

activated,

Released

induce

von

undergoing

adenosine

additional

Platelets

factor

a

diphosphate

platelet

bind

via

on

shape

change

(ADP)

aggregation

cum

glyco-

(vWF)

and

through

tissue

(C)

factor

binding

Local

and

and

cum,

throm-

to

fibrinogen,

and

form

the

activation

platelet

of

the

coagulation

phospholipids)

results

in

the

platelets

extracellular

into

a

definitive

secondary

Paee

acvaon,

brn

co

s

recorded

pasma.

as

e

he

para

sars

acor,

w

cacum,

acor

and

VII

and

s

naed

pospopds

o

by

pasma.

e

Ca-

e

e

proease

wo

a

occurs

sysems

ceaves

proease-acvaed

recepor

nas

paee

a

augmen

by

or

prorombn

specay

moded

pospopds

acor

IX

and

and

(provded

acor

X

acors

guamae

by

VII,

IX,

resdues

paees

compexes.

he

and

a

n

e

me

X,

a

bnd

body)

un

o

ca-

e

are

or-

o

a

brn

co

s

recorded

as

e

prorombn

me

(PT).

he

hemo-

seps

n

e

coaguaon

cascade,

common

o

bo

paways

are:

(involving



•

 converson o acor X o acvaed acor X (Xa), wc s med-



•

 converson

polymerization,

hemostatic

by

a

compex

o

acor

IXa

and

acor

VIIIa

plug.

o

prorombn

o

rombn

by

a

compex

o

acor

matrix.

aggregaon

and

coacor

wereas

Xa

bn,

a

o

platelet

primary

cascade

fibrin

a

requred

aed “cementing”

ECM,

o

pospopds,

(PT T).

patway

ssue

conan

maon

receptor

plug.

s

wc

exposed

key static

me

and

Normal hemostasis. (A) After vascular injury, local neurohumoral

extracellular

a

o

cacum

ormaon

rombopasn

Fig. 3.4

w

n

parae

work

ogeer.

brnogen

on

e

o

surace

acvaon

w

and

Mos

creae

o

coaguaon

noaby,

brn,

paees,

aggregaon.

aso

acor

rom-

ceaves

rggerng

Anoer

a

sg-

acor



•

 •

 he

or

and

Va

 converson o

eemens

X,

coacor

common

he

PT

uncon

acor

by

V ,

e

o

brn

exrnsc

prorombn,

medaed

and

and

by

rombn

nrnsc

paways

brnogen)

(ac-

comprse

e

paway.

and

bu

brnogen

sared

e

do

PT T

no

are

useu

recapuae

or

e

evauang

evens

a

e

ead

coaguaon

o

cong

acor

nvvo.

34

CHAPTER

Hemodynamic

3

CLOTTING

Intrinsic

IN THE

Disorders,

Thromboembolism,

LABORATORY

(e.g.,

Shock

CLOTTING

IN VIVO

pathway Vascular

Negatively

and

charged

glass

Exposure

surface

damage

of

tissue

factor

beads) TF

Extrinsic

pathway

TF XII

Tissue

XIIa

factor X* VII*

VIIa

TF

XI

XIa

VII*

IX*

IXa

X*

VIIIa

TF Va

IX*

IXa

VIIa Xa

XI

Xla

VIIIa

Va

Prothrombin*

Thrombin

Xa

Prothrombin*

Thrombin Fibrin Fibrinogen clot

Fibrin Fibrinogen

A

Fig.

ing

or

3.6

The

a

source

tors,

is

the

Factors

acts

min

exampe,

wereas

der.

In

rare

paens

conras,

beedng

w

n vvo

s

nvvo

by

e.

ssue

K

dark

is

hs

acvang

XI

and

acor

an

o

acor

oer

a

a

IX

XII

[see

e

raer

(*)

for

are

a

major

the

pathway).

involving

active

9])

do

X

o

VII

(Fg.

(B)

In

K

no

w

are

vivo.

and

the

all

of

of

light

as

the

these

Once



e

mus

conned

o

o

coaguaon

e

acors

mmedae

se

and

o

eum

coaguaon

cong

ac

Heparin-like

INHIBIT

pathway

near

ncude

acors,

e

serous

as

factor

  romb n ,

w   c

 rom

o

are as

o

laboratory

(intrinsic

initiator

are

e

S

(not

clotting

a

o

we

as

njur y.

co

o

an

a

fac-

cofactors.

Warfarin

factors.

o

Vita-

negave

hese

a

reguaors,

by

nac

mo s

or

and

nacvae

soube

 mp or  an

e nd o e u m

O ne

su r  a c e

w ay

  a

proe  n

as

  s

on



effects

t-PA and

NO

Thrombin III

tissue

complexes

Thrombin

Inhibits Protein

C

Active

protein

platelet

C aggregation

Inactivates

(also

factors

thrombin

IXa

and

(requires

Xa)

protein

S)

Activates

Inactivates

Fig.

tion

3.7

Anticoagulant

cascade

pathway

that

are

inhibitor)

plasminogen

properties

expressed

endothelium,

activator),

which

of

on

as

normal

endothelium.

(heparin-like

well

stimulates

as

and

of

VIIIa

are

of

fibrin

platelets

clot.

fibrinolysis

multiple

thrombomodulin)

inhibitors

breakdown

Va

Highlighted

molecules,

secreted

the

factors

or

inhibitors

secreted

(PGI

2

and

of

from

NO)

the

coagula-

(tissue

and

t-PA

s

a

a c  v ae d

w ase d

o c c u rs

Antithrombin

factor-VIIa

acors

s

factor

(tissue

by

w ay

  rou g 

e nd o e u m

Thrombomodulin

Endothelial

Inactivates

an-

varous

c ou ne r- re g u  a -

are

inhibitor

2

mos

endo-

endoeum-derved

nb

an  c o ag u  an

PGI

e

norma

3.7).

nor ma 

d amage.

o

inactive

to

nbors

(Fg.

 e

b e c ome s

coagulation,

produced

moecues

 nvov  ng

v as c u  ar

number

paee

o

add-

factors.

consuvey

se

by

pathway)

depicted).

coagulation

surace

  romb n

of

are

correspond

nvoves

s e ve r a 

me can s ms

b nd  ng

and

dssouon

R e ma rk aby,

commences,

preven

Tissue

molecule

THROMBOSIS

o

ces

promoe

3.6).

hs

wc

the

polypeptides

K–dependent

o

coaguans

major

red

C

in

beads

K–dependent

mporan

severe

the

proteins

vitamin

consequences.

ncom-

is

glass

polypeptides

beed,

compexes

paees

njur y

green

initiated

as

The

dsor-

Control

acvaon

be

factor

lines).

are

is

such

vitamin

or y

Coagulation

Clotting

tissue

(dotted

dependent,

of

(A)

substance

vivo,

-carboxylation

synthesis

or

in

thrombin

vitamin

assocaed

and

charged

factors,

beedng

naor

acor

negative

the

md

Caper

laboratory

a

are

decency

ave

acor/acor

an

are

inhibiting

cofactor

acors

ssue

loops

asterisk

by

the

(extrinsic

feedback

decency

emopas

suggess

acor,

with

in

either

polypeptides

essential

w

acor

(e

green

and

factor

by

anticoagulant

an

cascade

calcium,

tissue

marked

an

decences

dsorders

pabe

as

of

amplified

paens

w

coagulation

phospholipids,

which

For

B

clot

caed

CHAPTER

trombomodun.

o ge n

C

and

and

 s

c o a c or

d e n

s

by

s een

w   c

r sk

n

T e

 nc re as e d

p a  e n s

 a c ors

  romb n

su e

X.

or

o

re c e por

bre a kd ow n

o

a

o

 ae r.

on

 onge r

o

u r n

deep

v ar  an

  s

 a c or

by

e nd o e u m ,

c o s

o

ve nous

o

(  - PA ) ,

s

ab e

c e ave

 a c or

V

caed

C.

V ,

and

 e

 mp or  an

 br  n -

a

V

cong

ead

  a

ear

L eden,

a c  v ae s

o

o

acvaed

acor

et

 •

o

abnormaes

or

oowng

ara

urbuen

ders

re e as e

o

 s -

may

a c  v aor

o

 e

ed

s

e

daon

be

bood

due

acors

ound

and

a

n

Shock

and

or

o

e

low :

narcon,

mra

prone

o

acqured

35

mpedes

15%

varan

o

or

o

e

nlow

V

and

s

3.2).

ara

any

ncreases

vesses

o

an

he

norma.

mos

Norern

pasma

can

o

e

areres;

braon.

aeraon

Leden (aready

o

e

daons

aerosceroc

and

romboss

peope

a

ear

aneurysma

senoss;

(Tabe

ncude actor

2%

genec

o

afecng

Hypercoaguaby

more

nered

rsk

acors

bood

myocarda

 Hypercoaguabty.

 e

(  br  noy s s ) .

sass

coaguaon

and

nbors.

Numerous

e v -

re u r n

Thromboembolism,

wasou

c r   c a 

( DV T )

w

Disorders,

Proe  n

ma d e

 a c or

We

c e ave s

C.

s

  romb o s s

s  mu  a  ng

an

c e ave

re a c   on

proe  n

a s o

o

proe  n

 n a c  v ae

T  romb n

a c  v a  on

 br  n

n

 n a c  v a  on

DV T

p as m  no ge n

S,

no

ab   y

 mp or  anc e

r  sk

w  

re s s an

 e

proe  n

 a c or

 e

  romb n

a c qu  re s

c o a c or,

or

s

B ou nd

 nse a d

Hemodynamic

3

a

he

ren-

causes

common

ner-

menoned),

wc

European

eves

o

descen,

prorombn.

Inered rsk acors are assocaed w romboss a a young age;

THROMBOSIS n

genera,

ess Thrombosis,

the

abnormal

clotting

of

blood

within

intact

vessels,

an

e

50

occurrence

years

o

age

s

o

an

a

romboc

ndcaon

or

even

a

n

genec

an

ndvdua

workup.

Even

is

more common are acqured rsk acors: age over 50 years, mae sex, associated

with

a

serious

risk

of

mortality.

mmobzaon, Pathogeness.

hromboss

relecs

some

abnormay

nvovng

ora vesse

wa,

e

low

o

bood

(speccay,

sass

or

urbuen

conracepves),

bood

coaguaby,

an

aeraon

reerred

o

as

ree

acors

make

up

e

Vrcow

trad

(Fg.

3.8),

named

or

18

cenur y

paoogs

Rudo

n

 Abnormates

of

te

vesse

wa

pregnancy

ncrease

use

o

syness

and

o

e

proens

and

reduce

ormaon

o

ancoaguan

pro-

ver.

oer

causes

o

ypercoaguabe

saes,

wo

deser ve

Vrcow.

bre

 •

(e.g.,

Esrogens

e

Among amous

saes

smokng.

ypercoaguaby

ens hese

and

low),

procoaguan or

yperesrogenc

e

(endotea

njur y).

In

vesses

menon

because

o

er

unque

paogeness

and

cnca

car-

mporance: r yng

bood

a

g

pressures

and

under

g

sear

orces,

suc

 as

e

e

aora

areres

and

s

major

suppyng

e

brances,

CNS,

co

e

coronar y

ormaon

s

areres,

mos

•

 Heparn-nduced

thrombocytopena

o

reaed

5%

o

paens

o

aerosceroc

esons

(see

Caper

7).

Rupure

o

paques

acvaon

o

exposes

paees

abnormaes

coagen

and

assocaed

and

ssue

coaguaon

w

acor

acors.

aerosceross

and

he

ead

o

syndrome

unraconaed

occurs

eparn

and

a

n

eads

s

o

paens

caused

by

reaed

w

anbodes

a

ow-moecuar-weg

bnd

o

compexes

eparn.

composed

eparn

and

paee

eads

paee

acor

4.

hroug

uncear

mecansms,

maor y

ead

 •

acors

proromboc

o

processes

rombus

by

sae

suc

endoea

seen

as

n

ces,

wc

aerosceross.

vascus

a

may

o

acvaon,

paee

consumpon,

and

deposon

ncreased

conrbue

Trauma

damage

paee-rc

cos

n

e

arera

and

venous

crcuaon.

hese

or

vesses

o

nlam-

aso

may

Table

ormaon.

3.2

Hypercoagulable

States

 Abnorma bood ow. Turbuence and sass conrbue o romboPrimary

(Genetic)

ss n e ear and e arera sde o e crcuaon, wereas sass

s e major acor n e deveopmen o venous romb. Sass and Common

urbuen

bood

low

cause

canges

n

endoea

ce

gene

a

avor

romboss.

Stass

aows

paees

(>1%

exended

V

mutation

w

e

endoeum

vesse

or

wa,

areas

were

denuded

ey

o

may

encouner

endoeum;

Population)

V

Leiden)

mutation

dysuncona

sass

aso

sows

e

Rare

Antithrombin

ENDOTHELIAL

the

(factor

conProthrombin

ac

of

expresFactor

son

INJURY

III

deficiency

Protein

C

deficiency

Protein

S

deficiency

Secondary

Higher

Cardiac

Tissue

(Acquired)

Risk

Prolonged

for

bed

Thrombosis

rest

dysmotility

injury

or

immobilization

(myocardial

(surgery,

fracture,

infarction,

atrial

fibrillation)

burn)

THROMBOSIS

Disseminated

Prosthetic

cancer

cardiac

Disseminated

valves

intravascular

Heparin-induced

coagulation

thrombocytopenia

ABNORMAL

BLOOD

Antiphospholipid

antibody

Lower

Thrombosis

Risk

Nephrotic

Fig.

3.8

Virchow

triad

in

thrombosis.

Endothelial

integrity

is

the

for

syndrome

factor.

Abnormalities

of

procoagulants

or

anticoagulants

the

balance

in

favor

of

thrombosis.

Abnormal

blood

flow

(stasis

contraceptive

or Sickle

turbulence)

can

lead

to

hypercoagulability

directly

and

also

cell

indirectly Smoking

through

endothelial

dysfunction.

states

can Oral

tip

(due

to

loss

of

antithrombin

III)

most Hyperestrogenic

important

syndrome

HYPERCOAGULABILITY

FLOW

s

endoea

e

o

e

o

o

expresson o procoaguan acors and e decreased expresson o

ancoaguan

up

ower

aero-

HIT sceroc

w

commony

racon due

(HIT)

and

anemia

use

(during

pregnancy

and

following

delivery)

36

CHAPTER

cos

may

ead

syndrome



•

o

and

oss

ons,

may

o

mbs

cessaon

 Antpospopd

romboss,

Hemodynamic

3

an

or

e,

eparn

antbody

repeaed

be

o

and

soaed

recognon

erapy

syndrome,

mscarrages,

anomay

Disorders,

are

assocaed

and

or

o

ereore

w

cardac

e

o

and

Shock

HIT

crca.

recurren

vave

secondar y

Thromboembolism,

vegea-

an

auom-

mune dsorder (e.g., sysemc upus er yemaosus). he name o

s

dsorder

a

bnd

o

mporan

came

rom

e

pospopds

paoogc

deecon

n

e

efecs

n

ab.

o

I

crcuang

s

paens

beeved

are

anbodes

a

e

medaed

mos

roug

bndng o ese anbodes o epopes on proens a are some-

ow

nduced

peced

a

a

or

“unveed”

ese

ypercoaguabe

ever,

us

n

vro,

nb

sae

e

msnomer).

a

componen

he

o

roug

(ence

es

or

o

varous

e

oten



s

and

sus-

nduce

How-

pospopds

upus

cross-reac

syps,

vvo,

mecansms.

w

name

In

proens

unceran

nerere

anbodes

e

pospopds.

bnd

anbodes

coaguaon

a

by

anbodes

and

antcoaguant

w

producng

a

A

s

cardopn,

ase-posve

resu.

Morphology.

esons,

Arera

wereas

occur

a

o

underyng

e

ses

obsruced

propagae

o

sass.

and

oward

a

o

propagae

rerograde

he

and

prone

ses

or

o

drecon).

o

wa.

Venous

porons

ong

are

no

are

aaced

n

paray

romb

romb,

romb

ormng

are

ocaed

bood,

arera

aerosceroc

caracerscay

romb

Wen

lowng

(even

dsance,

overe

romb

naon,

cardac

ear

propagang

ypcay

cardac

exposed

e

some

umen.

and

A

vesse

vesses

n

romb

venous

end

wc

parcuary

cass

wn

aaced

o

o

grow

key

e

vesse

vesse

was

B are

o

ragmenaon

Mcroscopcay,

romb

and

ave

embozaon.

amnaons

caed

nes

of

Zan,

Fig.

3.9

apices,

wc

represen

aernang

pae

ayers

rc

n

paees

and

Mural

darker

ayers

rc

n

red

ces.

Layered

romb

ony

orm

bood,

and

e

presence

o

ese

ayers,

as

we

as

e

o

romb

rom

racon

o

romb.

emboc

o

sed

o

co

o

e

posmorem

red

In

cos.

wa,

V enous

n

days

and

oowng

or

weeks

romb

undergo

romb,

exraceuar

e

brn

may

marx

are

(red

an

o

conan

accompaned

by

connue

eFg.

and

e

var yng

or

speca

3.1).

In

depos-

degrees

o

romb

desgnaons.

ear

vaves

are

ypercoaguabe

era

and

or

may

o

boses

aortic

occurrng

hromb

n

occurrng

e

n

ear

e

or

ear

caed

saes

vegetatons.

and

unga

necons

ead

e

o

are

sere,

(necve

deveopmen

o

Some

aora

and

e

bu

vegeaons

oers

are

endocards;

arge

bear

aorc

occur

caused

see

romboc

(left

aneurysm.

on

the

left

Laminated

Numerous

advanced

side

necon

(DVTs)

emboze.

of

and

right

ventricular

thrombus

in

friable

mural

a

thrombi

dilated

are

atherosclerotic

lesions

of

the

more

also

proxi-

photograph).

by

n

bac-

Caper

8)

masses.

and

n

DVTs

cannes

varcose

arge

aso

eg

may

requeny

ucers.

vens

a

or

cause

pan

crcumven

By

conras,

above

and

e

edema,

e

deep

eve

venous

o

bu

e

coaera

obsrucon.

rom-

knee

oten

venous

Consequeny,

approxmaey 50% o DVTs are asympomac and are recognzed ony

ater

ey

he

umen (Fg. 3.9) are reerred o as mural thromb, wereas romb

on

aorta

skn

recanazaon.

Nonobsrucve

in

(B)

ger

arera

romboc

(Suppemena

ces

a

an

dssouon;

sroma

scar.

anemorem

cos)

na

undergo

organzaon

ngrow

dsngus

romb

enrapped

vascuar

embo;

vesse

ces

e

even,

organzng

on

e

Thrombus

rm mal

aacmen

(A)

fibrous

n superimposed

lowng

white

brn,

abdominal

and

thrombi.

overlying

ave

embozed

cnca

oversaed.

secondar y

narcon

he

o

o

e

mporance

greaes

o

aack)

n

romboemboc

s

aerosceross,

(ear

ungs.

o

aken

wc

e

by

s

e

Wesern

dsease

coronar y

major

word.

arer y

cause

Embo

canno

be

romboss

o

myocarda

sed

rom

e

ear and romboemboc dsease due o aerosceross o e carod

areres

(CNS)

DVTs

and

are

s

oer

an

aa

grea

vesses

mporan

n

cause

approxmaey

suppyng

o

3%

sroke.

o

e

cenra

Pumonar y

afeced

ner vous

sysem

embozaon

o

paens.

EMBOLISM Clncal

Features.

obsrucon

vesses

and

romb

areres

due

e

ss,

o

s

Cnca

vesses

organs

and

occusve

he

hromb

panu

and

and

e

dsease

90%

n

cause

o

s

afeced.

ence

bood

more

o

dea

congeson

and

rarey

edema,

var y

o

due

o

e

accordng

o

e

eared

are

compcaon

romb

cause

organs

romboses

vens

romb

wereas

arera

n

by

and

mos

key

suppy

dscussed

superca

he

aer),

beween

venous

caused

embozaon

(dscussed

reaonsp

cardac

an

o

sympoms

co

are

embozaon

are

More

and

a

obsrucon

bran.

es.

o

a

suc

oca

as

e

romboss,

n

Caper

occur

n

e

emboze,

n

o

smaer

narcon

ear

and

aeroscero-

8

predsposng

embolus

mass

tant

that

site,

function

he

ence,

ey

e

exrem-

may

be

overyng

(.e.,

or

vas

a

is

a

o

detached

carried

it

by

may

the

intravascular

blood

cause

from

vascular

solid,

its

liquid,

point

of

obstruction

or

origin

and

gaseous

to

a

organ

dis-

dys-

infarction.

majory

erm

lud.

orgn

o

embo

are

derved

tromboembosm.

dropes,

coesero

amnoc

se

is

where

e

ncude

ower

bu

An

bubbes

embo),

Embo

un

ey

o

ar

umor

are

Less

or

nrogen,

ragmens,

ranspored

odge

n

e

rom

bs

roug

rs

dsodged

common

vesse

ypes

romb;

o

embo

aerosceroc

o

bone

e

a

bood

s

debrs

marrow,

oo

rom

and

er

narrow

o

CHAPTER

Supplemental

stained

elastic

for

lamina

punctuated

spaces).

eFig.

elastic

(arrows)

by

3.1

tissue.

and

several

Low-power

The

is

original

totally

recanalized

Hemodynamic

3

view

lumen

filled

is

with

of

a

thrombosed

delineated

organized

endothelium-lined

by

the

Disorders,

artery

internal

thrombus,

channels

now

(white

Thromboembolism,

and

Shock

36.e1

CHAPTER

perm

son.

urer

he

scemc

ung,

passage,

major

necross

wc

as

Nevereess,

boembosm

morbidity

romb

and

ca

and

 •

o

cnca

vascuar

one

proecs

assocaed

compee

w

occu-

beds

excepon

agans

s

s

from

an

rom-

dsease.

95%

e

and

o

are

frequent

o

s

as

e

ound

w

per

embo

e

causes

rg

n

year

n

orgnae

knee.

vascuaure.

assocaed

number,

he

no

 A

vascuar

bend

arge

e

e

undergo

of

sde

A

anoxa.

o

embous

may

burcaon

o

occude

e

somemes

or

causng

webs

e

rg

Caper

rom

oer

 •

 Fa

a

ear

compee

n

he

cn-

s

embo

var y

become

recanazaon,

(Suppemena

man

and

eer

et

vruay

pumonar y

pumonar y

or

areres

nsananeous

 •

3.1)

arer y

aa

orrage,

bood

bu

roug

 Lodgng

oten

narcon

of

nac

embo

resus

genaon

an

o

n

s

n

bronca

te

narcon,

e

ung

s

uncommon

sma

may

cause

because

crcuaon

(dua

parcuary

n

by

aso

(sadde

ndvduas

congesve

n

o

emboc

em-

receves

Sot

ssue

o

10%

e

o

oxc

efecs

compcaon

moray

rae

deas

e

o

o

n

enson

and

Rarey,

and

an

eners

odgng

n

rg

venrcuar

embous

e

sysemc

end-arera

(paradoxca

passes

ear

aure

roug

crcuaon,

vascuar

beds

an

e

(cor

ara

were

n

cause

on

oxy-

o

raer

aure.

a



may

bran

yper-

 •

venrcuar

cause

(sroke)

deec

narcs

or

s

e

ay

ces

abor

e

odge

end

o

occur

or

marrow)

caber

ssue’s

n

n

no

end

o

e

vuner-

areres,

dsnc

causng

racure

can

a

anema,

mecanca

acds

cause

o

reease

cnca

ong

3.2).

by

bones

mcroscopc

embosm

eFg.

caracerzed

e

and

syndrome

hs

syndrome

pumonar y

nsu-

rombocyopena,

obsrucon

reeased

rom

e

o

and

sma

pd

ves-

gobues

njur y.

dever y

Uned

neuroogc

maerna

or

oowed

pumonae).

or

bu

uerne

Saes,

decs.

crcuaon

ven

(1

80%.

I

n

and

o

lud

ears

(Suppemena

brs)

responsbe

85%

Amnoc

roug

40,000

s

n

eFg.

s

o

ave

conens

pacena

3.3).

as

10%

sur vvors

and

e

a

or

he

mem-

onse

s

sudden and s caracerzed by severe dyspnea, cyanoss, and sock,

brances

pumonar y

on

afeced

oten

(Suppemena

and

e

by

sezures

componens

an

crss,

 Ar

Gas

vascuar

coma.

e

mecanca

embosm.

obsruc

and

o

dssemnaed

secondar y

o

e

njures

er

approxmaey

lud.

bed

o

endoea

amnoc

vascuar

n

sympoms,

Bo

deveops

pumonar y

dsease

crcuaon,

cases

poron

e

depend

and

embo

crus

a

paens

 Mupe sma embo occurrng over me may obsruc a suicen

o

suppy,

arera

abundan

no

permanen

wom

ear

(10%),

Emboli

beedng.

maerna

crcuaon).

pumonary

bran

 Amnoc lud embosm. Amnoc lud embosm s a rare bu ser-

a

dea.

area

or

oucome.

neuroogc

and

ous

odge

pumonar y

e

end-arteroar

compromsed

n

nearby

branes

capares

ave

mnory

he

o

embozaon

Because

orms

cency,

ncorpo-

somemes

eFg.

o

coaera

common

gobues

a

ener

rupure

e

embosm.

o

10.

(75%)

37

sengs:

(wc

e

exremes

Shock

In addon o rombus, embo may be composed o oer subsances.

 Smaer embo may obsruc smaer, brancng areres (Fg. 3.10).

subsequen

a

peeca

and

undergo

brous

s

Fragmened

more

pumonar y

e

ower

consequences

aby

oows:

organzaon

wa

brdgng

e

vesse,

on

ey

n

and

spared.

occuded

ses

me,

odge

s

narcon

deas

e

roug

embosm

and

cases,

pumonar y

eaures

sze

100,000

proxma

pass

Thromboembolism,

Nonthrombotic

DVTs

abou

vens

usuay

n

organ

e

narcon.

pumonar y

embo

hese

eg

pumonar y

e

embous),

 •

ssues;

a

or

mos

W

a

 •

n

 Most pumonary embo (60% to 80%) are sma and cncay sent.

eavng

 •

DVTs

paoogc

raed

 •

canges

cause

more

deep

arresed

o

para

mortality.

In

rom

accordng

afeced

suppy

sgncan

originate

embo

wn

dscusson

n

Disorders,

Thromboembolism

and

become

resu

embozaon

o

bood

cause

emboli

Saes.

romb

dua

crcuaor y

Pumonar y

Uned

ey

o

(nfarcton)

a

oten

Pulmonary

Pulmonary

were

consequence

Hemodynamic

3

o

paogeness

mmune

obsrucon.

I

nravascuar

e

bubbes

low,

he

nnae

reease

wn

causng

sysem

e

paen

coaguaon

o

nvoves

and

sur vves

(Caper

rombogenc

e

crcuaon

dsa

scemc

acva-

coaguaon,

e

9)

n-

oten

subsances

can

coaesce

njur y.

Gas

n

and

may

be

by

nroduced no e vascuaure accdenay durng surgca, obse-

esewere

rc, or aparoscopc procedures; oowng a severe ces wa njur y ;

embosm).

or

as

a

consequence

o

sudden

decreases

n

e

amosperc

pres-

sure (e.g., wen dvers surace oo rapdy, dssoved nrogen comes

Systemic

he

mos

(80%),

Thromboembolism

common

oowed

vavuar

by

vegeaons,

source

o

aerosceroc

and

ou

sysemc

DVTs

(by

romboembo

aorc

esons,

paradoxca

aorc

s

e

ear

o

souon,

condon

ormng

known

as

e

gas

bubbes

n

e

bood

and

e

ssues,

a

bends).

aneur ysms,

embozaon).

Mos

INFARCTION

An

infarct

the

is

vascular

and

an

important

Arera

V enous

area

supply

of

to

cause

ischemic

the

of

clinical

romboembosm

romboss

can

necrosis

affected

tissue;

by

occlusion

is

a

of

common

disease.

underes

cause

caused

infarction

e

narcon,

vas

bu

majory

more

o

narcons.

commony,

ere

s

smpy congeson, as coaera cannes open rapdy and resore e are-

ra

nlow.

Inarcs

caused

by

venous

romboss

occur

n

organs

w

a

snge eferen ven (e.g., ess or ovary) and ypcay sem rom a mecan-

ca probem (e.g., wsng o a esce, eadng o venous obsrucon).

No

weer

 •

a

bood

weer

w

3.10

Embolus

derived

from

a

lower-extremity

deep

venous

in

a

pulmonary

artery

branch.

ead

ncude

e

o

narcon.

Deermnans

o

oowng:

bood

o

s

o

e

an

suppes

narcon,

mos

mporan

ndvdua

(ung,

wereas

vesse

ver,

ose

and

w

acor

causes

and

kdney,

and

speen)

are

key

o

n

deermnng

damage.

and

narc.

Tssues

orearm)

end-arera

throm-

(ear, lodged

suppy

occuson

dua

ressan

bus

occusons

occurs

 Anaomy o he vascuar suppy. he presence or absence o an aer-

nave

Fig.

vascuar

narcon

are

crcuaons

38

 •

CHAPTER

 Rate

of

cause

 •

occuson.

narcon

 Ceuar

o

mnues,

rom

Morphology.

(anemc)

occur

ssues

ng

w

vabe

may

w

angopasy

w

arera

can

be

eer

venous

o

o

ours

eer

low

ater

n

o

o

n

red

o

ony

mnues,

3

and

o

4

bro-

(as

n

(e.g.,

Re d

ovaran

e

narcon

we

(Fg.

orson);

ung);

as

or

narcts

and

occurred

Whte

narcts

end-arera

n

oow-

(e.g.,

occur

crcuaons

Fig.

(e.g.,

ear,

wedge

speen,

saped,

w

and

kdney)

(Fg.

e

occuded

3.11B).

vesse

a

e

Inarcs

apex

end

and

e

o

3.12

Remote

ormng

e

base

(Fg.

3.11A);

wen

e

base

s

a

ere

s

oten

an

overyng

brnous

mos

 ssues,

n arc s

W n

de veops

a ong

a

e w

d sp ay

ours ,

co agu  a ve

an

ne c ros s

n   ammaor y

marg  ns

o

 narc s;

replaced

by

a

large

fibrotic

scar.

(cardac

(e.g.,

amponade)

pumonar y

(see Caper

8),

or

ou-

embosm).

 Hypovoemc

 e

es on

s

sock

resus

rom

oss

o

bood

or

pasma

voume

(s e e

due

o

emorrage

or

lud

oss

rom

severe

burns).

resp ons e

 •  e

compresson

obsrucon

(e.g., 1).

now

exudae.

 • In

C aper

infarct,

serosa

low surace,

kidney

be

organ

exrnsc perper y

Shock

suscepby

ater

(emorragc)

band.

w

key

and

crcuaons.

er

de

30

ess

Thromboembolism,

scema.

obsrucon).

organs

are

coaera

range

20

or

suppes

arera

occusons

or

sepc

o

Neurons

occusons

bood

an

as

many

may

coaera

Ces

occuson:

Disorders,

occusons

deveopmen

ypoxa.

ater

be

reesabsmen

ater

to

ces

Inarcs

and

deveopng

e

vascuar

myocarda

reman

3.11A)

o

vunerabty

damage

bass

Sowy

due

Hemodynamic

3

usu a  y

 S eptc

sock

s

rggered

by

mcroba

necons

and

s

assocaed

we 

w e sysemc nlammaor y response syndrome (SIRS). In addde ne d

w  n

1

o

2

d ay s.

In  amma  on

s

o owe d

by

rep a r,

on b eg n nng

n

 e

pres er ve d

marg ns

(s ee

C aper

2).

are

u  maey

rep ace d

by

s c ar

 ssue

(Fg .

3.12).

s

an

excep on

o

 es e

genera za  ons ,

as

s cem c

 Neurogenc

n

 e

CNS

resu s

n

queac  ve

ne c ros s

o owe d

by

(s e e

Caper

may

be

rggered

paogeness

o

by

sepc

severe

sock

burns,

s

rauma,

dscussed

sock

resus

rom

e

oss

o

vascuar

one,

aer.

as

oowng

spna

cord

may

njur y.

g  -

 • oss

SIRS

he

 ssue

occur njur y

mcrobes,

pancreas.

Te

 • bran

o

Mos

and narc s

 Anapyactc sock resus rom sysemc vasodaon and ncreased

17).

vascuar permeaby a s rggered by mmunogobun E–medSepc

narcs

occur

wen

neced

cardac

vave

vegeaons

aed emboze

narc

or

s

wen

mcrobes

convered

no

seed

an

necroc

abscess,

ssue.

w

a

In

ese

greaer

cases,

mmedae

Pathogeness. response

and

eang

by

organzaon

and

bross

ypersensvy

reacons

(see

Caper

4).

e

nlammaor y

(see

Caper

Sock,

regardess

o

s

cause,

as

ceran

common

ea-

2).

ures.

I

probem

n

e

aorc

sock

 •

s

a

s

progressve

no

seng

 Ina

are

Sock

n

and

sages

are

stage:

and

ypes,

stage:

organ

ssue

meaboc

eads

ends

(e.g.,

oer

va

a

njur y

hese

seen

 Progressve

cuaor y

 •

massve

nonprogressve

acvaed

 •

correced.

o

aneur ysm).

bu

dsorder

o

dea

evove



e

roug

exsangunaon

bes

as

o

underyng

sages,

rom

documened

n

a

excep

rupured

ypovoemc

we:

relex

peruson

compensaor y

s

mecansms

are

mananed

ypoperuson

occurs,

w

worsenng

cr-

derangemens

 Irreversbe stage, n wc ceuar and ssue njur y s so severe a

even



e

emodynamc

deecs

are

correced,

sur vva

s

no

pos-

sbe

In

oops

e

B

A

3.11

Red

and

white

pulmonary

infarct

infarcts.

(red

(A)

Hemorrhagic,

infarct).

(B)

Sharply

roughly

in

the

spleen

(white

nonprogressve

e

cardac

consrcng

and

pase,

oupu

e

decreasng

neura

and

areroes

e

urne

and

bood

(n

ormona

pressure

by

ypovoemc

oupu.

C oronar y

eedback

ncreasng

and

and

cardo-

cerebra

wedge-

demarcated

are

ess

sensve

o

sympaec

sgnas

and

manan

a

rea-

pale

vey infarct

rae,

sock),

vesses shaped

eary

manan

ear

genc Fig.

e

norma

caber,

bood

low,

and

oxygen

dever y.

hus,

bood

s

infarct).

suned

e

away

rom

e

skn

o

e

va

organs

suc

as

e

ear

and

bran.

Wou

correcon

o

e

underyng

cause,

sock

proceeds

o

e

SHOCK

Shock

is

a

circulating

diminished

state

volume

tissue

Proonged

oten

 •

aa.

in

Is

diminished

causes

perfusion

sock

causes

 Cardogenc

which

a

and

evenuay

a

sock

no

resus

fall

in

cardiac

blood

pressure,

consequent

eads

severa

rom

o

output

cellular

rreversbe

caegores

cardac

pump

effective

resulting

in

njur y

and

s

3.3):

aure.

I

may

pase,

a

oxygen

perssen

yss

nsead

ssue

hypoxia.

ssue

(Tabe

or

progressve

be

caused by myocarda damage (narcon), venrcuar arrymas,

pH

o

bood

pu,

owerng

dec,

aerobc

buns

and

caracerzed

poos

e

n

bood

ces

by

are

respraon,

vasomoor

e

wdespread

orced

causng

response;

mcrocrcuaon,

pressure,

and

pung

o

ssue

rey

acc

as

a

on

ypoxa.

Due

anaerobc

acdoss.

resu,

worsenng

he

owered

areroes

e

endoea

dae

cardac

ces

a

o

gyco-

ou-

rsk

or

anoxc njur y. Endoea dysuncon en ses e sage or e deve-

opmen

o

wdespread

ssue

edema

and

dssemnaed

nravascuar

CHAPTER

Supplemental

eFig.

circulation.

cellular

The

hematopoietic

cells,

3.2

Bone

marrow

elements

whereas

the

on

the

Hemodynamic

3

embolus

left

cleared

side

in

of

vacuoles

the

the

Disorders,

Thromboembolism,

The

relatively

uniform

red

area

on

the

right

of

represent

the

organizing

38.e1

are

marrow

embolus

is

eFig.

3.3

Amniotic

fluid

embolism.

Two

small

pulmo-

an

nary early

Shock

pulmonary

embolus

Supplemental fat.

and

arterioles

are

packed

with

laminated

swirls

of

fetal

squamous

cells.

thrombus.

There

is

marked

small

organizing

coagulation.

edema

and

thrombi

(Courtesy

Dr.

congestion.

consistent

Beth

Elsewhere

with

Schwartz,

the

lung

disseminated

Baltimore,

MD.)

contained

intravascular

CHAPTER

Table

Type

3.3

of

Major

Types

of

Shock

Disorders,

Thromboembolism,

and

Shock

39

Shock

Clinical

Cardiogenic

Hemodynamic

3

Examples

Myocardial

infarction

Ventricular

Principal

Pathogenic

Failure

myocardial

rupture

of

damage,

extrinsic

Mechanisms

pump

resulting

pressure,

or

from

intrinsic

obstruction

to

myocardial

outflow

Arrhythmia

Cardiac

tamponade

Pulmonary

embolism

Hemorrhage

Hypovolemic

Fluid

Septic

loss

Inadequate

(e.g.,

vomiting,

Overwhelming

microbial

diarrhea,

blood

infections

Activation

of

damage;

uson.

begn

o

In

o

wc

wdespread

may

ssue

urer

compromse

ypoxa,

va

organs

e

are

ssue

per-

afeced

and

a.

e

o

approprae

conrace

oxde

Pathogeness.

(mos

uncon

syness.

ner venon

worsens,

Progresson

o

or

n

pary

rena

severe

owng

aure

cases,

o

occurs

e

ncreased

because

o

and

ropages,

componens

Sepc

(PAMPs).

ensue

ung)

suc

wen

sock

on

ces

and

ssues

o

ypoxc

njur y

(see

Caper

1)

and

are

caused

(Fg.

by

a

o

ypoperuson

and

mcrovascuar

romboss.

acvae

by

bacera,

e

compemen).

consuens

oowed

nnae

ces,

leukocyte-induced

coagulation

by

mmune

endoea

hese

ces

o

mcrobes

gram-negave

sysem

ces,

and

(.e.,

and

acors

mac-

soube

recognze

acvaon,

or

ason

3.13).

o

a

o

produce

Facors

sepc

number

wdespread,

sock

o

nlammaor y

nerac

sepc

beeved

ncude

o

e

n

a

sock

pay

responses

compex,

and

major

ncom-

muorgan

roes

n

e

oowng:

 Inf  ammator y

resp on s es .

PA M Ps

a c  v ae

 n   am m aor y

combre sp ons e s

naon

rggered

activation/injury;

blood;

resembe

 • ose

s

dendrc

massve

paopysoog y o

as

undersood

dysuncon

efecs

a

of

intravascular

gram-posve

Foowng

a,

peey

he

sock

endothelial

pooling

and are acvaed by mcroba paogen–assocaed moecuar paerns

n

dea.

and

disseminated

neurops,

rena scema (see Caper 11). he downward spra oten cumnaes

Morphology.

volume

cascades;

vasodilation

commony,

bacera

absence

myocarda

nrc

bo

W

plasma

cytokine

peripheral

coaguaon,

or

burns)

Any

by

e ng ag  ng

re c e pors

on

 n n ae

 m mu n e

ce s,

su c

organ as

To - ke

rece ptor s

(s ee

C  ape r

2),

w   c

re c o g n  z e

a

os

o

may be afeced; e bran, ear, kdneys, adrenas, and gasronesm  c rob e - d e r ve d na

rac

are

mos

commony

nvoved.

Fbrn

romb

are

n

kdney

gomeru

bu

may

be

ound

rougou

he

ungs

are

ressan

o

ypoxc

njur y

n

occurrng

ater

emorrage,

bu

sepss

and

rauma

dfuse

alveolar

damage

and

acue

c y ok  n e s

respraor y

ce 

su c

(see

Caper

oss,

10).

afeced

Excep

or

ssues

can

rreversbe

recover

 ur  er

neurona

compeey

Features.

nsu.

ypoenson,

skn.

lused

s

e

due

In

a

he

ypovoemc

weak

rapd

conras,

o

perpera

even

necon).

pumonar y

manesaons

By

rggerng

bacera

canges

n

and

o

puse,

acypnea,

sepc

sock,

rapdy

sock,

and

coo,

may

prmar y

e

cardac,

on

e

precp-

paens

skn

narcon,

secondar y

aggravae

e

he

myocarda

However,

depend

cardogenc

vasodaon.

(e.g.,

sock

exb

cammy,

be

n

w

a

approprae

sock

s

(TNF)

an d

e n d o  e   a 

a d  e s  on

an d

m o e c u  e

c e m ok  n e

a c  v ae d

  rou g 

 r ag m e n s

na

severe

rea

o

oxde

e

rena,

and

suaon.

w

by

o  e r

ce s

( an d

e x pre s s  on

by

pro du c   on .

m  c rob a 

Te

c omp on e n s ,

 e

o

proe oy   c

a c  v  y

an apy  aox  ns

o

(C3a,

p a s m  n ,

C5a),

subsanay

worse

sepc

or

oucomes,

car-

even

care.

 Inducton

sock,

wc

admssons.

de.

s

ere

are

more

responsbe

Despe

or

mprovemens

an

750,000

cases

approxmaey

n

care,

20%

2%

o

per

o

30%

year

a

o

o

osp-

afeced

edema

e

o

and

op s on  ns

njury.

juncons,

a

body.

oer

an d

pro n   am m aor y

g

ms

(C3b),

resung

n

e

dever y

endoeum

nlammaor y

smoo

a

c e -

o

w   c

cyoknes

oosen

s  ae.

Inlammaor y

nuren

Acvaed

vasoacve

vascuar

a

procoaguant

drecy

endoea

many

by

of

coaguaon

aered

acors

ncrease

so

musce

as

ssue

endoea

low

vesses

sma

wasou

o

o

accumuaon

and

aso

wase

reaxaon

nrc

wc

and

o

remova

produces

medaors,

and

(e.g.,

may

sysemc

decrease

coaguaon

up

a

paens.

msed

o

by

e

brn-rc

sysemc

romb

sma

aers

producon

and

sass

acors.

o

and

hese

(see

s

rombn

and

In

(and

o

ac-

roug

expresson

cyo-

poss-

endoea

proen

peruson

vesses.

e

monocyes

coaguaon

Tssue

acvaon

n

e

producng

nravascuar

sepc

by

can

ndrecy

Pronlammaor y

rombomodun

dssemnaed

o

componens

and

sepss

producon

cause

o

XII

coaguaon.

decreases,

acvaed

Mcroba

acor

Moreover,

avor

acor

ces)

acors

n

state.

roug

uncon.

ancoaguan

e

Saes,

 e

(C5a),

ypoenson.

 •

vae

comparson,

and

conrbue

emorrage,

cerebra,

o

rougou

and

Shock

Uned

paens

managemen;

assocaed

sae-o-e-ar

sepc

a s o

pro du c   on

ce

knes

e

an d

endoea

sur vve

In

c y ok  n e

s

actvaton

o

Septic

cas cade

 e

proen-rc

cya-

warm

he prognoss vares w e orgn o sock and s duraon. More

w

upre g u  ae

 Endotea

an 90% o young, oer wse eay paens w ypovoemc sock

dogenc

o

s  mu  ae

d  re c  y

c on r  bue

noc

 a c or

 n du c e

sur vves.

 •

ang

n e c ro s  s

  a

e

m o a c   c

Clncal

u m or

and



re su   ng paen

pro -

dsress

b o  cardomyocye

as

m e d  aors

yp es)

c omp e m e n syndrome

ce s

oten an d

precpae

 m mu n e

ypovoemc o  e r

sock

 n n ae

e pro n   am m aor y

body.

Ac  v ae d

ready du c e

vsuazed

PA M Ps .

C).

Bood

dmnsng

derangemens

Caper

urer

e

u-bown

9)

n

compro-

deposon

dssemnaed

40

CHAPTER

Hemodynamic

3

Disorders,

Thromboembolism,

Microbial

and

Shock

products

(P AMPs) Neutrophil

and

monocyte

activation

Endothelial

Complement Factor

XII activation

activation

C3a

C3

TNF ,

Direct

and

Cytokines

Procoagulant

Antifibrinolytic

IL-6,

IL-8,

reactive TF

IL-1,

HMGB1

indirect

NO,

oxygen

and

cytokine-like

mediators

P AF ,

IL-10,

species,

apoptosis,

sTNFR

P AI-1 etc.

TFPI,

thrombomodulin,

protein

Secondar y

C

antiinflammator y

mediators

VASODILA TION MICROVASCULAR

SYSTEMIC INCREASED

THROMBOSIS

IMMUNOSUPPRESSION

PERMEABILITY

(DIC)

EFFECTS DECREASED

PERFUSION

Fever,

diminished

myocardial

TISSUE

Adrenal

insufficiency

Fig.

3.13

and

humoral

Major

multiorgan

nitric

nravascuar

ors

and

supermposed

 •

 Metaboc

and

and

neogeness.

suppress

acc

S epc

reease

ssues.

I

severe,

pospor yaon

may

suc

as

suc

and

ceuar

o

o

e

exb

umor

as

septic

ncreased

text.

sTNFR,

necross

ressance

and

acae

acor

drve

Sysemc

romboss

ypoenson,

decrease

e

dmns

and

or-

that

TF,

cells

lead

intravascular

e

ver

and

edema,

oxygen

o

tissue

and

Hg

ssue

and

to

cellular

end-stage

coagulation;

factor;

drome

Caper

he

a

(see

e

and

undere

TFPI,

luds,

remans

a

suc

o

and

ssue

daunng

o

e

NO,

tissue

organs,

n

and

e

cnca

vascuar

ese

medaors

urer

com-

permeaby

respraor y

acors

compexy

dsress

may

e

acor.

underyng

Even

caenge.

o

ner venon

necross

suppemena

ypoxa.

oupu,

and

syn-

conspre

kdneys,

o

ver,

dea.

e

umor

rea

secondar y

parcuary

erapeuc

as

and

cardac

acue

Umaey,

acors

anbocs

m

10).

mupe

precude

pressors,

and

ead

eves

and

Increased

cumnang

o

medaors,

remans

pressure

sepss

may

o

ear,

mupcy

specc

care

aure

cyokne

conracy

peruson.

njur y

ungs,

o

ssues.

myocarda

endoea

cause

guco-

producon

o

endothelial

events

receptor;

promsng

ox-

dever y

TNF

nurens

a

dmnsed

nersa

of

Disseminated

ac-

c yoknes

n

activate

cascade

n

ressance

grow

a

DIC,

a

soluble

reaenng.

nsun

products

initiating

nous

dysfuncton.

sma-vesse

FAILURE

Microbial

the

contractility ,

abnor malities

factor.

resung

pronlammaor y

ypoxa

in

inhibitor-1;

coaguaon

gucagon,

nsun

shock.

system,

provided

necrosis

acors,

caecoamnes

e

promoe

ead

be

are

activator

tumor

ese

paens

me,

and

TNF,

o

a

ormones

same

details

in

immune

acdoss.

 Organ

and

e

nsun

oer

dave

A

innate

consumpon

dsorder

Cyoknes

pathways

the

Additional

inhibitor;

e

gucocorcods,

of

plasminogen

decences

abnormates.

sress-nduced

mone,

 •

beedng

ypergycema.

IL-1,

and

causes

pathogenic

PAI-1,

pathway

coaguaon,

paees

MULTIORGAN

elements

failure.

oxide;

factor

metabolic

ISCHEMIA

oxygen

n

e

e

he

necon

o

bes

neracons

w

anagonss

sandard

and

manan

ceners,

o

nrave-

e

bood

sepc

sock

4

Diseases

of

the

Immune

System

O U T L I N E

Hypersensitivity

Immediate

Disorders,

(Type

I)

Antibody-Mediated

Immune

T

41

Rejection of Transplants, 52

Hypersensitivity,

(Type

II)

Complex–Mediated

Cell-Mediated

(Type

IV)

42

Immune

Hypersensitivity,

(Type

III)

44

Hypersensitivity,

Hypersensitivity,

47

of

47

Systemic

Lupus

Systemic

Sclerosis

Sjögren

he

o

Innate

ces

sysem

and

mmunty

pasma

50

Human

Life

51

nnae

s

e

proens

us

agans

mmuny

rapd

a

necons

and

aways

and

adapve

response

are

o

cancers

necons

presen

by

wo

 •

mmuny.

cyes,

macropages,

epea

mecansms.

a

no

hese

recognze

recepors,

moecues

nnae

sared

and

poc ye

ave

a

by

s

and

gy

s

medaed

ready

med

paogens

e

B

speccy.

he

and

o

bu

by

Cell

uraon

o

e

gen-recepor

o

umors

and

are

To-ke

necroc

B

aack

and

 •

ympoc yes.

derved

a

a

(see

or

e

are

and

ces.

a

unque

o

hese

mmunty

by

and

ces

neuraze

e

er

e

ces.

e

o

by

T

recepors

se

express

mecansms

medaed

by

dferenaed

opsonze

sysem.

a

occur

o

T

o

and

B

Lympoc yes

e

a

56

and

B

and,

s

o

ym-

rearranged

o

normay

e

ympoc yes

uncon

e

erm

angen

ypes

o

deense

emnae

an-

and

and

reacons:

eosnops,

can

go

progeny,

em

or

pasma

are

ces.

pagocyoss,

efecor

mcrobes

produced

Anbodes

and

ces.

CD4+

o

ces

are

ces

Heper

h1

ces

h17

make

ces

and

conss

acvae

ces

unc-

uncon

CD4+

poen

nduce

(APCs),

er

macropages

o

T

CD8+,

reacons.

acvaed

ces

perorm

and

acvae

B

c yoknes

and

T

o

o

desroy

anbodes,

severa

dferen

sub-

ypes

macropages,

smuae

d-

eper

h2

neurop-rc

e

awry

ces.

mmune

and

cause

sysem

ssue

evoved

njury

as

and

a

proecve

cnca

orce,

dsease.

In

a

mes

s

cap-

er, we dscuss e mos mporan paoogc reacons and dseases a

are caused by mmune responses, many adapve mmune responses, as

we

as

decences

Persistent,

tions

o

e

mmune

acvae

misdirected,

against

sysem

and

er

consequences.

DISORDERS

a

variety

or

of

inadequately

antigens

may

regulated

cause

immune

tissue

reac-

injury.

An ndvdua wo as been exposed o and reacs agans an angen

s

sad

o

be

senstvty

dicu

o

dseases

wc

T

paoogc

a

nlammaon.

ransormed

Aoug

sen

ncude:

anbodes,

ces,

ep

dferen

by

angen-presenng

smuaon

T

c yoknes

nlammaor y

by

and

mcrobes,

produce

acvae

medaed

by

adapve

produce

and

ma-

ympoc yes

are

(ence,

Structure

ence,

creaed

durng

Virus:

nlammaon. CD8+ c yooxc T ympoc yes (CTLs) k neced

o

spe-

os

secree

a

ces



ces

n

major

smuae

ses

(dam-

specazed

ces

and

moecuar

ces

reacon

recepor

presence

angens

acvaon,

mcrobes,

compemen

genes

marker

o)

mecansms

 Humora

B

ese

(adap

56

dspayed

repea

pagoc yosed

are

2).

E ac

T

hese

rggered

major

hese

angens.

dversy

hus,

53

54

Immunodeficiencies,

mmunty

angens

Two

ereny

recepors

ces.

damaged

Caper

poweru

express

reabe

rom

by

Foowng

possess

umor

s

Allografts,

58

requre

ons.

deense

ympocyes,

ey

rom

ympoc yes.

angen-recepor

genes

acvaed

mmuny).

ces

o

53

Transplantation,

Disorders,

HYPERSENSITIVITY rearrangemens

Allografts,

Solid-Organ

59

proen

and

ympo-

nrnsc

(paogen-assocaed

[DAMPs]).

recepors

progeny

T

as

o

dversy.

reeased

more

and

suc

o

ces,

possess

producs

nlammaon

s

dverse

cona

and

paerns

T

dendrc

aso

recepors

subsances

acue

and

ypes

recepors

ave

many

mmunty

unque

express

angen

by

ce

producs

and

and

medaed

and

oer

moecuar

mmuny

Adaptve

cc

e

[PAMPs])

responses

ces

specc

age-assocaed

neurops,

and

mcroba

unke

paogen

paerns

ces,

of

Immunodeficiency

Cycle,

 C e-medated

by

(ence, nnate). he prncpa ces o nnae mmuny are myeod ces,

ncudng

Stem

(Congenital)

Amyloidosis,

51

proecs

mecansms:

Organ

Acquired Immunodeficiency Syndrome, 58

(SLE),

(Scleroderma),

Syndrome,

mmune

ypes

Erythematosus

49

to

Rejection

Immunodeficiency

Primary

Autoimmunity,

of

Hematopoietic

Autoimmune Diseases, 49

Mechanisms

Responses

Mechanisms

 •

senszed,

reactons.

conro,

may

 R eactons

dseases

aer,

gens,

be

and

caused

aganst

ey

njurous

are

by

sef

cause

ndvduas

and

so

mmune

Hypersensvy

ereore

are

mporan

reacons

o

antgens

are

are

ree

normay

resus

end

wen

be

caed

probems.

ypes

o

As

er

yper-

cronc

o

we

sa

own

se-oerance

and

hese

angens.

auommuny,

dseases.

oeran

are

o

cnca

man

caed

autommune

auommuny

reacons

dseases

and

e

dscuss

(se )

breaks

an-

down.

41

42

CHAPTER

Table

4.1

Diseases

4

Hypersensitivity

Type

(type

I)

of

Immune

System

Mechanisms

Production

hypersensitivity

the

Reactions

Immune

Immediate

of

of

IgE

histamine

cells;

later

antibody

and

other

→

immediate

mediators

recruitment

of

release

from

Histopathologic

Lesions

Vascular

edema,

mast

inflammatory

dilation,

muscle

cells

contraction,

production,

tissue

Prototypical

smooth

Disorders

Anaphylaxis;

mucus

asthma

allergies;

(atopic

bronchial

forms)

injury,

inflammation

Antibody-mediated

(type

II)

Production

hypersen-

target

sitivity

of

of

cell

target

IgG,

or

cell

receptors;

IgM

tissue

by

→

→

binds

to

antigen

phagocytosis

activated

recruitment

or

complement

of

on

Phagocytosis

lysis

or

cells;

Fc

diseases,

leukocytes

and

lysis

inflammation;

ments

functional

without

cell

of

in

Autoimmune

some

hemolytic

Goodpasture

anemia;

syndrome

derange-

or

tissue

injury

Immune

complex–

mediated

(type

Deposition

III)

→

hypersensitivity

of

leukocytes

receptors

toxic

Cell-mediated

(type

IV)

Ig,

 •

→

→

complement

release

of

complexes

recruitment

products

enzymes

and

Inflammation,

of

and

litis

an

aganst

abnorma

neous

mmune

 E x cessve

 y

T

lymphocytes

→

cytokines,

inflammation

activation;

(2)

c u oss,

o

 e

resp ons e

b owe

he

reacon

T

(1)

release

and

cangeaby,

maon.

of

Perivascular

edema;

cytotoxicity

cell

cellular

infiltrates;

granuloma

Contact

formation;

erythematosus;

of

serum

glomerulone-

sickness;

dermatitis;

sclerosis;

destruction

mcrob e

 e

ey

c aus e

 oug 

o

w c

are

no

be

and

Arthus

type

1

multiple

diabetes;

tuberculosis

p ers sen

cua-

s

 e

suc

nor ma 

as

 e

ub er-

 m mune

In  am maor y

re ac  ons

mmune

ag ans

ce s

w en

synonymous.

I

s

requeny

assocaed

w

antibodies

are

oten

used

Hypersensvy

caused

by

mcrobes

and

oer

auommuny,

envronmena

bu

agens.

ner-

reers



some

auommune

svy,

suc

wou

as

reacons

depeon

accompanyng

o

do

no

red

ave

ces

a

and

componen

paees

by

o

an

aso

that

cells,

angens

based

on

hs

the

gens

are

reac

of

casscaon

nsms

and

(type

I)

mmunogobun

by

are

and

because

cnca

eac

eaures

ypersenstvty

E

(IgE)

medaors

s

eary

e

by

mas

ype

as

(Tabe

o

 •

armess

be

ew

 Actvaton

ypes

smuaes

dsnc

rgger

nlammaon,

 Immune

or

on

ces

ces

s

nduce

compex–medated

n

uncona

(type

III)

and

 •

desroy

ces,

s

caused

ses

and

ssues

and

ce–medated

ces,

wc

desroy

os

ec

(type

nduce

ces.

cronc

ypersenstvty

nlammaon,

s

or

caused

CD8+

T

by

IgE

sensitize

nsec

e

bu

srong

dea.

and

n

some

aergc

(ae-pase)

are

mos

suc

an-

sysem

does

ndvduas,

a

propensy

smoo

and

(were

mmune

reacons

he

ypca

venoms,

socees

can

o

o

deveop

reacon

musce

ead

nlammaor y

sg-

ese

consss

response,

no

ese

o

an

wc

response

over

4.1).

mmedae

ceuar

ypersensvy

responses

(Fg.

reacons

oow

a

4.2).

by

CD4+

ces,

T

wc

ces

srong

and

and

IL-5

IL-13

IL-5,

roes

specc

of

responses

IL-4,

negra

soype.

producon

h2

or

n

e

and

on

anbody.

some

IL-13,

o

ac

nd-

h2

on

ces

a

and

e

are

ces

severa

ypersensvy.

produce

eosnops

epea

Aopc

angens.

wc

mmedae

aergen

acvaes

acs

IgE

o

IgE

IL-4

mmu-

recrued

smuaes

o

mucus

IgE

Te



 es e

of

ma s

re cepor

a  erg c

s

ce s

re cepor

s

 key

 a

p or  on

express e d

ce s

ce s

anbody.

Fc

o cc ur

mas

Mas

IgE

 e

a s o

re ac   ons

re ac  ons.

by

or

n

are

bnd

on

 ssues

 e

IgE

Mas

o

 e

bo o d

and

maj or

and

ce s

ε

ce 

n

 e

 yp e



on

a

can

b as op  s,

no

re an

express

e av y

bu

crc u -

nvove d

 er

sur-

aces.

 •

nlammaon.

IV)

ec

sower

o

ces

 S ensz aon

n

by

compexes o anbodes and angens a become deposed n ves-

 T

B

reacon,

 a on,

abnormaes.

ypersenstvty

and

angens,

he

cyoknes

g -a  n y

ssues

and

secreon.

and

rggered

ces.

or

a

2

w

nogobun

meca-

e

h2

of

e

b e c aus e

angens

caused

mediators.

ndvduas,

vascuar

(Fg.

Mos

make

o

arge

atopy.

by

ours

oods,

even

mnues)

sequence

a

o

mos

and

caed

oowed

nex

 Antbody-medated (type II) ypersenstvty s caused by anbodes

bnd

of

ndusrazed

angens

morbdy

s

In

n

envronmena

(wn

ce

types

4.1).

by

release

is

antigens

ypersen-

major

Inlammaon

allergy,

may

auoanbodes

four

called

Conversey,

reaction.

caused

anbodes.

reeased

into

immune

the

areas

abundan).

vduas

classied

adaptive

useu

paoogc

 Immedate

many

s

the

to

also

environmental

envronmen,

urban

agans

ncan

may

e

n

normay

nlammaon.

reactions

nature

recognize

leading

n

requen

secree

Hypersensitivity

Hypersensitivity

reaction,

Aerges, e mos common mmunoogc dseases, are reacons o

reacons

d ee c  ve.

autommunty

I)

inammatory

mast

and

by

This

yp ers ens  v -

njur y.

c aus e d

a

drugs.

c as es ,

 ssue

s

(Type

wc

armess

wc

m crob es

ac  vae

are

aerg y,

normay

c aus e

s ome

o

may

me can sms

ypersenstvty

bu

n

and

a s o

agans

unusu a  y

b e comes

are

cemcas

sysem,

ncude

and

sensvy,

mc robes

d eens e

s

b ac er  a,

antgens

sereoypc

 •

lupus

forms

reaction

Pathogeness.

 •

some

other

mmunoogcay medaed ssue reacon a s domnaed by nlam-

 •

Systemic

phritis;

macrophage

cell–mediated

common

conac

agans

mmune

proe c  ve

and

aganst

A  oug 

ds e as es

erms

agans

subsances,

 e

s e

commens a 

nor ma 

envronmenta

reacon

reac tons

re ac  ons.

 unc  on

 •

vascu-

necrosis)

Fc

Immediate

 Reactons

envronmena

be

necrotizing

(fibrinoid

Immunoglobulin.

s

 •

by

activation

molecules

Activated

hypersensitivity

antigen–antibody

complement

 Acvaon

of

mas

ces

and

reease

of

medaors.

Wen

e

angen

s renroduced,  bnds o e IgE, us cross-nkng e assocaed

Fc

o

recepors,

e

wc

secreon

o

n

urn

ransm

medaors

rom

nraceuar

e

mas

ces.

sgnas

a

ead

CHAPTER

Immediate

Diseases

4

of

the

Immune

System

43

Late-

reaction

phase

reaction

Allergen

exposure

Mast

cells

snoitatsefinam

Vascular

lacinilC

Eosinophils congestion

Edema

B

0

1

A

Hours

after

4

allergen

Fig.

ate

4.1

8

exposure

and

in

a

late-phase

cells.

C

20

hypersensitivity.

smooth

muscle

previously

Morphology

The

16

exposure

Immediate

vascular

(B)

12

of

the

(Micrographs

sensitized

immediate

reaction

is

(A)

Kinetics

reaction

Dr.

an

individual),

reaction

characterized

courtesy

to

Daniel

by

is

of

the

immediate

allergen

develops

and

late-phase

the

characterized

an

inflammatory

Friend,

Department

by

and

minutes

reaction

rich

in

Pathology,

reactions.

after

develops

vasodilation,

infiltrate

of

late-phase

within

2

to

congestion,

eosinophils,

Brigham

and

The

immedi-

challenge

24

(allergen

hours

and

later.

edema.

neutrophils,

Women’s

(C)

and

T

Hospital,

Boston.)

hree

groups

o

medaors

are

mporan

n

mmedae

ypersens-

Morphology. vy

s

 •

he

 Vasoactve

amnes,

many

stamne,

are

sored

n

mas

ce

ypcay

ues

and

rapdy

reeased

upon

mas

ce

degranuaon.

rapd

vasodaon

causes

smoo

and

ncreased

vascuar

rggered

permeaby

musces

o

conrac.

Cemoacc

acors

and

eases

are

generae

aso

D

)

s

e

mos

paway

as

4

as

and

I

ypersensvy

va on.

4

are

w c

mmune

o

vduas

mos

I

re cr u

IL-4

o

asma,

Caper

causes

vasoacve

s e cree d

ne cross

ac  vae

I L- 5,

ave

2.

Prosagan-

nense

he

and

are

mu-

generaed

o ow ng

ac or

by

e

bronco-

eukorenes

spasmogenc

mas

( T NF)

eu ko c yes

w c

o

and

abnormay

o

n

ese

amp  y

medaors

ypersensvy.

reacons

acors

exposure

o

mmedae

rggered

a

may

be

e

ony

secreon

o

manesaons.

ere

may

be

sgncan

nlammaor y

bronca

nraes

n

gand

yperropy,

bronca

pugs

a

obsruc

e

umens

(see

Caper

was,

and

10).

aso

Cln cal

s e ver  y

Feature s.

 rom

(a  erg c

cronc

s

 e

rn s),

ds e as es

o c a ze d

 e

sk n

Imme d ae

m d

o

w en

 e

as

o

ves

s ome mes

bronc a 

an  gen

con ac )

Sysem c

yp ers ens  v  y

nus ance

s er  ous ,

suc

(o ow ng

nges on).

n

 e

 e

ce 

and

ac  -

cemo -

 ae-pas e

T 2-n  ae d

In

anapy  axs,

cng ,

s

or

 e

re ac   ons

( ur  c ar  a)

a a ,

as ma

con ne d

exp osure

and

by

sensve

accoun

no

cear

angens

accounng

angens

or

do

no

(caed

acvaon

are

nvove

manes-

some

ncude

cdood.

suc

h2

as

ces

aerg y),

nd-

gnored

reacons,

smu,

varous

e

wy

aopy

nonatopc

by

or

a

durng

ypersensvy

and

cases

o

o

s

nonangenc

exercse,

ese

I

n

genec

Tweny

especay

may

IgE.

mas

nonmmune

I

ces

smu.

by

Te

ac ue

(Tabe

o

a

o

proen

and

range

ay

Te

p ar  c u  ar

an gens

and

re ac  on

se,

 rac 

n

e ver

anapy  ax s

4.2).

gas rones na 

p a en

w  

may

o

by

n

suc

as

(o ow  ng

(e. g . ,

mme d  ae

n

prog ress

o

n

bee

 e

by

pressu re

crc u  aor y

s ens  ze d

by

os ,

proound

L ar y nge a 

c aus ng

en re

vom ng ,

a

bronco c ons r  c  on

muc us .

upp er

e d ema

ar way

g as ro nes na 

ab d om na 

ner ven on ,

bo o d

o

o

n

o owe d

pu monar y

bre a  ng

resu  an

a  

exp osure

app e ar,

yp ers e cre on

mus c u  aure

a

 e

er y ema

c aus e d

 e

w  

W ou

vas o d  a on

m nues

sk  n

d   c u  y

a e c e d,

d ar re a.

 ere

may

( anapy  ac  c

c o  ap s e

and

 rac 

cramps ,

be

and

s ysem c

so ck) ,

de a 

and

w   n

mnues.

Tre a m e n

empera-

or

exacerb ae

be

and

d  c u  y

accenu ae d

obs r uc  on.

 e

w   n

ur  c ar  a,

respraor y

may

many

and

exremes

beeved

and

njurous

he

30%

are

and

umor

and

acons

mmedae

deveop

samne

produce

eukotrenes,

and

secreon.

poen

and

o

re ac  on.

peope.

asma,

e

ncu d e

and

suscepby

percen

are

and

acd

medaor

ces.

mucous

n

by

venom) or dr ugs (e.g . , p en c  n) may resu  n sysem c anapy  ax s.

combned

aons

mas

ncreased

sy n esze d

Tes e

re ac  on,

he

LTD

n

descrbed

excessve

acors.

aracdonc

abundan

ssues

componens

known.

 Cy toknes

k nes,

we

damage

prostagandns

nlammaon,

2

may

nlammaor y

membrane

spasm,

agens

are

and

cycooxygenase

LTC

s

n

aer

compemen

ncudng

rom

(PGD

2

he

ceave

cemoacc

acons

dn

and

medators,

syneszed

pe

reeased.

knns

addona

 Lpd

ure

ype

pro-

mucous

mos

o

and

and

eosnop-rc

 •

appearance

C ongeson

Hsamne

In causes

unmpressve.

gran-

mucus

 •

soogc

reacons:

a c   ng

are

 e

or

 es e

a c   ons

an    s  am  n e s ,

n e p r  n e

( o

o

c on d   ons

v ar  ou s

c or   c o s e ro d s

c or re c 

 e

re   e s

m e d  a or s .

( o

pre c pou s

on

b o c k  ng

C om m on y

 re a

d rop

or

c ou n e r-

us e d

dr ugs

 n   am m a  on ) ,

n

b o o d

e p -

pre s s u re

n

44

CHAPTER

Allergen

Diseases

4

(e.g.,

of

the

Immune

System

pollen)

Table

4.2

Immediate

Clinical

Syndrome

Anaphylaxis

caused

Dendritic

Hypersensitivity

(Allergic)

Disorders

lining

ot

erusopxE

negrella

Mucosal

by

(may

Clinical

be

Fall

drugs,

in

and

blood

vascular

Pathologic

pressure

dilation;

Manifestations

(shock)

airway

caused

by

obstruction

due

cell bee

sting,

Bronchial

food)

to

asthma

laryngeal

Airway

edema

obstruction

caused

by

bronchial

Naive smooth

T

and

phase

Allergic

rhinitis,

sinusitis

cells

class

of

and

T

caused

inflamma-

by

late-

mucus

airways

secretion;

and

inflammation

of

sinuses

2

fever)

T

2

H

B B

upper

injury

reaction

Increased

(hay

tissue

H

IgE

switching

in

hyperactivity;

cell tion

Activation

muscle

Food

allergies

Increased

peristalsis

due

to

contraction

of

cell cell

cells

intestinal

and

muscles,

resulting

in

vomiting

diarrhea

IgE-secreting Production

of

IgE

IgE plasma

cell

Antibody-Mediated

Antibody-mediated

by

antibodies,

(Type

(type

usually

II)

IgG

II)

Hypersensitivity

hypersensitivity

or

IgM

disorders

autoantibodies,

are

directed

caused

against

FcεRI

target Binding

of

IgE

Mast FcεRI

on

mast

antigens

surface

of

cells

or

other

tissue

components.

cells

membranes

exogenous

o

be

he

or

angens

n

e

or

may

(e.g.,

oer

responsbe.

be

exraceuar

angens

mcroba

may

a

moecues

or

drug

angens

he

norma

marx,

ey

meaboe).

a

o

ce

be

Rarey,

cross-reac

mecansms

nrnsc

may

w

njur y

ce

anbodes

os

n

o

adsorbed

s

angens

orm

o

exposure

ypersensvy to

the

cell

Pathogeness.

Repeat

on

to

are

e

oowng:

allergen

 •

 Pagocytoss:

(suc

as

red

Anbodes

ces

or

compemen-medaed

mosy

Activation

cell;

of

mast

release

cnca

emnaed

bene

n

may

paees)

n

coa

and

desrucon.

e

speen,

(opsonze)

arge

em

Opsonzed

expanng

anbody-medaed

ces

pagocyoss

bood

wy

dseases

crcuang

or

eemens

spenecomy

marked

by

ow

or

are

s

o

bood

of

couns. mediators

 •

 Inlammaton: Anbodes a are deposed n exraceuar ssues

bnd

eukocye

Fc

recepors

or

acvae

compemen

(descrbed

Mediators

aer), bo resung n e recrumen and acvaon o eukocyes

(neurops

Vasoactive

 •

amines,

and

macropages)

and

acue

nlammaon.

 Ceuar dysfuncton: Anbodes can aso cause ceuar dysuncon

Cytokines lipid

mediators

wen

o

ey

ces,

ona Immediate

hypersensitivity

Late

phase

or

repeat

(minutes

exposure

to

after

(2–24

allergen)

hours

exposure

4.2

diate

The

sequence

hypersensitivity

allergen,

which

of

events

reactions

stimulates

in

are

Th2

immediate

initiated

cells

and

to

the

III

orms

IgE

binds

to

Fc

receptors

introduction

immunoglobulin

(Fc εRI)

on

mast

E

cells,

of

(IgE)

and

and

exposure

to

the

allergen

activates

the

mast

an

cells

that

are

responsible

for

the

pathologic

an  - Ig E

 er

 e

o

A n  b o d  e s

 n   b

  a

are

c   d  o o d

 e

re   e ve

o

re c e pors

E ar y

re du c e s

an d

an  b o dy

re a c   on .

 s.

or

recepors

moecues,

ssue

on

e

surace

producng

unc-

njur y.

to

pay

of

bre

an

essena

dscusson

o

roe

n

ype

compemen

II

and

acva-

oows.

and

Functions

complement

system

of

Complement

consists

of

several

circulating

and

mem-

subse-

secrete

reactions

a

proteins

that

play

important

roles

in

host

defense,

as

well

as

one

o

the

inammation

and

tissue

injury

in

immunologic

diseases.

immedi-

are

ree

paways

o

compemen

acvaon,

ony

hypersensitivity.

an apy  a x  s ,

or

ce

proens

ypersensvy,

uncon

here ate

compemen

o

Activation

in mediators

nb

pro-

brane quent

wou

or

essena

Imme-

The

duction.

acvae

depee

repeat

allergen)

hypersensitivity.

by

and

and

reaction

after

on

Fig.

o

o

decences

Because reaction

bnd

bnd

s

 e

b o ck

us e d

o

e x p o s u re

ncdence

m e c an  s m

bron c o s p a s m ) ,

n o

o

 e

an

o

u n d e rs o o d .

as ma

a   e rge n

  a

an d ,

m ore

 n   a or

c y ok  n e s

 re a

o

a   e rg y

pr  m ar y

a ge n

I L- 4 ,

an d

( e. g . ,

 a e r

o

re c e n y,

 e

I L- 5 ,

an d

aop c

  e,

I L- 1 3

d e r m a  -

p e anu

n

a   e rg  c

exrac)

a   ou g 

wc

nvoves

natve

patway

anbodes

s

acvaed

compemen

proens.

compemen

proens

orm

compexes

(Fg.

w

he

o

by

4.4).

pyogenecay

mcroba

cassca

anbodes

angens.

he

hs

moecues

patway

a

s

are

s

a

acvaed

deposed

mporan

n

oder

saby

by

on

ater-

bnd

bndng

suraces

adapve

o

and

mmuny

and s e ony paway a parcpaes n e anbody-medaed (ype

II)

and

mmune

compex–medaed

(ype

III)

orms

o

ypersensvy.

he ectn patway s acvaed by a pasma ecn a bnds o mcroba

CHAPTER

A

Opsonization

and

Diseases

4

of

the

Immune

System

45

phagocytosis

Phagocytosed

Opsonized cell

cell

C3b

C3b

Phagocyte

receptor Phagocytosis

Complement

B

Complement-

and

activation

Fc

receptor–mediated

inflammation

Fc

receptor

Neutrophil

Complement enzymes,

by

products reactive

(C5a,

oxygen

C3a) intermediates

Tissue

C

antigen

Antibody-mediated

Complement

cellular

Inflammation

activation

and

tissue

injury

dysfunction

Acetylcholine Nerve

Antibody

ending (ACh)

against

TSH

TSH

receptor

receptor

Antibody

Thyroid

to ACh

ACh

epithelial

receptor receptor

cell

Muscle

Thyroid Antibody

inhibits

neurotransmitter

Fig.

4.3

Mechanisms

plement

components

receptors

normal

of

function

carboydraes.

proeoyc

o

e

C3b,

mos

a

uncons

ceavage

o

producs.

abundan

ree

compemen

proen,

C3,

o

examples,

ead

o

a

to

the

antibodies

the

varous

ragmen,

a

proeoyc

samne

he

a

producs

rom

ermna

arge

oes

ceaves

n

pd

aby,

C5a

n

e

acvaon

a

o

and

we

C3a,

as

eads

s

wc

oer

o

osmoc

acvaon

by

ead

o

e

e

compex,

yss

severa

damage

durng

compemen

Among

smuae

aack

coaera

componen

pronlammaor y

acvaon

conroed

preven

ese

componens.

membrane

and

compemen

decences

as

compemen

membranes

proens

unresraned

compemen

ces,

canne,

Compemen

secreed

are

mas

seps

proen

aer

a

o

e

ead

o

a

oer

reease

o

acves.

ormaon

wc

o

creaes

ces.

norma

ces

deense.

o

ce

caed

Paroxysma

nocturna

emogobnura

o

ere

excessve

s

e

red

ces

bood

o

an

acqured

decency

o

an

enzyme

nvoved

C3

C1

ces

o

Fc

the

impair

hormone

are

er

factor,

ceaves

durng

seep,

acvy

a

o

C3.

and

ce

rom

yss

e

eary

serne

o

e

o

ces.

ncreases

nocurna

resus

rom

ms

s

e

or-

reguaor,

membrane

or

he

aack

urnar y

e

naure

o

a

pH

e

nered

many

excre-

suscepby

wen

nbor

proens,

o

compemen-med-

accounng

red

proease

compemen

normay

absence

sensve

was,

ence

e

ormaon

ysed

angoedema

pasma

wc

In

especay

n

reeased

Heredtary

nbor,

eoyc

a

breakdown

bood

decreases

and

ens,

and

accumuaon

Predc-

njur y

(PNH)

n

receptor

compemen-medaed

breakdown.

o

acceeratng

enzyme

emogobn

wc

e

red

ce

decency

ms

C1.

o

o

e

pro-

Decency

o

serous

s

ncrease

n

eaure

e

vascuar

skn,

because



permeaby

gasronesna

coud

ead

o

and

cause

rac,

ar way

and

epsodes

ar ynx

o

(e

lud

mos

obsrucon).

and Features.

In

many

auommune

dseases,

e

cnca

caused probems

by

to

disturb

thyroid-stimulating

decay

maon

Clncal

nlammaon.

com-

binding

antibodies

(ACh)

and

hormone

s nbor eads o excessve producon o numerous vasoacve pro-

ce-assocaed

o

norma

reguaors

anbody

reguaor

because

s

without

antibodies

antibody

acetylcholine

against

yss

aso

by

by

Antireceptor

o

C3b

cells

receptor

disease.

ceavage

o

antibodies

and

(C)

on

pagocyes.

ses

products.

of

induced

aed

on

or

by

e

generae

(mcrobes

gravis,

Graves

medaed

paways

suraces

in

breakdown

Opsonization

Inflammation

ors

expressed

nearby

cells

(A)

(B)

bndng). C3b opsonzes ces or pagocyoss by bndng o C3b recep-

are

on

are

these

myasthenia

thyroid

diseases.

phagocytes.

complement

In

in

by

stimulates

Red

proease

deposed

receptors.

compemen

A

by

transmission

activate

Antibody

compex.

a

s

he

receptor

of

ingestion

and

hormones

of

receptor

antibody-mediated

and

leukocytes

neuromuscular

(TSH)

of

binding

to

syness

o

are

caused

by

auoanbodes

by

nlammaon

(Tabe

4.3).

he

paoog y

a may

be

domnaed

(as

n

anbody-medaed

46

CHAPTER

Diseases

4

of

the

Immune

System

EFFECTOR

C5a,

C3a:

FUNCTIONS

Inflammation

Alternative Microbe pathway

Recruitment

activation

of

and

Destruction

leukocytes

by

C3b:

of

microbes

leukocytes

Phagocytosis

C3a

C3b

Classical

C3b pathway

C3b

is

deposited Recognition

Antibody on

of

bound

C3b

Phagocytosis

microbe by

phagocyte

C3b

receptor

of

MAC:

Lysis

microbe

of

Lectin microbe

pathway

For mation

Mannose

binding

membrane

lectin

complex

Fig.

4.4

ment

of

C3b.

tein

of

Pathways

system

C3b

4.3

called

polymerized

duced

at

of

complement

early

initiates

complex

complement

Table

(the

C9

the

the

late

are

steps

Antibody-Mediated

may

activation

be

steps

membrane

molecules

activation

different

steps)

that

the

are

and

initiated

of

by

functions

three

complement

attack

causes

complex

lysis

of

(MAC)

of

distinct

complement.

pathways,

activation,

(MAC),

thin-walled

inflammation-inducing

C3a

of

attack

culminating

which

is

a

microbes.

and

all

C5a.

The

activation

of

which

in

the

lead

formation

transmembrane

Peptide

The

of

to

of

functions

comple-

production

a

channel

by-products

principal

the

the

multipro-

composed

released

of

during

proteins

pro-

shown.

Diseases

Clinicopathologic

Disease

Target

Autoimmune

hemolytic

anemia

Red

Antigen

cell

Mechanisms

membrane

proteins

Opsonization

of

Disease

Manifestations

and

phagocytosis

of

red

blood

and

phagocytosis

of

platelets

Hemolysis,

anemia

cells

Autoimmune

thrombocytopenic

purpura

Platelet

Illa

Pemphigus

vulgaris

membrane

Proteins

in

intercellular

epidermal

Vasculitis

caused

by

ANCA

proteins

(Gpllb:

Opsonization

Bleeding

integrin)

Neutrophil

sumably

cells

junctions

of

(desmogleins)

granule

proteins,

released

from

Antibody-mediated

disruption

pre-

Neutrophil

of

activation

intercellular

degranulation

of

proteases,

Skin

vesicles

(bullae)

adhesions

and

inflammation

Vasculitis

activated

neutrophils

Goodpasture

syndrome

Protein

in

kidney

Acute

rheumatic

fever

basement

glomeruli

Streptococcal

body

cell

membranes

and

wall

cross-reacts

lung

antigen;

with

of

alveoli

anti-

Complement-

and

Fc

receptor–mediated

inflammation

Inflammation,

Nephritis,

lung

hemor-

rhage

macrophage

activation

Myocarditis,

arthritis

myocardial

antigen

Myasthenia

gravis

Acetylcholine

receptor

Antibody

inhibits

acetylcholine

down-modulates

Graves

disease

(hyperthyroid-

TSH

receptor

Antibody-mediated

ism)

Pernicious

stimulation

Muscle

weakness,

paralysis

of

TSH

Hyperthyroidism

receptors

anemia

Intrinsic

factor

of

gastric

parietal

cells

ANCA,

binding,

receptors

Antineutrophil

cytoplasmic

antibodies;

TSH,

Neutralization

absorption

thyroid-stimulating

hormone.

of

of

intrinsic

vitamin

factor,

B

12

decreased

Abnormal

anemia

erythropoiesis,

CHAPTER

Antigen

Immune

in

Complex

Diseases

4

Table

Formation

4.4

of

the

Immune

Immune

Complex

System

47

Diseases

circulation

Clinicopathologic

Disease

B

Antigen

Involved

Manifestations

cell

Systemic

lupus

Nuclear

erythematosus

antigens

lating

or

(circu-

“planted”

Nephritis,

in

kidney)

Poststreptococcal

skin

lesions,

arthritis,

others

Streptococcal

cell

wall

Nephritis

Plasma

Free

glomerulone-

antigen(s);

phritis

“planted”

may

be

cell

antibody

in

basement

Polyarteritis

Hepatitis

nodosa

in

B

some

glomerular

membrane

virus

antigens

Systemic

vasculitis

cases

AntigenReactive

arthritis

Bacterial

antigens

(e.g.,

Acute

arthritis

Endothelium

antibody

Yersinia) complex

Serum

Immune

sickness

Various

Complex

proteins

foreign

Deposition

such

(e.g.,

serum

as

mocyte

Arthritis,

protein,

horse

vasculitis,

nephritis

antithy-

globulin)

Neutrophil

Arthus

reaction

Various

foreign

proteins

Cutaneous

(experimental)

Pathogeness.

n

anbody

Typcay,

excess

pagocyes

bu

vascu-

litis

and

are

paogenc

are

o

capabe

a

o

sze

mmune

suc

a

deposng

compexes

ey

n

avod

vesses.

are

produced

emnaon

Tssue

by

deposon

Complement

eads

o

compemen

acvaon

and

acue

nlammaon

(Fg.

4.5).

Antigen-

Consumpon

o

compemen

durng

e

acve

pase

o

e

dsease

antibody

complex

Immune

Complex–Mediated

Inflammation

Tissue

and

eads

o

o

decreased

dsease

serum

acvy.

eves

Serum

o

C3,

sckness

wc

s

a

can

be

sysemc

used

as

mmune

a

marker

compex

Injury

dsease

n

wc

a

snge

anbody

produced

Immune

compexes

acvae

n

arge

oer

orm

compemen,

n

and

dose

o

speces,

e

nduce

a

s

bood,

oregn

njeced

become

nlammaon.

angen,

no

an

suc

deposed

he

as

an

ndvdua.

Artus

n

ssues,

reacton

s

Platelet

an

aggregation

expermena

vascudes

(Caper

Morphology.

compex

he

njury

brnod

Wen

mode

o

cuaneous

acue

necross

o

deposed

a

resembes

uman

7).

prncpa

s

vascus

e

n

morpoogc

vascus,

vesse

e

manesaon

wc

wa

kdney,

may

and

e

be

o

mmune

assocaed

neuropc

compexes

w

nraon.

can

be

seen

Vasculitis

on

Neutrophil

lysosomal

mmunoluorescence

4.5

Immune

complex

disease.

The

sequential

phases

in

the

of

systemic

immune

granuar

deposs

complex–mediated

diseases

(type

III

and

compemen

and

on

eecron

o

mcroscopy

as

induc-

eecron-dense

tion

as

enzymes

mmunogobun

Fig.

mcroscopy

deposs

aong

e

gomeruar

basemen

membrane.

hyper-

sensitivity).

Clncal

gomeruoneprs),

(auommune

uncona

e

gravs,

moor

ransmsson,

smuae

agans

yrod

end

anema

paes

w

o

ceuar

ces

o

In

depeon

Graves

(TSH)

yrod

dsease).

(AC)

dsease,

c omp e xe s

 n   am m a  on

aso

anbodes

recepor

ormones,

smuae

resung

c ap   ar  e s

o

j o n s

T e

T

(Type

III)

circulation

may

inammation.

(immune)

become

complexes

deposited

in

 e

( ar   r   s ) ,

proo y p c

s e s

k dne ys

an d

u m an

( SL E ) ,

Cell-Mediated

T e

o

 m mu n o o g  c

  ssu e

p a o o g  c

d e p o s   on

( c au s  ng

b o o d

 m mu n e

a ss o c  ae d

o

ds e as es

d e p o s   on

p c u re

o

s

c omp e xe s ,

ve ss e s

n

w  

any

  ssu e

ds e as e

p e rs  se n

s

o

a c ue

 y p c a  y

g  om e r u  on e p r   s ) ,

c omp e x

are

 m mu n e

 e

s y n ov u m

( v a s c u    s ) .

s y se m  c

an b o dy

upu s

re sp ons e s

types

of

(Type

T-cell

IV)

reactions

Hypersensitivity

are

capable

of

causing

tissue

injury

Hypersensitivity and

Antigen–antibody

4.4).

 e

an d

auo an  ge ns .

Two

Complex–Mediated

o

n

s y se m  c

or m a  on

( Tab e

e r y  e m ao su s

o

Many

 e

n

yperyrodsm.

Immune

w  

In

recepors

can

Features.

a ss o c  ae d

or

neuromuscuar

Anbodes

Graves

ormone

secree

ce

nb

weakness.

responses:

yrod-smuang

epea

and

aceycone

musces

musce

o

romboc yopena),

gravs

agans

skeea

resuan

efecs

and

(myasena

anbodes

excessve

e

secondar y

emoyc

derangemens

myasena

n

e

that

blood

are

formed

vessels

and

in

the

induce

disease:

(1)

delayed-type

duced

CD8+

hypersensitivity),

mainly

T

cells

cytokine-mediated

by

CD4+

(Fig.

4.6)

T

cells,

in

inammation

which

and

(2)

the

(also

cytokines

cytotoxicity,

called

are

pro-

mediated

by

48

CHAPTER

Diseases

4

Cytokine-mediated

of

the

Immune

System

inflammation

Inflammation

Cytokines + CD4

T

APC

cell

presenting

tissue

antigen Tissue

injury

Nor mal

tissue

A

T

cell–mediated

cytolysis

+

Cell

CD8

T

APC

killing

tissue

cell

and

injury

presenting

tissue

antigen

B

Fig.

4.6

injury

Mechanisms

and

disease

of

by

T

two

cell–mediated

mechanisms.

tissue

(A)

injury

(type

Inflammation

IV

hypersensitivity).

may

be

triggered

by

T

cells

may

cytokines

cause

tissue

produced

mainly

+

by

CD4

T

cells

in

which

tissue

injury

is

caused

by

activated

macrophages

and

inflammatory

cells.

(B)

Direct

+

killing

of

target

cells

is

mediated

by

CD8

cytotoxic

T

lymphocytes

(CTLs).

Pathogeness.

efecor

cay

ces,

n

APC,

Antigen-presenting

Cyokne-medaed

bu

cases

h17

were

ces

aso

cell.

ypersensvy

may

neurops

conrbue

are

s

o

promnen

a

reacon

e

n

o

reacon,

e

h1

espe-

nlammaor y

nrae. h1 ces secree cyoknes, many nereron-γ (IFN-γ), wc

are

responsbe

sensvy.

subsances

a

T

a

promoe

recru

ces

k

Clncal

A

B

4.7

Delayed-type

hypersensitivity

s

accumulation

(cuffing)

of

reaction

mononuclear

in

the

skin.

inflammatory

(A)

a

and

deposition.

perivascular

bodies.

Health

(B,

macrophages),

(B)

cellular

Courtesy

Sciences

with

associated

Immunoperoxidase

infiltrate

Dr.

Louis

University,

that

staining

marks

Picker,

dermal

reveals

prevousy

positively

Department

Portland.)

a

with

of

some

ypca

deveops

ssues,

ces

ces.

CD8+

nvoved

n

(Fg.

over

4.7).

1

ndvdua

o

I

2

(n

o

T

s

caed

days

medaors

cyooxcy,

ces

especay

s

ater

conras

yper-

produce

cyoknes

aso

nlammaor y

conac-senszng

manesaon

and

secree

ce-medaed

ypersensvy,

o

senszed

are

damage

h17

deayed-ype

macropages

a

CD8+

produce

reacons

oowng

vrus

agens.

orm

o

ypersens-

deayed-ype

an

w

angen

yper-

caenge

and

anti-CD4

hs

me

ag

s

due

o

e

mupe

mmedae

seps

nvoved

yper-

n

e

(lym-

ncudng

e

capure,

processng,

and

presenaon

o

e

fibrin

predominantly

Pathology,



arge

and

nlammaon

because

In

o

acvaed)

and

Acvaed

monocyes.

IFN-γ,

he

manesaons

Perivas-

cells

edema

and

exposure

Features.

reacon, phocytes

e

(casscay

mcrobes

deayed-ype

cronc

sensvy). cular

o

angen-expressng

and

sensvy

n Fig.

desroy

noaby

resembng

necons

many

nlammaon.

neurops

cyoknes,

vy

or

IFN-γ–acvaed

anti-

Oregon

angen,

angen

seen

n

acvaon

caenge,

many

anagonss

prognoss

o

TNF

s

T

and

ces,

erapeuc

paens

gy

mgraon

producon

mmunoogc

as

or

o

efecve

dseases

agens

w

o

ese

n

e

o

cyoknes.

(T abe

as

efecor

4.5).

T

hs

he

revouonzed

dsorders.

reamen

For

o

ces

ype

o

o

adven

e

exampe,

reumaod

e

se

reacon

o

o

s

cyokne

reamen

and

neurazaon

arrs.

CHAPTER

Table

4.5

T

Cell–Mediated

Disease

Specificity

Rheumatoid

Collagen

arthritis

Hypersensitivity

of

Pathogenic

T

self

of

the

Immune

Cells

Principal

Mechanisms

Inflammation

proteins

cytokines;

mediated

role

of

of

Tissue

by

Th17

antibodies

Injury

(and

and

Clinicopathologic

Th1?)

Chronic

immune

sclerosis

Protein

antigens

myelin

basic

in

myelin

(e.g.,

Inflammation

protein)

cytokines,

articular

mediated

myelin

by

Th1

and

destruction

by

Th17

1

diabetes

Antigens

of

pancreatic

islet

β

49

cells

T

cell–mediated

mellitus

islet

cells

by

inflammation,

cytotoxic

destruction

of

with

in

central

with

mation;

paralysis

of

nervous

perivascular

(chronic

islets),

synovial

destruction

system

Insulitis

lymphocytes

Manifestations

cartilage

Demyelination

activated

macrophages

Type

arthritis

inflammation,

complexes

Multiple

System

Diseases

(postulated)

Citrullinated

Diseases

4

inflam-

inflammation

destruction

of

β

in

cells;

diabetes

Inflammatory

bowel

Enteric

disease

bacteria;

self

antigens

Inflammation

(unknown)

Psoriasis

Self

antigen

mediated

by

Th1

and

Th17

Chronic

cytokines

(unknown)

Inflammation

intestinal

inflammation,

obstruction

mediated

mainly

mediated

by

by

Th17

Cutaneous

plaques

cytokines

Contact

sensitivity

Various

environmental

urushiol

from

chemicals

poison

ivy,

(e.g.,

Inflammation

therapeutic

Th1

(and

Th17?)

Epidermal

cytokines

mation,

drugs)

Examples

of

human

T

diseases

are

rash

inflam-

and

listed.

DISEASES

Genetic

Autoimmune

dermal

skin

blisters

cell–mediated

AUTOIMMUNE

necrosis,

causing

diseases

are

caused

by

adaptive

immune

Environmental

triggers

responses susceptibility

against

self

antigens. Infections,

I s es mae d  a  es e d s e as es a e c  1% o 5% o Weser n p opinflammation,

u  a ons,

re as ons.

and

 er

B as e d

auommune

on

 nc d ence

 e

ds e as es

sysemc

d s e as es

 a

c aus e d

s e ems

 nvove d

are

o

be

 ssues

bro ad y

(summar ze d

nc re as  ng ,

and

dv de d

n

Tabe

c n c a 

 no

4.6).

or

un k now n

organ -sp e c  c

In

tissue

injur y

man es a ons ,

sysemc

and

ds e as es Susceptibility

are

by

 mmune

compexes

and

auo an b o d es,

 e genes

esons

pr ncp a  y

o

nvove d

as

co  agen

a e c 

organs.

 e

conne c  ve

T ereore,

vas c u  ar

d s e as es

 es e

or

 ssues

d s e as es

and

are

conne c  ve

b o o d

o en

 ssue

Tissue

vess es

reer re d

d s e as es,

o

Failure

e ven

of Activation

self-tolerance

 oug 

 e

agans

mmunoog c

cons uens

Mechanisms

of

o

re ac  ons

con ne c  ve

are

 ssue

no

or

sp e c   c a  y

b o o d

d re c e d

of

tissue

Autoimmunity Influx

Self-tolerance

against

self

in

T

and

B

lymphocytes

prevents

harmful

reactions

lymphocytes

tissues.

norma

of

self-reactive

into

he

APCs

vess es .

mmune

sysem

can

reac

o

an

enormous

dversy

tissues

o

Self-reactive

oregn angens bu does no recognze or respond o se angens. he lymphocytes

ack

e

o

reacvy

presence

agans

resus

one’s

rom

mecansms

o

s

e

own

a

caed

angen);

ssues

s

breakdown

o

toerance

e

caed

o

(mpyng

absence

o

a

ces

mmune

sef-toerance.

se-oerance,

e

responsveness

Because

we

rs

“oerae”

auommuny

dscuss

e

major

Activation

of

self-reactive

oerance.

lymphocytes

 •

 C entra

toerance.

(deeed)

(or

T

gens

beore

ces)

are

and

presen

S e-reacve

ey

bone

n

compee

marrow

ese

ympoc yes

er

(or

organs,

B

and

are

mauraon

ces).

wen

n

emnaed

e

Numerous

mmaure

ymus

se

an-

ympoc yes

w g-ainy recepors or ese angens encouner em, e

ces

de.

C enra

oerance

emnaes

many

poenay

Tissue

dangerous

injury:

autoimmune

se-reacve

maure

 •

and

 Reguatory

escape

ympoc yes

ener

T

perpera

ces.

deeon

bu

s

he

s

mperec,

and

some

o

ese

ssues.

response

prevened

by

o

Fig.

se-reacve

e

acons

o

ympocyes

reguaor y

T

a

ces

4.8

model

Postulated

of

genetic

n

perpera

ssues.

he

bes-dened

Tregs

are

CD4+

loci

express

e

ranscrpon

acor

Foxp3.

A

severe

afecng

many

organs

occurs

n

boys

wo

such

ner

of

muaons

n

e

X-nked

FOXP3

cell–mediated

susceptibility

maintenance

of

to

In

this

proposed

autoimmunity,

autoimmunity,

self-tolerance.

various

probably

Environmental

by

trig-

as

infections

lymphocytes

and

into

other

tissues

inflammatory

and

the

stimuli,

activation

of

promote

the

antigen-pre-

deeersenting

ous

the

confer

autoimmunity.

auommune influx

dsease

may

T

of

ces

gers,

a

mechanisms

organ-specific

influencing

(Tregs)

disease

ces

cells

(APCs)

gene. ing

in

tissue

injury.

and

subsequently

of

self-reactive

T

cells,

result-

50

CHAPTER

Table

4.6

Diseases

4

Organ-Specific

and

of

the

Systemic

Immune

System

common y

Autoimmune

Diseases

Organ-Specific

Diseases

Systemic

“o dds

p are d

ndv du a s

Mediated

by

hemolytic

anemia

Autoimmune

thrombocytopenia

Systemic

lupus

pernicious

atrophic

gastritis

a

 an

ng

a

bu

 e

HL A

do

o c us,

r sk

no

o

w  

sp e c c

de veopng

n e r 

 a

a

HL A

a  ees

ds e as e

a  ee)

o

ess

com -

 an

n

d   eren

HL A

a

moe c u es

g ven

ds e as e

ds e as es.

HL A

Environmental

Factors

Environmental

factors

s

a e c  s

a  ee

rema ns

I

re as onab e

 e

o

2

p osu  ae

pres en a on

n uences

 e

r sk

o

o

s e

d e veop -

un k now n .

of

participate

in

causing

autoimmunity

in

a

anemia

susceptible

host.

gravis

A Graves

s

( re a ve

w o

or

ow

p ar  c u  ar

genetically Myasthenia

100

var  a on

an gens,

erythema-

tosus

Autoimmune

more

 a

Antibodies

Autoimmune

o

ra  os”

Diseases

o

Diseases

ncr mnae d

sow ng

nk

beween

necons

and

auommuny

as

been

posuaed

disease

based

Goodpasture

on

resus

rom

expermena

modes

and

because

o

e

ac

syndrome

a

necous

prodromes

somemes

precede

auommune

dseases

a

Diseases

Type

1

Mediated

by

T

Cells

n

diabetes

Multiple

Rheumatoid

sclerosis

Systemic

arthritis

sclerosis

paens.

and

In

(sclero-

I

may

overcome

e

addon

o

be

a

mcroba

norma

paogens

mecansms

necons,

e

o

dspay

acvae

mmune

ces

se-oerance.

o

ssue

angens

aso

may

be

b

aered

derma)

b

Sjögren

by

radaon

syndrome

angens Diseases

Postulated

Inflammatory

bowel

to

Be

diseases

a

varey

causes

a

o

ce

ec

envronmena

dea

and

paoogc

nsus.

may

ead

mmune

o

For

e

nsance,

uravoe

exposure

responses

(e.g.,

o

n

nucear

SLE;

see

Autoimmune aer).

Smokng

due

o

cemca

any

reason

s

a

rsk

acor

or

reumaod

arrs,

peraps

(Crohn

modcaon

o

se

angens.

Loca

ssue

njur y

or

c

disease,

ulcerative

colitis)

b

Primary

biliary

may

ead

o

e

reease

o

se

angens,

w

subsequen

b

cholangitis

Polyarteritis

nodosa

auommune

responses.

Many

auommune

dseases

are

more

com-

b

Autoimmune

(chronic

active)

hepatitis

Inflammatory

myopathies

mon

a

A

role

also

be

for

T

cells

involved

has

in

been

tissue

demonstrated

in

these

disorders,

but

antibodies

may

n

women

deveopmen

an

o

n

men,

suggesng

auommuny,

bu

a

e

ormones

underyng

nluence

mecansms

e

are

injury.

obscure. b

An

autoimmune

basis

of

these

disorders

is

suspected

but

not

established.

In

c

These

enteric

The

disorders

may

microbes,

features

of

result

from

autoimmunity,

many

of

excessive

or

these

a

immune

combination

diseases

have

of

responses

the

been

to

eases

summarized

in

Tables

and

oowng

a

afec

dscuss

and

seeced

usrae

auommune

mporan

ds-

aspecs

paogeness

and

manesaons

o

s

group

o

dsorders.

o

Oer

dseases

are

dscussed

n

reevan

capers.

 Inbtor y receptors. S e-re ac  ve y mpo c y es  a ave maure d Systemic c an

a s o

be

p er pera 

 a

T

or y

 us

w

nac  vae d

 ssues.

re cepors

and

ds c uss

 es e

(a s o

n

re cog n  on

 e

c a  e d

o 

“ce ckp ons”

and

5,

o

s e

 ur  er

n

umors

bo ck ng

s

express

no aby

 wo

 e

s raeg y

name d

we

express on

or

s

n  b-

As

Lupus

SLE

o

is

characterized

immune

cells

I

complexes,

and

s

resp ons es

aga ns

c ancer

ce s.

w  

de veop

ce ckp o n

bo ckad e

or

Pre d c  aby,

c anc er

s

bes

and

the

genes

he

factors

contribute

of

environmental

suscepby

envronmena

dspay

o

to

the

breakdown

autoimmunity,

insults

genes

acors,

and

ese

dseases

may

suc

responses

dverse

are

as

o

(Fig.

self-tolerance

including

susceptibility

4.8).

nluence

necons

se

of

n

women

erms

o

an

e

hallmark

antigens,

50%

of

cases),

ympocye

or

angens.

ssue

he

oerance,

njur y,

compex

may

and

aer

anbodes

compexes

svy).

er

genec

and

envronmena

and

damage

and

many

n

men

(∼10:1

rao)

and

ends

anbodes

a

are

produced.

of

SLE

including

is

autoantibodies

double-stranded

produced

DNA (present

nucleoproteins,

no

compeey

diseases

are

n

Anbodes

desrucon

bodes

em,

depos

orm

and

by

mmune

wc

may

ead

compexes

and

e

others.

reeased

kdneys

and

oer

bnd

and

opsonze

aso

o

pagocyes

compexes

o

w

a

a

n

(ype

II

usuay

serum

organs

angens,

(ype

bood

III

ces,

ypersensvy).

acvae

e

compemen

and

e

ypersen-

eadng

hese

o

an-

compemen

sys-

eves.

neracons

acors

n

e

eoog y

and

mecansms

o

SLE

are

no

esabsed,

auom-

pausbe

ypoess

s

e

oowng:

Exposure

o

uravoe

g

(a

undersood.

Susceptibility

Autoimmune

n

The

nuclear

about

known

Genetic

autoantibodies

m muno er apy

a mune

of

inammation

p a en s

Aoug beween

elicit

auom mun  y.

development

and

which

common

undersood

he

Numerous

(SLE)

production

s mu  a ng

in a s o

the

o occur n women o reproducve age. he paogeness o e dsease

against  re ae d

by

tissues.

more

Pathogeness. mmune

Erythematosus

n

ac  va on ,

resp ons es .

nduce

a

an gens

nac  va  on

y mpo c ye

mmu ne

a s o

 em

s e

o

an gens

conbtors),

su

o

me can s ms

resp ond

 a

C aper

re cepors,

o

 a

PD-1,

es absng

up on

O ne

y mpo c yes

CTL A-4

e

we

organs

4.5 .

organ-specc

 •

secons,

mupe

4.3,

e 4.4,

e

commensal

two.

multigenic,

meaning

that

rsk

ance

o

ance

causes

acor)

nucear

eads

o

ragmens

acvaon

o

apoposs

combned

o

varous

w

ympocyes

ces;

aure

specc

or

o

B

se

mproper

and

T

ce

nucear

cear-

oer-

angens.

polymor-

Hg-ainy anbodes produced agans ese angens orm mmune phisms

in

many

different

genes

are

associated

with

an

increased

or

compexes, decreased

risk

of

the

cyes. E xcep

or

s ome

rare

mend e an

c aus es

o

auommune

he

auommune

ds e as e

c an

be

a r bue d

o

a

s ng  e

gene.

wc

p oy mor pc

are

endocyosed

genes

n ke d

o

auo mmun  y,

by

ar

DNA

and

RNA

by

dendrc

smuae

acvae

ympocyes

Among

perssen  e

nucear

ces

and

producon

o

B

ympo-

ype

I

ner-

ds e as e,

erons, no

wc

disease.

 e

mos

auoanbody

producon.

and

APCs,

seng

up

a

cyce

o

CHAPTER

Diseases

4

anbodes

Morphology.

SLE

can

afec

vruay

any

organ.

he

esons

resu

rom

mmune

compex

deposon

cong,

vesses,

kdneys,

and

a

 Bood

es,

vesses.

sma

he

An

areres,

arers

cronc

acue

sages,

o

areroes

brnod

vesses

System

pospopd–proen

51

o

e

anpospopd

compexes

anbody

nvoved

syndrome

Neuropsycarc

manesaons

(ncudng

(see

sezures,

skn:

necrozng

and

eads

orm

3).

psycoss,

 •

o

Immune

n Caper

bood

bnd

the

mos n

caracersc

a

of

vascus

may

be

necross

undergo

brous

nvovng

presen

o

e

n

any

vesse

ckenng

capar-

ssue.

was.

w

ever

are

and

neuropay)

common.

compex

Md

and

sysemc

arrs

may

manesaons

occur

secondar y

suc

o

as

mmune

deposon.

In

umna

Systemic

Sclerosis

(Scleroderma)

narrowng. Systemic

 •

 Kdney.

Up

o

50%

o

SLE

paens

ave

cncay

of

rena

nvovemen,

dence

e



kdney

examned

vruay

by

(Suppemena

men

o

akes

a

number

deposon

o

orms,

mmune

a

eFg.

sows

ev-

mcroscopy

and

4.1).

Rena

nvove-

Pathogenes s.

poory

are

assocaed

w

and

e

gomeru.

Pro-

annucear

o

e

paoog y

(see

Caper

11).

reason

nraes

produce

and

seen

or

on

e

50%

e

vacuoar

ss

may

be

paens,

4.2).

In

or

a

maar

smar

Exposure

o

e

e

basa

derms,

ayer

juncon

eFg.

aso

may

e

n

be

nces

areas

epderms

paee

even,

n

brnod

necro-

n

aong

sows

e

deveopmen

e

o

e

e

presence

and

eoog y,

oten

and

by

brosis

o

o

conan

probroc

of

the

skin

and

walls

dsease

a

puzzng

sysem,

crcuang

e

h2

suc

o

nvoves

bood

afeced

reevan

s

known.

and

especay

sugges

angen

he

bu

s

nor

mmune

macropages

grow

endoea

eaure,

a

acor-β.

acvaon

bass

a

vesses,

skn

se

ransormng

evdence

conssen

n

ces

as

dsease

sma

auoanbodes,

nraes

neer

CD4+

w

s

s

abnormalities.

se-oerance

c yoknes

aggregaon

o

mmune

T-ce

bu

aure

vascular

s

and

aso

no

known. One ypoess saes a e vascuar dsease s e nang

edema

mcroscopy

or

Mcrovascuar

varabe

compemen

(Suppemena

seen

nvoved

o

s

w

s

sung

e

Immunoluorescence

and

ras

ere

Vascus

ras)

o

Hsoogcay,

mmunogobun

moepderma

bu

runk.

nlammaon.

promnen.

o

and

er yema.

eFg.

pervascuar

deposs

buerly

degeneraon

(Suppemena

and

o

(e

exremes

accenuaes

sow

ceeks

tract

anbodes,

auommune

o

nose

characterized

nerpay

brobass.

 Skn. Caracersc er yema afecng e ace aong e brdge

e

e

dened

wc

an

rena

is

gastrointestinal

wn

o

compexes

aways

eecron

the

erave gomeruoneprs s e mos common manesaon

approxmaey

 •

and

abnormay

mmunoluorescence

e

 •

o

sclerosis

sgncan

and

ssue

a

njur y

brobass



causes

and

a

e

bross.

are

cronc

scema

Aernavey,

sponaneousy

e

a

umaey

prmar y

acvaed

o

deec

produce

resus

may

e

excessve

coagen.

der-

4.3).

 Cardovascuar system. here may be damage o any ayer o e Mor pholog y.

ear.

Sympomac

or

asympomac

percarda

nvovemen

mos

presen

n

up

o

50%

o

paens

and

may

be

acue,

subacue,

Sysemc

sceross

s

a

mu-sysem

dsease.

he

s promnen

canges

occur

n

e

skn,

amenar y

rac,

mus-

or cuoskeea

sysem,

and

kdney,

bu

esons

aso

are

oten

pres-

cronc. Durng e acue pase, brnous exudae s seen on e en

percarda

surace

and

an

efuson

may

be

presen.

W

n

e

o

e

exudae

may

ead

o

bross

and

a

Myocards

s

ess

common

and

may

cause

and

eecrocardograpc

Lbman-Sacks)

abnormaes.

endocards

ave

4.9),

(Suppemena

more

common

pror

endocards

o

akes

e

e

wdespread

orm

o

use

snge

o

or

any

 •

verrucous

ear

 Oter

seen

serosa

n

e

brnous

 •

 Oter

vs.

vave,

s

I

may

vague

exudaes,

a

bu

be

may

rees

acue

and

on

or

no

s

a

n

serods.

mupe,

generc

specc,

wereas

o

surace

smar

peura,

a

o

o

souders,

o

e

a

musysem

by

syno-

nma

requre

paens

an

asue

anbodes

ound

n

anbodes

and

ndngs.

presen

w

pyscan

(ANAs)

vr uay

o

dsease,

morpoogc

Many

100%

a

o

o

bnd

paens

doube-sranded

DNA,

deeced n 40% o 60% o cases, are gy specc or SLE, and ence

a

useu

o

dagnosc

ndngs,

neproc

s

a

ncudng

syndrome

presenng

cnca

es.

Rena

emaura,

(see

Caper

manesaon

probem.

nvovemen

n

red

11).

some

romboemboc

ce

may

paens

produce

cass,

Anema

or

and

penomena

a

proenura,

are

skn

e

and

ngers

assocaed

and

dsa

aropy

regons

exends

proxmay

o

nvove

e

o

upper

neck,

and

ace.

oss

Fbross

o

ree

oten

pegs,

s

accompaned

aropy

o

e

by

derma

and

and

yane

ckenng

o

e

was

o

derma

ar er-

capares.

  nge rs

be

a

and

s   

dy spag  a

or

s ce m  a

R ay nau d

D    us e

aca

and

o

 nvove me n .

pro g re ss ve

c ou rs e,

and

Two

and

are

s

  m e d

bu

are

d e ve opme n

DNA

w  

a

n

s

o

 e

o e n

T e

C R E ST

c on   ne d

and

s

 re qu e n ,

o

s

an

no

s ow y

om  nous

s c e ro s s .

sp e c    c

pu  mon ar y

 bro s s

an  c e n rome re

  nge rs ,

or

d e ve op

a

  g  y

s y nd rome,

 ae

an

s y se m  c

o e r,

o

ave

s

caed

 nd  c a  ng

s ome   me s

I,

 e

e ads

re sp ons b e

we a e r,

p a  e n s

  ke  o o d

c a  c    c a  ons ;

c o d

w  

o

e s op ag us

y p e r e ns  on

ass o c  ae d

d s e as e.

 e

p a  e n s

Mo s

op o s ome r as e

g re ae r

w  

d s e as e,

sub c u ane ous

re as ons ,

 m mob   z a  on

o

n ar row  ng

e sp e c  a  y

proe  nu r  a

s rong y

ass o c  ae d

Vas c u  ar

y p e r e ns  on .

v as c u  ar

sk  n

pu  monar y

M  d

c aus e s

Invove me n

o e s ,

u nc e ar

ag a ns

p e r pe r a 

ace;

and

A NAs

ass o c  ae d

an b o dy,

For

s y se m  c

d  re c e d

s

and

pe nome non .

or

O ne,

 bro s  s

ob s r u c   on .

  nge rs

pu  monar y

sgn.

sk  n

e au re s .

n

w   c

 e re

ore ar ms ,

e s op age a 

and

 e s  ons

y p e r e ns  on .

varey

and

romboc yopena

may

and

epderms,

Clncal Features.

re na 

and

e

n

o

a

eadng

nonerosve

vesses

o

begns

eales.

o

by

sma

varabe

onse.

are

e

Mos

o

CNS.

annucear

angens

eer

o

ner ves.

hs

1-

bross.

seroogc,

n

e

nvoved

e

gy

cnca,

sympoms

nucear

be

on

Inlammaon

occuson

seen

orm

surace

nvove

and

may

nsdous

puzzng

o

be

may

eer

may

efusons,

jons

SLE

S o-caed

varey

are

he

on

nvovement.

Nonnlammaor y

Features.

dagnose.

o

cavty

organs.

dagnoss

wc

percardum

proeraon

Clncal

deposs,

dsncvey

perpera

4.4)

oes

3-mm

bross

usuay

exremes

appendages,

sere

and

Vavuar

eFg.

nnng

was

dfuse

wc

upper

arms,

(so-caed

ungs,

resng e

acycarda

ear,

resrcve (Fg.

percards.

vesses,

me, paens

organzaon

bood

domnan

secondar y

o

Sjögren

In

this

and

Syndrome

disease,

salivary

chronic

glands

inammation

lead

to

reduced

and

destruction

production

of

tears

of

lacrimal

and

saliva.

CHAPTER

A

B

C

D

Diseases

4

of

the

Immune

51.e1

System

E

Supplemental

2

o’clock

increase

ing

by

in

a

light

San

with

microscopy.

University

of

of

Lupus

stain).

(E)

the

Deposition

Brigham

Southwestern

California.)

(A)

Focal

of

(H&E

immune

IgG

and

Medical

not

stain).

dense

antibody

Women’s

is

complexes

Subendothelial

of

proliferative

proliferation

glomerulus

deposits

nephritis.

Pathology,

Texas,

Francisco,

SLE

nephritis.

Extracapillary

throughout

subendothelial

patient

Department

4.1

(H&E

cellularity

extensive

from

eFig.

positions

in

a

School,

(C)

Lupus

(periodic

deposits

granular

Hospital,

Dallas,

glomerulonephritis,

prominent

this

nephritis

case.

pattern,

stain).

on

detected

Courtesy

of

two

a

(D)

necrotizing

proliferative

glomerulus

Electron

with

membrane

Courtesy

Jean

of

Olson,

Dr.

several

of

(arrow)

(A

Edwin

lesions

to

a

the

“wire-loop”

renal

C,

of

11

Courtesy

to

of

the

lesions

Dr.

represent-

loops”

Helmut

University

of

of

and

marked

capillary

“wire

Department

Pathology,

o’clock

Note

glomerular

correspond

Eigenbrodt,

Department

at

glomerulonephritis.

micrograph

immunofluorescence.

D,

Dr.

focal

Diffuse

basement

by

Massachusetts.

E,

with

(B)

showing

acid-Schiff

(arrowheads)

Boston,

Texas.

in

loop

seen

Rennke,

Pathology,

California,

51.e2

CHAPTER

Diseases

4

of

the

Immune

System

Supplemental

the Supplemental

eFig.

4.2

Systemic

lupus

erythematosus

involving

skin.

An

H&E

stained

section

shows

liquefactive

degeneration

of

of

Ig

layer

of

the

epidermis

and

edema

at

the

dermoepidermal

(Courtesy

Boston,

lupus

Boston,

Bhawan,

eFig.

4.4

erythematosus.

thickened

Schoen,

Jag

Boston

University

School

of

Medicine,

MA.)

Supplemental

in

Dr.

valve

leaflet

Department

Libman-Sacks

The

are

of

Massachusetts.)

endocarditis

vegetations

indicated

Pathology,

by

attached

arrows.

Brigham

to

of

the

the

(Courtesy

and

mitral

margin

of

Women’s

valve

of

Dr.

Systemic

lupus

erythematosus

micrograph

along

the

dermoepidermal

Department

of

stained

junction.

Dermatology,

juncwestern

tion.

4.3

for

involving

IgG

(Courtesy

Dr.

reveals

Richard

the Sontheimer,

basal

eFig.

immunofluorescence

the deposits

skin.

An

the

Fred

Hospital,

Medical

School,

Dallas,

Texas.)

University

of

Texas

South-

52

CHAPTER

Diseases

4

of

the

Immune

System

A

B

C

Fig.

4.9

Systemic

extensive

and

foci

of

creating

Richard

Pathogeness.

dsorders

auommune

owards

s

as

o

e

dsease

eoog y.

even

he

s

O

been

savar y

deveopng

rggers

oten

gands,

o

e

a

w

(C)

w

of

and

oer

dsease

perssen

s

SS-B

are

naed

Skin

dermis

extensive

of

are

by

specc

vra

an

or

and



necon

T-ce

reacon

subsequeny.

from

virtual

has

University

dreced

known,

with

supply

auommune

wo

biopsy

subcutaneous

blood

supporng

no

auommune

(B)

the

Loss

auoanbodes,

ormaon

in

Dermatology,

auoanbodes,

SS-A

skin.

The

deformity.

Department

varous

e

a

Normal

collagen

(arrow).

assocaed

anbody

(A)

dense

flexion

serum

angens

or

suggesed

clawlike

Sontheimer,

presence

of

inflammation

a

rbonuceoproen

dsease.

e

he

and

sclerosis.

deposition

of

patient

fibrosis

led

to

e

n

some

seen

and

e

Te

and

s a var y

g  ands

are

 e

maj or

o

abou

 e

ds e as e,

bu

o er

exo cr ne

g  ands ,

ncud ng

 e

respraor y

and

gas ro nes na 

 rac  s

and

 e

a

may

be

nvove d.

T e

 acr ma 

and

s a var y

g  ands

dens e

n   raes

o

C D 4+

T

o  ces

ce s

w  

(Fg .

4.10);

ger m na 

n

 e

ceners ,

 arger

ce 

re ac  on,

may

a s o

be

s e en .

S a v ar y

g  ands

mos

Lack

dr yness

sepum.

ncude

More

an

e

o

may

o

and

sava

ead

Lesons

synovs,

a

requeny

acrma

gands,

causes

o

paens

reumaod

o

dr yness

uceraon

ousde

perpera

e

ere

uceraon

e

and,

gands,

neuropay,

ave

anoer

arrs.

TRANSPLANTS

o

damaged

organs

rom

or

oer

unconay

ndvduas

mpared

as

organs

become

by

rans-

sandard

Abou

30,000

organ

ranspans

are

perormed

med-

yeary

Uned

Saes,

e

mos

common

beng

e

kdney

(accounng

n

or

s a var y

nd c a ve

may

o

pracce.

o

a ),

be

oowed

by

e

ear,

ver,

ung,

and

pancreas.

Trans-

a panaon

B

OF

e

o

nlammaon

scca).

Nasa

paens,

dsease,

repacemen

amos y mpod

desrucon

Dr.

Dallas.)

c on a n e

g  ands,

o

bross.

School,

secondar y

o

fingers,

vag na, ca

a s o

o

the

Courtesy

 o s e panaon

nng

Medical

the

follicles)

 arhe

ges

and

(C,

Note

hair

immobilized

Because

eyes

(e.g.,

ulcerations.

peroraon

pumonar y

auommune

 acr ma 

virtually

(xerosoma).

cases,

REJECTION

Morphology.

sclerosis.

(keraoconjuncvs

mou

n

systemic

appendages

Southwestern

o

cornea

o

has

Features.

dr yness

e

with

of

cutaneous

Texas

Clncal

s

a

absence

o

emaopoec

sem

ces

s

dsorders

o

wdey

used

o

rea

bo

v s by neopasc

and

nonneopasc

bood

ces.

Excep

n

rare

en  arge d. cases

o

denca

wns,

e

grat

donor

and

recpen

are

genecay

CHAPTER

A

4.10

Sjögren

infiltration

ment

of

Burns,

em

and

Some

are

rejecton.

same

o

ese

Grats

caed

syndrome.

ductal

or

of

are

mmune

beween

(A)

epithelial

Dermatology,

Department

excanged

are

with

dferences

responsbe

speces

Enlargement

hyperplasia

University

Pathology,

recognzed

of

e

o

nondenca

Texas

a

of

Texas

mmune

e

the

salivary

salivary

grat,

sys-

caed

ndvduas

o

e

(A,

Immune

system

and

Responses

principal

are

As

e

as

(so,

ssue)

among

encoded

by

T

School,

Medical

dferen

o

grat

en

up

ces

ces

by

e

or

In

grat

cause

grat

ypes

paoogc

ese

T

grat

e

(drec

s

dspay

rejecon.

immune

both

moecues

and

and

or

e

Recpen

resung

n

s

n

MHC

grat

and

MHC

presened

mgrae

B

ces

e

o

CD4+

aso

may

be

T

ces

no

o

by

may

(ndrec

CD8+

T

e

a

e

n

CD4+

of

T

be

o

ces

o

grat

Rejection

allografts

nlammaon

bnd

of

is

specc

n

e

ssues

crcuang

Solid-Organ

mediated

or

grat;

of

grat

T

angens

CD8+

(noaby

by

CTLs

acvae

grat

because

ces;



compemen,

s

e

and

a

and

e

cause

e

cell

Depart-

Dr.

Dennis

paerns

eaures,

eac

s

s

were

dened

caused

medaed

presen

rapdy

n

anbodes

and

and

bood

e

by

on

e

specc

bnd

o

scemc

group

grat

bass

mmune

necross

o

a

o

e

e

ackng

angen.

grat

a

vas-

lood

acvang

grat

e

or

ranspan-

anbodes

causng

was

specc

o

endoeum,

cascade,

ndvduas

agans

pror

preormed

ncompaby

snce

anbodes

anbodes

connecon

wen

coaguaon

by

recpen

oowng

crcuaon,

rejecon,

Careu

bood

w

donor

rejecon.

CTLs

group

T

and

macng

eads

grat

o

(Fg.

o

argey

rapd

(Fg.

e

rom-

4.11).

greaes

rsk

parcuar

Recpens

recpens

grat

In

aure.

acue

damage

Immunosuppressve

reang

acue

rejecon

an

In

ces

and

In

or

ABO

wo

ave

prospecve

e

any

as

oer

weeks

ceuar

e

A

bnd

e

grat,

vascuar)

o

ater

rejecon,

same

wc

rejecon,

grat

endo-

compemen-dependen

ceuar

erapy

(or

probem.

o

4.12).

n

angens,

by

s

days

acue

(Fg.

umora

donor

many

Oten,

coexs.

deveops

nlammaon

agans

4.13).

emnaed

rejecon

parencyma

damage.

cause

o

smuae

produced

and

ave

orm

ces

e

are

ssue

hs

k

CD4+

mecansms

or

and

been

umora

more

reacons

successu

n

orm.

 Cronc rejecon. W ncreasngy efecve erapy o acue rejec-

on,

cronc

rejecon,

wc

deveops

over

mons

o

years,

as

become e major cause o grat aure. Cronc rejecon s carac-

nduce

erzed

anbodes

mos

Courtesy

hs

ver y

os

vesses

make

eum,

antibodies.

cyoknes

plasma

Dallas.)

are

sysem

ABO

anbodes

Allografts

and

secree

k

endoeum

anbodes),

cells

a

hese

exacerbaes

and

specc

 Acue

me,

specc

moecues

rsk.

CD8+

aken

ranspan,

B,

and

Sontheimer,

aoug

cnca

ranspanaon

recogn-

ces

anbodes

on

recp-

be

a,

e

e

reacve

 •

 •

Rejection

53

donors and cross-mac esng or serum anbodes n e recpen

moecues.

Mechanisms

System

been senszed by bood ransusons or prevous ranspan are aso

dfer

presened

recognzed

recognze

producon

be

d-

by

o

pas,

angen

proens

a

Dallas.

rejecon.

yperacue

recognon

oregn

moecues

and

back

as

e

HLA

a

MHC

or

moecues

grat

or

Richard

School,

occurs

o

grat.

boss

grats

acceped

genes

o

recognzed

e

be

(MHC,

angens

dscov-

ssue

woud

uncon

APCs)

recpen’s

acvaed,

I

cuaure

cellular

were

no

compex

pepde

grat

or

poymorpc

expresses

e

ces

e

ndvduas

pysoogc

o

APCs

are

evoke

moecues

weer

gy

recognon),

cases,

oregn,

o

donor

MHC

recpen’s

angens

Immune

lymphocytic

Dr.

angens

compemen

beween

recpen,

ces.

recipient’s

s

and

 Hyperacue

aon.

the

which

socompaby

he

genes

e

n

by

molecules,

deermne

coecon

ese

bo

s

as

major

(parencyma

T

on).

a

the

mecansms.

Allografts

recognized

socompaby

a

excanged

he

s

I

ose

recpen’s

mpes,

ndvduas.

by

ces.

rom

Organ

Intense

Medical

responses.

moecues

umans)

er

immune

name

e

(compabe).

n

to

antigens

histocompatibility

humoral

ered

graft

(B)

Courtesy

Southwestern

 •

aograts.

gland.

gland.

Southwestern

University

by

desrucon

of

in

donor

The

of

B

Fig.

dferen.

Diseases

4

o

access-

njury

by

vesses

vascuar

and

nlammaon

njur y

scema,

and

and

and

scemc

nma

bross,

nersa

ssue

njur y

eadng

bross

(Fg.

due

o

narrowng

o

proonged

4.14).

o

e ssues. A ree mecansms may be nvoved smuaneousy, bu as

Treatment

of

Graft

Rejection

s dscussed aer, ey pay domnan roes n dferen ypes o rejecon. In

The

major

graft

injury

hese

kdney

a

patterns

and

have

paerns

ranspans,

sod

organ

of

rejection

different

were

bu

rs

e

ranspans.

reect

morphologic

descrbed

same

he

different

and

prncpes

uy

o

and

are

mechanisms

clinical

bes

appy

o

features.

esabsed

e

cassyng

of

or

rejecon

rejecon

o

no

a

grat

excep

denca

sur vva.

wns,

mmunosuppresson

Corcoserods,

an–T-ce

s

needed

anbodes,

and

o

proong

drugs

a

nb T-ce uncon are e mansays o reamen. Immunosuppres-

son

carres

vaon

o

e

rsk

aen

o

opporunsc

vruses

(e.g.,

unga

and

poyomavrus

vra

and

necons.

Reac-

cyomegaovrus),

as

54

CHAPTER

Diseases

4

of

the

Immune

Complement Blood

System

activation,

inflammation vessel

and

damage,

thrombosis

cell

Alloantigen

(e.g.,

endothelial

Endothelial

blood

Circulating

group

antigen)

specific

alloantigen-

antibody

A

B

Fig.

4.11

causes

Hyperacute

thrombosis.

neutrophil

rejection.

(B)

infiltration,

Hyperacute

and

+

A

Alloantigen-specific

CD8

(A)

severe

Deposition

rejection

ischemic

of

of

a

injury

antibody

kidney

on

endothelium

allograft

(necrosis)

in

a

showing

and

activation

platelet

and

of

fibrin

complement

thrombi,

early

glomerulus.

+ and

CD4

T

cells

+ +

CD8

Direct

Cytokines

CD4

killing

Recruitment

of

Parenchymal

macrophages

cells and

neutrophils

B

+ CD8

Neutrophil

+ CD8

Macrophage

Parenchymal

Interstitial

cell

damage

inflammation

C

Fig.

4.12

involves

T

cells.

direct

(B)

between

tory

Acute

cells

cellular

killing

Acute

of

rejection.

graft

cellular

epithelial

cells

damaging

rejection

of

the

cells

the

(A)

by

of

CD8+

a

tubules

endothelium

Destruction

CTLs

kidney

of

and

graft,

(tubulitis).

(C)

graft

cells

by

T

inflammation

manifested

Acute

by

cellular

cells.

caused

Acute

by

inflammatory

rejection

T

cell–mediated

cytokines

cells

involving

in

an

produced

the

rejection

by

CD4+

interstitium

artery

with

and

inflamma-

(arrow).

we as an ncreased rsk o cancers, are aso seen n mmunosuppressed

paens.

he

process

because

e

was

HSCs

sorcay

were

soaed

caed

rom

bone

e

marrow

donor’s

ranspanaon

bone

marrow,

bu

now ese sem ces are mobzed rom e marrow o donors by rea-

Hematopoietic

The

transplantation

treat

rect

Stem

leukemias

numerical

and

or

of

Cell

Transplantation

hematopoietic

other

stem

hematologic

functional

cells

men

(HSCs)

malignancies,

deciencies

of

blood

cells.

is

and

used

to

to

cor-

er

rom

w

grow

marrow

e

acors

“nce” ,

perpera

or

agens

aowng

HSCs

a

o

be

nb

bndng

ar vesed

n

o

mos

HSCs

o

nsances

bood.

Recpens o HSCs need “condonng” o abae er own mmune

sysem

(o

preven

grat

rejecon),

creae

“space”

or

e

ranspaned

Blood

Endothelial

cell

vessel

Alloreactive

antibody

Endotheliitis

Complement

activation

A

C

B

Fig.

4.13

vessels.

graft.

tesy

Blood

vessel

(C)

Dr.

Acute

(B)

antibody-mediated

Light

micrograph

Immunoperoxidase

Zoltan

Antibody

Laszik,

(humoral)

showing

staining

Department

shows

of

rejection.

inflammation

C4d

Pathology,

(A)

Graft

(capillaritis)

deposition

University

in

of

damage

in

caused

peritubular

peritubular

California

by

capillaries

San

antibody

capillaries

and

deposition

(arrows)

a

in

glomerulus.

in

kidney

(Cour-

Francisco.)

binding Chronic

to

a

inflammatory

reaction

endothelial in

vessel

wall

antigens Intimal

smooth

muscle

proliferation

Vessel

Cytokines

occlusion

+ CD4

Alloantigen-

specific

CD4

+

T

cell

Cytokines

A

Vascular

smooth

muscle

cell

B

C

Fig.

4.14

Chronic

rejection.

(A)

D

Graft

arteriosclerosis

caused

by

T -cell

cytokines

and

antibody

deposition.

(B)

Graft

arteriosclerosis in a cardiac transplant. (C) T ransplant glomerulopathy, the characteristic manifestation of chronic anti-

body-mediated

eruliitis),

fibrosis

and

(asterisk)

ing

tubular

shows

prominent

Hospital,

rejection

accumulation

in

of

the

atrophy,

fibrosis,

C,

courtesy

(B,

Dr.

The

glomerulus

matrix,

resulting

contrasted

arteriosclerosis.

Boston;

kidney.

mesangial

from

with

Dr.

inflammatory

of

narrowing

normal

Laszik,

shows

duplication

vascular

the

Courtesy

Zoltan

and

kidney

Richard

the

and

on

the

Mitchell,

Department

of

cells

capillary

ischemia.

top

right.

In

At

Department

Pathology,

within

basement

of

this

the

the

trichrome

bottom

Pathology,

University

capillary

membrane.

of

stain,

right

is

the

an

Brigham

California

loops

(D)

blue

artery

and

San

(glom-

Interstitial

area

show-

Women’s

Francisco.)

56

CHAPTER

sem

ces,

umor

and

ces.

versus-os

maure

and

T

beng

e

ver,

jaundce,

ndoen

o

(probaby

ympocyes).

can

canno

wc

due

o

he

o

T

rac,

and

cronc

magnances)

ony

ssues

and

e

oregn,

e

skn

nlammaon)

(because

soogc

o

o

may

o

decency

a

B ecause

e

s

ake

o

HSC

e

and

severa

T

ranspans

aso

ranspaned

may

ces

ympocyes.

ave

produce

Recover y

o

proound

adequae

mmune

grs

mos

mmuno-

o

make

T

e

o

individuals

susceptible

to

infections

and

common,

ous

w

decences

cncay

dseases

necons.

he

paens

and

cancers

Paradoxcay,

deveop

auommuny,

reason

or

mecansms

mmune

s

are

or

may

mos

some

a

mmune

deecs

ge

be

oten

relecon

s

because

are

e

vrus

w

o

a

sysem

resu

or

o

nduced



he

new

may

bu

be

be

uae

nec-

o

can

because

nduce

que

or

secondary

to

may

other

 e

o

n

o

o

a

X

e

o

are

X-nked

IL-2

T-ce

boys

by

eads

cromosome

cans

proound

dseases,

bo

SCID

ese

deamnase,

n

e

o

o

wc

or

and

e

IL-7.

progenors,

decenc y

are

oer

recessve

T-ce

and

auosoma

s

s

n

e

afeced

o

and

purne

a

g

ave

been

e

eves

n

decenc y

meaboes,

ces

he

encodng

deamnase

proerang

genes

recessve.

gene

expressed

Adenosne

oxc

rapdy

Many

are

cases

ymus.

be

primary

(resulting

sysems

on

sysem.

ns

oerance

by

excessve

from

recurren

wc

suc

as

are

mma-

dened

n

rare

SCID.

B-ce

necons

(cyomegaovrus,

e

paens

w

responses

w

X-SCID

s

varcea).

norma

a

are

wde

e

rs

HSC

mmune

dsease

agammagobunema

and

s

a

an

resuan

od

name

muaons

yrosne

n

knase.

maure

B

aure

or

e

mpared,

range

o

ranspanaon

ces

a

due

e

a

s

and

as

s

been

e

paens

paogens,

can

repop-

mansay

reaed

a

deec

anbodes).

a

ce

n

anbodes

w

w

recepor

requred

or

deec

o

gene

maura-

B

B-ce

B-ce

ce

gobu-

s

moecue,

e

n

B-ce

(gamma

he

sgnang

assocaed

pre-B

are

o

produce

encodng

knase

and

sgnas

s

o

crcuang

gene

hs

ces

devers

caused

Bruon

recepor

progenors,

proeraon

and

muta-

are

c aus e d

by

mu a  ons

 a

Wou

ese

sgnas,

B

ces

de

a

e

pre-B

sage,

er m

congenta

mmunode f c enc y

s

n

e

absence

o

anbody-producng

B

ces

and

pasma

are

ces. so

cases

e

ep

disorders.

mmunode f c e nc es

n er e d,

ces

w

resung

usu a  y

one

T-ce

nereukns

proeraon

eads

X-nked

accumuaon

mauraon.

Pr mar y

cases

muaon

auosoma

 X-nked

and

tions)

e

e

on

suscep-

caused

and e ces are ranspaned no e paens.

 •

n

diseases

a

(γc),

o

oten

erapy, n wc a norma γc gene s nroduced no HSCs o paens

acvaon.

Immunodeciency

w

a

gene

ncudng

sgnang

damagng

reamen.

aen

be

mmune

necons

que

necons

mmune

yperacve

uncear ;

rare.

o

reacvaon

deecve

perssen

seem

reavey

mcrobes

paens

assocaon

os

e

paogenc

are

dverse.

he

o

sgncan

ese

opporunsc

or

e

can

mos

absence

Abou

n

s

nanc y

ncudng ung (Candda, Pneumocysts), bacera (Pseudomonas), and

vruses

md

γ

e

I

n

and

DISORDERS

cancers.

Aoug

IL-7

ympoc yes.

presen

Immunodeciencies

muaon

requred

As

and

c yoknes,

adenosne

Because

IMMUNODEFICIENCY

necons.

presens

mmuny

carrers.

o

cases

a

common

remanng

especay

ure

s

requen

eads

mons.

e

o

o

(SCID)

ce-medaed

producon.

by

many

ces.

deveopng

compeence

range

anbody

or

and

mauraon,

caused

IL-7

are

he

sys-

numbers

T-ce

T

mmunodeicency

umora

dverse

absence

maure

var-

n

encodes

recepors

enzyme

beore

granuocyes

n

reduced

acvaon

resembe

a

(X-SCID),

more

are

o

deecs

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proonged

pcure

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oer

and

aso

epea

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w

recpen,

GVHD

and

 •

serous

aackng

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k

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he

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grat-

bu

cause

non-MHC

skn,

s

HSCs

response.

and

o

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rases.

auommuny

and

no

ce–medaed

bross

cnca

oer

sma,

rejec

by

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ec

the

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conan

Even

can

and

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aack

probems.

of

sceross.

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may

ces

gasronesna

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w

Grats

recpen

boody

manesaons

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ces

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even

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4

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cdren

are

suscepbe

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many

bacera

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one

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pres en

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 aer

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mmunodeicences

are

muc

more

common

an

ones.

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ger-ncome

counres,

e

mos

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cause

mmunodecency

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a

desroys

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radaon

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or

cancer)

or

a

s

used

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o

sysem

ower-ncome

mmunodecency.

(e.g.,

or

grat

counres,

rejecon

manuron

and

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a

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an

he

acqured

major

mmunodecency

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wordwde,

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Because

n

mmuny.

e

on

eper

T

acvae

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B

on

B

ces

B-ce

w

a

proound

e

de-

gene

he

or

dsease

s

mos

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ces

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a

mecansm

by

wc

wc

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and

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macropages,

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devers

CD40L

sgnas

bnds

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responses

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as

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ce-medaed

macropage

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acvaon

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cdren

cen-

sufer

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by

pyogenc

and

nraceuar

bacera,

vr uses,

ung.

components

of

are

caused

innate

or

by

o er

mutations

adaptive

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that

o

e

e

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genec

bass

use

o

o

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Tabe

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and

Suppemena

eFg.

ecnoog y

mmunodecences

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Pa ens

ave

a  oug 

 e

ese.

Seeced

dseases

a

usrae

summarze

e

beow.

de  c ences

o

more

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numb er

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ce s

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mporan

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d eren  a  on

o

maure

B

c e s.

Te

gene  c

a

b ass

k now n

n

e wer

 an

10 %

o

c as es;

mu a ons

a e c  ng

re c ep -

s

or

g row 

ac ors

and

o er

y mpo c ye

sg na   ng

p a ways

mos

b e en

prncpes

 ons. dscussed

s

d s c uss e d,

n

ave o

mmunodef ce nc y

impact

ors known.

var abe

mmuno de c enc es

immunity.

s medcne,

are

assocaed

s

Immunodeficiencies

immunodeciencies

more

common

muaons

reacon

bo ck

now

usuay

aer.

Primary

one

s

cause

 •

Primary

I

syndrome

and dscussed

e

auommune

rom (AIDS)

IgM.

ce-medaed

by

ces

ra o

by

ence,

nenonay

uae In

o

expressed

CD40

dseases).

and,

(e.g.,

T

suppress

dened

anbodes,

o

s

cemoerapy

orgnay

IgA

pr-

caused mar y

was

and

e.

cenc y Secondary

IgG

sy mpoms

domnance app e ar

sy ndrome

n

rep or e d.

Pa  ens

are

sus cep be

o

b ac er  a 

n e c-

CHAPTER

BONE

Diseases

4

of

the

Immune

56.e1

System

MARROW

THYMUS

Pluripotent

stem

cell

ADA

deficiency

Pro-B

cell

Pro-T

cell

X-linked

SCID

Common γ

(cytokine

chain)

myeloid-lymphoid

progenitor

Pre-B

cell

Immature

Di

receptor

heavy

agammaglobulinemia

cell

T-cell

IgM

X-linked

T

George

syndrome

chain

(BTK)

MHC

class

II

deficiency

CD40L

IgM

+

CD4

T

cell

Mature

T

cells

IgD

Hyper-IgM

Immature

B

cell

syndrome

(CD40L)

+

+

CD8

CD4

CVID

IgA

deficiency

IgM

Mature

Supplemental

in

these

ADA,

eFig.

pathways

adenosine

in

4.5

B

IgA

IgE

cells

Primary

selected

deaminase;

immunodeficiency.

IgG

immune

primary

CD40L,

deficiency

immune

CD40

diseases.

deficiency

ligand

(also

Shown

diseases.

known

as

The

are

the

principal

affected

CD154);

CVID,

genes

pathways

are

common

of

indicated

variable

lymphocyte

in

development

parentheses

for

immunodeficiency;

some

SCID,

and

of

the

blocks

the

disorders.

severe

combined

CHAPTER

Table

4.7

The

Major

Primary

Immunodeficiency

Disease

A.

Functional

Defects

in

lymphocyte

Severe

combined

X-linked

SCID

Diseases

4

of

the

57

Diseases

Deficiencies

Mechanism

immunodeficiency

of

Defect

(SCID)

Markedly

decreased

reduced

T

cells;

serum

normal

or

increased

B

Cytokine

Ig

tions,

of

cell

System

maturation

cells;

B

Immune

receptor

common

defective

IL-7

T-cell

ℽ-chain

maturation

gene

due

muta-

to

lack

signals

immunodeficiencies

X-linked

agammaglobulinemia

Decrease

in

all

serum

Ig

isotypes;

reduced

B-cell

Failure

numbers

of

maturation

because

of

beyond

mutation

in

pre-B

Bruton

cells,

tyrosine

kinase

Ig

heavy-chain

deficiencies

Deficiency

with

Disorders

DiGeorge

of

T-cell

in

Decreased

lymphocyte

hyper-IgM

variable

IgA

or

sometimes

associated

Chromosomal

IgE

deletion

involving

Ig

heavy-chain

locus

T

cells;

normal

B

cells;

normal

or

decreased

Anomalous

Ig

chial

development

pouches,

leading

of

to

3rd

and

thymic

4th

bran-

hypoplasia

activation

syndrome

Defects

in

phage

Common

subclasses;

maturation

syndrome

Defects

X-linked

IgG

absent

serum

B.

of

immunodeficiency

helper

T-cell–dependent

B-cell

and

macro-

Mutations

in

CD40

ligand

Mutations

in

receptors

activation

Reduced

or

no

subtypes

bacterial

of

production

of

selective

immunoglobulins;

infections

or

no

isotypes

susceptibility

clinical

or

to

tors,

for

B-cell

growth

fac-

costimulators

problems

+

Defective

the

class

bare

II

MHC

lymphocyte

expression:

Lack

syndrome

of

T-cell

and

X-linked

lymphoproliferative

class

disease

T

Chronic

in

innate

Uncontrolled

disease

deficiency-1

adhesion

Absent

deficiency-2

Complement

C2,

deficiency

C4

Defect

or

deficiency

in

and

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Disorders

of

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T- c e  

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m ay

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bo o d,

o

 e  a ny,

In

as

and

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gene

protein

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gene

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encoding

in

SAP

signaling

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adaptor

lymphocytes)

responses

we 

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functions

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failure

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for

comple-

in

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of

Mutations

encoding

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gene

components

of

enzyme

encoding

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chain

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integrins

in

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genes

gene

synthesis

nent

pathway

clear

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in

in

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and

encoding

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activation;

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e

pago-

cye oxdase enzyme (Caper 2). hs dsease s caed cronc gran-

uomatous

dsease

(CGD)

because

srong

macropage

acvaon,

oten resung n granuoma ormaon, compensaes or e nab-

y

o

neurops

o

desroy

pagocyosed

mcrobes.

he

eukocyte

adeson deicences are caused by muaons afecng e uncons

58

CHAPTER

o

e

adeson

kocye

moecues

recrumen

mpared

n

ese

neurops

no

Diseases

4

negrns

ssues,

dsorders.

resu

n

and

and

the

seecns

ence

Decen

ncreased

of

acue

(Caper

o

2).

System

Leu-

nlammaon,

recrumen

suscepby

Immune

and

uncons

bacera

conamnaed

are

bood

o

roune

 •

necons.

can

occur

bu

s

bood.

now

Transmsson

ver y

by

uncommon

bood

or

because

o

screenng.

occur

breas

IMMUNODEFICIENCY

HIV-neced

can

 Moter-to-nfant transmsson s e major cause o pedarc AIDS.

I

ACQUIRED

w

producs

by

mk.

ranspacena

Abou

2%

o

spread

new

cases

durng

are

n

dever y

babes

and

born

roug

o

neced

SYNDROME moers.

AIDS

virus

is

caused

(HIV),

by

which

infection

destroys

with

CD4+

human

T

cells

immunodeciency

and

leads

to

Human

profound

Life

immunodeciency.

hs

e

dsease

grea

drugs

was

scourges

ave

rs

o

provded

dened

e

modern

ope

o

n

e

1980s,

word.

paens,

and

Recen

bu



as

become

successes

remans

a

o

one

o

HIV is

anvra

major

grates

medca

to

ere

word,

on

o

de

he

ree

 •

are

more

wom

eac

 S exua

n

Asa,

or

are

by

hs



20%

n

ndvduas

Asa,

and

n

amos

1

ans

m-

and

e

domnan

o

rapdy

or

carred

o

neced

luds.

he

are:

75%

accouns

ranser

n

a

or

e

or

o

Abou

bsexua

ncreased,

a

mode

cases.

necon,

50%

men,

bu

especay

more

semen

o

and

o

new

e

here

caed

HIV-1

e

e

occurs

20%

by

o

cases

sarng

o

are

n

needes

capsd

infects

cells

genome,

o

are

and

coner

vra

wo

(e

Structure

via

and

CD4

kills

o

and

cells

and

coreceptors,

when

corecepors,

ces.

HIV

necon,

T

n

o

bu

it

is

inte-

activated

are

we

o

and

gene

and

ce

are

some

rare

we

(Fg.

o

HIV ,

To

ener

subsequeny

corecepors

membrane

ose

a

CCR5

muaons

or

and

s

express

macropages

encodng

ceran

orms

HIV-2.

and

con-

as

repcaon

(caed

os

core

negraon,

proens,

and

CD4

neced

ces

e

wose

vra

reaed

CCR5

e

n

ese

AIDS)

bnds

or

w

many

Poymorpsms

o

dferen

a

a

expresson

gp120

ces

vrus

nvoved

encode

cause

CXCR4

uses

e

enveoped

gene

requen

en

an

wc

vra

proen

hereore,

e

RNA,

recepors

vrus

s

enzymes

genecay

mos

capsd

he

HIV

proens,

reguaors

ouer

dendrc

nravenous

and

cell

rerovruses,

cemokne

vrus).

CD4

body

that

host

srands

suscepby

Anoer

Transmsson

wo

nernazed.

abrasons.

transmsson:

oer

numerous

e

necons

eners

the

4.15).

o

Arca

retrovirus

srucura

ces,

e

eero-

n

a

into

Lke

e

as

omosexua

as

s

and

drec

s

an

n

vrus

mucosa

users.

Arca

HIV-neced

dsease.

ransmsson

more

were

he

 Parentera

drug

o

ransmsson

roug

 •

n

mon

ransmed

cases

adus.

35

e

transmsson:

repored

and

s

are

rom

modes

accounng

sexua

70%

year

dsease

man

an

Virus:

replicate.

and socea probem, especay n deveopng counres. I s esmaed

a

Immunodeficiency

Cycle

and

aer

n

e

CCR5

ressance.

syrnges

VIRUS

gp120

CD4

Conformational

binding

gp120,

change

bind

CD4

gp41

CCR-5

membrane

Fusion

penetration

with

Membrane

of

host

entry

HIV

cell

of

into

fusion

membrane

membrane;

viral

genome

cytoplasm

gp41

gp120

Cytokine VIRUS

gp41

p17

ENTRY

matrix

Cytokine

receptor

gp120

p24

capsid CD4

Lipid

Chemokine

bilayer

HIV

RNA

genome

receptor

Reverse

transcriptase–mediated

synthesis

of

proviral

DNA

Integrase Cytokine

of

cell;

of

HIV

activation

transcription

Protease

RNA

genome;

transport

RNAs

VIRUS

Reverse

Integration

REPLICATION

into

transcriptase

Synthesis

of

assembly

HIV

of

host

of

cell

to

provirus

genome

proteins;

virion

core

structure

HIV

HIV HIV

DNA

RNA provirus

core transcript

structure

Nucleus

A

VIRUS New

HIV

RELEASE virion

Budding

of

B

Fig.

4.15

covered

(B)

The

with

The

by

life

a

structure

lipid

cycle

permission

Macmillan

and

bilayer

of

HIV

from

Magazines

life

cycle

derived

showing

from

the

Wain-Hobson

Limited.)

of

the

the

steps

S:

HIV.

human

host

from

One

cell

mature

release

virion

immunodeficiency

and

viral

on

and

studded

entry

one

to

the

meets

with

virus

viral

production

two.

Nature

(HIV).

(A)

The

glycoproteins

of

infectious

viral

gp41

virions.

1996;384:117.

particle

and

is

gp120.

(Adapted

Copyright

1996,

of

viral

cytoplasm

CHAPTER

Ater

enr y

produce

pasm

be

o

or

n

ce

us),

provra

compee

s

e

ces

DNA

are

ce,

years,

(e.g.,

s

vra

persss

genome

or

acvaed

vrons

e

wc

no

neced

neced

no

DNA,

negraes

sen

e

HIV

provra

by

o

o

s

an

e

neced

necon

vra

connue

reverse

epsoma

esabsng

ranscrbed,

reeased

RNA

n

a

ce.

aen

or

n

he

e

cyce

are

o

o

neuropaes,

cyo-

vrus

necon.

nlammaor y

proens

e

ranscrbed

orm

caed

may

I

e

smu-

produced,

and

necon.

Diseases

4

B ecause

ree

500

viral

replication

Exacy

s

y

ow

uncear ;

caused

ce

HIV

in

CD4+

infected

e

buddng

syness.

mainly

as

a

consequence

of

vrons

an

and

medaes

ncrease

s

n

membrane

compeve

consequence

s

a

cyopac

s

permeab-

nererence

progressve

efec

w

oss

o

T

os

ces,

prmary CD4+ ces. hs decne s nay mos promnen n muco-

sa ssues (e major se o vrus enr y), en s seen n dranng ymp

nodes,

In

o

and

ony

addon

mmune

e

hese

o

s

e

a

e

numbers

oer

deeced

drec

decency

obser vaon

an

aer

ave

o

T

ces.

neced

T

posuaed

o

neced

mecansms

bood

oss

severy

o

n

been

e

o

ces,

decs

(measured

e

dea

o

oer

accoun

mmune

ces

ncude

useu

o

mecansms

or

s

mosy

e

requen

muc

n

unneced

greaer

e

ces

Te

on

499

vaed

pds,

s

nsun

erapy,

AIDS

sde

cardovascuar

or

s

necon

ewer

RNA

assocaed

Dsease

couns:

and

greaer

an

and

s

o

and

paens

an

200

n

w

C onro

sraes

eves

prevousy

reaed

efecs

and

are

a

dsease,

w

erapy

w

ressance,

kdney,

encepaopay

or

equa

ces/μL.

e

vaue

he

bood,

n

e

s

a

man-

ndvduas.

eradcaed,

paens

ce

HIV-1

anrerovra

no

HIV

progresson

ndvduas

sgncan

cardovascuar,

CD4+

as

progressve

59

dsorder.

C eners

o

descrbed

or

a

System

conanmen

e

ces/μL,

dsease

course

acve

vrus

are

and

HIV

decenc y

ere

erm

o

measured

Curreny,

e

mmune

couns,

HIV-neced

(gy

mmune

ever,

o

o

commony,

neurocognve

o

based

vrema,

Immune

casscaon

200

dsease

paens.

drugs

oss

groups

marker

agemen

vrus

ncude

he

cells,

cells.

repcang

possbes

by

proen

depletes

mos

T-ce

(CD C)

ces/μL,

exen

Pathogeness.

e

CD4+

Prevenon

o

and,

the

HIV-assocaed

decnng

no

of

s

so

o

e

[HAART])

s

a

anvra

deveop

and

ncudng

ee-

and

dseases

How-

cure,

Furermore,

or

unreaed

o

no

no

neuropay,

rsk

unknown

do

medcaons,

dsease.

o

compcaons.

reamen

ese

ncreased

or

ypca

aendan

perpera

ver

s

combnaons

premaure

w

suc

as

ong-

cancer

reasons.

bood).

as

a

con-

AMYLOIDOSIS sequence

on

o

o

er

ympod

cronc

ssue

acvaon,

deecs

n

APCs,

and

e

desruc-

arcecure.

Amyloid Oer

ce

ypes

a

are

afeced

ncude

B

ces

(wc

are

bu

sow

excessve

acvaon),

macropages,

and

is

many

e

CNS.

Macropages

and

mcroga

may

be

reser vors

o

n

ae

sages

o

HIV

necon,

wen

CD4+

T-ce

greay,

macropages

may

be

an

mporan

se

o

nsoube

proens

of

brillar

protein

that

can

a

brs

are

are

produced

produced

n

by

excess

e

aggregaon

amouns,

are

o

no

var-

ceared

or

od

mpropery.

he

proen

deposs

bnd

carboy-

a

resembe

connued

drae-rc vra

deposit

tissues.

numbers

adequaey, decne

and

nec-

ous on;

extracellular

organs

mcroga

hese n

an

no

affect neced

moecues,

mparng

sanng

properes

repcaon.

sarc

(ence,

e

name).

Amyodoss,

reerrng

o

amyod

deposs

and er paoogc efecs, s dscussed ere because some o e mos Clncal

Course.

HIV

dsease

may

be

dvded

no

ree

sequena

common pases

 •

(Fg.

 Acute

CD4+

T

Vrus

ces

a

eners

e

roug

se.

mucosa

Dendrc

ces

and

a

necs

mucosa

and

ses

desroys

carry

e

vrus o regona ymp nodes, were e vrus repcaes and evenu-

ay spreads o oer ssues. he ndvdua mouns anvra umora

and

ce-medaed

wn

cc

 •

3

o

7

CD8+

HIV

many

oer

pod

ce s

do

no

no

ave

 •

o

T

a

hs

n

T

no des

p er o d

ce s

n

paens

o

 e

n

 s

n

oten

n

s

a

o

4

weeks.

ne c e d

p a ens

 e

pas e

depe on,

de cne

n

 e

opporunsc

ra

by

oncogenc

cer vca

o

e

o

DNA

ana

s

a

ncude

cepas

or

vruses,

B-ce

carcnoma

an

(e.g.,

ceran

common

na

asepc

 •

Pneumocysts

canddass,

umors,

many

ncudng

ympoma

(uman

and

o

Kapos

and

n

amyod

cursor

se-med

are

sarcoma

(Epsen-Barr

vra

caused

(Kapos

vrus),

and

Invovemen

manesaon

presumed

vacuoar

cyomeg-

o

AIDS.

menngoen-

myeopay,

perpera

or

by

(see

anbody

the

disease,

chemically

cona

moecues.

each

associated

distinct

serum

o

dsorders

deposs

AL

protein

with

in

a

the

mor-

depos-

amyodoss.

durng

wc

A

s

nrequen

seen

(ubercuoss

especay

o

o

mmunogobu-

can]),

neopasm

he

s

(SAA)

s

now,

a

o

wc

pasma

pasma

deposs

generaed

proen.

nlammaon.

SAA

an

by

made

gt

ces

are

ces

pro-

caed

wou

over 

9).

proen,

amyod

are

[amyod

proeraons

Caper

(AA)

produced

he

amouns

secondary

A

amyodoss

 •

of

but

(caed

excessve

amouns

num-

mycobace-

wc

papomavrus).

mporan

menngs,

jrovec,

cans

 Reactve

en

forms

amyodoss.

g

queny

cr ypococcoss,

and

erpesvrus),

and

CNS

Lesons

o

4.17).

myeoma

bo o d.

necons

necons,

necons)

sarcoma

composed

identical

myeoma,

o

ound mmune decency. Paens w AIDS ave a g ncdence

aovrus

are

several

 P rmar y

duced

and

 AIDS. he progressve oss o CD4+ T ces umaey eads o pro-

o

(Fig.

n

y m-

bu

c a  e d

 •

n

ne c e d

y mpo c ye

 ere

2

its

se-med

ose

are

phologically

(usuay

s e cond ar y

 ssues,

B e c aus e

s

sow

ye ars,

 es e

a

There

vrus-spe-

resembng

resoves

man y

bo o d.

o

deveop

sympoms

ce s

 e

seroconverson

deveopmen

ypcay

sy mpoms,

Ly mp

over

me,

n

e

repc aes

des roys

numerous

and

sysemc

v r us

s e vere

CD4+

s

w

necons.

and

resung

exposure)

Around

he

 aenc y.

e venu a  y,

b er

acue

organs

cnc a 

o

syndrome,

pas e.

are

responses,

weeks

CTLs.

acue

 C ronc

orms

4.16).

pase.

n

n

n

cronc

SAA

pas;

s

an

o

s

acue-pase

nlammaon,

o

o

producon

so

cronc

reumaod

deveoped

composed

proeoyss

Proonged

compcaon

e

are

by

s

o

e

pre-

pro-

arge

orm

o

nlammaory

arrs

more

re-

counres).

 O ter forms of amyodoss. Deposs o Aβ amyod are seen n e

brans

o

o

paens

demena.

peraps

e

mos

Mederranean

wc

one

paens

muan

SAA.

In

e

and

pas,

deposs

an

o

o

In

a

composed

deveop

ner ves,

e

some

assocaed

o

sysemc

producon

orms,

ransporer

undergong

o

s

and

oer

amyodoss

e

known,

w

ama

gvng

rse

o

emodayss

β2-mcrogobun

I

dsease

n

nlammaon,

o

amyod

yroxne.

orms

are

“auonlammaor y”

ncreased

ama

perpera

paens

s

o

wc

nered

wc

oer

dsease

orms

sponaneousy

ransyren,

auonomc

Azemer

ama

common

ever,

consequence

precursor

w

S evera

e

s

s

amyod

made

up

o

deposed

n

poyneuropaes.

deveoped

proen

amyod

because



dd

60

CHAPTER

Infection

mucosal

Diseases

4

System

+

Dendritic

cell

cell

mucosal

memory

T

Immune

of

T

of

the

tissues

CD4

Death

of

CD4

+

cells

Virus

to

transported

lymph

ACUTE

nodes

Primary

CHRONIC

AIDS

infection

8

10

1200 Acute

HIV

syndrome

Death

Infection

Wide

1100

established

dissemination

lymphoid

e.g.,

tissues,

lymph

of

lymphoid

virus

organs

7

10

1000

Opportunistic

node 900

diseases

)amsalp

Seeding

in

of

6

Clinical

10

latency

3

of

infection Viremia the

5

10 symptoms

500

T

throughout

Constitutional 600

body

VIH(

4DC

4

10

400

300

10

100

Anti-HIV

HIV-specific 2

0

antibodies

CTLs

10

0

3

6

9

12

1

2

3

4

5

Weeks Partial

control

of

viral

Establishment

infection;

Clinical

in

latency

virus

Other

microbial

infections;

7

8

Years

B

chronic

concentrated

lymphoid

low-level

of

replication

6

virus

tissues;

production

cytokines

Increased

Destruction

viral

of

replication

lymphoid

tissues:

AIDS depletion

of

CD4+

T

cells

A

Fig.

4.16

involving

to

Pathogenesis

mainly

viremia

and

the

and

patient

then

continues

a

erosion

gradual

G,

et

al:

N

of

of

enters

CD4+

J

Med

T

a

phase

but

cells,

AIDS.

(B)

328:327,

course

cells

seeding

unabated,

full-blown

Engl

clinical

CD4+

widespread

rophages

symptoms

and

memory

of

of

and

HIV

clinical

is

1993.

cells,

tissue.

latency.

some

ultimately,

Clinical

infection.

dendritic

lymphoid

there

and

of

course

Copyright

The

this

CD4+

T -cell

infection.

1993

initial

is

to

infection

lymph

controlled

phase,

containment

of

HIV

The

spreads

viremia

During

immune

(A)

and

numbers

CTL,

Massachusetts

viral

of

starts

nodes.

by

the

host

replication

virus

decline

(not

and

Cytotoxic

Medical

T

in

in

mucosal

Viral

immune

both

illustrated).

the

patient

lymphocyte.

Society.

All

tissues,

replication

T

cells

There

and

rights

mac-

continues

develops

(B,

leads

response,

from

clinical

Pantelo

reserved.)

9

10

11

aimeriV

3

200

Immune

response

ANR

mm/sllec

Spread

700

Lm/seipoc

800

CHAPTER

PRODUCTION

AMOUNTS

Diseases

4

OF

OF

of

the

Immune

ABNORMAL

System

PRODUCTION

PROTEIN

AMOUNTS

PROTEIN

Native

folded

OF

OF

(e.g.,

61

NORMAL

MUTANT

transthyretin)

Acquired Chronic

inflammation

Inherited

mutations

mutations

protein

Macrophage

Monoclonal activation

B-lymphocyte

proliferation Amyloidogenic

intermediate IL-1,

(e.g.,

misfolded

IL-6

protein)

Plasma Liver cells cells

Monomers

assemble

to

Immunoglobulin

Mutant SAA

form

β-sheet

structure

light

FIBRIL

AL

A

4.17

Pathogenesis

amyloidosis,

in

of

serum

(TTR)

the

pass

roug

in

excessive

form

no

transthyretin

Limited

Limited

proteolysis

proteolysis

PROTEIN

AA

which

production

amyloid.

amyloid

lead

of

to

(C)

A

amyloidosis.

unknown

of

(SAA),

deposition

as

General

cause

is

and

amyloidosis,

converted

amyloid

mechanism

monoclonal

immunoglobulin,

systemic

which

(A)

mutations

one

Reactive

fibrils

to

the

(ATTR,

in

the

B

of

amyloid

amyloid

formation

cell

light

which

or

(AA)

TTR)

form

amyloid

cell

the

amyloid

(D)

of

fibrils.

(B)

proliferations,

AL

inflammation

protein.

in

of

plasma

chains

chronic

A

PROTEIN

(amyloid

leads

to

Mutations

aging,

Primary

resulting

light

chain)

production

in

of

transthyretin

especially

affecting

heart.

oder

emnaed

ATTR

PROTEIN

D

dayss

membranes,

bu

newer

ers

ave

Morphology. argey

Aggregation

C

B

Fig.

Protein

chains

s

Exraceuar

deposs

o

amyod

may

be

presen

n

probem.

vruay any parencyma organ. In roune secons, ey appear as

 •

 L ocazed

amyodoss.

e

prmar y

and

secondar y

amyodoses

pnk, gassy, aceuar maera, oten n vesse was. Deposs can be descrbed

earer

are

sysemc

n

naure

and

afec

many

ssues

dsngused and

ses.

By

conras,

n

some

cases

e

amyod

deposs

are

mpars ed

o

a

snge

organ

or

se

(e.g.,

skn,

ung,

ongue).

A

eas

a

may

 •

ocazed

us

 Amyod

paens

s

be

of

(n

a

orms,

er

In

a

pro du c e d

amy  o d,

are

Unke

 es e

n

 o d

n o )

acd

or

o

e

Bu

n

ear,

e

 e

any

are

agng

n

s

 e

  a

n o ,

p ar   c u  ar

amyod

s

and

by

e

Congo

yeow-green

red

san,

wc

brerngence

(Fg.

o

e

4.18).

and

as

a

wd

In

 e

p ar   c u  ar

  a

d e e r m  n e s

w y

edery

cases

ere

resrcve

o

rans-

ype.

re sp ons  b e

 mpy  ng

c a s e,

afecs

many

comprsed

s e qu e n c e.

c a n

AL

presenng

amyod

su g ge s

  g 

and

ransyren

u nu su a 

o  e rs

o

subsances

coor

amyodoss.

w

eges)

orms,

an

d a a

o

prmar y

amy  o d o s  s ,

as

an d

s e qu e n c e

u n k n ow n .

and

o

ama

yp es

or m .

o

consss

assocaed

Bocemcay,

e x p e r  m e n a 

  br   s

s

sevenes

n

e xc e ss

amy  o d o ge n  c

am  n o

Amyod

nvovemen

cardomyopay.

yren.

amyod

manesaon

agng.

domnan

e

oer

caracersc

n

deposs some

rom

m-

proe  n

 e

o

s

AL

c a ns

pr  m ar y

w e er

amy  o d

organ

resu

Features.

were

rom

(congesve

cas e

  g 

Clncal

amy -

or ms

( or

he

n



poor,

Amyod

he

o

n

aure),

he

e

and

amyodoss

prognoss

parcuary

nereres

deposed.

deposon

ear

dagnoss

ssues.

s

ose

o

w

mos

kdneys

depends

sysemc

norma

on

rac

o

e

compcaons

syndrome),

ear

(maabsorpon).

demonsraon

w

AL

uncon

cnca

(neproc

gasronesna

ndvduas

w

e

requen

sysemc

amyodoss.

o

amyod

amyodoss

he

course

s

o

reacve sysemc amyodoss depends on e conro o e underyng

condon.

62

CHAPTER

Diseases

4

of

the

Immune

System

A

B

C

Fig.

the

4.18

walls

observed

by

the

Amyloidosis.

of

blood

by

a

polarizing

massive

Courtesy

Medical

Dr.

(A)

vessels

section

Worrell

Dallas.)

along

of

and

of

liver

stained

sinusoids.

microscope.

accumulation

Trace

School,

A

and

(C)

In

amyloid.

Sandy

(B)

with

Note

the

kidney,

The

stain,

Hinton,

Congo

the

the

red

glomerular

called

Department

reveals

yellow-green

a

of

PAS

pink-red

architecture

stain,

Pathology,

deposits

birefringence

reveals

is

of

the

almost

totally

glycogen-rich

University

of

of

Texas

amyloid

deposits

in

when

obliterated

deposits.

(B,

Southwestern

5

Neoplasia

O U T L I N E

Definition

Benign

of

and

Neoplasia,

Malignant

Nomenclature,

63

Hallmarks

Neoplasms,

Benign

Nomenclature

of

Malignant

of

Benign

Differentiation

of

Invasion,

Metastasis,

Molecular

Cancer

of

Role

of

of

Neoplasia,

Saes.

of

of

feared

death

a

cancer

both

deas

1.69

were

of

n

and

o

Cancer

and

remains

reamen,

morbdy

new

n

boog y

ras

moray

cases

2017

second

n

o

e

srkng

mass

e

cancer

and

the

adults.

undersandng

recorded

ony

n

o

counr y.

sudy

cardo-

and

Uned

ay

e

cancer

neo-

and

over

o

Our

sudy

pologc

oowed

and

e

e

o

ogos,

by

a

dscusson

common

so-caed

and

DEFINITION

Neoplasia

cells

that

because

In

a

se

o

posed

ce,

ons

the

cause

and

and

o

bologc

a

bass

magnan

we

and

neoplasms.

moecuar

by

Fnay,

dagnoss

of

reaed

dscuss

mor-

hs

o

s

cancer

neopasms,

e

cnca

cancer.

neopasa

sur vva

are

ce

o

e

(descrbed

be

clonal

a

proliferation

control

gven

a

ces

of

mechanisms

sas

81

Enabler

of

as

Malignancy,

an

83

Enabler

83

of

Tumors,

of

83

84

Cancer,

84

85

rom

cona

o

neopasms

n

genes

ereby

a

are

rom

snge

orgn

a

sares

n

are

snge

progen-

he

mua-

reguae

conerrng

e

ce

mos

neopasms,

a

umor

caed

o ”).

aso

er

(rom

oncoog y

he

may

aby

e

produce

tumere,

e

a

nered.

o

L an

(rom

muaons

be

Greek

cause

We

w

a

o

ocazed

swe).

oncos,

neopasms

reurn

o

he

“umor, ”

are

e

usu-

ssue

o

aer.

begn

ssues

e

s

o

ceared,

AND

do

not

neoplasms

to

are

mcroscopc

ormones

e

uerus

mpes

compee

generally

a

response

s

o

sweng

pror

o

yperpa-

enargemens

and

pregnancy.

node

o

n

resu,

ncude

durng

revers

as

medaors

Lymp

to

inltrate

distant

dened

o

a

a

are

from

as

e

Unke

abaes

sae

o

uerus

neo-

as

ater

an

dev-

gven

a

surgca

well

and

e

w

remova.

of

origin,

are

easily

whereas

malig-

tissues

and

have

the

(metastasize).

umor’s

umor

circumscribed,

surrounding

sites

o

NEOPLASMS

their site

bengn

appearance

predcve

 Bengn

o

yperpasas

reversbe:

spread

often

spread

Neopasms

s

and

sgnas;

nlammaor y

MALIGNANT

and

 •

are

o

smuaneousy

grow

eus.

neoplasms

wc

by

gesaona

excised,

and

proerae

Exampes

caused

Benign

capacity

o

paopysoogc

yperpasas

necon

o

or

poycona.

response

pasas,

com-

a

o

as

cancer

ssues

ympod

nant

neopasm

derved

orgn

uncon

aer),

an

In conras o neopasa, yperpasa occurs wen many ces wn

er y

aberrations.

er

o

a

wn

ndcang

sad

aer

to

growth

“dauger”

B ecause

ces

refers

genetic

ever y

79

80

Neoplasia,

s

bu

and

BENIGN

normal

muaons,

ce.

neopasc

denng

malgnan

sared

cancer. ”

from

nsances,

oundng

genec

are

growth)

acquisition

a

genecay

a

grow

new

“escaped”

paogenc

o

aberran

or

of

vruay

o

e

and

NEOPLASIA

(literally,

have

e

a

aboraor y

OF

w

bengn

o

eaures

“amarks

manesaons

begns

o

o

“sudy

acqured

muaons

Incdence

5.1

neoplasa

caracerscs

(Immortality),

80

Inflammation

Staging

umors

pysoogc

Fg.

and

propery

ed,

n

of

Effects

reerred

afeced

presened

79

Surveillance,

as

75

73

neoplasia,

mon

Instability

74

Signals,

77

Potential

Metastasis,

Immune

Diagnosis,

daa or e mos common orms o cancer, w e major kers den-

are

and

Aspects

Grading

72

children

progress

cause

71

Cancer,

Death,

Malignancy,

Clinical

Mutations,

dagnoss

as

of

Clinical

Directed

70

in

Cell

Metabolism,

Angiogenesis,

of

Signals,

Growth-Inhibitory

Tumor-Promoting

70

Process

form

in

69

73

Growth

Replicative

Sustained

Mutations,

Passenger

er

dsease

of

Limitless

Genomic

Cancer,

Agents

Approxmaey

600,000

in

Evolution,

most

n

66

66

Mutations,

Multistep

consderabe

and

vascuar

Evasion

Neoplasms,

69

“Driver”

Carcinogenic

cause

Despe

pasms

A

Infectious

the

leading

64

to

in

Cellular

Invasion

Alterations

Significance

Cancer,

Tumors,

Malignant

Neoplasms,

and

Darwinian

Origin

Altered

68

Carcinogenesis:

by

and

64

Evasion

Genes

Epigenetic

Tumors,

68

Basis

Cancer,

Insensitivity

of

Characteristics

of

Self-Sufficiency

64

Nomenclature

Local

63

magnan

proeraon

probabe

reman

Afeced

based

cnca

ocazed

paens

on

e

(descrbed

gross

aer),

beavor.

and

s

amenabe

generay

sur vve,

bu even “bengn” umors may occasonay cause serous morbdy

63

64

CHAPTER

A

2019

ESTIMATED

Men

Melanoma

of

the

Neoplasia

5

CANCER

INCIDENCE

870,970

Women

BY

SITE

AND

B

SEX*

2019

891,480

7%

5%

Men

CANCER

321,670

DEATHS

Women

BY

SITE

4%

the

Brain

skin

4%

Thyroid

13%

Lung

and

24%

bronchus Lung

23% Esophagus Lung

and

13%

bronchus

and

bile

Pancreas

30%

3%

Breast

3%

Kidney

3% Colon

7%

bronchus

5%

and

and

4%

and Liver

bronchus

Kidney

SEX

282,210

3% of

cavity

AND

Melanoma

skin

Lung

Oral

ESTIMATED

Kidney

3%

Pancreas

7%

Colon

Pancreas

15%

Breast

4%

Liver

8%

Pancreas

8%

Colon

duct

and

9%

9%

and

rectum 7%

rectum

Colon

rectum

and

Urinary

rectum Urinary

4%

7%

4%

Uterine

5%

Ovary

corpus

bladder bladder

Prostate

20%

Leukemia

4%

Non-Hodgkin

5%

7%

Uterine

3%

Ovary

4%

Non-Hodgkin

other

Prostate

10%

Leukemia

4%

3%

Leukemia

Non-Hodgkin

4%

3%

Non-Hodgkin

lymphoma

lymphoma

lymphoma

All

corpus

sites

21%

23%

Fig.

cell

5.1

Estimated

and

Cancer

squamous

Facts

and

cancer

cell

incidence

skin

Figures

All

cancers

2019.

other

and

and

sites

death

in

American

situ

All

rates

by

site

carcinomas,

Cancer

other

Society.

lymphoma

sites

and

sex

except

24%

in

the

those

24%

United

of

States.

urinary

Excludes

bladder.

All

other

sites

basal

(Adapted

from

www.cancer.org/research/cancer-facts-statistics/

all-cancer-facts-figures/cancer-facts-figures-2019.html )

or

even

crca

 •

moray,

organ

 Mag nant

cen

n

de a .

cers

s

 ssues

or

(e.g.,

appe d

and

exampe,

e

o

(der ve d

 rom

 ra ve

g row 

ad ere

 g  y,

 e

c aus es

pursue

a

de ad y

a s o

among

 e

L a  n

a

mos

a

oca

o

c urabe,

or

mass

efec

ono

b eav or.

s ome

 e

o

and

des roy

u  maey

reer re d

“crab”)

“g rab”

and

nvade

s es ,

co e c  vey

word

crab’s

cours e

c an

d s an

are

 em

o

 a

o

umors

sm  ar

cers

causng

n

a

5.2).

b e c aus e

nor ma 

mos

desg na on

as

can-

 er

n   -

 ssues

A  oug 

 e

o

no

a

and

s

he

a

are

nens:

(1)

neopasc

connecve

cussed

n

depends

aso

on

uae”

ssue,

e

no

e

n

bengn

and

ces

bood

on

naure

order

o

o

and

(2)

vesses,

Hamarks

ony

magnan,

o

Cancer

nrnsc

e

sroma

er

composed

nonneopasc

and

e

avor

a

are

secon,

e

response,

grow

and

ces.

beavor

o

e

wc

wo

sroma,

nlammaor y

properes

o

bengn

made

As

o

w

a

umor

ces

poypod

s

used

or

grows,

bengn

umors,

parcuary

n

e

some

gu.

umors

up

be

Tabe

5.1),

umors

w

essenay

ceran

addons

oows

and

a

o

excepons:

 S arcomas

er

subdvded

ose

 •

o

ound

on

and

sod

ces.

Caper

he

ncude

o

ce

ype

or

are

nvove

ssues.

ssue

ces

ces

mos

are

gve

rse

nvove

smar

node

rom

bood

marrow

(ymp

resembe.

derved

o

o

desgnaed

cosey

neopasms

a

ssues

dferenaon.

o

Sarcomas

ey

preerenay

ympod

and

composed

magnan

progenor

Leukemas

grow

and

and

and

bood,

speen)

9).

resembe

neopasc

paerns

neopasms

ympomas

ransormed

usuay

on

mesencyma

norma

and

ympomas

(see

e

n

e

based

magnan

emaopoec

mmune

“manp-

are

 Leukemas

e

bu

sur vva.

(see

Tumors

magnan

 •

ds-

ces

Malignant

o

 Carcnomas are magnan neopasms o epea ces, and are ur-

neopasm

neopasc

commony

as

 •

re d

compo-

of

nomencaure

based

umors,

erm

begn

Nomenclature

c an-

ag g ress ve

mag nant

s

umors

adj a -

resu  ng

  ag .

A

Aoug

magnan

esons

me  as asze

Ma g nan

by

bran).

e

ces

ces

n

ces

oow

peomorpc

a

o

a

neopasm,

snge

more

adenoma

an

o

weer

neage.

one

e

In

ne

bengn

some

o

savar y

or

magnan,

umors,

owever,

dferenaon.

gand,

a

cassc

hese

mxed

NOMENCLATURE tumor,

The

nomenclature

each

are

name

related

of

carries

to

the

various

with

it

biology

neoplasms

certain

of

the

is

associated

neoplasm

important

because

characteristics

and

its

likely

that

clinical

behavior.

of

Benign

Tumors

Mos bengn umors are desgnaed by aacng e suix “

ype

rom

wc

e

umor

arses

(Tabe

5.1).

Oers

oma” o e

ave

names

a relec er grow paerns. A papoma s a bengn epea neo-

pasm

growng

nger-ke

surace,

as

conss

o

on

a

surace

projecons.

n

e

gu,

A

o

a

poyp

orm

produces

s

a

a

mass

mcroscopc

a

projecs

macroscopcay

or

macroscopc

above

vsbe

a

mucosa

srucure

(Fg.

(aoug

magnan

nosarcomas,

wc

componens.

Nomenclature

ce

wc

cona)

s

comprsed

o

neopasc

epea

and mesencyma eemens (Fg. 5.3). Uncommony, magnan umors

o

rom

opoena

ce

bng

dferenaon

ype

many

Some

above

oma,

and

dferen

garng

may

be

anoer

ces

a

conan

dferen

bo

ype

ave

neages,

suc

mesencyma

o

umor

eFg.

e

5.1).

a

and

o

arranged

as

carc-

epea

sows

Teraomas

capacy

apazardy

mupe

orgnae

dferenae

eemens

no

resem-

ssues.

nconssences

noed

meanoma,

neopasms.

s

o

(Suppemena

germ

may

rom

composed

Teratoma

nes

any

eemens

are

n

and

Tabe

n

5.1.

semnoma

e

For

namng

exampe,

“sound”

convenons

ympoma,

bengn

bu

are

a

ad

ou

mesoe-

magnan

CHAPTER

A

5

Neoplasia

B

Supplemental

of

hair,

glands,

eFig.

sebaceous

fat

cells,

5.1

(A)

material,

and

a

tract

Gross

and

of

appearance

tooth.

neural

(B)

tissue

A

of

an

opened

microscopic

(arrow).

cystic

view

of

teratoma

a

similar

of

the

ovary.

tumor

Note

shows

the

skin,

presence

sebaceous

64.e1

CHAPTER

Table

5.1

Tissue

of

Nomenclature

Connective

of

One

tissue

Parenchymal

and

Cell

Benign

Malignant

Lipoma

Liposarcoma

Type

derivatives

vessels

Chondroma

Chondrosarcoma

Osteoma

Osteosarcoma

Hemangioma

Angiosarcoma

Mesothelium

Brain

Mesothelioma

coverings

Meningioma

Hematolymphoid

Smooth

Epithelial

of

Leiomyoma

skin

lining

of

or

meningioma

Leukemias,

squamous

cells

Invasive

cells

muscle

Stratified

Basal

65

Tumors

Origin

Composed

Blood

of

Neoplasia

5

Squamous

cell

papilloma

Squamous

adnexa

glands

or

Basal

ducts

lymphomas

Leiomyosarcoma

Adenoma

cell

cell

carcinoma

carcinoma

Adenocarcinoma

Papilloma

Cystadenoma

Liver

cells

Urinary

Hepatic

tract

Placental

epithelium

(transitional)

epithelium

Testicular

epithelium

adenoma

Urothelial

Hydatidiform

(germ

Hepatocellular

papilloma

Urothelial

mole

Choriocarcinoma

cells)

Seminoma

Embryonal

Tumors

of

melanocytes

Composed

Salivary

of

More

Nevus

Than

carcinoma

carcinoma

One

Neoplastic

gland

Cell

Malignant

Type:

Mixed

Pleomorphic

Tumors,

adenoma

(mixed

Usually

tumor

of

Derived

salivary

from

gland)

One

carcinoma

melanoma

Germ

Malignant

Cell

mixed

Layer

tumor

of

salivary

gland

Renal

anlage

More

T otipotential

Fig.

5.2

colonic

Wilms

Than

One

cells

Colonic

lumen

in

Neoplastic

gonads

polyp.

and

is

This

or

in

Cell

embryonic

glandular

attached

to

Type

the

tumor

Derived

rests

Mature

(adenoma)

mucosa

by

a

from

More

teratoma,

projects

distinct

stalk.

into

Than

One

dermoid

the

Germ

Cell

Layer:

cyst

Immature

Fig.

5.3

and

myxoid

present

tumor

Teratogenous

Mixed

in

Brigham

tumor

stroma

this

and

field.

of

the

forming

parotid

(Courtesy

Women’s

gland.

cartilage

of

Hospital,

Dr.

and

Vicky

Boston.)

teratoma,

Small

bone

Jo,

teratocarcinoma

nests

(an

of

epithelial

unusual

Department

cells

feature)

of

are

Pathology,

66

CHAPTER

Neoplasia

5

Endometrium

Fallopian

tube

T umor

Vein Ovar y

BENIGN

MALIGNANT

(Leiomyoma)

(Leiomyosarcoma)

Small

Noninvasive

Large

Well

Nonmetastatic

Poorly

Well

Rapidly

demarcated

Slow

growing

differentiated

Locally

demarcated

growing

hemorrhage

Fig.

5.4

similar

Comparison

origin

CHARACTERISTICS

OF

between

a

benign

tumor

of

the

myometrium

with

and

(leiomyoma)

invasive

Metastatic

Poorly

differentiated

necrosis

and

a

malignant

tumor

of

(leiomyosarcoma).

BENIGN

AND

MALIGNANT

NEOPLASMS

Most

on

benign

the

invasion,

In

s

and

evaluation

and

mos

made

nsances,

w

e

remarkabe

crera.

o

bengn

and

as

an

he

tumors

features:

can

be

degree

are

of

usng

a

of

distinguished

based

differentiation,

n

o

usng

Fg.

bengn

versus

ong-esabsed

usuay

neopasms,

summarzed

Differentiation

Differentiation

deermnaon

accuracy

eaures

magnan

exampe,

their

three

local

metastasis.

anaomc

ble

malignant

of

5.4

perm

umors

and

e

o

magnan

cnca

and

dferenaon

e

descrbed

myomerum

n

dea

nex.

Neoplasms

refers

to

parenchymal

the

cells

extent

of

to

origin,

which

both

tumor

cells

resem-

morphologically

and Fig.

5.5

Pleomorphic

malignant

tumor

(poorly

differentiated

sarcoma).

functionally. Note

In

ces

genera,

a

bengn

cosey

magnan

neopasms

magnan

naure.

o

be

neopasms

resembe

anapasc,

er

exb

Tumors

a

are

a

s

a

o

we-dferenaed

counerpars.

morpoogc

composed

eaure

composed

norma

o

By

aeraons

conras,

a

undferenaed

reabe

ndcaor

o

beray

ces

mos

er

are

the

nuclei,

rell,

ical

marked

and

the

magnancy.

 •

 Nucear

mupe

dferenaed

oowng

 •

e

ces.

exampes

or

and

Anapasc

uncona

ces

oten

caracerscs

dspay

one

or

o

norma

more

o

szes

(varaon

ncude

negbors,

severa

umor

w

nuce.

n

ce

gan

eac

sze

ces

and

a

possessng

sape;

are

Fg.

5.5).

consderaby

eer

one

Exreme

arger

enormous

n

nucear

nuclear

giant

sizes,

cells.

University

nuceo.

ncudng

sze

 •

a

approac

of

the

hyperchromatic

(Courtesy

Texas

Dr.

Trace

Southwestern

Wor-

Med-

ar

nuceus

 •

e

ypercromasm

sape,

rao,

o

unusuay

nuce

and

dameer

or

o

may

nuceo

norma

(dark-sanng),

promnen

resu

may

n

an

aan

snge

or

ncreased

asoundng

ympocyes.

 Atypca mtoses, wc may be numerous. Abnorma separaon o

cromads

an

and

Enargemen

nucear-o-cyopasmc

e

eaures:

 Peomor psm

er

srucura

and

tumor

Pathology,

abnormates,

aon,

o

of

cell

Dallas.)

varaon

oss

of

in

sad

Anapasa eray means “backward ormaon, ” mpyng dedferen-

or

presence

Department

School,

variation

moc

 L oss

of

durng

gures

poar ty,

p aer ns

o

ce

(Fg.

suc

dvson

may

produce

rpoar

or

quadrpo-

5.6).

 a

or en a  on

g roups

o

one

o

ne op as c

ano e r.

In

ce s

 e

 ack

mos

nor ma 

anap as c

CHAPTER

umors,

nze d

ce s

g row

s r uc ures

n

Neoplasia

5

d s organ ze d

suc

as

g  ands

se es,

or

w  

s ra   e d

67

o a 

 oss

s qu amous

o

orga -

arce c -

ure.

We  - d   e re n  ae d

  ona 

c ap ab    e s

p as  c

u mor

re g ard  ng

c e s

u mor

 e

In

and

o

and

5.6

High-power

nuclear

field

has

an

variation

detail

in

abnormal

view

size

of

and

tripolar

anaplastic

shape.

The

tumor

cells

prominent

shows

cell

in

 nsu   n ,

cellular

the

( AC T H ) ,

g u c agon ,

p ar ane op as  c

center

Dysplasia

spindle.

mal

but

is

not

o

c e 

s y nd rome s

disordered

do

re  a n

 e  r

c e 

ana -

 ae r,

ne op as ms

 re qu e n y

o

c aus e

or  g  n .

pro du c e

e me rge.

s  g ns

su c

as

s

s a d

S m   ary,

ke r a  n

(F  g .

s e c re e

Mo s

and

and

e ab o -

b  e.

no aby,

s y mpoms

by

a d re no c or   c o rop c

or mone - re ae d

More

 u nc -

( d s c uss e d

c arc  nomas

 u nc   ons

may

so

 e

w e re as

b engn

c arc  nomas

or mone s ,

o e rs .

o

g  ands

e p ao c e u  ar

p ar a y ro d

and

o

e x amp e,

or  g  n

e c op c

  key

c ou ne r p ar  s ,

e nd o c r  ne

u nan  c p ae d

none nd o c r  ne

are

  key

car a c e r s  c

s o-caed

or mone

Fig.

For

s qu amous

 ns anc e s ,

s e c re   ng

 e ss

o

we  - d   e re n  ae d

o e r

c anc e rs

mu c

c anc e rs

or mone s

c e s

nor ma 

g r a d  ng ) .

we  - d   e re n  ae d

5.7)

 e  r

are

we  - d   e re n  ae d

r ae

u mor

o

proe  n

ab ou

 e s e

( P Tr P ) ,

s o-caed

 ae r.

growth

of

epithelial

cells

that

are

abnor-

malignant.

Dyspasa s mporan o recognze because  s a we-documened

precursor

rum,

pasa

 •

o

and

ncude

 Ceuar

may

 •

carcnoma

e

and

arge,

 •

ey

e

tumor

with

cells

are

intercellular

strikingly

bridges

similar

and

to

nests

normal

of

of

squamous

keratin

the

skin.

epithelial

superca

no

e

are

ypcay

n

o

sraed

5.8

Carcinoma

dysplastic

cells

subepithelial

nuclear

and

in

situ.

lacking

stroma.

cellular

(A)

orderly

(B)

Low-power

view

differentiation.

High-power

pleomorphism,

view

and

of

shows

The

usua

progressve

canges

e

are

sage

prog resson

a

cancer

as

and

the

region

mitotic

endome-

assess

dys-

orm

o

abnor-

epeum,

b eng

a

n

e

sraed

badder,

basa-appearng

nvove

o

compeey,

as

ces

n

o

as

e

entire

thickness

membrane

shows

figures

is

of

intact

a

cancer

s

no

p ar  c u  ary

genera 

ncre as e d

failure

of

extending

the

and

normal

toward

ces.

enre

carcnoma

squamous

resung

Wen

ckness

n

su,

a

n

a

dys-

o

e

prenva-

5.8).

dyspasa

Ne ver  eess,

 ssue

dark

reerred

(Fg.

o

reg ress

s

o

epeum

o

severe

eson

he

may

o

mauraon

ransona

sve

basement

another

numerous

that

e

squamous

r u e,

r sk

 e

or



ne v abe,

nc ng

pres ence

de veopng

B

Fig.

o

seen

cancer.

A

cer vx,

used

nuce

ayers

normay

odgepodge

marks

cells,

(arrow).

n

dsordered

remove d

The

peomor psm,

or

pasas

carcinoma

nucear

are

epeum,

cell

as

a

oowng:

epeum

pasc

squamous

suc

Feaures

 Arctectura dsarray. Exampes ncude e para or compee oss

o

Well-differentiated

ssues,

rac.

ypercromac

moses

were

5.7

many

 Abnorma mtotc actvty, ncudng more numerous moc gures

and

Fig.

n

gasronesna

epithelium

there

is

no

consists

tumor

differentiation,

the

surface.

in

of

the

marked

and

dys-

caus es

o

are

dyspasa

an

nvasve

68

CHAPTER

Neoplasia

5

A

B

Fig.

5.9

from

Fibroadenoma

the

tumor

Texas

whiter

from

the

of

breast

the

tissue.

surrounding

Southwestern

breast.

(B)

The

tan-colored,

Microscopic

tissue.

Medical

(A)

(B,

School,

encapsulated

appearance.

Courtesy

Dr.

Trace

The

fibrous

Worrell,

5.10

causing

breast

ogy,

that

As

son

on

and

University

ductal

carcinoma

retraction,

of

umors

umors

bross,

may

a

by

are

Invasve

fat

by

Texas

and

sowy

grow

(Fg.

sroma

dscree,

can

sowy

and

nests

is

of

the

breast.

stony-hard

and

cords

Southwestern

of

on

tumor

Medical

(A)

The

lesion

palpation.

cells.

School,

(B,

(B)

infiltrates

Courtesy

demarcated

sharply

delimits

of

Pathology,

the

University

of

Dr.

surrounding

view

Trace

breast

illustrates

Worrell,

the

substance,

invasion

Department

of

of

Pathol-

Dallas.)

be

cancers

and

5.9).

ces,

a

s

sroma

a

usuay

on

o

depo-

encap-

easy

o

assocaed

gross

nspec-

he

bood

vesses,

unes

newy

an

or

sma

hs

nrave

an

ssue

umors

surgca

excson

dsngusng

eaures

emangomas)

ack

are

o

no

capsues

a

magnan

absoue:

and

are

no

umor

Some

s

aemped.

bengn

dscreey

umors

dened.

hese

(e.g.,

spread

occu

cancers,

asze

o

measac

the

tumor

cancer

as

may

ner vous

hus,

poena.

be

ce

e

tumor

perms

and

body

umors

evden

are

a

more

em

sites

and

that

the

are

ability

key

assocaed

sysem,

o

me

are

w

o

o

s

o

cancers

and

an

and

aways

In

bu

dsease.

mos

aggressve

no

w

oer

addona

dagnoss.

measasze,

skn

no

oppor-

paens

skn

measac

e

ocay

nvade

o

penerae

provdng

30%

measases,

e

o

caves,

(excudng

carcnoma

aby

to

tumor

malignant.

measases

cancers

a

Approxmaey

sod

cncay

basa

cenra

rarey.

as

of

primary

ces

5.11).

(dden)

umors

the

cannes,

(Fg.

ave

spread

with

magnan

suc

e

ony

a

o

anapasc

prmar y

grow necessaes remova o a wde margn o surroundng “norma”

by

ympac

meanomas)

nrae,

5.10).

marks

dagnosed

arge,

(Fg.

dened

nvasveness

era,

ssues

is

discontinuous

metastasize

appear o be crcumscrbed, ack rue capsues and progressvey nvade,

surroundng

ose

to

ave

desroy

even

Metastasis

physically

rm

by

Bengn

response

cancers,

feature

tumors.

deveop

and

umors

However,

the

ormed

brobass.

magnan

encapsuaed.

mos

capsue

as

is

benign

(nonxed),

nduce

growng

from

expand,

he

suc

movabe

aso

invasiveness

20%

wen

the

Microscopic

a

and

o

metastases,

capsue

cancers

appear

of

distinguishes

caed

coagen

sharply

Metastasis

reliably

ssue

o

excse.

stroma

development

bengn

suaed

w

the

most

brous

Invasive

tissue

Invasion

to

Department

is

(right)

B

Fig.

Next

tumor

capsule

Dallas.)

A

Local

small

gen-

even

Cer-

prmar y

bu

meas-

predcve

o

CHAPTER

MOLECULAR

BASIS

Cancer

and

All

of

Genes

forms

genes

cer

s

o

ave

consder

liver

studded

with

metastatic

even

a

caed

ways.

cancer.

or

cancer

number

or

cancer

are

a

e

ce

cells.

genec

dsease.

Genes

hey

are

a

One

a

our

Mos

suicen

genes

o

n

as can-

numerous

dicu

compexy

uncona

or

recur-

o

are

s

casses:

muaed

ranscrpon

progrow

because

produce

pro-

counerpars

encode

parcpae

function

are

ony

ceuar

oncogenes

a

a

a

smpy

norma

domnan

s

no

names

major

the

reerred

overexpressed

her

moecues

o

be

are

or

way

no

can

and

acronyms

grow.

aee

ces

undreds

consdered

snge

cancer

wen

protooncogenes.

alter

normal

exper.

a

that

of

n

genes

genes

sgnang

nvovng

s

n

e

mutations

behavior

dysreguaed

ncreased

acors

the

Mutations

from

unpronounceabe

 O ncogenes

are

A

or

hese

oten

moe

5.11

essence,

remember,

 •

Fig.

regulate

muaed

genes.

bu

o

n

stem

69

NEOPLASIA

“Driver”

neoplasia

that

hus,

reny

of

OF

Neoplasia

5

a

a

pa-

muaon

prooncogenc

efec.

Magnances

ca

a

o

crcumsance:

crcuae

hereore,

e

roug

w

dssemnaed

bood

hese

ony

e

are

excepons,

a

and

derved

boodsream

rare

dseases

(eukemas

umors

dagnoss

ympomas)

rom

and

spe-

ces

mgrae

eukemas

and

a

bood-ormng

are

o

and

aways

are

dsan

ympomas

consdered

 S eedng

wtn

cuary

and

peronea

sysem

e

orms

he

e

dranage.

o

A

cancer

 •

e

and

ree

mode

o

ceran

neopasms

e

adjacen

s

oten

o

e

ependymoma)

roug

suraces

wc

e

bran

may

e

Aoug

may

“sentne”

ymp

node

wc

a

or

cause

w

n

y mp

o

afeced

node

s

a

are

may

e

by

node

bopsy

rs

o

o

aso

tat

are

cers.

e

o

on

regona

gauge

Lymp

e

reacons

enargemen

and

ymp

umor

reamen.

spread

node

umor

can

ony

sopaoogc

o

node

resus

o

deer-

encode

are

 •

ar eres

ces

and

are

are

oten

e

sysem

o

e

o

w

exampe,

e

b ones.

are

o

o cazaon

w oy

and

g 

carcnomas

omc

no

e

e

expan

ung

bran,

C onvers ey,

rarey

ses

o

near

e

a

e

o

yrod

vae

 •

an

 Large

 •

ends

and

umor

roug 

s

 Cromosome

(Fg.

s

o

spre ad

oten

mus ces,

measas es.

o

e

spreads

aoug 

proen.

an

n

cnomas,

as

due

o

a

umor

o en

suppressor

grow.

ac 

by

en ancng

p er

s e.

overex press e d

ap opo ss

end

o

n

be

ce 

G enes

c anc er

und erex-

tumor

genes

os

a

Mos

a

and

n

enance

mmune

or

drver

encode

ces

aered

ost

ces

ceran

or

can-

nb

e

sysem.

progresson

muaons

reguaor y

o

cancers

afec

RNAs,

genes

suc

as

and

ncude:

and

sma

nsertons

and

deetons.

as

a

g ands

s

In

a

requeny

umor

suppressor

remove

an

oer

one

oncogene,

nsances,

or

proen.

more

cancers

o

and

orm

e

genes

o

w

oncogenes,

o

(eer

rear-

promoer

o

gene

a

composed

o

may

s

creaed

porons

rearrangemens

bu

a

sruc-

e

overexpresson

cmerc

sarcomas,

cromosome

cromosome

eemen

eadng

a

proen

ypes

e

n

nvovng

reguaor y

uson

hese

n

canges

nsances

srong

near

In

(oten

gross

some

a

bood

represen

anoer

acvy

an

abnorma

meapase

or

may

DNA

be

ncrease

he

genec

s

w

wn

p or ons

speca

ab erraon

dened

e

as

ereo

eve

amped

ragmens

presen

cromosome

wc

arge

o

5.13).

omogeneous-sanng

common

aneupody,

somes

or

way

(Fg.

exracromosoma

Anoer

and

nacvae

are

be

o

a

wo

parcuary

ound

n

car-

 Gene ampcatons produce exra copes o one or more oncogenes

oncogenc

For

or

we.

cromosomes,

capar es,

uncon-

neopasms

pro era on

deveopmen

genes

oncogenc

n

n

preven

n

uncon.

proens.

can-

ver

e

produce

enancer)

ana-

e

ce

between

e

mutatons.

wc

paces

common

and

paens

adrena

os

unconay

are

by

substtutons

5.12).

e

o

r c

 •

proba-

me as as es.

or

rearrangements

dranage

Howe ver,

venous

o

n

rs

oten

an

dferen

p or  a

coumn

dverse

suppressor

encodes

umor

e

ces

bu

oncoproen

norma

encouner :

pa way

me as as es

pros ae.

and

we.

me as asze

ver ebra

dsrbuon

neurobasoma

skeea

e

 e y

are

nteractons

promoe

ransocaons)

ck-waed

Bo o d-b orne

oten

pexus;

as

aees

pr mar  y

promoe

muaed

drver

deetons,

umor

examnaon

cours e,

an

b ed

spread

ver ebra

neopasm

sysemc

spread.

cancers

paraver ebra

carcnoma

and

oer

s

easy

capar y

 requeny

 requenc y

o

o

rs

arsng

oow

more

avenue

e

w ereas

C ancers

roug 

expans

n

cancers

ver,

ungs.

emb oze

by

e

usua

arresed

Gasronesna

carcnomas

as

srucuray

or

bu

p eneraed

bo

s mu  a ng

mporan

 Snge-nuceotde

ure

are

by

 a

umor

proens,

paway

vens

s

Dependng on er precse ocaon and ype, ese may eer ac-

nodes.

sarcomas,

o

a

rangemen

or

o

unreguaed

ap oposs

 os e

reguate

o

 Hematogenous spread. Spread roug  bo o d vess es s e avored

hn-waed

normay

genes

mcroRNAs, aso can be afeced by drver muaons. Drver muaons

angens.

be

a

suc

apoptos s

agans

Parcuary

reerred

a

va

spread

aow

 an

recurreny

Muaons

are

enarge-

measac

o

se

ympac

he

sem

rom

e

oca

umor.

cannes.

uncon

o

reg uate

w ere as

 Genes

carcnomas,

ympac

depends

prmar y

mmunoogc

ymp

ypca

paways

used

gudes

umor

cerany

mos

roug

naura

rom

urn

rom

s

nvovemen

e

bopsy

prmar y

ces

and

low

node

s

dssemnae

genes

o

press e d.

 •

lud,

or

are

uncon

e

os

ra er

proe c 

ce s,

cenra

a

cerebrospna

o

 a

par-

spread

be

tat

sur v va ,

dssemnaon

genes

e

nsances,

mus

 G enes

paways:

carcnomas,

rave

menngea

ymp

ymp

near

mned

o

hs

o

meduobasoma,

neopasm

ympacs,

hus,

one

ovaran

venrces,

cancer

receves

senne

o

o

suraces,

spread.

o

prmar y

men

gene

recognon

paern

a

mos

be

cord.

 Ly mpatc

a

on

by

cavtes.

(e.g.,

cerebra

mpan

spna

 •

body

spread

caracersc

ner vous

ener

neopasms

grow;

o dsrupve muaons or epgenec sencng (gene represson). In

are

o

suppressor

roed

 •

Magnan

aong

 Tumor

ssues.

magnan.

 •

 •

gans

(s ee

known

a

o

genes

a

proen

may

as

doube

cromosome

regon,

be

deeced

mnue

and

by

w

carred

appear

sanng

dyes.

a

or

s

ound

osses

Caper

o

6).

n

cancer

woe

How

ces

cromo-

s

causes

70

CHAPTER

Neoplasia

5

CHRONIC

NORMAL

MYELOID

CHROMOSOMES

LEUKEMIA

9

22

9

22

HSR

BCR BCR

NMYC

locus

ABL-BCR

locus

hybrid

gene

ABL

oncogene

Tyrosine Tyrosine kinase kinase inhibitor

ABL Activation

of

oncogene growth

factor

signaling

Double pathways

minutes

NORMAL

BURKITT

CHROMOSOMES

LYMPHOMA

8

14

8

14 Fig.

5.13

The

Amplification

NMYC

fied

and

is

gene,

seen

chromosomally

chromosome

other

to

Brodeur

MYC

oncogene

the

as

than

and

activation

gene

in

human

chromosome

chromosome

is

an

Sather

becomes

minutes

region,

NMYC

oncogenic

RC,

human

2.

neuroblastoma.

2p,

double

homogeneous-staining

Seeger

in

on

extrachromosomal

also

GM,

NMYC

normally

integrated

fied

of IG

IG

either

structure

from

of

present

is

et

al:

neuroblastomas.

on

related

factor.

Clinical

Cancer

as

usually

closely

transcription

H,

ampli-

or

a

a

in

(Modi-

implications

58:541,

1986.

gene Reprinted

Increased

by

permission

of

Wiley-Liss,

Inc.,

a

subsidiary

of

John

Wiley

gene MYC

&

Sons,

Inc.)

protein MYC

oncogene

MYC

oncogene

Carcinogenesis:

A

Multistep

Process

Directed

Increased

expression

pro-growth

of

by

Darwinian

genes

Cancers Fig.

5.12

Chromosomal

translocations

and

associated

oncogenes.

are

myeloid

leukemia,

a

balanced

translocation

involving

9

and

22

creates

a

chimeric

gene

containing

pieces

the

BCR

protein

of

with

genes

Even and

ABL

genes

that

encode

a

chimeric

BCR-ABL

fusion

ng constitutively

anced

translocation

sequence

in

the

MYC,

active

for

the

tyrosine

involving

MYC

immunoglobulin

an

oncogenic

kinase

activity.

In

chromosomes

gene

adjacent

heavy-chain

transcription

to

gene,

8

Burkitt

and

strong

leading

14

lymphoma,

places

the

regulatory

to

a

ce,

coding

elements

overexpression

of

factor.

a

A

s

ncompeey

n

mosoma

e

underso o d,

expresson

o

cancer

bu



s

a

b eeved

resde

n

o

nvove

afeced

cro-

oug

ereby

Epigenetic

sion

of

a

Gene

changes

gene

that

expresson

are

Cancer

dened

occur

s

in

as

without

akn

seecve

reguaed

orgn

heritable

mutation

by

changes

of

the

in

the

expres

gene.

posransaona

cancer

pars.

s

How

poory

rom

ces

e

wen

ese

aeraons

undersood,

aered

compared

bu

are

expresson

n

w

e

key

o

er

norma

modcaons

epgenome

n

cancer

mos,

genes.



ceuar

conrbue

no

a,

o

that

by

the

disrupt

stepwise

sets

o

couner-

neopasa

nsances

o

prooncogenic

of

can-

o

s

evove

functions.

naed

rom

genecay

a

(Fg.

snge

5.14),

a

ound-

process

sem

a

o

o

umor

a

ese

prmar y

and

muaons

e

Dar wnan

or

a

seecon,

ypcay

ses

o

genecay

more

come

o

o

umors

n

a

es).

a

B ecause

were

a

e

rom

o

can-

cancer

grow,

resung

e

eerogeneous

resu

dferen

uncon

adep

a

progresson.

o

domnae

measass.

magnan

umor

e

evason,

(sur vva

may

as

beeved

aer

ces

mmune

evouon

o

s

ndependeny

may

afeced

or

subcones

se

reerred

progresson

accumuae

measass,

advanage,

are

penomenon

n

Due

o

umor,

o

sur-

progres-

s

eer

connung

monocona

me

o

n

cnca

presenaon.

Genetic

heterogeneity

gression

but

Wen

sones and by DNA meyaon, bo o wc are requeny aered

n

progress

aberrations

ormaon

eve,

makng

nvason,

e

o

muaons

S ome

muaon

Alterations

umor

connue

moecuar

ces.

son

a

regons.

Epigenetic

subsequently

genetic

complementary

cancers

addona

cer

genes

with

conrbues

e

vva,

canges

and

multiple

bal-

genes,

cancer

of

chromo-

cer somes

initiated

In

acquisition chronic

Evolution

amos

umors

aways

ressance

(or

also

evouon

has

the

recur

ressan

sems

epgenec

for

rom

ater

o

e

by

to

not

orgna

a

dar wnan

only

for

cancer

pro-

therapy.

cemoerapy,

e

ougrow

aeraons)

orged

implications

response

o

mpar

drug

e

subcones

drug

seecon

recurren

regmen.

a

ave

ressance.

can

expan

umor

hs

muaons

hus,

e

s

acqured

genec

wo

mos

CHAPTER

Accumulation

passenger

Carcinogen-induced

Additional

mutation

of

driver

Neoplasia

5

71

and

mutations

driver

Additional

mutations

Emergence

mutations,

of

subclones

Diagnosis

Nor mal

Initiated

cell

stem

precursor

cell-like

with

Founding

proper ties

cancer

cell

Genetically

heterogeneous

cancer

Acquisition Initiating

5.14

order

perncous

properes

become

more

Origin

of

o

in

Development

which

cancers:

aggressve

Further

and

various

e

ess

of

cancer

driver

endency

responsve

through

mutations

or

o

hallmarks

stepwise

occur

cancers

evolution

over

is

accumulation

usually

me

unknown

o

o

erapy.

of

and

an

Carcinogenic

mutations

monly

acquired

Facors

muaons

 •

 Age.

a

a

In

mos

ors

and

 Exposure

w

erapy

par

Some

ca

s

age

an

s

bu

resu

o

(many

cancer

mporan

carcnogens

DNA,

causng

agens

(e.g.,

Some

rsk

o

a

muaons.

e

 •

com-

55

arge

somac

w

and

and

par

are

muaona

75.

by

he

e

w

rsng

by

noma

ac-

assocaed

reacons,

resdues

suc

o

damage

agens

hese

cancers,

DNA),

varey

o

are

a

do

DNA

ssues.

as

poen

creae

wo

no

are

 •

assoc-

ndvduas),

cemo-

array

o

(oten

n

T abe

groups

casses:

requre

gven

ors)

cemcas.

Major

Carcinogens

and

Associated

Agent

Associated

Tobacco

Lung,

renal

Ultraviolet

light

Skin

e

cancer

Lung,

head

cell

esophageal,

Ionizing

chemotherapy

agents

radiation

Aflatoxin

B

Many

Liver

1

Nitrosamine

Acute

and

nitrosamides

myeloid

and

(n

Cronc

o

o

o

women

as

e

paways.

cyocrome

converson

are

par

cronc

exposed

key

wc

e

o

s

paogeness

drec-acng

occur

may

repar

ncdence

ormones

n

o

be

process.

o

carc-

dsorders

aso

s

asso-

ormone-responsve

g

eves

endomera

o

esrogen

epeum)

Another

con-

ited)

DNA

can

case

o

and

breakage

genes

B

ces)

o

oncogenes

B-ce

important

and

source

reguaed

and

T-ce

of

B

rejonng

o

(mmunogobun

mmunogobuns

creae

mutageness.

and

and

and

angens.

are

mporan

ympo-

T-ce

muageness

or

T

assembe

Errors

o

n

a

vas

recep-

mprove

ese

conrbuors

pro-

o

e

umors.

driver

mutations

is

germline

(inher-

aberrations.

hese

pacng

nered

e

Cancers

neck,

afeced

muaons

are

ndvdua

a

presen

a

g

n

rsk

ever y

or

ce

n

deveopng

e

body,

cancer.

Mechanism

pancreatic,

and

DNA

in

squamous

cell

carci-

damage

tobacco

DNA

caused

smoke

by

carcinogens

(e.g.,

and

procarcinogens

benzo[ a]pyrene)

damage

carcinoma)

gastric,

and

colon

esophageal

carcinoma;

Uncertain.

Activates

inflammation.

leukemia

cancer

(a

over

Cancers

and

o

assocaed

nlammaor y

mogenc

and

o

ncreased

carcnoma

mammar y

more

dvson,

nlammaon

as

e

many

rearrangement

e

o

damage

cancer

cancer,

ceuar

par,

rsk

angen-recepor

a

cancers

Gastric

DNA

cesses

mesothelioma

Alkylating

or

n

aerng

Muaons

and

exposure

eevaed

exampe,

Cem-

(melanoma,

basal

an

reguaed

ainy

carcinomas

noma,

Asbestos

Human

bladder,

seng

Increased

5.2.

meaboc

e

by

suc

carcnogens.

proeraon

eas

meaboc

enzymes

carcnoma.

 Reguated

use

zo(a)pyrene, azo dyes, alaoxn), wc are no acve un convered

5.2

For

n

acve

acors.

ceuar

mogen

cyes

radaon

severa

a

endogenous

susaned perods o me ave an ncreased rsk o breas and endo-

verson o become carcnogenc, and ndrec-acng agens (e.g., ben-

Table

w

obacco

envronmena

sed

no

5.3).

caed

ncudng

eecrope

wc

(Tabe

o

proferaton.

expan,

seen

mera

damage

pgmened

reacve

agens),

o

may

by

The

tumor.

endogenous

repcaon

ncreased

hs

o

mutations.

to

carcnogeness

agens

ceuar

by

driver

tumor

carcnogen

nluence

DNA

ncreased

accumu-

expaned

burden

cemca

a

varey

a

may

 Increased

w

age,

from

poymorpsms

durng

oowng:

mey-cyosne

gy

wc

gy

akyang

e

most

oncogenc

ncreases

muaons

Agens

carcnogenc

ave

o

ages

n

are

inherited.

respecvey.

o

(n

erapy),

o

and

agents.

g

ncude

cancer

sponaneous

cyosne

ncreased

e

o

expaned

resdues,

function

be

beween

mos

o

also

occurrence

durng

key

mutagenc

drugs

e

occurrng

uravoe

o

o

vary

ndrec-acng

gene

may

requency

beow,

e

cancer

but

muaons.

ymne

to

smokng,

as

w

deamnaon

aed

e

somac

agng

urac

 •

o

life

acqured

deas

descrbed

w

e

are

genera,

ncdence

alter

during

conrbue

cancer

aon

that

Mutations

complementary

may

umae

Hence,

P-450

Driver

genetic

mutation cancer

Fig.

of

DNA

damage

DNA

damage

DNA

damage

DNA

damage

the

inflammasome,

leading

to

local

In

72

CHAPTER

Table

5.3

Chronic

Pathologic

Inflammatory

Disorders

Condition

Asbestosis,

and

Cancer

Associated

silicosis

Inflammatory

Lichen

Neoplasia

5

bowel

disease

Colorectal

sclerosis

Vulvar

squamous

Pancreatic

Chronic

Gallbladder

cholecystitis

esophagus

Sjögren

Opisthorchis,

Hashimoto

thyroiditis

Extranodal

cholangitis

Hepatocellular

Osteomyelitis

Carcinoma

ames

ma

w

more

sor

a

gene

afeced

some

ra.

ndvduas

nsances,

cancer

a

preven

provde

Tumor

he

encodng

a

ypcay

LM:

muaons,

nered

acves

genes

us,

n

n

Coussens

mupe

rsk

cause

umor

ceuar

adequae

are

stroma

cancers

mos

acs

suppressor,

a

norma

arse),

e

draining

cancer

an

s

a

n

carcinoma

MALT

a

compeey

emnaes

e

uncon

o

e

w

mutations

pylori

B

and/or

C

virus

infection

Schistosomiasis

a

Ann

Rev

arose

durng

Pathol

n

eary

e

Mech

Dis

germ

1:119,

ces

o

2006.

e

parens

or

occurred

n

e

eus

embr yogeness.

one

Role

suppres-

he

germline

stones

flukes

Helicobacter

Bacterial

development.

auoso-

arses

e.

umor

particles

acid

Hepatitis

of

Infectious

sae;

Infectious

(and,

of

rans-

this,

agents

some

causative

ormed ces ypcay conan a second, sporadc muaon n e norma

aee

Liver

lymphoma

sinuses

germne

T umor

cancer

eary

colon

carcinoma

eerozygous

un

oten

of

proen

ransormaon.

n

in

ke

nsances

silica

lymphoma

carcinoma

regulation

usuay

n

uncon

perecy

and

Gastric

zone

adenocarcinoma,

Bladder

TD,

ese

domnan

muaon

or

Tlsty

Alcoholism,

Gallbladder

Cholangiocarcinoma,

cystitis

fibers,

carcinoma

carcinoma

Hepatitis

from

cell

marginal

Gastric

Chronic

Agent

Asbestos

cancer

Gastritis/ulcers

Adapted

Etiologic

carcinoma

carcinoma

Esophageal

syndrome,

lung

carcinoma

Pancreatitis

Barrett

Neoplasm(s)

Mesothelioma,

cancers

agents

number

o

and

necous

up

can

or by

Epdemoogc

suppressor.

Agents

cause

in

to

be

Cancer

25%

effective

cancers

n

e

worldwide;

through

treatment

mecansc

agens

of

prevented

sudes

eoog y

of

established

ave

o

because

vaccination

rmy

varous

against

infections.

mpcaed

cancers

a

(Tabe

he need or a second  (e two-t ypotess) o creae a “procancer”

5.5). Inecous agens appear o ncrease e rsk o cancer roug wo

penoype

major

one

and

suc

as

was

cancer

argey

Imporan

cancers

are

reveaed

caed

ou

borne

g

5.4

e

ou

n

by

Tabe

o

subsequen

5.4.

Presumaby,

Inherited

genes,

many

o

Predisposition

o

n

ese

to

cdren

n

are

are

cdren

new

Disorder

syndrome

(various

tumors)

Melanoma

Familial

adenomatous

polyposis/colon

Neurofibromatosis

1

Breast

tumors

and

Hereditary

Nevoid

ovarian

and

nonpolyposis

basal

cell

pes

aso

ncude

nduce

asso-

ceuar

w-

epas

cronc

ver

carcnoma

2

syndrome

pigmentosum

(ver

and

and

cancer),

epas

are

srongy

C

vrus,

and Hecobacter

Bloom

syndrome

Fanconi

anemia

o

w

pyor, a

wc

epao-

bacerum

a coonzes and damages e gasrc mucosa, wc as been nked

muaons

o e deveopmen o gasrc carcnoma and gasrc ympoma.

Dominant

Cancer

Syndromes

Functional

Defect

TP53

Increased

p16-INK4A

Loss

APC

Increased

signaling

Increased

progrowth

Increased

genomic

instability

Increased

genomic

instability

Increased

signaling

in

Increased

genomic

instability

Increased

genomic

instability

Increased

genomic

instability

Increased

genomic

instability

NF2

MSH2,

BRCA2

MLH1,

MSH6

PTCH1

Recessive

Diverse

genes

Syndromes

involved

in

of

Defective

nucleotide

DNA

excision

of

of

cell

cycle

control

genomic

cell

cycle

instability

control

in

the

Wnt

ATM

BLM

Diverse

links

genes

involved

in

repair

of

DNA

cross-

pathway

signaling

the

Hedgehog

Repair

repair

Ataxia-telangiectasia

bo

assocaed

Loss

BRCA1,

cancer

vrus

RB

NF1,

colon

carcinoma

cancer

B

damage

Cancer

Autosomal

Xeroderma

and

Gene(s)

Retinoblastoma

Li-Fraumeni

mecansms:

 By nducng cronc nlammaton and tssue repar, ereby ncreasng

e rae o acquson o drver muaons, as descrbed earer. Exam-

as

Autosomal

Inherited

 •

aer),

genes

genomes

even

o

sudes.

assocaed

occurrng

cancer

nerance

(descrbed

moecuar

and

Sequencng

cancers

n

domnan

renobasoma

syndromes

muaons

sor y.

auosoma

ama

cancer

racon

germne

amy

Table

been

ama

a

rom

syndrome,

summarzed

a

w

any

predced

pathway

CHAPTER

Table

5.5

Infectious

Agents

Agent

DNA

Linked

to

73

Cancer

Cancers

Mechanism

Viruses

Human

papillomavirus

(HPV)

Squamous

tonsil,

Epstein-Barr

virus

(EBV)

B

cell

cell

carcinomas

vulva,

and

lymphomas,

of

the

cervix,

Virus

Human

herpesvirus

8

Kaposi

encodes

oncoproteins

that

inactivate

p53

and

RB

penis

nasopharyngeal

Uncertain.

carcinoma

Virus

encodes

proteins

that

activate

oncogenic

signaling

encodes

proteins

that

activate

oncogenic

signaling

pathways

sarcoma,

B

cell

lymphomas

Uncertain.

(HHV8)

Virus

pathways

Hepatitis

RNA

Neoplasia

5

B

virus

Hepatocellular

carcinoma

Uncertain.

Causes

chronic

liver

inflammation

and

associated

repair

Hepatocellular

carcinoma

Uncertain.

Causes

chronic

liver

inflammation

and

associated

repair

Uncertain.

Virus

Viruses

Hepatitis

C

virus

Retroviruses

Human

virus

T-cell

1

lymphotrophic

Adult

T-cell

leukemia

(HTL V1)

T

encodes

proteins

that

causes

expansion

of

infected

cells

Bacteria

Helicobacter

pylori

Gastric

carcinoma,

gastric

B

cell

lymphoma

Uncertain.

lates

a

Causes

chronic

chronic

immune

gastritis

and

associated

repair

and

stimu-

response.

Parasites

Schistosoma

Liver

 •

 By

haematobium

sood

many

s

e

cases

dscussed

and

te

functon

ceuar

exampe

wc

o

p53

s

ead

aer,

and

Significance

wo

RB,

of

agen

and

HPV

Uncertain.

he

n

neck

e

by

uman

cases

wo

mos

cancer

genes

mporan

squamous

Passenger

inuence

s

mos

encodes

o

made

mos

Uncertain.

and

or

by

bes

papomavrus

o

cer vca

ce

mporan

E6

and

umor

stm-

As

E7,

create

host

response

that

to

the

do

not

cystitis

bile

Avoiding

and

duct

associated

inflammation

immune

Evading

destruction

repair

and

associated

repair

growth

suppressors

w

a

Enabling

replicative

signaling

immor tality

be

bnd

suppressor

alter growth

Sustaining

proliferative

and

pro-

Deregulating

T umor-

cellular

promoting

energetics

inflammation

Mutations

variants

chronic

chronic

(HPV),

carcnoma

carcnoma.

proens,

Causes

Causes

under-

respecvey.

Passenger mutations

but

protens

mecansm

eoogc

o

of

proferaton.

nacvae

ens,

carcinoma

Cholangiocarcinoma

aterng

uatng

erties

Bladder

flukes

prop-

tumor.

Activating

hey

greay

ounumber

drver

muaons,

parcuary

n

cancers

Resisting invasion

caused

by

exposure

o

muagens,

suc

as

mos

meanomas

and

cell

smok-

and

death metastasis

ng-reaed

passenger

 •

ung

 Passenger

tance

rare

cancer.

muaons

to

are

mutatons

terapeutc

ces

evenuay

o

may

er

n

create

agents.

arborng

come

Despe

mporan

genetc

Under

ressance

domnae

appareny

severa

e

seecve

umor

naure,

ce

tat

confer

pressure

gan

an

o

erapy,

advanage

and

Fig.

5.15

instability

acquire

popuaon.

 Passenger

mutatons

may

create

tumor

neoantgens

(mutator

angiogenesis

ress-

Eight

and

these

mutations

 •

Genomic

Inducing

varants

muaons

e

nnocuous

ways:

in

cancer

hallmarks

tumor-promoting

properties

critical

during

genes.

and

enabling

inflammation).

their

(From

two

instability

phenotype)

development,

Hanahan

D,

factors

Most

typically

Weinberg

(genomic

cancer

RA:

cells

owing

to

Hallmarks

(proen

of

cancer:

the

next

generation.

Cell

144:646,

2011.)

sequences a dfer rom ose o norma ces). Suc angens may

be

seen

ng

w

o

a

be

as

“oregn”

os

dscussed

HALLMARKS

All

cancers

are

As

e

as

ypc

5.15

can

properes

and

OF

the

aready

undreds

conss

ces

o

e

response.

mmune

sysem,

Neoangens

poenay

and

os

ead-

mmuny

 •

 S e-suicency n grow sgnas

 •

 Insensvy o grow-nbor y sgnas

 •

 Aered ceuar meabosm

 •

 Evason o ce dea

 •

 L mess repcave poena (mmoray)

 •

 Susaned angogeness

n

 •

 Invason and measass

peno-

 •

 Evason o mmune sur veance

aer.

display

considered

by

anumor

CANCER

fundamental

hallmarks

been

be

of

changes

o

cancer

o

e

ces.

n

cancer

e

hese

oowng:

cell

physiology,

which

cancer.

menoned,

consdered

in

genes

conex

numberng

o

properes

e

are

a

common

eas

usraed

n

Fg.

In

a

addon,

coner

e

ese

acquson

properes

o

may

e

be

genec

and

acceeraed

epgenec

by

aeraons

cancer-promong

74

CHAPTER

Table

5.6

Cancer

Important

Gene

Gene

TP53

Neoplasia

5

Cancer

Genes

Class

Tumor

Function

suppres-

Sensor

sor

Effect

of

cell

stress,

DNA

Loss

repair

of

of

Mutations

function

instability,

Associated

leads

to

resistance

genomic

to

Diverse

Cancers

cancers

proapoptotic

stresses

RB

Tumor

suppres-

Negative

sor

regulator

of

cell

Loss

cycle

of

function

growth,

leads

failure

to

to

increased

Mutated

differentiate

in

retinoblastoma,

sarcoma;

dysregulated

osteo-

in

diverse

cancers

HER2

Oncogene

Growth

factor

receptor

Gain

of

function

leads

to

factor–independent

ABL

Oncogene

Nonreceptor

tyrosine

kinase

Gain

of

function

leads

to

factor–independent

RAS

Oncogene

Signaling

molecule

Gain

of

function

Oncogene

Signaling

molecule

Gain

of

leads

function

D

Oncogene

Cell

cycle

regulator

Gain

of

RB,

leads

function

leads

to

growth

to

in

cancers

Activated

by

several

growth

Diverse

NMYC

Oncogene

Transcription

factors

ming

of

IDH2

Oncogene

Metabolic

enzyme

Mutation

that

to

growth

opposes

Commonly

the

action

of

leads

leads

to

to

mutated

tion

or

in

reprogram-

breast

Translocated

enzyme

activity

Acute

oncometabolite

due

in

melanoma

to

amplification

amplified

new

an

breast

translocations

Overexpressed

proliferation

metabolism

produces

of

carcinomas

cancers

in

in

regulated

IDH1,

other

signaling

increased

Overexpression

subset

leukemias

phoma,

MYC,

a

and

signaling

factor–independent

Cyclin

Amplified

signaling

factor–independent

BRAF

growth

signaling

transloca-

in

lym-

cancer

Burkitt

lymphoma,

neuroblastoma;

in

diverse

myeloid

leukemia,

chondrosarcoma,

dys-

cancers

glioma,

cholangiocar-

cinoma

BCL2

Anti-apoptosis

Opposes

the

activity

proapoptotic

of

Overexpression

factors

leads

to

resistance

to

Translocated

apoptosis

phoma;

in

follicular

dysregulated

lym-

in

diverse

cancers

PDL1,

PDL2

Host/cancer

cell

Activates

interactions

immune

pathways

in

T

checkpoint

Overexpression

cells

leads

to

immunoeva-

Amplified

sion

in

Hodgkin

overexpressed

in

lymphoma,

diverse

cancers

nlammaon

erscs

umor

seen

n

oowng

we

by

ey

genomc

promoe

nsaby,

ceuar

wc

are

enabng

ransormaon

and

carac-

w

dened

cusson

 •

genes

ever y

(by

o

dscuss

roes

n

a

cancer ;

dscusson

aso

producs

n

a

cancer

no

(e.g.,

reguae

some

accordngy,

e

o

gene

RB

n

and

RB

o

genes

are

o

ras

Tabe

symbos

gene

a

orgns

cancer

(summarzed

or

ese

moecuar

subse

convenon)

are

ceuar

subsequen

progresson.

Muaons

are

and

because

ese

orm

ceuar

e

cancer,

w

5.6).

bass

durng

requen

and

o

er

e

 Progresson

of

a

Self-Sufficiency

often

that

stems

reduce

hese

encode

grow

ow

from

or

even

oncogenes

 Bndng

ds-

den

proen).

drve

acve

n

a

factor

proens

e

absence

can

be

to

ts

signaling

no

(oncoproens)

o

ce

resoved

factor

in

cells

most

proteins

dependency.

proooncogenes

napproprae

growt

mutations

cancer

grow

grow,

no

e

specc

a

acors.

on

wc

ransm

To

a

oowng

receptor

sep

on

and

proens,

RAS.

S ome

pro-

apprecae

grow

ac-

seps:

e

 •

protens

n

the

mem-

vaes

vaed.

by

second

messengers

proens

or

a

cascade

o

sgna

cytoso

to

te

nuceus

ransducon

moe-

cues

 •

of

genes

reguae

a

transcrpton

DNA

factors

a

repcaon

ncrease

and

e

e

a

s

and

oppose

descrbed

suscepbe

cyce,

resung

dauger

ces;

and

umaey

s

process

ces

same

(grow

n

s



(RB,

p53,

corrupon

a

varous

sgnang

proens

grow

and

acor

knase

cycn-depen-

aer)

o

are

acors,

cycn/cycn-dependen

oncoproens

ceran

ese

expresson

bosyness

mutaton

to

o

o

oer

and

w

ave

delver

o

c auses

are

n

cancer

mpar

grow

acors

a

arges

growth

mtogenc

growth

cause

ow.

smuaes

yrosne

e

o

ces.

grow

acor

ac

he

acor

recepors,

downsream

efecve

One

actor

sgnals

actor.

eer

e

o

o

an

acvy

smuae

muaons

creae

a

occur

exampe

convered

o

to

Many

o

erapeuc

common

re ceptors

cells

or

typ e

acor

o

relate d

contnuously,

grow

o

a

sgnang

are

e

nvovng

consuvey

overexpresson

sgnang

An

downsream

knase

capacy

Oncogenc

proens

ng

 Actvaton

ce

wo

progresson

moecues,

cancer

absence

acors

 Transmsson

te

componens,

e ven

recepors

ave an nrnsc yrosne knase acvy a s acvaed by grow

ce

 •

across

o

oncogenc

s

sgna

te

o

 Grow t factor receptors and reated protens.

 Transent actvaton of te growt factor receptor, wc n urn ac-

transduced

cyce

muaed

RAS

 •

te

troug

ose

above

ndependence

ens

of

membrane

dvson

“br”

nbors,

requeny

brane

sgna-ransducng

organees,

ce

drugs.

oncogenes,

reca

ce

and

knase

E ac

characterizes

ce

e

sgnang

compexes)

proen

Signals

that

growth

conver

sgnang

of

growth

eliminate

consuvey

sgnas

Growth

in

gain-of-function

muaons

or–nduced

 •

in

self-sufciency

te

and

promoe

recepors,

mos

The

dvson

(e.g.,

or

normay reguaed on mupe eves by a baance beween proens

we-

e

needed

ce

wc

or

hrougou

taczed

ras

componens

rbosomes)

o

e

even

wen

by

cascades.

surace

same

genes

cromosoma

a

encode

suc

eves

knase

bu

ac-

knase

recepors,

acor

yrosne

pro-

wen

yrosne

norma

grow

Oer

recepors

paways

acvaed

srucuray

nonrecepor

oncogene

no

are

gene

ransocaons

or

aow-

ver y

a

s

s

ABL,

CHAPTER

RAS Growth

as

an

nrnsc

Neoplasia

5

guanosne

rpospaase

75

(GTPase)

acvy

factor

a Growth

factor

ydroyzes

o

GDP ,

reurnng

e

proen

o

s

quescen

receptor

GDP-bound

pon Far nesyl

membrane

e

bound

 •

Inactive

In

cancers,

eadng

o

 on

by

 es e

acvy :

and

sgnas

fac tors

Ac  vae d

RAS

Activation

GTPase

orm

 S g nang

Active

RAS

sae.

muaons,

s

saeguard

amno

acd

s

oten

abrogaed

subsuons

a

by

nerere

anchor

w

Bridging

GTP

R AS

and

RAS

us

ac ors

fac tors

dow ns re am

nercon ne c e d

dow ns re am

rapped

trans c r pton

s mu  aes

s e vera 

s

n

s

acvaed,

GTP-

ncessany.

dow nstream

regu  aors

p a ways.

mmcs

 e

o

Mu a on

of

R AS.

proera-

o

s ome

g row  -promo ng

o

e e c  s

protein GDP

GTP

o

ac  vae d

o

PI3-k nas e

R AS

(e. g . ,

mu a  ons

o

BR A F

n

me anomas

and

Activates

Inactivation

of

nuceus

umors).

Tes e

sg na s

converge

and

upregu  ae

 e

express on

o

genes

 a

on

supp or 

NF1

GTP

ce 

g row ,

ncud ng

prog resson,

Active

mu  pe

by

 e hydrolysis

n

e e c s

RAS

are PI3K

RAF

on

and

anab oc

ds c uss e d

c ycn

M YC ,

a

D,

a

ac or

 rans cr p on

me ab osm

and

re qure d

ac or

ce 

or

w  

g row  ,

c e 

c yc e

w de-rang ng

b o 

o

w c

 aer.

PTEN

Insensitivity

to

Growth-Inhibitory

Signals

Pro-growth MAPK

Mutation

of

oncogenes

is

not

sufcient

to

produce

the

unbridled

metabolism

MYC

proliferation Increased

that

is

characteristic

of

cancer cells;

excessive

growth

protein

also

requires

complementary

mutations

that

inhibit

the

function

synthesis

Activation

of

of

tumor

to

cellular

suppressor

Many D

cyclins

Cell

umor

ce

cycle

cyce,

ces.

As

crca CELL

Fig. 5.16

ulated

normal

cells

apply

“brakes”

and

activity

(a

a

growth

so-called

activated

to

a

factor

receptor

receptor

tyrosine

GTP-bound

state.

with

kinase),

intrinsic

inactive

Activated

a

umor

RAS

tyrosine

kinase

(GDP-bound)

transduces

RAS

RB:

RB

to

the

nucleus

along

two

kinase

pathway

and

the

pathways:

PI3

the

the

expression

of

D

cyclins

pass

kinase/AKT

and

MYC.

pathway,

The

held

in

check

by

GAPs

(GTPase-activating

of

eps

a

or

g

been

descrbed,

RB,

manan

racon

ndrecy

Cellular

the

beore

key

e

o

dsrup

a

bu

wo

reguaor

are

genomc

cancers

e

e

negry

conan

uncon

o

o

o

genec

ese

wo

G1/S

DNA

Proliferation

checkpont,

replcaton

the

portal

through

whch

cells

commences.

activity

members

o

proeraon

e

and

renobasoma

dferenaon

(RB)

amy

o

are

orcesraed

proens,

reerred

which

of

proteins)

ceuar

RAF/

ere

smpy

as

RB.

RB

was

e

rs

umor

suppressor

gene

o

be

RAS

dscovered normally

ave

prolifer-

so-called

o upregulate

wc

beow,

drecy

Governor

must

by ERK/MAP

genes

carcnogeness:

suppressors.

regulates

Norma

signals

TP53,

n

GROWTH

Oncogenic growth factor signaling. When a normal cell is stim-

through

suppressor

mporan

dscussed

aeraons

is

in

p16

progression

ative

which

proliferation.

parcuary

is

genes,

transcription

such

and

s

a

prooypca

represenave.

Approxmaey

40%

o

as

renobasomas are ama, w e predsposon o deveop umors NF1,

whereas

the

activity

of

PI3

kinase

is

antagonized

by

PTEN.

Factors

beng shown

in

green

mutations

in

suppressors

GDP ,

are

oncoproteins

various

that

Guanosine

gen-activated

cancers,

are

often

missing

diphosphate;

protein;

that

PI3K,

are

whereas

GTP ,

activated

factors

due

to

by

shown

red

loss-of-function

guanosine

triphosphate;

phosphatidylinositol-3

are

tumor

mutations.

MAP ,

e

afeced

mito-

kinase.

presence

ed

e

s

n

RAS.

n

encodes

breas

same:

acors

 •

rearranged

wc

cancer.

a

ceran

he

overacvaon

downsream

RAS

genes

o

are

eukemas.

recepor

ne

o

a

yrosne

efec

o

sgnang

In

conras,

knase,

bo

ypes

cascade

s

o

e

oten

HER2

amp-

aeraons

nvovng

RAS

s

and

s

commonly

mutated

oncogenes

n

muc

acqure

oer

ndrecy.

acqured

requred.

DNA;

ces

ener

a

bnd

and

guanosne

and

or

sae

and

grow

by

guanosne

a

hs

an

quescen

muaon

and

dpospae

beween

acor

o

e

[GDP]).

exced

(eer

recepor)

amy

by

Normay,

eads

sae

o

e

canges

sae

(Fg.

grow

s

G

proens

RAS

5.16).

excange

or,

lps

back

o

Acvaon

as

sor

n

GDP

generae

normay

[GTP]

sgna-ransmng

acors

a

o

rpospae

(GTP-bound)

conormaona

sgna-emng

a

(guanosne

(GDP-bound)

recepors

subsequen

exced

nuceodes

o

or

acve

ved

o

cancers,

GTP

RAS.

because

1

,

a

a

pase

copy

domnan

o

e

ama

o

2

specrum

suc

resu,

a

o

by

RB

ra

gene

a

n

s

e

or

sporadc,

caused

by

germne

aways

a

ead

1

.

ree

(and

o

pases

eng;

pase

o

ses

cancers,

RB

a

a

o

sow

com-

one

RB

and

deecve

muaons

many

a

cancers

(CDKs),

o

proens

e

pase

o

revew

ce

varabe

cyce

durng

eng;

o

n

specc

cycns;

and

one

ces

e

wc

ces

M,

wo

roug

cycns,

enzymac

CDK

ce

ave

on

or

RB

more

ces

wc

dauger

e

s

are

repcae

durng

proens

ce

ces

cyce

wose

s

eves

cycn-depen-

acves

nbors

cyce

growng

and

generang

acors:

wose

cancers

mpnge

ave

copy

occur

uncon.

moss,

o

a)

bre

o

S,

o

ner

aee.

modcaons,

progresson

major

wo

oer

peraps

oss

compee

he

e

dferen

uncon,

second

G

o

o

epgenec

mos

RB

and

ndvduas

and down dependng on e ce cyce pase;

knases

bndng

as

varabe

,

no

oscae up

e

a

n

muaon

successve

G

reurn

conroed

den

a

he

er

members

n

deecs

G

are

key

undersand

muaons.

proens

auosoma

weer

somac

As

human tumors. Approxmaey 30% o a uman umors ave RAS

RAS

more

a

aeraons,

To

most

an

deecve

ndvduas.

sporadcay

RAS.

the

as

one

Renobasomas,

and

gene,

o

pee oss o RB uncon due o nacvaon o bo RB aees, an even

a

wc

ransmed

gain-of-function

in

depend

(CDKIs),

on

proens

a ac as negave reguaors o cycn/CDK compexes (Fg. 5.17). he

ranson

rom

e

G

1

pase

o

e

S

pase

consues

an

mporan

CHAPTER

Neoplasia

5

inhibito

K CD

rs

C

p21

in

h

ib

o it

family

rs

in

K y il m fa

C

h ib

it o r

p 2 1

E

D

D K

Cyclin

s

fa m

il y

6 1 p

CDK2

Cyclin

D

D

CDK4

CDK6

Cyclin

C

Cyclin

K

A

D

76

ih ib

2 1

o s

f a A

m li y

Cyclin P

RB

i n

CDK2

RB

CDK1

S

G

1

G

2

M

Cyclin

B

CDK1

i

l

m a f

1 2 p

r

t i

o

i n i

K D

Fig.

5.17

which

CDK6

is

Cell

inhibited

complexes.

complexes,

throughout

ce

cyce

ceckpon,

commed

“governs”

 •

 E ary

and

o

G

1

n

G

1

 Sgnas

ors

RB

a

RB

needed

orm

RB

o

s

are

a

e

and

or

as

a

E2F

enr y

M

e

once

ce

ces

as

This

move

D

(Fg.

or

the

p16

of

e

S

by

family

the

pase

he

p21

acve

ey

acvy

orm

amy,

acvaed

o

wc

a

proliferation

phosphorylation

family

another

are

vruses

e

no

S

recep-

a

e

are

express

RB.

genes

hs

a

TP53:

D/CDK4

resu

n

he

was

compexes,

exampes

o

consuve

mporance

recognzed

n

suc

ces

e

e

move

abnormaes

eadng

RB

par

o

aernave

acvaon

o

n

o

e

roug

pospae

groups

ypopospor yaed

back

no

ncrease

nacvaon

mecansms

grow

conro

e

S

phase

D/CDK4

inhibiting

transition,

and

cyclin

cyclin

cyclin/CDK

D/

D/CDK4

complexes

encode

bnds

nbon.

over

and

e

sow

e

deveopmen

suscepbe

o

HPV

a

nacvae

ypopospor yaed

Perssen

years

e

oncoproens

o

vra

necon

seeds

o

or

(e.g.,

e

ce

In

o

o

and

and

yper-

addona

carcnomas

cer vx

HPV ,

RB

susaned

acquson

squamous

necon

and

RB.

orm

e

a

ses

cr yps

o

onss).

Guardian

of

the

Genome

The TP53 tumor suppressor gene, the most commonly mutated gene in

e

G

1

pase.

I

p53,

RB

can

acor

o

ce

dscover y

e

o

are

acvaon

RB.

mos

muaons

recepors

grow

a

he

or

and

ceran

o

a

ces,

a

s

o

acor,

as

sabze

genes.

a

a

sressed

a

s

exerna

cenra

efecs

conro

RAS

due

p53

o

undergong

o

or

DNA

s

grow

magnan

and

and

ce

o

s

desrucon.

o

In

drve

ransormaon.

nonsressed,

w

ran-

expres-

a

smu

eay

MDM2,

wen

proens

preven

TP53,

a

Sresses

e

mody

ranscrpon

o

s

progrow

conras,

e

ac

by

ncreased

assocaon

In

p53

sur vva.

“sensor”

genes

encoded

sress.

roug

ypoxa.

damage),

arge

proen

nerna

napproprae

because

aby

ese

e

o

medaed

damage,

a-e

enancng

producs

are

acvy),

sor

sgnas,

monor

ce

DNA

arges

(e.g.,

p53,

he

and

a

o

as

ncude

unbrded

proen

rom

“sensor”

vewed

p53

p53

n

oncogenc

a

genes

RAS.

cancer

s

be

scrpon

(e.g.,

common

by

to

1

human cancers, functions to protect cells from stress-induced damage.

remove

cells show dysregulation of the G1-S check point.

cycn

G

cyclin

multiple

HPV)

oropar yngea

cer

ese

the

control

proen

E2F

muaons

acvae

par,

E7

proeraon

son

mos

of

is

by

compexes

nacvae

o

pase.

acor

orm

e

RB phosphorylation are commonly found; as a result, virtually all can-

e

RB

regulate

(e.g.,

HPV

In cancers with normal RB genes, mutations in other genes that control

For

of

level

negatively

RB

bnds

prevenng

grow

and

ces

regenerang

dvded

cellular

provide

pase.

pase,

of

prevens

progresson

permng

released

5.18):

E2F

cycns,

pospaases

newy

of

is

determinant

phases.

no

pospor yae

acors,

S

o

by

block

dvdng.

e

requred

creaed

a

o

key

inhibitors

cycle

and

oows

The

inhibitors

CDK

cell

cyce

acors

are

no

ceuar

CDK

whereas

expresson

CDK6

rom

RB.

ypopospor yaed

normay

durng

RB

n

regulation.

by

various

ranson

genes

 Subsequeny,

rom

e

ranscrpon

o

CDK4

reeases

are

,

upreguae

w

 •

pase

nbs

expresson

 •

because

compeng

-S

cycle

o

ce

and

arge

sressed

ces

CHAPTER

he

GROWTH

INHIBITORS

GROWTH

acors

a

deermne

Neoplasia

5

weer

a

ce

repars

77

s

DNA,

becomes

FACTORS

senescen, or undergoes apoposs are unceran; bo e duraon and p53

(EGF,

PDGF)

e

o

eve

be

o

p53

earned

acvaon

abou

e

may

be

nuances

decdng

o

p53

acors.

here

s

s

muc

uncon.

Stimulate

he

e

CDK

Inhibitors

 •

Activate

p16

and

mporance

oowng

 More

o

TP53

dysreguaon

n

cancer

s

gged

by

consderaons:

tan

70%

of

uman

cancers

ave

defects

n

TP53,

and

oer

p21

cancers

oten

ave

deecs

n

genes

upsream

or

downsream

o

TP53. Baec abnormaes o e TP53 gene are ound n vruay

Inactivate

ever y

ype

breas,

Cyclins

D/CDK4,6

 • Cyclins

Cyclin

 e

ertabe

he

Hypophosphorylated

RB

a

25-od

mos

e

 •

P

 e

P

Cell

p53

to

S

site

E2F

phase

S

site

genes

of

G

o

a

binds

are

to

phase

DNA

required

by

the

for

the

transition

RB

and

cyclin

he

few

Wn

E2F ,

phosphorylation

which

of

s

a

S

in

complex

inhibits

phase

D–CDK4

through

E2F

with

the

transcription

of

the

and

cell

cyclin

tran-

of

E2F

genes

cycle.

When

D–CDK6

o

–S

1

o

syndrome

o

Paens

w

deveopng

compared

cancers

w

seen

eukemas

activates

RB

is

transcription

inhibited

complexes.

checkpoint

as

by

Virtually

a

age,

and

target

of

a

e

are

and

and

s

s

due

to

a

wde

syndrome

specrum

o

genera

popuaon.

sarcomas,

carcnomas

bran

many

vra

caracerzed

TP53,

cancer

ce

umors;

paens

ese

deveop

can-

mupe

o

oncoprotens.

by

e

ese

As

bndng

s

E6,

a

w

o

RB,

ceran

vra

nor-

DNA

oncoproen

carcnoma.

Tumor

which

other

Suppressor

are

tumor

Genes

commonly

suppressor

lost

genes

in

many

are

different

strongly

linked

types.

exampe

s

e

APC

paway.

s

o

yperacve.

of

S-phase

CDKIs

all

such

cancer

as

cells

gene,

APC

wc

promoe

s

e

acvaor,

a

encodes

cyopasmc

a

componen

degradaon

and

w

o

oss

proen

wose

β-caenn.

o

APC,

β-ca-

β-caenn

co

ner

(rom

one

result

of

a

mutation

in

at

coonc

o

genes,

deecve

wc

APC

epeum

β-caenn

suc

copy

akes

o

s

eads

as

(unke

o

cycn

APC

D

and

deveop

name),

a

mos

ncreased

ces

MYC.

oer

Indvduas

adenomatous

dsease

o

ranscrpon

poyposs

caracerzed

by

e

and

e

com-

o

undreds

o

coonc

poyps

by

eary

aduood

genes.

p16,

show

In

yperacvy

grow-promong

wo

o

coon

carcnoma

by

age

50.

hese

umors

ave

somac

which

or

muaons

a

emnae

e

uncon

o

e

remanng

dysreg-

norma G

aee.

nonuncona

ranscrpona

neages),

deeons cyclin–CDK

the

coon,

ypes.

te

sgnang

deveopmen

of

50

young

squamous

uncon

appearance

releases

a

s

bes

and

cassc

e

becomes

activation

–S

1

Hypophosphorylated

factors

phosphorylated

ulation

ung,

Transcriptional

block

inactivate

e

phase

genes

enn

regulation

a

rendered

cancers,

domnan

Transcriptional

s

RB

only

A E2F

The

L-Fraumen

TP53

cance

age

ypes

Lineage–Specific

human

it

one

ceran

dferen

proten

onsar

Unlike

plexes,

o

deas.

encoded by HPV , dscussed earer as an mporan cause o cer vca

and

products

and

occur

o

p53

vruses.

E2F

is

cancer

P

P

P

factors.

by

common

oten

ma

RB

syndrome

n

greaer

umors

breas,

umors P E2F

whose

o

RB

cers

transcription

carcnomas

causes

Hyperphosphorylated

o

scription

cancer

mutaton

magnan

RB

ncudng

eadng

D/CDK4,6

ave

5.18

cancer,

ree

E/CDK2

germne

Fig.

o

e

least

one

copy

o

APC.

Smar

baec

oss

o

APC

s

aso

seen

n

a

sub-

of

se o sporadc coon cancers. Oer exampes o neage-specc umor four

genes;

RB,

CDK4,

cyclin

D,

and/or

CDKN2A

[p16].

EGF ,

Epidermal

suppressor growth

factor;

PDGF ,

platelet-derived

growth

Altered

 •

 Trggerng

morda

G

1

RB

n

nduces

e

and

p21

s

By

o

s

ce

e

DNA

caused

cycng

p53-medaed

damage

many

and

o

by

cycn

successuy,

arress

o

cyce

5.19).

I

ce

s

arres

occurs

ces

n

e

DNA

repar

ae

p21

G

1

a

o

I

pr-

n

o

e

e

prevens

pase.

damage

genes).

aowed

s

expresson

compexes,

repar

damage

e

ce

p53-dependen

me

DNA

(Fg.

D–CDK4

ereby

provdes

expresson

repared

ce

arrest.

nbng

pospor yaon

pause

age

cyce

response

pase

CDKI

ce

genes

(and

oncogenes)

are

dscussed

n

aer

capers.

factor.

(p53

DNA

proceed

Even

aso

roug

cyce.

Cellular

the

distinctive

els

of

form

glucose

hs

aerobc

Metabolism

presence

of

via

of

and

the

penomenon,

gycoyss,

s

ample

cellular

uptake

(fermentation)

hs

dam-

in

a

oxygen,

cancer

metabolism

increased

glycolytic

caed

e

cells

demonstrate

characterized

conversion

of

by

high

glucose

to

a

lev-

lactose

pathway.

Warburg

caracersc

o

many

efect

and

rapdy

aso

known

proerang

as

ces,

ncudng ea ssue, acvaed ympocyes, and umor ces. he “gu-

cose

unger”

son

omograpy

o

umors

s

(PET)

used

o

scannng,

vsuaze

n

umors

wc

va

paens

posron

are

ems-

njeced

w

18

 •

 Inducng ceuar senescence. I e DNA damage canno be repared,

ces

w

acve

p53

may

undergo

senescence,

a

orm

o

perma-

nen ce cyce arres. he mecansms o senescence are uncear bu

seem

e

 •

o

nvove

expresson

p21

o

and

genes

epgenec

a

are

canges

requred

or

a

permaneny

aer

oc

rreversbe

genes.

DNA

damage

by

upreguang

severa

up

e

no

umor

bone

ones

are

Wy

grow.

 Kng stressed ces troug apoptoss. p53 nduces apoposs o ces

w

F-luorodeoxygucose, a gucose dervave a s preerenay aken

proapop-

wo

ces

marrow).

markedy

do

o

pospor yaon

we

as

norma,

umors

are

acvey

dvdng

PET-posve,

and

ssues

rapdy

suc

as

growng

so.

cancer

moecues

(as

Mos

ces

ATP

rey

per

(wc

on

neicen

moecue

generaes

up

o

o

gycoyss

gucose)

36

(wc

nsead

moecues

o

generaes

o

ATP

oxdave

per

mo-

ecue o gucose)? he answer s a aerobc gycoyss provdes rapdy

78

CHAPTER

Neoplasia

5

Ionizing

radiation

Carcinogens

Mutagens

Nor mal

(p53

cell

Cell

nor mal)

loss

Oncogenic

with

mutations

of

or

p53

Stress

DNA

Hypoxia

p53

damage

accumulates

binds

to

DNA

and

damage

p53-dependent

DNA

not

genes

activated

No No

DNA

cell repair,

T ranscription

dependent

and

cycle

no

arrest senescence

independent

effects

on

targets

Mutant

cells

Expansion

GADD45

p21

and

Senescence (CDK

(DNA

inhibitor)

repair)

additional BAX

mutations

(apoptosis

G1

arrest

Successful

Nor mal

Fig.

5.19

aging

The

agents

upregulation

repair

of

dvdng

e

umor

syness

o

ces

pospor yaon

cue

o

gucose

w

ceuar

does

or

and

In

combnes

p53

the

cells

with

genetically

Durng

w

O

to

to

loss

or

damaged

wereas

oxdave

cycle

kinase

with

a

are

H

2

O

and

inhibitor

the

cell

of

CO

2

,

in

G

fails

if

rise

or

moe-

wc

s

and

1

induction

damage

Beyond

cancer

and

(see

grow

yss

moees

(proens,

yeds

pds,

meaboc

needed

and

o

nucec

nermedaes

bud

e

acds).

a

In

are

ceuar

componens

conras,

useu

as

aerobc

ceuar

or

gyco-

e

bocks.

reprogramming

downstream

are

of

deregulated

genes

In

in

o

 unc  on.

sg na ng

5.20).

by

factor

mutations

produced

receptors,

in

by

the

oncogenes

signaling

same

and

cascades

pathways

tumor

that

suppressor

cancers.

c ancer

ac  ons

growth

is

ce s,

ac ors

 s

reprog rammng

oncoproens

mp or  an

and

ce u  ar

and

p ons

o

 e

p ersss

oss

o

cross a  k

me ab osm

ave

b e c aus e

umor

b e we en

b e en

o

er

own

1).

genes.

cycle

Successful

apoptosis

arrest

wo

or

oer

mporan

seen

severa

n

a

oss

o

n

a

o

or

DNA

nks

mer

beween

bre

prog row 

a

ne

cancer

new

efec

afec

genes.

rggerng

promoe

o

meabosm

menon:

e

group

c yce.

o

auop-

S ome

o

n

expresson

or

s

In

o

and

eac

cause

acvy

keepng

o

n

a

w

suppressors.

aeraons

enzymes

muaons

oer

aogeer

muaons

umor

ese

sur vve

envron-

suggesng

In

oncogenc

muaons

wereas

acves

are

o

o

margna

deranged.

auopag y

consss

membranes

under

auopag y,

are

oncomeaboes.

e

and

grow

auopag y

uncon,

caed

proens,

oten

surprsng

Krebs

enzyme

been

a

A

e

acqure

e

wou

neopasms

a

ave

ces

nduce

genes

ceran

parcpae

osm

organees,

condons

enzymes

(Fg .

DNA-dam-

transcriptional

either

efec,

Tumor

suppress or

ds covere d

 e

cell

by

by

neoplasms.

suiceny

 Oncometabosm.

e

mu ae d

S e vera 

 •

induce

Warburg

are

paways

s,

Metabolic

triggers

tumor

p53

repair,

GADD45

p53

malignant

Caper

mena

budng

e

DNA

the

not

normal

 Autopag y s a sae o severe nuren decency n wc ces can-

nbaze

carbon

to

of

“oncomeabosm. ”

any

e

of

fails,

does

eventually

ag y

and

repair

os roug respraon. hs yeds abundan ATP , bu  does no yed

o

Activation

(p21)

DNA

and

 •

Malignant

genome.

CDKN1A

DNA

giving

oxdave

a

the

cycle;

TP53,

needed

pospor yaon,

of

arrest

proliferate,

mocondra

produce

integrity

mutations

cells

Repair

Apoptosis

the

cell

proceed

nermedaes

o

2

leads

repair

cells

maintaining

cyclin-dependent

cells

meaboc

in

hypoxia

allows

componens,

no.

of

by

of

DNA

senescence.

repair,

role

gene)

cases

e

generae

o

afeced

producs

nsance,



canges

n

curreny

a

ead

appears

meab-

unknown

CHAPTER

QUIESCENT

CELL

GROWING

Glucose

CELL

(NORMAL

OR

Neoplasia

5

79

TUMOR)

Growth

Glucose

factor Glucose

Glucose

transpor ter

RTK

RTK

transpor ter

PI3K

Autophagy

Protein

Lipids Akt

Increased

synthesis

glycolytic

inter mediates Nucleotide, Lysosome Lipid

and amino

amino

acid

GROWTH

acid synthesis

catabolism Lactate

Krebs

Mitochondrial Lipogenesis

cycle

metabolites

Increased A TP

CO

2

glutamine

MYC

utilization

RTK

RTK

Glutamine

Growth

factor

Fig.

5.20

starved,

normal

thesis

Metabolism

autophagy

cells

of

Evasion

In

of

certain

Cell

markedly

and

Warburg

cell

growth.

(self-eating)

other

is

upregulate

nucleotides,

pathways

the

and

proteins,

key

induced

glucose

and

factors

Quiescent

as

provide

and

lipids.

such

to

In

cells

a

rely

source

glutamine

cancers,

MYC

the

of

uptake,

deregulate

these

mutations

that

the

fuel.

Krebs

When

provides

mutations

metabolic

cycle

for

stimulated

carbon

involving

ATP

by

sources

growth

pathways,

production;

growth

an

for

factor

alteration

if

factors,

the

syn-

signaling

known

as

effect.

accumulation

of

neoplastic

cells

overexpresson

o

w

o

provide

resistance

to

regulated

g

eves

BCL2,

and

expresson

many

o

oer

BCL2

or

cancers

oer

are

assocaed

anapopoc

mem-

results bers

from

on

which

oncogenic

Death

cancers,

mainly

cell

o

e

BCL2

amy.

death

 •

 Inactvaton of sensors and efectors o ce stress that woud normay

(apoptosis).

As

ces

dscussed

no

n

Caper

componen

1,

peces,

apoposs

a

process

s

e

a

ordery

may

be

dsmanng

rggered

by

trgger

apoptoss s

dea.

As

or

exrnsc

paway

a

umaey

acvaes

a

nvovng

caspases;

ese

n

urn

are

responsbe

or

o

e

ce.

he

sequence

o

evens

a

ead

paways

be

rggered

by

sress-nducng

ceuar

njures

or

o

(e

nrnsc

paway),

or

by

acvaon

o

members

recepor

amy

(e

exrnsc

O

ese

wo

e

paways

o

mocondra

ces

escape

efecor

sense

ce

sress.

Wen

acvaed,

p53

o

canges

p53

o

promoe

uncon

(due

o

apoposs

muaon

n

o

severey

TP53

or

sressed

p53

ces.

nacvaon

ndrec

ordnary

mecansms)

k

aows

ces

o

sur vve

sresses

a

em.

protein

expression

and

TP53

mutation

status

have

import-

paway).

apoposs,



s

e

nrnsc

paway

implications

paway)

a

s

mos

requeny

for

treatment

and

prognosis.

(aso Drugs

as

cancer

downsream

e

ant

known

wc

e

acor

o

BCL2 TNF

by

s

apoposs

grow

woud decency

a

expresson

o

roug can

p53

ordery Loss

dsassemby

mecansm

prevousy,

proeoyc gene

cascade

menoned

e severa

nrnsc

anoer

o

a

bnd

BCL2

and

bock

s

uncon

are

used

o

rea

can-

dsabed cers

assocaed

w

BCL2

overexpresson.

Conversey,

e

presence

n cancer (Fg. 5.21). A decae baance beween proapopoc and ano apopoc

members

no

undergoes

o

e

BCL2

proen

amy

deermnes

weer

TP53

muaons

s

assocaed

w

a

worse

oucome

n

vruay

a

or orms o cancer, key because oss o p53 makes ces ressan o orms

a

ce

apoposs.

he

reease

o

cyocrome

c

by

moo

condra

permeabzaon

promoes

apoposs

va

e

erapy

(e.g.,

radaon

erapy

and

ceran

ypes

o

cemoerapy)

proapopoc a

cause

DNA

damage,

a

poen

nducer

o

apoposs

n

ces

w

proens BAX and BAK, wc are ed n ceck by anapopoc memnac bers

o

e

amy

(e.g.,

BCL2).

A

rd

se

o

proens,

e

cause BH3-ony

oc

and

Wn

n

wc

proens,

appears

anapopoc

s

ramework,

apoposs

o

amy



st

baance

beween

e

DNA

ces

(Fg.

possbe

by

e

o

usrae

nrnsc

e

paway

mupe

damage

ese

ces

ypes

o

reamen

w

agens

are

key

o

be

deecve

n TP53

uncon,

a

because

ave

a

seecve

advanage

a

aows

em

o

sur vve

ese

s

erapes.

rusraed

by

of

BCL2

s

a

we

caracerzed

mecansm

of

Replicative

growth

Potential

umor

ces

rom

apoposs.

Approxmaey

85%

o

carr y

a

cromosoma

ransocaon

a

is

not

(Immortality)

enough

tumor

cells

also

must

for

develop

ocsenescence

ympomas

restraints

tumors

to

achieve

a immortality:

uar

oowng

5.21).

 O verexpresson

proecs

recur

ways

Loss

 •

a

proapop-

Limitless cancer

Cancers

members.

s

medaed

e

p53.

so-caed

drves

e

and

mitotic

catastrophe.

ways

to

avoid

cellular

80

CHAPTER

Neoplasia

5

Deficiency

ROS

growth

Radiation

and

Chemicals

Lke norma ssues, umors requre dever y o oxygen and nurens

of

and

factors

survival

o

signals

remova

1

o

sze

2

o

mm

wase

n

represens

and

wase

grow

can

beyond

wc

as

e

a

producs.

absence

rom

sze

sprou

dua

rom

dsance

ey

ony

across

ave

prevousy

on

are

angogeness,

preexsng

m,

efec

Tumors

o

maxma

dfuse

s

vesses

zaon

e

umor

wc

bood

o

abe

grow

exsng

a

sze

because

s

oxygen,

vesses.

smuae

grow:

o

presumaby

For

o

nurens,

neopasms

o

neoangogeness,

n

capares.

Peruson

Neovascuar-

suppes

needed

DNA

nurens

and

oxygen,

and

newy

ormed

endoea

ces

smuae

e

damage

grow

e Mutation

of

adjacen

resung

umor

umor

ces

by

vascuaure

s

secreng

efecve

grow

a

acors.

deverng

Aoug

nurens

and

p53

p53

Overexpression

of

o

removng wases,  s no norma: he vesses are eaky and daed w

response

a

MDM2

Activation

apazard

penerae

of

Tumor

various

BAX/BAK

sensors

 a

are

paern

ese

o

connecon.

vesses,

angogeness

pro duced

by

Invasve

conrbung

may

 e

be

o

smuaed

umor

umor

ces

may

ready

proangogenc

ac ors

measass.

ces,

by

nlammaor y

ces

(e.g.,

mac-

BCL-2

ropages),

and

o er

resden

sroma

ces

(e.g.,

umor-ass o caed

BCL-XL

brobass).

Proe as es

eab oraed

by

 e

umor

ces

or

by

s roma

MCL-1

Mitochondria

ces

may

as o

exraceuar

s

Cytochrome

c

•

APAF-1

 ur  er

o

In

renorced

by

vas c uar

ac or Caspase

p epdes

mar x.

c yokne.

IAP

ree as e

endo ea

Mos

(HIF),

 u-bown

s e vera

angogenc

cancers,

o er

grow 

no aby,

an

w 

ssue

(VEGF),

yp oxa

 rom

proangogenc

aera ons

ac or

oxygen-s ensve

 e

ac  vy

 a

a

ke y

s abzes

rans cr p on

ncre as e

 e

s ae

e ves

proangogenc

yp oxa-nduced

ac or

 a

drec  y

9

upreguaes

 a Caspase

VEGF

smuaes

expresson.

 e

hs

proeraon

o

cre aes

an

angogenc

endo ea

ces

and

g raden

gudes

 e

3

grow 

o

ne w

suppress ors

p53

vess es

oten

repress es



 e

oward

 e

 e

baance

expresson

umor.

o

o

Mu a ons

avor

VEGF

nvovng

angogeness.

and

For

s muaes

umor

exampe,

 e

expres-

Apoptosis son

Fig.

5.21

tumor

are

in

Intrinsic

cells

red

to

pathway

evade

and

cell

include:

of

apoptosis

death.

(1)

Loss

and

Evasion

of

p53,

mechanisms

mechanisms

leading

to

in

used

tumor

reduced

by

cells

function

o

anangogenc

provdes

a

more

ac or–recepor

moec ues.

p er mssve

sgnang

hus,

oss

envronmen

and

MYC

as o

o

or

p53

n

umor

angogeness.

s muae

 e

ces

Grow 

expresson

o

of

VEGF.

proapoptotic

factors

such

as

BAX.

(2)

Reduced

egress

of

cytochrome

Te c

from

mitochondria

as

a

result

of

upregulation

of

antiapoptotic

dep endence

 erap eu c a  y. such

as

BCL2,

BCL-XL,

and

MCL-1.

(3)

Loss

of

apoptotic

factor

1

(APAF1).

(4)

Upregulation

of

inhibitors

of

Te

umors

proo yp e

on

ang ogeness

an  ang o genes s

c an

dr ug ,

be

ex poe d

b e vac  zumab,

peptidase-acti-

s vating

o

factors

apoptosis

an

an b o dy

 a

neu ra  zes

VE GF

and

s

approve d

or

 e

 re a -

(IAP).

men

no

o

mu  pe

b e en

as

c ancers .

e e c  ve

as

Howe ver,

or g na  y

ang o genes s

op e d;

n  bors

presumaby,

ave

sub cones

o

As dscussed prevousy n e conex o ceuar agng (see Caper umor

1),

mos

norma

uman

ces

can

doube

60

o

70

mes,

ater

wc

ce s

w  

g re aer

 nvasve

c ap ac  y

and

 e

ab  y

o

mg rae

e o

exs ng

bo o d

vess es

emerge,

 ereby

s deseppng

 e

ne e d

or

ces ose e aby o dvde and ener senescence. hs penomenon s ne o ang ogeness.

due o progressve sorenng o teomeres a e ends o cromosomes.

he

are

consequences

drasc.

Sor

o

eomere

eomeres

are

sorenng,

recognzed

as

wen

pronounced,

doube-sranded

Invasion

Invasion

breaks

by

e

ce’s

DNA

damage

“sensors, ”

eadng

o

c yce

arres

and

apoposs

or

senescence

Even

n

ces

w

cancer

aemps

o

repar

e

damage

roug

Metastasis

metastasis

oer

DNA

cells,

stromal

result

cells,

from

and

complex

the

interactions

extracellular

involv-

matrix.

TP53 Mos

muaons,

and

p53-medaed ing

ce

and

DNA

sudes

peran

o

carcnomas,

wc

are

our

ocus

ere.

For

repar e purpose o dscusson, nvason and measass can be broken down

paways

eads

o

cromosome

nsaby,

wc

evenuay

eads

o

eomerase

(a

no

ce

dea.

I,

specazed

pae

or

owever,

e

RNA-proen

addng

ce

reacvaes

compex

nuceodes

o

a

e

e

uses

ends

o

enzyme

s

own

RNA

cromosomes),

as

a

ce

em-

a

successve

Invasion

be

Teomerase

are

s

acve

n

norma

sem

ces

and

s

absen

rom,

wo

a

ver y

eomere

ow

eves

n,

manenance

mos

s

somac

due

o

ces.

In

upreguaon

85%

o

o

95%

o

eomerase.

nex.

no

Matrix

comparmens

remanng

umors

a

o

aternatve

express

eomerase

engtenng

of

and

teomeres

use

a

anoer

depends

and

a

o

manan

separaed

rom

ssue,

proeogycans

mus

e

sages

rs

(see

n

eac

composed

Caper

e

breac

nersa

crcuaon

eac

oer

membranes

o

coagens,

and

gycopro-

2).

measac

Tumor

ces

cascade

nerac

(Fg.

5.22).

w

A

e

carc-

e

underyng

connecve

ssue,

basemen

and

membrane,

umaey

gan

en

access

s

by

penerang

repeaed

n

reverse

e

vascuar

wen

umor

basemen

ces

membrane.

o

exravasae

a

hs

dsan

Angiogenesis

grow,

solid

tumors

develop

their

own

blood

supply

Invason

o

e

ECM

naes

e

measac

cascade

and

s

an

by acve

inducing

basemen

eomeres.

ses.

to

connecve

severa

ce

process

order

(ECM),

DNA

e

Sustained

marx

meca-

on

raverse

recombnaon

exraceuar

he

noma

ermed

o

can-

ECM

In

dscussed

or

ens,

nsm

Extracellular

organzed

ypes

nersa

cers,

evens,

avered. by

presen

the

o

dea Tssues

may

of

sequence

process

angiogenesis. oows:

a

can

be

resoved

no

severa

sequena

seps,

as

CHAPTER

metaoproteases

(MMPs)

Neoplasia

5

produced

by

umor

81

ces

or

sroma

ces

Transformed

(e.g.,

brobass

and

nlammaor y

ces)

reacng

o

e

umor.

he

cell PRIMARY Clonal

eves

expansion,

o

meaoproease

nbors

aso

are

reduced

n

carcnomas,

TUMOR growth,

diversification,

urer

ng

e

baance

oward

ssue

degradaon.

angiogenesis

 •

 Locomoton,

e

degraded

yss.

Metastatic

e

Suc

sep

basemen

movemen

ce–derved

subclone

na

o

nvason,

membranes

may

cemoknes.

be

In

propes

and

poenaed

addon,

umor

zones

o

and

ceavage

ces

roug

marx

proeo-

dreced

by

producs

o

umor

marx

Basement

componens

(e.g.,

cemoacc

acvy

coagen,

amnn)

and

some

grow

acors

ave

membrane Adhesion

invasion

of

to

and

or

umor

ces,

and

sroma

ces

aso

produce

basement

paracrne

efecors

o

ce

moy.

membrane

Vascular Passage

Dissemination

and

Homing

of

Tumor

Cells

through

extracellular

matrix

T umor

ces

requeny

escape

er

ses

o

orgn

and

ener

e

crcua-

on roug bood vesses or ympacs. Mons o umor ces are sed

day

Intravasation

rom

even

sma

cancers.

Severa

acors

seem

o

m

e

mea-

sac poena o crcuang umor ces: We n e crcuaon, umor

ces

are

vunerabe

o

desrucon

by

os

mmune

ces,

and

e

process

o adeson o vascuar beds and nvason o norma ssues may be more

Interaction

with

lymphoid

host

cells

dicu

an

e

na

nvason.

Even

oowng

exravasaon,

umor

ces a grow we n er prmary se may ack crca sroma suppor

or be suppressed by resden mmune ces. Despe ese mng acors, Host



negeced,

vruay

a

magnan

umors

w

evenuay

produce

mac-

lymphocyte

roscopc

The Platelets

Tumor

measases.

sites

of

metastases

are

related

to

two

factors:

the

anatomic

cell

location

embolus

and

the

and

vascular or lymphatic

tropism

of

particular

drainage

tumors

for

of

the

specic

primary

tumor,

tissues.

Extracellular

Mos measases arse n e rs capar y bed avaabe o e umor,

matrix

bu Adhesion

naura

paways

o

dranage

canno

woy

expan

e

dsrbu-

to

on

o

measases.

As

menoned

earer,

or

exampe,

ung

carcnoma

basement

as a g procvy or spread o e adrena gands and e bran, and

membrane

meanoma

ropsm

o

may

e

be

eye

amos

reaed

o

aways

e

spreads

expresson

o

o

e

ver.

Suc

ssue-seecve

organ

adeson

Extravasation

moecues,

or

wc

ces

Metastatic

deposit

a

eren

e

producon

umor

ces

suppor

ssues

e

o

specc

express

grow

avorabe

or

cemoknes

recepors,

o

umors.

unavorabe

and

A

“so”

e

o

n

ese

or

dferen

presence

o

acors

dferen

ssues

sroma

make

d-

umors.

Metastasis Angiogenesis

T umors

vary

greay

n

er

aby

o

measasze,

n

par

because

o

METASTATIC

neren

dferences

n

beavor.

In

genera,

arge

umors

are

more

key

TUMOR

o

measasze

an

sma

umors,

presumaby

because

arge

umors

are

Growth

ypcay presen n e paen or onger perods o me, provdng add-

ona cances or measass o occur. However, umor sze and ype can-

no

adequaey

open

o

muped

neren

Fig.

5.22

The

metastatic

hematogenous

spread

of

cascade:

a

The

sequential

steps

involved

in

of

nterceuar

host

connec tons

between

tumor

ce s.

of

ce s

are

nor ma  y

suc

E-c ad er n.

ed

oge er

by

ad eson

evolve

E-c ad er n

 unc  on

s

o en

c arcnomas

due

o

e er

deeer ous

os

mu a ons

n

n

or

s encng

ass o c ae d

w  

o

E-c ad er n

canges

n

expresson.

ce 

sap e,

L oss

o

ncre as e d

upregu  a on

(e.g .,

o

genes

 brob ass).

 a

Tes e

are

more

canges

 ypc a 

are

o

reer re d

 rans on

 Loca

degradaton

of

te

tssue

by

umor

o

s

s

cance

(relecng

umor).

or

is

capable

inhibit

of

destroying

immune

tumors,

but

can-

responses.

ces

can

be

recognzed

mmune

as

surveance

“oregn”

reers

o

and

e

emnaed

roe

o

e

by

e

mmune

n

consany

“scannng”

em.

e

body

Tumor-specc

T

or

ces

emergng

and

magnan

anbodes

are

ces

ound

many

paens,

s

oten

and

e

exen

correaed

w

and

e

quay

cnca

o

mmune

oucome

nraes

(e.g.,

coon

n

can-

mes ency ma 

o

as

here

s

an

ncreased

ncdence

o

ceran

cancers

n

mmuno-

ep e-

saes.

Receny,

erapeuc

T-ce

responses

(descrbed

agens

a

ac

by

smuang

(EMT).

basement

membrane

and

proeoyc

enzymes,

os

nterstta

n connectve

deermnsc

rom



o

mo   y,

aen

 •

or

and

maer

Surveillance

system

evade

sysem;

decency a -mes ency ma 

me)

poena

(a

E-c ad er n

ce 

cer). ce s

to

desroyng

cancers and

and

cancers,

probabsc

E-c ad-

n s

ndvdua

s

me a -

and er n

number

measac

o

C ar-

sysem s a c

beavor

measass

proens,

mmune as

ce

n

Immune

immune

Tumor cnoma

umor

dferences

Evasion

cers

 L oos enng

by

e

weer

the

tumor.

The

 •

expan

queson

parcuary

matrx

some

advanced

cancers.

aer)

ave

sown

efecveness

82

CHAPTER

Because

nang

nvsbe

ny.

e

nascen

o

hs

mmune

cancers,

e

os

Neoplasia

5

sysem

cancer

mmune

undersandng

s

capabe

sur vva

sysem

as

ed

or

o

o

recognzng

requres

a

a

acvey

e

suppress

modern

and

umor

os

revouon

em-

ces

angens.

be

oucome

mmu-

n

rae

cancer

he

o

(e

oer

presence

many

o

mmunoscore)

kng

uncona

cancers,

and

as

mecansms

some

(e.g.,

CD8+

T

quancaon

predcve

macropages

ces

o

s

e

vaue.

and

predcve

mmune

he

o

ce

e

n-

sgncance

NK

ces)

s

by

being

o

uncear.

mmunoerapy.

Immune

Tumor

The

the

Antigens

major

antigens

products

of

MHC-binding

Because

are

seen

ens,

as

ger

and

o

oers

by

o

are

nove

os’s

T

immune

produce

responses

neoantigens

are

are

mmune

bu

presen

Lke

dspayed

Some

umor

expressed

ces

expressed

no

sysem.

and

are

Escape

cells

lymphoid

with

(e.g.,

eary

n

as

a

cyosoc

cass

angens

cancer

yrosnase

n

normay,

regulation

I

ave

pro-

 •

of

are

no

a

muc

repressed

oten,

nens

o

 •

 Inbton

ess

and

because

presen

o

n

anumor

er

oer

recognon

norma

ces

angens

by

and

ave

been

anbodes,

ey

are

bu

neer

dened

mos

o

nducers

n

ese

nor

umors

are

aso

arges

engage

o

agans

he

mos

Mechanisms

mporan

of

Tumor

mecansm

Destruction

o

umor

o

of

T

T

a

er

nbed.

mmuny.

o

ose

CTLA-4.

CD8+

Immune

o

system

either

inhibitory

mmune

(Fg.

pathways

invisible

designed

evason

ave

been

descrbed

emnaon

s

e

kng

o

e

angens

expresson

ces

usng

Wen

gands,

ces.

are

cass

I

arges

MHC

paways,

ceckpont

o

os

mmuny

moecues

prevenng

e

and

and

s

e

o

or

rae.

n

wo

uncon

preven

umors

by

bes-known

on

o

ese

mmune

umor

because

are

CD8+

ces

umor

o

PDL-1

Bockng

o

and

eer

PDL-2

PD-1

or

on

oer

CTLA-4

ces

w

n

e

T umor

peptide-MHC

Primed

of

CTL

killing

capable

tumor

TCR CD28

B7 B7

CTLA-4

CTLA-4

CD8+

CD8+

cell

T

Anti-

CTL

cell

CTLA-4

NO

COSTIMULA TION

COSTIMULA TION

Activated

Inhibited

Cytotoxic

CD8+

CD8+

granules

CTL

CTL

CTL

CTL

TCR

TCR

Peptide-MHC

PeptidePD-1 MHC

PD-1

Anti-PD-1

ligand

Killing

tumor

Tumor

Tumor

of

cell

cell

cell

Anti-PD-1

ligand

B

T umor

tissue

Fig.

5.23

surface

ceptors,

signals

AH,

Activation

m olecule

leading

to

transmitte d

Pillai

S:

of

with

Cellular

T

hos t

by

a n titum or

inh ibito ry

c ell

im m uni t y

a nt i bod y

ac tiv a tio n.

PD- 1,

and

are

sence

mmune

anbodes

cell

peptide-MHC

TCR

node

ces

ces

ces

CD28

Lymph

PD-1

T

responses

Dendritic

cell

A

or,

compo-

presenaon

acvaon

expressed

“jacked”

engaged

he

T-ce

and

evoved

are

n

CTLA-4

acvaon

ceckpons

PD-1

receptors.

“ceckpons”

PD-1

se-angens

T

a

o

ces.

mpose

hese

expresson

Dendritic

T

and

oten

express e gands or ese recepors (PDL-1 and PDL-2) or nduce

umor ces by CD8+ cyooxc T ympocyes (CTLs) specc or umor

T umor

to

for

5.23):

angen-processng

angens

recepors

Many

vaue

expresson

maure ces, and derepressed n cancer ces (e.g., e so-caed cancer–

angens).

immune

hijacking

immunity.

more

o

n

the

by

mecansms

erapeuc

ose

e

meanomas),

deveopmen,

or

 Antgen oss varants. As umor subcones evove, ey end o eer

MHC-as-

ces

n

ey

evade

cells

Severa

and

ces.

norma

normay

elicit

that

processed

genes

n

genes

are

CD8+

muaed

an

e

are

that

sequences.

angens

angens

eves

tumors

mutated

oregn

pepdes

producs

of

mutated

ese

ese

socaed

Tumor

a g ain

mole c u la r

(B)

all o w s

Bl oc k ad e

le a di ng

to

by

c hec k poi n t

cy t ol y t i c

of

P D -1

a ct i v a t i on

im mu no log y ,

ed

C D8 +

7,

of

T

inh i bi t or s .

c el l s

rec e pt or

CT Ls .

or

(A )

( CTL s )

P D -1

( Re pr i nt e d

Philadelphia ,

2 0 1 2,

Bl o ck a de

to

en ga ge

l i g an d

f r om

of

B7

t he

a br og at e s

A bba s

Sa un ders .)

CTL A- 4

f a mi l y

AK,

c o- r e -

i nh i bi t or y

Li c ht m a n

cells

n-

eads

o

CHAPTER

e

regresson

ce

ung

hs

approac,

componen

normay

oten

as

 •

o

cancer,

o

o

caed

preven

deveop

Hodgkn

Because

auommuny,

e

mecansms

by

o

mmunosuppressve

wc

organs,

umors

reguaor y

cyoknes

T

as

now

gven

an

ese

ncudng

ear,

and

non–sma

and

and

dsease. he rae o somac muaon n sun-exposed skn s greay acce-

eraed, resung n an exraordnary g ncdence o skn cancers suc

evoved

as

basa

cos,

as

we

Defects

in

Instability

magnancy,

a

a

wc

genes.

cancers

o

gged

repar

secon

o

norma

mporance

DNA

mutations

cancer

muagens,

because

s

of

precedng

nvovng

an

responses

producon

o

TGF-

Enabler

DNA repair pathways

accumulation

he

as

DNA

by

dened

o

Aoug

Diseases

are

abe

repar

o

n

tumor growth

he

umans

rare

sense

w

(msmac

by

are

allowing

o

repar

e

nered

n

negry

deecs

aeraons

encouners

damage.

o

n

o

envronmen-

ese

DNA

nuceode

eaures

genec

awas

oucomes

and

repar,

denng

by

genes

e

ypes

repar,

nered

repar

syndromes,

genes,

as

we.

sporadc

dscusson

cancers

Presumaby,

as

n

oten

beow

ncur

ndvduas

ocuses

w

o

and

a

n

o

o

a

Boom

ereby

e

deveopmen

o

he

roe

o

Nonpolyposis

DNA

msmac

Colon

repar

Cancer

genes

n

Evdence

muaons

usraed

by

e

eredtary

nonpoyposs

coon

cancer

wo

and

subsanay

DNA

ger

o

srand

ac

as

w

o

DNA

“spe

T ,

correc

raer

e

s

beng

ceckers. ”

an

deec.

repared,

For

e

e

exampe,

norma

Wou

A

ese



proens

ere

w

T ,

s

encoded

an

e

msmac

“prooreaders, ”

by

erroneous

errors

n

paens

repar

gene

s

w

HNPCC.

nered,

and

a

One

deecve

second

“”

n

copy

e

o

ese

genes

parng

repar

addon

o

G

oer

DNA

aee

a

an

msmac

o

e

same

gene occurs n coonc epea ces. In s respec, ey resembe umor

suppressor genes. DNA repar genes afec ce grow ndrecy by aow-

ng

A

muaons

n

caracersc

deecs

repeas

e

s

o

eng

w

oer

genes

ndng

n

mcrosaee

one

o

o

sx

ese

HNPCC,

durng

e

genome

nsaby

nuceodes

saees

process

o

norma

w

ce

consan.

unsabe

and

e

dvson.

msmac

Mcrosaees

rougou

remans

are

o

paens

(MSI).

ound

mcrosaees

ese

e

are

genome.

However,

ncrease

or

of

n

repar

andem

Usuay,

paens

decrease

n

eng. HNPCC syndrome accouns or ony 2% o 4% o a coonc can-

cers, bu MSI can be deeced n abou 15% o sporadc cancers. MSI-asso-

presumaby

because

e

deec

n

msmac

repar

eads

o

a

g burden o muaons producng umor neoangens. In ac, s ype

o

mmunoerapy

mac

repar

s

deecs

now

approved

regardess

o

or

e

a

umor

recurren

umors

ype—e

rs

w

me

as

or

o

or

o

DNA

are

cancer,

or

E ac

by

s

neura

s

o

and

syn-

agens

suc

repar

by

deecs

recomb-

a

damaged

cross-nked.

ncude,

sympoms

(n

o

Boom

caused

covaeny

and

(n

omoogous

used

compex

anema),

ataxa-teang-

ypersensvy

cross-nkng

repar

DNA

by

radaon

anema).

broken

dseases

sy ndrome,

onzng

DNA

srand

been

Boom

n

he

addon

aaxa-eangec-

deveopmena

deecs

(n

oncogenc

roe

o

deecve

omoogous

recomb-

rsk

rsk

o

breas

ger

o

rsk

aso

are

o

copes

o

n

women

ovaran

n

and

uncon

ound

cancer ;

cancer

meanoma,

bo

a

cancer,

prosae

breas

genes,

o

o

genes

BRCA2,

o

BRCA2

recombna-

breas

cancers.

muaons

men

women,

Smar

and

and

muaons

and

ympomas.

ama

BRCA1

carcnoma

men

BRCA1

omoogous

o

w

germne

bo

n

50%

n

as

as

a

sgy

ncrease

oer

umor

be

ave

a

BRCA2

we

oer

mus

ave

car-

suppres-

nacvaed

or

deveop.

a

Inflammation

as

an

Enabler

Inammatory cells can facilitate tumor cell growth and survival by

producing

ms-

rea-

soluble

Inrang

paens

w

exensve

(e

as

may

sroma

a

cancer

pasc

n

ces,

umors,

cer

(Fg.

o

s

more

As

o

and

enzymes

new

our

a

conceps

undersandng

ope

efecve

a

e

nex

argeed

oca

anumor

erapeuc

ave

o

on

a

umor

and

umor

and

resden

endoe-

may

ac

efecs

ces

oer

mmune

mcro-

hese

promoe

on

sur vva

e

neo-

paways

nvason

and

responses.

In

genes.

provded

agens

ew

anema

ces

ce

so

Anma

e

ces

In

be

as

brobass

acvang

suppressor

suc

can

nlammaor y

acors

enance

cancer.

cacexa.

cancer.

sroma

grow

efecve

umor

o

nlammaor y

resden

and

mody

beween

angogeness,

paopysoogc

5.24).

o

aso

amarks

of

reacon.

reacon

sympoms,

ague,

ces

e

producng

resembe

o

and

cancer-assocaed

ces

suppressng

ey

reason

many

by

promong

deveopmen

ere

efecs

parcuary

and

o

hallmarks

nlammaor y

nlammaor y

sgns

neracons

ndrec

producng

respec,

hese

e

many

drec

deveopmen

s

nlammaor y

enabe

the

cronc

nlammaon),

Inlammaor y

measass,

s

or

ces,

ces.

a

o

rom

ces,

sysemc

inuence

a

cancers,

cronc

sugges

sem

umor

cause

that

provoke

advanced

o

envronmen

factors

cancers

o

anema

modes

caed umors end o be more responsve o mmune ceckpon nbor

erapes,

Homologous

Malignancy

proens

accumuae

a

paens.

syn-

ncreased rae. Muaons n a eas our msmac repar genes ave been

ound

ese

cancer

(HNPCC)

drome, a dsorder caracerzed by ama carcnoma o e coon. Wen

a

by

caracerzed

Fancon

Fancon

e

n

cancer

predsposon

(n

BRCA1

DNA

cancer.

as

ese

o

n

Syndrome

e

o

(n

Tumor-Promoting s

n

naon aso comes rom e sudy o eredar y breas cancer. Germne

sor

Hereditary

carcnoma

syndrome).

cnomas,

and

are

suc

“good”

a

anema

muaons

genes

ce

Repair

dsorders

requred

a

predsposon

asa),

e

cancer

are

DNA

repar deecs, ese somac muaons speed e accumuaon o drver

n

agens,

wc

ese

nered

DNA

anema

musard

on

muaons

in

recessve

Fancon

penoypes

genome

ree

excson

he

pece

In

e

squamous

aaxa-eangecasa)

n

or

Aoug

and

nrogen

on,

cancer.

and

as

recombnaon repar), a o wc are assocaed w an ncreased rsk

deveopng

and

Defects

auosoma

ectasa,

naon,

eg

mananng

born

Malignancy

produced

with

DNA-damagng

genes.

e

be

reavey

persons

sysems

enable

cancer

appear

are

ces

in

of

carcnoma

Recombination

ssues.

drome

Genomic

ce

reamens

oer

oca

nuceode excson repar sysem, wc s deecve n paens w s

mporan

mmune

e

83

oers.

ceckpons

nb

ces

suc

s

e

paens

nlammaon,

endocrne

meanoma,

ympoma,

bockade,

erapy.

auommune

nducon

ncudng

cancer,

ceckpon

o

ncude

umors,

ancancer

nlammaon

 Oter

many

badder

Neoplasia

5

or

cancer

years

e

a

road

paogeness

w

map

reamen

see

e

o

or

can-

expands,

deveopmen

erapes.

men as been approved based ony on a muaona sgnaure.

CLINICAL Xeroderma

Umaey, Paens

w

e

auosoma

recessve

dsorder

xeroderma

a

ncreased

rsk

or

cancers

arsng

n

sun-exposed

skn.

rays

n

sung

cause

cross-nkng

o

pyrmdne

norma

DNA

repcaon.

Suc

DNA

damage

s

e

mporance

dscusson

resdues,

and

pre-

neopasms. venng

NEOPLASIA

o

consders

cancer

e

s

s

efecs

mpac

o

on

umors

paens.

on

er

he

o-

oss,

e

Uravoe

gradng (UV)

OF

pgmentosum

owng are

ASPECTS

Pigmentosum

repared

by

e

cnca

sagng

o

cancer,

and

e

aboraor y

dagnoss

o

84

CHAPTER

Neoplasia

5

Checkpoint

Anti-CTLA-4,

inhibitors

Avoiding

anti-PD-1/PD-L1

immune

Evading

destruction

Reactivation

growth

MDM2

suppressors

Sustaining

Enabling

proliferative

replicative

signaling

immortality

of

p53

inhibitors

EGFR

inhibitors

Deregulating

Tumor-

cellular

promoting

energetics

inflammation

Activating Resisting BCL2

inhibitors

invasion cell

and

death metastasis

Inhibitors

Genome

Inducing

of

PARP VEGF

instability

angiogenesis

signaling

inhibitors

and

mutation

Fig.

5.24

trials

are

Therapeutic

listed.

targeting

(From

Hanahan

of

D,

hallmarks

Weiberg

of

cancer.

RA:

The

Therapies

hallmarks

of

approved

cancer:

for

the

use

next

or

in

advanced

generation.

Cell

clinical

144:646,

2011.)

Clinical

Benign

lems

Effects

and

through

efecs

puar y

gand,

bones

by

L o ca  y

or

nan

 e

produce

paoogc

and

duc

oca

o

e

a

may

due

cancers

or

may

e ad

o

ca as ropc

s e condar y

o

nor ma 

a

sympoms

and

varey

magnan

n

e

o

cancer

prog ressve

crc u a ng

ac ors

me ab osm

exp endure

p ar  y

a r bue d

(TNF),

o o d

o

 ems eves,

w c

p oproen

10%

o

or

15%

o

severa

cancer

paens,

reasons:

 hey may be severe and, n some nsances, may even be ea

 hey

aa

“space--

sma

bar y

ncude

cord

o

a

sur ace,

w 

concurreny :

o

or

rod

ormone,

boacve

or unaey

rare

pasc

me cansms

wounds

by

measac

syndromes

Broncogenc

ca

ves-

non e a ng

mmc

dsease,

ereby

conoundng

rea-

are

dverse

and

are

assocaed

w

many

dferen umors (Tabe 5.7). One umor may nduce severa syndromes

maj or

no

may

pannng

Paraneopasc

rac

spna

compromse

a

men

carc-

 •

avng

e

carcnomas

efecs

seroonn,

subsances.

o

ACTH,

uman

he

may

coronc

oowng

eaborae

andurec

are

e

producs

ormone,

gonadoropn,

and

mos

common

oten

caused

den-

paray-

oer

paraneo-

syndromes:

 Hypercacema

ess

ma g-

o

e

endocrne

ses

o

adrena

adoserone,

 rom

b o dy

and

and

a

o

a

n

cancer

parayrod

may

eadng

o

o

 e

 e

as

 e

hes e

ac  ons

o

 e

ac  vae d

 e

pre ven ng

Tumor

umor

and

b as a 

cacexa,

skee a 

app e e

a

sodum

by

and

me ab oc

c yokne

app e e

o

rae

s

caus e d

ncre as e

n

canges

n

s

C a or e

ncre as e d,

abnor ma  es

or

ne cross

by

umor

n bs

 re e

ay

s

accomp a-

mus ce.

umor

and

ree as e

an

caus e

skee a 

me ab oc

w c

mus ce

cacexa

bu

macropages

 e

paens

s

mos

ormone–reaed

proen

by

(PTHrP)

e

by

syn-

umor

syndrome,

 •

ce

 e

are

ac-

ce s

ac  on

acds

 rom

carcnoma

 Hypercoaguabty,

ra

romboc

e

Suspeced

reaed

o

reeased

Grading

is

rom

reaed

cancer

e

o

venous

s

coaguaon

ncude

ces

mos

o

ACTH

commony

(suc

romboss

prmary

efecs

as

reaed

acors

canges

pronlammaor y

umor

producon

s

seen

or

w

ung.

endocards,

o

o

ces,

(raer

n

o

mucns)

and

o

nonbace-

canges

an

endoea

cancer,

a

and

drecy

a

paees).

uncon

subsances

acvae

e

cascade.

and

and

used

o

conrbuors

Staging

staging

aggressiveness

that

by

eadng

acvy

e

coaguaon

Grading

usuay

ormones

of

a

when

of

are

given

Cancer

used

to

estimate

neoplasm

comparing

the

and

the

to

outcomes

probable

provide

of

a

different

clinical

standard

treatment

protocols.

he sage o e cancer (ow exensve  s n e paen) s assessed

many

by

cnca

and

radoogc

sudes,

wereas

gradng

s

done

by

paoogc examnaon usng eaures a are descrbed beow. In gen-

Paraneopastc

w

sma

can

eabo-

 Cusng

ACTH-ke

gands.

Langerans

corex

 •

enance

tumor

and

anorexa

suc

suppress es

p as e,

o

n

common

ypokaema).

n a ke.

by

arsng

are

p oproens.

paens

n

mporan

 •

producon

pancreac

(e.g.,

suppress

 e

pro duce d

e

umors

demands

g 

ormone

sufer

oss

 ssues,

remans

re duce d

and

 a

o

o

ormones

we a kness

nu r  ona 

o

neopasms

and

p a ens

proound

 e

despe

ces

yperenson,

ne d

by

β

serod

by

by

reaed

ypernsunsm,

Many

s

norma

be e dng,

rep ar

appear

surroundng

Eroson

o

hey

recognon

 hey may be e eares manesaon o an occu neopasm

 roug 

ne c  on

umor

 •

A

comparaby

ne c  on

e

cnca

 •

oca,

srucura

u cerae

s e condar y

o

er

(1-cm)

nduce

o

orgn

sma

e

compcaons

racures

o

and

effects.

umors.

desroy

prob-

umors.

can

marke d

o

and

be

ner erence

arsng

reenon,

or

magnan

systemic

ces.

and

bengn

Tumors

 e

indirect

and

ce s.

w

no

and

local

deermnan

and

compress

common y,

o

cruca

mporan

be e dng

e ar 

a

cause

ypopuarsm,

nvasve

due

Sgns

rae

and

s

may

direct

common

Oer

More

be

o

e

of

bengn

can

magnan

cons e quen

e ven.

bo

rse

wn

compresson

may

ocaon

o e umor or by e eaboraon o ormones ndgenous o e ssue

tumors

variety

adenoma

obsrucon.

s es

a

o

gvng

noma

Tumors

malignant

Anaomc

ng”

of

syndromes

cancer

a

are

canno

sympom

be

compexes

expaned

by

oca

or

a

occur

dsan

n

spread

era,

aoug

vaue

an

e

bo

are

umor

useu,

grade.

e

umor

sage

s

o

greaer

prognosc

CHAPTER

Table

5.7

Clinical

Paraneoplastic

Neoplasia

5

85

Syndromes

Syndrome

Associated

Neoplasms

Causal

Mechanism(s)/Agent(s)

Endocrinopathies

Cushing

syndrome

Small

cell

lung

Pancreatic

Neural

Syndrome

mone

of

inappropriate

secretion

antidiuretic

hor-

Small

(SIADH)

Breast

Hypoglycemia

cell

ACTH-like

Antidiuretic

substance

lung

carcinoma

Parathyroid

TNF ,

or

atrial

natriuretic

hormone–related

protein,

TGF- α,

IL-1

leukemia/lymphoma

Insulin

mesenchymal

Ovarian

hormone

hormones

Fibrosarcoma

Muscle

or

carcinoma

T-cell

Other

and

carcinoma

neoplasms

carcinoma

cell

Adult

Nerve

lung

Squamous

Renal

ACTH

tumors

cell

Intracranial

Hypercalcemia

carcinoma

carcinoma

or

insulin-like

substances

sarcomas

carcinoma

Syndromes

Myasthenia

Lung

carcinoma

Immunologic

Thymoma

Disorders

vous

of

the

central

and

peripheral

ner-

Breast

systems

Dermatologic

Acanthosis

carcinoma

Disorders

nigricans

Gastric

Lung

carcinoma

Lung

Articular,

of

the

Soft

Tissue

and

and

Hematologic

thrombosis

Lung

(Trousseau

Pancreatic

aplasia

carcinoma

products

syndrome

 Gradng.

umor

Gradng

ces

presence

eac

grade

o

essence,

and,

s

n

o

g

umors

o

hormone;

based

some

ceran

ype

and

specc

IL-1,

on

e

arcecura

grade)

are

interleukin-1;

cancers,

magnancy

judge

norma

Erythropoietin

o

descrbed

e

o

range

n

aer

aggressveness

o

wo

e

or

o

e

e

counerpars.

Aoug

soogc

gradng

as

TNF ,

vaue,

boogc

e

beavor

correaon

s

ar

rom

beween

soogc

mar y

eson,

e

presence

sagng

sysem

Cancer

TNM

or

exen

n

cc

orms

eson

used

T

spread

bood-borne

or

hs

use

s

sysem

prmar y

o

e

n

based

clotting

secretion

by

tumor

cells

ymp

a

N

nodes,

Jon

he

regona

and

major

caed

ymp

and

M

cancer,

or

measases.

bu

ere

caracerzed

wereas

and

wereas

M1

number

o

an

n

N1

o

range

o

or

as

T1

su

are

o

T4

eson.

N3

somemes

M0

M2

based

N0

denoes

nodes.

TNM

genera

sagng

on

no

nvovemen

sgnes

e

he

ncreasng

ndcaes

relecs

vares

prncpes.

no

sze;

noda

o

an

dsan

presence

or

spe-

prmar y

T0

s

nvove-

ncreasng

measases,

and

esmaed

measases.

Diagnosis

and

C ommee

casscaon

or

o

complexes

factor.

prog-

appearance

measases.

Amercan

uses

umor,

regona

necrosis

ndcae

number

No

s

s

o

men,

o

perec.

o

curren

Sagng.

sysem:

o

absence

tumor

nvovemen,

(ow

aemp,

oten

factor- α;

dfer

gradng

a

ces,

growth

and

scemes

bu

umor

Immune

caegores

Crera

capers,

o

moses

Gradng

rom

caegores.

cancers

transforming

dferenaon

number

eaures.

and

our

degree

e

TGF- α,

 Stagng. he sagng o sod cancers s based on e sze o e pr-

on

tumor

activate

carcinoma

Cancer nosc

e

secreted

that

hemangioma

on e exen o wc e umor ces resembe (or a o resembe)

 •

to

Immunologic

carcinoma

Various

Adrenocorticotropic

er

due

mucins)

factors

Thymoma

Renal

(e.g.,

Dysfunction

Nephrotic

or

Hypercoagulability

cancers

Hepatocellular

 •

Unknown

carcinoma

Cerebellar

ACTH,

Immunologic

carcinoma

Changes

phenomenon)

Polycythemia

Renal

growth

carcinoma

carcinoma

Other

cell

epidermal

Changes

clubbing

Lung

Red

of

fingers

Vascular

Venous

and

osteoarthropathy

secretion

factor

carcinoma

Breast

Hypertrophic

Immunologic;

carcinoma

Uterine

Dermatomyositis

Osseous,

Immunologic

Teratoma

e

node

matter

diagnosis

of

cancer

Ever y

becomes

Eac

o

strongly

cancer

sampling

of

is

suspected

tissues

and

on

clinical

histologic

grounds,

identication

cells.

year

more

e

avodng

how

requires

e

approac

compex,

oowng

deas

o

o

more

secons

e

aboraor y

sopscaed,

aemps

ecnooges.

o

dagnoss

and

presen

more

e

o

cancer

specazed.

sae

o

e

ar,

86

CHAPTER

Morphologic

In

mos

n

many

 e

 O pen

sue

no

w  

or

d  c u 

ma  g nan

e quvo c a 

are

o

ce s

 e

o

ar r ve

ana ys s

a

c an

c anc er

b as e d

m cros c op e.

mor po og c

ess en  a 

mor poog  c

d ag nos e

under

canges ,

 e

be

on

cn c a 

d ag nos s.

ac e ve d

 e

Howe ver,

and

S ampng

  roug 

 e

pro ce dures :

(surgca)

or

bopsy.

sampng

examned

on.

s

 e

e aures

umor

o ow ng

 •

o

c as es

radoog c

o

Methods

ns ances,

app e arance

Neoplasia

5

In

by

e

some

secton.

hs

saned,

on

roune

cases,

e

meod,

and

evauaon

hs

based

gross

s

wc

sen

a

under

severa

e

opporuny

appearance.

he

emaoxyn-and-eosn

bopsy

n

examned

wn

afords

s

or

sampe

e

mnues.

rapd

s

e

seec

sans

evauaon

vas

by

be

xa-

frozen

seconed,

perms

majory

s-

can

ater

quck-rozen,

mcroscope,

In

o

bopsy

soogc

o

cases,

ro-

A

zen-secon

dagnoss

ngusng

some

 •

 Fne-neede

evauang

spread

can

aso

se.

ands

a

used

s

ess

e

 Cytoogc

luds

cancer.

cer vx

o

a

rapd,

(Fg.

s

bu

and

s

n

ds-

denyng

used

I

bopsy,

specc

meod

or

aspraon

s

used

mos

mage

n

means

re-

gudance

vruay

and

are

any

body

experenced

o

deny

(or

esons.

rom

ssue

meod

deny

ecnque

useu

and

by

w

nvovng

surgca

preparatons

o

wdey

examned.

morpoogc

deveoped

be

umors

wdrawn

masses

cancerous

anoer

5.25),

and

sensve,

o

(Papancoaou)

Inay

anoer

esons,

an

can

necon).

Ces

saned,

examne

presence

provde

s

papabe

and

magnan

(e.g.,

(FNA)

nvasve

accuracy

and

masses.

sde,

evauae

provdes

excude)

or

on

be

FNA

bengn

aspraton

o

g

processes

suspcous

ou

queny

 •

beween

nonneopasc

as

or

scrapes,

e

precancerous

now

used

o

FNAs,

deecon

esons

evauae

o

o

e

suspeced

B magnancy

na,

n

peura,

many

oer

percarda,

ses;

and

o

deny

umor

cerebrospna

ces

luds;

n

and,

abdom-

ess

com-

Fig.

5.25

smears,

mony,

or

evauaon

o

oer

orms

o

smear

nuclei.

Protein

few

o

proens

or

oer

moecues

expressed

by

umor

broad

roe

n

esabsng

e

dagnoss

o

specc

cancer

 •

Severa

compemenar y

 Immunostocemstry

Tssue

secons

are

s

meods

a

saned

are

poweru

ce

o

among

pe,

e

cancers

dagnoss

 Fow

usng

bodes

In

o

aed

w

a

meod

s

n

used

ce

e

o

a

roune

empoys

n

o

e

can

 •

containing

Nuclear

eary

dsease

Markers

be

o

drugs

and

magnan

and

o

oer

ess

or

umor

uterine

are

cervix.

(A)

typical.

In

(B)

normal

Abnormal

sheet

of

malignant

is

cells

evident,

with

and

large

one

cell

hyperchromatic

a

recurrence

are

n

n

paens

curren

use

are

Cytogenetic

much

smaller

in

size

is

and

in

mitosis.

with

A

compact,

are

seen.

(Courtesy

University

of

of

Dr.

Richard

M.

DeMay,

Department

Chicago.)

o

For

demonsrae

and

en

and

ym-

luorescen

an-

anayzed

angens

or

a

sed

nances

umor

 •

or

markers

cancers;

are

used

owever,

known

n

Tabe

cancer

dagnoss

o

emaopoec

cancers

suc

as

eu-

and

o

parain-embedded

acd

probes

ecnque

o

deny

bnd

can

be

secons

w

used

parcuar

n

specc

o

wc

arge

subype

luoresceny

regons

emaoogc

cromosoma

aberraons

o

e

mag-

n

any

ype

genome

n

anayss.

w

hs

 Hybrdzaton

e

umor-assoc-

or

nucec

genome.

san-

e

ympomas.

sampes

abeed

canges

assays

ceran

suppor

and

 Fuorescence n stu ybrdzaton (FISH) s a meod perormed on

res

e

ces.

umor

w

 •

anbodes.

eukemas

o

exam-

o

bran

of

tumor

perms

copy

hs

DNA

e

number

meod

s

to

arrays

dencaon

a

used

are

o

of

o

beow

DNA

sma

e

dagnose

probes

deeons

resouon

and

subype

o

a

and

span

oer

kar yoypc

ceran

knds

umors.

ey

dagnoss.

5.9

Nucleic

A

Acid

number

response

o

o

Markers

ecnques

erapy

sequences

or

used

nvove

o

e

ragmens.

dagnose

umors

dencaon

Cncay

o

and

oow

specc

reevan

DNA

exampes

o

er

and

suc

Markers markers

subypes

o

cancer

aberraons;

a

ew

are

gy

saen

assocaed

exampes

o

w

suc

parcuar

assocaons

cromo-

are

gven

n T abe 5.8, aong w nucec acd markers dscussed aer. Cyogenec

meods

neutrophils,

 Conventona karyotypng o meapase cromosomes s requeny

kemas

esabses

dferenaon

are

Bocemca

screenng

used

combnaons

wc

nuclei,

Pathology,

RNA

soma

a

pleomorphism

interspersed

used

dsngusng

are mos useu n assessng e response o erapy and n deecng

Many

the

nuclei

soog y.

anbodes

appearances.

casscaon

moecues

markers.

and

dferenaed

erapeuc

suspenson,

ormones,

as

aso

varous

surace

n

cancers

morpoogc

poory

I

penoype

tumor

success

a

arges

meod,

ces

enzymes,

var yng

smar

carcnoma.

s

oban

dferenaed

o

proen

o

 Crcuatng

poory

keran

agans

bound

ng

•

o

o

o

cytometry

pomas.

are

orgn

deecon

presence

•

from

small

used:

adjunc

specc or proens o neres. hs meod s useu n deermnng

e

with

subof

ypes.

smears

cells

ces lobate

a

flat

Markers

Idencaon

as

Papanicolaou

large,

neopasa.

commony

used

o

deny

cromosoma

aberraons

ncude:

wc

 •

are

sed

esng

 Cmerc

oten

hese

s

n

done

nucec

creae

Tabe

mos

acd

uson

sequences

5.8

e

are

sequences.

genes

are

Among

requeny

encodng

ypes

e

o

abnormaes

Cromosoma

cmerc

umor-specc

and

or

oowng:

rearrangemens

mRNAs

can

be

and

proens.

deeced

even



CHAPTER

Table

5.8

Affected

Examples

of

Cytogenetic/Molecular

Markers

of

Importance

in

Specific

Neoplasia

5

87

Cancers

Gene/

Chromosomal

Region

Chromosomal

Event

Detection

Translocations/Fusion

ABL

Fusion

with

through

BCR

9;22

Clinical

Importance

Genes

gene

Karyotype,

FISH,

RT-PCR

Diagnosis

translocation

of

of

chronic

therapy;

tic

myeloid

marker

response

and

used

leukemia;

to

diagnose

follow

target

therapeu-

minimal

residual

disease

Gene

Amplification

NMYC

Gene

amplification

FISH

HER2

Gene

amplification

FISH,

Marker

IHC

Target

of

of

poor

prognosis

therapy

in

in

neuroblastoma

“HER2-positive”

breast

cancer

Chromosomal

Deletion(s)

1p

Segmental

deletion

FISH,

DNA

array

Diagnosis

good

Point

of

oligodendroglioma;

marker

of

prognosis

Substitution

JAK2

Valine

for

phenylalanine

substitution

Table

5.9

Circulating

Tumor

in

codon

DNA

sequencing

Diagnosis

617

blood

Tumor

antigen

polycythemia

vera

(a

type

of

Markers

Marker

Prostate-specific

of

cancer)

(PSA)

Use

Prostatic

carcinoma

Screening

test

(controversial);

following

response

to

therapy

Human

chorionic

gonadotropin

(HCG)

Choriocarcinoma

Some

Alphafetoprotein

(AFP)

Germ

mixed

cell

germ

antigen

(CEA)

Colonic

CA-125

presen

n

ver y

ow

abundance

usng

carcinoma

sensve

poymerase

can

reacon (PCR) meods. Many emaopoec neopasms, as we as

a

ew

sod

genes.

o

In

drugs

erapy.

can

be

er wse

 •

umors,

oer

and

so

are

Fnay,

used

o

are

dened

nsances,

by

deec

o

presence

o

deec

PCR-based

sma

asympomac

e

producs

mporan

sensve

 Snge-nuceotde

e

numbers

or

ess

o

o

uson

parcuar

genes

purposes

or

cancer

uson

are

o

cmerc

resdua

arges

seecng

sequences

ces

n

o-

paens.

varants

and

“ndes. ”

As

w

cmerc

gene

producs, snge-nuceode varans (pon subsuons) and ndes

(sma

and

nserons

ereore

oncoproens

deec

 •

or

based

a

ve)

are

purposes

unque

deecon

dsncon

deeons)

dagnoscay

 Antgen-receptor

exbs

and

o

gene

drug

arges

proeraons

o

recepor

monocona

o

and

and

rearrangements.

T-ce

beween

specc

or

n

some

oer

ereore

cancer

cases

are

ypes

generae

mporan

o

erapy.

rearrangemens

o

are

mporan,

gudng

 •

s

or

T

angen-recepor

mmunogobun

(neopasc)

ympocyes.

eac

and

therapy

Following

response

to

therapy

and

B

genes,

genes

poycona

ce

PCR-

aows

(reac-

Following

response

to

therapy

Following

response

to

therapy

prong

deveoped

o

assess

of

anayze

epgenec

cancers.

a

snge

Dverse

gene,

modcaons

ecnooges

sequence

an

genome-wde,

ave

enre

quany

been

genome,

a

o

e

RNAs expressed n a ce popuaon, measure many proens smu-

aneousy,

advances

and

ave

aeraons

cay

cos.

nex

For

owever,

suppressor

perormed

accurae

uar

be

genes.

on

mos

ceners

esons

a

on

ecnques.

a

o

new

e

he

mey

ceners

e

o

o

o

and

mpac

now

a

n

usuay

oreseeabe

prognoss

perorm

w

and

normaon

uure,

e

cancer

and

gene

umor

bomarker

n

morpoogc

o

n

reasonabe

rouney

su

been

erapeu-

a

compemen

and

as

deny

ason

hese

caaogng

proooncogenes

ecnques

assessmen

meaboes.

specmens,

soog y

combnaon

man

seekng

a

umor

For

ce’s

sequencng

muaed

secons.

and

by

are

n

academc

convenona

ssue

a

cancers.

commony

hese

o

sysemac

uman

many

dagnoss

arrved

e

sequencng

cover

rom

snapso

genec

exampe,

a

a

varous

generaon

panes

w

n

ake

enabed

“aconabe”

obaned

Because

to

 Moecuar

researc;

sma

response

carcinoma

carcinoma

Ovarian

Following

tumors

tumors

Hepatocellular

Carcinoembryonic

cell

ess

mos

paens

new

moec-

6

Genetic

Diseases

O U T L I N E

Mendelian Disorders: Diseases Caused

by

Single-Gene Defects,

Transmission

Diseases

Proteins,

Diseases

of

Single-Gene

Disorders,

88

by

Mutations

in

Genes

Encoding

Structural

by

Mutations

in

Genes

Encoding

Receptor

or

Channels,

by

97

Disorders

Involving

Autosomes,

Cytogenetic

Disorders

Involving

Sex

Trinucleotide

Caused

Proteins,

Abnormalities,

Cytogenetic

Single-Gene Disorders

90

Caused

Proteins

Diseases

Patterns

Caused

Structural

88

with Atypical

Repeat

Mutation

Diseases

Caused

by

Mutations

Diseases

Caused

by

Alterations

Patterns

Diseases,

in

98

Chromosomes,

100

of Inheritance, 101

101

Mitochondrial

Genes,

102

90

Mutations

in

Genes

Encoding

Enzyme

Prader-Willi

and

Angelman

of

Imprinted

Syndromes,

Regions:

102

93 Diagnosis of Genetic Disorders, 102

Complex

Multigenic

Disorders,

96 Genetic

Cytogenetic

Disorders,

Test

Indications

Numerical

Genec

Abnormalities,

abnormaes

Modalities

and

Applications,

102

97

a

for

Genetic

Analysis,

104

97

cause

ceuar

dysuncon

are

one

o

e

produced

prnc-

or

pa causes o dsease. Some genec dseases are nered (ama) due o e

by

sgnang

muaons

n

genes

beongng

o

e

same

meaboc

paways.

presence o germne muaons, wereas oers sem rom acqured somac

Transmission

Patterns

of

Single-Gene

Disorders

muaons (e.g., cancer) and are no ransmed rom one generaon o e

nex. I s mporan o dsngus beween congena and genec dsorders.

Congena

means

“born

w ”;

some

genec

dseases

are

congena

(e.g.,

penykeonura), wereas oers are manes aer n e (e.g., Hunngon

dsease).

Conversey ,

congena

or

syps).

paogencay

no

In

a

s

congena

caper,

neresng

we

genec

dseases

dscuss

dseases.

are

genec

some

W e

o

e

n

orgn

more

concude

e

(e.g.,

common

caper

Autosomal

Dominant

Disorders

Autosomal

dominant

disorders

fested

mal

the

by

revewng curren ecnooges a are used o dagnose genec dsease.

DISORDERS:

DISEASES

allele

Wen

c d

 •

CAUSED

the

heterozygous

(out

as

one

a

SINGLE-GENE

e aures

 Reduced

three

caused

patterns

autosomal

by

of

single-gene

Mendelian

recessive,

Aoug

rare

or

defects

(mutations)

inheritance:

follow

autosomal

one

of

 •

dominant,

6%

o

dseases

ype

8%

o

oow

ndvduay

a

assocaons

are

6.1),

aken

ogeer

mendean

kep

 •

n

mnd

ospa

paerns

o

somemes

wen

admssons.

nerance,

compex,

bu

Mos

snge-gene

consderng

reecng

mendean

dsease-assocaed

e

dverse

unc-

o

some

correae

cases,



w

may

dsorders:

genoype

are

penoypcay

 Mutatons

types.

88

n

hs

genes)

is

of

are

one

sufcient

mani-

abnor-

to

cause

o

and

av ng

o

and

o er

e

s

ds e as e.

auos oma 

varable

ner

 e

 e

on

o ow  ng

dom  nan

expressvty

deecve

no,

Te

gene

are

aver age

e ac

add -

ds e as es :

common.

deveop

e

No

a

dsease,

genoypes

be

n

expaned

dferent

genes

penomenon,

knd

o

dsease,

even

wn

one

or

amy.

and

symptoms. Because a 50% oss o enzyme acvy usuay

suc

by

cases

s

no

conerance

we

o

undersood.

varans

n

may

cause

ermed

smlar

genetc

or

dentcal

eterogenety,

dsorders

encode

compexes,

componen”

proens

oer

an

enzymes,

suc

as

or

a

wc

may

nereres

mumerc

be

w

dsruped

e

assembes.

by

ormaon

A

proen

e

o

a

presence

e

o

a

uncona

“posons”

e

 •

 In many autosomal domnant condtons, te age at onset s delayed,

 •

 Not all afected patents ave afected parents. Assumng e absence

wt

symptoms

and

o

nonpaerny,

o

new

were

n

muaons

derved.

sgns

suc

rst

paens

nvovng

her

appearng

sbngs

e

are

e

egg

n

adultood.

dsorder

or

e

unafeced

s

usuay

sperm

and

rom

no

a

arbuabe

wc

ey

rsk.

In

oer

Disorders

Autosomal

peno-

s

usuay

acvy o s norma counerpar s caed a domnant negatve.

norma;

genes a mpac e penoype; ese are caed moder genes.

 •

a e c e d

p er  a n

wo

muproen

n s suaon, e ra s sad o ave low penetrance. Wy penoypes

a

sgns

“bad

uas, a penomenon caed varable expressvty. In oer nsances, some

a

a s o

ger-order

genoype–peno-

duce many penoypc efecs (pleotropy) a may dfer among ndvd-

w

and

srucura proens, ranspor proens, or proens a uncon wn

 Penotypc efects o specc sngle-gene mutatons vary wdely. Some pro-

persons

s

cance

penetrance

same

nan

ons o varous afeced gene producs (Tabe 6.2). Severa caveas mus

be

autosomal

sexes

inheritance

can be compensaed or, e genes a are afeced n auosoma dom-

(Tabe

pedarc

smpe

for

both

the

 A 50% reducton n te normal gene product s suicent to produce cln-

cal

X-linked.

dsorders accoun or approxmaey 1% o a adu ospa admssons

and

two

so

DEFECTS e

Diseases

the

p aren

50%

ndvduas

BY

of

affect

state,

disease.

 ona 

MENDELIAN

in

oten

lian

a

of

Autosomal

recessive

disorders,

gene.

are

Recessive

diseases,

caused

by

which

genetic

Inheritance

are

the

defects

largest

that

group

alter

of

both

mende-

alleles

of

CHAPTER

As

by

 •

e

he

a

 •

a

genera

rue,

auosoma

recessve

dsorders

are

caracerzed

 •

 Reduced

oowng:

ra

25%

does

cance

n

no

o

usuay

beng

afect

te

parents,

wereas

eac

sblng

as

afected.

te

eous

afected

patent

(te

proband)

s

te

product

o

a

rers

consangun-

of

S e l e c te d

Disorder

Me ndelian

Estimated

o

te

 Dseases

Dominant

kidney

disease

1

in

500

1

in

1000

resultng

because

spherocytosis

1

syndrome

in

5000

(Northern

disease

Recessive

1

in

5000

1

in

10,000

1

rers

in

400

(U.S.

be

afected.

Aoug

new

rom

enzyme

are

decences

normay

are

usually

presen

n

arge

deecs

n

bo

autosomal

excess

resulng

rom

and

alleles,

produce

are

penoypes.

fibrosis

to

cance

1

in

3200

(U.S.

Caucasians)

1

in

3500

(U.S.

Ashkenazi

Jewish;

1

Mucopolysaccharidoses—all

types

1

in

in

1

in

are

X-linked

frequently

recessive

are

than

and

therefore

caracerzed

by

females.

e

oowng:

o

ofsprng,

as

wo

emzygosty).

ave

ony

Sons

o

one

X

cromosome

eerozygous

women

(a

sae

ave

French

n

wo

o

recevng

e

muan

one

gene.

 An afected male does not transmt te dsorder to sons, but all daug-

 •

 Because males ave only one “dose” o most X-lnked genes, deects n

 •

 Heterozygous

o

afected

males

are

carrers.

Canadians)

genes

are

lkely

to

produce

dsease

n

males.

10,000

emales

rarely

ave

te

ull-blown

dsease

because

tey

25,000

ave

diseases—all

dsorders

male

X-lnked Phenylketonuria

more

 •

ters disease

disorders

much

African-Amer-

icans)

storage

o

males

reerred

Glycogen

may

 he dsease s transmtted by asymptomatc eterozygous emale car-

Inheritance

anemia

Tay-Sachs

one

Disorders

X-nked

Cystic

least

Europe)

 •

cell

at

enzymes

decences,

X-linked

affect

Sickle

or

Prevalence

Most

Autosomal

gene,

Inheritance

hypercholesterolemia

Huntington

mutant

severe

X-Linked

Marfan

tan

Dis o rd e rs

suicen

Hereditary

common

muaons or recessve dsorders do occur, ey rarey produce peno-

ony

Polycystic

less

 Most autosomal recessve dseases are nerted rom parents wo are car-

recessve

Familial

are

ypes because o e keood a e oer aee w be norma.

Prevalence

Autosomal

expressvty

dsorders.

 Onset s requently early n le.

 •

6.1

varable

89

 •

marrage.

Table

and

domnant

Diseases

 •

I te mutant gene s rare n te populaton, tere s a strong lkelood

tat

penetrance

autosomal

Genetic

6

a

normal

allele.

However,

genoype–penoype

assocaons

50,000

n

emaes

are

compcaed

by

e

penomenon

o

X-nactvaton

types

(lyonz aton),

X-Linked

Duchenne

Inheritance

muscular

 wo

dystrophy

1

in

3500

males

(U.S.)

1

in

5000

males

(U.S.)

X

cromos omes

cromos ome

average, Hemophilia

 roug 

express

a 

 e

 a

o

s

are

mo s

s ence d

 nac  vae d

ce s

nor ma 

w c

express

a  ee.

s

 e

In

o

 e

e ary

n

“cos en”

mu ae d

mos

genes

on

one

de veopmen .

a

r andom ;

a  ee

 ns anc es ,

and

  s

s

o

 e

T e

enc e,

a 

o

X

on

c e s

su  c en

o

a

G6PD

deficiency

1

in

10

males

(U.S.

African-

bun

or

compeey

suppress

 e

d s e as e

peno yp e,

bu

on

o c c a-

Americans)

son

 ere

s

pronounce d

ske w ng

oward

s  enc ng

o

 e

nor-

a

Glucose-6-phosphate

dehydrogenase.

ma 

Table

6.2

Biochemical

Basis

and

Disease

Marfan

Pattern

Abnormal

Autosomal

Familial

Inheritance

Dominant

of

Selected

a  ee

(unavorabe

Mendelian

Protein

yon za on ).

Und er

suc

Disorders

Protein

Function

Inheritance

hypercholesterolemia

Low-density

syndrome

lipoprotein

receptor

Cholesterol

transport

Fibrillin

Extracellular

matrix

protein

Collagen

Extracellular

matrix

protein

a

Ehlers-Danlos

Hereditary

syndrome

spherocytosis

Neurofibromatosis,

Adult

polycystic

Autosomal

Cystic

type

kidney

1

ankyrin,

Neurofibromin-1

disease

Recessive

fibrosis

Spectrin,

Polycystin-1

CF

Hexosaminidase

disease

β-Thalassemias

cell

X-linked

anemia

Recessive

Hemophilia

Duchenne

Fragile

X

dystrophy

syndrome

a

Some

forms

are

autosomal

Cell

membrane

Regulator

Cell:cell,

of

stabilizer

RAS

signaling

cell:matrix

interactions

regulator

hydroxylase

Ion

channel

Enzyme

Enzyme

Hemoglobin

Oxygen

transport

Hemoglobin

Oxygen

transport

Factor

Coagulation

Inheritance

A

muscular

(NF-1)

transmembrane

Tay-Sachs

Sickle

4.1

Inheritance

(CF)

Phenylalanine

and

protein

(PKD-1)

Phenylketonuria

α-

or

recessive

disorders.

VIII

Dystrophin

Cell

FMRP

RNA

factor

membrane

translation

stabilizer

regulator

crc ums anc es ,

90

CHAPTER

ema es

ess er

may

exb

deg re e

Diseases

 an

Caused

Genetic

6

e aures

a e c e d

by

o

 e

Diseases

ds e as e,

 oug 

usu a  y

o

a

Ehlers-Danlos

Mutations

in

Genes

Ehlers-Danlos

syndromes

orders

by

caused

are

a

collagen

heterogeneous

genes

or

genes

group

that

of

dis-

regulate

assembly.

are

sngle-gene

dsorders

a

may

ave

auosomal

Syndrome

domnan Marfan

syndrome,

a

connective

tissue

disorder

of

autosomal

inheritance,

is

caused

by

mutations

affecting

e

Fbrn-1

s

encoded

by

e

FBN1

recessve

modes

o

nerance.

A

leas

sx

varans

are

clncal

varans

are

and

recognzed.

brillin-1.

 • Pathogeness.

or

domgenec

inant

in

Proteins

Pathogeness. EDSs

Marfan

(EDS)

defects

Encoding collagen

Structural

Syndromes

ma es.

gene,

wc

maps

molecular

 Deicency

of

bases

e

o

e

enzyme

more

ysy

common

ydroxyase.

In

s

as

ollows:

varan

called

e

o kyposcoloss ype, decreased ydroxylaon o lysne resdues n ypes

cromosome

15q21.

I

s

a

gycoproen

secreed

by

broblass

a

s I

e

major

componen

o

mcrobrls

ound

n

e

exracellular

and

III

collagen

molecules. o

many

ssues.

Mcrobrls

provde

a

scafold

a

enables

nereres

w

e

covalen

cross-lnkng

o

collagen

marx

e

As

w

oer

enzyme

decences,

s

dsease

s

nered

e

vascular

proper as an auosomal recessve dsorder.

assembly

o

elasc

bers

and

are

parcularly

abundan

n

e

aora,

 •

 D eicen

syness

of

ype

III

coagen.

s

varan,

e lgamens, and e clar y zonules o e ocular lens, predcably e ype, ssues

a

are

mos

promnenly

afeced

n

Maran

s

nered

abnormales

n

Maran

syndrome

are

arbuable

o

by

alure

o

connecve

ssues.

However,

oers,

suc

as

weakness

bowel

appear

o

be

relaed

o

excessve

domnan

dsorder

and

s

ransormng

o

ssues

rc

n

ype

III

collagen

carac-

(e.g.,

wall),

predsposng

em

o

rupure.

e

blood

causave

bone muaons

overgrow,

auosomal

a vessels,

srucural

an

syndrome. erzed

Many

as

grow

oten

lead

o

e

expresson

o

a

deecve

collagen

III

acmonomer a nereres w assembly o normal collagen, a classc

or-β

(TGF-β)

acvy.

Normal

mcrobrls

sequeser

TGF-β,

and

loss example

o

mcrobrls

ereore

ncreases

e

boavalably

o

s

 • Excessve

TGF-β

sgnalng

as

deleerous

efecs

on

o

a

“domnan

negave”

muan.

cyokne.

vascular

 D eicen

syness

of

ype

V

coagen.

s

varan

s

also

nered

smoo as an auosomal domnan dsorder and resuls n classc EDS. More

muscle

developmen

and

e

negry

o

e

exracellular

marx.

O an

noe,

angoensn

recepor

blockers,

wc

lower

blood

pressure

90%

encode nb

mouse

e

acvy

models

o

o

TGF-β,

Maran

mprove

aorc

and

cardac

uncon

e

eye,

 •

and

 Skeea

Abnormales

e

mally

suc

Paens

long

arced

cardovascular

abnormaes

syndrome.

legs,

palae;

as

 Baera

e

Clncal

ocular

mos

promnen

sysem,

e

a

as

mos

and

may

excavaum

skeleon,

eaure

o

Maran

abus;

(aracnodacyy);

jons.

presen.

(a

e

deeply

Spnal

e

ces

depressed

abnor-

a

g-

deormes

s

deormed,

sernum)

s

abnormal

or

a

and

(subuxaon)

lgamens

s

of

(ecopa

e

ens

ens)

abnormaly

suggesve

 C ardovascuar

sysem

Fragmenaon

because

o

n

8).

o

o

a

s

dagnoss

abnormaes

o

e

elasc

aneurysmal

ese

yperenson

o

and

o

ssue

jons

n

collagen,

mos

lack

rauma

are

suc

varans

adequae

n

njures

as

o

ensle

ypermoble

Mnor

ssues

also

ncludng

cornea

and

s

so

due

e

o

weakness

mos

e

genes

a

skn,

EDS.

sreng,

e

skn

produce

lgamens,

Because

e

also

gapng

e

skn

s

s

ragle

deecs,

and

may

ack

lead

rupure

renal

o

norma

o

oer

e

deacmen;

ense

colon

and

sreng.

serous

and

njures

large

e

n

areres;

dapragmac

deec

e

n

absence

rupure

o

erna.

specc

a

s

Diseases

Caused

Receptor

Proteins

o

Maran

consue

a

bers

dlaon

n

e

and

canges,

and

w

called

cysc

agng.

Loss

meda

medal

e

aorc

valve

rng,

gvng

rse

rea

o

e

also

suppor

o

in

Genes

Encoding

Channels

pres-

Hypercholesterolemia

hypercholesterolemia

aorc

is

caused

most

commonly

by

muta-

o in

the

gene

that

encodes

the

receptor

for

low-density

lipopro-

aora

dssecon

medonecross,

o

Mutations

or

syndrome.

serous

aorc

by

o

caracer-

(LDL)

and

is

characterized

by

high

serum

cholesterol

levels

(see early-onset

atherosclerosis.

occur

causes Pathogeness.

dlaon

rc

n

bers

connecve

rauma,

e

and Caper

Tssues

nvolved

collagen

connecve

tein predsposes

are

vulnerable

tions fe.

muaons

surgcal repar or ner venon s accomplsed only w grea dicuy

Familial

 •

carr y

deormy.

cange.

gly

paens

collagen.

Features.

jons,

Familial

ence

afeced

V

yperexensble

elongaed

ngers

be

n

ollows:

obvous

slender,

yperexensble

dsocaon

suspensor y

sc

arms,

and

pecus

pgeon-breas

 •

are

ave

kyposcooss

exbng

are

ype

n

syndrome.

and

Morphology.

o

and

Famlal

ypercoleserolema

s

an

auosomal

domnan

ncomdsorder w a requency o 1 n 500 n e general populaon, makng  one

peence.

e

cardac

valves,

especally

e

mral

valve,

may

be o e mos common mendelan dsorders. Undersandng s paogeness

excessvely

dsensble

and

regurgan

(loppy

vave

syndrome), requres a workng knowledge o normal coleserol meabolsm.

gvng

rse

o

mral

valve

prolapse

and

congesve

cardac

alure Coleserol may be derved rom e de or rom endogenous syne-

(see

Caper

8).

Dea

rom

aorc

rupure

may

occur

a

any

age ss. Deary coleserol s ncorporaed n e nesnal mucosa no cy-

and

s

e

mos

common

cause

o

dea.

Less

commonly,

cardac lomcrons,

alure

s

e

ermnal

Some

s

Clncal Features. e prevalence o Maran syndrome s esmaed o

be

1

res

n

5000.

are

cells

o

more

mos

sporadc,

an

600

paens

exbs

par,

Approxmaely

parens.

wde

rom

arsng

dsnc

70%

 rom

Molecular

are

de

causave

penoypc

efecs

o

85%

novo

dagnoss

dagnosed

dferng

wc

are

delvered

o

e

lver

and

aken

up

by

epaocyes.

even.

cases

FBN1

no

on

a

specc

n

e

n

large

o

e

a

e

germ

ere

FBN1

sem,

muaons.

and

e

because

eaures.

beleved

FBN1

amlal

muaons

clncal

s

are

roune,

muaons

based

varaon

o

s

o

are

gene;

dsease

leas

n

o

s

excreed

erol

also

coleserol

no

s

e

eners

blary

syneszed

by

e

rac

as

meabolc

ree

epaocyes

pool

coleserol

and

(see

or

released

laer),

ble

no

and

acds.

e

some

Coles-

crculaon

(Fg. 6.1). e rs sep n s process s e secreon o rglycerde-rc

very-low-densy

lpoproen

(VLDL)

no

e

blood.

Wle

n

e

crcu-

laon, e VLDL parcle loses rglycerdes roug e acon o lpases

expressed

by

lpoproen

endoelal

(IDL)

and

cells

and

low-densy

s

convered

lpoproen

o

nermedae-densy

(LDL).

e LDL recepor paway akes up wo rds o crculang LDL par-

cles, as well as IDL parcles, wereas e res o e LDL parcles are aken

CHAPTER

Genetic

6

Diseases

91

wc s e rae-lmng enzyme n e synec paway; (2) smulaes e

ormaon o coleserol esers, a sorage orm o coleserol; and (3) nbs

e

syness

and

down-regulaes

e

number

o

LDL

recepors

on

e

cell

surace, proecng cells rom e excessve accumulaon o coleserol.

In

most

mutations

lism,

instances,

in

the

resulting

Overall,

familial

LDL

in

hypercholesterolemia

receptor

accumulation

LDL receptor

protein

that

of

cholesterol

mutations

LDL

account

impair

for

90%

is

caused

LDL

in

of

by

metabo-

the

plasma.

cases.

e paucy o LDL recepors on lver cells also mpars e ranspor o

IDL no e lver, so a greaer proporon o plasma IDL s convered no

LDL.

Paens

levels

o

bosyness.

upake

w

amlal

coleserol

no

as

a

ypercoleserolema

resul

o

bo

Hypercoleserolema

macropages

and

reduced

leads

vascular

o

walls

us

ave

caabolsm

an

ncrease

medaed

g

and

n

by

serum

excessve

coleserol

e

LDL

scav-

enger recepor, resulng n premaure aeroscleross and coleserol-rc

deposs

n

sot

ssues

called

xantomas.

Mos

o

e

remanng

cases

o

amlal ypercoleserolema are caused by muaons n e gene encod-

ng

Apo

wc

ese

B-100

proen

conrols

(6%–10%

degradaon

muaons

are

o

clncally

o

LDL

cases)

or

recepor

muaons

(2%

ndsngusable

o

n

cases).

rom

PCSK9

gene,

Paens

ose

w

w

amlal

ypercoleserolema caused by LDL recepor muaons.

Clncal

caused

Features.

by

plasma

LDL

Heerozygoes

recepor

coleserol

w

muaons

levels,

wereas

ave

amlal

a

wo-

o

omozygoes

ypercoleserolema

ree-old

may

ave

elevaon

n

excess

o

o

a

ve-old elevaon. Aloug er coleserol levels are elevaed rom br,

eerozygoes

coleserol

reman

deposs

aeroscleross

more

severely

asympomac

(xanomas)

resulng

afeced,

n

unl

along

coronary

developng

adul

endon

arery

le,

wen

seas

dsease.

cuaneous

ey

and

develop

premaure

Homozygoes

xanomas

n

are

cldood

and oten dyng o myocardal narcon beore e age o 20 years.

Recognon o e crcal role o LDL recepors n coleserol omeo-

sass led o e desgn o e san amly o drugs a s now wdely used

o lower plasma coleserol. ey nb e acvy o HMG-CoA reduc-

ase,

ncreasng

Smlarly,

PCSK9

e

level

recognon

uncon

led

o

a

o

LDL

recepors

paogenc

e

on

epaocyes

PCSK9

developmen

o

muaons

PCSK9

(see

cause

nbors,

Fg.

6.1).

ncreased

wc

also

are now approved or reamen o ypercoleserolema.

Fig.

6.1

normal

with

of

Low-density

individuals

normal

levels

low-density

(IDL)

bearing

uptake

Apo

B-100

(LDL)

(left),

and

delivers

cholesterol

metabolism

In

intermediate-density

the

cholesterol

bearing

to

is

packaged

Apo

B-100

step

for

and

clearance

lipoproteins

hepatocytes,

rate-limiting

in

in

Cystic

Fibrosis

Cystic

brosis

individuals

receptor-mediated

cholesterol

reductase,

(VLDL)

and

hypercholesterolemia.

receptors

hepatocyte

lipoproteins

(LDL)

familial

LDL

HMG-CoA

Some

low-density

of

in

lipoproteins

inhibits

synthesis.

lipoprotein

and

where

its

cholesterol

export

into

Apo

proteins.

E

transport

exocrine

and

that

of

VLDL

by

lipoprotein

lipase

in

capillaries

releases

glands

are

then

stored

in

fat

cells

and

used

as

a

source

of

and

autosomal

to

recessive

secretion

the

linings

of

of

disorder

abnormally

the

of

epithelial

viscid

respiratory,

mucus

ion

from

gastrointestinal,

tracts.

very

Cysc

bross

(CF)

s

e

mos

common

le-sorenng

triglycerides,

genec which

an

reproductive

Pathogeness. Lipolysis

is

leads

energy

in

dsease

n

Caucasan

populaons,

w

an

ncdence

o

skel-

approxmaely 1 n 2500 brs. I s caused by muaons n an epelal on etal

muscle.

Lipolysis

converts

VLDL

into

IDL

and

some

LDL,

completing

cannel the

cycle.

In

individuals

with

familial

hypercholesterolemia,

a

deficiency

proen

(CFTR) dysfunction

and

els

of

increased

of

blood

B-100

tional

LDL

receptors

cholesterol

LDL

prevent

(the

LDL

deficiency

of

“bad”

and

LDL

leads

to

synthesis,

IDL

form

of

binding

receptors,

decreased

which

cholesterol).

to

the

LDL

thereby

LDL

together

and

IDL

produce

Mutations

receptors,

causing

encoded

by

e CF

transmembrane

conductance

reguator

or

gene

locaed

a

cromosome

7q31.2.

Penoypes

vary

wdely

clearance

elevated

affecting

creating

a

lev-

Apo

func-

hypercholesterolemia.

dependng

on

e

underlyng

causave

muaons.

e

mos

common

CFTR muaon s a deleon o ree nucleodes codng or penylalanne

a

amno

leadng

acd

o

s

poson

508

degradaon

(ΔF508)

and

loss

o

a

causes

uncon.

msoldng

e

small

o

CFTR,

amoun

o

e

muaed ΔF508 proen a reaces e cell surace also s dysunconal. up

by

a

scavenger

recepor

or

oxdzed

LDL.

Aoug

LDL

recepors

are Muaons

wdey

dsrbued,

approxmaey

75%

are

ocaed

on

epaocyes,

so

meable ver

as

a

cenra

roe

n

LDL

meabosm.

e

paway

nvolves

LDL

o

e

LDL

recepor,

endocyoss,

and

enzymac

degradaon

LDL

parcle

wn

lysosomes,

releasng

e

coleserol

load.

e

no

only

s

used

or

membrane

syness,

bu

also

conrols

omeosass

roug

a

sopscaed

eedback

conrol

o

sysem

suppresses

coleserol

syness

by

nbng

e

acvy

o

e

epelal

6.2);

membranes

owever,

e

relavely

consequences

mper-

are

ssue-specc.

In

swea

ducs,

e

major

uncon

o

o

s

CFTR

reabsorb

lumnal

ereore,

loss

o

clorde

CFTR

ons

and

uncon

augmen

leads

o

sodum

decreased

reabsorp-

reabsorpon

sodum

clorde

and

producon

o

yperonc

(“saly”)

swea

(see

a Fg.

(1)

(Fg.

coo

leserol

render

ons

ree on.

coleserol

CFTR

clorde

o s

e

o

bndng deec

o

n

e

6.2,

top).

In

conras

o

swea

glands,

n

respraory

and

nesnal

enzyme epelum,

CFTR

s

mporan

or

lumnal

secreon

o

clorde,

and

3-ydroxy-3-meylgluaryl–coenzyme A reducase (HMG-CoA reductase), as

a

resul

o

CFTR

muaons

reduce

clorde

secreon

no

e

lumen

92

CHAPTER

Genetic

6

Diseases

NORMAL

LUMEN

OF

CYSTIC

SWEA T

DUCT

LUMEN

FIBROSIS

OF

SWEA T

DUCT

+

Cl

Na +

Cl

CFTR

Na

ENaC

NORMAL

CYSTIC

FIBROSIS

AIRWA Y

AIRWA Y

Nor mal

Dehydrated

mucus

mucus

+

Cl

Fig.

6.2

and

sodium

epithelial

6.2,

bottom).

s

In

Cl

O

2

cystic

sodium

cells,

and

defective

regulator;

causes

in

water

(CF),

H

a

channel

Bottom,

reabsorption

mucociliary

in

airways,

and

sodium

sodum

defect

Patients

the

action,

epithelial

lumnal

Cl

O

2

chloride

sweat.

ENaC,

ncreased

+

Na

fibrosis

concentration

conductance

Fg.

H

Top,

increased

(see

+

Na

with

the

CF

leading

mucous

channel

in

sweat

have

to

plugging.

CFTR,

for

epelal

clorde

drves

sodum

waer

cannels.

Increased

reabsorpon

rom

e

nracellular

lumen,

sodum

o

mucus

coang

e

underlyng

epelal

cells.

deydrang

In

leads

o

deecve

mucoclary

acon

and

e

of

the

Cystic

increased

chloride

Na

H

O

2

chloride

secretion

mucous

fibrosis

intracellular

e

lungs,

bronc s

layer

and

coating

transmembrane

sodium

and

abs cess es

s

conduction.

bronce c  ass.

D e vel opmen

o

lung

common .

 Pancreatc

abnormates

e are

presen

n

85%

o

90%

o

paens.

In

s severe

deydraon

causes

Cl

O

2

and

 • layer

H

absorpon cronc

roug

duct

decreased

dehydration

responsible

+

Na

cases,

e

pancreac

ducs

are

obsruced

by

mucous

plugs,

accumulaon causng aropy o e exocrne glands and progressve bross (Fg.

o

vscd

secreons

a

obsruc

ar

passages

and

predspose

o

recur6.4).

ren

pulmonary

necons.

Vscd

secreons

also

may

obsruc

e

on, ac

ducs

and

e

vas

deerens,

leadng

o

pancreac

loss

o

pancreac

exocrne

secreon

mpars

a

absorp-

pancre-

nsuicency

leadng

o

vamn

A

decency,

wc

may

conrbue

o

and squamous meaplasa o e pancreac duc epelum.

mae nery, respecvey. In addon, CFTR reguaes e ranspor o

 • bcarbonae

ons

n

e

epea

ces

o

e

exocrne

pancreas,

and

 Meconum

small dysuncon

causes

e

acdcaon

o

pancreac

secreons.

s

precpaon

o

mucn

and

mpars

e

acvy

o

dgesve

as

rypsn

a

uncon

bes

under

alkalne

a

o

ype

o

nans

bowel

obsrucon,

because

o

e

may

presence

occur

o

n

ck

e

plugs

mucus.

enzymes

 • suc

nesne

resuls o

n

eus,

s

condons,

bo

 Lver nvovement may lead o mucus pluggng o ble canalcul,

o accompaned by ducular proleraon and pora nammaon.

wc

exacerbae

pancreac

nsuicency. Hepac

seaoss

resung

n

nvovemen Morphology.

Lesons

var y

n

dsrbuon

and

severy

s

epac

encounered

Over

me,

crross

noduary.

n

ewer

Suc

an

10%

may

deveop,

severe

o

epac

paens.

 Azoosperma

and

nfertty

are

ound

n

95%

o

e

afeced

genoype. maes

 •

common.

dependng

 • on

s

dfuse

 P umonar y

d s eas e

semmng

 rom

ob s r uc   on

and

 e

ar

p ass ages

broncoles

w  

o en

marke d

cre ng

cel ls.

s

are

 e

mos

s er  ous

d send e d

yp er pl as  a

and

Sup e r  mp os e d

w  

e aure

 ck

yp er  ropy

 ne c  ons

(Fg .

muc us

o

g ve

 e

r s e

sur vve

o

aduood;

baera

absence

of

e

vas

def-

 ne c  on erens

o

wo

6.3).

s

a

requen

indng.

Te

ass o c  ae d

muc us -s e-

o

s e vere

Clncal

and

Features.

sympoms

e

vary

clncal

rom

mld

manesaons

o

severe,

may

o

CF

are

presen

a

proean.

br

or

Sgns

years

CHAPTER

Fig.

are

6.4

Pathologic

dilated

glands

and

are

Enzyme

changes

plugged

atrophic

Diseases

Genetic

6

and

Caused

of

with

cystic

fibrosis

eosinophilic

replaced

by

Diseases

by

fibrous

Mutations

in

the

mucin,

in

93

pancreas.

and

the

The

ducts

parenchymal

tissue.

Genes

Encoding

Proteins

Phenylketonuria

Fig.

6.3

Lungs

of

a

patient

who

died

of

cystic

fibrosis.

Extensive

Phenylketonuria mucous

plugging

and

dilation

of

the

tracheobronchial

tree

are

phenylalanine The

pulmonary

secretions

parenchyma

and

pneumonia;

is

consolidated

the

greenish

by

a

combination

discoloration

is

of

the

Pseudomonas

of

infection.

Pittsburgh,

(Courtesy

of

Dr.

Eduardo

Yunis,

by

mutations

that

disable

the

enzyme

both

Penylkeonura

(PKU)

s

an

nborn

error

o

meabolsm

Children’s

a Hospital

caused

hydroxylase.

product

Pathogeness. of

is

apparent.

afecs

1

n

10,000

lve-born

Caucasan

nans.

e

mos

common

PA.)

(classc)

orm

s

relavely

common

n

persons

o

Scandnavan

descen

and uncommon n Jews populaons and n persons o Arcan descen. aer,

and

may

be

reaed

o

e

nvovemen

o

one

o

aenon

organ

or

many. s

Approxmaey

5%

o

10%

o

e

cases

come

a

br

o soon

ater

because

o

meconum

leus

Exocrne

pancreac

auosomal

penyaanne

n

a

majory

(85%

o

90%)

o

paens

w

CF

dsorder

ydroxyase

s

(PAH),

caused

wc

by

a

blocks

severe

e

decency

converson

o

nsuicency penylalanne

occurs

recessve

or

and

s

o

yrosne

and

leads

o

yperpenylalannema.

Afeced

assocaed nans are normal a br bu wn a ew weeks exb a rsng plasma

w

nerance

o

wo

“severe”

CFTR

muaons

(e.g.,

ΔF508/ΔF508), penylalanne level, wc mpars bran developmen. As penylalanne

wereas paens carryng a eas one “md” CFTR muaon oten rean levels pancreac

exocrne

uncon.

Pancreac

nsuicency

s

assocaed

rse,

yeldng maabsorpon

o

proen

and

a.

e

auly

a

absorpon

may

normally

mnor

meabolc

paways

become

more

acve,

w nermedaes

a

are

excreed

n

large

amouns

n

e

urne

nduce and

n

e

swea,

mparng

a

srong

musy

or

“mousy”

odor

o

afeced

decency saes o e a-soluble vamns A, D, and K. Hypoproenema nans. may

be

severe

enoug

o

cause

generalzed

edema.

Perssen

o resuls

n

e

oer

recal

prolapse

gasronesna

demonsrae

exceen

Cardorespraor y

ons,

obsrucve

common

Saes).

w

n

as

pancreas-suicen

cause

By

18

o

suc

Sgncan

sadowed

sur vval,

by

grow

as

and,

dsease,

s

paens

dsease

and

now

n

suc

and

s

w

no

ese

w

paens

perssen

o

severe

aaes

CF

oten

aerugnosa

lae

pancreac

rd

n

e

and

ung

are

n

mos

Uned

colonzed

Burkodera

and

w

common

nec-

e

e

are

course

nvolvemen;

mos

Clncal

menal

o

pumonae,

yrosne,

paens

w

CF

(ater

cardopulmonar y

and

s

ore-

mproved

cause

o

Features.

I

unreaed,

dsably

ese

swea

elecrolye

s

usually

suspeced

concenraons,

based

caracersc

on

or

neurologc

eczema

never

also

seen.

nake

mmedaely

adulood;

walk

abnormales,

are

penylalanne

PKU

(nellgence

cldren

s

melann

due

o

e

deecve

syness

syness.

owever,

and

6

mons

wo

decreased

ese

early

ater

by

quoen

rds

n

le;

le

an

PKU

60).

canno

can

ereore,

Deary

o

o

pgmenaon

complcaons

br.

women

less

age

rd

Sezures,

oer

ar

s

severe

one

and

avoded

nans

reamen

cldbearng

alk.

o

be

produces

Abou

are

skn,

by

screened

dsconnued

wo

ave

and

lmng

PKU

or

ater

mus

go

on a low penylalanne de pror o concepon because o e eraogenc

efecs o penylalanne and s meaboles on e eus.

Storage

Diseases

ransplan-relaed

Lysosomal

dagnoss

coloraon

requred

dea

complcaons).

e

pale

s

Lysosomal n

nans’

wc

CF .

assocaed

genera,

as

cor

80%

w

occurs

e

cldren

deveopmen.

Pseudomonas

lver

dsease

and

o

usuay

(approxmaey

age,

pulmonar y

lver

10%

compcaons,

dea

o

as

compcaons

pumonar y

years

paogens

cepaca.

many

penoype

Afeced

darrea

perssenly

clncal

elevaed

ndngs

(pulmo-

ciencies

olites

of

and

storage

enzymes

certain

diseases

stem

required

from

for the

mutations

degradation

that

of

lead

various

to

de

metab-

organelles.

nary dsease and gasronesnal manesaons), and amly sory, and

s

esablsed

pancreac

by

sequencng

enzyme

e

replacemen

CFTR

gene.

erapy,

as

e

well

use

as

o

anbocs

blaeral

lung

and

rans-

Pathogeness.

number

o

planaon, as mproved oucomes n paens w severe CF . New drug

complex

erapes

derved

rom

may

aken

also

expresson,

ave

and

exended

dsease

o

are

now

avalable

uncon

e

o

medan

cldood

no

a

a

muaed

le

mprove

CFTR

expecancy

cronc

dsease

e

oldng,

molecules.

o

o

40

years,

aduls.

membrane

ese

advances

cangng

a

leal

be

Lysosomes,

ydrolyc

subsraes

no

soluble

nracellular

up

no

e

enzymes

e

dgesve

a

end

are

producs.

organelles

cell

by

sysem

nvolved

a

are

o

n

cells,

e

ese

subsraes

undergong

pagocyoss.

I

an

conan

breakdown

may

auopag y

enzyme

a

o

be

or

requred

or e caabolsm o a subsrae s mssng, parally degraded nsoluble

meaboles

accumulae

wn

e

lysosomes

(Fg.

6.5).

In

addon,

94

CHAPTER

Genetic

6

Complex

Diseases

T ay-Sachs

substrate

ndase

Dsease

Tay-Sachs

by Normal

lysosomal

Lysosomal

(G

Ganglosdoss:

M2

Deicency

n

Hexosam

A)

loss

of

disease,

the

function

most

common

mutations

gangliosidosis,

affecting

expression

of

is

caused

the

enzyme

enzyme

hexosaminidase A. degradation

deficiency

Pathogeness.

A

In

Tay-Sacs

dsease,

glycolpds

called

gangosdes

A

accumulae

and

glal

njur y

and

n

many

cells

s

no

s

ssues,

rougou

e

undersood.

may

nduce

e

bu

In

damage

CNS.

many

s

e

conned

molecular

cases

unolded

mosly

e

proen

bass

muan

o

neurons

or

neuronal

proen

msolds,

response

(see

Caper

1),

Small B

B

wc

can

lead

o

apopoc

cell

dea.

diffusible

end

products

Morphology.

Elecron

Afeced

mcroscopy

cells

appear

reveals

swollen

worled,

and

onon

somemes

skn–lke

oamy.

layers

o

C

membranes

rougou

swollen

ganglon

nonmetabolized

STORAGE

nans

red”

rena

spo

o

wn of

autophagosome

with

2

or

degradation

and

unafeced

bu

pallor

resuls

cenral

varan

moor

canges

are

auonomc

e

rena

common

br,

ese

were

perperal

mos

a

nerves,

nvolved,

relavely

e

of

intracellular

by

severe

years.

neurologc

neurologc

Tay-Sacs

Askenaz

carrers

o

n

ound

nervous

produced

a

by

conrasng

macula.

Tay-Sacs

weakness

begns

dsease,

a

mparmen,

3

o

blndness,

6

dysuncons.

dsease,

lke

oer

Dea

lpdoses,

and

occurs

s

s

Jews,

esmaed

among

o

be

1

wom

n

e

mos

requency

o

30.

organelles

Niemann-Pick

tion

Accumulation of

e

ollowed

among

Type A and

Disease

type

mutations

B

Types

A

and

Niemann-Pick

that

affect

the

B

disease

enzyme

is

acid

caused

by

loss

of

func-

sphingomyelinase.

SECONDARY of

toxic

In

more

3

eerozygous

Accumulation

n

s

6.6).

lysosome

common

Defective

perperal

e

normal

age,

progressvely

fusion

n

(Fg.

products

mons

Defective

lysosomes

usually

cells

Features.

appear

e

CNS,

e

Clncal

Stored

e

sysem.

“cerry

PRIMARY

wn

proteins

aberrant

STORAGE mitochondria

Pathogeness.

myenase,

breakdown

Induction

of

Generation CELL

cell

e

more

o

damage

free

Pathogenesis

of

s

ype

spngomyeln

caused

A

no

an

by

n

a

decency

ype

ceramde

B,

and

resulng

o

spngo-

n

mpared

posporylcolne.

of

radicals

pagocyes 6.5

n

DEATH

Morphology.

Fig.

dsease

severe

lysosomal

storage

diseases.

In

this

In

and

ype

A,

neurons.

excess

e

spngomyeln

macropages

accumulaes

become

sufed

n

w

example,

droples or parcles o e complex lpd, mparng a ne vacuolaon a

complex

enzymes

or

substrate

(A,

B,

malfunction

and

insoluble

this

primary

from

as

of

dysuncon

naure

o

Ceran

the

o

e

of

nereres

wc

are

and

common

in

B),

the

and

cearance

leads

o

o

a

deficiency

of

based

mos

dseases

 Hepatospenomegay,

In

addition

accumulaon

o

on

e

eFg.

6.1).

Wen

to

result

n

s

(Table

group:

parally

dgesed

pagocyes

dysfuncton,

maeral

bu

caused

also

by

a

no

only

cascade

o

by

accumulaon

secondar y

evens

o

und-

rggered, Fig.

by

macropage

acvaon

and

release

o

6.6

lysosome

sorage

dsorders

are

ver y

rare;

only

a

ew

o

the

are

consdered

cells

electron

in

Tay-Sachs

microscope

disease.

shows

A

portion

prominent

of

a

neuron

lysosomes

with

e whorled

condons

Ganglion

cyoknes under

common

(Supplemenal

bocem-

meaboles

 Ceuar

more

cyoplasm

radcas.

 Frequent CNS nvovement w assocaed neuronal damage

Mos

e

organees

ree

 •

example,

o

dysfunctional

 •

or

oamness

dea.

accumulaed

 Onset of dsease n nfancy or eary cdood

gesed

or

incomplete,

deecve

cell

 •

o

lysosomal

effects

desrucve

 Autosoma recessve transmsson

due

is

toxic

accumulation

 •

n

is

lysosomes.

 •

meaboles

there

of

catabolism

subdvded

o

If

series

wastes.

generae

e

a

storage

the

w

may

dsorders

are

to

toxic

ulmaely

subsraes

eaures

(e.g.,

secondary

leading

by

products.

accumulate

deecs

sorage

end

enzymes

defect,

mocondra,

degraded

soluble

accumulation

combnaon

6.3).

into

autophagy,

and

Lysosomal

cal

one

normally

intermediates

defective

suc

s

of

C)

storage

mitochondria

ysosome

and

is

configurations.

Part

of

the

nucleus

is

shown

above.

(Courtesy

ere. Dr.

Joe

Rutledge,

Children’s

Regional

Medical

Center,

Seattle.)

CHAPTER

Table

6.3

Selected

Lysosomal

Disease

Storage

Deficient

Tay-Sachs

Gaucher

disease

disease

Enzyme

Genetic

6

Diseases

95

Disorders

or

Protein

Accumulating

Metabolite(s)

Hexosaminidase

GM2

Glucocerebrosidase

Glucocerebroside

Clinical

ganglioside

Features

CNS

disease

Mild

forms:

organomegaly,

bone

marrow

failure

Severe

Niemann-Pick

types

A

disease,

and

Sphingomyelinase

Sphingomyelin

Type

B

forms:

A:

B:

CNS

type

MPS

disease,

NPC1

C

or

lipid

Type

I

(Hurler

NPC2;

part

transport

of

a

Cholesterol,

gangliosides

Type

II

α-L-Iduronidase

Heparin

and

dermatan

sulfate

L-iduronate

sulfatase

Heparin

and

dermatan

sulfate

by

e

2,

a

Lysosomal

mcroscopy,

oten

o

enlargemen

glucosidase

bone

may

e

marrow,

be

vacuoes

myeln

mos

lymp

srkng.

are

membranous

lamellaed

pagocyes,

lver,

e

conan

concenrc

conen

spleen,

variable

including

ataxia,

organomegaly

cardiovascular

disease,

disease

Similar

to

Hurler

syndrome,

but

milder

(acid

Glycogen

Cardiac

failure

maltase)

eecron

resemblng

g

type

disease

ysosomes

late-onset

phenotype

Glycogenosis

vewed

organomegaly,

symptoms,

Organomegaly,

CNS

(Hunter

early-onset

dementia;

syndrome)

Pompe

disease,

disease

Neurologic

complex

syndrome)

MPS

disease

CNS

organomegaly

Type

Niemann-Pick

CNS

early-onset

engorged

gures.

severely

nodes,

Neurons

secondary

cyoplasmc

Because

afeced

and

lungs.

rougou

bodes

o

er

organs

e

e

are

splenc

CNS

Morphology.

so-called

Pagocyes

Gaucer

sufed

ces—become

w

markedly

glucocerebrosde—

enlarged

and

acqure

a

paognomonc cyoplasmc appearance caracerzed as “wrnkled

ssue

paper”

marrow

may

(Fg.

be

6.7).

largely

Splenomegaly

replaced

by

may

sees

o

be

massve,

Gaucer

and

e

cells.

also

accumulae spngomyeln, wc resuls n neuronal enlargemen and

vacuolzaon.

Type

B

s

assocaed

w

less

severe

spngomyelnase Clncal Features. One varan, ype 1, accouns or 99% o cases o Gaucer

decency and e manesaons are mlder. dsease.

I

absence

Clncal

Features.

organomegaly

occurs

ype

B

wn

and

e

varan

Type

rs

ave

A

severe

3

presens

neurologc

years

o

le.

organomegaly

In

bu

n

nancy

w

deeroraon

comparson,

no

neurologc

massve

Dea

paens

usually

w

e

Jews

and

s

Type

port,

C

Disease

Niemann-Pick

leading

to

lipid

Nemann-Pck

genes,

NPC1

and

Type

NPC2,

ype

is

wc

C

bone

compable

w

lesons,

Type

long

1

le.

s

epaosplenomegaly,

mos

Types

2

common

and

3

are

n

and

e

Askenaz

caracerzed

by

or laer n le (ype 3). Aloug e lver and spleen also are nvolved, e

convulsons

and

progressve

menal

deeroraon.

O

neres,

eerozygous carrers o Gaucer dsease are a ncreased rsk o Parknson

caused

accumulation

dsease

w

nvolvemen.

clncal eaures n ypes 2 and 3 are domnaed by neurologc dsurbances,

manesaons.

C

disease

assocaed

CNS

neurologc sgns and sympoms, wc may appear durng nancy (ype 2)

ncludng

Niemann-Pick

s

o

in

resuls

encode

by

defects

in

lipid

trans-

dsease, or reasons a are unceran.

relaed

sdes

Curren

cells.

rom

muaons

proens

a

orm

n

a

wo

complex

a

a

by

erapy

nuson

nb

s

o

amed

a

reducng

recombnan

glucocerebrosde

e

burden

o

glucocerebrosdase

glucocerebro-

and

w

drugs

synase.

s nvolved n nracellular raickng o coesero and oer pds. Deec-

ve

pd

ranspor

and

gangosdes

resus

suc

as

n

e

GM1

nraceuar

and

GM2.

accumuaon

Afeced

cldren

o

coesero

exb

aaxa,

Mucopolysaccharidoses

Mucopolysaccharidoses

tion

vsual dsurbances, dysona, dysarra, and psycomoor regresson.

and

ious

Gaucher

rebrosidase

phagocytes

that

and

is

caused

result

more

in

by

the

loss

of

function

accumulation

variable

mutations

of

in

glucoce-

glucocerebrosides

accumulations

in

in

Gaucer

varable

dsease

expressvy

Gucocerebrosdase

ssue

s

due

normally

an

o

cleaves

auosomal

muaons

a

glucose

o

recessve

dsorder

dferng

severy.

resdue

rom

enzymac

deecve,

degrada-

in

var-

coronar y

normally

e

removed

s

rom

macropages

glucocerebrosde

derved

and

e

are

rom

senescen

crculaon

acvaed

release

a

by

cells,

macropages

wle

number

red

o

aempng

cyoknes.

wc

n

o

ese

dges

ese

are

common

causes

cloudng

lesons,

w

and

varable

degrees

occasonally

o

oseopena,

oseonecross.

oseopoross,

and

o

e

wn

Morpholog c

are

syneszed

exracellular

lysosomes.

manly

I

any

eparan

o

o

all

excreon

o

o

and

lesons

e

by

marx.

o

ese

sulae

connecve

T urnover

enzymes

and

or

are

dermaan

Mos

n

Hepaosplenomegaly,

deposs

ear

valves

(parcularly

and

mucopolysaccardoses

oten

and

cases

cornea,

areral

lesons

e

narcon

dea

o

Features.

subendoelal

areres),

myocardal

o

dsease

par

degradaon

subendoelal

suspeced o alerng bone meabolsm and may explan e assocaon

Gaucer

are

sulae, accumulae wn e lysosomes o pagocyes and oer cells.

o

oseolyc

defective

ceramde.

deormes,

glucocerebrosde

and

mucopolysaccardes,

Clncal

e

by

mucopolysaccharides

remodelng o mucopolysaccarde s medaed by upake no pagocyes

neurons.

parcularly n e spleen, lver, and bone marrow. s s because muc

ssues.

of

Mucopolysaccardes

broblass

Is dec leads o an accumulaon o glucocerebrosde n macropages,

are

characterized

tissues.

Pathogeness.

and

Pathogeness.

e

are

accumulation

Disease

Gaucher disease

w

excessive

lead

cardac

are

jon

o

myocardal

assocaed

and

oten

s

w

coarse

menal

e

(MPSs).

decompensaon

sfness,

mucopolysaccardes

n

n

bran

scema,

are

e

are

Coronar y

and

mporan

acal

dsably

ncreased.

skeleal

eaures,

Urnar y

CHAPTER

Supplemental

cytes

from

Basic

Dr.

and

eFig.

Kupffer

deposition

Pathology,

Arthur

6.1

cells

of

lipids.

10th

ed.,

Weinberg,

Southwestern

Medical

Niemann-Pick

have

a

foamy,

(From

St.

Kumar

Louis,

Department

Center,

disease

vacuolated

V,

Abbas

Elsevier,

of

Dallas.)

in

A,

2018,

Pathology,

liver.

The

appearance

Aster

Fig.

J:

7.10;

University

hepato-

resulting

Robbins

Courtesy

of

Texas

6

Genetic

Diseases

95.e1

96

CHAPTER

Genetic

6

Diseases

A

B

Fig.

6.7

Gaucher

cytoplasm.

thew

Severa

cency

mer

 •

o

cnca

a

bre

o

exs,

Only

wo

involving

micrograph

Department

MPS

enzyme.

disease

Electron

of

the

of

Pathology,

eac

resung

bone

marrow.

Gaucher

cells

University

rom

well-caracerzed

e

of

(A)

with

Gaucher

elongated

Texas

Southwestern

de-

o

mus cle

sve

o

due

n

o

ave

a

cardac

o

 e

swol len

o

rons

accouns

 MPS

engorge d,

type

s

cloudng.

Unlke

nae

e

II,

mode

I

or

or

o

also

lae

because

requres

e

Hunter

oten

as

(a

o

e

s

n

acc umu lae

smo o 

afe c e d

 rom

oten

 e

cel ls

are

n

rom

and

e

rom

an

mlder

a

 •

a

 Pompe

neu-

cogen

o

α-L-durondase).

sulae

subsraes

and

course.

The

various

ciencies

in

Storage

of

glycogen

enzymes

excessive

glycogen

Diseases

in

storage

accumulation

of

n

blo o d

d s eas e

mus cle

mus cl e

l ac  ae

( yp e

c ramps

and

le vels

V

we a k ness

or ms

o

a er

a lure

exerc s e,

o

b e c aus e

s

 e

exerc s e

o

g lycogenos s ) ,

pospor y l as e,

due

g lyc ogen

a

bl o ck

resu l ng

proo yp e

o

(ype

II

e

s

glycogenoss)

(acd

rougou

mos

afeced

promnen,

owng

enzyme

o

can

s

malase),

e

cell

and

caused

wc

body

ype

mos

s

cardac

paens

cardac

a

decenc y

o

requred

(Supplemenal

e

cardorespraor y

reverse

by

s

de

muscle

gly-

eFg.

6.2).

myoc ye.

Car-

wn

alure.

or

2

years

erapy

damage

w

and

o

e

ncrease

dermaan

sulae

COMPLEX

MULTIGENIC

DISORDERS

enzymes.

diseases

in

are

caused

glycogen

glycogen

multiple

or

by

inherited

metabolism

some

and

abnormal

de

result

form

of

multigenic

gene

Genec

allele

sorage

dseases,

e

specc

enzyme

disorders

variants

varans

requency

n

are

e

and

are

caused

by

environmental

reerred

o

populaon

o

as

a

interactions

polymorpsms

leas

between

factors.

1%.



ey

Accordng

o

ave

e

an

com-

mon dsease–common varan ypoess, complex mulgenc dsorders

occur

glycogen

by

and

Myop a c

myog lob nur  a,

mus cle

glucosdase

onse

wen

penerance,

In

mus cles

Despe

tissues.

Pathogeness.

n

accumu-

(Glycogenoses)

involved

o

Mat-

Dallas.)

longevy.

Complex

Glycogen

o

granular

Dr.

g lycogenos es .

breakdown

mssng

(Courtesy

marke d

McArde

dsease

dsease

L-duro-

are

le adng

de cenc y

domegaly

corneal

lipid-laden

pro duc   on .

ele va  on

g lycolyss.

lysosomal

syndrome

o

clncal

decency

dencal

eparan

Hurler

absence

an

myop a c

acc umu la-

g lycogen

ds e as es

nduce

 rom

mus cle

o

Center,

energ y

njur y

However,

prolonged,

enzyme

o

de a 

Acc umu la on

dfers

resuls

bo

and

cel ls.

lys os omes.

decency,

breakdown

uncon

and

Afe c e d

ds ab ly.

more



ye ars,

resu l ng

(X-lnked)

a

dferen

enzyme

10

o er

syndrome,

syndrome,

dferen

and

men a l

o

α-L-durondas e.

endo elum

vac uolae d

 e

6

c yoplasm,

nerance

Hurler

sulaase

wa l l,

cle ar

o

o

Mucop olys accar des

broblass,

ave

 on

decenc y

exp e c  anc y

vas c u lar

and

a

complca ons.

macropages,

cel ls

n

le

by

abundant

lysosomes.

Medical

mp are d

sorage

caus e d

with

acc umu l a on

syndromes

dscusson.

ds order

cells

distended

 M PS ty pe I, a ls o k nown as Hurer sy ndrome, s an auos oma l re ces-

c ldren

 •

Fries,

varans

dferen

(B)

n

s

several

are

group,

polymorpsms,

conered.

ncludng

eac

auommune

and

allergc

e

cyoplasm

glycogenoses

and

are

somemes

nered

Approxmaely

a

as

dozen

Glycogen

wn

e

auosomal

may

nucle

o

recessve

glycogenoses

ave

accumulae

afeced

wn

cells.

Mos

been

mulgenc

 •

dseases.

descrbed.

On

e

dsorders,

 Aloug

o

several

complex

several

oer

dsorders

polymorpsms,

dseases,

ceran

oten

sould

rom

e

be

no

low

o

all

dabees,

kep

collecve

polymorpsms

n

mnd:

nerance

may

enzymes

lver

nvolved

o

resulng

(Fg.

rom

epac

 Myopatc

ae d

n

type.

 a

glycogen

6.8).

o

o

and

lack

orm

mus cle.

enzy mes

a

syneszes

o

caused

meabolsm

accumulaon

ypoglycema

Von

Gerke

and

by

ave

o

due

dsease

also

deecs

wo

a

or

alure

(ype

s

I

breaks

n



epac

major

normal

o

glucose-6-pospaase,

efecs:

abnormal

o

mos

Glycogen

s

an

re qu re d

or

50%

ave

ds e as es

g lycogen

energ y

c aus e d

s ource

by

 •

mpor-

bre a kdow n

n

e

same

 Many

l e ad

o

n

 e

ype

genec

uaor y

s r  -

d ee c  s

o

e

20

o

a

30

rsk.

(e.g.,

auommune

dsorders),

wereas

oers

are

dsease-specic.

cange

 •

varans

regons

quanave

mp or  an

sorage

an

n

 S ome poymorpsms are assocaed w mupe dseases, usuay

o

glucose

glycogenoss),

e

more

 •

glycogenoss.

Glyco gen

are

glycogen

Glycogenoses

due

glycogen,

producon

 •

lver

glucose.

enlargemen

orms

an

e

ree

varans

o

genes are mpcaed n ype 1 dabees, a ew HLA aees conrbue

type.

aoug

possble

 •

no

exampe,

s

and

domnan

down

For

prncples

resul



efec

oug

bass o paopysologc ndngs, ey all no ree groups (T able 6.4):

 Hepatc

nuence.

bu

are

pnpon a specc causave polymorpsm. Wen consderng complex

dsrbuon.

dsease,

modes

yperenson,

ssue

ear

a

dseases

locaon,

s

scemc

w

common

decency dcaes e ype o glycogen a accumulaes, s nracellular

and

and

Many

n

e

e

nked

n

encoded

acors

mugenc

o

genome

varaon

 Envronmena

compex

o

dsease

and

gene

us

a

are

expresson,

n

e

key

raer

noncodng

assocaed

an

a

reg-

w

a

srucura

proen.

pay

a

sgnican

dsorders.

Type

2

roe

n

dabees

e

s

an

expresson

exampe

o

o

a

CHAPTER

Table

6.4

Subgroups

Clinicopathologic

of

Genetic

6

Diseases

97

Glycogenoses

Category

Specific

Hepatic

von

Type

Gierke

Myopathic

McArdle

Miscellaneous

Pompe

Enzyme

Deficiency

Organs

disease

(type

I)

Glucose-6-phosphatase

syndrome

(type

V)

Muscle

disease

(type

II)

Liver,

phosphorylase

Lysosomal

Skeletal

glucosidase

numb er

 a

Affected

kidney

s

(acid

no

maltase)

an

exac 

Cardiac

mu l ple

muscle

and

o

n

skeletal

s

muscle,

c a l le d

liver

aneupod.

Te

omologous

p ar

NORMAL Liver

ce

o

c aus e

o

aneuplody

cromos omes

croma ds

o

a

 e

s ep arae

s

nondsjunc  on

 rs

meo c

dur ng

 e

o

dv son

s e cond

a

or

a

meo c

a lure

o

dv son.

sser

Te

l a-

Glycogen

er

Various

Glucose

a ls o

may

pro duc  on

tissues

o cc ur

o

 wo

cromos omes

dur ng

moss

aneuplod

ol lowe d

by

cel ls.

n

s oma c

Fa lure

random

o

cel ls,

le adng

p ar ng

ass or  men

o

o

 e

omologous

(anapas e

l ag)

a ls o

Blood

c an

le ad

o

aneuplody.

Wen

nondsjunc  on

o cc urs

a

 e

 me

o

glucose

meoss,

1)

or

 e

one

gamees

less

or me d

cromos ome

ave

(n

−

e er

1).

an

ex ra

Fer   lza on

cromos ome

o

suc

(n

gamees

+

by

Glycolysis

Glucose

nor ma l

gamees

may

resu l

n

 wo

 yp es

o

zygoes,

 r s omc,

w  

Muscle Energy

an

ex ra

cromos ome

(2n

+

1),

or

monos omc

(2n

−

1).

Monos omy

Glycogen

nvolv ng

an

 r s omes

o

auos ome

cer  an

cromos omes

GLYCOGEN

STORAGE

DISEASE—HEPATIC

o

TYPE

des cr b e

d eren

 yp e

o

are

 e

s

comp a ble

pres ence

complemens

mos acsm

embr yogeness,

a a l

s

dur ng

auos omes

o

o

and

w  

 wo

e a l

a

le.

or

c aus e d

resu l ng

by

n

mo c

 e

Mos ac sm

more

cromos omes

de velopmen,

monos omy

s

a

p opu l a ons

n

 e

s ame

o

er m

o

cel ls

w  

dur ng

 r s omc

and

s ex

us e d

ndv du a l.

nondsjunc  on

pro duc  on

w ere as

nvolv ng

One

e arly

mono -

Glycogen

s omc

d aug er

Mos acsm

cel ls,

a e c  ng

w os e

s ex

des cend ans

cromos omes

s

 en

pro duce

common,

a

mos ac.

w ere as

auos o-

Glucose

ma l Low

blood

mos acsm

Structural

Srucural

somal GLYCOGEN

STORAGE

s

no.

glucose

DISEASE—MYOPATHIC

Abnormalities

canges

breakage

n

e

cromosomes

ollowed

by

loss

or

ypcally

resul

rearrangemen

o

rom

cromo-

maeral.

Suc

TYPE

canges

p

usually

denoes

e

are

desgnaed

sor

arm

o

a

usng

a

cyogenec

cromosome

and

q

sorand

e

long

n

wc

arm.

Eac

arm s en dvded no numbered regons (1, 2, 3, and so on) rom e

Glycolysis Glucose

cenromere ouward, and wn eac regon e bands are numercally Low

ordered.

energy Glycogen

e

output

are

 •

Fig.

the

6.8

liver

ciency

The

Top,

and

of

A

simplified

skeletal

hepatic

scheme

muscles.

enzymes

consequences

of

a

of

normal

Middle,

involved

genetic

in

The

glycogen

effects

glycogen

deficiency

in

the

of

metabolism

an

inherited

metabolism.

enzymes

in

man

e

ypes

 Transocaton

anoer

glycogen

in

skeletal

mples

mens

are

and,

ranslocaons

that

excanged

dsease

a

as

mporan

neracons

rsk

because

dsease

or

afeced

only

dabees

e

persons

oten

exb

clncal

long

arm

ater

weg

gan.

In

s

s

“unmasked”

by

caused

by

that

50%

of

rst-trimester

spontaneous

has

chromosome

a

o

Cyogenec

abnormalities

chromosome

dsorders

are

are

and

that

1

in

every

o

cromosome

recprocal

cromosomes).

by



order,

o

ndcaes

a

In

ollowed

or

(.e.,

genec

by

e

example,

recprocal

cromosome

5,

regon

excanged,

armul

cromosomes

durng

ormed,

fuson

occur

o

rag-

sor-

nvolved

46,X X,(2;5)

2

a

ranslocaon

regon

3,

band

1,

nvolv-

and

1,

band

4.

Wen

e

e

broken

o

e

e

resulng

carrer,

baanced

wo

as

recproca

e

and

e

ull

gameogeness,

complemen

abnormal

o

normal

genec

mae-

(unbalanced)

o

are

resulng

nvolvng

n

abnormal

wo

zygoes.

acrocenrc

A

specal

gam-

cromosomes

paern

type,

or

robertsonan,

transocaton.

e

s

called

breaks

close

o

e

cenromere,

afecng

e

sor

arms

o

yp-

bo

aberration.

dened

auosomes

or

by

e

sex

presence

o

numercal

Transer

o

e

segmens

leads

o

one

ver y

large

or and

one

exremely

small

one.

e

sor

ragmens

are

cromosomes. and

e

arms

afeced

o

all

ndvdual

acrocenrc

as

45

cromosomes.

cromosomes

carr y

Because

gly

e

redundan

Abnormalities

genes  e

nor ma l

cromos ome

coun

s

46

(.e.,

2n

=

46).

(e.g.,

mu l ple

o

 e

aplod

numb er

(n)

s

c a l le d

eupod.

rbosomal

RNA

genes),

suc

loss

s

compable

w

Any sur vval.

exac 

one

200

sor

umans,

(q)

no

ranslocaon

los,

In

wo

ndcaed

numercal

evenly

s

cromosome aleraons

Numerical

are

cromosome

cromosomes.

srucural

o

usually

abortions

cally newborns

beween

noaon

arm

However,

centrc are

par

s

DISORDERS

o estimated

a

e

ees

is

o

process

obesy.

ral.

It

e

man-

nsance,

number

CYTOGENETIC

ranser

w

transocaton genec

n

s

ragmens o

6.9)

metabo-

sor acors,

(Fg.

muscles.

mugenc

esaons

abnormales

defi-

ng

oer

cromosomal

Bottom,

(q31;p14).

compex

srucural

cromosome.

cromosomes lize

o

ollowng:

Any

However,

dicues

agan

arse

durng

gameogeness,

CHAPTER

A

6

Genetic

Diseases

B

Supplemental

abundant

dial

fibers

logic

of

eFig.

6.2

eosinophilic

full

Basis

of

Pathology,

of

glycogen

Disease,

Pompe

cytoplasm.

seen

9th

University

of

ed.,

as

disease

(B)

(glycogen

Patient

clear

spaces.)

Philadelphia,

Texas

with

(From

Elsevier,

Southwestern

storage

Pompe

Kumar

2015,

Medical

disease

disease

V,

Fig.

Abbas

5.16;

Center,

type

(same

A,

II).

Aster

Courtesy

Dallas.)

(A)

Normal

magnification

J:

Dr.

myocardium

showing

Robbins

Trace

and

the

Cotran

Worrell,

with

myocar-

Patho-

Department

97.e1

98

CHAPTER

Genetic

6

Diseases

Trisomy resung

n

abnorma

 •

e

unbaanced

gamees

a

may

ead

Down

ay

older

raer

a

s

an

en

os,

cromosome

mos

long

common

arm

o

erlzaon

mosome,

genes

on

 D eeton

break

an

e

One

e

X

o

wo

resul

s

a

wo

arm

sor

and

gamee

monosomy

or

n

s

a

arms

s

arms

presen

cromosome

by

e

remanng

ony

socromosome

e

cromo-

dupcaed,

resung

or

o

wo

lve

ong

brs

desgnaed

conans

genes

on

a

arms.

(Xq).

normal

Xp

e

nvolves

and

e

Wen

X

e

nernal

s

are

loss

a

o

poron

ermnal

proxmal

segmen.

almos

a

segmen.

and

e

never

o

dsal

a

cromosome.

Two

nersal

segmens,

removed

reaned,

resuls

ragmen,

and

e

 •

e

s

w

lacks

a

cen-

by

 •

w en

and

 e

 ere

are

 nvolve d

 wo

ners   a l

s eg men

reun es

bre a ks

a er

n

rom

 About

eac

end

o

e

cromosome,

e

arms

une

o

orm

a

 •

4%

ree

syndromes

5p,

and

and

Disorders

auosomal

(cr

22q11

ave

deleon

of

rsomes

du

cat

deeton

18,

sy ndrome,

sy ndrome)

caracersc

syndrome

Involving

(13,

clncal

occur

and

Autosomes

21; Fg.

caused

are

Only

suicen

disorder

in

o

requenc y

wo

wo

22

major

causes,

age:

20

e

wt

bu

provdes

s

s

e

and

ova

rsomy

Down

e

of

21

and

1

n

n

1550

25

lve

lve

exra

ncreased

o

e

exra

1

21;

er

syndrome

s

brs

brs

n

cromosome

suscepbly

o

undersood.

arm

14.

s

trsomy

Down

e

syndrome

penoypcally

avng

o

o

cases,

no

long

cromosome

rses

o

or

Down

e

ave

orm

ncdence

95%

reason

nvolves

21

Is

years

In

syndrome

s

nondsjuncon

or

or

Down

years.

persons

a

rsk

cases

an

resul

early

n

21

o

Aloug

deleon

cromosome

common

rsomy

lve

and

brs

22q11

mer

bre

been

known

elusve.

rom

sage

e

or

o

carry

a

robertsonan

cromosome

ranslocaed

cromosomal

normal.

Oer

21

and

segmen

maeral.

sblngs

o

e

are

a

syndrome.

moc

nondsjuncon

embryogeness.

Mouse

cromosomal

many

models

mosome

21

RNAs

responsble

s

producs

consderaon.

Clncal

o

cromosome

manesaons

bearng

gve

rse

years,

sugges

loc

o

or

e

abnormaly

e

a

encodng

e

gan

o

a

mulple

obser ved

clncal

n

paogeness

Down

o

e

parcular

proens

penoype,

eaures

reman

o

regon

and

bu

be

syndrome

dsease

21

are

ow

Balanced

Centric

fusion

Robertsonian Lost

ISOCHROMOSOMES

DELETIONS

Fragments

INVERSIONS

RING

CHROMOSOMES

Paracentric

Fragments Pericentric

6.9

Types

of

chromosomal

rearrangements.

on

cro-

mcro-

ese

gene

deermned.

reciprocal

as

remans

several

TRANSLOCATIONS

Fig.

the

varable and mlder, dependng on e proporon o abnormal cells.

and

deleon

relavely

eaures.

w

by

6.10)

o

carrer

ese

durng

Cytogenetic

chromosome

nondisjunction

 Rarey, persons wt a Down syndrome penotype are mosac for trsomy

21.

rng.

as

kar yoype.

an

45

orgn.

ovum

ncreased

 A rng cromosome s a varan o a deleon. Ater loss o segmens

meiotic

wt

maernal

an

maernal

agng

o

younger

older

parenal

 lpp ng

common

by

syndrome

norma

lnked

cromosome

a

most

patents

a

transocaton

around.

 •

of

cromosome

o cc ur

cromos ome

o

Down

ave

women

e

s

the

caused

ransocaon.

95%

women

los.

 Inversons

 About

srongly

or

removal

encoded

frequently

parens

sngle

breaks,

n

wc

genes

A

Syndrome)

is

mothers.

n

delee

o

most

robersonan

cro-

rsomy

(Down

syndrome

Pathogeness.

Xq.

nvolves

romere,

regon

and

w

occurs

e

may

reunon

o

vercay.

21

o

is

n

 •

o

 Isocromosomes are ormed wen e cenromere dvdes orzon-

some

 •

ormaon

zygoes.

CHAPTER

Intellectual

Genetic

6

Diseases

Epicanthic

disability

folds

and

facial

flat

profile

Abundant

neck

TRISOMY

21:

Incidence:

1

DOWN

SYNDROME

skin

Single

in

palmar

Karyotypes:

crease

Trisomy

700

21

type:

Translocation

Mosaic

births

47,XX,

type:

type:

+21

46,XX,der(14;21)(q10;q10),+21

46,XX/47,XX,

+21

Congenital

heart

defects

Umbilical

Intestinal

hernia

stenosis

Predisposition

to

leukemia

Prominent

occiput

Intellectual

disability

Hypotonia

Micrognathia

Gap

between

first

and

second

toe

Low

set

Short

ears

neck

Overlapping

fingers

Congenital TRISOMY

18:

EDWARDS

SYNDROME heart

Incidence:

1

in

8000

defects

births

Karyotypes: Renal Trisomy

Mosaic

18

type:

type:

47,XX,

malformations

+18

46,XX/47,XX,

+18

Limited

Microphthalmia

Microcephaly

intellectual

hip

abduction

and

disability

Polydactyly

Cleft

lip

and

palate

Rocker-bottom

feet

Cardiac

defects

Umbilical

Renal

hernia

defects

TRISOMY

13:

Incidence:

1

in

PATAU

15,000

SYNDROME

births

Karyotypes:

Trisomy

13

type:

Translocation

Mosaic

Rocker-bottom

Fig.

6.10

Clinical

syndrome;

features

trisomy

18,

and

karyotypes

Edwards

of

syndrome;

the

and

three

47,XX,

+13

46,XX,+13,der(13;14)(q10;q10)

46,XX/47,XX,

+13

feet

most

trisomy

type:

type:

13,

common

Patau

autosomal

syndrome.

trisomies:

trisomy

21,

Down

99

100

CHAPTER

Clncal

Features.

obque

e

papebra

Genetic

6

acal

appearance

issures,

and

o

Diseases

e

epcanc

nan—a

ods

(see

aca

Fg.

proie,

emaes.

X

6.11)—s

cepon.

Durng

nacvaon

occurs

process,

ea

abou

o

carres

 •

50.

ave

a

Mosacs

norma

g

rsk

 Congenta

w

or

o

Down

oer

eart

syndrome

near-norma

deveopmena

dsease

ave

a

negence.

occurs

n

and

ave

an

mder

penoype

Down

syndrome

acqured

approxmaey

aso

dsorders:

40%

o

a

o

paens,

mos commony ara sepa deecs, arovenrcuar vave maorma-

X

 •

s

o

nacvaed.

e

Penoypc

occurs

ood.

cromosome

Aresas

 Cdood

o

e

acute

ger

esopagus

eukema

an

 Neuropatoogc

ose

(see

n

canges

neurodegenerave

dsease

age

 Abnorma

uary

bass

o

or

naa

21,

mmune

e

and

medca

dagnoss

screenng

maerna

o

ess

care

(see

rey

o

occurs

o

common.

a

raes

10-

o

17),

occur

as

n

dsease,

vruay

ncreased

on

e

a

e

and

and

s

a

s

oer

o

span

parc-

common.

persons

50

rsomes

he

w

years.

s

ea

drecy)

he

resus

n

22q11

deeon

possbe

DNA

usng

ound

karyoypng

o

n

ces

Syndrome

syndrome

he

are

in

Mos

a

he

exra

rom

X

assocaed

range

a

specrum

o

penoypes

a

 •

penoypes

ncude:

ncrease

durng

 •

 Parayrod ypopasa resung n ypocacema

 •

 S czoprena and bpoar dsorder

and

poson

penoypes.

domnae,

Paens

paogeness

because

e

suspeced

deeon

aso

and

are

a

sczoprena,

22q11

deeed

on

by

o

e

Wen

paens

are

pronounced

g

rsk

wc

deeons

T-ce

sad

o

s

oug

n

su

or

psycoses

n

syndrome

encodes

grounds

uorescence

o

be

Numerical

ranging

and

many

s

up

DGeorge

s

uy

he

by

(FISH)

and

as

25%

no

genes.

ybrdzaon

suc

o

esabsed

other

in

45,X

to

patien ts

syn-

wh o

Sex

i nv o lv ing

4 9 ,XXXXY,

somes

ave

been

cromosomes

o ften

ones

a

abnormaes

maes

denied.

produce

are

nvovng

In

aypca

md

dose”

because

o

o

oss

a

and

o

are

rom

an

X

severa

cromosome,

regons

one

acve

gans

Turner

X

e

as

X

cromosome

on

or

on

bo

osses

syndrome,

X

o

cro-

X

cro-

respecvey.

the

most

from

the

common

presence

cause

of

at

of

hypogonad-

least

one

extra

X

may

e

he

be

cnca

sex

o

paens

presence

mder

syndrome

o

eer

are

o

a

ave

a

47,X XY

cromosomes

maerna

mosacs,

46,XY

or

suc

ne

n

kar yoype

durng

meoss.

paerna

as

orgn.

46,XY/47,X XY ,

mosacs

usuay

s

condon.

manesaons

s

wde,

and

ey

oten

ncude

e

bpoar

o

he

undersood,

dagnoss

may

deecon

(descrbed

o

be

e

aer).

are

w

wo

conras,

the

se x

c h ro m os o m e s ,

with

i nf e r t il it y

compared

auosoma

w

and

even

numerca

penoypes

n

ose

wc

promnen,

o

oss

evauaon

o

and

Hsoogc

may

ack

as

a

resu

o

ubues.

nfery.

Sery

examnaon

spermaogona

o

yperpasa

he

s

reveas

enrey.

or

dagnoss

due

s

an

o

yan-

Ley-

apparen

oten

made

nery.

appearance

ar

and

md,

n

some

esoserone

eves

persons

be

may

Kneeer

norma

body

s

deic

e

w

ower

a

arge

w

cancer

upus

deecabe.

germ

(20

o

exra

an

Paens

assocaed

exragonada

s

number

are

eevaed.

breas

sysemc

no

w

eves

are

syndrome

as

cases,

mosacs

ncudng

maes),

suc

eongaed

correaes

gonadoropn

dsorders,

an

g ynecomasa

and

Serum

o

are

he

a

norma,

rarey

ger

and

ere,

o

and

n

urnar y

and

46,XY

requency

more

umors,

reducon

cromosomes.

proporon

mes

ce

X

o

common

suc

ces.

severa

an

auommune

n

ds-

er yemaosus.

Chromosomes

c o m pa t i bl e

exh ibi t

aropy,

 Mena mparmen. he degree o neecua mparmen ypcay

ds-

cases.

escuar

 •

l ife

a nd

a nd

c e r t ai n

Turner

bo

ree

In

and

w

arge

syndrome,

females,

of

results

the

X

characterized

from

partial

or

by

primary

complete

hypogonadism

monosomy

of

the

in

short

chromosome.

cromo-

abnormaes

maes

observed

cromosomes.

Y

Syndrome

Turner

arm

norma

“ exra

 Eunucod body abus, marked by reduced aca, body, and pubc

cardac

abnormaltie s .

Penoypcay

abe

Involving

abnor ma l i ti es

from

observed

Disorders

an

a

 •

eases

Cytogenetic

ave

Noe

 Increase n eng beween e soes and e pubc bone, wc creaes

mmunodeicency

ave

dysmorpoog y

deveops

deeon

regon

cnca

o

reaed

e

negence

and

is

Kneeer

ubues,

are

s

order

no

 •

e

o

ces

md

deecs.

a

o

drome, wereas ose w e so-caed veocardofaca syndrome ave

mmunodeicency

hus,

genes

spermaogeness.

o

 hymc ypopasa and mpared T-ce mmuny

dferng

w

 Hypogonadsm,

 Abnormates of te paate, faca dysmor psm, deveopmenta deay

or

oss

because

resung

nondsjuncon

15%

w

 •

ypocacema

w

syndrome

results

47,X XY/48,X X XY .

 •

and

do

cromosome.

appear

ose

cromosome

Approxmaey

dg

responsbe

and

paens

sems

zaon

sze

o

Kneeer

males

 Congenta eart dsease afecng e ouow racs

e

assocaed

dsorders

syndrome

ism

 •

n

wo

Syndrome

some

Varaon

emaes

X

oowng:

encompasses

hese

e

nacvaon.

Klinefelter

mpared

(de22q11).

escape

monosomy

resu rom nersa deeons o band 11 on e ong arm o cromo-

22

resu,

syndrome,

Klinefelter

he

Deletion

canges

Turner

mosomes

r-

pre-

obaned rom e concepus by amnoceness or coronc vus sampng.

22q11

a

on

chromosome.

o

around

ce-ree

(mos

s

As

ound

a

uncear.

e

dea

anayss

sudes,

necons,

auommuny,

dsurbance

age

o

n

mosomes.

Azemer

predsposes

yrod

syndrome

magng

are

cdren.

Caper

a

medan

Down

a

bood,

and

curren

9)

aso

40.

mmunoogc

e

bowe

Caper

unafeced

functon

ungs,

s

Improved

somy

an

sma

caracersc

paens

oder

and

genes

embryo

one w an acve maerna X and e oer w an acve paerna X.

are responsbe or a majory o e deas n nancy and eary cd-

20-od

 •

one

deveopng

con-

cro-

yonzaon, norma emaes are mosacs composed o wo ce popuaons,

ons, and venrcuar sepa deecs (see Caper 8). Cardac probems

 •

bu

mos

e

ater

Moreover,  exra X cromosomes are presen (e.g., n 48,XXXX emaes),

25

may

alced

o

days

maerna

and

o

ose

ce

16

e

and remans genecay sen n e progeny o ese ces rougou e.

o

eac

or

mosome

80%

n

e,

paerna

IQ

approxmaey

nacvaed

n

e

dsaby

common;

randomy

eary

eer

caracersc and mmedaey suggess e dagnoss. Severe neecua

s

s

s

o

X

emaes,

numerca

par,

e

ack

Pathogeness. Norma oogeness occurs beore yonzaon and requres

bo

X

nay

cromosomes

deveop

o

be

normay

acve.

eary

n

In

T urner

syndrome,

embr yogeness,

bu

ea

e

ovares

absence

o

e second X cromosome eads o an acceeraed oss o oocyes, wc

o a penoype reaed o abnormaes o sex cromosomes reaes o wo

s

acors: (1) e sma amoun o genec normaon carred by e Y cro-

srands,

compee

by

age

mosome (ncudng e gene SRY a species mae sex) and (2) X nac-

syndrome aso causes nongonada abnormaes, genes requred or e

vaon (yonzaon), wc ends o baance gene expresson n maes and

grow

devod

and

o

2

years.

ova

he

and

deveopmen

o

ovares

oces

somac

are

reduced

(sreak

ssues

o

ovares).

aso

mus

aropc

ibrous

Because

T urner

resde

on

e

X

CHAPTER

cromosome.

s

s

one

Clncal

X

o

An

e

exampe

genes

Features.

cromosome

e

and

s

a

e

are

sor

acve

majory

a

45,X

o

saure

on

paens

kar yoype.

omeobox

bo

X

afeced

and

are

dagnosed

a

complee

paens

br

loss

are

o

e

one

mos

or

early

n

Short

posterior

eaures

6.11

and

assocaed

w

45,X

Turner

syndrome

stature

hairline

cldood.

Webbing

Typcal

Fg.

101

(SHOX).

Low

severely

Diseases

cromosomes.

ave

ese

gene

Genetic

6

are

sown

of

neck

n

nclude:

Coarctation

 •

Growt

retardaton

and

sor

saure

(below

e

rd

of

percenle) aorta

 •

 Swellng o e nape o e neck due o dsended lympac cannels

(n

nancy)

a

s

seen

as

webbng

of

te

neck

n

older

Broad

and

cldren

spaced

 •

 Low posteror arne

 •

 Cubtus vagus (an ncrease n e carr yng angle o e arms)

 •

 Sed-ke cest w wdely spaced npples

 •

 Hg-arced paate

 •

Lympedema

chest

widely

nipples

Cubitus

valgus

Streak

o

e

ands

and

ovaries,

ee infertility,

 •

Maformatons

coarcaon

o

suc

e

Cardovascular

dea

cen

n

al

o

orsesoe

abnormales

cldood.

grls

as

kdney,

bcuspd

aorc

valve,

and

amenorrhea

aora

B ecause

develop

are

o

e

mos

ovaran

secondar y

sex

common

aropy,

cause

afeced

caracerscs:

e

o

adoles-

genala Pigmented

reman

nanle,

appears.

caused

In

Mos

by

a

developmen

paens

ave

auoanbodes

sgncan

mosacsm

46,XX

breas

(n

cells)

wc

or

by

e

prmar y

occurs

mnory

o

n

as

s

mnmal,

and

amenorrea.

many

paens,

ndvdual

srucural

s

as

T urner

made

abnormales

up

o

lle

o

paens.

syndrome

a

e

s

mxure

X

nevi

ar

Hypoyrodsm

50%

o

pubc

caused

o

45,X

cromosome.

by

and

e Peripheral

mos

common

s

deleon

o

e

sor

arm,

resulng

n

paral

monolymphedema

somy

are

o

e

X

repored

cromosome.

and

accoun

Combnaons

or

sgncan

o

deleons

varaons

n

and

e

mosacsm

at

TURNER

Some

mal

paens

w

appearance

mosacsm

and

may

or

paral

presen

only

deleons

w

ave

prmary

an

birth

penoype.

almos

SYNDROME

nor-

amenorrea.

Incidence:

In

1

in

3000

female

births

Karyotypes:

adul

paens,

a

combnaon

o

sor

saure

and

prmary

amenorrea Classic:

sould

promp

srong

suspcon

or

T urner

syndrome.

e

dagnoss

45,X

s Defective

usually

esablsed

by

karyoypng. second

X

chromosome:

46,X,i(Xq)

46,XXq–

SINGLE-GENE

DISORDERS

WITH

PATTERNS

INHERITANCE

ATYPICAL

46,XXp–

46,X,

OF

Mosaic

ree

groups

o

genec

dseases

resulng

rom

sngle-gene

no

ollow

mendelan

rules

o

r(X)

45,X/46,XX

muaons

Fig.

do

type:

6.11

Clinical

features

and

karyotypes

of

Turner

syndrome.

nerance:

 •

 Dseases caused by rnucleode repea muaons

 •

 Dseases caused by muaons n mocondral genes

A

unque

eaure

o

dseases

caused

by

rnucleode

repea

mua-

ons s a penomenon called antcpaton, n wc e dsease becomes

 •

 Dseases assocaed w aleraons o mprned regons o e genome more

severe

relaed

Trinucleotide

Repeat

Mutation

o

repeat

diseases

are

eac

successve

dynamc

naure

o

generaon.

s

rnucleode

unusual

repea

eaure

muaons.

s

An

Diseases example

Trinucleotide

w

e

caused

by

mutations

that

can

be

ound

n

Hunngon

dsease,

n

wc

expanson

o

amplify a

CAG

repea

sequence

wn

e

Hunngn

gene

(HTT)

gene

s

a DNA sequence consisting of three base pair (trinucleotide) repeats. responsble

ey Pathogeness.

Fragle

X

syndrome,

Hunngon

dsease,

and

are

all

assocaed

w

neurodegeneraon,

are

among

e

examples

o

genec

dseases

caused

by

rnucleode

a

e

expansons

may

nvolve

e

promoer,

o

(as

e

n

encoded

mRNA

Hunngon

(as

n

dsease,

ragle

X

descrbed

syndrome),

n

Caper

or

gene.

o

s

Wen

muaons

suppressed

and

ere

afec

s

noncodng

“loss

o

regons,

uncon. ”

By

nvolvng

codng

sequences

o

e

gene

encode

oten

gve

rse

ablty

racs,

wc

c yoplasm,

a

cause

proen

common

msoldng

eaure

o

dseases

and

encode

polygluamne

aggregaon

suc

as

number,

a

s

more

spermaogeness,

severe

and

occurs

an

earler

aler-

n

compared

o

e

dsease

n

e

paren.

Snce

le

CAG

polygluamne

are

oten

racs

called

n

e

afeced

ploygluamne

proens,

dseases.

For

CAG

unclear

oer

rnucleode

repea

repea

nsably

dseases,

s

more

suc

as

ragle

pronounced

n

X

ds-

develop-

and

wn

Hunngon

down

ence

ancpaon

roug

e

s

seen

wen

e

abnormal

alleles

moer.

o

by

a

dsease

muaon

oocyes,

passed

dsease.

repeas

ceran

RNA

Frag le

CAG

n

rple

and ave a oxc “gan-o-uncon” acvy. s propery s conerred

nvolvng

n

ofsprng

dseases

msolded proens a bo nerere w e uncon o e proen

muaons

a

conras, are

muaons

durng

reac

e

ng ranslaon

expansons

repeas

codng

16)

ease, afeced

ese

repea

reasons, regons

urer

Once

unranslaed repea

porons

resuls

afeced

repeas expansons.

o

dsease.

more n

promnen

prone

e

myoonc aon

dysropy,

or

e

dsease.

I

X

syndrome

It

s

(ater

resuls

wc

the

Down

rom

encodes

s

the

second

a

e

prototypc

most

trnucleotde

common

genetc

repeat

cause

o

mutaton

mental

ds-

syndrome).

rple

repea

amlal

muaon

menal

afecng

reardaon

e

proen

FMR1

gene,

(FMRP).

As

102

CHAPTER

w

a

males.

cles

30

X-nked

Afeced

are

presen

CGG

dseases,

males

n

repeas

n

rage

ave

90%

o

e

Genetic

6

a

long

cases.

FMR1

X

syndrome

ace

In

Diseases

and

unafeced

gene,

afecs

large

males,

wereas

predomnanly

mandble.

n

Large

ere

afeced

are

es-

and e paen develops Angelman syndrome. e precse way a e

afeced

genes

conrbue

males

200

ons

o

w

52

muaons

e

4000

o

by

200

marked

o

ese

repeas.

urer

ranslaon

causes

repeas.

“ull”

e

menal

arse

premuaons

amplcaon

synapc

muaons

durng

proens,

and

are

absence

FMRP

n

syndromes

s

no

undersood.

OF

GENETIC

DISORDERS

premua-

convered

oogeness.

s

rom

ese

ere

DIAGNOSIS are

o

around

o

ull

regulaes

afeced

males

dsably.

Once

der,

a

penoype

pedgree

s

recognzed

analyss

may

be

a

used

o

suggess

urer

a

parcular

evaluae

e

genec

dsor-

possbly

a

a

genec dsease s segregang wn a amly. e absence o oer afeced

amly

members,

owever,

does

no

exclude

a

genec

dsorder,

as

many

muaons arse de novo. An addonal conoundng acor s nonpaerny,

Diseases

Caused

by

Mutations

in

Mitochondrial

Genes

esmaed o nvolve 2% o 5% o brs. Conrmaon o a suspeced genec

dsorder

Mitochondria

in

the

fertilized

zygote

are

entirely

derived

from

reles

on

specc

ess,

wc

also

ave

mporan

roles

n

evalu-

the ang euses a are deemed o be a ncreased rsk or genec dsorders.

ovum;

thus,

only

mothers

transmit

mitochondrial

genes

and

their e

defects

to

their

erang

s

unusual

paern

o

ransmance

s

reerred

o

as

o

A

esng

Dseases

caused

by

muaons

n

bre

or

genec

revew

o

dsorders

curren

s

esng

evolvng

a

modales

a

rapdly

and

er

accel-

use

or

materna e

nertance.

eld

pace.

offspring.

mocondral

genes

dagnoss

o

genec

dsorders

s

ofered

below

and

s

summarzed

n

are T able 6.5.

rare.

One

class

dral

dsorders

on,

and

as

o

mocondral

encode

mg

be

genes

enzymes

a

nvolved

expeced,

e

s

n

ssues

muaed

n

oxdave

a

are

mocon-

pospor yla-

mos

afeced

Genetic

Test

Modalities

and

Applications

n Tess a are used o conrm e dagnoss o varous genec dsorders

ese

dsorders

are

ose

a

are

mos

dependen

on

oxdave

posare

por ylaon,

a

s,

skeleal

muscle,

e

ear,

and

e

desgned

o

deny

e

causave

genec

abnormaly

or,

n

some

bran. nsances, e efec o e abnormaly on proens encoded by muaed

genes.

Diseases

Caused

by

Alterations

of

Imprinted

1.

Prader-Willi

and

Angelman

ese

genes

through

and

are

normally

epigenetic

disturbances

abnormal

gene

this

process

expression

and

in

to

differential

male

(termed

and

“silencing”

female

imprinting)

developmental

gametes,

can

lead

were

blood

to

e

acves

on

o

omologous

e

male

and

maernal

emale

and

abnormalities.

alleles

paernal

o

some

dfer.

ese

mprnng

reers

o

ranscrponal

slencng

o

e

maernal

ovum

derved

Two

an

o

or

e

rom

syndrome

e

sor

(Fg.

gonadsm.

ound

 •

n

ype

also

as

e

be

nal

all

are

Afeced

ga,

n

uncon

gene

Prader-Wll

some

15q12

uncon

deleed

o

all

by

occurs

n

somac

deecs

syndrome

e

e

and

dsnc

s

no

greaer

and

nvolvng

ton

Angelman

nellecual

n

o

all

cromosome

and

w

and

band

q12

e

dsably,

and

n

e

long

dsably,

syndrome.

Afeced

15q12,

cromosome

a

bu

15

e

scope.

s

o

as

(a

peno-

o

ese

s

o

paens

an

e

depends

on

s

A

e

(and

paernal

dferen

on

syndromes

compleely

e

depends

maernal

wo

mprnng.

on

allele,

gene

e

gene

allele.

and

a

s

se

ence

los

paernal

A

complex

o

genes

slenced),

I

e

e

also

maps

uncon

allele.

agan

s

suc

a

o

I

can

a

Tests

compleely

s

los

a

w

and

s

beng

several

caegores:

anayss,

n

w

ybrdzed

a

dye

a

bands

replaced

(CGH),

DNA

a

dark

labeled

sde

span

n

e

on

by

n

wc

wo

o

e

DNA

dferen

an

array

genome.

rao

produces

eac

mea-

o

o

a

a

unque

cromosome.

array-based

wc

correspondng

cange

o

a

and

tat

3.

can

are

s

rom

compar-

a

paen

uorescen

o

probes

Over-

or

dyes.

dspayed

underrep-

parcuar

uorescen

se

ag

genomc

1

o

(PCR),

s

a

genome,

uo-

rsomes

snge

can

and

or

n

beng

a

18,

used

requres

ave

bood

n

o

n

and

regons

sex

by

n

parc-

a

norma

many

by

(NGS),

a

poymerase

w

bu

cromo-

21.

genes,

ybrdzng

sequencng

wdey,

aso

maerna

sequence

specay

e

numbers

compared

and

on

mcro-

ransocaons

muaon

sequencng

DNA

nerpase

ess

ampied

o

afec-

denicaon

canges

DNA

sequences

s

be

easer

capurng

and

or

sequence

ncude

I

ybrdza-

uorescence

osses,

13,

genes.

generaton

and

compex

a

muc

dscree

conanng

spreads

ound

number

regon

nuceode

next

DNA

as

o

stu

woe-cromosome

becomng

by

n

Moecuar

appcaons

sequenced,

s

gans,

aso

abnormaes

probes

w

6.13).

ea

copy

n

and

number

compemenar y

assess

o

e

meapase

(Fg.

ncudng

mutatons

o

o

s

ree

o

by

Fuorescence

vsuazed

Curren

afordabe

resus

ce

nerpre,

cromosoma

cromosoma

deecon

caed

o

en

use

I

o

ony

array.

apped

bopsy)

sequence.

easy

Fuorescen

regons

suspeced,

enre

e

regons.

auosomes,

s

n

s

med

deny

deec

eus.

detect

s

ybrdzes

a

e

meod,

e

o

genomc

qud

ncreasngy

o

presen

wc

reacton

e

cuure,

wc

used

probe

known

hs

ce

neres

and

gene

even

e

gene

a

are

and

genomc

FISH

reerence

cromo-

s

s

o

he

sex

can

genes

a

are

deveoped

somes

2.

develops

suc

as

requre

deveopng

ea

maer-

paernal

paen

cromosome,

maernal

bu

on

on

resouon,

so-caed

uar

mprned

uncon

no

karyotype

saned

lg

paen

scored

parcuar

e

deleon

raer

mxed

o

cromosome,

been

lauger,

conrol

spos

specic

nuce.

ypo-

deleon

by

ybrdzaton

are

(FISH)

ng

15.

nellecual

cromosome

derved

ee,

cases

napproprae

Prader-Wll

conex

15q12

gene

DNAs

does

cells

cromosome.

bass

e

by

ands

deleons

assocaed

nvolvng

mprned

s

rom

s

rom

syndrome.

s

derved

maernally

derved

ave

small

(15q12),

sezures,

dsnc

molecular

deleed,

o

caused

caracerzed

obesy,

15

paernally

cromosome

gene

are

Prader-Wll

paens

syndrome

undersood

s

ypoona,

e

paernally

Imprnng

he

sequences

deleons

n

sperm.

ransmed

dsorders

regon,

syndrome

aaxc

ave

occurs

e

6.12).

e

que

n

sably

normal

probes

genec

cromosome

 Angeman

well

allele

en

dvded

rescen ag 2. Array CGH as severa advanages over kar yoypng: I

zygoe.

saure,

o

s

genomc

 Prader-W

arm

and

uncommon

mprned

 •

paernal

sperm

a

regon

are

kar yoypng

genomc

resenaon

allele n e ovum, wereas paernal mprnng reers o ranscrponal

slencng

solely

alernang

and

as

dferences arse rom an epgenec process called genomc mprnng.

Maernal

o

Increasngly,

cromosomes,

genes

dened

lympocyes)

paern

Pathogeness. Aloug all umans ner wo copes o eac auosomal

carred

broadly

pase cromosomes prepared rom culured cells (usually perperal

atve

gene,

be

Syndromes

subject

modications

in

can

T ests tat detect structura abnormates of cromosomes. Hsorcally,

ese

Certain

ess

Regions:

a

s

o

ese.

becomng

nerpreaon

raned

ndvduas.

Tests tat detect bocemca abnormates assocated wt partcuar

genotypes.

In

many

nsances

nvovng

snge-gene

dsorders,



s

CHAPTER

Imprinted

MA TERNAL

P A TERNAL

(M)

(P)

Prader-Willi

Active

genes

Active

Angelman

Deletion

in

Deletion

mater nal

Prader-Willi

Imprinted

Angelman

Active

Testing

Modalities

for

Genetic

Genetics

of

Angelman

Prader-Willi

SYNDROME

syndromes.

Applications

and

Examples

Assays

assays

for

metabolites

or

electrolytes

Detection

of

detection

of

and

Disorders

Type

Assay

deletion

gene

PRADER-WILLI

6.12

of

Angelman

SYNDROME

Fig.

Quantitative

Prader-Willi

genes Site

ANGELMAN

Biochemical

(P)

deletion

gene

Test

pater nal

(M)

Imprinted

6.5

in

chromosome

genes

Table

Angelman

gene

(P)

Active

of

103

Prader-Willi

Imprinted

chromosome

Site

Diseases

genes

gene

(M)

Genetic

6

enzyme

activity

Detection

abnormal

of

high

metabolite

sodium

of

enzyme

of

abnormal

levels

deficiencies

levels

in

in

metabolic

sweat

(e.g.,

(cystic

acid

disorders

(e.g.,

phenylketonuria);

fibrosis)

maltose

in

Pompe

disease;

G6PD

defi-

Down

syn-

ciency)

Hemoglobin

electrophoresis

Cytogenetic

Detection

hemoglobins

(e.g.,

sickle

hemoglobin)

Assays

Karyotyping

Grossly

evident

structural

changes

in

chromosomes

(e.g.,

trisomy

21

in

drome)

Fluorescence

in

situ

hybridization

(FISH)

Subtle/submicroscopic

structural

changes

in

chromosomes

(e.g.,

del(5)

in

cri

du

chat

syndrome)

“Molecular”

Multiplex

Cytogenetic

ligation-dependent

Array-based

genomic

NextGeneration

Assays

probe

amplification

hybridization

sequencing

Small

deletions

changes

Copy

number

changes,

changes

(e.g.,

and

(e.g.,

partial

trisomy

21

in

deletion

Down

translocations

(mainly

translocations

in

used

cancer

of

BRCA1

in

familial

breast

cancer)

syndrome)

clinically

to

identify

somatic

copy

cells)

Assays

Allele-specific

PCR

and

related

techniques

Specific

CFTR

Sanger

insertions

number

number

Genetic

and

Copy

DNA

sequencing

base

pair

mutations

Mutations

in

changes

in

cystic

individual

(single,

e.g.,

sickle

hemoglobin

mutation,

or

multiple,

e.g.,

fibrosis)

genes

(e.g.,

glucose-6-phosphatase

mutations

in

von

Gierke

disease)

NextGeneration

sequencing

Mutations

in

mutations

unusual

many

in

genes

cancer

and/or

cells

phenotypes)

and

in

in

noncoding

research

to

regions

(used

discover

clinically

mutations

to

identify

responsible

somatic

for

104

CHAPTER

Genetic

6

Diseases

B

A

Fig.

6.13

trisomy

Fluorescence

18.

Three

centromere

specific

cent

to

for

probes

with

deletion

ceaper,

er

drecy.

ss;

or

uncons

Exampes

dencaon

aser

an

o

o

abound

o

g

onura;

dencaon

dsease;

and

o

of

o

es

o

red

probe

of

used,

one

22q11.2

for

or

ncude

indicating

(Courtesy

n

emoglobn

enzyme

DNA

n

n

levels

red

decences

n

a

Y

used:

copies).

chromosome

two

Nancy

R.

22q13

proens

bro-

sckle

(B)

this

22q13

One

region.

and

Jeff

or

precedng

e

meods,

esng



and

dsorder.

esng,

on

o

nclude

bes

genetc

e

can

se

anayss

ree

by

eal

or

be

o

ollowng:

e

wc

deecon

cell

varey

ecnques

persons

o

no

avalable

applcaon

e

o

ese

requre

genec

suspeced

genec

prenaal

and

posnaal

ndcaons.

be

ofered

abnormal

amnoceness,

DNA

o

judcous

dvded

sould

cyogenecally

obaned

cell

own

some

For

recognze

ecnque

esng

s

dseases.

o

and

two

and

the

suspected

chromosome

an

which

aqua

two

other

gives

Cytogenetics

probe

fluores-

hybridizing

chromosomes

abnormality

Doolittle,

X

does

rise

to

not

the

Laboratory,

greaer

rsk

o

rsomes

carrer

robersonan

saus

or

ranslocaon,

a

or

balanced

recprocal

ranslocaon,

nverson

 •

 A cromosoma abnormay afecng a prevous cld

 •

 D eermnaon

carrer

of

o

genec

fea

an

sex

wen

X-lnked

anayss

e

genec

usually

s

paen

or

parner

s

a

con-

dsorder

perormed

on

perperal

blood

Analysis

descrbed

genec

mporan

w

avng

or

o

Genec

eac

cells

ral,

s

e

Prenata

rsk

dscusson

dagnoss

in

with

 Conirmed

lympocyes

e

This

the

copy),

spread

(green)

the

for

 •

Posnaa

Genetic

(one

patient

 Advanced materna age (beyond 34 years), wc s assocaed w

rmed

for

of

male

 •

dsorders.

Indications

a

specific

metaphase

region

in

from

probe

centromere

A

signals.

Schneider

penylke-

n

green

Dallas.)

muaon

wde

nucleus

a

chromosome

microdeletion

cysc

n

cells

to

are

a

Interphase

been

(three

Center,

muaed

esng

penylalanne

Dr.

Medical

the

18

There

(A)

have

for

hybridizing

underyng

swea

specific

(red).

22q11.2,

aeraons

e

(FISH).

probes

chromosome

Southwestern

deny

sckle

hybridization

fluorescent

syndrome.

Texas

serum

dencaon

been

probe

and

a

region

22q11.2

University

or

copy),

have

the

situ

centromere

chromosome

stain

easer,

(one

the

in

different

obaned

on

o

all

progeny.

I

coronc

rom

paens

may

vllus

maernal

be

wo

a

perormed

bopsy

blood.

are

mae-

Indcaons

because

o

ease

o

samplng.

Indcaons

are

as

ollows:

 •

 Mupe congena anomaes

 •

 Unexpaned neecua dsaby and/or developmenal delay

 •

 Suspeced aneupody (e.g., eaures o Down syndrome)

 •

 Suspeced unbaanced auosome (e.g., Prader-Wll syndrome)

 •

 Suspeced sex cromosome abnormay (e.g., Turner syndrome)

 •

 Suspeced frage X syndrome

 •

 Infery (o rule ou a sex cromosome abnormaly)

 •

 Mupe sponaneous aborons (o rule ou a balanced ranslocaon

n

a

paren)

7

Diseases

of

Blood

Vessels

O U T L I N E

Mechanisms of Vascular Diseases, 105

Kawasaki

Congenital

Thromboangiitis

Vascular Anomalies,

Hypertension,

105

106

Atherosclerosis,

Small-Vessel

107

Infectious

Aneurysms and Dissections, 110

Disorders

of

Vasculitides,

Vasculitis,

Veins,

Aneurysms,

110

Varicose

Dissections,

111

Thrombophlebitis,

112

Cell

Takayasu

ease

(Temporal)

Arteritis,

arges

o

because

e

and

can



s

a

bran,

rom

as

dseases

un,

and

surgca

o

low

oer

va

aso

are

and

common

e

ear,



e

soud

be

e

o

as

organs.

oowng

o

n

reaed

e

and

ner venons,

moray

bood

and

Aoug

a

Saes.

aerosceross,

serous

In

vascuar

Uned

causes

dscusson

o

crcuaor y

cncay

sysem

a

ea

efecs

yperenson

separaes

recognzed

nersum

he

many

deeerous

addon,

ds-

and

dsurbances

low

se

sgn-

dseases

e

prmar y

o

(see

uncon

componen

neracons

n

Caper

w

be

oten

ave

o

e

o

sass

sage

gged

mporan

mpacs

rougou

e

on

anoer.

oowng

Caper

bood

or

or

o

VASCULAR

Common

vascuar

o

dsease

eer

progressvey

romboss

 •

compete

or

(e.g.,

by

caper

and

Anaomc

Anaomcay,

arera

uson

o

venous

ck

and

gases

pressure

umna

wc

roug

of

vesse

aerosceross)

and

CO

n

reguaon,

voume

o

a

norma

2

)

reurn

rc

can

suppy

and

wo

umens,

or

bre

prncpa

o

wereas

vesses

s

manans

lud

e

capar y

appens;

ear.

musce

venous

owng

covered

crcumsances

baances

a

dsurbances

dsease.

ranson

can

aer

vascuar

Aso

rom

o

endo-

mporan

norma

endoea

are

amnar

uncon

and

dsease.

ANOMALIES

bood

and

vesses

are

common

ner venona

caenges.

Severa

may

bu

are

cardoogss,

cause

argey

or

dsease,

o

con-

wom

ey

owever,

and

menon:

 Berry

aneurysms

(e.g.,

by

by

ces

a

nbs

and

er

ayer

pay

 •

ave

e

no

or

o

d-

nner

endoea

and

vascuaure

vens

can

n

was

he

ces,

n-waed

arera

 •

deecs

an

or

vens,

oupoucngs

n

cerebra

are

may

e

medum-

produces

and

arera

orm

cardac

o

e

s

a

senoss

o

o

a

nracerebra

vascus.

aure

by

can

arera

as

areres

be

deve-

aneur ysms

areres

vesses,

and

may

Arerovenous

sunng

rreguar

be

o

may

arge

vens,

occur

suas

voumes

o

crcuaon.

muscuar

or

beween

hey

perce

adjacen

venous

oca

bed.

rupure

njures

orms

arge-szed

umna

aa

connecons

capar y

ater

necross

dyspasa

and

abnorma

oowng

oer

causng

17).

ner venng

g-oupu

rom

 Fbromuscuar

o

stuas

nlammaor y

cause

sponaneousy,

Caper

wou

necons

bood

rupure

(see

adjacen

rom

w

ave

roe

dsensby.

coaguaon

beween

g-pres-

were

key

may

 Arterovenous

opmena

vesses

a

ey

emorrage

ow-pressure

Arera

and

vesses

o

no

beds,

are

vesses, mos commony ound a branc pons around e crce o

occurrng

acuey

subdvded

soues

bood

capacy,

be

bood;

smoo

o

surgeons

deser ve

and

vascuaure

wc

wc

surace

and

2

was

bood

under

maon

(O

vesses,

g

e

o

VASCULAR

varans

o

cnca

embosm)

vesses,

muscuar

bood

ony

presen

 Weakenng o vesse was, causng daon and/or rupure

sure

low

ypes

dscuss,

DISEASES

deveop

obstructon

because

urbuen

severa

w

vascuar

hese

Ws;

or

low,

we

n

ear

mecansms:

 Narrowng

As

W s as a bre prmer, we now urn o specc dseases o bood

 •

orms

3).

common

vesses.

cern

OF

115

deecs

8

MECHANISMS

 •

115

116

are

CONGENITAL one

114

115

Sarcoma,

Angiosarcomas,

compcaons

romboss

dsease.

114

114

Hemangiomas,

113

cause

compromses

venous

uncon

by

112

Kaposi

medca

eadng

aken

ear,

vesses

n

Arteritis,

113

Nodosa,

advances

remans

Disease),

Tumors of Blood Vessels and Lymphatics, 115

Polyarteritis

Despe

Veins,

(Buerger

114

114

Aortic

Giant

n

114

Obliterans

Aortic

Vasculitis,

on

Disease,

ckenng

areres.

assocaed

he

o

wa

w

e

was

ckenng

abnorma

ves-

nlam-

se spasm a reduces vascuar low. In e rena areres,  can ead

and

o

e

renovascuar

ypertenson.

105

106

CHAPTER

Diseases

7

of

BLOOD

Blood

Vessels

HUMORAL

VOLUME

FACTORS

Sodium Constrictors

Dilators

Mineralocor ticoids Angiotensin

Atrial

natriuretic

II

Prostaglandins

peptide Catecholamines

Kinins

Thromboxane

NO

Leukotrienes

Endothelin

LOCAL

BLOOD

CARDIAC

PERIPHERAL

PRESSURE

OUTPUT

RESISTANCE

FACTORS

Autoregulation

pH,

Constrictors CARDIAC

Dilators

FACTORS

α-adrenergic Hear t

hypoxia

β-adrenergic

rate

Contractility NEURAL

Fig.

7.1

Blood

pressure

regulation.

ave

NO,

b een

FACTORS

nitric

oxide.

mpcaed

n

e

rsk

o

de veopng

yp er enson,

bu

n

HYPERTENSION 95%

Sustained

high

end-organ

damage

Bood

ensure

blood

pressure

dever y

o

peruson,

organ

Low

a

(hypertension)

major

be

and

2

wases.

is

mus

O

meaboc

pressure

and

risk

factor

mananed

nurens

pressure

dysuncon,

o

wn

ssues

and



severe

narrow

remova

resus

and

vessel

and

atherosclerosis.

a

and

(ypotenson)

causes

for

range

o

n

CO

o

and

2

nadequae

sysemc,

sock

and

somemes dea (see Caper 3). Muc more common s ypertenson,

an

nsdous

bu

mporan

cause

o

morbdy

and

ta

o

cas es

e

y per tenson).

s econdar y

(e.g.,

o

umors

R arey,

Resng

bood

pressure

s

a

ncreas e

kdne y,

s ecreng

ressance

empaszng

(Fg.

o

7.1).

low,

A

o

wc

ese

s

dcaed

acors

are

uncon

by

e

subjec

o

cardac

muscuar

o

by

ormones

produced

by

e

one

reguaon

o

and

as

we

as

by

neura

npus

rom

e

kdney

and

e

ear

adrena

o

es e

or

o

o cc ur

umors

epneprne).

ndvdua

reabs or pon

mp or ance

essen-

genes

s o dum

mecansms

by

o

a

e

bo o d

Hyp er enson

sympaec

ner vous

canges

n

acceeraes

 e

wa  s

o

a erogeness

 arge-

and

and

c aus es

me d u m -s ze d

 a

can

ead

o

(descrbed

aorc

aer

dssecon

and

n

and

Caper

cerebrovascuar

17).

Areroes

can

(Fg. be

afeced

by

ese

canges.

sysem,

 Hyane

arteroosceross

s

marked

by

ckenng

o

e

arer-

oows: was

by

pnk,

amorpous,

yane

maera

and

narrowng

 Renn s a ormone a s produced n e kdney by ces a sense o rena

peruson.

renn,

a

Decreased

peruson

smuaes

producon

vesse

umens

proease

a

ceaves

crcuang

angoensnogen

o

ensn

and

pds

7.3A).

a

he

eak

ckenng

across

njured

s

caused

by

endoea

pasma

ces

no

angovesse

was

and

by

ncreased

producon

o

exraceuar

marx

I. proens

 he

(Fg.

o proens

 •

or

n

caed

yp er enson

norepneprne,

muaons

s

are-

oar

 •

by

pro ducon

e

o

ormone-s ecreng

adoserone,

caus ed

cas es



coun-

 • as

remanng

or

(ence

oupu

aso 7.2),

unknown

conro.

emorrage erreguaon

e

s

moray.

ar er es roes

o

s

adoserone

pressure

caus e

ds eas e

yp er enson

degenera ve and

Mos

rena

Morphology. Pathogeness.

sp ecc

acve

orm

o

angotensn

s

a

ormone

w

wo

(1)



ncreases

vascuar

smoo

musce

by

smoo

musce

ces.

mporan

 • acves:

one

and

 Hyper pastc arteroosceross s more ypca o severe yperen-

ressson.

Vesses

exb

“onon

skn, ”

concenrc,

amnaed

ck-

ance o low and (2)  smuaes e reease o adosterone rom e enng adrena

gand,

eadng

o

ncreased

reenon

o

sodum

by

e

and

ncreased

bood

voume,

wc

n

urn

enances

sroke

voume,

and

cardac

oupu.

Bo

o

ese

and

bood

pressure.

he

acve

orm

o

angoensn

s

deposon

umna

due

o

proeraon

o

smoo

musce

o

narrowng

basemen

(Fg.

membrane

7.3B).

In

ver y

maera,

severe

eadng

yperenson,

aeraons brnod

rase

was

cardac o

ng,

areroar

kdces

ney

o

creaed

necross

o

vesse

was

may

occur.

by

successve ceavages o angoensnogen by renn oowed by ango-

ensn-converng

rea

 •

 he

o

ear

ara

bood

rena

voume

sympatetc

cardac

ob esy,

mporan

arge

o

drugs

used

o

reeasng

on

bood

ese

nervous

a

o

respond

atra

sodum

o

ncreased

natruretc

and

waer

srec

ormone,

and

ereby

due

wc

owers

or

o

s

ormona

system,

dened,

130

greaer.

smokng,

Clncal

wc

reguaors

ac

o

are

ncrease

npus

vascuar

rom

one

e

and

mm

B o

Hg

s ome wa

or

greaer

genec

pysca

and

nacvy,

arbrary,

or

a

as

dasoc

envronmena

and

g

sa

a

resng

pressure

ac ors

sys-

o

80

(sress,

consumpon)

Features.

many

carda

ons

years

ncude

areroes.

(e.g.,

Uness

un

narcon,

enance

pressure.

oupu.

pressure

Hg

by

and

Hyp er enson

mm

ces

excreon

 Supermposed

oc

an

or

conans

daon

ncreases

 •

enzyme,

yperenson.

aorc

sowy

hese

rena

severe,

aneur ysm)

progressve

compcaons

sodum

or

aces

o

>

mm

200

prevenve

Hg)

and

aered

can

ead

dea

yperenson

o

and

s

ess

sensorum.

a

aure

be

or

o

hs

varan,

emergency

due

mos

s

a

sroke,

rena

and

screenng

mporan

(sysoc

w

magnant

a

producon

hereore,

efecve

requres

o

medcaons

angoensn

aure,

myo-

presena-

narrowng

by

assocaed

ermed

rena

asympomac

dramac

yperenson

and

be

(e.g.,

o

nbors).

e

Severe

Less

prevened

nb

commony

emorrages,

medca

deveop.

enzyme

one

medcne.

occurs

rena

s

may

compcaons

rena

can

excreon

angoensn-converng

paens

yperenson

cardovascuar

pressures

eadace

ypertenson,

cerebra

mmedae

edema,

and

reamen.

CHAPTER

Atrial

natriuretic

Diseases

7

of

Blood

Vessels

107

peptide

Cardiac

volume

sensors

+

Excretes

and

Vasodilation

Na

water

Blood

volume

BLOOD

Normotension

PRESSURE

BLOOD

PRESSURE

Blood

Vaso-

volume

(Low

volume

renal

or

low

ar ter y

constriction

resistance;

stenosis)

+

Resorbs

and

Na

water

Aldosterone Low

renal

pressure

Low

renal

sodium

Adrenal

Liver

Renin

Angiotensin

II

AngioAngiotensin

I

tensinogen Angiotensin-conver ting

enzyme Endothelium

Fig.

7.2

Interplay

of

renin,

angiotensin,

aldosterone,

in

and

many

atrial

tissues

natriuretic

o

 es e

peptide

a re

in

blood

ox  d  z e d

pressure

 ow - d e n s  y

regulation.

 p opro e  n

( L DL )

and

co-

ATHEROSCLEROSIS  e s  e ro 

Atherosclerosis

underlies

and

vascular

peripheral

mortality

in

the

Orgnay

ross

s

des

and

conned

ncreasngy

esyes

ateromatous

low.

e

More

aer

and

daon

o

many

and

o

provokes

on

n

e

vesse

aeromaous

o

causes

any

cnca

more

paques

vesse

counres

caed

and

can

rapd

re c o g n  z e d

and

by

aerosce-

as

resrc

or

o

or

as

vesses

consequences.

chronc,

Atheroscleross

repettve

appears

endothelal

njury

to

the

leadng

to

consequence

inlammaion

o

and

vesse wa damage

he

over

ng

 •

evens

decades

scenaro

a

(Fg.

s

 •

an

hs

are

eves

or

resus

smoo

o

 r  g ge r  ng

In

oer

rsk

pre s e n ,

“d a n g e r

an

 e y

a re

s  g n a  s” )

 n   a m m a or y

o

o

Facors

T

ce

ces,

marx

conrbues

a

o

be

o

dyspdema

assocaed

are

reease

and

e

naon,

e

suc

pro-

esons.

(yperenson

major

naors

assocaed

aso

ncreased

o

w

g

assocaed

w

aerosceross.

w

nlam-

componens

acors

e

condons

sgncan

o

wc

proeraon

aerosceroc

beeved

genera,

cncay

accumuaon

and

emodynamc

are

orms

o

mupcave.

and

low)

e

musce

nlammaon

bood

n

exraceuar

compcaons

damage.

ncreased

cumnae

7.4)

and

are

n

ormaon

no

enrey

o

an

aeroma

undersood,

bu

pay

e

ou

oow-

 •

 Hy percoesteroema.

speccay

LDL,

ss

fama

seen

kocye

deecs

adeson,

wa

(so-caed

macropages

deposon

and

urbuen

s

ve ss e

n or m a   y

Rsk

rsk

acors

ncude

e

oowng:

avored:

and

and

 Ac c umu  at  on

and

nduce

Hypercoeseroema

and

 Endotea njury eads o ncreased vascuar permeaby and eu-

nlammaon

n o

m a c rop  a g e s ,

ncudng

a

coagen.

endoea

be

as

a re

sub s anc e s

nlammaton

ces,

gresson,

sec-

aneur ysma

wa

syness

LDL

Pathogeness.

 es e

 ore  g n

suc

c yoknes

racure;

o

 Vesse

maor y

bood

Inlammaon

eadng

 •

Wesern

ateromas

beed

ce s

as

Snce

re s p on s e

occuson

ssues.

was,

morbidity

counres,

umens

causng

cerebral,

disorder.

nma

downsream

weaken

coronary,

other

ower-ncome

romboss,

can

of

ger-ncome

Lesons

narcon

sgncan

and

than

n

mpnge

mporany,

and

disease,

spread.

aeromas

pathogenesis

world

prevaen

paques

oten

scema

ondar y

western

the

cr ys a s.

of

aers

endoea

gene

expresson,

avorng

romboss.

p o prote n s

b e c au s e

o

esero

an d

e n d o  e   a 

a s s o c  ate d

d amage.

p  d s

Te

o cc urs

mos

n

 e

 mp or  a n

n

caracerzed

n

e

o

by

LDL

he

cenra

gged

roe

by

e

o

recepor.

LDL

ssues

poproen

coesero

serum

(HDL)

rom

LDL

(“bad”

ncudng

e

coesero,

acceeraed

y percoesteroema

eevaed

perpera

g-densy

mobzes

s

(see

Caper

eves

due

coesero)

e

coesero

perper y

vesse

o

6),

more

wc

nered

devers

wa,

(“good”

and

and

aeroscero-

co-

wereas

coesero)

ranspors



o

e

108

CHAPTER

Diseases

7

of

Blood

Vessels

Endothelium

Intima

Media

Adventitia

1.

Chronic

endothelial

“injur y”:



Hyperlipidemia



Hyper tension



Smoking



Homocysteine



Hemodynamic



T oxins



Viruses



Immune

factors

Response

to

injur y

reactions

A

2.

Endothelial

(e.g.,

dysfunction

increased

per meability , Platelet

leukocyte

adhesion), Monocyte

monocyte

and

3.

adhesion,

migration

Macrophage

activation,

B

Smooth smooth

muscle

recruitment,

muscle accumulation Fig.

7.3

Hypertensive

vascular

disease.

(A)

Hyaline

arteriolar

teinaceous

wall

(B)

Hyperplastic

nal

obliteration

MD,

Brigham

ver

is

material

or

thickened

with

(hyalinized),

arteriolosclerosis

(periodic

and

bar y

lumen

stain).

Hospital,

excreon.

deposition

the

is

(onion-skinning)

acid–Schiff

Women’s

the

and

(B,

w

a

reduced

of

amorphous

markedly

(arrow)

Courtesy

pro-

Fatty

narrowed.

causing

Helmut

Rennke,

S evera

oer

ger

acors

eves

o

HDL

assocaed

cor-

w

4.

Macrophages

rsk

smokng,

dabees)

o

aerosceross

ower

HDL

(de,

sedenar y

eves

or

esye,

eevae

LDL

and

muscle

cells

an engulf

ncreased

streak

lumi-

Boston.)

C onsequeny,

rsk.

cell

in

wall

smooth

reae

lipids

arteriolosclerosis. vessel

The

of

lipid

obesy,

eves.

Sa-

Lymphocyte

n

drugs,

eves,

wc

aso

ower

nb

e

coesero

rsk

o

syness

and

aerosceross-reaed

suppress

LDL

cardovascuar

Fibrofatty

atheroma

dsease.

 •

 Hemody namc

bu en

bo o d

branc

aor  a.

p ons,

Te

s ceross

 a 

fac tors .

 ow :

s

and

roe

o

A eromas

 e

os  a

a ong

o

 e

due

o

o

n

 e

o cc ur

vess es ,

p oser or

y p er enson

presumaby

end

ex  ng

wa  

a

a

o

ses

maj or

 e

d e veopmen

emo dy nam c

e e c  s

o

u r-

ar er  a 

ab dom  na 

o

on

a ero -

end o e-

 unc  on. 5.

 •

 Genetcs. Famy sor y s an mporan rsk acor or aeroscero-

ss.

Fama

ypercoeseroema,

an

auosoma

domnan

Smooth

muscle

proliferation,

and

dsease,

other

collagen

ECM Lipid

deposition,

and

mugenc

aso

are

dseases

suc

as

yperenson

and

ype

2

extracellular

dabees,

debris lipid

 •

assocaed

w

ncreased

rsk.

Lymphocyte

Collagen

 Age. Sympoms rom advanced esons appear n mdde age or aer. Fig.

he

40

ncdence

and

rse

60

w

o

years

eac

myocarda

o

age,

and

successve

narcon

dea

decade.

raes

ncreases

rom

ve-od

scemc

beween

ear

dsease

7.4

events

Summary

of

of

the

atherosclerosis.

morphologic

features

and

main

pathogenic

CHAPTER

A

Diseases

7

of

Blood

Vessels

109

B

Fig.

7.5

Atherosclerotic

denoted

arrow),

by

and

the

a

arrow.

lesion

lesions.

(B)

with

Aorta

(A)

with

overlying

Aorta

with

severe,

mild

diffuse

thrombus

atherosclerosis

complicated

(closed

composed

lesions,

including

of

an

fibrous

plaques,

ulcerated

plaque

one

(open

arrow).

FIBROUS

(smooth

foam

CAP

muscle

cells,

elastin,

cells,

collagen,

neovascularization)

CENTER

debris,

foam

macrophages,

proteoglycans,

NECROTIC

(cell

cells,

lymphocytes,

cholesterol

crystals,

calcium)

MEDIA

Fig.

 •

 G ender.

Premenopausa

women

are

7.6

reavey

The

structure

proeced

of

an

atheromatous

plaque.

agans e exraceuar marx (remodeng) and rombus organzaon, and

aerosceross

compared

w

age-maced

men,

possby

because oten undergo caccaon, wc can be seen radograpcay.

o

e

beneca

efecs

o

esrogen

and

progeserone

on

pd

proAcue

and

cronc

canges

n

aeromas

can

ave

serous

es. consequences:

 •

 Cona

ematopoess.

he

perpera

bood

ces

o

over

10%

o

 •

 Rupture

or

uceraton

exposes

rombogenc

subsances,

nduc-

adus over e age o 70 years w norma bood couns ave cona ng

muaons n genes a are assocaed w varous ypes o myeod

neopasms,

suc

as

acue

myeod

eukema

(see

Caper

9).

 •

rombus

 Hemorrage,

dyng

w

rom

cona

emaopoess

cardovascuar

ave

dsease,

a

wo-od

possby

eevaed

because

rsk

ese

o

wn

eads

In

descendng

abdomna

order,

aora,

aerosceross

e

coronary

mos

oten

areres,

e

e

nerna

Lesons

a

carod

varous

or

capares

paque

n

e

a-

rupure.

cause

scema

n

formaton

downsream

s

caused

by

organs.

oss

areres,

sages

o

and

e

severy

vesses

oten

o

e

coexs

srucures

Features.

rom

Myocardia

e

o

meda

easc

ayer

infarcion

o

bers

e

and

(ear

vesse

oer

aack),

wa.

cerebra

nvoves

(sroke),

aoric

aneur ysm,

and

peripera

vascuar

dis-

popea

crce

(Fg.

(gangrene

of

exremiies)

are

e

major

cinica

consequences

o

of Ws.

rage

aeromas.

ease areres,

o

expanson

 Aneurysm

infarcion nrarena

damage

paque

 •

Clncal

e

rapd

 Embosm o sma ragmens o aeroma durng paque rupure

supporng

Morphology.

o

 •

may

nlammaon

by

7.7).

mua-

ons dysreguae e uncon o macropages and ereby enance

oca

caused

(Fg.

Inderoma,

vduas

ormaon

aeroscerosis.

7.5).

hese compcaons may sem rom sow progresson o aerosceAeromaous paques are we o yeow rased esons w sot pd

roc cores

covered

by

brous

caps

conanng

smoo

musce

ces

 • coagen,

assocaed

w

macropage

and

T-ympocye

esons

or

rom

dramac

acue

evens,

as

oows:

and

 Ateroscerotc stenoss. Sowy advancng senoss may presen w

nraes

sympoms o scema n ssues supped by e afeced vesses. he and

varabe

degrees

o

neoangogeness

(Fg.

7.6

and

Suppemena

occuson s descrbed as a crtca

stenoss wen  bocks 70% o e

umen,

beyond,

eFg. 7.1). Macropages sufed w pd, so-caed oam ces, may be

promnen.

Exraceuar

coesero

s

oten

presen,

requeny

n

because

o

crysane

aggregaes

(coesero

cets).

he

meda

s

pon

and

e

ssue

demand

oten

e

oupaces orm

a

e

bood

suppy.

Presenaons

ncude

angna

pectors,

benea

wc

ypcay

appears

w

exeron

and

rems

w

res;

cronc

e paque may be aenuaed and broc, w smoo musce aropy.

scemc Paques

progressvey

enarge

roug

syness

and

degradaon

eart

dsease,

w

sympoms

reaed

o

ear

aure;

o

ntermttent

caudcaton,

due

o

eg

scema

w

exeron.

and

CHAPTER

Diseases

7

of

Blood

Vessels

109.e1

L

F

C

Supplemental

a

is

central

plaque

ated

and

fibrous

eFig.

necrotic

free

photograph

of

the

cap

C

B

A

7.1

core

(arrow);

a

and

of

core,

of

the

features

containing

the

section

media

Histologic

(C)

lesion

the

therefore

plaque

artery

showing

is

is

of

atheromatous

cholesterol

shown

thinned

scattered

and

other

“eccentric.”

in

(A)

under

In

stained

the

most

inflammatory

plaque

lipids.

this

for

The

the

coronary

lumen

section,

elastin

advanced

cells,

in

(L)

collagen

(black),

plaque

calcification

has

artery.

been

has

(A)

been

demonstrating

(arrow).

(C)

(arrowhead),

Overall

moderately

stained

that

architecture

blue

the

(Masson

internal

and

Higher-magnification

and

demonstrating

compromised.

neovascularization

Note

that

trichrome

external

a

stain).

elastic

photomicrograph

(small

fibrous

segment

arrows).

(B)

the

of

(F)

the

and

wall

Higher-power

laminae

at

cap

are

attenu-

junction

of

the

110

CHAPTER

Diseases

7

of

Blood

Vessels

B

A

Fig.

7.7

died

tion

Atherosclerotic

suddenly.

of

the

plaque

fibrous

rupture.

Correlations

 •

 Acute

paque

(B)

cange.

Acute

cap,

(B,

and

Acue

plaque

rupture.

coronary

triggering

Reproduced

Basic

paque

Plaque

thrombosis

fatal

from

Principles,

(A)

FJ:

Philadelphia,

canges,

suc

as

without

superimposed

myocardial

Schoen

rupture

infarction.

on

In

both

Interventional

Saunders,

rupure,

superimposed

an

and

1989,

p.

(A)

and

Surgical

an

arrow

in

a

points

Cardiovascular

patient

with

focal

to

the

Pathology:

who

disrup-

site

of

Clinical

61.)

Pathogeness.

he

ces,

oten

ave

serous

consequences.

Supermposed romboss and rapd, compee occuson may ead o

son,

myocarda

here

s

bu

may

narcon

rapdy

and

and

sroke,

reaed

medca

w

emergences

ancoaguans

a

mus

(parcuary

be

an-

wc



a

paee drugs) and romboyc agens or endovascuar sens. Oer

sceross,

mes,

paque

daons

ear,

wou

rupures

ead

narcon,

angna,

wc

o

a

ncreased

cange

may

scema,

marked

srke

even

by

wen

parcuary

ncreasngy

e

paen

s

n

e

severe

a

res.

be

Aneurysms

and

AND

in

the

of

are

blood

caused

vessels

or

by

the

durng

sysoe

are

congenital

or

produces

(nma,

oupoucngs

meda,

a

nvove

a

ree

ayers

o

and

advena)

or

e

aenuaed

wa

o

rena

and

or

may

sem

ransmura

rom

nered

myocarda

arera

surace

and

dssecons

cause

ure—oten

he

ons

w

bood

mos

nvove

puses

sass

deecs,

yperenson,

narcons.

gans

apar

and

enr y

common

aora

and

and

e

Dssecons

o

e

arera

underyng

romboss

caasropc

e

Aortic

and

ayers.

wa

roug

ave

a

Aneur ysms

catastrophic

Aneur ysms

ors:

horacc

ass o cae d

aor  c

w 

E  ers-D an os

syp s

(AAAs)

over

are

 e

mporan

are

vascuar

descrbed

enson

are

o

e ac

and

ye ar.

more

60

 a

he

are

propensy

aneur ysms

o

wa

and

and

aready

aone

or

exraceuar

seng

e

sage

or

prove

and

dssec-

aorc

e

aneur ysms

aorc

ypcay

burcaon;

ey

occur

can

be

beween

n

sape

and

up

o

15

cm

n

dameer

and

saccuar

25

(Fg.

7.8).

In

mos

cases,

exensve

aerosceross

s

cm

n

presen,

nnng

sac

and

oca

usuay

desrucon

conans

o

band,

e

underyng

amnaed,

meda.

poory

he

organzed

rombus,

wc

can



muc

o

e

daed

segmen.

Clncal Features. Mos AAAs are asympomac un an acue comp-

and

and

n

cond ons.

1%

o ows

o

s

ma es

I

s

and

on

n

and

yp er-

w  

AAAs.

are

examnaon

dagnosed

urasound.

and

Acue

may

szed

revea

by

a

pusang

magng

compcaons

o

abdom-

sudes,

AAAs

mos

ncude

e

of

a

brancng

areres)

due

romboss,

spna

cord,

or

vesse

o

(e.g.,

e

expanson,

resung

n

dsa

gasronesna

rena,

ac,

exenson,

and

scema

o

verebra,

oten

e

or

super-

kdneys,

rac

 Embosm rom a rupured aeroma or a mura rombus

 •

 Impngement on adjacent structures (e.g., compresson o a ureer or

 •

 Rupture no e peronea cavy or reroperonea ssues, eadng

eroson

o

o

verebrae

massve,

oten

by

aa

e

expandng

aneur ysm)

emorrage

Women are ess key o ave AAAs, bu ose a occur n women

an

r upure

Pysca

 •

 a

ave

 Obstructon

egs,

adu s

es mae d

S aes

esons

o c us e d

aneur ysms

abdomna

mposed

n

cardovas c u-

hey

mesenerc

are

as

deveops.

mass.

oowng:

ac-

and

ma r x,

aor  c

Une d

 es e

r sk

uncommon

ex race u ar

 e

prone

 •

A eros ceross

n

are

dferen

ab domna 

smoke.

and

fatal.

ave

p ar  c u ary

ndvdua s

 a

abdomen

syndrome,

w ere as

w o

the

 e

Mar an

6),

0.5%

ds c usson

and

rup-

caon

rea vey

n

pre dsp osng

1,000,000

b ewe en

vesse

musce

as

acors,

a

nex.

ab domen

dee c s

common,

ye ars

mp or  an

approxmaey

AAA

C aper

in

often

and

aneur ysms

syndrome,

muc

occur

which

 orax

n er e d

(s e e

age

 e

smoo

wc,

hese

aero-

resus.

often

ruptures,

n

scarrng.

and

Aneur ysma

and

oten

most

smoke.

orm.

wen

Aneurysms

aneurysms

e

yperenson

obacco

ey

undersood,

aerosce-

occur

na

Aortic

weakenng

o

once

we

e

mura deec

oss

no

aerosceross,

meda

o

Abdomna

areres

aneur ysm g-pressure

ead

o

o

s

mos

daon.

usorm

w ross,

areas

o

n

AAAs

e

an

eng ear,

w

rsk

oxns

o

a

aora,

acquired

or arer y

may

smokng

eevaed

o

nrarena

expanson

w

efecs

e

heart. e

Aneur ysms

an

o

n

DISSECTIONS

dissections

walls

rae

conrbue

Morphology. defects

o

e

componens,

aneur ysma

ANEURYSMS

as

combnaon,

marx

e

concde

can

urbuence

assocaon

reaed

we

oten

dscussed,

n

enances

srong

as

and

produced

common se o AAAs. hese wa sresses are exacerbaed by yperen-

nlammaory

sress

wave

reeased

rom

wa

pressure

maxma

“unsabe”

ar

(B),

plaque

nrapaque emorrage, or weakenng o e brous cap by proeases

dagnosed

to

thrombus,

atherosclerotic

are

more

key

Aneur ysms

5

o

cm

rupure.

n

he

dameer

rsk

or

or

arger

rupure

are

s

deermned

consdered

g

by

rsk

sze:

and

CHAPTER

requre

surger y.

eecve

gency

Tmey

procedures

surger y

ater

s

ner venon

s

approxmaey

rupure

s

crca:

5%,

rougy

e

wereas

moray

e

rae

rae

or

or

Pathogeness.

emer-

men

50%.

40

cases)

Aortic

and

the

Dissections

dissection

splays

aortic

when

media

arterial

to

form

blood

a

penetrates

blood-lled

intima

yperropy

within

vesse

roug

e

may

produce

advena

and

aa

escapes

emorrage

no



adjacen

e

bood

rup-

wa);

smoo

marx.

ssues.

gans

pa

e

o

eas

ces

e

ear

(see

or

In

aora

canne

cystc

7.8

Abdominal

aortic

ruptured

at

site

is

(A)

External

indicated

by

view

the

of

a

arrow.

large

(B)

with

the

location

of

the

rupture

tract

indicated

by

a

of

layered

the

aneurysm

is

attenuated,

and

the

lumen

is

probe.

filled

by

canges

s

n

ssue



mos

Pa ens

o

aor  c

or

Aortic

occurred

arrows)

the

in

lies

a

region

at

dissection.

elastic

dissection.

(identified

layers

the

(B)

are

by

(A)

the

largely

edge

of

a

and

opened

probe)

free

Histologic

black,

An

of

a

large

blood

aorta

with

of

is

red

are

 e

narc  on

by

emor rage

re ae d

ne ck

w c

proximal

an

or

may

o

o

no

bood

and

e

oss

bood

aong

e

 ypc a  y

s abbng

md d e

may

pres en

o

 e

d s r up

 e

be

e

o

 e

musce

abnorma

(Suppemena

 e

sud den

n

 e

sp ac e.

dss e c -

 u nc  on ,

ar er es,

O  er

ons e

aner or

R e rog rade

va ve

c oronar y

p er c ard a 

o

dened.

w  

b ack.

o

vascuar

Hsoogcay,

b eg nn ng

aor  c

or

sac.

umen

a

smoo

seen

s

e

areres

percarda

aorta).

oss

deec

p a n ,

compressng

 no

may

specc

oward

creang

n

he

emorrage,

reeners

by

ound

7.9A).

emora

e

ear,

s

(Fg.

accumuaon

marx,

no

and

massve

(doube-barreed

exenson

 e

rena ,

b e come

plaque.

this

the

dissection

intramural

The

atherosclerosis

showing

in

a

with

atherosclerotic

area

once

meda

rerograde

o

 e

dss e c  on

mes ener  c ,

  ac,

o

or

 e

c aus e

or

 e ad

comp c a-

g re a

spna 

obs r uc e d.

R apd

d ag nos s ,

large,

associated

preparation

o

exraceuar

bu

usuay

vave

ac

nma

caracerzed

 e

ro o

e

occurs

ragmenaon,

e ar  ng

exend

as

dssecng

meda

orgn

aorc

causes



dsa

e

B

tear

suppy

ar er es

ar er  es,

any

The

A

7.9

(see

meda

eadng

e

e

*

intimal

sow

a

unknown,

thrombus.

Fig.

syndrome

meda,

o

connecve

aortic

o wall

e

rad a ng

 e

massve

vesses

e

(1)

(>90%

Opened

o view,

In

myo c ard a 

aneurysm.

the

a

degeneraton,

Features.

and

 ons that

e

excr uc a ng

no

o

sengs:

o

paens

roug

e

can

ar

rupure

amponade

second

wn

as

nsances,

o

aneurysm

Exerna

o

meda

exraceuar

 on

Fig.

e

cm

eFg.

ces

B

unnes

proeogycan-rc

o

dseases

sma

earng

markng

10

nsances,

easc

Clncal

A

ear

roug

7.2).

(e

peruson



occasonay

cardac

meda

ces,

wa

wo

Eers-Danos

degenerave

wn

wn

7.9B).

some

e

pane

n

genec

and

n

yperenson

yperensve

nma

nma

aora

dsay,

Fg.

resus

occurs

111

ressance.

ascendng

dssecon

w

agng

and

e

Vessels

aneceden

vasorum

vesse

Morphology. he

e

o

dmns

naes

many

w

syndrome

vasa

may

musce

access

o

o

Blood

paens

aoras

s

Wa

age

Maran

he

of

dssecon

o

younger

as

6).

the

o

dssecon

years

(2)

channel

wall.

Aorc

ures

the

Aorc

60

suc

Caper

occurs

apart

o

and

ssue,

Aortic

Diseases

7

distal

(white

dissection

section,

stained

edge

arrow),

and

with

originating

hematoma.

of

the

which

intramural

Movat

Note

from

that

intramural

arrested

small,

the

oblique

intimal

hematoma

the

hematoma

stain.

a

tear

(black

propagation

(asterisk).

of

Aortic

an  yp er ens ve

CHAPTER

7

Diseases

of

Blood

Vessels

A

B

Supplemental

eFig.

Marfan

syndrome,

but

actually

are

layered

pattern

filled

of

7.2

Cystic

showing

with

elastic

medial

elastin

degeneration.

fragmentation

proteoglycans

tissue.

In

both

and

(asterisks).

A

and

B,

(A)

Cross

areas

(B)

elastin

Normal

is

section

devoid

of

media

stained

of

aortic

elastin

for

black.

media

that

from

resemble

comparison,

a

patient

cystic

showing

the

with

spaces

regular

111.e1

112

CHAPTER

 erapy,

o

85%

s e c  ons

c a  y

ave

and

o

or

surg c a 

 e

 a

rep ar

p a ens

do

no

manage d

s ome w a

Diseases

7

w  

o

 e

 nvove

 e

Blood

n ma 

nvov ng

aor  c

c ons er va vey

b eer

aor  c

d ss e c   on

of

w  

arc

e ar

 e

c an

Vessels

c an

aor  c

be

s ave

65%

Pathogeness.

arc.

Ds -

caon

rep a re d

an  yp er ens ve

surg -

dr ugs

and

oucomes.

peuc

w

he

response

arers

key

response,

caracersc

ceran

o

HLA

cass

serods

occurs

as

presumaby

a

o

a

granuomaous

II

apoypes,

suppor

resu

o

angens

a

an

e

mmune

cronc

presen

nlammaon,

and

h1

n

e

an

exceen

eoogy.

Gan

ce–medaed

vesse

wa.

asso-

era-

ce

mmune

he

deny

o ese angens and e bass or e predecon or vesses o e ead

are

unknown.

VASCULITIS

Vasculitis

encompasses

a

group

of

disorders

with

highly

varied Morphology.

pathophysiology

and

clinical

features

that

are

dened

by

the

ds r bu on ence

of

vessel

wall

a ong

 e

eng 

nl amma on

o

afe c e d

o cc urs

vess es.

a

p acy

Invove d

n

ar er  a 

inammation. s eg mens

Cnca

Granu omaous

pres

manesaons

depend

on

e

specc

vascuar

bed

exb

no du  ar

n ma 

 ckenng

(and

o cc asona 

a  romb os es)  a mpnge on  e umen and c aus e ds a  s cem a.

s

afeced

and

somemes

ncude

sgns

and

sympoms

o

sysemc Fu  y

nlammaon.

Many

orms

o

vascus

are

recognzed,

some

w   overappng

eaures.

Eoog y

s

dverse

and

ncudes

de veop e d

mu  nuce ae d

nlammaon,

necons,

drugs

and

cemcas,

and

rauma.

I

s

crca

o

dsngus

necous

njur y

approprae

w

mon

y

or

resrc

or

o

afec

e

our

aer

because

bu

dscusson

greaes

arge

orms

coud

o

paogenc

mmunosuppressve

exacerbae

orms

o

neres,

necous

vascus

sarng

a

w

erapy

Giant

that

Cell

vascus.

are

ose

mos

cell

a

prmar-

principally

he

be

affects

empora,

nvoved.

permanen

Arteritis

arteritis

a

chronic

large-sized

verebra,

Opamc

bndness;

is

and

arteries

opamc

arer y

ereore,

granulomatous

in

nvovemen

promp

the

can

dagnoss

disorder

head.

ar eres

and

e

cause

and

w c

s

oten

s

ass o c ae d

cus

sudden

can

and

reamen

 e

are

essena.

among

years

me d a,

o

oder

age.

(ever,

 rag mene d

w  

and

Sgns

mos

papaon.

Ocuar

range

bopsy,

s

rom

ypcay

pacy,

a

coserod

n ma 

adven   a 

arers

n

and

 e

(Fg .

7.10).

dpopa

e

oss)

aong

sympoms

o

o

e

bopsy

or

e

mos

may

ake

7.10

tion.

cells

(B)

Giant

near

Elastic

associated

cell

the

arteritis.

tissue

medial

(A)

fragmented

staining

attenuation

Hematoxylin-and-eosin

internal

elastic

demonstrating

and

scarring.

 nnng

does

necross

n

no

acor

oss.

(H&E)–stained

membrane

focal

(arrow),

destruction

of

section

along

the

with

of

a

medial

internal

temporal

and

elastic

artery

adventitial

membrane

showing

and

rare

o

and

wc

s

50%

vas-

beore

pan

panu

o

Dagnoss

e

o

nlamma-

aca

e

are

or

o

paens

requres

arers

dagnoss.

erapes

inflamma-

(arrow)

orm

s

because

excude

(TNF)

o

abou

owever,

I

sysemc

orm

arer y,

vson

arer y ;

resu

relec

abrupy

compee

common

counres.

e

empora

appear

empora

an–umor

s

B

A

giant

e as c

He a ng

bross.

reamens.

Fig.

g ranu omas

ner na 

 ckenng ,

ger-ncome

sympoms

weg

nense

negave

or

ce

adus

maase,

eadace,

and

aora

o

Clncal Features. Gan

50

(temporal)

on

We

com-

vesses.

(Temporal)

nonne cro zng

s

on

Giant

o

cenere d

rom s c ar r ng

mmune-medaed

ce s

radaon  e

exposure,

conss

g  an

mmune-memembrane,

daed

esons

w

Cor-

efecve

CHAPTER

Takayasu

Takayasu

Arteritis

arteritis

bu

is

a

arteries

characterized

pulses

the

in

Takayasu

ng

o

e

upper

granulomatous

by

ocular

vasculitis

disturbances

of

large-sized

and

maness

aora—parcuary

Polyarteritis

w

e

ransmura

aorc

arc

scarrng

and

grea

and

cken-

vesses—and

umna narrowng o e major branc vesses. Is eaures overap w

ose

made

years

ce

o

gan

argey

o

age

on

arers

e

beng

arers,

uomaous

ce

bass

e

o

a

Takayasu

dsncon

paen’s

desgnaed

as

arers

T-ce–medaed

age,

avng

appears

mmune

beween

w

ose

Takayasu

o

be

wo

o

enes

younger

arers

caused

response

e

by

an

a

an

Lke

cronc

unknown

Polyarteritis

cular

he

and

usually

50

gan

aora,

akeofs

7.11),

o

e

eadng

rena,

e

grea

o

Inlammaor y

and

aorc

arc,

vesses

upper

o

T

may

exremy

nraes

accumuaons

coronar y

and

s

n

ces

areres,

brances,

be

narrowed

weakness

vesse

and

may

was

and

or

be

gran-

vesse

as

we

range

macropages

afeced.

oberaed

an

carod

rom

o

1

o

vsua

2

or

years

and

are

neuroogc

113

compabe

w

decs.

that

is

a

systemic

commonly

the

vasculitis

involves

of

medium-sized

renal

and

visceral

mus-

vessels

lung.

e

dsease

ore

s

ave

he

cause

responds

beeved

cronc

o

ave

epas

compexes

composed

depos

vesse

n

o

poyarers

o

an

B

was

compexes

o

we

mmunoogc

necon

vra

and

and

angens

provoke

ocaze

nodosa

mmunosuppressve

n

bass.

may

and

an

s

One

ave

unknown,

agens

rd

o

crcuang

specc

areres

paens

mmune

wc

response.

and

bu

ere-

anbodes,

nlammaor y

medum-szed

and

no

n

Wy

oer

as s

unknown.

he

(Fg.

puses.

nonspecc

granuomaous

nlammaon, bo o wc may be assocaed w wa ckenng

and

ater

w

Vessels

Nodosa

spares

Pathogeness.

vesses pumonar y,

abe

nodosa

arteries

mmune

e

quescen

Blood

s

angen.

Morphology.

become

sur vva,

of

weakened

extremities.

arers

oers

ong-erm

Diseases

7

Morphology.

vesses

Fuy

deveoped

necrozng

areres,

bross.

Vesses

rac

are

o

e

esons

w

n

are

nlammaon

oten

kdney,

afeced

o

ear,

ver,

descendng

composed

o

gasronesna

o

requency.

segmena

medum-szed

supermposed

and

order

or,

romboss.

ransmura

occasonay,

Acue

sma

esons

ave

brnod necross o e vesse wa and nrang neurops (Fg.

7.12),

Clncal

Features.

Invovemen

o

e

aorc

arc

and

major

wereas

oder

nlammaon.

produces

reduced

upper-exremy

bood

pressure

and

puse

decs,

vsua

ed

deecs,

and

bndness.

o

nvovemen

o

e

dsa

aora

(eg

are

and

broc

cronc

and

assocaed

esons

w

coexs,

cronc

suggesng

recurren

nlammaor y

damage.

he

vascuar

njur y

may

Sympoms mpar

reaed

Acue

sreng, ongong

neuroogc

esons

brances

caudcaon),

e

e

peruson

o

downsream

ssues,

eadng

o

uceraons,

punarcs, and scemc aropy, or may provoke aneur ysm ormaon

monar y

arer y

(pumonar y

yperenson),

e

ear

(myocarda and

narcon),

appear.

he

and

e

dsease

rena

as

a

areres

varabe

(sysemc

course.

yperenson)

Some

cases

aso

rapdy

e

aendan

rsk

o

emorrage.

may

progress,

Clncal Features. Poyarers nodosa s more common n young adus

bu

can

ong

occur

weg

oss—are

vascuar

o

a

age.

reaed

proean

nvovemen

gasronesna

neurs,

he

cnca

ner vas.

nvovemen

puzzng,

arer y

era

any

sympom-ree

s

o

vared

and

may

esons;

abdomna

dfuse

predomnany

ypcay

and

be

suc

as

and

muscuar

are

epsodc,

boody

aces

moor

and

ner ves.

due

soos

pans;

Rena

and

and

dsrbued,

yperenson

w

ever,

nonspecc,

wdey

pan

afecng

s

sympoms—maase,

nlammaon

manesaons

and

course

Ina

e

eadng

o

rena

caused

and

by

perp-

nvovemen

s a major cause o dea. Unreaed, poyarers nodosa s usuay aa,

A

B

Fig.

7.11

flow

of

Takayasu

contrast

brachiocephalic,

tions

of

strating

circles

is

the

the

carotid,

right

marked

intimal

of

to

intimal

the

(A)

into

and

carotid

correspond

area

arteritis.

material

Aortic

the

arch

great

subclavian

artery

from

thickening

original

arteries

the

and

vessel

hyperplasia.

angiogram

vessels

wall;

the

showing

shown

(B)

in

narrowing.

inner

reduced

narrowing

(arrows).

patient

luminal

and

core

of

Cross

(A)

demon-

The

of

the

sec-

tan

white

tissue

Fig.

7.12

necrosis

vessel

MD,

ical

Polyarteritis

and

thrombotic

(upper-right,

Department

School,

of

Dallas.)

nodosa,

associated

occlusion

arrow)

is

of

a

small

uninvolved.

Pathology,

University

with

artery.

segmental

Note

(Courtesy

of

Texas

that

Sidney

fibrinoid

part

of

the

Murphree,

Southwestern

Med-

114

bu

CHAPTER

w

90%

o

Diseases

7

mmunosuppressve

erapy

of

remsson

Blood

or

cure

s

Vessels

aceved

n

cases.

res—probaby

smoke,

grene.

Kawasaki

Kawasaki

and

Disease

disease

childhood

sized

an

acute,

associated

febrile,

with

an

self-limited

arteritis

of

illness

large-

of

to

Smokng

vascuar

sgncance

sems

rom

requen

nvovemen

o

coro-

oer

on

a

he

seasona

rggers

an

cause

o

varaon

mmune

Kawasak

n

dsease

ncdence,

response

a

s

unknown.

suggesng

njures

a

areres

he

a

dsease

vra

are

he

vascus

aoug

brnod

resembes

necross

a

s

seen

usuay

secondary.

n

no

o

can

a

rem

vascus

nerves.

I

and

e

paen

progress

progresson,

w

smokng

prmary

cytopasmc

vascudes

agans

wo

varous

orms

reerred

o

as

o

over

bu

connues

me

once

o

o

gan-

esabsed,

absnence.

afec

antbody

are

sma

vesses.

Aoug

(1)

by

o

e

presence

neurop

an-proenase-3

dreced

consuen

(ANCA)–assocated

dened

componens

ANCA:

c-ANCA),

granue

agans

PR-3,

(PR3-ANCA);

and

o

granues.

ANCA

a

vascu-

auoan-

neurop

(2)

here

(ormery

azuro-

an–myeoperox-

poyarers dase

nodosa,

no

o

deveop

Vasculitides

orms

hese

bodes

nec-

pc

Morphology.

do

 Antneutrop

tdes.

sows

may

er paogeness s ncompeey undersood, wo groups ave emerged:

 •

areres.

Pathogeness.

nvovemen

absnence

esons

Small-Vessel

Many

cnca

o

uceraons

infancy

medium-

vessels.

Is

nar y

is

e

due

cronc

as

ANCA

(ormery

reerred

o

enzyme,

myeoperoxdase

as

p-ANCA),

dreced

agans

promnen. a

neurop

ysosoma

(MPO-ANCA).

Afeced vesses ave a dense ransmura nlammaor y nrae a Severa

orms

o

ANCA-assocaed

vascudes

are

recognzed

w

ncudes neurops and mononucear ces. I et unreaed, damage paray

caused

by

e

nlammaon

may

ead

o

aneur ysm

overappng

eaures.

hey

ncude

PR3-ANCA

posve

ormaon. granuomaoss

w

poyangs

and

MPO-ANCA

posve

mcro-

scopc poyangs. Bo are assocaed w gomeruoneprs and

Clncal Features. Kawasak dsease ypcay maness w conjuncva

pumonar y dsease, requeny eadng o emopyss. I s uncear 

and ora eryema accompaned by bserng, eryema and edema o e

e

ands

presen

and

ee,

a

desquamave

ras,

and

cervca

ymp

node

enarge-

men. Approxmaey 20% o unreaed paens ave cardovascuar com-

pcaons,

wc

or

mos

may

sudden

noaby

rupure

dea.

(speccay,

or

he

e

deveopmen

rombose,

dsease

nravenous

o

eadng

responds

coronary

o

we

mmunogobun

arery

myocarda

o

aneurysms,

narcon

annlammaory

and

asprn),

wc

ANCAs

n

dagnosc

 •

and/

agens

Thromboangiitis

strongly

I

egs,

and

Obliterans

obliterans

associated

prmary

and

with

afecs

oten

o

a

severe

tobacco

sma

produces

ampuaon

is

(Buerger

and

of

vasculitis

that

is

e

ses

scema,

o

uceraons,

e

arms

and

mmune

oberans

smokng

drecy

o

depend

s

oxcy.

mody

Ceran

e

on

uncear.

damages

drec

may

Bo

gangrene

ssues.

exposure

One

e

naon

dea

o

s

vesse

wa

HLA-ypes

obacco

a

endoeum

Aernavey,

a

some

and

more

smoke,

and

o

bu

e

o

vascuar

compound

nduce

suscepbe,

an

romboangs

e

componen

a

reacve

componens

are

progresson

precse

obacco

canges

n

obacco

mmune

conssen

w

roe

o

smoke

are

due

smoke

response.

a

roe

or

he

e

s

w

exampe

wa

n

dfer

In

e

be

vascuar

dependng

compexes.

and

on

e

sysemc

kdney

s

anbodes

ereore

hese

may

deposed

w

njur y

naure

upus

vascudes

o

e

e

o

upus

er ye-

cn-

auoanbodes

afeced

(see

o

mmune

resuan

er yemaosus

severey

are

drecy

par

sysemc

o

deposon

bnd

as

and

are

are

agens.

compemen

Anbodes

or

ese

and

mmunosuppressve

assocaon

o

bu

paens

vascutdes.

njur y.

vesse

dsrbuon

syndrome,

Infectious

Drec

and

vascuar

o

roe,

afeced

and

or

Good-

Caper

11).

and

Vasculitis

vascuar

parcuary

Pathogeness.

Treamen

by

o

ndngs

pasure

areres

o

sma-vesse

ca

smoking.

mdde-szed

severe

afeced

form

paogenc

mmunogobun

compexes,

Disease)

drec

racon

caracerzed

maosus.

Thromboangiitis

vaue.

componens

reduce e ncdence o sympomac coronary arery dsease.

a

g

 Immune-compex,

a

sarpy

ave

a

ocazed

arers.

(e.g.,

bacera

may

arse

or

nvason

rysm)

arera

or

can

Vascuar

pneumona

rom

embozaon

weaken

by

Pseudomonas,

necous

nvason

or

was

nduce

o

spread

necve

usuay

and

can

adjacen

emaogenous

rom

agens,

Aspergus,

be

par

romboss

o

and

cause

spp,

a

or

ung,

may

ssue

or,

bacera

endocards.

suiceny

o

abscesses),

o

bacera

Mucor

cause

necon

ess

commony,

durng

sepcema

Vascuar

aneur ysms

necons

(mycotc

can

aneu-

narcon.

or

mmune njury. Ceran enc groups (Israe, Indan subconnen, Jap-

DISORDERS anese)

are

aso

a

greaer

rsk,

ponng

o

one

or

more

genec

Varcose

Morphology.

cronc

Caracerscay,

ransmura

vascus

o

ere

s

medum-

segmena

and

acue

sma-szed

cay

and

vens

reevan

nlammaory

n

e

exremes.

nraes,

wc

may

In

gve

e

rse

eary

o

sages,

mcroabscesses,

Varicose

are

and

adjacen

W

me,

srucures

romb

become

organze

encased

n

and

evenuay

brous

rombopebs

accoun

or

a

eas

90%

o

cn-

dseases.

Veins

e

veins

chronically

wall

no conguous vens and nerves (a eaure rarey seen n oer orms

vascus).

and

venous

mxed

accompaned by umna romboss. he nlammaon oten exends

o

VEINS

areres,

Varicose predomnany

OF

acors.

 •

ssue.

abnormally

dilated

intraluminal

tortuous

pressures

veins

and

produced

weakened

by

vessel

support.

Venous

arery

are

increased

daon

can

occur

a

mupe

ses:

 Varcose vens o e exremes occur n up o 20% o men and one

rd o women; obesy and pregnancy ncrease e rsk. hey mos

commony

Clncal

Features.

Paens

smokng

sory

more

ans

by

may

presen

exercse,

vascuar

or

o

w

usuay

20

Raynaud

superca

nsuicency

are

an

penomenon,

noduar

ends

o

younger

pack-years.

be

pebs

an

45

and

hromboangs

nsep

(venous

accompaned

by

oo

pan

ave

nduced

nlammaon).

severe

a

ober-

he

pan—even

a

afec

e

superca

vens

o

e

egs.

Varcose

daon

renders e venous vaves ncompeen and eads o ower-exremy

sass,

congeson,

and

secondar y

and

uceraons,

posed

edema,

scemc

necon.

wc

pan,

skn

oten

and

romboss.

canges

ea

may

poory

ead

and

Perssen

o

are

sass

prone

edema

dermas

o

superm-

CHAPTER

 •

 Esopagea

son

varces

secondar y

obsrucon

agea

or

varces

may

o

ver

epac

are

one

arse

n

crross

ven

o

e

seng

and

(ess

romboss

severa

ypes

o

o

pora

requeny)

(see

Caper

yperen-

pora

13).

porosysemc

 •

ven

Esop-

suns

ncude

reca

perumbca

vens

ancu

or

ke

 •

e

erm

vens

o

e

vens

(producng

e

because

somemes

aa

wa

magned

ead

sgncan

(emorrods,

o

upper

are

known

resembance

Medusa).

ey

s

descrbed

o

Esopagea

prone

o

as

caput

e

and

are

eadng

e

medusa,

daed

varces

rupure,

gasronesna

beow)

7.13A).

o

w

 •

a

on,

juncon.

mos

resu

commony

Hemorrods

and

hey

panu

are

a

rom

massve,

due

source

o

o

pregnancy

beedng

pevc

or

and

sranng

are

prone

o

o

conges-

deecae.

esons

are

romboss

 C avernous

deep

of

thrombophlebitis

Oer

ses

ac

venous

we

as

e

were

pexus

arge

veins

and

is

deep

n

n

the

source

venous

maes

vens

accounts

and

e

of

pevc

and

more

most

romb

e

sku

for

may

90%

pulmonary

orm

venous

e

than

dura

are

e

pexus

n

snuses

of

cases

emboli.

(especay

and

n

Kaposi

pesvirus-8

vera;

see

Caper

9)

may

ead

ypercoaguaby

o

pora

ven

(e.g.,

poycyema

romboss.

sarcoma

Vrcow

and

rad:

n

ong

venous

pane

romboss

aby

see

low

(e.g.,

(see

o

e

ncreased

Mae

sex

o

3).

exended

eg

one

or

more

endoea

Caper

(e.g.,

magnancy

3).

reaed

auomobe

(DVT)

Caper

w

sass

or

s

abnormaes,

ypercoaguaby

resus

or

hromboss

bed

res

rps)

ncreases

vens,

as

do

componens

njury

Proonged

n

e

deep

causng

nered

deecs,

suc

and

age

an

years

50

o

as

a

T-ce

and

 •

sae,

venous

are

V

sarcoma

uncon.

rsks,

are

 C  a ss c

Je w s ) .

bu

Leden;

as

assocaed

rsk.

cases,

e

pan

ca

ever,

e

can

be

musces,

sympoms

absence

o

manesaon

preven

be

ncude

or

orced

are

ndngs

DVT

recurren

emporar y

eced

oten

o

or

edema,

by

pressure

dorslexon

absen,

does

s

DVT,

redness,

a

no

over

o

e

especay

excude

pumonar y

ancoaguan

eong,

sweng,

dependng

and

afeced

oo

n

In

reamen

e

vens,

(Homan

many

embosm

on

pan.

bedrdden

DVT.

(see

s

eoog y

In

BLOOD

VESSELS

AND

mas

sze

o

bood

(exremey

surround

monar y

and

common),

nrequeny,

neopasms

vesses

may

bood

arer y,

and

rare,

arse

and

ocay

gy

rom

vesses.

ympacs

e

sgn).

How-

e

Caper

and

cava)

umors

occur

o

rs

3).

wc

 Endemc

bu

occur

vscera.

emango-

varees

o

emangomas

n

newborns:

are

o

red

a

peduncu-

beed

resembe

more

arge,

easy

exuberan

nrave,

excson

are

17),

one

requeny

be

hey

requred

componen

wc

bran

vascuar

emangomas,

regress.

may

n

daed

capar y

sponaneousy

neoplasm

known

mos

o

as

o

vascuar

sem,

nvove

may

n

be

some

von

Hp-

esons

rena,

caused

Kaposi

common

KS,

n

based

o d e r

by

are

pancreas,

human

sarcoma

ndvduas

on

men

Eu rop e an

s

her-

herpesvirus

w

popuaon

o

mpared

demograpcs

or

 e

usu a  y

Me d  e r r an e an ,

d e s c e n

susp e c e d

p  a qu e s

 me

KS

and

s

( e sp e c  a  y

n

n o

n o du  e s ,

 e s  on s

re m a n

ypcay

can

occurs

n

e

 n d  v  du a  s ,

pre s e n .

I

usu a  y

m ay

M d d  e

As  ke n a z 

a e c  e d

o

 e

m an  e s  s

on

 n c re a s e

c on   n e d

occurs

oow

n

seng

course

Lesons

bu

a

e

e

and

oten

rsk

 AIDS-assocated

o

an

cdren

o

o

KS

n

 e

n

 ow e r

sze

sk n

HIV-negave

ndoen

oten

and

or

an d

an d

sub -

cdren

aggressve

organ

vruay

n

aways

and

course.

I

w

e

aa.

sod-organ

mmunosuppresson.

nvoves

regress

s

occurs

T-ce

ymp

aenuaon

nodes,

o

ranspan

I

pursues

mucosa,

an

and

mmunosuppres-

rejecon.

(epdemc)

mos

ncdence

vduas

angosarcomas.

Vascuar

era

or

ces

arge

a

vesses

nrequeny

suppor

(aora,

and

are

or

composed

of

recognzed,

ncudng

KS

common

s

an

AIDS-denng

HIV-reaed

ness

magnancy

and

wordwde.

and

w

an

aen

more

erapy,

bu

ncdence

popuaon.

an

KS

a

s

wdey

o

n

popuaons

occurs

1000-od

AIDS-assocaed

dssemnaes

80%

s

vscera

KS

n

an

nvoves

s

w

access

HIV-neced

ger

oten

eary

n

n

e

ymp

nd-

gen-

nodes

course.

pu-

mosy

blood-

ypes

as

anrerovra

measa-

Pathogenes s.

and

e

preerenay

are

 Transpantaton-assocated

son,

vessels.

Severa

e

may

compeey.

mucosa

ey

o

and

 ssue.

Afrcan

adus

a

tumors

skn,

growng,

ora

w

cerebeum,

n

sk n

 e y

a

KS

proeraon

eukn

benign

or

 m mu n o d e   c  e n c y

nu mb e r,

sroma

common

s

W 

ve

are

regress

composed

no

e

orms

e x  re m   e s .

aggressve

may

Hemangiomas

lled

are

 m mu n  y

T- c e  

recpens

To

sarcomas.

Hemangiomas

mos

rapdy

C ompared

do

E aser n

nvovemen,

 •

DVT.

bengn

neopasms

endoeum

Prmar y

vena

magnan

as

e

LYMPHATICS

ncude

aggressve

bu

emangomas)

nvove

Mcroscopcay,

vascular

o cc urs

re d - pu r p  e

he

Tumors

(Fg.

capares

7.13C).

also

(KS)

A  e re d

remans

OF

kdneys

n-waed

n

ora

oten nvoves ymp nodes. A severe orm, w promnen vscera

 •

TUMORS

a

Four

or

ov e r 

young

squeezng

cases,

e

 •

some

paens,

gven,

o

e

recognzed:

KS

c u an e ou s

Clncal Features. DVTs produce ew reabe sgns or sympoms. Loca

manesaons

is

(HHV-8,

E aser n,

ypercoagu-

acor

aso

e

dysuncon,

possurgca

rsk

acors

and

oder

or

o

mmobzaon

e

and

occur

o

[KSHV]).

Kapos

Pathogeness.

o

strawberry

gngva

(Caper

n

speen,

brs),

emangomas

ound

ese

Sarcoma

an

w

200

surgca

dsease

ver,

ype;

membranes

ver.

Kaposi

assocaed

e

115

as

e seng o necon or nlammaon). Peronea necons and cer-

condons

or

7.13D).

Cavernous

commony

perpros-

emaes,

(Fg.

and

common

mucous

composed

rapdy,

emangomas

pe-Lndau

n

manes

skn

desrucve;

mos

and

are

n

emangomas

srucures,

cases.

leg

ssue

as

(1

uceraed.

(Fg.

cavernous

Thrombophlebitis

deep

oten

e

Vessels

7.13B).

grow

e

Blood

(so-caed

common

on

are

ey

(Fg.

hey

of

ssues,

we

granuomas

cannes

uceraon.

of

are

granuaon

 •

as

sroma

mupe.

ocay

Thrombosis

ps,

emangomas

 P yogenc

and

vascuar

scan

aed

emorrages.

proonged

and

Hsoogcay,

 Juvene

be

 •

 Hemorrods are varcose daons o e venous pexus a e ano-

reca

emangomas

subcuaneous

newborn

snake-

cncay

skn,

caves

a

may appear w pora yperenson; oer common ses o sun-

ng

 Capary

e

Diseases

7

ces.

6,

as

sss;

w

hese

we

nerere

absence

as

w

o

me

magnanc y.

s

an

unusua

smuaed

ncude

vra

e

an

and

by

neopasm

acors

vra

acors

uncon

efecve

cona

a

omoogs

a

o

T-ce

o

begns

ce

may

s

as

HHV-8

suc

c yce

suppressors

response,



by

c yoknes

enance

umor

evouon,

key

produced

a

reac-

neced

as

ner-

progresson

suc

as

RB.

proeraon

progress

o

a

In

per-

u-ledged

116

CHAPTER

Diseases

7

of

Blood

Vessels

Pathogeness. Morphology. Cu aneous

esons

progress

 roug 

 ree

(e.g., s ages:

patc,

paque,

and

nodue.

Paces

are

pnk,

red,

or

oowng

comp os ed

o

daed,

r reguar,

and

anguaed

ces.

ass o caed

Paques

daed

w 

(Fg.

der ma

an

n rae

7.14A)

vas c uar

are

o

cronc

ee vaed

cannes

ndweng

corde

as

comp os ed

and

sur rounded

spnde

ces.

No duar

esons

are

ncre as ed

numb ers

o

pump,

over  y

neopas c

w 

s age

oten

nersp ers ed

s-ke

proera ng

spaces

(Fg.

n

e

seng

breas

o

cancer),

ympedema

radaon,

o

oregn

bodes

(e.g.,

srapne).

Hsorcay,

and,

poyv-

been

assocaed

w

angosarcoma

o

e

ver.

spnd e

7.14B).

he

In

e

skn,

angosarcomas

rs

appear

as

sma,

and

demarcaed,

red

nodues.

Advanced

esons

are

arge,

lesy

ces,

red-an oten

or

o

sarpy con an

arse

by

Morphology. pump

can

resecon

nlammaor y

esons

ned

node

bo o d ny

vess es

ymp

pur pe rarey,

mac ues

Angosarcomas

s equen a

o

gray-we

masses

(Fg.

7.15A)

w

-dened

margns

no duar

a bend mpercepby w surroundng srucures. he exen o s

accompaned

by

no da

and

vs cera

nvovemen,

dferenaon par c uary

n

 e

A r can

and

AIDS-ass o caed

cannes

wou

Clncal Features. he

ca

and

seng.

Cassc

surgca

w

resecon

s

anrerovra

o

usuay

oten

erapy

KS

argey

mmunosuppresson,

mmunosuppresson

KS,

course

KS

s

vares

adequae

resoraon

s

wdey

resrced

efecve.

generay

s

o

o

accordng

e

surace

reamen.

T-ce

In

or

o

o

KS

uncon

Smary,

s

varabe,

rangng

rom

umors

a

e

e

7.15B)

dscernbe

o

bood

undferenaed

spnde

s

a

magnan

dened

mos

AIDS-assocaed

are

oten

nvove

aggressve

resecon

by

evdence

o

oten

e

umors

s

no

skn,

sot

a

ssue,

nvade

possbe,

and

breas,

ocay

curren

and

and

ver.

5-year

sur vva

30%.

endo-

A

B

C

D

7.13

Hemangiomas.

hemangioma.

and

D,

(C)

Courtesy

Brigham

Medical

and

John

Hemangioma

granuloma

Sexton,

Women’s

School,

(A)

Pyogenic

MD,

Hospital,

Dallas.)

of

Beth

Boston.

of

the

Israel

C,

the

lip.

tongue.

(D)

Hospital,

Courtesy

(B)

Histologic

Boston.

Thomas

Histologic

appearance

appearance

B,

Courtesy

Rogers,

MD,

in

in

cavernous

Christopher

University

of

juvenile

capillary

hemangioma.

D.M.

Texas

Fletcher,

Angosarcomas

measasze.

dferenaon.

Fig.

umors

Clncal Features. Oder adus are more commony afeced, and esons

reducng

beneca.

neopasm

vascuar

vesses.

Angiosarcomas

ea

ce

cn-

assocaed

by

(Fg.

body,

abou

Angosarcoma

orm

var ans.

(A

MD,

Southwestern

Compee

raes

are

ony

CHAPTER

A

7

Diseases

of

Blood

Vessels

B

Fig.

7.14

logic

Kaposi

view

spaces.

of

the

sarcoma.

nodular

(Courtesy

(A)

Characteristic

stage,

Christopher

coalescent

demonstrating

D.M.

Fletcher,

sheets

MD,

with

7.15

and

red-purple

proliferating

Women’s

macules

spindle

Hospital,

and

cells

plaques.

and

(B)

slit-like

Histo-

vascular

Boston.)

B

Angiosarcoma.

dense

plump,

Brigham

A

Fig.

cutaneous

of

clumps

of

(A)

Angiosarcoma

atypical

cells

lining

of

the

distinct

right

ventricle.

vascular

(B)

lumina.

Moderately

differentiated

angiosarcoma

117

8

Heart

O U T L I N E

Congenital

Heart

Malformations

Malformations

Heart

Angina

Chronic

Systemic

s

a

eadng

ease,

n

121

year

125

and

ever y

o

o

Uned

126

126

organ,

more

n

e

may

moray

o

body,

be

beang

an

mporance

dsease

e



s

severe:

wordwde

more

7500

L

an

o

crcuaor y

no

surprsng

accouns

or

m-

a

day.

sysem

Cardovascuar

and

40

bood

genetic

a

or

e

dsease

one

n

s

our

a

o

domnan

ser ve

e

esons

ocus

on

and

e

mos

acqured

common

orms,

and

orms

en

o

ear

ns

our

a

30%

of

all

ds-

Clncal

be

aure.

Congena

ear

genes

o

DISEASE

heart

or

year),

Deecs

as

aso

be

sages

caused

Srucura

(1)

wc

cardac

mpared

o

by

cardac

genec

anomaes

maormaons

causng

(3)

contribute

vessels,

which

to

afec

ranscrpon

deveopmen.

by

ransen

he

acors

uncon

envronmena

deveopmen,

gvng

rse

o

acors.

a

rg-o-le

maormaons

n

congena

causng

sun

causng

a

ear

dsease

e-o-rg

(cyanoc

sun;

congena

can

(2)

ear

obsrucon.

a

permis

bood

o

low

from

e

et

o

e

rig

side

of

congenital

account

for

ear

(or

vice

versa)

20%

 Le-o-rg

suns

ncrease

bood

low

no

e

pumonar y

cr-

defects.

dsease

afecs

neary

1%

o

brs

(rougy

and

w

a

ger

ncdence

n

premaure

nans

compabe

w

ve

br

usuay

nvove

ony

expose

e

ow-pressure,

ow-ressance

pumonar y

40,000

and

o

ncreased

pressures

and

voumes,

resung

n

rg

svenrcuar

borns.

may

eary

o

o

A shunt is an abnorma communicaion beween cambers or bood

factors

great

and

crcuaon per

some

reguaors”

ose

Features.

caegorzed

cuaon

nans

muaons,

crca

maormaons

environmental

the

birth

136

136

“maser

smar

ds-

 • to

as

same

sresses

e of

135

Failure,

Saes.

we

HEART

and

abnormalities

134

Mos snge-gene deecs a dsrup cardac deveopmen are auo-

soma

vesses Both

Disease,

135

Failure,

Heart

Tumors,

dseases);

CONGENITAL

Myocardial

Failure,

127

resen

e

of

Heart

Right-Sided

132

133

133

Heart

Left-Sided

Disease,

Cardiac

pumpng

congena

ear

Disease,

Heart

126

organ

ear

Heart

131

131

Cardiomyopathy,

Causes

Congestive

Hypertensive

Endocarditis,

Cardiomyopathy,

Myocarditis,

126

Disease,

and

Cardiomyopathy,

Restrictive

Hypertensive

128

130

Thrombotic

Hypertrophic

Disease,

Valve

caper,

w

Dilated

Disease,

Disease,

Cardiomyopathies and Myocarditis, 131

121

Heart

Disease,

Valvular

Endocarditis,

Nonbacterial

120

121

(Pulmonary)

o

ncudng

cusson

to

Infective

Other

cause

e

s

120

workoad

uncon

In

Shunts,

remarkaby

per

consequences

deas

Right-to-Left

Obstruction,

(Left-Sided)

s

mes

Gven

with

Leading

Heart

Heart

ear

Associated

Disease,

Degenerative

on

119

Infarction,

Right-Sided

he

Shunts,

125

Hypertensive

Valvular

Left-to-Right

Ischemic

Arrhythmia,

Rheumatic

with

Pectoris,

Myocardial

e

118

Associated

Ischemic

e

Disease,

Malformations

yperropy

and,

evenuay,

rg-sded

ear

aure

snge (cor

pulmonale).

ead

o

W

me,

ncreased

pumonar y

ressance

may

cambers or regons o e ear. Tweve enes accoun or 85% o cases

o

congena

ear

dsease;

er

requences

are

sown

n T abe

menger

 • Pathogeness.

Congena

ear

dsease

usuay

arses

rom

 W

durng

gesaona

weeks

3

roug

8,

wen

cases.

srucures

Known

deveop.

eoogc

he

acors

cause

ncude

s

unknown

acqured

n

amos

condons

rubea

necon,

eraogen

exposure,

maerna

and

ae-onse

cyanoss

(Esen-

because

suns,

dabees,

e

a

dusky

pumonar y

bueness

crcuaon

o

s

e

skn

bypassed

(cyanoss)

and

bood

eners

e

sysemc

poory

crcuaon.

90%

suc

 S ome congenal anomales obsruc vascuar low, by narrowng e

as vaves,

or

major

bood

vesses.

A

maormaon

and erzed

genec acors suc as rsomes 13, 15, 18, and 21 and T urner syndrome.

118

et)

car-

cambers, congena

o

auy

major

 • o

(rg

syndrome).

oxygenaed dovascuar

reversa

rg-o-le

resus embryogeness

sun

8.1

by

compee

obsrucon

s

caed

an

aresa.

carac-

CHAPTER

Table

8.1

Frequency

of

Congenital

Heart

8

119

Cardiac

a

Malformations Ao

Incidence

Malformation

Live

per

1

LA

Million

Births

Percentage PT

Ventricular

Atrial

septal

septal

Pulmonary

defect

42

4482

defect

10

1043

stenosis

LA

8

836

RA

Patent

ductus

arteriosus

7

781

L V RV Tetralogy

of

Fallot

Coarctation

of

aorta

Atrioventricular

5

577

5

492

septal

A

4

396

defect

Aortic

stenosis

Transposition

great

ASD

4

388

of

4

388

Ao arteries Ao

Truncus

arteriosus

1

136

PT Total

anomalous

pulmo-

1

120

PT nary

venous

connec-

LA

LA

tion

Tricuspid

atresia

RA

1

118

RA

L V TOTAL

9757

L V RV

Malformations

Let-o-rg

Associated

suns

are

with

assocaed

Left-to-Right

w

ara

sepa

Shunts

deecs,

RV

B

C

venrcVSD

uar

sepa

deecs,

and

paen

ducus

arerosus

and

are

e

Fig.

common

ype

o

congena

cardac

maormaon

(Fg.

8.1).

8.1

deecs

ypcay

ncrease

ony

rg

venrcuar

and

oulow

voumes,

wereas

venrcuar

sepa

deecs

and

arerosus

cause

ncreases

n

pumonar y

bood

low

and

o

e

Cyanoss

sun

rreparabe

repared

due

s

o

an

eary

pumonar y

cardac

beore

no

eaure

reversa

ese

yperenson

dysuncon

sun

o

hus,

occurs,

deecs,

can

cause

et-o-rg

usuay

w

bu

direction

septal

left

Septal

Aria

sepa

Defects

defecs

and

and

Patent

paen

Foramen

foramen

are

right

common

congenia cardiac anomaies diagnosed in adus.

Durng

and

et

cardac

ara

by

deveopmen,

e

foramen

paency

ovae,

s

wc

aer

cosed

beween

by

on

are

a

e

ssue

rg

laps.

sepa

In

w

low

sneezng

o

bood

embous

(e.g.,

or

sranng

pus

paens

rom

deep

rg-o-et

durng

a

eg

rsk

bowe

or

vens)

a

a

bood

low,

movemens.

paradoxca

eners

e

as

Suc

may

rg-o-et

embosm:

arera

occur

a

venous

crcuaon

o

Atrial

(C)

Patent

ventricle;

w

ormed

rom

grows

e

sunng

ear

s

e

septal

ductus

PT,

defect

( arrows

(ASD).

arteriosus

pulmonary

oer

by

ear

downward

poron

deecs

cdood.

transent

(A)

(B)

indi-

Ventric-

(PDA).

trunk;

RA,

Ao,

right

aorta;

atrium;

s

e

cardac

e

uson

apex

o

and

mee

se

o



a

maormaons.

o

a

muscuar

nner

ven-

a

membranous

par-

(Suppemena

approxmaey

he

rdge

eFg.

70%

o

8.1).

he

venrcuar

deecs.

Sma

foramen

aow

left

assocaed

upward

wa

may

(VSD).

L V,

sepum

80% o peope, ese sepa evenuay use. In e remanng cases, a patent

ovae

defect

membranous

mananed

s

flow).

ventricle.

Mos

grows

mos

blood

be

surger y.

e

shunts

and

mus

Ovale

ovae

of

atrium;

rcuar

Atrial

left-to-right

reversa

c yanoss

suns

of

bood RV,

pressure.

causes

paen LA,

ducus

congenital

pumoular

nar y

Common

Ara cate

sepa

PDA

mos

may

sepum

Larger

be

may

deecs,

compcaed

aure.

asympomac,

cose

Eary

by

surgca

and

deecs

sponaneousy

owever,

resu

pumonar y

correcon

durng

n

n

cronc

yperenson

s

e

mperave

muscuar

nancy

and

or

or

eary

et-o-rg

congesve

suc

esons.

va

Patent

Ductus

Arteriosus

an ara deec due o ncreased rg-sded ara pressures. hs may gve

rse o sroke due o odgng o paradoxca embo n vesses o e cenra

he

nervous sysem. In conras, an ara sepa deec s a xed openng n e

arer y

ara sepum a aows unresrced bood low rom et o rg arum.

Ara

sepa

deecs

wen

ong-sandng

oads

may

reversa.

cronc

evenuay

hese

usuay

asympomac

rg-sded

produce

compcaons

are

do

voume

pumonar y

no

occur

un

and

pressure

yperenson

w

paen

aduood,

and

oramen

over-

sun

ovae.

ducus

I

a

arses

o

e

perms

e

Septal

Defecs

in

are

mos

e

mos

cose

e

Defects

venricuar

common

o

sepum

congenia

sponaneousy

and

do

aow

et-o-rig

cardiac

no

come

anomaies

o

cinica

suning

a

bir,

aenion

and

bu

aora

rom

orgn

bood

e

o

consrcs

ssen

paen

suns)

cases

are

o

ungs.

E

2

e

n

1

arer y

o

2

vascuar

e

days

paogeness.

o

o

e

e

e

and

(e.g.,

gene

jus

ducus

causes

deecs,



o

nor-

oxygen-

decnng

due

ds-

e,

bypassng

arera

Known

ypoxa

aora

aora,

br,

ressance,

domnan

pumonar y

nrauerne

ncreased

pacena.

ncude

auosoma

jons

Durng

arer y

o

bewe en

bir

and

arer y.

response

rom

ink

ater

pumonar y

arerosus

ceran

coses

Wn

coses

derved

unceran

connecing

subcavan

pumonar y

ducus

and

a

pumonar y

et

rom

and

decreased

is

normay

et

e

low

prosagandn

et

a

unoxygenaed

may

aon,

Ventricular

and

areriosus

eves

o

per-

rg

bu

90%

o

o

CHAPTER

Supplemental

William

D.

eFig.

Edwards,

8.1

MD,

A

ventricular

Mayo

Clinic,

septal

defect

Rochester,

(membranous

Minnesota.)

type),

denoted

by

the

arrow.

8

Heart

(Courtesy

119.e1

120

CHAPTER

Sma

duca

suns

Heart

8

generay

cause

no

sympoms,

bu

arger Morphology.

deecs

evenuay

ead

o

sun

reversa,

cyanoss,

and

ear

T eraogy

dspacemen Paen

ducus

arerosus

creaes

a

g-pressure

et-o-rg

o

Fao

resus

rom

anerosuperor

aure.

sun

o

e

muscuar

sepum

a

separaes

e

pumonar y

a runk and e aorc roo (Fg. 8.2A). he ear s enarged and boo-

produces

a

ars,

“macner y-ke”

murmur.

Isoaed

paen

ducus saped

due

o

rg

venrcuar

yperropy ;

e

proxma

aora

s

requres surgca ner venon as eary n e as possbe o preven ese daed;

and

e

pumonar y

runk

s

ypopasc.

he

venrcuar

compcaons. sepa

deec

usuay

s

arge

and

s

overrdden

by

e

aorc

vave,

wc receves mos o e oupu rom bo venrces. Obsrucon

Malformations

Associated

with

Right-to-Left

Shunts

o

rg

venrcuar

oulow

may

be

due

o

narrowng

jus

beow

e

Cardac maormaons resung n rg-o-et suns gve rse o cyapumonar y noss

due

o

admxure

o

venous

bood

w

e

arera

mos

common

condons

assocaed

w

cyanoc

ses

dsease

(Fg.

are

eraog y

o

Fao

and

ransposon

o

or

pumonar y

vave

senoss

In

suc

cases,

a

paen

ducus

arerosus

or

daed

or

bronca

e

grea

provde

e

ony

roue

or

bood

o

reac

e

ungs.

ves-

8.2).

Cln cal

Tetralogy

of

Fallot

o

Feature s.

pu monar y

T eraog y of Fao is e mos common cause of c yanoic congenia

obs r uc  on

ear

and

disease

he

common)

congena areres

ear

(mos

crcuaon. aresa.

he

vave

(⁓5%

eraog y

of

congenia

consss

o

e

cardiac

oowng

maformaions)

our

abnormaes:

pu monc

 Venrcuar sepa deec

I

 •

 O verrdng o e venrcuar sepa deec by e aora

s o ae d

 •

 Rg venrcuar oulow rac obsrucon (subpumonc senoss)

e 

 •

 Rg venrcuar yperropy

pu monar y

 e

r g .

ds e as e

are

s e en,

s

as

emb o za  on .

compc ae d



c aus e

 e

 e

 e

r sk

C ompee

pu monar y

res

o

 e

( due

surg  c a 

s

g rows.

o c c urs

 rom

e ar 

R g  -o -

end o c ard  s

rep a r

s

an

 rom

c yano c

yp ox  a).

 ne c  ve

a res  a

e ar 

proe c  on

o

o

sun ng

ma or me d

res embes

sun ng

prov des

deg re e

pu  mon  c

 e

cond  on

s e qu e ae

or

 e

r g  -o -e 

b e c aus e

o er

on

c as es ,

b e c aus e

as

p oyc y em a

 ncre as es

mos

  me

senoss

bu

d ep ends

In

m d,

d ee c ,

pu mon c

suc

a s o

o

w  

exp and

s ep a 

Te

sun ng

more

no

yp er ens  on ,

p aradoxc a 

s

enoug 

obs r uc  on

ven r c u  ar

s e ver  y

obs r uc   on .

wors ens

do es

pu monc

o

cnc a 

s e vere

w c

or  ce

 •

e 

s

c yanoss,

Te

ou  ow

and

p oss be

bu

pres en.

Ao

Transposition

of

the

Great

Vessels

PT

In

ransposiion

of

e

grea

vesses,

e

aora

arises

from

e

rig

venrice and e pumonary arery emanaes from e et venrice.

LA

I

s

ncompabe

w

posnaa

e

uness

a

sun

exss

a

dev-

RA

ers

oxygenaed

bood

o

e

aora

suc

as

a

venrcuar

sepa

deec

(one

rd o cases) (Fg. 8.2B; Suppemena eFg. 8.2). In ese cases, e rg

L V

venrce

s

sysemc

crcuaon,

yperroped

because



s

e

pump

or

e

g-pressure

RV

and

e

et

venrce

s

ypopasc

because



pro-

vdes bood o e ow-pressure pumonary crcuaon. In oer nsances,

suns are provded by a paen oramen ovae or ducus arerosus; ese

end

o

cose

soon

nervenon. Classic

A

tetralogy

of

he

ater

br,

domnan

and

suc

eaure

s

nans

requre

cyanoss.

emergen

Improved

surgca

surgca

ec-

Fallot

nques now perm repar, and paens oten survve no aduood.

Malformations

Leading

to

Obstruction

Ao Ao

Congena

vaves,

aer

PT

a

obsrucons

e

mos

eve

o

o

e

commony

bood

vaves,

nvove

low

or

e

can

occur

dsay

aora

and

proxma

wn

mer

a

a

o

grea

bre

e

ear

vesse.

he

dscusson.

PT

LA

Aortic

LA

RA

Coarctation

Coarcaon

RA

o

L V

L V

RV

as

emaes.

oer

here

 •

are

 An

c

VSD

Without

wo

B

Common

disease).

flow).

septal

(B)

(A)

congenital

T etralogy

T ransposition

defect.

Ao,

Complete

of

aorta;

of

RA,

right

may

the

LA,

right-to-left

great

left

vessels

atrium;

L V ,

dsa

shunts

(arrow

(cyanotic

indicates

with

left

and

atrium;

RV ,

right

ventricle;

VSD,

wc

o

dsease.

be

form

e

a

o

e

Maes

soary

mos

coarcaon

eaurng

beween

arerosus

without

ventricle;

PT ,

low,

congenital

direction

of

blood

ventricular

o

 •

ventricular

e

aora.

and

e

 An

s

e

(reerred

man

he

aora

are

s

a

common

afeced

deec

o

common

(Fg.

s

or

a

may

wce

be

as

orm

oten

as

bcuspd

assocaed

aorc

vave.

8.3):

crcumerena

et

“adut”

source

o

pumonar y

because

narrowed

subcavan

preduca).

narrowng

arer y

In

s

and

a

o

e

paen

aor-

duc-

e

rg

segmen,

form

(unoxygenaed)

crcumsance,

runk

sde

e

conssng

o

s

e

rg

o

daed

ear

due

o

devered

s

o

ncreased

peruses

venrce

rdge-ke

bood

e

e

e

bood

body

dsa

yperroped.

nodng

o

e

aora

pulmonary

adjacen

trunk;

consrcon)

ear

VSD

transposition

Fallot

o

orms

“nfante”

ducus

8.2

Coarcaon

deecs,

segmen

us With

heart

or

congena

RV

w

Fig.

(narrowng,

obsrucve

septal

o

e

gamenum

arerosum,

a

remnan

o

e

ducus

defect.

arerosus

(reerred

o

as

posduca)

(Fg.

8.4).

Proxma

o

e

CHAPTER

Supplemental

Rochester,

eFig.

8.2

Minnesota.)

Transposition

of

the

great

vessels.

(Courtesy

William

D.

Edwards,

MD,

8

Mayo

Heart

Clinic,

120.e1

CHAPTER

ISCHEMIC

Ao

Ao

Ischemic

HEART

heart

Heart

8

121

DISEASE

disease

encompasses

several

related

syndromes

caused by insufcient delivery of oxygen and nutrients to meet myo

PT

cardial

demand.

PT

I LA

s

mos

oten

due

o

coronar y

arer y

dsease,

e

ce

cause

o

LA

moray

RA

n

e

Uned

Saes

and

oer

g

ncome

naons.

Encour-

RA

agngy,

as

moray

decned

by

reaed

50%

o

scemc

snce

1963.

ear

hs

dsease

n

e

mprovemen

s

Uned

argey

Saes

due

o

L V L V

RV

ner venons

RV

a

ave

reduced

coronar y

arer y

aerosceross,

ncudng smokng cessaon programs, beer reamens or yperen-

son

With

PDA

Without

Coarctation

of

and

dabees,

advances

suc

coronar y

care

8.3

Coarctation

of

the

aorta

with

or

preductal

form)

a

patent

left

indicates

ductus

arteriosus

ventricle;

direction

PT,

of

pulmonary

blood

(PDA)

flow.

trunk;

RA,

uns,

o

coesero-owerng

efecve

arryma

angopasy,

and

drugs.

conro,

endovascuar

herapeuc

mprovemens

senng

ave

n

aso

(“adult”

Ao,

or

right

aorta;

postductal

LA,

atrium;

left

RV,

reduced

a

arge

bood

majory

low

o

caused

cases,

by

scemc

ear

aerosceross

dsease

o

e

sems

coronar y

form);

atrium;

right

In

and

areres, arrow

use

aorta

(“infantile”

rom without

and

more

conrbued.

PDA

Pathogeness. Fig.

as

oten

reerred

o

smpy

as

coronar y

arer y

dsease.

Aero-

coronar y

areres,

L V,

ventricle.

sceross

(see

sngy

n

or

Angina

Angina

any

can

afec

any

o

e

man

Pectoris

hree

varans

angna

cuar

is

intermittent

chest

pain

caused

by

reversible

ischemia.

 Stabe

s

7)

combnaon.

pectoris

myocardial

 •

Caper

eves

usuay

are

s

o

recognzed.

predcabe

exeron

assocaed

epsodc

or

w

ces

ncreased

sabe

pan

demand

assocaed

(e.g.,

aerosceroc

w

par-

acycarda).

paques

a

I

narrow

e umen o a coronary arery by 70% or more (crtca stenoss). he

pan

o

a

 •

s

e

a

crusng

et

arm

vasodaor

 Prnzmeta

onar y

o

or

squeezng

e

a

or

arer y

responds

or

et

jaw

ncreases

varant

spasm,

subserna

I

s

coronary

angna

vasodaors

suc

near

as

by

res

a

or

by

may

radae

nrogycern,

peruson.

occurs

ypcay

sensaon

reeved

a

res

and

s

aerosceroc

nrogycern

and

caused

by

paques.

cacum

cor-

I

aso

canne

bockers. Fig.

8.4

Coarctation

of

the

aorta,

postductal

type.

The

coarctation

is

a

 • segmental

narrowing

of

the

aorta

(arrow).

Such

lesions

typically

 Unstabe angna (crescendo angna) s caracerzed by ncreasngy

mani-

requen fest

later

in

life

than

preductal

coarctations.

The

dilated

ascending

even and

major

branch

vessels

are

to

the

left

of

the

coarctation.

The

lateral

ogy,

are

perfused

channels.

University

e

et

(Courtesy

of

coarcaon,

predominantly

Texas

e

s

Sid

arc

way

Murphree,

Southwestern

aorc

venrce

of

by

and

MD,

Medical

s

of

branc

dilated,

tortuous

Department

School,

vesses

of

coronar y

paque

Pathol-

be

daed

and

Features.

narrowng

 •

 Preducta

e

w

on,

 •

and

e

hese

coarctaton

cyanoss

mos

depend

paency

n

afeced

o

wt

e

e

a

on

nans

e

ducus

patent

ower

do

a

no

a

poson

severy

o

rupure

Myocardial

e

and

sur vve

usuay

body.

e

presens

Wou

neonaa

eary

n

ner ven-

ncdence

e

ross.

presence

Men

gender

gap

are

aerosceroic

deveops

assocaed

roug

ncreased

bood

“nocng”

o

e

low

e

w

caudcaon.

nercosa

and

rbs

on

and

daon

o

radoogc

ypoenson

Coaera

nerna

ese

vesses

sudes.

e

ower

crcuaon

oten

mammary

can

n

areres,

produce

T reamen

progressvey

w

ess

severe

exeron

or

narrowng

o

>

90%

o

e

vesse

umen)

o

or

by

romboss.

Unsabe

angna

can

narcon.

is

necrosis

of

the

heart

muscle

resulting

o

o

myocarda

ncreasng

narcon

numbers

sgncany

w

rses

o

more

rsk

oten

progressvey

acors

an

or

w

age

aerosce-

women,

bu

s

age.

perod.

s

exremes

by

assocaed

supermposed

myocarda

afeced

romboic

reave

and

o

narrows

Pathogeness.

and

be

Infarction

eary n e and may reman unrecognzed no aduood. here oten

yperenson

may

(obsrucon

infarction

 Postducta coarctaton wtout a patent ductus usuay s asympomac

upper-exremy

precpaed

I

ischemia.

he

e

arerosus:

ductus

o

and

s

res.

arer y

arbnger

Myocardial

yperroped.

from

Clncal

a

a

col-

Dallas.)

are

occurs

lower

a extremities

pan

aorta

w

and

vsbe

baoon

daon or surgca resecon generay yeds exceen oucomes.

he

Mos

paque

nang

ypcay

myocardia

obsrucion

sudden.

of

(Fig.

paque

a

infarcions

coronar y

due

caused

o

by

a

o

conan

myocarda

arge

narcon

pd-rc

cores

or

an

no

e

occusve

paque

can

rombus

of

an

(MI)

or

n overyng brous caps are parcuary vunerabe o rupure

orrage

acue

rupure

8.5).

dsrupon

Paques

are

arer y

cause

can

rapd

orm

paque

because

expanson

o

exposure

and

o

s

ave

Hem-

rupure,

coagen,

122

CHAPTER

Heart

8

and

Adventitia

Media

e

duraon

cardum,

and

o

e

e

occuson,

exsence

o

e

meaboc

coaera

demands

vesses.

Mos

o

e

narcs

myo-

nvove

Intima

e

et

ower

NORMAL

uson

An

venrce,

bood

durng

narc

bo

usuay

ner venon

e

because

pressure

narc

e

(and

dasoe

aceves

wn

wn

s

rg

us

and

s

crca

“error y

e

poson

(due

exen

wndow

a

s

reavey

meaboc

sysoe

u

e

venrce

ower

o

ower

wn

o

3

me

proeced

demands)

o

can

wa

6

and

by

per-

pressures).

ours.

essen

Cnca

e

sze

o

rsk. ”

Atherosclerosis

Dependng

on

and

degree

o

coronar y

arer y

obsruc-

Adventitia

on,

wo

paerns

o

narcon

are

seen:

Media

 •

 Transmura

nfarcts

ckness

e

resu

n

e

dea

o

myocyes

across

e

u

Intima

FIXED

CORONARY

o

myocardum,

excep

or

a

n

ayer

o

subendocar-

OBSTRUCTION

da

Lipids (Typical

myocyes

a

receve

er

oxygen

and

nuren

suppy

drecy

angina)

rom

Atherosclerotic

bood

n

e

venrces.

hese

narcs

are

generay

caused

by

plaque

compee

narcs

obsrucon

usuay

(ECGs),

ey

o

an

produce

are

aso

epcarda

eevaed

caed

ST

coronary

segmens

ST-segmen

vesse.

n

Because

suc

eecrocardograms

eevaed

MI

(STEMI).

Platelet

 •

 Endocarda

nfarcts

resu

n

e

dea

o

myocyes

n

e

nner

aggregate

poron

o

e

myocardum.

hs

ype

o

narc

may

be

caused

by

obsrucon o more dsa coronar y vesses or by severe, bu ncom-

pee,

obsrucons.

because



s

n

e

he

aer

dsa

may

preerenay

dsrbuon

o

e

k

endocardum

coronar y

areres

and

Healing

aso

er y

o

are PLAQUE

DISRUPTION

SEVERE

FIXED

s

exposed

bood.

caed

o

On

g

e

venrcuar

bass

o

non-ST-segmen

pressures,

common

eevaed

ECG

MI

wc

mpede

ndngs,

ese

dev-

narcs

(NSTEMI).

CORONARY

Myocarda

scema

aso

dsurbs

eecrca

conducance

n

e

OBSTRUCTION

(Chronic

ischemic

heart

disease)

ear,

ncreasng

e

rsk

o

arrymas.

Indeed,

aoug

myocarda

scema and narcon can resu n dea due o pump aure, n 80%

o

Thrombus

90%

o

cases

dea

ea

da

he

narcon

caracersc

necross;

(2)

Myocarda MURAL

WITH

THROMBUS

OCCLUSIVE

VARIABLE

THROMBUS

OBSTRUCTION/?

(Unstable

EMBOLI

angina,

or

(Acute

acute

transmural

infarction

or

myocardial

sudden

or

by

venrcuar

braon,

a

parcuary

acue

and

narcs

o

exposng

myocardum

o

cronc

an

more

o

age

appearance

e

morpoogc

en

ess

narcs

mcroscopc

e

12

va

3

canges:

od

ours

sans

(Fg.

a

can

8.7).

a

gy

coaguave

and

(3)

are

be

myocar-

s

(1)

usuay

od

o

here

nlammaon;

ours

an

njur y.

bross.

no

grossy

vsuazed

by

Mcroscopcay,

death)

eaures

o

coaguave

necross

become

deecabe

wn

myocardial

sudden

o

12

usuay

by CORONARY

o

narcon

(Fg.

8.8).

By

12

o

24

ours,

an

narc

sequential

can

rapped

be

grossy

bood.

dened

Necroc

by

red-bue

myocardum

dscooraon

ecs

acue

caused

nlammaon

SYNDROMES

(wc of

ours

death)

ACUTE

Diagram

and

on

sequence

bu

4 infarction

gross

depends

apparen,

ypca subendocardial

8.5

caused

arryma.

Morphology.

Fig.

s

Thrombus

progression

of

coronary

artery

ypcay

peaks

1

o

3

days

ater

narcon)

oowed

by

an

lesions

nlux o macropages, wc remove necroc myocyes and neuroleading

to

various

acute

coronary

syndromes.

(Modified

and

redrawn

p ragmens, and s mos pronounced 5 o 10 days ater narcon. from

Schoen

clinical

p.

FJ:

Interventional

correlations

and

basic

and

surgical

principles,

cardiovascular

Philadelphia,

pathology:

Saunders,

1989,

Durng

as

63.)

sot,

gy

on von

Webrand

and

aggregaon

acor,

and

ssue

acvaon

acor,

o

eadng

coaguaon

o

paee

acors

(see

are

cenra

o

rombus

ormaon

n

e

g

narcs

areas

o

become

a

by

granuaon

nlammaor y

ces

10

progressvey

o

14

ssue.

and

days

Heang

ngrow

o

beer

become

deneaed

rmmed

requres

new

e

vesses

by

mgra-

rom

e

adeson

Fg.

sear

margns,

and

arge

narcs

ake

onger

o

ea

an

sma

8.5).

ones. Paees

me,

vascuarzed

narc and

s

yeow-an

Evenuay,

over

a

perod

o

weeks,

brous

scar

repaces

e

sress

narced

ssue.

envronmen n areres. hereore, anpaee agens (e.g., asprn) are

useu

n

bo

Wn

n

e

o

40

orm

prevenon

o

myocardum,

meaboes

wn

e

seconds

a

(e.g.,

mnue

mnues

o

dsrbuon

so

causes

coaguave

morpoogc

adenosne

acc

or

e

acd)

o

e

reamen

o

a

accumuae.

onse

(see

o

vesse

myocarda

aerobc

rpospae

eves

Loss

o

scema.

damage

and

Caper

1).

myocarda

nvoved

o

obsrucon,

rreversbe

necross

eaures

o

and

vascuar

narc

(Fg.

8.6),

a,

and

myoc ye

dea

rae

on

o

occurs

asng

ocaon,

depend

ceases

noxous

conracy

Iscema

he

e

narcon.

gycoyss

n

sze,

e

sze

20

e

Clncal

severe,

neck,

jaw,

assocaed

In

a

ac.

Suc

and

dabecs

pan).

e

pan

s

o

o

or

et

paens,

narcs

myocarda

ces

perssen

“sen”

(due

cassc

subserna

epgasrum,

mnory

and

deveopmen

Features.

crusng

pan

arm.

and

s

or

In

no

conras

reeved

myocarda

are

auonomc

narcon

pressure

reavey

o

by

neuropaes

a

s

eraded

radaes

angna

may

n

e

pecors,

e

be

oder

bun

e

by

o

nrogycern

narcon

common

a

or

res.

asympom-

paens

and

percepon

o

CHAPTER

TRANSMURAL

INFARCTS

Heart

8

NON-TRANSMURAL

Restoration

of

flow

123

INFARCTS

(reperfusion)

Per manent T ransient/par tial occlusion

of obstruction

left

anterior regional

descending subendocardial branch infarct

Posterior

Per manent

occlusion

left

Global

of

hypotension

RV

circumflex

L V circumferential

branch

subendocardial

infarct

Anterior

Per manent

occlusion

the

of

Small

posterior

intramural

descending

branch

right

of

vessel

the

occlusions

coronar y

microinfarcts

ar ter y

Fig.

8.6

Dependence

Patterns

involved

from

dle),

of

with

partial

or

of

transmural

occlusion

or

of

transient

occlusion

of

myocardial

infarction

the

right

occlusion

small

infarction

resulting

main

(top),

on

from

coronary

global

intramyocardial

the

major

location

artery

(not

hypotension

vessels

and

coronary

nature

artery

of

the

diminished

occlusion.

depicted).

Right,

superimposed

on

The

right

Patterns

fixed

of

perfusion.

ventricle

infarction

three-vessel

Left,

may

be

resulting

disease

(mid-

(bottom).

and

s

ocaon

n

e

ear.

Serum

eves

o

proens

a

eak

rom

njured myocarda ces are useu n dagnoss. Cardac roponns T and

I

ave

g

More

acue

even,

oowng

 •

speccy

an

90%

bu

and

o

sensvy

paens

neary

ree

compcaons

(Fg.

or

wo

myocarda

make

ours



o

a

damage

ospa

experence

one

or

(Fg.

8.9).

sur vve

more

o

e

e

8.10):

 Contracte dysfuncton. Inarcs mpar et venrcuar pump unc-

on

n

proporon

o

e

voume

o

damaged

myocardum.

Severe

“pump aure” (cardogenc sock) occurs n rougy 10% o paens

w

o

 •

ransmura

e

et

 Papary

musce

nrequeny

o

 •

bu

myocardial

infarct

of

the

posterolateral

left

s

w o

r upure

Acute

necrosis

by

a

lack

(arrow);

of

the

triphenyltetrazolium

absence

of

staining

chloride

is

due

to

cell

death.

staining

in

enzyme

(asterisk)

in

this

The

Note

the

anterior

is

myocardial

scar

(arrowhead),

due

patient

to

hemorrhage

ventricular

(specimen

is

rupture,

oriented

at

and

with

the

was

the

right

indicative

the

edge

acute

posterior

of

of

at

he

puse

and

usuay

nauseaed.

conracy

and

s

rapd

Dyspnea

dysuncon

and

s

o

weak

and

common,

e

paens

due

mra

o

vave

are

 e

death

s

mos

dapo-

 •

cardogenc

sock

deveops

due

o

pump

w

resu-

can

ep

o

deermne

e

ype

o

narcon

(STEMI

or

o

5

s ep a

and

days

cas es,

narc 

w en

oten

papar y

are



o cc urs.

 erapy.

usuay

musces

rupure

dysuncona,

I

L et

resung

 amp onade

r upure

may

papar y

s

n

(Fg.

 e

50%

me

consss

 Arrytma.

ar

aure.

eadng

s

more

common

ven r c uar

n

rapd y

 ree

a a

n

wa

(s ee

Fgs.

8.7

and

emo-

8.10A).

cre ae

mus ce

a

et-o-r g 

r upure

may

sun

e ad

(s ee

o

s e vere

o

o

8.10C).

cas es

Rupure

dur ng

s ot,

braon)

responsbe

s

or

he

90%

rsk

greaes

e

n

 e

 r abe

Approxmaey

dsurbance.

and

or

e

majory

e ang

usuay

 e

o cc urs

w n

o

paens

serous

weeks

n

muc

o

ssue.

deveop

and

wo

w en

arryma

our

deas

rs

pro cess

granuaon

rs

o

w n

some

(e.g.,

decnes

occurrng

orm

ereater.

pror

o

o

venrcu-

I

ospa-

zaon.

Caracersc eecrocardograpc abnormaes are usuay presen

and

cardac

regurg aon

rs

rym

an acue pumonar y congeson and edema. W massve myocarda

narcon,

a a

 romb oyc

common,

and

8.10B),

90%

top).

myocarda

apparaus,

ey

infarct

of

the

oten

mpared

more

areas

 e

rec

or

remote

the

cause

wall

40%

leakage

mra infarction.

damage

ventricle

Fg. after

a

regurgaon.

 requen y

receve

Venr c uar of

Aoug

narcon,

mra

p er cardum demonstrated

ose

 Myocarda r upture. Rupure compcaes on y 1% o 5% o narc-

 os e

8.7

ypcay

dysfuncton.

ater

posnarc

ons

Fig.

narcs,

venrce.

NSTEMI)

 •

 Percardts.

orragc

Transmura

percards

narcon

due

o

can

ec

underyng

a

panu

myocarda

brnoem-

nlammaon

124

CHAPTER

Heart

8

A

B

C

E

D

Fig.

8.8

ulative

by

Microscopic

necrosis

edema

removal

ized

by

of

fluid.

(B)

loose

A

few

collagen

of

myocardial

fibers,

compared

neutrophilic

myocytes

connective

scar.

stains

features

wavy

Dense

necrotic

collagenous

which

and

by

tissue

infiltrate

phagocytic

and

residual

infarction

with

abundant

cardiac

and

adjacent

in

the

its

area

macrophages

capillaries.

muscle

cells

(E)

are

repair.

normal

of

(7

a

2-

to

(A)

fibers

to

10

Healed

present.

One-day-old

(right).

3-day-old

days).

(D)

and

(E)

infarct.

infarct

are

showing

cells

(C)

are

tissue

consisting

Masson’s

coag-

separated

Nearly

Granulation

myocardial

(D)

infarct

Necrotic

complete

character-

of

a

dense

trichrome

stain,

blue.

(see

40

Fg.

8.10D).

narcon

 •

and

Percards

resoves

over

ypcay

e

nex

appears

ew

2

o

3

days

ater

days.

 V entrcuar daton and aneurysm formaton. Because necroc mus-

)timil

ce

s

weak,

ere

may

be

dsproporonae

srecng,

nnng,

and

In Troponin

some

arge

ransmura

narcons,

s

eads

o

venrcuar

aneu-

I

rysms

(see Fg.

8.10F),

wc

are

prone

o

mura

romboss

and

are

CK-MB

assocaed

 •

Myoglobin 20

 Mura

and

w

arryma

trombus.

endocarda

Sass

and

due

damage

o

ear

aure.

dmnsed

osers

mura

Rupure

s

myocarda

romboss

uncommon.

conracy

(see

Fg.

8.10E),

fo selpitlum=(

evitaleR

reppu

n oi tartnecn oc

ecnerefer

daon o e narced regon (especay w anerosepa narcs).

30

w

 •

rsk

or

 Reper fuson

low

o

et-sded

njury.

scemc

As

romboembosm

dscussed

musce

may

n

Caper

paradoxcay

2,

resoraon

cause

e

o

dea

bood

o

va-

10

be

“a-rsk”

ncreased

myocardum.

producon

o

damaged

mocondra,

damaged

membranes,

he

precse

reacve

ncreased

and

mecansm

oxygen

upake

deeerous

speces

o

o

unceran:

rom

cacum

efecs

s

ces

no

w

ces

w

nlammaor y

ces

0

ave 4

20

he Hours

after

onset

of

chest

8.9

Increases

in

myocardium-derived

troponin

I,

myocardial

kinase

(CK-MB),

and

myoglobin

following

injury.

are

particularly

sensitive

and

specific

ong-erm

myocardial

acors,

o

conrbue

markers

of

e

prognoss

mos

ater

mporan

myocarda

o

wc

narcon

are

et

depends

venrcuar

on

unc-

and

e

severy

o

aerosceroc

coronar y

arer y

dsease.

he

infarction.

overa Troponins

proposed

cre-

on atine

been

pain

many Fig.

a

40

moray

rae

wn

e

rs

year

s

abou

30%,

ncudng

myocardial

deas

occurrng

beore

e

paen

reaces

e

ospa.

ereater,

CHAPTER

A

B

C

D

E

F

Fig.

8.10

rupture

with

a

Complications

(arrow).

infarct

aneurysm

cardiovascular

of

e

annua

narcon

moray

s

3%

o

William

rae

or

D.

of

septal

roughened

with

wall

(arrow).

pathology:

Edwards,

paens

myocardial

Ventricular

hemorrhagic,

anteroapical

tricular

(B)

(A

wo

epicardial

stretching

to

E,

clinical

MD,

surface

and

sufered

a

to

by

and

an

Chronic

thy,

is

Ischemic

ischemic

Heart

characterized by

myocardial

Disease

disease,

also

progressive

(A)

Anterior

rupture.

infarct.

mural

from

(D)

(E)

Recent

thrombus.

Schoen

FJ:

Philadelphia,

free

wall

Fibrinous

(F)

apical

Interventional

Saunders,

myocardial

pericarditis,

expansion

Large

125

and

1989;

F ,

of

left

an

ven-

surgical

Courtesy

Minnesota.)

Clncal

severe,

heart

acute

principles,

sodes

Chronic

rupture.

muscle

and

permission

Rochester,

myocarda

Cardiac

Papillary

(arrow)

basic

4%.

C)

(C)

overlying

thinning

Reproduced

Clinic,

(A

(arrow).

correlations

Mayo

ave

infarction.

rupture

Heart

8

Features.

Cronc

progressve

o

angna

ear

or

scemc

aure,

narcon.

ear

dsease

occasonay

Arryma,

s

assocaed

puncuaed

ear

aure,

by

and

new

w

ep-

nercur-

ren myocarda narcon accoun or mos o e assocaed morbdy

called

heart

ischemic

failure

due

cardiomyopa-

to

and

moray.

cumulative

damage.

ARRHYTHMIA

Pathogeness.

narcons:

or y

Usuay,

Cronc

mecansms

cardac

cronc

over

uncon.

o

myocarda

e

In

scema

ere

s

scemc

a

resdua

oer

cause

sor y

ear

o

dsease

one

myocardum

cases,

severe

wdespread

or

occurs

can

myocarda

wen

compensa-

no

coronar y

myocarda

more

onger

arer y

manan

dsease

dysuncon

Aberrant

ting

he

eecrca

propagaes

narcon.

scemc

ear

dsease

ypcay

resus

n

daon

and

yperropy,

oten

w

dscree

areas

rom

prevous

eaed

narcs.

Invaraby,

ere

s

severe

aerosceross

sows

pacy,

o

e

brous

coronary

areres.

ckenng,

and

he

mura

presen.

may

and

a

Mcroscopc

ses

o

pror

ndngs

ncude

myocye

is

arises

a

in

major

the

set-

cause

of

ce

e

sar

a

o

coordnae

ce

roug

snoara

node

o

any were

node

e

n

myocarda

gap

(e

n

a

wave

cardac

pacemaker)

o

venrces.

base

e

conracon

juncons

e

conducon

sysem

and

are

a

roug

Aberran

on

e

se

o

orgn,

eer

e

are

supravenrcuar

subd-

(ara)

can

myocardum.

manes

as

Arrymas

ryms

a

may

are

be

oo

susaned

sow

or

spo-

(bradycarda),

endocardum

romb

as

(tacycarda),

yperropy

rreguar,

or

a

precude

efecve

cardac

may (ventrcuar

ibraon

and

asysoe).

Ara

braon

and occurs

bross

rom

based

pumpng

be

sgnas

rom

venrcuar

oo

generay

and

moderae radc,

o

frequently

scarring

o or

scarrng

or

et vded

venrcuar

(arrhythmia)

ischemia

arovenrcuar

ryms

Cronc

rhythm

death.

ransmed

e

Morphology.

heart

myocardial

sudden

and

wou

of

wen

ara

myoc yes

become

“rrabe”

and

depoarze

nde-

narcon. pendeny

and

sporadcay

(as

occurs

w

ara

daon);

e

sgnas

126

are

CHAPTER

varaby

ransmed

Heart

8

roug

e

arovenrcuar

node,

eadng

o n

e

“rreguary

rreguar”

ear

rae

and

rym

o

ara

sze

(boxcar

ncudng I

e

arovenrcuar

node

s

dysuncona,

var yng

degrees

o

W

ragmenaon

aure,

and

oss

degenerave

o

myocye

canges

appear,

conrace

bers.

ear ere

bock

nuce).

braon.

oten

are

scaered

oc

o

nerceuar

bross,

represenng

occur ses

o

myocye

venrcuar Pat h o g e n e s  s .

A c q u i re d

myocardial

diseases

and

of

ion

transport

a re

important

causes

dropou

due

becomes

o

sf,

scema.

mparng

Inay

dasoc

e

ckened

ng

and

et

eadng

inherited o

disorders

wa

of

et

ara

daon,

bu

w

progresson

o

congesve

ear

aure

rhythm venrcuar

daon

appears.

disorders.

Acqured

ncude

ceuar

mos

aed

acors

scema,

maera

da

eecrca

and

In

a

are

s

mos

o

myocarda

scarrng,

cases,

on

sgna

and

arer y

s

are

o

usuay

cannes

and

assocaed

be

myocardum.

and

o

exra-

amyodoss).

dsease

no

appears

conducon

deposon

cardac

ere

us

abnorma

common

cardac

(e.g.,

coronar y

arryma

ess

encode

or

myoc yes

acor

“rraby”

arrymas

genes

rsk

njur y.

narcon,

dsurb

beween

mporan

scemc

a

nlammaon

myocar-

rggered

Inered

due

(so-caed

o

e

assoc-

by

e

orms

muaons

by

used

a

muaon

medcaons

syndrome.

cay

n

a

rgger

Canneopaes

perormed

nonea

afecng

can

paens

poassum

are

n

dagnosed

w

a

amy

Many

paens

by

sor y

or

ong

esng,

an

Features.

suspeced

ncdenay

roed

yperenson

poenang

Efecve

yperenson

QT

yp-

unexpaned

Right-Sided

Right-sided

disorders

Ar ry m a

may

or

a

be

asy mpoma c,

rapd

e ar 

rae,

be

or

re ae d

o

nade qu ae

c ard ac

oupu,

suc

as

e

rsk

dsease

o

venrcuar

conro

greay

asympomac

bood

yperropy.

or

ear

s

eevaed

scemc

aerosceross),

braon,

s ens e d

c aus e

(Pulmonary)

the

to

lung

rena

aure,

essens

pressure

Poory

ear

damage,

and

e

o

with

Hypertensive

heart

disease

parenchyma

left-sided

associated

cerebro-

sudden

rsk

o

con-

dsease

a

dea.

o

ese

ventricular

left-to-right

soaed

may

or

Heart

be

Disease

caused

vasculature,

failure

or

by

or

primary

may

congenital

occur

heart

dis-

shunts.

rg-sded

yperensve

ear

dsease

(aso

as

as

cor

pumonae)

ncude

dverse

dsorders

afecng

pumo-

sy mp-

nar y oms

coronar y

ara

hypertensive

of

secondary

(paptatons)

et

ear

dscover y

compcaons.

known b e as

e

ncreases

sroke,

Causes Features.

dscovered

vascuar

arryma.

abnor ma 

yperensve

rom

(by

ease

Clncal

E ary

ony

commony

w

genec

or

s

o

canneopaes).

canne.

arrymas

and

n

e prooypca canneopay s e ong QT sy ndrome, caused mos

oten

Clncal

an ng

ar

excange

or

e

pumonar y

vascuaure

(Caper

10).

A

(sy n-

produce ncreased pumonar y vascuar ressance, eadng o yperencope).

Sudden

de a 

c aus e d

by

ven r c u  ar

br    a on

or

asysoe

son, o cc urs

n

roug  y

400,000

p e ope

e ac

ye ar

n

 e

Une d

S aes.

rg

due

be

o

 e

coronar y

rs

ar er y

ds e as e

manes a on

o

n

80%

coronar y

o

90%

ar er y

o

c as es

ds e as e.

and

In

venrcuar

ear

aure.

nona eros cero c

canneop a es,

congen a 

c aus es

are

more

abnor ma  es

common,

n

va ves

 es,

o er

myo c ard s

and

and

myo c ard a 

nl ammaor y

yp er  ropy

ds orders,

s e cond ar y

o

younger

or

coronar y

ncude

ncreases

arera

congesve

e

vesses

dsease

of

ear

workoad

Caper

aure

and

dfuse

pumonar y

nersa

prmar y

vesses,

pumonar y

suc

as

bross

recurren

romboembosm

yperenson

and

 •

 Dseases afecng ches movemen, suc as kyposcooss and obesy

 •

 Dseases

causng

seep

pumonary

vascuar

consrcon,

suc

as

obsruc-

apnea

ear

embosm)

or

aure

may

may

appear

be

acue

sowy

and

n

onse

(e.g.,

nsdousy

w

pumo-

because

o

pro-

DISEASE

cardac

(see

rg-

are:

 Dseases

onged

on

evenuay

 •

Rg-sded

efecs

and

dsorders

 Dseases of pumonary parencyma, suc as cronc obsrucve pu-

nar y

Hyperenson

8.11B),

suc

 •

ve

HEART

(Fg.

common

c ardomyop a-

yp er enson

ac ors.

HYPERTENSIVE

mos

ncudng

and ar er es,

he

may

monar y p a ens,

yperropy

I

sded s

and

7).

aa

and

he

aso

as

cardac

arryma.

pressure

overoad

n

e

seng

o

cronc

pumonar y

dsease.

deeerous

compcaons

Aoug

e

et

VALVULAR

HEART

DISEASE

sde o e ear s mos commony afeced due o e requency o sys-

emc

aso

yperenson,

occur

n

some

rg-sded

dsease

yperensve

canges

(cor

pumonae)

sengs

Valvular

and/or

disease

results

insufciency

in

cardiac

dysfunction

(regurgitation

or

by

causing

stenosis

incompetence).

Senoss s e aure o a vave o open compeey, obsrucng or-

Systemic

Systemic

ular

the

(Left-Sided)

hypertens i v e

hypertrophy

absence

of

Hypertensive

hea rt

d is ea s e

s eco n d ary

other

to

is

Heart

Disease

d ene d

d o c ume nt e d

ca rdio v a scul ar

by

le f t

ward

v e n t r ic

hy per t e ns io n

pa t ho lo g y

(e . g . ,

in

v a lv ul a r

stenosis).

or

resus

e

(e.g.,

nduces

et

Even

venrcuar

workoad

agans

onged

severe,

or

md

yperenson

yperropy

ressance

e

ear

(Fg.

may

(>140/90

as

8.11A).

no

an

I

onger

Hg),

adapaon

e

be

mm

o

o

adap

proonged,

e

yperensve

abe



ncreased

sress

s

efecvey

pro-

and

amos

rom

eale

mon

aure

cusps

scarrng

on

e

sounds

et

as

a

vave

o

or

cronc

or

rom

o

e

cose

roug

murmurs;

or

o

rupure)

and

s

ocaon,

low

or

usuay

vaves

quay,

and

may

due

more

acqured.

Tabe

o

com-

Causes

o

8.2

produces

mng

srucures

nsdousy

muc

o

dsease

Insuicenc y

s

abnormaes

bood

rom

supporng

dsease

n

caccaon

Insuicency

aowng

resu

musces).

summarzed

dseased

can

e

(e.g.,

cusps.

compeey,

Vavuar

ear

severe

vave

nsuicenc y

corda

are

process

more

papar y

reracon.

he

a

one

endocards)

dsease

hrs.

o

Vavuar

cords

sde

low

caed

papaed

and

due

afecs

(e.g.,

(e.g.,

vavuar

Abnorma

may begn o a.

o

endnous

abrupy

acqured

a

(backlow).

vave

e

appear

aways

scarrng)

regurgae

o

Pathogeness.

low,

vave

abnorma

may

o

be

e

ear

exernay

murmur

are

Morphology. he ear s eavy and e et venrcuar wa s ckdeermned ened.

Mcroscopcay,

myocyes

and

myocye

nuce

are

by

e

vave

afeced,

e

efec

o

e

ncreased versus

senoss),

and

e

severy

o

e

deec.

eson

(regurgaon

CHAPTER

Heart

8

127

*

A

Fig.

8.11

Hypertensive

concentric

atrium

the

are

right

ulae.

Table

8.2

shown

diastolic

on

The

Etiology

thickening

ventricle

impaired

(shown

of

B

the

on

the

the

and

volume

Acquired

Heart

this

also

to

dilated

of

Systemic

the

Valve

wall,

left

left

atrial

atrial

and

(left-sided)

causing

four-chamber

the

leading

markedly

(A)

ventricular

in

Note

relaxation,

is

disease.

left

right

(arrow).

left)

shape

heart

of

view

volume

have

hypertensive

reduction

of

dilation

the

with

been

(B)

a

in

heart.

(asterisk)

overload.

hypertrophied

ventricle

a

Valve

Disease

Aortic

Stenosis

Postinflammatory

Aortic

scarring

Calcification

heart

of

mitral

(rheumatic

ring

Senile

 Cacicaons,

Regurgitation

Abnormalities

of

Aortic

leaflets

and

aortic

of

commissures

 a

The

ventricle

right

n

in

and

ventricle

trabec-

ventricle.

c ard  ac

re qure

va ves

are

subs an  a 

re ae d

va ve

o

rep e  ve

d eor ma on

T e

mos

common

d egenera ve

w  

canges

 •

 Aeraons

wc

can

be

cuspa

(n

e

aorc

vave)

(Fg.

are:

8.12A

B)

or

annuar

n

e

(n

e

mra

exraceuar

vave)

marx.

(Fg.

8.12C

here

can

and

be

D).

ncreased

pro-

stenosis

and

dmnsed

brar

coagen

and

easn

(myxoma-

congenitally

degeneraon)

or

bross

and

scarrng.

valve

Regurgitation

Intrinsic

canges

left

hypertrophied

right

left

incidentally

disease)

ous

Mitral

and

enlarged

op enng .

 •

eogycan

deformed

the

pulmonale.

wall

marked

and

scarring

heart

calcific

Calcification

the

present

of

is

ventricle

Stenosis

Postinflammatory

disease)

cor

free

s ress es

nor ma 

and

(rheumatic

is

There

left

Disease

e ac

Mitral

The

stiffening

D egenera ve

Disease

Valve

to

Chronic

by

disease.

size.

pacemaker

thickened

me canc a  Mitral

A

due

distorted

heart

lumen

valvular

disease

Postinflammatory

Calcific

Aortic

Calcic

aortic

Degeneration

degeneration

is

the

most

common

cause

of

aortic



be

scarring

stenosis.

Postinflammatory

scarring

(rheumatic

heart

disease)

Cacc Infective

endocarditis

Infective

enoug Mitral

valve

prolapse

Aortic

degeneraon

usuay

s

asympomac,

bu

may

severe

endocarditis

o

cause

senoss,

necessang

surgca

nervenon.

e

nc-

disease

dence ncreases w age, and mos paens presen a e age o 70 years “Fen-phen”–induced

valvular

Degenerative

aortic

dilation

or fibrosis

Syphilitic

Abnormalities

Rupture

of

Papillary

of

tensor

papillary

muscle

apparatus

muscle

Ankylosing

Marfan

a

spondylitis

Rheumatoid

dysfunction

o

arthritis

of

o

chordae

Abnormalities

of

An

dsorder

ree.

mporan

aorc

n

and/or

ventricular

senoss

s

bcuspd

aorc

1

o

2

vave

eary

conans

occurs

n

decades

e

n

bu

earer

wo

aorc

vave,

1%

s

uncona

a

congen-

o

2%

prone

an

o

o

a

cusps

ve

caccaon

norma

rcuspd

nsead

brs.

I

s

eadng

vaves.

left

ventricular

Rsk

acors

or

aorc

vave

degeneraon

and

cac-

annulus

ncude

mae

sex,

g

ow-densy

poproen

coesero,

enlargement

yperenson, (myocarditis,

acor

vave

tendineae

caon Left

rsk

e

asympomac

Pathogeness.

cavity

wc

Bcuspd

generay

syndrome

(fibrosis)

Rupture

greaer.

aortitis

dilated

and

smokng,

a

o

wc

are

aso

assocaed

w

a-

cardiomy-

erosceross.

e

accumuaon

o

poproens

nduces

oca

nlamma-

opathy)

on, Calcification

of

mitral

wc

vave, Fen-phen,

Data

Schoen

Hum

Pathol

FJ:

Surgical

18:558,

pathology

of

removed

natural

and

prosthetic

njur y

predsposes

Valve

cusps

Disease

a

aer

valve

disease

is

an

umbrella

term

that

in

the

valvular

extracellular

matrix

that

(Fg.

describes

o

function.

e

vave

negatively

affect

Heaped-up

prorude

senoss Degenerative

valve

exacerbaed

by

low

abnormaes

endoea

ce

(e.g.,

uncon.

e

bcuspd

resung

or

caccaon.

1987.

Morphology.

Degenerative

changes

be

yperenson)

Fenfluramine-phentermine.

from

valves,

may

ring

bross.

and

8.12A

caced

masses

mecancay

and

B).

e

on

mpede

cusps

e

oulow

vave

oten

sde

openng,

sow

o

e

causng

ckenng

due

128

CHAPTER

Heart

8

A

B

C

D

Fig. Fig.

8.12

Calcific

valvular

degeneration.

(A)

Calcific

aortic

stenosis

of

8.13

normal

valve

(viewed

from

above

the

valve).

Nodular

calcium

are

heaped

up

within

the

sinuses

of

Valsalva

hooding

(arrow).

the

atrium;

commissures

are

not

fused,

as

in

rheumatic

aortic

valve

Fig.

11.19C).

(B)

Calcific

aortic

stenosis

occurring

on

a

(arrow).

annulus

view.

the

valve.

(C

One

and

D)

(attachment

(D)

Cut

the

has

a

partial

of

the

myocardium.

the

Such

septum

with

mitral

demonstrating

interventricular

fusion

calcification,

margin)

section

underlying

near

cusp

Mitral

at

its

leaflets

impinge

on

called

nodules

(arrows).

extension

involvement

can

center,

calcific

of

the

of

the

in

the

this

a

o

30%

o

In

norma),

severe

cronc

dsease

oulow

(aorc

vave

(C)

Left

obsrucon

adjacent

into

structures

conduction

may

Clncal

et

o

20%

venrcuar

e

o

as

dysuncon,

es.

ear

ay

aure,

or

occurrng

syncope

wn

5

appears,

years.

he

e

aure.

Once

prognoss

reamen

s

s

angna,

poor,

surgca

w

congesve

dea

repacemen

Mitral

Valve

e

left

leaets

atrium

Prmar y

aon

more

o

an

and

of

the

mitral

prolapse,

valve,

ballooning

one

or

back

both

into

vave

o

ear

proapse

o

dsease;

s

a

orm

adus.

women

I

s

are

o

myxomaous

one

o

afeced

e

mos

amos

degener-

common

seven

mes

men.

he

due

s

manesaon

ear

As

o

a

usuay

connecve

dscussed

n

reflecting

long-standing

the

valvular

The

left

(Courtesy

ventricle

of

William

is

shown

D.

on

Edwards,

the

MD,

are

asympomac;

e

vavuar

abnor-

s

dyspnea,

cck,

usuay

usuay

requres

or

aypca

somemes

bengn,

(see

aer)

sgncan

oowng

repar

or

oug

and

ces

w

a

pan.

ere

s

an

approxmaey

mra

rupure

Auscuaon

regurgan

3%

regurgaon

o

e

repacemen

o

cordae

e

murmur.

ncreased

o

and

or

mra

rsk

paens

conges-

vave

ea-

vave.

Valvular

heart

acute

Disease

disease

is

the

cardiac

immunologically

manifestation

mediated

of

multisystem

rheumatic

inamma

unknown

(dopac).

Rarey,



Caper

ssue

6,

dsorder,

Maran

parcuary

syndrome

s

Maran

mos

that

occurs

after

group

A

β-hemolytic

streptococcal

rggerng

s

vavuar

dsease

necon

vruay

ypcay

aways

nlammaon

as

decned

n

nvoves

caused

and

by

scarrng.

many

pars

e

par ynx.

reumac

e

o

e

Mra

ear

ncdence

Wesern

se-

dsease,

o

s

reumac

word

over

e

pas severa decades, due o mproved socoeconomc condons, rapd

e

and

reamen

vruence

o

many

o

srepococca

srans

o

group

par yngs,

A

and

srepococc.

a

decne

However,

n

s ncome

counres

and

economcay

depressed

areas

n

e

Uned

synSaes,

drome.

view.

paens

endocards

aure,

dagnoss

eoogy

Mos

course

wc

o

ow a

an

e

n Pathogeness.

overload.

papaons,

disease

noss,

2.4%

dilated,

infections.

the

systole.

0.5%

vavuar

oten

“oppy”

mtra

afecng

orms

are

is

Disease

degeneration

during

promi-

into

Minnesota.)

mdsysoc

Rheumatic

tory

mitral

volume

Rochester,

Treamen

fever,

myxomatous

also

emodynamcay

ear

Rheumatic

Myxomatous

is

usu-

o

dseased vave.

In

a

necve

ve

ear

and

Features.

cnca

deveop

congesve

There

(arrow)

may s dscovered ncdenay on pysca examnaon. A mnory o

yperroped myocardum s prone o scema and sysoc and dasoc

o

atrium

four-chamber

Clinic,

pressures o 200 mm Hg or more, causng et venrcuar yperropy. he

eadng

valve.

leaflet

system.

reduced

rase

mitral

mitral

atrial

calcification

orce

the

the

dscoses

Features.

of

posterior

raphe

within

paens

Clncal

the

congenitally

Mayo bicuspid

of

stenosis

right (see

degeneration

prolapse

Note

insufficiency that

with

masses

left of

Myxomatous

a

nent previously

reumac

ear

dsease

s

an

mporan

pubc

ea

probem,

commony and



remans

e

mos

common

cause

o

acqured

vavuar

dsease

n

caused by muaon n e gene encodng brn. e

Morphology.

ere

s

baoonng

(oodng)

o

e

afeced

word.

mra Pathogeness.

eales

(Fg.

8.13),

wc

are

enarged,

redundan,

ck,

and

cocca ber y.

he

endnous

cords

are

eongaed

and

nned,

and

srans

On

soogc

myxomaous

(mucod)

examnaon,

e

vave

sows

cross-reac

agans

w

e

M

proens

proens

ound

n

o

e

ceran

srepo-

myocardum

and

may cardac

rupure.

Anbodes

rub-

deposon

vaves.

ese

anbodes

are

oug

o

cause

njur y

by

ac-

o vang

compemen

CD4+

T

and

Fc

recepor–bearng

ces

(e.g.,

macropages).

maera. ces

a

recognze

srepococca

pepdes

and

os

angens

CHAPTER

aso

appear

and

may

ec

cyokne-medaed

nlammaor y

Heart

8

129

responses. reumac

ear

dsease

w

vave

dysuncon

nvovng

e

mra

Ony abou 3% o paens neced w srepococc deveop reumac vave

n

95%

o

cases;

25%

o

ese

cases

aso

afec

e

aorc

vave.

ever, suggesng a os genec varans may nluence suscepby. Fbross

o

Morphology.

afecng

a

In

acue

varey

o

reumac

ssues,

ever,

ere

ncudng

a

are

ree

nlammaor y

ayers

o

e

oc

ear.

 Percardts assocaed w a brnous exudae

 •

 Myocardts

n

e

orm

o

scaered

Ascof

bodes

wn

e

connecve

ssue;

paognomonc

Ascof

becomes

8.14A)

conss

o

coecons

o

ympocyes

scaered

(prmary

pasma

ces)

ces,

w

and

pump,

assocaed

acvaed

brnod

daed

 Vavus,

rs

na

e

resung

nes

o

n

brnod

cosure,

necross

oten

vegeaons

and

(Fg.

o

senoss.

occur,

E)

eads

Fbross

urer

o

uson

and

uson

exacerbang

vave

pressure

overoad.

reumac

aso

occur

ever

s

n

adus.

mos

o

wo

Two

o

common

ree

n

weeks

c-

ere

s

one

conseaons

o

ater

sympoms:

macropages mos

and

assocaed

brn

w

commony,

by

a

mgraor y

cards;

or

(2)

arrs

n

abou

n

one

20%

o

or

more

jons

paens,

oten

neuroogc

deposon

sma

mos

noaby

Sydenam

corea

(S.

Vus

dance),

car-

romby

nvounar y

movemens,

musce

weakness,

and

emo-

8.14B). ona

Percards

mra

aso

8.14C

necross

acerzed boc

may

o

Acue

aacks

necon,

sympoms, aong

owng

Features.

bu

accompaned

 •

severe

endneae

(Fg.

T

(1) (Ansckow

and

eales

e

e ces),

vave

bodes dren,

(Fg.

mra

commssures

cordae

Clncal nersa

e

dysuncon. W g mra senoss, e et arum progressvey

Acue cardac nvovemen may ead o one or more o e oowng:

 •

e

o

o

myocards

may

ead

o

oca

scarrng

bu

dsurbances.

Fever

may

aso

be

seen

n

some

cases.

here

s

no varabe

nvovemen

o

e

skn

(ras

and

subcuaneous

nodues).

perssen abnormaes. In conras, vavus oten eads o cronc hroa

cuures

are

negave

wen

sympoms

begn,

B

A

C

D

Fig.

8.14

carditis;

cells,

there

etations

(B)

(C).

tion

the

of

(D)

(E)

the

visible

have

shortening

Surgically

cusps

of

of

leaflet

along

the

of

the

heart

line

fibrous

with

specimen

closure

thickening

distortion

From

Pathol

is

mitral

mitral

valve;

18:568,

the

left

note

stenosis,

FJ,

St

1967.)

of

central

leaflet

chordae

leaflets,

marked

aortic

Aschoff

body

in

wavy

the

disease.

(arrows).

as

demonstrating

John-Sutton

M:

(C

fusion

seen

inflammatory

chromatin

Small

Previous

tendineae.

dilation

rheumatic

inflammatory

(caterpillar)

heart

commissural

atrial

acute

mononuclear

rheumatic

valve

of

valve

Schoen

and

chronic

fusion

the

an

collection

nucleoli

on

the

and

of

rheumatic

(E,

Hum

of

There

rheumatic

of

fusion.

of

circumscribed

prominent

tendineae.

opened

disease,

a

appearance

superimposed

of

and

chordae

an

with

valvulitis

thickening

commissural

valvular

Microscopic

macrophages

mitral

removed

with

E

(A)

associated

caused

fibrous

Anterior

pathology

necrosis

activated

are

diffuse

and

disease.

rheumatic

valvulitis

with

thickening

(arrow).

some

Acute

rheumatic

heart

central

(verrucae)

stenosis

valve

is

including

(arrows).

of

Rheumatic

and

veg-

episodes

D)

Mitral

(arrows),

from

above

and

the

neovascularization

thickening

and

Contemporary

distor-

issues

in

bu

serum

ers

130

o

CHAPTER

anbodes

DNase)

da

rcon

ear

he

agans

usuay

rubs,

aure,

bu

dagnoss

on

n

are

s

cardac

acue

srepococca

1%

based

w

dsease

o

on

e

sgns

mra

paens

de

o

srepoysn

cards

addona

o

acue

pror

cnca

reacvaon

causng

(e.g.,

o

ncude

nsuicenc y,

evdence

ypca

subsdes,

necons,

angens

Cnca

daon,

an

made

conjuncon

Ater

srepococca

eevaed.

ess

Heart

8

reumac

descrbed

occur

njury

o

w

e

or

Sma romb a orm a ses o pacemaker nes, ndweng vascuar

caeers,

congesve

srepococca

eaures

may

and

O

percar-

seedng

ever.

necons

nec-

aso

arum

and

produces

ear

romboembosm.

e

pumonary

aure;

w

me,

rsk

Cronc

vascuar

rg

e

and

o

mura

pumonary

parencyma

venrcuar

ear

venous

canges

(cards)

vaves

n

e

et

congeson

o

and

are

caused

lora.

o

By

e

skn)

or repacemen o dseased vaves can oresa many o ese compcaons

ons

are

reeased

and as greay mproved e ouook or ese paens.

o

be

e

Seedng

may

occur

the

endocardium

of

thrombus

to

underlying

he

devces

ra

aora,

may

on

apy

that

presence

lead

to

of

heart

vegetations

varying

degrees

become

and/or

 Subacute

and

sacs,

oer

neced.

o

bood

Mos

endocards

severy

n

a

valves

or

s

composed

o

Pathogeness.

we

as

nvove

s

e

vesses,

cases

are

cassed

cnca

prevousy

sgncan,

of

e

reers

even

onse

proraced

Acqured

s

w

as

and

e

more

aack

vrdans,

vruen

eay

as

a

componen

ear

acue

by

n

In

probaby

no

o

bood

w

obvous

o

drug

we

10%

as

o

n

ver y

w

dena

sma

mcrobes

or

occu

or

rva

s

norma

(com-

vaves

and

s

surgca

organsm

s

soaed

wn

vegea-

numbers.

e

proxmae

necon,

maera

njures.

predsposng

or

no

embedded

a

no

acors

cause.

dena

e

(e.g.,

or

hs

surgca

boodsream

Anboc

propyaxs

prosec

ear

procedures.

or

are

subacue

necons

ear,

over

weeks

anboc

vaves.

nous

usuay

and

o

o

nvovng

even

wen

mons.

o

o

ear

and

necve

endocards,

buky

and

poenay

8.15

Infective

myxomatous

mitral

Staphylococcus

abscess

(arrow).

endocarditis.

valve.

The

aureus

on

(A)

large,

(suc

users,

ear

n

wc

abscess

e

vaves

common

somemes

rom

e

Cln cal

senoss)

e

(rng

rabe

(Fg.

ses

8.15).

o

no

abscess)

e

(see

vegeaons,

e

necon

rcuspd

erode

deveopmen

bross

o

ecs

n

and

Feature s.

endo c ard s,

endocards.

a

Subacute

friable

endocarditis

vegetations

congenitally

bicuspid

desruc-

vave

s

aorc

excep

o

mra

nrave-

nvoved.

myocardum

8.15B).

eadng

n

requeny

underyng

Fg.

and

Sepc

sepc

o

embo

narcs

and

mycotc

ess

aneurysms

vavuar

(see

desrucon

Caper

and

s

7).

Sub-

assocaed

w ormaon o vegeaons, cronc nlammaor y nraes, and

paens

vaves

aorc

e

mos

endocards

vavuar

proapse,

predspose

o

acue

erapy.

vave

on

e

an

sed

ead

or

unreaed

Mos

acue

abscess ormaon were ey odge. Seedng o e vesse was may

vr-

scarred

drug

produce

er-

ow

are

Vegeaons

Morbdy

anboc

organsms

abnormaes

mra

vaves

by

presen

vaves

course.

norma

In

ve vegeaons conanng brn, neurops, and mcroorgansms

oder

bu

adu s),

caccaon.

Fe ver



may

n

s

be

w  c

 e

mos

abs en

on y

n

cons sen

sub ac ue

vague

are

caused

by

denoted

aortic

valve

Streptococcus

by

with

arrows.

(B)

extensive

viridans

Acute

sy mpoms

cuspal

on

a

previously

endocarditis

destruction

caused

and

sg n

ds e as e

B

by

e

aureus

deormed

cases,

organsms

conamnaed

users,

paens

undergong

abou

because

e

bood

an

njecon

Morphology.

bace-

A

Fig.

o

Stapyococcus

damage

prosec

caused

approprae

nsdous

srucura

senoss,

prosec

o

abnorma

approprae

mra

crca

are

prevousy

s

can

e

nravenous

vaves)

surger y.

ater

reumac

are

vaves.

course

recover

may

endocardts

deormed

e

a

abuse)

tissues.

Inecve

moray

uence

as

the

the

 Acute endocardts reers o desrucve necons by gy vruen

and

as

organisms

empo

organsms

 •

by

aneur ysma

aso

e

marked

cardiac

necons.

based

 •

and

by

of

Streptococcus

cupr.

due

procedure,

Endocarditis

infection

drug

oucomes.

speces, oten commensa n e ora cavy, and even ung on occason

bood,

microbial

bacera

n necons occurrng n nravenous drug users. Many oer bacera

e

a

nravenous

bacera

o

et-sded

rom

is

and

afecs

or

rg-sded

prove

endocarditis

neuropena

adversey

so

responsbe or 10% o 20% o cases overa;  aso s e major ofender

suscepbe o necve endocards. Mra vavuopasy or surgca repar

Infective

by

conras,

ear aure may ensue. In addon, scarred and deormed vaves are more

Infective

o

and

ere

he causave organsms var y dependng on e underyng rsk ac-

romb

yperropy

rsk

a

suscepby

ors. From 50% o 60% o cases o endocards o damaged or deormed

mon

ncreasng

secondar y

e

provde

Increased

earer.

eads

braon,

(e.g.,

endocardum

endocards.

subsequen

ora

ara

damaged

ensung

ncreases

and mra vave (mra senoss). W mra senoss, ara daon oten

o

or

and

ring

o

ne c  ve

( p ar  c u  ary

suc

as

a  gue,

CHAPTER

weg 

oss,

and

endo c ard s

c  s,

and

and

 u  ke

as

we a k ness .

e -sde d

bed

a

o en

esons.

re na 

a

sy ndrome

sor my

Mur murs

are

M cro emb o

emor rages,

are

ons e

ound.

w  

pres en

c an

n

g ve

p an ess

By

r ap d y

o

o

e ver,

p a en s

w  

p ee c  ae,

er y emaous

p a m

na 

or

s oe

LA

LA

Ao

esons,

by

or

p an u 

p os ve

bo o d

  nger  p

c u ures

no du es.

and

 e

T e

d ag nos s

de n   c a on

o

s

131

ac ue

de veopng

90%

r s e

con ras ,

Heart

8

Ao

con  r me d

vege a ons

by

e co c ardog rapy.

he

prognoss

depends

on

Adverse

sequeae

e

necng

organsm

and

e

exen L V

o

compcaons.

o

rappng

ncude

gomeruoneprs

due L V

er

11),

o

sepcema,

myocardum

Let

angen–anbody

and

unreaed,

ong-erm

men

(6

necve

weeks

reduce

(e.g.,

necons,

cure

due

o

umaey

or

S.

raes.

For

aerobc

range

n

and

e

generay

cure

erapy

rae

60%

gram-negave

no

o

s

s

bac

aa.

nvovng

98%,

or

underyng

Approprae

vave

repace-

Nor mal

Dilated

cardiomyopathy

ow-vruence

and

or

owever,

ung,

Cap-

embozaon.

and/or

90%;

(see

e

sysemc

necons

rom

gomeru

nvason

anboc

v rdans),

raes

(rom

sysem),

endocards

more)

moray

organsms

ons

arryma

conducon

compexes

S.

aureus

w

a

o

nec-

paens

succumb.

LA

LA

Ao

Nonbacterial

Thrombotic

Ao

Endocarditis

Nonbaceria romboic endocardiis (NBTE) is caracerized by e

deposiion

of

sma

(1

o

5

mm),

serie,

nondesrucive

romboic L V

L V

masses on cardiac vaves

Prevous

occurs

on

vavuar

(Suppemena

damage

prevousy

s

norma

no

a

vaves.

eFg.

8.3).

prerequse.

Dseases

Indeed,

assocaed



ypcay

w

genera

deby or wasng are assocaed w an ncreased rsk or NBTE, as are

ypercoaguabe

saes

(e.g.,

cronc

dssemnaed

nravascuar

coaguHyper trophic

Restrictive

cardiomyopathy

cardiomyopathy

aon, yperesrogenc saes, and underyng magnances, parcuary

mucnous

adenocarcnomas)

and

endocarda

rauma

(e.g.,

ndweng Fig.

caeer).

he

oca

efec

on

e

vave

s

usuay

rva,

bu

embo

8.16

opathy

NBTE

esons

can

cause

narcs

n

e

bran,

ear,

and

oer

The

leads

esons

aso

ncrease

e

rsk

o

necve

endocards.

changes

ness.

CARDIOMYOPATHIES

These

that

diseases

may

cardiac

be

characterized

coned

to

manifestation

Incuded

are

are

among

necous,

AND

e

the

of

a

mmunoogc,

by

cardiac

systemic

disorder

dseases

meaboc,

myocyte

(primary)

a

and

ead

dysfunction

or

may

be

 •

ose

myopaes,

a

wc

are

can

nonnlammaory

be

urer

in

Ao,

cardiomyopathies

atrial

aorta;

o

genec

myocye

a

no

subdvded

e

no

hose

caegory

ree

more

o

skeeon

a

resu

o

or

cardo-

ess

 •

are

 Hyperropc cardomyopay

dagnoss,

 •

 Resrcve cardomyopay

 •

cardomyopay

eas

s

mos

common

and

Dilated

cardiomyopathy

dilation

and

contractile

is

 •

characterized

by

progressive

gressed

o

by

dagnoss,

end-sage

myocarda

daed

A

dsease

conracy.

cardomyopay

envronmena

marked

he

can

as

L V,

in

diastolic

dilation

left

by

ear

naed

oows:

a

by

aure

as

usuay

secondar y

cumnaes

nered

n

o

pro-

poor

end-sage

abnormaes

or

n

and

dysfunction.

in

ventricular

Note

and

wall

the

thick-

ventricle.

over

domnan

 •

commony

e

50

genes

ave

nerance.

nvoved,

B

and

myocardum

n

wc

cardomyopay

nlammaon

can

o

daed

suc

aso

or

unceran

cardomyopay

damage

be

exposures,

cardiomy-

restrictive

been

Genes

mpcaed,

a

encode

ypcay

by

muaons

a

s

oer

o

enerovruses

end-sage

necous

ave

been

are

daed

myocards

as

documened.

occason-

cardomyop-

By

progressed

e

me

o

absen.

as

cause

cardomyopay,

doxorubcn

daed

and

by

unknown

reaed

mecansms.

cemoerapeuc

cardomyopay.

 Perpartum cardomyopaty. Daed cardomyopay occurs ae n

gesaon

cardiac

dysfunction.

daed

n

agens,

paens

Pathogeness.

Dilated

whereas

 Acoo and oter toxns. Rarey, acoo abuse s assocaed w e

Toxc

common.

(systolic)

mos

deveopmen

and

Cardiomyopathy

Muaons

nsances

daed

drugs,

Dilated

atrium;

Coxsackevrus

 •

cardomyopay

left

result

ventricular

auosoma

deeced

o

resrcve

cardiomyopathy.

dysfunction,

oss-o-uncon.

 Infecton.

ay

ds-

n

ay,

daed

LA,

cases.

 Daed cardomyopay

paerns,

and/or

w

 •

ese

of

cyoskeea proens or proens a nk e sarcomere o e cyo-

dysuncon

dsorders.

50%

usuay

(secondary).

nc uncona and paoogc paerns (Fg. 8.16 and T abe 8.3):

O

forms

systolic

 Inerted gene defects. Daed cardomyopay s eredar y n 20%

o

a

are nlammaory n naure are generay consdered orms o myocards,

wereas

to

MYOCARDITIS

myocardium

dverse

major

primarily

organs. hypertrophic

NBTE

three

rom

severa

and

may

weeks

be

sponaneousy

o

mons

muacora.

recover

posparum.

he

Approxmaey

norma

eoog y

a

o

s

ese

uncon.

 Iron overoad. Daed cardomyopay can be seen n e seng o

eredar y

mupe

on

n

e

speces.

emocromaoss,

red

ce

ear

ransusons

and

cronc

due

o

ron-medaed

nefecve

njur y

emaopoess,

caused

producon

o

by

ron

reacve

or

depos-

oxygen

CHAPTER

8

Heart

t

C

A

Supplemental

botic

eFig.

vegetations

showing

bland

thrombus

is

8.3

along

thrombus,

only

Nonbacterial

the

loosely

line

with

of

virtually

attached

thrombotic

closure

to

no

the

of

the

endocarditis

mitral

inflammation

cusp

(arrow).

valve

in

(NBTE).

leaflets

the

valve

(A)

Nearly

(arrows).

cusp

(c)

or

(B)

the

complete

row

Photomicrograph

thrombotic

of

of

deposit

throm-

NBTE,

(t).

The

131.e1

132

CHAPTER

Table

8.3

Heart

8

Cardiomyopathies:

Functional

Patterns

and

Causes

Secondary

Functional

Left

Ventricular

Pattern

Ejection

Dilated

70

Here,

rey

dencaon

emaopoec

derved.

are

cnca

Saes.

we

numerous

norma

umors

a

crera,

enes

o

wde

abou

sysems

markers

recognzed

wc

are

moecuar

proen

dsorders

ave

occur

ere

Casscaon

compexy

(e.g.,

er

speen

acvae

nodes

magnances

w

mmuny

rsng

rauma,

nonmcroba

mporan

o

T-cell

a

n

wn

oten

aggregae,

dagnosed

e

neced

mos

expresson o vral proens and perss or e le o e paen. In paens

deecve

dagnoss

w

(e.g.,

vr-

magnan,

ese

maness

presenaons

vrus

he

nae

regons.

acvaed

o

neced

smuae

casscay

aypca

e

(3)

mnor

ces)

necross),

persss n aen orm. Severa EBV-encoded proens expressed n aeny

ces

and

resoves

NEOPLASTIC ons,

bu

ncrease

ympadens,

necons),

spreads

he

Mononuceoss

ympadens

bu

en

no

and

cancer

caseous



o

Lymphadenitis

Inecons

sava conanng vrus. EBV may rs nec oroparyngeal epelal cells,

neced.

gron

ympocyes.

ympadens,

mononuceoss

canges

T ransmsson

and

popuaon

mmune

seng ony abou 20% o ose wo are neced connue o sed e vrus.

Pathogeness.

aypca

(Monospo

angens.

Epsen-Barr vrus (EBV), a member o e erpesvrus amy, s ubq-

cdood

axary,

expanded

ures: (1) aypca ympocyoss; (2) a posve eerop anbody reac-

uous n uman popuaons. In ower-ncome counres, EBV necon n

eary

by

Features.

and

epas)

Infectious

cervca,

an

nec-

ous mononuceoss, wc gves rse o a dsncve syndrome assoc-

w

poseror

conan

T ces a may mmc ympoma. he speen s usuay enarged and

infection

eukema

e

nodes

virus)

nraed

enoug

n

brucellosis)

we

a

o

aberraons.

as

and

coun),

mmune

ocus

on

on

morpo-

neage-spe-

he

number

relecng

sysems

reavey

e

rom

common

148

CHAPTER

Table

9.6

Acute

Hematopoietic

9

Leukemias

Entity

B-cell

and

Cell

acute

lymphoblastic

of

Myeloid

and

Lymphoid

Neoplasms

Origin

Immature

B

Systems

Salient

cell

Pathologic

Marrow

leukemia

Features

replacement

blasts,

absence

of

by

Commonly

lymphoid

Auer

rods

form

(subset

acute

lymphoblastic

Immature

T

cell

Marrow

leukemia

replacement

blasts,

absence

frequent

Acute

myeloid

leukemia

Hematopoietic

myeloid

stem

cell

or

early

Marrow

progenitor

of

mediastinal

often

with

lymphoid

Auer

replacement

blasts,

by

rods,

of

molecule

rods

syndrome

Hematopoietic

myeloid

stem

cell

or

early

Dysplastic

progenitor

marrow

peripheral

blood

and

Genes

elements

myeloid

leukemia

Hematopoietic

stem

cell

Increased

marrow

precursors

and

leukocytosis,

granulocytic

vera

Early

myeloid

progenitor

Increase

in

all

myelofibrosis

Early

myeloid

progenitor

Increased

cytes,

aly,

or

cncopaoogcay

emaoogc

or

eary

marrow

pasms,

immature

elements,

Acue

(T-ce

(acue

o

enes.

orgnae

e

wc

acue

are

n

We

w

rs

emaopoec

eukemas

summarzed

and

n

are

a

diverse

hematopoietic

leading

to

eukemas

(B-ce

acue

o

arres

a

major

umor

eary

bock

n

bass.

o

B-

or

popuaon

n

T-

n

neoplastic

to

replace

dferenaon

presence

o

a

eas

mmunopenoypc

mas aso ave

 B-ALL

dence

s

s

or

factor

genes,

(e.g.,

by

RARA);

signaling

genes

epigenetic

factors,

regulators,

and

transcrip-

factors

tyrosine

kinase,

fusion

in

the

form

of

in

the

JAK2

tyro-

in

the

JAK2

or

gene

elements,

atypical

marrow

Activating

sine

megakaryo-

fibrosis,

Activating

splenomeg-

tyrosine

leukoerythroblastosis

in

mutations

kinase

the

gene

mutations

kinase

CALR

genes;

MPL

mutations

gene

ces

neo-

ALL

ce

proliferations

normal

marrow

or

and

mmaure

ere

s

a

ssues.

B-ce

umors

myeod

umors

compee

In

no

T-ce

neopasc

dferenaon

of

marrow

failure.

B-ALL),

T-ALL),

he

nvoved

oten

mos

beween

ncompee

e

ng

sympoms

marrow

ages

and

cyopasm

man

sma

mos

nvoves

marrow

na

cay

e

and

ces

are

mauraon

bass

conras,

and

n

dagnoss

aure,

masses

nuceo

denca

o

as

more

due

2

and

o

o

(Fg.

an

o

bood.

are

AML

s

e

e

based

I

(weakness,

(necon).

w

w

amos

e

a

as

9.11

Acute

and

bass

ney

er

nc-

arses

resu-

rom-

mucosa

ave

scan

spped

cro-

9.11A).

as

a

o

bone

adoescence

marrow.

T-ALLs

nvovemen.

B-ALL

and

can

In

presen

Bass

ony

be

and

addon

w

are

oten

o

medas-

morpoog-

dsngused

occurs

oder

an

Unke

leukemia

TdT,

small

(ALL).

terminal

nucleoli,

and

Lymphoblasts

deoxynucleotidyl

scant

agranular

with

cyto-

transferase.

myeod

neopasm

myeodyspasc

prodrome

o

asng

marrow

bass

and

amouns

9.12A).

In

ave

a

(Fg.

mmaure

subse

bass

Lke

o

In

w

cases,

ey

oer

are

morpoogcay

ALL,

bass

ncusons

9.13).

myeoproerave

descrbed

croman,

c yopasm

a

a

years.

Myeod

ne

neede-ke

bass

or

aure.

o

(eer

syndrome,

end

ese

o

o

sympoms

be

arger

nuceo,

granues

are

neopasm

somemes

numbers

ake

o

e

and

dsngus

mmunopenoypng

or

a

ater

a

reaed

ympod

moderae

granues

e

bass

are

an

orm

paognomonc

nsances,

dcu

and

mos

dsnc

varabe

a

aer),

o

or

(Fg.

Auer

myeod

AML

rom

s

o

are

so

ympod

necessar y

or

dagnoss.

Pathogeness. Among e mos common drver muaons n a ypes o

rougou

60.

shown.

chromatin,

by

mmunopenoypng.

 A ML

are

rods,

durng

e

plasm

nuclear

oows:

aways

ague),

lymphoblastic

on

euke-

peak

eemens,

skn

he

decae,

acue

eaures,

marrow

no

Beyond

myeod

eukema,

norma

presens

we

or

and

years.

beeds

nuce

ymc

ose

10

anema

[sma

commony

marrow

T-ce,

cncopaoogc

repaces

and

ymus,

e

cdood

neuropena

basopc

and

o

reaed

and

n

B-ce,

dsnc

(peecae

membranes]),

 T-ALL

bass

common

e

wn

n

20%

dferences,

somewa

e

bocyopena

 •

often

genes

splicing

BCR-ABL

basophilia

condensed

 •

by

splenomegaly

marrow

Fig.

 •

often

9.6

mmunopenoype

eukema,

AML).

Typcay,

sages

by

eukema,

or

of

often

related

ympobasc

eukema,

ce

that

subcassed

ympobasc

as

group

cells

symptoms

are

acue

myeod

reerred

e

genes,

signaling

consder

sem

myeod

Tabe

in

gene

Leukemias

leukemias

umors

a

progenors,

caracerscs

Acute

Acute

dsncve

magnances

and

fusion

by

kinase,

basophilia,

polycythemia,

Primary

ABL

megakaryocytes,

thrombocytosis,

Polycythemia

factor

encoding

RNA

tion

Chronic

BCR-ABL

translocations

progenitors

often

tyrosine

cases)

Transcription

molecule

Myelodysplastic

a

Genes

genes,

ABL

translocations;

myeloid

Auer

of

Transcription

involvement

by

factor

translocations;

the

T-cell

Mutated

T ranscription

e

ALL,

bu

s

AML

mos

oten

common

arses

n

rom

a

ndvduas

preexsng

acue eukema are gene rearrangemens and base par subsuons a

nerere

w

e

uncon

o

ranscrpon

acors

a

reguae

norma

CHAPTER

9

Hematopoietic

(>100,000

aways

ces/μL)

presen,

Neuropena

 •

and

bu

and

s

Lymphoid

e

w

cyomer y.

somemes

paee

coun

norma.

usuay

149

Anema

s

beow

s

amos

100,000/μL.

common.

 Immunopenotypng.

ormed

s

Systems

Denve

anbodes

For

o

exampe,

dagnoss

neage-specc

deecon

o

rees

on

angens,

ermna

sans

usuay

per-

by

deoxyrbose

low

rans-

erase (TdT) s useu or denyng earer B and T ce progenors.

Hsocemca

seen

 •

n

acue

 Cytogenetcs.

subypes

deny

 •

o

sans

aso

be

used,

eukema.

Specc

ransocaons

acue

eukema,

erapeuc

 Moecuar

may

myeod

ave

ncudng

are

myeoperoxdase,

assocaed

prognosc

w

parcuar

mporance,

and

may

are

now

arges.

Genetcs.

Ceran

orms

o

acue

eukema

dened by e presence o drver muaons n specc cancer genes.

Mos

acue

eukemas

sequencng. Fig.

9.12

nuclear

Acute

myeloid

chromatin,

leukemia

prominent

(AML).

nucleoli,

and

Myeloblasts

fine

with

azurophilic

are

o

are

em

curreny

are

evauaed

dscussed

by

argeed

DNA

aer.

delicate

cytoplasmic

Clncal granules

Some

Features.

Acue

eukema

s

an

aggressve

dsease.

In

addon

shown.

o

sympoms

opena,

 •

reaed

ere

 B one

pan

may

o

marrow

repacemen

and

e

aendan

pancy-

be

resung

rom

marrow

expanson

and

nraon

o

e

subperoseum

 •

 Lympadenopay,

mon

and

more

 In

T-ALL

 C enra

w

promyelocytic

leukemia,

abnormally

a

variant

coarse

and

of

AML.

The

numerous

dfer

and

T-ALL

characteristic

finding

is

a

cell

in

the

center

of

the

field

Auer

wo

of

rods

(arrow).

Pathology,

(Courtesy

University

of

of

Dr.

Texas

Robert

with

W.

mos

caracersc

o

AML

w

sysem

compresson

manesaons

eadace,

acue

ALL

are

nvovemen,

o

arge

vesses

medasnum

eukema

w

and

cured.

vomng,

and

vares

combnaon

AML.

Hgy

More

resung

ner ve

rom

accordng

o

cemoerapy

an

efecve

80%

o

argeed

menngea

pases

subype.

usng

cdren

erapes

Mos

regmens

w

are

B-ALL

avaabe

moecuar

subypes

by

e

o

acue

presence

o

a

eukema:

BCR-ABL

(1)

BCR-ABL–postve

uson

gene

(descrbed

multiple

dea

under

cronc

myeod

eukema)

and

(2)

acute

promyeocytc

McKenna,

Southwestern

a

dsncve

subype

o

AML

caracerzed

by

e

presence

o

Medical

a School,

as

o

dened

eukema, Department

gums,

neo-

n needle-like

ymc

reaed

or

and

granules.

B-ALL, A

are

skn

e

ner vous

a

or have

n

suc

Treamen

paens

e

com-

dferenaon

ar ways

spread,

Acute

o

more

AML

 Inraon

 •

promyelocytes

epaomegay,

an

 Tescuar enargemen due o eukemc nraon

and

9.13

and

ALL

 •

 •

plastic

n

 •

monocyc

Fig.

spenomegay,

pronounced

(15;17)

ransocaon

a

creaes

a

PML-RARA

uson

gene

encodng

Dallas.)

an

aberran

orm

o

e

renoc

acd

recepor

a

bocks

ermna

d-

erenaon o promyeocyes. hs orm o acue eukema s now amos

emaopoec ce dferenaon. hese muaons ypcay nvove ac-

aways cured w argeed reamen conssng o a-trans renoc acd,

ors

a vamn A anaog a bnds e PML-RARA uson proen, combned

a

reguae

e

neage

o

wc

e

eukema

beongs.

For

exam-

pe, B-ALL oten conans muaons n ranscrpon acors requred or

w

eary

reamen

sages

arres

ead

o

genes

o

and

o

B-ce

accumuaon

grow

o

sgnang

ncudng

severa

hese

mmaure

acor–ndependen

encodng

RAS,

dferenaon.

bass.

sgnang

moecues

grow

muaons

a

acor

ac

cause

Muaons

and

n

mauraon

oer

genes

proeraon. RAS

upsream

recepors,

are

and

and

downsream

oten

muaed.

arsenc

neurops,

a

combnaon

 •

he

o

 Mor poog y.

marrow,

gy

and

compemenar y

Bass

aoug

dagnoss,

are

dagnoss

can

bopsy

parcuary

varabe.

be

he

n

subypng

acue

eukema

requres

n

o

ssue

a

T-ALL.

ce

e

mass

he

coun

bood

may

perpera

may

be

be

and

bone

requred

bood

markedy

or

e

degradaon

rapdy

reamen

de,

o

o

mmaure

cearng

B-ALL

e

w

o

PML-RARA.

ces

neopasc

cyooxc

T

hs

presumaby

cone.

ces

A

no

recen

bearng

c-

ces

expressng

responses

e

n

B-ce

angen

CD19.

reapsed/reracory

hs

B-ALL

erapy

n

as

cdren

produced

and

adus,

bu a e cos o permanen oss o norma B ces and somemes severe

or

perpera

s

cause

dferenaon

merc angen recepors (CARs) engneered o speccay recognze and

k

ess:

seen

we

o

wc

e

wc

deveopmen

dramac

Pathology.

sas,

nduces

even

aa

acvaed

oxcy

njeced

Caenges

ndngs

rangemens

eevaed

encodes

an

o

T

caused

ces

reman.

e

by

Inane

KMT2A

epgenec

producon

(cyokne

acue

gene

reguaor,

o

cyoknes

by

e

massvey

sorm).

eukemas

(prevousy

ave

a

poor

assocaed

known

as

prognoss.

w

MLL),

he

rear-

wc

prognoss

150

or

CHAPTER

adus

or

w

paens

kema

w

BCR-ABL–negave

w

remans

parcuary

TP53

poec

AML

poor,

subypes

caengng

ce

probem

wc

ALL

oer

parcuary

muaons,

sem

Hematopoietic

9

n

s

ave

s

guarded,

an

adus

e

acue

oder

sma

dsma

and

and

e

prognoss

promyeocyc

an

subse

oucomes

Lymphoid

o

age

60

acue

even

eu-

years.

A

Systems

argeed

cay

erapy.

dsnc

prmar y

s

a

arge

emao-

dene

AML

ons).

hese

(>20%

I

(MPNs;

afecs

n

myeod

bass

and

a

syndrome

dscussed

abou

ncreasng

o

neopasms

myeodyspasc

pasms

Syndromes

group

Chronic

Myeloid

Chronic

myeloid

15,000

specc

no

aer).

as

wo

(MDS)

e

ack

e

AML-denng

and

per

a

broad,

MDS

paens

requency

derived

neopasms

e

s

n

popuaon

drver

as

e

common

Uned

a

ABL

mua-

groups,

myeoproerave

neary

year

eaures

overappng

dscuss

CML

and

wo

neopasms,

oer

cncopaoog-

poycyema

vera

and

myeobross.

liferative

here

w

eukemas

w

ranspanaon.

Myelodysplastic

We

myeoproerave

as

Saes

e

neo-

he

e

neoplasms

from

gene

(CML)

by

portions

on

o

e

is

the

of

BCR

ave

DNA

smar

of

gene

a

on

from

other

BCR-ABL

myelopro-

fusion

chromosome

22

gene

and

the

9.

breakpons

BCR-ABL–posve

bu

distinguished

presence

the

chromosome

posons

and

ways

Leukemia

leukemia

B-ALL

downsream

n

cronc

(descrbed

myeod

earer)

eukema

dfer

n

sub-

consequences.

AML.

and

s

ages.

Pathogeness.

proen

n

he

wc

BCR

e

ABL

ABL

gene

ound

yrosne

n

knase

CML

becomes

encodes

a

cmerc

consuvey

acve

because o uson o par o e BCR proen and mmcs sgnas produced

Pathogeness. MDS s caracerzed by mauraon deecs assocaed w

by

nefecve

dferenaon, e eary dsease course s marked by excessve producon

emaopoess

and

a

g

rsk

o

ransormaon

o

AML.

he

marrow s pary or woy repaced by e cona progeny o a ransormed

mupoen

neage

sem

ce

a

dferenaon.

demonsraes

he

marrow

s

nefecve

and

yperceuar

or

dsordered

cdren

muaed

ng

cancer

agens

appears

and

or

o

be

young

gene

or

onzng

caused

adus,

exposure

radaon).

by

MDS

o

In

sporadc

s

oten

muagens

adus

muaons

n

e

acor

recepors.

Because

BCR-ABL

does

no

nb

o reavey norma bood ces, parcuary granuocyes and paees.

normoceuar,

bu

Morphology. he eukocye coun s eevaed, oten exceedng 100,000

due

(e.g.,

over

grow

mu-

e perpera bood sows one or more cyopenas.

In

acvaed

o

erapeuc

age

cancer

nerance

o

60

genes.

o

a

akya-

years,

MDS

T ransorma-

ces/μL,

due

eosnops,

as

o

e

and

meamyeocyes

aso

requeny

and

o

ncreased

we

as

myeocyes

eevaed.

(Fg.

marrow

s

numbers

o

9.14).

he

orms

paee

yperceuar,

and

and

oer

sgnang

moecues.

In

addon,

rougy 10% o MDS cases ave oss-o-uncon muaons n TP53; ese

be

spenc

emaopoess.

e

I

suc

coun

s

speen

suppy canno keep up w e massve spenomegay, e resu may

RAS

exrameduary

neurops,

granuocyc

s

n

by

he

earer

suc

muaons

enarged

as

on o AML s assocaed w addona muaons a drve ce grow,

as

markedy

presence

basops,

e

bood

narcs.

paens ave parcuary poor cnca oucomes.

Clncal

Morphology.

a

he

exb

marrow

s

popuaed

dsordered

“megaobasod”

megaobasc

emaopoec

dferenaon

eryrod

anemas,

by

precursors

eryrod

(dyspasa),

resembng

orms

precursors

w

ron

ose

ncudng

seen

deposs

n

wn

e

er

are

Features.

nonspecc.

ura

sor y

o

cases,

crss

e

bas

B-ALL,

granues

mupoen

nucear

mauraon,

and

sma

megakaryocyes

w

snge

sma nuce or mupe separae nuce.

onse

varabe,

ransormaon

mocondra (rng sderobasts), granuocye precursors w abnorma

or

s

he

wc

o

Spenomegay

s

bu

acue

CML

may

unreaed

eukema

resembes

conssen

emaopoec

s

be

s

(so-caed

e

n

and

eares

CML

AML;

w

sem

nsdous

e

dea

evenuay

bas

e

na

CML

he

aa

crss).

remander,

a

sympoms

sympom.

In



na-

due

o

70%

o

resembes

orgnaes

rom

ces

T argeed erapy as dramacay aered e dsease course. Tyrosne

knase nbors a arge e BCR-ABL uson proen nduce susaned

remssons

Clncal

Features.

cyopenas,

ss

rees

on

Mos

necons,

e

paens

anema,

presence

o

are

and

50

o

70

beedng

cyopenas

and

years

are

o

age.

As

common.

caracersc

a

he

resu

o

ease.

he

and

preven

bas

crss,

BCR-ABL–posve

cone

parcuary

persss,

n

and

paens

paens

w

mus

eary

be

ds-

reaed

dagno-

morpoogc

and genec ndngs. Cyogenec sudes oten revea cona abnorma-

es;

oss

o

common.

a

majory

o

MDS

s

panaon.

dcu

and

poron

o

o

cromosomes

sudes

rea;

mos

w

me



does

paens

T ransormaon

survva

assocaed

a

sequencng

5

deny

and/or

drver

7

s

parcuary

muaons

n

e

cases.

cemoerapy,

medan

or

DNA

o

ranges

ncreased

are

AML

rom

marrow

no

oo

respond

od

occurs

9

o

29

bass,

o

n

we

o

undergo

10%

mons

o

40%

and

cyogenec

convenona

sem

s

o

ce

rans-

cases.

worse

n

he

cases

abnormaes,

or

TP53 muaons.

Myeloproliferative

The

common

Neoplasms

pathogenic

feature

of

myeloproliferative

neoplasms

is the presence of mutated, constitutively activated tyrosine kinases

or

other

acquired

aberrations

in

signaling

pathways

that

lead

to Fig.

growth

factor

9.14

Chronic

myeloid

leukemia:

peripheral

blood

smear.

Granulo-

independence. cytic

forms

at

various

stages

of

differentiation

are

present.

(Courtesy

of

hese dverse myeod magnances are rare bu are noabe because Dr.

o

e

remarkabe

response

o

cronc

myeod

eukema

(CML)

o

Robert

W.

Southwestern

McKenna,

Medical

Department

School,

of

Dallas.)

Pathology,

University

of

Texas

CHAPTER

or

e.

Reapses

somemes

occur,

oten

due

o

ougrow

o

cones

9

Hematopoietic

n

BCR-ABL

a

preven

nbors

rom

bndng.

In

remssons

can

be

obaned

by

swcng

o

dferen

a

he

s

marrow

seen

are

acve

agans

parcuar

muaed

orms

o

BCR-ABL.

151

appearance

occasonay

s

ae

denca

n

e

o

e

course

spen

o

oer

nbors myeoproerave

a

Systems

some pase

nsances,

Lymphoid

w Morphology.

muaons

and

For

neopasms

suc

as

PCV .

Inay,

e

marrow

s

oers, yperceuar

and

mdy

dsored

by

bross.

Megakar yocyes

are

emaopoec sem ce ranspanaon ofers a cance o cure. arger

an

marrow

Polycythemia

Vera

Polycythemia

vera

s

norma

exrameduar y is

a

myeloproliferative

disorder

marked

production

of

all

myeloid

lineage

cells

and

markedy

to

increased

red

cell

mass

and

n

cusers.

dfusey

emaopoess

In

advanced

broc,

occurs.

he

and

cases,

e

compensaor y

abnorma

(Fg.

9.15).

Red

perpera

ces

exb

bood

bzarre

smear

sapes,

symptoms and

related

presen

by s

increased

and

ypoceuar

nuceaed

er yrod

precursors

are

commony

seen,

aong

(polycythemia). w

a

mmaure

we

combnaon

o

ces

ndngs

(myeocyes

reerred

o

and

as

meamyeocyes),

eukoerytrobastoss.

Pathogeness. Poycyema vera (PCV) s assocaed w acvang pon Abnormay muaons

n

e

yrosne

knase

JAK2,

a

sgnang

moecue

n

arge

paees

are

oten

presen.

Marked

spenomegay

paways due

o

exensve

exrameduar y

emaopoess,

oten

assocaed

downsream o e eryropoen recepor and oer grow acor recepw

subcapsuar

nfarcts,

s

ypca.

he

speen

may

weg

up

o

ors. he JAK2 muaons reduce e dependence o emaopoec ces on 4000 g, rougy 20 mes s norma weg. Moderae epatomegay, grow acors or grow and survva, eadng o excessve proeraon o aso

due

o

exrameduar y

emaopoess,

s

commonpace.

eryrod, granuocyc, and megakaryocyc eemens.

Clncal

Features.

Prmar y

myeobross

usuay

occurs

n

ndvduas

Mor pholog y. he marrow s yperceuar due o ncreased numbers oder

o

er yrod,

myeod,

and

megakar yocyc

orms.

Marrow

an

60

years

seen

n

10%

o

paens

a

dagnoss.

hs

can

progress

o

a

were

e

marrow

s

repaced

by

brobass

and

bood

o

voume

many

and

vscosy

ssues.

Paees

due

are

o

poyc yema

oten

may

be

dysuncona,

eadng

o

romboss

are

oten

ncreased

n

e

perpera

and

norma

Sympoms

oms,

PCV

ncude

cyanoss,

emaemess,

areres

and

can

appears

and

ead

o

nsdousy,

eadace,

meena.

sroke,

dzzness,

myocarda

n

ae

mdde

gasronesna

may

nvove

narcon,

and

age.

symp-

vens

or

pumonary

embosm. Epsaxs s common, and e-reaenng emorrages occur

n

5%

n

5%

o

10%

o

paens.

Because

o

e

g

he

10%

o

ce

urnover,

gou

s

greaer,

on

o

W ou

w  n

ab ou

or

10

ye ars

o

n

mos

AML

are

leads

a

sp en

a er

 re a

bu

of

and

gou

sudes

by

due

sow

o

a

a

g

rae

moderae

are

o

o

eukoer yrobasoss.

mdy

coun

rombocyopena

he

reduced

s

romboss

n

5%

o

oten

myeobross

medan

sur vva

and

20%

spenomegay

o

s

4

beedng,

cases.

and

ranspanaon

requen

and

com-

ce

urnover

severe

are

normocyc

bu

can

he

be

we

eevaed

ce

coun

eary

n

usuay

norma

or

eevaed

a

e

dagnoss,

s

super venes

more

o

5

and

JAK2

years.

be

e

o

o

ransormaon

are

dsease

rea

hreas

nbors

consuona

may

as

dcu

an

e

o

PCV

and

ncude

AML,

efecve

sympoms.

progresses.

a

CML.

necon,

wc

occurs

decreasng

Hemaopoec

sem

e

ce

curave.

Lymphomas

and

Chronic

Lymphoid

Deec-

o

comp c a  ons

 me

emao c r 

as

o

 ner va 

pas e

a

and

b as

 re quen y

s

ne ar

 e ad

cr s s

 an

nor ma 

a

hese

common

10

o

by

pomas

rom

and

are

Fig.

9.15

derved

pasma

maure

and

emaoogc

are

ce

maure

neopasms

ympocyes,

dscussed

magnances

rom

bu

and

ave

ncude

ympod

reaed

unque

a

wde

ces.

enes

varey

Hodgkn

are

aso

cncopaoogc

o

ym-

derved

eaures

aer.

myeo -

ye ars .

JA K2

mprovemen

den c a 

n

o

a

prop ens  y

pr mar y

o

o c c urs

nc re as e d

re ve a e d

res emb ng

average

Leukemias

neopasms

sur v va 

sur v v a 

sp en

ess

rombocyoss.

vas c u  ar

pas e

an

 e

muc

primary

brosis,

cytopenias

ncrease

acor

sweas

o

 a

o

CML.

Myelofibrosis

Pathogeness.

a

 e

Trans or ma on

o cc urs,

marrow

to

o

o

and

dagnoss.

me d an

Proonge d

 aer)

us e d

hallmark

erative

o

e

 rom

 e

ower ng

e vove

p a ens.

a s o

Primary

The

by

basopa,

d e a 

owe ver,

(des cr b e d

n bors

w

conrms

 re a men,

p eb oomy.

PCV

bross

muaons

mon s;

rep e ae d

ng

paens.

granuocyoss

JAK2

and

seen

Common aboraor y ndngs ncude a emaocr a s oten 60%

or

or

paee

Non-Hodgkin o

oss,

bood.

usuay

hromboses

anema

beedng.

Prmar y

Features.

weg

Laboraor y

accompaned

usuay

bu

Clncal

o

arge

course.

Basops

reaed

cause

abnormay

s

and

Fague,

Hyperurcema

seen.

anema

congeson

sympoms

coagen. oten

Increased

w

spent pans.

pase,

presen

bross spenomegay.

s

wo

and

Prmar y

he

reduces

extensive

sgnang,

mos

requen

is

the

development

marrow

a

o

s

caused

paway

ese

of

oblit-

hematopoiesis

extramedullary

myeobross

JAK/STAT

recepors.

myelobrosis

which

by

varous

muaons

downsream

are JAK2

and

hematopoiesis.

o

grow

muaons,

wc

are presen n 50% o 60% o cases. I s no known wy JAK2 muaons

are

n

assocaed

oers.

w

Fbross

PCV

s

n

some

caused

by

paens

and

prmar y

pro-brogenc

acors

myeobross

suc

as

grow

acor

and

TGF-

a

are

eaboraed

by

Primary

precursors

megakar yocyes.

TGF-

promoes

angogeness

as

we

as

bo

o

wc

are

promnen

n

myeobroc

peripheral

several

blood

smear.

teardrop-shaped

red

Two

cells

nucleated

are

myeloid

cells

were

present

in

other

fields.

An

evident.

identical

histo-

coagen logic

deposon,

and

neopasImmature

c

myelofibrosis:

paeerythroid

e-derved

marrows.

and

picture

fibrosis.

can

be

seen

in

other

diseases

producing

marrow

distortion

152

CHAPTER

Hematopoietic

9

and

Lymphoid

Some genera aspecs o magnances o maure ympod ces bear

empass:

 •

 e

erms

sue

eukema

nvovemen.

apparen

n

Leukemas

perpera

refer

ypcay

bood,

o

arse

wereas

e

n

usua

bone

ympomas

paerns

marrow

presen

of

s-

and

are

as

Wesern

masses

e

CLL,

word.

Pathogeness.

paen

wc

For

s

dagnosed

uncear

CLL/SLL

“ympomas”

and

nvovemen.

n

ve

n

for

dagnoss

o

e

s

as

perpera

masses,

based

umor

on

ces,

bood

wou

e

nvove-

perpera

morpoogc

regardess

o

er

and

oca-

neopasms

sysem;

oten

dsrup

mmunodecency

e

and

funcon

of

e

auommuny

s

mos

an

w

o

or

acqured

neopasms,

mmunodeicences

parcuary

ose

are

assocaed

at

unema

EBV

pocyes

sowy

s

ess



ympoma

recrcuae

by

a

umors

because

oten

ke

are

are

appears

norma

dagnoss.

erapes

 B-ce

o

be

ocazed,

ympocyes

hereore,

w

and

ew

neopasc

umors

are

umor

and

Many

ons

he

excepons,

ym-

a

ony

muc

muaons

use

pod

eukemas

mned

by

secons,

common

and

an

muaons

mporan

enes

ncrease

n

B-ce

mmunogobun

o

T-ce

reaed

consders

presence

w

o

ocus

vra

on

(summarzed

a

e

or

umors,

o

o

cnca

a

Tabe

ave

oc

eac

mos

We

bre

acvaon.

o

ransoca-

Chronic

Lymphocytic

Cronc

ympocyc

bood

(SLL)

are

aso

and

ce

o

and

eny.

cronc

orgn

w

e

n

n

e

Asa.

wc

9.7

eukema



e

(CLL)

ouc

because

on

o

dferng

perpera

Characteristics

lymphocytic

Follicular

red

of

ony

bood

sma

ew

e

e

yrosne

NF-κB,

oten

resung

15%

or

knase

o

o

n

(BTK)

and

conrbues

ces.

CLL/SLL

ces

ypogammagob-

deveop

Wen

auo-

presen,

n

e

exen

ympocye

of

o

an

Mature

B

nvoved

an

Features.

s

cell

are

are

a

o

are

caed

sma,

efaced

areas

sma

(see

marrow,

In

w

maure-ookng

and

caed

he

wc

and

ver

CLL,

ere

ympocyes.

requeny

smudge

sees

9.16B).

ceners,

speen,

paens

by

conanng

ympocyes

Fg.

proferaon

he

cases.

are

he

cyopasm

rage

ey

dfusey

-dened

9.16A).

CLL/SLL.

ces

o

aso

he

bood

dagnoss

and

ces

g

can

ymp

course.

s

I

s

based

conrmed

expressng

expressed

prognoss

ndoen

dsruped

on

ces.

on

s

generay

T

kappa

or

good

e

ympocyes

cyomer y,

and

suc

In

wc

as

cona

ambda).

or

CD20,

surace

SLL,

lymphoma

Naïve

mature

B

cell

CD5

mmu-

ssue

bopsy

CLL

usuay

paen

s

oows

a

ver y

asympomac,

marginal

zone

lym-

Mature

B

and

Chronic

in

Lymphoid

Leukemias

Characteristics

older

adults;

blood;

Translocations

Translocations

cell

usually

involves

lymph

nodes,

marrow,

spleen;

and

indolent

involving

BCL2;

presents

with

generalized

lymphadenopathy;

involving

Arises

at

sites

of

the

cyclin

moderately

chronic

D1

gene;

presents

with

generalized

aggressive

inflammation;

very

indolent

phoma

Diffuse

large

B-cell

lymphoma

Germinal

minal

Burkitt

lymphoma

center

center

Germinal

or

B

center

post–ger-

cell

B

Heterogeneous,

translocations

cell

Usually

all

Hairy

cell

leukemia

Mature

B

cell

arises

cases;

Spleen

and

at

may

arise

involving

at

extranodal

subset

of

marrow

extranodal

BCL2,

BCL6,

sites;

cases

and

MYC;

variably

most

with

involving

EBV;

cases

associated

with

aggressive

translocations

associated

involvement;

sites;

MYC

in

virtually

aggressive

have

BRAF

mutations;

indo-

lent

Adult

T-cell

leukemia/lymphoma

CD4-positive

T

cell

Usually

presents

ciated

Peripheral

T-cell

lymphoma

Mature

T

cells

Epstein-Barr

virus;

HTL V-1,

human

T-cell

lymphotropic

with

virus

1.

with

HTL V-1

Heterogeneous;

from

EBV,

e

omac paens are reaed w anbodes agans CD20, nbors o

lymphadenopathy;

Extranodal

n

reveas

dagnoss.

because

wen

ncreased

markers

ces),

requred

dagnosed

on

low

B-ce

norma

(eer

node

by

medan sur vva s greaer an 10 years, even wou reamen. Symp-

Occurs

B

(Fg.

scany

ces

ympocyoss

preparaons;

enarged

Associated

center

n

crcuang

popuaon

peripheral

Germinal

and

acve

nodes

scaered

ces

nuce

mocay

perpera

he

ym-

Lymphomas

cell

and

dvdng

round

absoue

(wc

exceeds

Origin

ymp

amos

a

or

perpera

coun

Invoved

or

Lymphoma

leukemia

lymphoma

cell

e

oerance.

indolent

Mantle

by

sgnas

CLL/SLL

o

paens

paees.

BCR

wc

sur vva

pro-

generaed

BCR).

accumuaon

ces

mmune

paognomonc

e

rare

unusua

ympocyc

Non-Hodgkin

lymphoma/

lymphocytic

Lymphocytic

mpar

aso

Clncal

cncay

a

o

nogobun

and

Cell

chronic

acor

sgnas

or

ce

(e.g.,

oowng

and

ces

acvey

soogc

(deer-

genoype

In

common

menon

Leukemia/Small

Entity

Small

Bruon

approxmaey

own

ympocyes

dark,

hese

ym-

caracerscs.

denca,

nvovemen;

Table

er

are

recepor,

promoe

uncon,

are

o

poma

a

mecansms,

are

s

proooncogenes.

eaures,

o

are

9.7).

conss

sma

arger,

proba-

doube-srand

oncogene

ympomas

morpoog y,

deser ve

normave

rsk

genes

genomes)

ose

n

nevereess

paogencay

e

magnances

non-Hodgkn

mmunopenoypng),

we

genes

B-ce

agans

caed

ranscrpon

Paradoxcay,

CLL/SLL

o

more

cass-swcng)

casscaon

kar yoype,

o

uncear

Morphology.

sys-

curave.

ransocaons

drver

a

e

mporance

B-ce

umor

cr-

n

usuay

DNA breaks n mmunogobun genes (durng somac ypermua-

on

crca

(e

an

e

adus

common

growng

mporan

cases

o

auoanbodes are made by nonmagnan bysander B ces, ndcang

wdespread

emc

o

nermedar y

norma

anbodes

necon.

Aso

on

expresson

hroug

ger

w

an

urn

suppresses

nered

ympod

 Atoug

roug

e

coexs

nsances.

w

apoposs.

mmunogobun

more

Mos

eukema

CLL/SLL

ndoen,

s

CLL.

common

reasons,

sur vva

surace

low

adap-

ce

nbs

umaey

ympod

 Paens

rsk

he

ave

presen

body.

mmune

some

may

caracerscs

e

 Maure

occasonay

“eukemas”

umor

s

e

eraon per se. CLL/SLL ces express g eves o BCL2, a proen a

on

 •

or

absoue:

moecuar

 •

ces/μL,

era

ncreased

bood

 •

ympoma

5000

n ymp nodes and oer ssues. However, ese dsncons are no

men

 •

and

Systems

cytokine

lymph

node

infection;

often

associated

release;

and

blood

frequent

with

aggressive

involvement;

hypercalcemia;

systemic

uniformly

asso-

aggressive

symptoms

stemming

CHAPTER

B-ce

recepor

sgnang,

and

BCL2

anagonss.

he

presence

o

9

Hematopoietic

and

Lymphoid

Systems

153

TP53 Morphology.

Lymp

nodes

are

usuay

efaced

by

a

dsncy

muaons porends a worse prognoss. Cure may ony be aceved w noduar emaopoec

sem

ce

ranspanaon,

wc

s

reser ved

or

proferaton

wo

a

convenona

erapes.

A

sma

racon

o

ransorm

o

aggressve

umors

resembng

dfuse

ces

(Rcer

ransormaon);

once

arge

ransormaon

sur vva

me

s

ess

an

1

occurs,

e

predomnan

so-caed

a

centrocytes,

ave

ces

anguar

sgy

“ceaved”

arger

an

nuce

and

near

nodngs,

coarse

condensed

w

croman,

and

e nuceo

(Fg.

9.17B).

Cenrocyes

are

mxed

w

varabe

year. numbers

severa

o

centrobasts,

nuceo,

cenrobass

Follicular

commony,

B-ce

ndsnc medan

are

ympocyes

ndenaons ympoma

Mos

CLL/SLL resng

cases

9.17A).

younger neopasc

paens

(Fg.

and

arger

modes

predomnae,

ces

amouns

a

w

o

eaure

vescuar

cyopasm.

a

croman,

Uncommony,

correaes

w

more

Lymphoma

aggressve cnca beavor. he umor ces express e B-ce marker Follicular

lymphoma

is

strongly

associated

with

a

(14;18)

transloCD20,

cation

that

increases

the

expression

of

the

antiapoptotic

BCL2

and Focuar

ympoma

consues

approxmaey

25%

o

cases

germna

o

g

eves

ympoma

n

e

Uned

Saes,

makng



e

mos

o

B-ce

BCL2.

markers,

Because

surace

BCL2

s

no

mmunogobun,

expressed

n

norma

adu germna

non-Hodgkn

cener

gene.

cener

B

ces,

sans

or

BCL2

ep

dsngus

ocuar

comympoma

rom

ocuar

yperpasa.

mon “ndoen” non-Hodgkn ympoma. Lke CLL/SLL,  occurs ess re-

queny n Asan popuaons. he ce o orgn s a germna cener B ce.

Clncal

Pathogeness.

ersc

18

o

14,

(14;18)

e

(see

genes

an

85%

ransocaon

IGH

resung

oss

More

o

a

ocuar

uses

(mmunogobun

n

“overexpresson”

Caper

encodng

1).

In

abou

a

e

eavy

o

rd

o

BCL2

can)

BCL2

sone-modyng

ympomas

gene

ocus

proen,

cases,

proens

an

ave

on

on

carac-

usuay

Features.

Focuar

maness

as

ympoma

paness

afecs

generazed

adus

oder

an

ympadenopay.

50

he

and

mar-

cromosome

row s nvoved a dagnoss n approxmaey 80% o cases. Aoug e

cromosome

naura

nbor

addona

are

a

o

apop-

muaons

n

sor y

buky,

proonged

sympomac

anbodes

seen.

s

(overa

medan

sur vva

s

approxmaey

10 years), e dsease s no curabe; erapy s reser ved or paens w

o

agans

paens,

dsease.

CD20,

ocuar

Treamen

and

BCR

ympoma

ncudes

sgnang

progresses

“gene”

nbors.

o

dfuse

cemoerapy,

In

30%

arge

o

B-ce

40%

ym-

poma (DLBCL). DLBCL arsng rom ocuar ympoma as a worse

prognoss

Mantle

Mantle

an

Cell

cell

location

I

a

increases

ce

are

ces

5).

RB,

A

rom

aso

n

men

Cycn

e

been

or

G

1

marrow

n

an

nvoved

rom

a

50

e

aer.

S

by

e

ympod

trans-

naïve

B

oces.

ympomas

ormng

RB,

o

a

a

compex

promong

e

Addona

and

ce

varey

cyce

e

o

(see

brakng

drver

w

progresson

Cap-

efec

muaons

sgnang

o

ave

moecues,

reguaors.

efaced

by

he

ympocyes

cases

(11;14)

gene.

resembng

norma

over wems

paerns.

nuceo,

an

D1

non-Hodgkn

pase

D1

are

norma

mos

ces

o

grow

encodng

nodes

with

cyclin

years.

epgenec

noduar

n

o

grow.

genes

and

nconspcuous

s

o

the

nacvang

cycn

ce

Lymp

6%

an

and

o

of

zones

smuaes

pase

vaguey

arger

nuceus,

descrbed

associated

derved

mane

oder

D1

acors,

Morphology.

sgy

s

knases

dened

dfuse

strongly

e

ympoma

ranscrpon

n

n

Overexpresson

drvng

DLBCL,

expression

approxmaey

many

cycn-dependen

er

is

ympoma

ound

Pathogenes s.

o

dfuse

Lymphoma

consues

occurs

novo

lymphoma

that

Mane

ces

de

and

and

and

scan

e

umor

umor

ces

ces

ave

an

cyopasm.

perpera

growng

usuay

are

rreguar

he

bood

n

bone

abou

20% o cases. he umor ces express surace IgM and IgD, e B-ce

angen

ndng

Clncal

CD20,

a

s

and

Features.

ay

and

are

row,

speen,

CD5,

and

dagnoscay

Mos

ound

ver,

o

and

ave

paens

ave

g

presen

generazed

(oten)

eves

o

cycn

D1

proen,

a

epu.

e

w

ague

dsease

and

nvovng

gasronesna

rac.

ympadenop-

e

hese

bone

mar-

umors

are

B

moderaey

Fig.

9.16

Chronic

lymphocytic

leukemia/small

lymphocytic

aggressve

and

ncurabe.

T reamen

nvoves

e

use

o

ow-

lymphoma:

dose cemoerapy, anbodes agans CD20, and drugs a nb B-ce

lymph

node.

(A)

Low-power

view

shows

diffuse

effacement

of

nodal

recepor sgnang. he medan survva s 4 o 6 years. architecture.

appearance

(B)

of

At

high

small,

power,

round

a

majority

lymphocytes.

of

A

the

tumor

cells

have

“prolymphocyte,”

a

the

larger

Extranodal cell

(A,

sity

with

a

centrally

Courtesy

of

Texas

of

Dr.

placed

José

nucleolus,

Hernandez,

Southwestern

Medical

also

is

present

Department

School,

of

Dallas.)

in

this

field

Pathology,

Marginal

Zone

Lymphoma

(arrow).

Univer-

Extranodal

that

arises

marginal

within

and

zone

is

lymphoma

sustained

by

is

an

chronic

example

of

a

cancer

inammation.

154

CHAPTER

Hematopoietic

9

and

Lymphoid

Systems

B

A

Fig.

9.17

out.

(B)

outlines

Dr.

Follicular

At

high

lymphoma:

magnification,

(centrocytes)

Robert

W.

are

McKenna,

lymph

small

mixed

node.

(A)

lymphoid

with

Department

a

of

Nodular

cells

with

aggregates

condensed

population

of

Pathology,

University

Exranoda margna zone ympoma s an ndoen umor derved rom

larger

 •

angen-smuaed B ces. I occurs mos commony n organs w epe-

a

nngs,

suc

as

e

gasronesna

rac

(so-caed

MALT omas

cells

of

with

 B CL6.

pon

sa-assocaed ympod umors]), savary gands, ungs, orb, and breas.

nlamed

due

Hasmoo

gasrs).

o

ympoma

yrods)

o

secreed

by

oug

a

e

H.

or

o

umor

H.

pyor

ces,

dsease

subsequen,

oten

w

begns

as

s-unknown

or

a

on

er

Hecobacter

erapy

grow

oten

and

mmune

muaons,

a

a

are

 •

reacon,

neopasc

I

be

o

drve

angen,

grow

suc

as

H.

and

survva.

pyor

Hence,

proens,

wdrawa

causes

umor

o

e

s

 MYC.

ssues

he

and

he

cona

coec

cyopasm

dferenaon.

n

may

he

B

ces

sma

be

nrae

abundan

umor

ces

e

aggregaes

In

ons

and

express

epeum

o

nvoved

esons).

pae

e

or

exb

B-ce

pasma

angen

addon

mes

B

en

as

Features.

swengs

ncdenay

n

o

Exranoda

e

e

savary

seng

o

gand,

H.

zone

ympomas

yrod,

or

orb,

pyor–nduced

or

ypcay

are

gasrs.

pres-

dscovered

Unke

oer

non-Hodgkn ympomas, wen ocazed ey are oten cured by smpe

excson

dsease)

oowed

may

by

aso

radoerapy,

compeey

or

regress

(n

n

e

case

response

o

o

H.

pyor-assocaed

anboc

Large

Diffuse

large

phoma,

Dfuse

in

the

arge

common

smuaed

a

Cell

B

ces

demonsrae

genoypc

fo r

adus

and

is

the

mo s t

ap pro xi ma te ly

Un i ted

B-ce

n

c o m m on

35%

of

t y pe

of

States .

ympoma

oder

an

encompasses

subsana

he

o

are

cromosoma

era

dferen

10%

o

a

aberraons

B

ave

resu

ranscrpona

n

reg-

ces.

a

(14;18)

overexpresson

DLBCLs

ave

ranscrpon

ransocaons,

and

a

afec

ransocaon

o

e

anapo-

rearrangemens

acor

numerous

varous

ranscrpon

neopasc

resng

B

ces

a

oer

reguaes

drver

epgenec

acors

are

ympocyes;

Ces

w

dsnc

(Fg.

vescuar

arge,

a

a

owever,

ova

nuceo,

predomnae

muobae

mua-

reguaors,

ave

mporan

nucear

and

eas

ere

or

nuceus,

e

one

our

dspersed

amouns

ces

or

o

consderabe

conours,

modes

9.18),

ree

s

o

may

wo

pae

ave

a

promnen

e

umor

ces

are

anapasc

and

ncude

umor

gan

ces resembng Reed-Sernberg ces, e magnan ces o Hodgkn

ympoma

and

(descrbed

many

suc

as

 •

(DLBCL)

50

a

Severa

caegor y

aer).

express

BCL2,

years.

I

occurs

s

derved

eerogeneous

morpoogc,

a

a

ages

rom

group

o

bu

s

he

umors

surace

BCL6,

and

IgM

express

and/or

MYC

are

e

IgG.

varaby

B-ce

angen

Oer

proen

expressed.

 EBV-assocated

persons.

neopasms

begn

and

In

as

regress

 •

e

mos

ransocaons

oncogenes,

common

a

ncudng

ead

e

drver

o

e

muaons

n

DLBCL

overexpresson

oowng:

o

sev-

cncopaoogc



 Human

DLBCLs

mmune

n

e

ty pe

wc

s

may

peroneum.

encodes

8

s

seng

ranspan

poycona

uncon

[KSHV])

wc

n

posranspanaon

er pesv rus

or

HHV8,

e

arse

(e.g.,

EBV-drven

y mphomas,

dum,

subypes

are

ncuded

n

e

DLBCLs.

mmunosuppresson

angen-

mmunopenoypc,

dsncve

o

erpesvrus

Among

ese

severa

Occasonay,

ly m-

n on - Ho dg k in

varaon.

Pathogeness.

n

ave

BCL6,

Lymphoma

l y mp h oma

accountin g

lymphomas

mos

B

B-cel l

o

encodng

dened

may

or

markers

Diffuse

cener

umors

resus

Bo

o

racon

cenray paced nuceo, and abundan pae or basopc cyopasm.

CD20,

erapy.

a

5%

gene

varaon.

croman,

margna

gene

ger

mporan

germna

o

rearrangemens

even

ces.

sze

cyopasm

Clncal

a

moecues,

n

e

round

o

been

soogc

and

surace mmunogobun, usuay IgM.

BCL2

n

30%

an

promoer.

an

of

Dallas.)

ave

and

proen,

expresson

MYC,

Morphology.

ce

CD20

e

BCL6

BCL6

Approxmaey

ave

sgnang

(ymphoepthea

o

e

School,

DLBCLs

3q27,

nuclear

Courtesy

efec.

uncons

Morphology.

n

(A,

many aspecs o grow-promong meabosm, suc as e W arburg

cone

nvouon.

o

through-

cleaved

Medical

rd

Approxmaey

nvovng

and

respons-

one

gene

present

or

(centroblasts).

cromosome

eves

are

ocuar ympomas, wc vruay aways ave e (14;18).

 •

emerges a remans dependen on angen-smuaed T-eper ces or

sgnas

o

 BCL2.

cells

irregular

oc B CL2 proen. Some o ese umors may represen “ransormed”

o

cyoknes

survva.

on

nvovng

pyor

eads

Abou

ncreased

syndrome,

nlammaory

poycona

drver

ssues

Sjögren

(e.g.,

anboc

depend

ces

n

(e.g.,

necon

wc

T

mos

dsorders

cronc

pyor–specc

e

arses

auommune

Eradcaon

regresson

ater

hs

and

Southwestern

muaons

uaor

Pathogeness.

lymphoma

nucleoli

Texas

ocaed

[muco-

of

chromatin

o

AIDS,

recpens),

seng,

B-ce

ese

and

arogenc

n

edery

umors

proeraons

a

oten

may

resored.

(HHV8,

assocated

arse

hese

aso

w t

wn

umors

proens

e

are

caed

rare

Kapos

peura

cavy,

aeny

omoogous

sarcoma

prmar y

o

euson

percar-

neced

severa

w

known

CHAPTER

Fig.

9.18

have

tesy

Diffuse

large

of

Texas

Dr.

nuclei

large

B

with

Robert

W.

Southwestern

cell

open

lymphoma:

chromatin

McKenna,

Medical

lymph

and

Department

School,

node.

The

prominent

of

tumor

nucleoli.

Pathology,

9

cells

(Cour-

University

of

Hematopoietic

Fig.

9.19

nuclei

high

fairly

level

“starry

Dallas.)

Burkitt

are

of

sky”

of

ncudng

c ycn

D1.

Mos

afeced

paens

Dr.

Robert

a

Systems

node.

by

and

at

a

lower

Department

155

tumor

cells

prominent

lightly

their

Note

the

nucleoli.

staining,

magnification.

of

and

appearance.

interspersed,

appreciated

McKenna,

The

monotonous

(arrowheads)

produced

better

W.

lymph

giving

activity

pattern

is

Lymphoid

lymphoma:

uniform,

mitotic

macrophages

oncoproens,

and

Pathology,

The

normal

(Courtesy

University

of

are Texas

Southwestern

Medical

School,

Dallas.)

mmunosuppressed.

 •

 Medastna

women

ymc

B

caons

a

proens

an

 •

arge

and

B-ce

appears

ces.

hs

ead

PD-L1

mporan

o

roe

orgnae

umor

e

and

ympoma

o

requeny

s

mos

an

o

suggesng

oten

unusua

as

overexpresson

PD-L2,

n

occurs

rom

n

cromosoma

e

a

young

popuaon

mmune

mmune

o

amp-

ceckpon

evason

pays

paogeness.

BCL2.

and

he

a

MYC

combnaon

srong

exb

an

nvovng

ver y

and

o

prosur vva

aggressve

convenona

anoer

a

poen

oncogene,

progrow

oncogene

beavor

IGH

ces;

gene

varan

on

cromosomes

o

eac

s

proen.

e

In

2

w

(BCL2)

mos

mos

oncogene

yeds

subsanay

pays

n

(MYC)

umors

worse

a

e

oucomes

DLBCL.

round

a

or

Paens

mass

a

ypcay

one

or

presen

severa

gasronesna

ses.

Exranoda

are

and

λ

obser ved.

he

overexpresson

abou

20%

o

acve

g-can

ne

o

sporadc

n

oc

B

on

resu

e

MYC

cases,

e

o

cdood

enargng,

oten

presenaons

are

ympomas.

sympomac

common;

Wou

nensve

compee

uncommon

reamen,

combnaon

remssons

approxmaey

50%

a

DLBCL

nvovemen

are

s

aceved

ree

o

e

bu

ces

and

are

wo

o

nermedae

ve

dsnc

n

sze

nuceo

and

(Fg.

ave

9.19).

conans

IgM,

and

numerous

a

e

ssue

creae

B-ce

sma,

pd-ed

apoposs

a

vacuoes.

caracersc,

macropages

“starry

marker

are

sky”

CD20,

conanng

pattern.

and

Ver y

e

Tumor

germna

g

aer

raes

ngesed

ces

cener

o

assocaed

nucear

express

B-ce

surace

markers.

e

ver,

speen,

dagnoss.

n

and

and

rapdy

an-CD20

60%

o

dsease

o

dsease

aggressve

cemoerapy

reman

o

se,

umor

nuce

30%

s

ympoma),

exranoda

unceran.

cdren and young adus: Burk ympoma accouns or approxmaey

marrow

common

s

pomas

ocuar

mos

and

and

Clncal Features. Bo e endemc and nonendemc orms afec many

bone

e

15%

rapdy

aso

κ

can arse n vruay any organ or ssue. Unke e more ndoen ym-

and

s

a

cases

ranscrponay

Ig

DLBCL

(e.g.,

rac

w

abou

he

ova

oten

debrs

consues

respecvey,

endemc

s

e

here s a moderae amoun o basopc or ampopc cyopasm

w



wc

dysreguaon

paogeness

Morphology.

occur

age;

22,

e

14,

nvovng

commony

Clncal Features. Aoug mos common n oder adus, DLBCL can

any

and

same:

proeraon

a

cromosome

ransocaons

umor ces are aeny neced w EBV , bu e precse roe a EBV

 D oube-t ympoma reers o unusua umors a ave dua rans-

ocaons

e

80%

and

o

aa.

W

mmunoerapy,

paens;

appear

o

be

o

ese,

cured.

For

as

cdood

usuay

maxary

nvovng

Burk

or

e

non-Hodgkn

arses

a

mandbuar

bowe,

ympoma

s

ympomas

exranoda

ses.

masses,

wereas

reroperoneum,

gy

aggressve;

n

e

Endemc

and

n

Uned

umors

Nor

ovares

owever,

more

very

he

manes

Amerca,

are

w

Saes.

oten

umors

common.

nensve

ce-

moerapy regmens, a majory o paens can be cured.

oers, oer aggressve reamens (e.g., emaopoec sem ce rans-

panaon)

ofer

ope.

Other

Neoplasms

Among

Burkitt

Burkitt

MYC

Lymphoma

lymphoma

gene

that

Hea

is

result

associated

in

with

translocations

overexpression

of

the

MYC

involving

the

transcription

e

eaures

Burk

ympoma

s

endemc

n

pars

o

Arca

and

occurs

sporad-

cyopasmc

muaons

e Arcan and nonendemc dseases are denca, aoug ere are cn-

sream

ca and vroogc dferences. he ce o orgn s a germna cener B ce.

ons

s

Pathogeness.

MYC

gycoyss),

Caper

umor.

o

casscaon,

are

wory

o

a

Cells

ympod

severa

bre

neopasa

w

n

dsncve

e

or

Word

cncay

dscusson.

 Hary ce eukema s an uncommon, ndoen B-ce neopasm w a

cay n oer geograpc areas, ncudng e Uned Saes. Hsoogcay,

(see

Lymphoid

orms

dsncve morpoogy caracerzed by e presence o ne, arke

factor.

obc

Mature

oer

Organzaon

mporan

 •

of

many

Mos

5).

a

s

a

maser

cancer

Burk

reguaor

amark

ympoma

ransocaons

use

e

o

Warburg

assocaed

may

be

MYC

e

gene

w

meabosm

rapd

ce

ases-growng

on

(aer-

o

n

uman

sensve

8

w

I

rom

Vruay

a

serne/reonne

occurs

many

nraon

enarged.

o

n

e

Pancyopena

cases

knase

oder

bone

s

seen

are

assocaed

w

BRAF ,

wc

maes,

and

s

and

speen,

marrow

n

more

an

acs

drver

down-

manesa-

a

o

wc

cases.

Scaered “ary ces” can be dened n e perpera bood smear

grow

cromosome

e

RAS.

resu

usuay

projecons.

n

mos

BRAF

cases.

o

he

dsease

ceran

nbors.

s

progressve

cemoerapeuc

he

overa

prognoss



unreaed

agens

s

and

exceen.

bu

s

exremey

responds

we

o

156

 •

CHAPTER

Hematopoietic

9

and

Lymphoid

Systems

 Mycoss fungodes and Sézary syndrome are umors o neopasc CD4+

T

ces

a

are

ound

n

e

skn,

and

are

ence

grouped

under

cua-

neous T-ce ympoma. Mycoss ungodes usuay maness as a ras

a

by

progresses

sysemc

appearance

and

s

ey

over

produced

nrae

caracerzed

presence

o

dagnosed

years,

me

o

dssemnaon.

by

umor

w

wereas

by

e

paques

he

marked

upper

a

(Sézary

eary-pase

paens

T

and

ces

o

e

ces)

n

umors,

ave

e

oowed

cerebrorm

membranes,

Sézary

syndrome

eryroderma

perpera

ungodes

umor-pase

a

nucear

epderms.

exoave

mycoss

w

cuaneous

nodng

derms

generazed

ces

and

neopasc

oten

dsease,

and

bood.

survve

e

Paens

or

many

dssemnaed

ds-

ease, or Sézary syndrome survve on average or 1 o 3 years.

 •

Adut

T-ce

caused

by

HTL V-1

and

eukema/ympoma

a

rerovrus,

necon

W es

Arca,

s

uman

endemc

and

(ATL)

T-ce

n

occurs

s

a

neopasm

eukema

souern

vrus

Japan,

sporadcay

o

CD4+

ype

e

1

T

Carbbean

esewere,

ces

(HTL V-1).

basn,

ncudng

n

e

Fig.

9.20

berg

soueasern

Uned

Saes.

he

roe

o

e

vrus

n

ympogeness

cell

Hodgkin

with

surrounded

uncear

bu

key

nvoves

ceran

vra

proens

and

susaned

lymphoma:

large,

lymph

inclusion-like

node.

nucleoli

A

binucleate

and

abundant

Reed-Stern-

cytoplasm

is

s

by

lymphocytes,

macrophages,

and

an

eosinophil.

(Cour-

proertesy

of

Dr.

Robert

W.

McKenna,

Department

of

Pathology,

University

of

aon o neced T ces. Adu T-ce eukema/ympoma s assocaed Texas

w

skn

esons,

ympadenopay,

ma,

and

varabe

ympocyoss.

epaospenomegay,

Mos

cases

are

very

Southwestern

Medical

School,

Dallas.)

ypercace-

aggressve

and

respond poory o reamen. he medan survva me s ony 8 mons.

 •

 Perpera

umors

genera,

Hodgkin

Hodgkin

tive

rom

even

ese

e

o

umors

are

sympoms

wen

10%

a

umors

reaed

umor

a

eerogeneous

non-Hodgkn

o

o

respond

poory

uncona

T

s

reavey

o

ces,

umor-derved

burden

group

ympomas.

o

In

erapy.

paens

nlammaor y

ow.

Lymphoma

giant

Hsorcay,

cells

are

characterized

known

Hodgkn

ympomas

appearance

e

Aoug

and

e

as

e

by

was

presence

comprse

ony

cells

consdered

dagnosc

Hodgkn

the

Reed-Sternberg

ympoma

because

dsncve

umor.

encompasses

abou

aggressve

lymphomas

tumor

Hodgkn

are

up

because

sufer

producs,

ympoma

make

ese

Moreover,

oten

T-ce

a

a

apar

ympomas

racon

are

now

distinc-

variants.

rom

Reed-Sernberg

sma

of

and

ces

o

e

non-

ave

ces

undersood

o

a

n

be Fig.

umors

o

B-ce 

or  g  n ,

 e y

con nue

o

be

ds nguse d

9.21

Hodgkin

low-power

o

 er

unque

bo og y

and

resp ons e

o

subypes

sceross,

(2)

depeon,

e

o

mxed

and

(5)

eaures

ogeer

under

ces

sare

(descrbed

e

ympoma

ceuary,

ympocye

Reed-Sernberg

noypc

Hodgkn

rubrc

(3)

are

ceran

cassc

recognzed:

ympocye

predomnan.

aer),

In

rc,

e

as

Hodgkn

a

(4)

rs

morpoogc

and

resu

(1)

ympocye

our

and

noduar

ert

A

subypes

o

Hodgkn

western

Medical

are

umped

e

caused

by

mos

bae

commony

upreguaed

by

varous

acor

a

muaons,

suppors

and

B-ce

genes

School,

survva,

encodng

s

o

ces,

nuceus,

mmune

wc

cases

o

EBV

e

s

ound

n

e

mxed-ceuary

Reed-Sernberg

subype

and

a

ces

n

smaer

as

many

racon

ces

o

 •

oer “ cassc” orms o Hodgkn ympoma.

he

Reed-Sernberg

sne

ce

qua

(Fg.

non

9.20),

o

a

cassc

very

Hodgkn

arge

ce

ympoma

w

an

s

ave

abundan

a

CD30

cyopasm.

caracersc

and

angens,

do

or

no

mmunopenoype:

express

T-ce

Reed-Sernberg

CD45

angens.

hey

(eukocye

Dferences

ces

and

express

common

n

e

er

varans

CD15

angen),

appearance

and

B-ce

o

e

or

into

nodules.

Pathology,

e

o

ssue

lymph

node.

acellular

(Courtesy

University

response

cassca

young

sma

cyes,

 •

nodues

reacve

drawn

sroma

oder

o

Hodgkn

adus.

I

s

A

collagen

of

of

Dr.

Texas

Rob-

South-

ese

ces

denes

ympoma:

dened

varans

nuceo

 he

sc

n

are

9.21).

by

n

and

w

by

a

e

presence

snge

abundan,

50

and

Reed-Sernberg

eosnops,

pasma

and

ympoma

caracerzed

by

muo-

pae-sanng

produced

ces,

s

comprses

ces

by

varyng

pro-

macropages,

Reed-Sernberg

and

are

mos

penu

conanng

25%

o

wn

sma

n

cases

a

e-

ympo-

macropages.

rare.

presence

common

abou

ympocyte-depeted

bo

are

and

ssues.

nrae

are

e

presen

ympoma

years

nlammaor y

Aso

eosnops,

cyoknes

nvoved

Hodgkn

ympocyte-rc

Hodgkn

(Fg.

ympocyes,

ces

an

Cassc

erogeneous

enormous

muobae nuceus, exceponay promnen ncuson-ke nuceo,

and

cells

of

Reed-Sernberg

 Mxed-ceuarty

overa.

e

o

are

and

paens

Morphology.

type:

pink,

cyopasm, and coagen bands, wc dvde nvoved ssues no

PD-L1

porons

response.

and

mupe

crcumscrbed

o

of

Dallas.)

subypes

adoescens

acunar

eads o er overexpresson and eps Reed-Sernberg ces evade e os

70%

tumor

varans

common

and PD-L2, wo mmune ceckpon acvaors, are oten amped, wc

as

sclerosis

bands

 Noduar sceross Hodgkn ympoma oten nvoves e medas-

num

drver

ympoma.

ranscrpon

the

Department

Reed-Sernberg

o

a

nodular

well-defined

mmunope-

ese

are

subdivided

McKenna,

muaons n cancer genes; ese are bes caracerzed n cassc Hodgkn

NF-κB,

shows

subypes,

ympoma.

ympoma

have

W.

 •

Pathogeness.

view

 er apy. that

Fve

lymphoma,

b e c aus e

o

As

e

subypes

names

unusuay

o

mpy,

cas-

ey

promnen

or

sparse nraes o reacve sma ympocyes, respecvey. he

CHAPTER

9

Hematopoietic

he Reed-Sernberg

ces

and

varans

resembe

ose

seen

n

ceuary

 Se

apar

rom

cassca

mmune

Hodgkn

ympoma

s

e

and

dened

by

subtype,

e

wc

accouns

or

abou

5%

o

 S evera

presence

o

ymposocyc

(L&H)

e

deeerous

kdney,

a

o

efecs

wc

on

e

conrbue

skeeon,

o

morbd-

acors

ead

ces

popped

w

corn

a

decae

(popcorn

muobed,

ce).

L&H

pufy

varans

o

produced

by

myeoma

ypercacema

and

ces

cause

paoogc

bone

resorpon

racures,

mos

re-

varan n

e

spne

and

emur.

nuceus

 • resembng

and

cases.

queny Reed-Sernberg

sysem,

moray :

and s

ave

157

ympo-

 • cyte-predomnant

I

ces

Systems

subype. y

 •

pasma

Lymphoid

e e

mxed

proerang

and

are

 Myeoma

causes

deecs

n

umora

mmuny,

ncreasng

e

rsk

ound or

bacera

necons.

wn arge nodues conanng many sma B ces admxed w

 •

 Myeoma

eads

o

rena

aure

owng

o

(1)

obsrucve

proen-

varabe numbers o macropages. Unke e Reed-Sernberg varaceous ans

n

cassc

Hodgkn

ympoma,

L&H

varans

express

cass

comprsed

o

precpaed

Bence-Jones

proens;

B-ce (2)

g-can

deposon

n

e

gomeru

or

e

nersum,

markers (e.g., CD20) and do no express CD15 and CD30. eer Regardess

o

subype,

e

dagnoss

s

based

on

e

Reed-Sernberg

ces

or

varans

n

e

approprae

amyod

background

deydraon

and

ces.

Ces

resembng

Reed-Sernberg

ces

near

deposs;

(3)

ypercacema,

may

be

rena

sones;

and

(4)

requen

wc

bous

o

eads

bacera

o pyeoneprs

reacve

or

dencaon o

o

as

seen

due

o

deecve

umora

mmuny.

n

oer cancers and some reacve condons; us, mmunopenoypng

Morphology.

s oten requred or dagnoss.

desrucve

Mupe

skeea

myeoma

esons

a

usuay

mos

maness

commony

w

nvove

coumn, rbs, sku, pevs, emur, cavce, and scapua Clncal

Features.

Hodgkn

ympoma

usuay

maness

as

or,

w

e

noduar

sceross

subype,

verebra

Radoogcay,

paness e

ympadenopay

muoca

e

bone

esons

appear

as

punced-ou

deecs

1

o

4

cm

n

dameer

sympoms (Fg.

9.22A).

he

ces,

ypcay

marrow

conans

ncreased

numbers

o

pasma

reaed o e presence o a medasna mass. he sysemc efecs o cyo-

knes

cause

anema

o

cronc

nlammaon,

eukocyoss,

and

more

an

30%

o

e

ceuary

(see Fg.

9.22B).

Rena

so-caed nvovemen (myeoma nepross) s assocaed w proenaceous cass

B

sympoms

(ever,

weg

oss,

ng

sweas).

Sagng

gudes

erapy

and a

deermnes

e

prognoss.

Y ounger

paens

w

more

avorabe

obsruc

e

dsa

convoued

ubues

and

e

coecng

ducs.

subypes Oten, epea ces adjacen o e cass become necroc or aropc

end

o

presen

w

ow-sage

dsease

and

are

ree

o

so-caed

B

sympbecause

Bence-Jones

proens

are

oxc.

Oer

common

paoogc

oms, wereas paens w more exensve dsease are more key o ave processes B

sympoms

and

anema.

Ina

reamen

s

w

cemoerapy,

nvovng

e

kdney

ncude

measac

caccaon,

g-

somecan (AL) amyodoss, and bacera pyeoneprs.

mes w nvoved ed radoerapy or arge umor masses.

he overa ouook s exceen. he 5-year survva rae or paens w

ow-sage

dsease

s

over

90%.

Even

w

wdespread

dsease,

e

overa

Clncal

Features

he

dagnoss

5-year dsease-ree survva rae s around 50%. Immune ceckpon nb-

monocona

mmunogobun

ors

and/or

eves

ave

produced

exceen

responses

n

paens

w

reapsed,

reracory

dsease and may soon be added o ronne erapeuc regmens.

or

e

g

urne;

marrow ;

Plasma

These

Cell

B-cell

plasma

cells

globulin

or

Neoplasms

and

abou

15%

mporan

virtually

are

o

pasma

o

e

ese

ce

deas

Related

Entities

composed

always

immunoglobulin

Coecvey,

or

and

proliferations

secrete

entirely

a

or

in

monoclonal

part

of

immuno-

fragments.

neopasms

caused

neopasms,

by

reaed

ympod

mupe

dsorders

neopasms.

myeoma,

s

dscussed

mos

nex.

aure

varabe.

s

sur vve

oped

more

are

may

unoded

a

nduce

adomde-ke

new

cases

are

dagnosed

n

e

Uned

Saes

eac

myeoma

and

wc

n

peope

usuay

s

he

IgG

o

cans.

a

are

ng

mos

n

Ony

pasma

rarey

are

are

ree

esons

(20%

o

produce

IgM,

IgD,

excess

g

n

prncpay

e

g

o

ony

cans

n

κ

IgE

e

or

λ

as

Once

marrow

skeea

by

myeoma

Even

eavy

secreed,

mporan

15%

n

mmunogobun

e

protens.

ces

o

s

20%

g

myeomas

cans

cans,

resu-

As

ree

g

descrbed

n

efecs.

angens

Other

A

use

e

e

IGH

cycn

been

Myeoma

ocus

D1

gene.

descrbed.

cyokne

on

A

oten

wde

6

cromosoma

varey

Proeraon

nereukn

as

cromosome

(IL-6).

o

14

o

o

oer

myeoma

ransocaons

proo-oncogenes

drver

ces

s

a

muaons

suppored

as

ave

by

e

sem

arge

e

o

be

many

a

ces

aby

o

dsposes

are

Bsposponaes,

o

CAR-T

1).

o

w

n

e

and

progno-

rarey

“smoder-

receny

sress

a

acva-

o

e

proens,

erapes.

he

acvy

agans

ubqun

gases,

markng

and

by

Inbors

as

ceran

deve-

mmunogobun

efecve

em

a

m

proongs

ces

he

msoded

dr ugs

racures

ranspanaon

Tras

ce

aso

ereby

serum

unreaed,

severa

cause

and

e

ces

years.

Caper

acvae

ubqun,



Msoded

and

(see

serum

Hypercacema

paens

aceved,

ces

a

myeoma)

n

pasma

presenaon.

wereas

o

or

cans

o

esons,

enadomde

paoogc

ce

o

oucomes.

response

g

ndngs.

bony

or

deecon

proen,

number

me

mons,

organee

s

e

M

e

or

nb

pro-

bone

ypercacema.

bu

recognze

as

no

pasma

ye

ce

ongong.

Cell

Neoplasms

mmunogobuns,

 •

ye

w

curave.

umors

B

12

myeoma

o

reduce

Plasma

producng

suc

be

are

ese

mer

Morphology.

o

a

myeoma

degradaon.

Hemaopoec

proven

o

a

asympomac

n

on

radoogc

mproved

proens

resorpon,

o

mupe

compound

because

ag

easoma

g

sma

paoogc

and

sysem.

mmunogobun

produced.

Bence-Jones

ave

e

remanng

mmunogobun

cans.

urne

e

produced

25%);

or

nvoves

rougou

mmunogobuns,

n

unpared

oowng,

IgA

ces

compee

excreed

yc

I

mmunogobun

by

syneszed

ree,

cans

e

e

orgn.

w

requen

oowed

produce

oten

Arcan

assocaed

(60%),

cases,

o

o

proen

apoposs

year. he medan age a dagnoss s 70 years. I s more common n maes

6

ceuar

Approxmaey

w

ave

ave

Mupe myeoma s one o e mos common emaoogc magnances:

20,000

be

accumuae

proeasome,

common

an

rees

so-caed

mmunogobun

caracersc

cures

erapes

e

ree

Paens

myeoma”

cans

Myeloma

or

o

dencaon

aso

Aoug

ng

Multiple

e

ss

accoun

he

and

rena

ng

and

e

(a

are

and

assocaed

markng

ympocyes

em

or

Related

w

as

pasma

Entities

e

producon

cona

ces.

o

proeraons

hree

umors

monocona

o

n

anbody-

s

group

dscusson.

 Monocona gammopaty of undetermned sgnicance (MGUS) s seen

n

paens

wou

sgns

or

sympoms

wo

ave

monocona

mmu-

nogobuns n er bood. MGUS s very common n oder adus, and

abou 1% o cases ransorm no a sympomac neopasm, mos oten

mupe myeoma, eac year.

158

CHAPTER

Hematopoietic

9

and

Lymphoid

Systems

as

ver y

rare

wereas

socyc

oers

exremes

e

Langerans

a

are

group

ce

sarcomas,

bengn

o

are

reacve

umors

stocytoses,

gy

comprsed

wc

magnan

yperpasas.

mer

a

o

neopasms,

Beween

ese

Langerans

bre

wo

ces,

e

descrpon.

Pathogeness. A orms o Langerans ce socyoss are assocaed w

drver muaons a acvae e serne/reonne knase BRAF . BRAF s a

componen

on

n

and

a

o

e

survva.

dferen

RAS

sgnang

T umors

paway

wou

serne/reonne

BRAF

knase

a

suppors

muaons

caed

ceuar

oten

MAP2K1

ave

a

proera-

muaons

acs

down-

sream o BRAF , urer mpcang s paway n e paogeness.

Morphology.

Proerang

Langerans

ces

ave

abundan

cyopasm

and vescuar nuce, smar o a o ssue macropages (aso known

as

socyes);

eosnops

proen

ence,

are

caed

oten

e

erm

admxed.

angern

and

can

stocytoss.

Langerans

be

dened

Numerous

ces

by

express

sanng

reacve

a

or

unque

angern

and CD1a.

Clncal

severa

•

Features.

Langerans

cncopaoogc

ce

socyoss

can

be

grouped

no

enes.

 he mos common subype s unfoca unsystem dsease, n wc e

A proeraon s conned o a snge se n a snge organ sysem, mos

commony

I

may

be

racures.

 •

bone

I

 Mutfoca

maness

o

deecs,

aso

s

ndoen

unsystem

w

nvovemen

eads

bu

asympomac

and

e

dabees

dabees

neous

a

usuay

maness

ons

and

he

and

are

n

cuaneous

requeny

eads

o

oca

excson

In

sak

e

younger

a

s

an

2

mmc

ypcay

50%

o

o

bone

as

e

spona-

cemoerapy.

aggressve

years

o

dsorder

age.

seborrec

epaospenomegay,

cases,

cavara

reerred

w

an

gu.

rradaon.

and

experence

efecvey

or

paoogc

ypoaamus

o

s

paens

dsease)

or

abou

o

skn,

and

cdren

masses.

Some

esons

ung,

combnaon

reaed

cdren

e

exopamos

(Letterer-Swe

occurs

w

bony

as

enderness,

afecs

puar y

trad.

oers

by

usuay

nspdus.

dsease

suc

pan,

cured

poseror

nspdus,

regressons;

 Mutsystem

s

erosve

Hand-Scüer-Crstan

•

ssues

cause

dsease

mupe

o

sot

or

I

skn

oten

erup-

ympadenopay,

B pumonary

Fig.

The

(B)

9.22

Multiple

sharply

Bone

plasma

punched-out

marrow

cells,

nucleoli,

myeloma.

and

bone

aspirate.

including

(A)

defects

Normal

atypical

cytoplasmic

Radiograph

marrow

forms

droplets

are

of

the

most

obvious

cells

with

skull,

are

largely

multiple

containing

in

lateral

the

nraon

by

Beeding

es,

ces.

n

a

marked

 •

pasma

ce

componen

ypervscosy

by

nnus,

secrees

syndrome

vsua

monocona

(W adenström

mparmen,

and

IgM

a

oten

macrogobunema)

neuroogc

dysuncon.

or

Tabe

vesse

evan

disorders

9.8).

wa,

o

may

coaguaion

As

descrbed

paees,

emosass

and

macyc ympoma s responsve o agens used or oer ndoen B-ce

peced

coaguopaes

ympomas

 •

nbors

o

B-ce

recepor

sg-

paees.

he

paways.

o

VII,

ave

over

he

o

because

Histiocytic

erm

deposed

mupe

popuaon

ease

are

e

ces

bu

a

syness

o

(see

Caper

oers

ave

nevereess

a

paogenc

4).

ony

causes

Some

a

dsorders

s

o

an

 •

mnor

sgncan

 Parta

dendrc

ces

desgnaon

or

or

macropages.

a

varey

Some,

o

suc

and

by

abnormaiies

or

Caper

and

in

3,

acors.

of

vesses,

combinaion

norma

e

nvoves

ess

a

caracerze

ess

or

pae-

(summarzed

cong

Laboraor y

unconay

mporan

proonged

PT

prorombn;

tme

coaguaon

decences

or

A

X;

trombopastn

rombn;

ds-

are

e

re-

coaguaon

nvesgaon

o

sus-

o

(PTT).

hs

paways.

acors

V ,

can

or

resu

rom

decences

brnogen.

es

assesses

Proongaon

VIII,

IX,

X,

o

XI,

e

nrnsc

PT T

and

can

XII;

be

pro-

brnogen.

 •

 Pateet count. he norma reerence range s 150,000 o 450,000/μL.

 •

 T ests of pateet functon. No snge es provdes an adequae assessmen

o

“umbrea”

V ,

common

caused

cona

mmunogobun.

acors

and

paens

Neoplasms

stocytoss

proerave

amyod

myeoma,

pasma

o

as

Exensve

predspose

 Protrombn tme (PT). hs es assesses e exrnsc and common

coaguaon

a

esons.

and

ncude:

 Prmary or mmunocyte-assocated amyodoss resus rom a mono-

cona proeraon o pasma ces producng mmunogobun g

n

mos

nang). e overa survva me ater dagnoss averages 4 o 5 years.

cans

pancyopena

from

aone

cong

quany

and

CD20,

sem

facors,

acors

agans

o

DISORDERS

Evenuay , nvovemen o e marrow eads o cyopenas. Lympopas-

(anbodes

ead

bone

immunoglobulin.

composed o a mxure o sma B ces and varabe numbers o pasma

he

may

oseoyc

W nensve cemoerapy, 50% o paens survve 5 years.

 Lympopasmacytc ympoma s a B-ce neopasm o oder adus a s

causes

desrucve

prominent

BLEEDING

 •

and

paen o recurren necons. he dsease s rapdy aa  unreaed.

calvaria.

replaced

nuclei,

marrow

view.

esons,

paee

uncon.

Aggregaon

ess

a

measure

e

response

o

paees o ceran agonss and quaave and quanave ess o von

Webrand acor (descrbed aer) are bo used n cnca pracce.

CHAPTER

Table

9.8

Bleeding

9

Hematopoietic

and

Lymphoid

Systems

159

Disorders

Mechanism

Causes

Vascular

Vitamin

fragility

Clinical

C

Systemic

Chronic

deficiency

(scurvy)

amyloidosis

connective

skin

and

mucous

mem-

branes

glucocorticoid

Inherited

Features

Ecchymoses,

use

tissue

disorders

Vasculitis

Platelet

dysfunction

Thrombocytopenia

Petechial

Immune-mediated

Consumptive

Marrow

(DIC,

HUS,

TTP)

underproduction

Prolonged

(tumors,

other

infiltrative

disorders,

aplastic

minor

anemia)

Qualitative

Drugs

factor

other

platelet

defects

(von

Willebrand

disease,

Glanzmann

A

Hemophilia

B

cal

Delayed

inhibitors

specc

ence

o

cong

acors

crcuang

and

ess

brn

msceaneous,

and

sites

bleeding

subject

to

mechani-

joints)

after

surgery

(e.g.,

K

deficiency,

liver

disease)

Bleeding

drugs)

in

deep

soft

tissues

(e.g.,

psoas

muscle)

used

o

measure

producs

or

o

e

assess

eves

e

o

pres-

Table

9.9

Causes

Decreased

of

Production

Thrombocytopenia

of

Platelets

ancoaguans.

o

vesses

a

uncommon

coaguaon

in

(e.g.,

(DIC)

are

sp

(vitamin

(antibodies,

Generalized Abnormaes

trauma

circumcision)

Consumptive

specazed

from

thrombasthenia,

Hemorrhages

Hemophilia

Underproduction

more

bleeding

syndrome)

Acquired

Addona

immediate

trauma

inhibitors)

Inherited

Factor

skin

Menorrhagia

Bernard-Soulier

deficiencies

and

neoplasms

Inherited

Coagulation

mucosae

defects

(aspirin,

Myeloid

bleeding,

Epistaxis

acors

are

ead

o

dsorders,

reavey

beedng

wereas

ncude

dsorders

a

range

o

Bone

Marrow

Dysfunction

o Aplastic

anemia:

congenital

Marrow

infiltration:

and

acquired

paees leukemia,

disseminated

common. cancer

Selective

Impairment

of

Platelet

Production

Thrombocytopenia

Drug-induced:

alcohol,

thiazides,

cytotoxic

drugs

hrombocyopena s dened as a paee coun o ess an 150,000/μL.

Infections:

Excessve

are

posraumac

reduced

unkey

rom

o

un

sma,

eccymoses

20,000

couns

e

o

beow

bood

skn,

s

seen

50,000/μL,

a

superca

n

beedng

e

ony

and

5000/μL.

vesses

and

mucous

wen

e

paee

sponaneous

Beedng

produces

membranes

peecae

o

s

occurs

or

arge

e

gasrones-

eared

compcaon

Ineffective

and

urnar y

racs,

and

oer

ses.

he

mos

infection

Megakaryocytopoiesis

Megaloblastic

Decreased

anemia

Platelet

Immunologic

na

HIV

couns

beedng

ypcay

measles,

Survival

Destruction

Autoimmune:

o

rombocyopena

s

emorrage

no

e

cenra

ner vous

sysem, Primary:

wc

s

uncommon

bu

may

be

immune

Secondary:

Maj or

c aus es

o

 romb o c yop en  a

are

se d

n

Tabe

9.9.

B-cell

mp or  an

pro duc  on

depress es

bu

n

or

and

o

s e

d o es

con ras,

 a

ncre as e d

abnor ma  y

b e c aus e

no

n

a e c s

s

o

 e

be

p aee s .

cnc a  y

ce 

o

and

by

 a

o

sg n  c an

due

o

may

mer 

a

be

a

re duc e d

Sp enomega y

p aee s

  romb o-

probem

g ranu  o c ye

p aee s

ds orders

c aus e d

s e qu es ra on

genera  y

re d

d es r uc  on

s e vera 

o

c aus e

pro duc  on

a s o

may

d es r uc  on

couns

R e duce d

emaop oess

 ae d

ncre as e d

p aee

c yop en a.

In

 romb o c yop en  a

w  

pro duc   on .

s e en

br  e

as

tumors

an

s o -

ds c uss on .

infections

Isoimmune:

autoimmune

(infectious

Thrombocytopenic

Purpura

by

anibodies

opsonizaion

of

e

a

bind

paees

paee

and

eir

surface

remova

proeins,

from

e

lymphocytic

eading

o

(systemic

mononucleosis,

quinidine,

and

lupus

HIV)

neonatal

heparin,

sulfa

compounds

Nonimmunologic

Disseminated

Thrombotic

Destruction

intravascular

Hemolytic-uremic

Dengue

Immune rombocyopenic purpura (ITP) is an auoimmune disease

caused

purpura

chronic

disorders

posttransfusion

Drug-associated:

coagulation

syndrome

thrombocytopenic

Microangiopathic

Immune

(e.g.,

C nleukemia);

c a  y

thrombocytopenic

aa.

hemolytic

purpura

anemia

fever

Sequestration

Hypersplenism

circuaion Dilutional

by macropages. Multiple

he

dsease

as

wo

cnca

subypes.

Acue

ITP

s

a

HIV,

orm

seen

reavey

mosy

n

common

cdren

dsorder

ater

a

vra

mos

necons.

oten

afecs

transfusions

(e.g.,

for

massive

se-med

Cronc

women

ITP

s

a

beween

human

immunodeficiency

virus.

blood

loss)

erythematosus);

160

e

CHAPTER

ages

paee

o

20

and

anbody

IgG-coaed

soaed

40

years.

he

speen

producon

and

e

paees,

dsorder

Hematopoietic

9

so

a

spenecomy

mus

be

s

an

major

s

mporan

se

o

beneca.

dsngused

and

rom

Lymphoid

se

o

desrucon

Cronc

an-

o

ITP

secondar y

e

s

ITP

an

due

o oer condons (e.g., sysemc upus er yemaosus, drug exposure,

HIV

necon,

he

onse

peecae,

mnor

rare,

o

and

o

easy

Serous

occur.

he

rs

and

reaed

rapdy

responses,

ce

w

erapes

drugs

are

Heparin-Induced

hs

speca

menon

ype

because

bocyopena

reamen

and

ress

e

or

on

an-CD20

a

cnca

o

erapy.

deciencies

Acqured

 •

oers,

anbodes),

e

e

Mos

paens

produce

are

o

drug-nduced

s

cnca

n

eparn.

3%

are

I

s

o

caused

K

syness

paens

by

IgG

o

ater

1

o

anbodes

2

weeks

a

o

bnd

vamn

he

ver

many

epac

o

decences

med

Heredar y

dened.

O

o

a

o

snge

rea.

Bo

marked

o

mbs)

paee

venous

and

arera

rombocyopena,

and

dea.

acvaon

condon

romboses

and

Cessaon

and

e

may

o

occur,

cause

eparn

a

eparn

even

severe

n

e

morbdy

erapy

breaks

s

used

o

seng

o

e

o

syness

and

a

severe

o

or

pro-

coagua-

acors.

severa

coaguaon

coaguaon

acors

dseases

are

acors

rom

e

common

and

crcu-

causes

o

ese,

acors.

ony

o

many

von

coaguaon

Webrand

acors

dsease,

aso

ave

emopa

been

A,

and

emopa B are suceny common o warran urer consderaon.

o

as-

(e.g.,

by :

acor.

decences

disease

romboss,

eparn-dependen

K-dependen

mupe

tive

exacerbang

a

X

caused

seng

maabsorpon,

nadequae

and

e

 Autoantbodes agans coaguaon acors cause acqured decen-

ereby

n

nesna

IX,

oten

n

acquired

 •

Disease

membranes

mos

occurs

or

clotting.

 Dssemnated ntravascuar coaguaton (DIC; dscussed aer) oten

Willebrand

paee

are

for

dsorders.

Willebrand

on

n

VII,

parencyma

coaguaon

Von

4

resus

acvaed

Von

acor

erapy,

syneszes

on. Anbody bndng acvaes paees and nduces er aggregaon,

paee

and

usuay

acors

congenital

required

common

hs

and

either

are

 •

bre

rom-

us,

compex

eads

severe

more

cong

o

dsease.

removes

ces

Moderae

from

that

anboc

nuron,

aon;

an–B-

a

are

and

aso

susaned

mers

result

factors

deicency.

rombn

 Lver

uncon

rombopoen-ke

rombocyopena

5%

decences

mpared

e

 •

rombocyopena.

mporance.

o

protein

on deec. Wararn s an ancoaguan drug a acs by nbng

presence

spenecomy,

and

ater

Thrombocytopenia

o

Disorders

disorders

of

 Vtamn

ncude

emorrages

macropage

somemes

For

ndngs

emorrages

eaures,

nb

and

conrong

and

subaracnod

e

wc

coun

Common

beedng,

response

paee

deveops

w

gum

dsconnuance.

efecve

Coagulation

broad-specrum

nsdous.

nracerebra

e

ater

(e.g.,

oten

s

gucocorcods,

correc

even

ITP

epsaxs,

dagnoss

rombocyopena,

Coagulation

magnances).

cronc

brusng,

rauma.

bu

B-ce

Systems

oss

cyce

o

or

quantitative

Von

rom

or

Webrand

mucous

surger y,

is

dsease

membranes,

and

a

defects

bleeding

in

s

von

caracerzed

excessve

menorraga

disorder

Willebrand

I

s

by

beedng

more

caused

by

qualita-

factor.

sponaneous

ater

prevaen

dena

n

beedng

procedures

persons

o

Euro-

pean descen and s beeved o afec approxmaey 1% o peope n e

consumpon.

Uned Saes, makng  e mos common nered beedng dsorder.

Thrombotic

he

erm

Microangiopathies

trombotc

Von

mcroangopates

encompasses

a

specrum

o

cn-

ca syndromes a ncude romboc rombocyopenc purpura (TTP)

up

and emoyc-uremc syndrome (HUS). her causes are dferen, bu a

um,

are

 •

caracerzed

e-rc

and

romb

anema.

In

by

abnorma

n

e

conras

paee

acvaon

mcrocrcuaon,

o

DIC,

acvaon

and

eadng

o

deposon

o

o

pae-

coaguaon

acors

s

no

o

20

MDa

were

 vWF

 •

 vWF

ay norma or ony sgy deranged. Because bo dsorders promneny

e

nvove e kdney, ey are dscussed n Caper 11

o

o

s

many

syneszed

e

(Fg.

prmar y

aso

as

a

s

(see

Fg.

coacor

and

ound

wo

X

enancng

acor

IX,

dever y

o

Collagen

Clotting aggregated

cascade

VIII

Platelet

Fibrinogen

GpIIb/IIIa

GpIb Platelet

Subendothelial

Fig.

9.23

circulate

takes

Structure

as

part

adhesion

a

in

of

complex.

the

vWF

and

vWF

coagulation

platelets

to

Endothelial

function

also

of

is

factor

present

cascade

by

subendothelial

VIII–von

in

the

collagen,

Willebrand

factor

subendothelial

activating

endoea

factor

primarily

X

by

means

through

defect

(vWF)

matrix

the

of

of

complex.

normal

factor

IX

glycoprotein

Factor

blood

(not

Ib

VIII

vessels.

shown).

(GpIb)

subendoe-

o

and

ser ve

as

paees

a

o-

9.23).

or

platelets

Factor

e

vWF

emosass.

Activated,

with

n

uncons:

coagen

Xa

vWF

n

major

aowng

subendoea

damage

VIII,

crcuaon

I

vWF

gycoprotens,

beween

factor

9.23).

VIII

vWF

Circulating

(vWF)

coagen.

pateet

endoea

bnds

n

to

“gue”

Endothelium

Factor

acor

weg

bnds

bnds

owng

a

n



moecuar

rombocyopena

promnen eaure o HUS or TTP; consequeny, e PT and PTT are usu-

Webrand

ces and megakar yocyes and exss n e pasma as arge mumers o

and

vWF

Factor

vWF

platelet

VIII

causes

receptor.

ncreasng

acor

s

VIII

o

a-

ses

CHAPTER

Von

Webrand

paee

uncon

cnca

brand

ndngs,

dsease

he

an

auosoma

measurabe

ave

and

n

us

rare

severe

mos

acor

dsorder

cncay

assocaed

ony

paens

common

domnan

bu

s

coaguaon;

excep

wo

cassc

dsease

and

e

w

VIII

varan

w

nsgncan

w

deecs

paee

deec

omozygous

n

9

bo

produces

von

We-

arge

or

he

causng

sma

quaave

vWF

von

reduced

decrease

dagnoss

deecs

mumers,

s

reaced

by

n

vWF

prevenng

measurng

as

a

“oregn”

erapy

greay

angen.

usng

a

Webrand

crcuang

n

acor

dsease

vWF

VIII

s

and

eves

a

a

a

norma

e

ead

o

prmary

quany,

abnormay

Hemophilia

Severe

IX

sze,

and

uncon

son

o

o

cump

Disseminated

(aggunaon),

an

many

lation

A

caon

ing,

dsorder

cases

are

amy

a

caused

sor y.

decences

cences

o

may

disorder

afeced

by

new

Severe

acor

ony

caused

ndvduas

muaons;

emopa

VIII

manes

ater

n

A

(acvy

by

are

s

deciency

maes.

e

remander,


1000

(chronic

g)

myeloid

leukemia,

primary

myelofibrosis)

Lymphoid

fetus

abortion

Amniotic

Splenomegaly

(weight

Complications Myeloproliferative

Abruptio

of

Coagulation

leukemias

(chronic

lymphocytic

leukemia

and

hairy

cell

leukemia)

embolism

Lymphoma

Toxemia

Infectious

Storage

diseases

diseases

(e.g.,

(e.g.,

malaria)

Gaucher

disease)

Infections

Moderate Sepsis

(gram-negative

and

Mountain

Chronic

spotted

(weight

500

to

1000

g)

gram-positive)

Meningococcemia

Rocky

splenomegaly

fever

vein

congestive

splenomegaly

(portal

hypertension

or

splenic

obstruction)

Histoplasmosis

Acute

Aspergillosis

Hemolytic

leukemias

anemias

nohemolytic

(hereditary

spherocytosis,

thalassemia,

immu-

anemia)

Neoplasms

Amyloidosis Adenocarcinomas

of

pancreas,

prostate,

lung,

and

stomach Niemann-Pick

Acute

promyelocytic

Chronic

Massive

Tissue

disease

leukemia

Injury

infections

(tuberculosis)

Sarcoidosis

Trauma

Mild

splenomegaly

(weight


80%

10%

(coinfection);

100%

Detection

of

serum

Detection

antibodies

of

antibody

for

HBsAg

to

or

ELISA

HBcAg;

HBV

for

antibody

detection;

DNA

HCV

PCR

Detection

for

IgG

Double-stranded

ssRNA,

2005,

quence

o

o

HBV

onger

HBeAg

HBcAg,

rsk

o

hepatitis

B

infectious

cronc

n

muaons

and

and

ncreased

core

antigen;

diseases

encodes

necon.

cronc

acqured

regeneraon

genome

HBsAg,

hepatitis

B

of

the

liver.

In

RNA

core

proten

poypepde

(epas

surface

RNA

antigen;

Iacobuzio-Donahue

o

durng

sur vvng

severa

he

epas,

e

rsk

or

key

as

CA,

epao-

he

conse-

an

proonged

perod

deeced

epaocyes.

proens

a

ave

o

paogenc

Be

(HBcAg,

w

a

epas

precore

and

B

core

core

angen)

regon,

serum

usng

sympoms

necons,

and

desgnaed

in

IgM

and

serum,

in

D

liver

hosts

Detection

HDV

IgM

or

of

and

only

serum

IgG

antibodies;

biopsy

antigen;

HEV

ELISA,

PCR

angen)

enzyme-linked

immunosorbent

Gastrointestinal

and

liver

pathology,

e

HBsAg

w

HBV

requred

paogeness

or

o

vrus

repcaon

HBV-assocaed

and

ver

as

been

cancer

Subclinical

oowed

peaks

Sma

ess.

durng

ypcay

HBsAg

persss

o

s

e,

monorng

HBV

DNA

beore

dsease.

undeecabe

deeced

or

by

o

appears

sympomac

decnes

anbody

and

cncay

amouns

soon

ater

provdng

In

eves

12

HBsAg

proecon

(ndcave

an-HBc

HBsAg

and

s

o

persss

DNA

IgM

epaocye

repaced

n

and

by

e

IgG

an-HBc

IgG

njur y).

serum

or

an-HBc

s

Over

an-HBc

more

an

anbody.

dagnosc

o

e

nex

anbody.

acue

6

In

ew

mons,

hus,

mons,

e

necon,

Acute

presence

wereas

disease

hepatitis

20

40%

Chronicity

Cirrhosis

scarring

per

without

year

years

liver

failure

30% (~20%

of

chronic

~1.5%

126 mg/dL



cronc

yperpospaema.

a

Adipose

cema

cases

a

 •

or

resung

mon

 •

wc

paraneopasc

In

be

or

dsease,

o

dsease.

umors,

a

esmaed

PTH

mu a ons

seng

s

ncude

c arc noma.

ass o c  ae d



es

e

ns anc es ,

may

dabees.

organs.

com-

exc ess ve

p ara y rod

parayrod

ncreases

ng

more

cum eves, and e cnca probems are reaed many o e rena

a

an

Saes;

enoug

Insulin

occurs

and

g

dsorder

c aus e d

re ar rangemen s

bood

Many

ypercacema,

muc

Uned

dabec, and a one rd o ese peope are unaware o er dsease.

reeasng

bood

MEN1

excreon

overacvy

Compensaor y

o

sen

ess.

common y

gene

gene

depresses

pospae

cncay

yp er p as a

o

aure.

common y,

are

cacum

decen

common

ne ary

L ess

genes

suppress or

Hypercacema

as

(by

cacum;

eevae

prmar y

rena

ad enoma

16. 6).

 wo

a

or

as

o

producon.

bood

yper paratyrodsm

decreased

urn

n

umors:

umor

 S econdary

men

p ara y ro d

Abnor ma  es

 y rod

n

a

o

roune

p ara y ro d

( Suppemen a 

 g  andu  ar

 an

s

cause

durng

rom

o

sm-

wc

reeasng

cacum

ser ve

cacum

cacum

(PTH),

breakdown

PTH

cronc

bood

converson

excessve

sem

o

requen

women

c aus e d

o

may

e

reguae

reabsorpon

ncreases

acves

w

o

o

ereby

ncreases

urer

secondar y

deeced

n

ese

assocaed

be

ubuar

wc

y per paraty rodsm

e

usuay

orm;

s

ormone

excreon,

ncreases

A

Hyper paratyrodsm

or

rena

kdneys,

rac;

are

concenraons

ncreases

e

gands

parayrod

pospae

cacum.

parayrods

gands

parayrod

pospae-bound

acve

cum

o

producon

ncreases

More

GLANDS

uptake

caccaon.

Lipogenesis

Hypoparatyrodsm

remova

o

s

parayrod

rare

and

gands

s

mos

durng

oten

yrod

caused

or

by

oer

nadveren

neck

Lipolysis

surger y.

he mos requen cnca manesaons are ncreased neuromuscuar

rraby

(eany)

ENDOCRINE

Mos

o

dgesve

e

a

ac

pancreas

o

produce

e

e

poypepde,

nsun

cardac

arrymas.

PANCREAS:

enzymes

componen

and

s

no

composed

e

pancreas

eac

s

e

sets

nsun,

secreed

or

o

duodenum

ormones

producon

DIABETES

uncon

by

a

exocrne

(see

of

13).

Langerans,

gucagon,

dsnc

causes

gands,

Caper

wc

he

wc

somaosan,

popuaon

dabees,

wc

o

s

secree

endocrne

conan

and

ces.

one

o

ces

Insulin

pancre-

Decen

e

grea

medca scourges o e modern word and e ocus o e dscusson a

oows.

Overview

of

Diabetes Liver Striated

Diabetes

mia,

is

a

resulting

metabolic

from

disorder

defective

characterized

production

or

by

inadequate

action

of

insulin.

e

because

Glucose

uptake

Glycogen

ncdence

one

o

o

e

s

wo

dsease

major

as

rsen

orms

o

aarmngy

dabees

n

recen

(ype

2

years,

Protein

aer)

s

assocaed

w

obesy,

an

ncreasng

Gluconeogenesis

synthesis

Glycogen

synthesis

synthesis

Lipogenesis

dabees, Fig.

dscussed

muscle

hyperglyce

probem

16.7

muscle,

Insulin

adipose

physiology.

tissue,

and

Metabolic

liver.

actions

of

insulin

in

striated

CHAPTER

16

Endocrine

System

B

A

Supplemental

is

delineated

variation

ogy,

in

eFig.

from

nuclear

University

of

16.6

the

Parathyroid

residual

size

and

Chicago,

adenoma.

normocellular

occasional

Chicago.)

follicle

(A)

gland

In

on

this

the

formation.

low-power

upper

view,

right.

(Courtesy

Dr.

(B)

a

solitary

hypercellular

High-power

Nicole

Cipriani,

detail

adenoma

shows

Department

minimal

of

Pathol-

272.e1

CHAPTER

Ora

uaes

by

nake

nsun

ceran

acs

a,

va

bood

e

ood

ormones

e

us

o

rases

producon

nsun

gucose.

I

degradaon

e

aso

o

eve

se

(ncretns)

recepor

provdng

e

rom

o

smuaes

and

gucose

ces,

reeased

ncrease

subsrae

pds

o



or

e

an

n

rom

gucose

upake

so

o

s

bood

a

s

nesna

upake

generang

proens,

e

efec

amno

ne

ces.

no

energy

nsun

wc

Insun

eves

ay

nbs

anaboc.

e

ver,

urer

nsun

are

ces

pancreac

n

reducng

couneraced

ses.

gycogen

breakdown

n

gucose.

bood

eves

acae

syness,

n

bood

gucose

gucagon,

he

major

Durng

asng

gycogen

aemp

o

a

eves.

n

saes,

e

o

a

ow

we

e

s

and

o

o

o

by

α

smuae

an

g

ncrease

gucagon

decreasng

bood

efecs

produced

eadng

nsun

norma

o

s

gucagon

ver,

breakdown

manan

Many

ormone

uncon

(gycogenoyss)

epac

an

by

gycogen

gucose.

of

 •

are

s

a

nlammasome

(suc

reduced

sae

n

(see

as

secrees

promoe

o

ces

e

n

2),

e

and

we

and

sensng

smuang

nereukn-1),

some

sensvy

ressance;

acvae

Caper

c yoknes,

nsun

obesy

epn

273

wc

o

o

epn

(3)

ree

paway

e

produc-

nduce

nsun

 β ce dysfuncton.  ce uncon may ncrease eary n e deveop-

men o T2D, n response o ncreased bood gucose, bu umaey,

deecve

men

ay

e

o



ce

over

acds

uncon

dabees.

dened

(wc

raer

an

o

an

or

essena

genec

be

gucose

deecs;

an

conrbuor

dysuncon

or

efec

o

may

se

nsun-reeasng

may

s

s

s

(pooxcy)

producon

poory

Diabetes

eves

ere

accumuae

c yoknes

ssue

epn)

System

ressance.

od

Pathogenesis

e

o

a

adpose

and

ncreased,

acds

on

(2)

adponecn

are

caed

In

addon, nsun reduces e generaon o gucose rom gycogen sores

n

sgnang;

(adponecn

ssues;

and

reducng

and

are

sm-

musce

and

acds

efecs

and

augmened

Endocrine

16

be

o

due

e

o

(gucooxcy);

ormones

rom

repacemen

o

ong-sandng

ses

ree

deecs

e

se

deveop-

excess

n

nesne;

w

amy-

dysuncon

cause).

The two major forms of diabetes, type 1 (accounting for 5% to 10% of

cases) and type 2 (90% of cases), are caused by different mechanisms.

Type

1

Type

1

attack

As

and

Diabetes

diabetes

and

n

e

uaon

mos

are

sysem

s

an

ces

no

a

e

varans

an

HLA

A

a

e

reason

genes

ncreased

II

or

in

genes.

which

of

wy

or

se

n

e

wy

envronmena

cells

Abou

5%



ces

dsease,

ore-

reguaon

s

afecs

acors,

s

reg-

o

and

of

Diabetes

cases

are

arbuabe

expressvy

a

o

oow

snge

gene

deecs

Mendean

w

g

nerance.

he

pen-

mos

common o ese s maturty-onset dabetes of te young (MODY), wc

may

as

mmune

Deecve

bu

T

insulin.

oerance

own

nvoved

rsk

ypoess,

roe

disease

deciency

ndvdua’s

n

cass

popuar

known.

in

dseases,

w

beng

s

autoimmune

resulting

aacks

dferen

ese

T

is

cells,

assocaed

among

ses

β

auommune

Many

reguaor y

e

(T1D)

mmune

unknown.

Forms

erance

destroy

oer

Other

resu

rom

muaons

n

one

o

severa

genes

nvoved

n



ce

uncon. Congenta eary-onset dabetes, wc s usuay deeced n e

neonaa perod, s caused by muaons n e nsun or nsun recepor

gene

or

genes

a

afec

recepor

expresson

or

sgnang.

Dabees

may

aso appear durng pregnancy (gestatona dabetes), especay n women

by

ony

ncudng

Obesity

necons

bu

no

cear

and

mcrobome

esabsed.

a

paens.

T

and

Muc

ympoc yes,

desrucve

are

e

useu

B

o

Regardess

ces

e

wc

a



ce

k

markers

s

or

o

reac

e

ces,

s

and

e

dsease,

se

by

CD4+

specc

bu

er

T

s

are

CD8+

ces,

or

suspeced

mecansm,

angens

caused

by

Anbodes

mcrobes),

underyng

w

damage

se

nlammaon.

desrucon

(commensa

s

ce

conrbuon

Vasculature

n

c yooxc

wc

se



presen

T

Adipocytes

nduce

angens

o



ce

unceran.

FFAs

Adipokines

Type

2

Diabetes

Type

2

diabetes

resistance

in

(T2D)

is

peripheral

a

complex

tissues

disease

(failure

to

resulting

respond

to

from

insulin

insulin)

and

β Insulin

cell

for

dysfunction

the

plasma

T2D

glucose

remans

env ronmen a 

(Fg .

manifested

a

as

insulin

secretion

that

is

resistance

inadequate

level.

p o ory

ac ors ,

und erso o d

and

d s e as e

n   amma on

a

n

w  c

s e em

o

gene c s ,

p ay

a

Pancreatic

ro e

β-cell

β-cell

compensation

failure

islet

16.8).

β

 •

Inflammation

 Genetcs.

80%

o

T1D).

Genec

90%

acors

are

concordance

Despe

many

ceary

n

sudes

nvoved,

denca

and

e

as

wns

evdenced

(even

more

dencaon

o

by

cells

e

an

n

dozens

o

Insulin

genec

poymorpsms

a

are

sascay

assocaed

w

T2D, secretion

an

undersandng

o

ow

genec

varans

cause

nsun

by

or

 •



ce

dysuncon

remans

Increased

Normal

Decreased

ressance β

cells

eusve.

 Obesty. Obesy s assocaed w e deveopmen o nsun ress-

Blood

Normal

to

impaired

Type

2

Normal

ance,

a

even

and

s

n

e

absence

ocaon

(cenra

o

ypergycema.

more

an

e

perpera)

amoun

o

nluence

body

e

glucose

deveopng

T2D.

s

assocaon

as

ed

o

e

erm

or

e

combnaon

o

vscera

obesy,

16.8

gucose

with

Pathogenesis

obesity

cardovascuar

dsease,

and

abnorma

pd

proes.

meaboc

promoe

uar

nsun

syndrome

ressance

rgycerdes

and

are

by

a

g

mupe

producs

o

rsk

or

T2D.

mecansms:

ay

acd

of

type

induced

by

2

diabetes.

adipokines,

Insulin

free

resistance

fatty

acids,

and

associ-

chronic

in

adipose

tissue.

Pancreatic



cells

compensate

for

insulin

Indvduresistance

as w

is

noerinflammation

ance,

diabetes

metaboc ated

syndrome

tolerance

rsk Fig.

o

glucose

Obesy

(1)

may

nrace-

meabosm

nb

by

hypersecretion

compensation

free

fatty

is

acids.

resistance

and

followed

by

(Reproduced

pancreatic

of

insulin.

-cell

with

-cell

However,

failure,

and

permission

failure.

J

Clin

at

some

diabetes

from

Invest

point,

ensues.

Kasuga

M:

116:1756,

-cell

FFA,

Insulin

2006.)

274

CHAPTER

Endocrine

16

System

wo are aready predabec; pregnancy-assocaed ormones avor nsu-

e

n

ve oxygen speces, ncreased procoaguan acvy o endoeum,

ressance.

In

rare

cases,

dabees

may

resu

rom

desrucon

pancreas by cronc pancreas or emocromaoss,

exocrne

pancreas

a

secondary

afecs

e

o

e

or a umor n e

producon

proeraon

ses.

marx.

bu

Clinicopathologic

The

morbidity

complications

he

cassc

(requen

Features

associated

of

with

of

hyperglycemia

cnca

urnaon,

Diabetes

diabetes

and

presenaon

due

o

e

the

o

osmoc

is

og y,

mainly

resulting

T1D

efec

n

due

to

chronic

vascular

s

e

o

gucose

rad

o

n

 •

injury.

toxc

bood

depees

o

o

conras,

bdy

o

bo

s

mos

dscovered

orms

resus

ndvduas

on

roune

rom

e

w

T2D

are

aboraor y

cronc

asympomac;

esng.

compcaons

he

o

mor-

areres;

sma

ckenng,

he

ve

e

 •

mos

o

bood

wereas

severey

dsrupon

ssue

njur y

vesses

arger

afeced

o

e

nvoves

deveop

areres

organs

bood

a

deveop

are

a

(Fg.

ree

basemen

acceeraed

ose

suppy

eas

dfuse

are

16.9).

paogenc

he

by

 •

membrane

gucose-derved

proens,

a

o

a

process

recepor

caed

nlammaor y

vascuar

a

ces

smoo

s

moecues

acceeraed

RAGE

(recepor

(macropages

musce

ces.

suc

by

o

or

and

Bndng

as

gyoxa

AGE)

T

a

ces),

or

AGEs

s

bnd

expressed

endoeum,

o

RAGE

on

ceuar

AGEs

on

and

eads

o

te

conrbuors

s

no

because

requre

meabozed

coacor

an

a

s

vascular

In

o

e

dened

cs

n

paways,

as

an

undened

marx

we

afecng

ncreased

os

and

vascuar

roe,

pao-

ncrease

ssues

or

(ner ve,

gucose

n

or

a

and

ens,

upake,

reacon

e

a

regeneraon

(see

dscuss

TGF-

some

due

o

o

Caper

Cataracts

infarct

Atherosclerosis

Islet

cell

loss

Insulitis

Amyloid

(type

(type

Nephrosclerosis

Glomerulosclerosis

Ar teriosclerosis

Peripheral

Pyelonephritis

vascular

atherosclerosis

Gangrene

neuropathy

Infections

neuropathy

complications

of

diabetes.

acor

o

e

wc

smuaes

producon

1).

o

act-

severa

grow

(wc

ac-

smuaes

neovascuarzaon

(wc

e

In

smuaes

1)

2)

mos

serous

addon

necons.

reduced

abnormay.

Myocardial

o

organs.

suscepby

deenses

dacygycero,

enzyme

grow

Glaucoma

Chronic

exraceuar

produc-

proens).

dferen

mmunoogca

to

ncreased

Retinopathy

16.9

gucose

sorbo

hs

infarcts

Fig.

of

some

anoxdan

conrbung

renopay)

secon

reduced

o

C.

endoea

Hyper tension

Autonomic

o

reac-

pysoogc

e

nsun

o

converted

knase

proeraon,

exraceuar

nex

aso

eadng

vascuar

dabec

esons

sow

relecs

s

proten

Hemorrhage

Peripheral

a

o

requred

mporan

Microangiopathy

Cerebral

ser ve

concentratons

hs

do

s

a

gucose

enzyme

suc

seen

and

syness

acves

o

sress.

endoea

paways.

ypergycema.

vesses)

guaone,

oxdave

ors

 Advanced gycaton end-products (AGEs) are ormed by neracons

beween

ntraceuar

gucose

 Intraceuar

sgnang

sens-

deveopmen

major

and

generaon

aer.

NADPH,

reduced

vates

aerosceross.

parcuary

are

ces,

ese

acors,

hese ces ereore ave ncreased suscepby o damage caused

poory

conroed bood sugar, parcuary damage o sma and medum-szed



grow

and, n e seng o ypergycema, nraceuar gucose eves rse.

Inraceuar

By

ey

and

musce

known

consequences.

and poypaga (excessve eang, due o ssue “sar vaon” n e mds

peny).

cyoknes

smoo

tssues,

poydpsa (requen drnkng, due o deydraon rom urnar y osses),

ypergycema

o

no

descrbed

kdney,

urne),

s

dabees

some

ave

poyura

e

 In

I

o

I

ssue

o

s

and

ese,

no

bood

we-

dabe-

cear



suppy

s

or

an

CHAPTER

Vascular

hallmarks

of

diabetic

vascular

disease

are

accelerated

and

hyalinization

of

small

and

medium-sized

o

gomeruar

ar Pathogeness.

he

ypergycema-assocaed

abnormaes

o

proeraon

o

vascuar

endoea

and

and

eson

ces,

smoo

deposon

arera

o

exraceuar

basemen

membrane,

marx

a

proens

propensy

n

or

severe

e

sma

vesse

e

and

cronc

umens

o

nlammaon.

vesses

and

Coecvey,

acceerae

ese

processes

agng-assocaed

o

vascuar

compromse

and

aso

he

consequences

o

e

vascuar

esons

are

 Myocarda nfarcton s e mos common cause o dea n dabecs.

 Iscemc

necross

dabecs

of

an

te

egs

(gangrene)

s

100

mes

more

n

e

dsease

o

genera

e

(mcroangopaty)

capar y

basemen

caracerzed

membranes

by

eyes,

and

complications

leading

other

o

an

n

ckenng

necons

11)

nondabecs;

o

and

an

he

e

ave

do

gomeruar

u-bown

vascuar

a

vascu-

prevaen



s

and

caracerzed

wa

o

e

areroes.

by

Paens

a

ger

ncdence

normogycemc

o

pyeone-

ndvduas.

dsease

rena

neproc

presens

dsease

rom

syndrome.

w

proenura

a

Abou

combnaon

o

40%

o

a

paens

esons

causng

wdespread

scemc

gomeruar

scar-

damage.

Retinopathy

ner ves,

to

descrbed

diabetes

scarring

include

glomerular

(glomerulosclerosis),

disease

a

lesions

affecting

retinal

blood

vessels,

and

vision.

renopay

e

ages

o

25

s

e

and

75.

prncpa

here

cause

may

be

a

o

vsua

genec

mparmen

predsposon,

some

as

well

paens

wereas

w

oers

unconroed

w

ypergycema

reasonabe

bood

never

gucose

deveop

conro

do.

as

Pathogeness.

vas-

he

paogeness

o

dabec

renopay

s

compex

and

ncompeey undersood. he ce rsk acor s susaned ypergycema,

may

ead

of

(see

smuae

e

producon

o

cyoknes

s

o

e

ncreased

syness

o

marx

beeved

o

damage

vesses

due

o

aeraons

n

bood

low,

or-

and maon

acors

result

nex.

lesions.

AGEs

the

compromise

esons

renopay

of

is

seriously

wc Pathogeness.

grow

more

dfuse

underes

Nephropathy

and

bo

popuaon.

because

cular

o

end-sage

and

beween kdney,

Chapter 11),

yane

Features.

progress

Dabec ckenng

Renal

areroosceross,

s

common

can

 Sma-vesse

Diabetic

dabecs

Caper

Retinopathy

e

n

prone

(see

Diabetic

o

Hyane

yperenson,

evden

 •

 •

bross.

w

ssues.

 •

n

by

ubuar

scema.

rng numerous

caused

w

narrow

deveop

n

areroes

aerosceross,

may

Clncal Features.

o

neprosceross,

o

Clncal eadng

n

wa

romb

prs orm,

narrowng

resu

mus-

are and

nersa

assocaed

amorpous, ce

esons,

may

descrbed more

ead

dsease

arteries. aropy

above

275

atheromcrovascuar

sclerosis

System

Lesions addon

The

Endocrine

16

o

AGEs,

and

possby

oer

mecansms.

hese

vascuar

canges

proens nay ead o mnue emorrages, scema, sma narcs (coon woo

n

e

gomeruar

mesangum.

Mcrovascuar

dsease

eads

o

reduced spos), and macuar edema, a o wc mpar vson. I scema s severe,

bood

low

and

acvaon

o

e

renn–angoensn

sysem,

wc

comoca producon o VEGF nduces neoangogeness (proerave renop-

pensaes by ncreasng low roug e gomeru. he resung gomeray), uar

yperraon

and

ncrease

n

vascuar

pressure

n

e

wc

s

emorrages. may

ave

deeerous

efecs

on

e

gomeruar

oten

assocaed

w

more

exensve

rena

and

vreous

pacng

racon

gomeru

permeaby

hese

may

organze

and

undergo

bross,

barrer. on

e

rena

a

eads

o

rena

deacmen,

mpared

vson,

and

even

Many oer abnormaes n sgnang paways n gomeruar epea bndness. ces

bu

(podocyes)

er

and

proens

conrbuon

o

e

o

e

esons

s

dapragm

remans

ave

been

repored,

uncear. Morphology.

ave. Morphology.

e

soogc

amarks

o

dabec

gomeruar

are

deposs

o

marx

maera

n

e

mesangum

and

dsease

may

be

renopay

s

nonproerave

caracerzed

or

by

proer-

ckenng

dso

ease

Rena

Nonproerave

capares,

aneur ysms,

emorrages,

edema,

and

exudaes

o

capeaked pasma proens and pds. Proerave renopay s a pro-

ar y

wa,

dfuse

gomeruar

basemen

membrane

ckenng,

and cess

progressve

deposed

scarrng

n

e

(Fg.

16.10).

gomeruus

Somemes,

appears

e

noduar,

marx

gvng

o

rse

o

noduar

gomeruosceross

(Kmmese-Wson

vesse

ormaon

and

bross.

e Clncal

erm

new

maera

esons).

Features.

Vsua

mparmen,

somemes

even

can

A

resu

rom

proerave

renopay,

especay

B

Fig.

men

16.10

from

thickened,

Diabetic

a

patient

tortuous

tesy

Dr.

Lisa

Y erian,

lam,

Department

of

nephropathy.

with

(A)

Nodular

long-standing

afferent

arteriole.

Department

Pathology,

of

glomerulosclerosis

diabetes.

The

University

(B)

Severe

amorphous

Pathology,

of

oa

bndness,

In

nature

University

T exas

of

Health

(Kimmelstiel-Wilson

renal

of

hyaline

the

thickened

Chicago,

Science

lesions)

arteriolosclerosis.

Chicago.

Center,

vascular

B,

San

wall

Courtesy

Antonio,

in

Note

is

Dr.

a

renal

the

evident.

M.A.

T exas.)

speci-

markedly

(A,

Cour-

Venkatacha-



e

macua

s

276

CHAPTER

afeced.

Organzaon

and

Endocrine

16

bross

o

vreous

System

emorrages

rom

e (Fg.

newy

ormed

vesses

can

cause

rena

deacmen.

In

addon

o

16.11B).

composed rena

dsease,

paens

are

prone

o

deveopng

caaracs

and

sow

s

conras,

uncona

norma-appearng

adenomas

ces

are

surrounded

soary

by

a

esons

capsue

D).

more

Carcnomas

aypa

and

are

ave

uncommon;

a

endency

n

o

ese

(Fg.

nvade

magnances,

vens

and

ces

ympa-

Neuropathy cs.

s

o

gaucoma. 16.11C,

Diabetic

By

e

ypcay

a

symmerc

perpera

neuropay

o

e

egs

a

W

unconng

adrena

umors,

bo

bengn

and

magnan,

afecs e adjacen adrena corex and a o e conraaera adrena gand

many

sensory

nerves

bu

may

aso

mpar

moor

uncon.

Auonomc are

aropc

as

a

resu

o

suppresson

o

endogenous

ACTH

produc-

neuropay aso occurs, resung n bowe and urnary dsurbances. hese on canges

are

probaby

e

resu

o

mcroangopay

afecng

vesses

by

g

corso

eves.

Carcnomas

o

oer

organs

measac

o

supe

adrenas

bu

usuay

are

muc

more

common

an

prmary

adrena

cancers,

pyng e nerves, bu may aso ave a componen o drec axona damage. cause

ypoadrenasm,

no

Cusng

syndrome.

Acute Diabetic Ketoacidosis and Nonketotic Hyperosmolar Coma

Aoug

n

cronc

dabecs,

moray

paen

uary

on,

n

e

and

gucose

o

markedy

Insun

eves

as

worsens

aernave

or

and

consue

s

(and

e

occasonay

o

as

rggers

source

o

Excessve

deveopng

500

o

osmoc

1

700

o

(parcuary

a

edema,

e

meaboc

wc

can

o

s

parc-

de,

nec-

dabees

n

may

bood

ypergycema

severe

deydraon.

keones,

bran)

acdoss

be

and

n

dabees,

ncreases

acdc

or

presens

aered

eve

n

probems

morbdy

known

hs

resung

2

or

on

generang

o

ype

sudden

mg/dL.

cnca

o

dsease

dabees

eadng

eads

cerebra

e

compcaes

duress,

energy

keoss

ow

ype

poyss,

major

cause

supermposed

mbaance,

g

e

sress

e

eadng

oten

Unrecognzed

ypes

decency

rsk

dabees

meaboc

sarvaon.

e

1

obese.

oer

e

o

ype

keoacdoss

popuaon)

n

worsen

an

compcaons

acue

aa

wc

durng

and





are

saes

ncreases

s

no

rec-

ognzed and reaed mmedaey. Deydraon and eecroye mbaances

mus

may

be

careuy

deveop

correced

yperosmoar



e

paen

nonkeoc

s

o

coma.

survve.

s

Type

syndrome

2

dabecs

resus

rom

severe deydraon due o susaned osmoc duress n ndvduas wose

waer nake s nadequae. Afeced paens are ypcay oder adus wo

Clncal

Features.

enson

and

runca

obesy,

ror

neck

aropy

musce

and

o

“moon

back

mass

and

secondar y

brused,

e

resorpon

cods

a

o

o

mensrua

ncudng

rena

on

o

area

bone

suppress

varey

o

e

e

usuay

s

mb

e

skn

and

assocaed

becomes

and

a

caused

meanoc ye-smuang

o

a

and

by

paens

rage

a

o

o

skn

e

seecve

decreased

and

s

easy

n

e

gucocor-

ncreased

ncude

rsk

or

rsusm,

sympoms,

psycoss.

Exraad-

ACTH

pgmenaon

ACTH

nduce

resung

ncreases

ecopc

as

pose-

parcuary

psycarc

or

yper-

e

ces,

B ecause

are

rank

puar y

ncreased

by

C orso

oseopoross.

and

n

causes

(srae),

manesaons

acvy

a

Gucocorcods

16.7).

number

w

manesed

resuan

gucose

n

eFg.

response,

w

o

emorrages

depresson,

syndrome

w

weakness.

upake

Addona

presen

ssue,

Hypercorsosm

consequen

swngs,

adpose

accumuaon

(Suppemena

mmune

o

myobers,

cuaneous

abnormaes,

Cusng

and

II)

nb

necons.

mood

ypercorsosm

ump).

(ype

dabees.

abdomna

aces, ”

proxma

and

eadng

w

redsrbuon

(bufao

as-wc

guconeogeness

n

Paens

cenrpea

secre-

secondar y

precursor

moecue.

ave been dsabed by sroke or some oer debang ness.

Hyperaldosteronism

ADRENAL

GLANDS

Excessive,

chronic

overproduction

of

aldosterone

causes

hypertension. Eac

adrena

gand

consss

o

wo

dsnc

regons,

e

corex

and

 •

 Prmary

yperadosteronsm

s

caused

mos

oten

by

baera

nod-

medua. he corex produces ree ypes o serod ormones: gucocoruar cods

(many

corso),

mneraocorcods

(adoserone),

and

sex

yperpasa

(esrogens

and

androgens).

he

medua

produces

epneprne.

Mos

o

e

known

dseases

o

e

adrena

reaed

o

excessve

or

deecve

uncon

o

e

gands

or

an

adrena

umor,

mos

a

soar y

adrena

n

e

adenoma.

kdney,

Adoserone

eadng

o

lud

ncreases

reenon

and

sodum

ncreased

gands bood

are

adrena

caecoamnes, reabsorpon

many

e

secommony

rods

o

pressure.

Because

rena

bood

low

ncreases,

e

producon

corex. o renn n e kdney s reduced. Paens presen w yperenson,

and up o a rd ave reduced serum poassum (because o reduced

Cushing

Syndrome:

Hypercortisolism

reabsorpon This

syndrome

is

caused

by

increased

levels

of

ncreased resulting

in

metabolic

and

other

 S econdary

n In

cnca

pracce,

s

e

admnsraon

kdneys).

adoserone

Dagnosc

and

e

mos

common

cause

o

yperadosteronsm

response

reduced

aboraory

renn

ndngs

are

acvy.

o

serods

o

rea

o

acvaon

o

s

e

caused

by

adoserone

renn–angoensn

producon

sysem,

seen

n

Cusng condons

syndrome

e

serum

abnormalities.

 •

Pathogeness.

n

glucocorticoids,

nlammaory

o

reduced

rena

peruson,

as

n

vascuar

dseases

o

e

dskdney

and

congesve

ear

aure.

I

aso

s

a

bass

or

yperen-

eases. Endogenous Cusng syndrome may be caused by ncreased ACTH son. producon

by

a

puary

adenoma

(aso

caed

Cusng

dsease,

∼70%

o

cases), a umor or yperpasa o e adrena corex (15% o 20%), or eco-

Adrenogenital pc

ACTH

producon

by

some

oer

umor,

suc

as

sma

ce

ung

Excessive cer

(∼10%).

In

a

orms,

urnary

ree

corso

concenraon

s

puary

Cusng

dsease

and

Cusng

syndrome

caused

production

secreon,

serum

ACTH

eves

are

eevaed

due

o

by

oss

eedback

conro

by

corso.

Wen

Cusng

syndrome

s

umor

or

prmary

yperpasa

o

e

adrena

corex,

causes

changes

in

ACTH

are

produced

n

e

gonads

and

adrena

corex.

e

nega-

caused

eves

corex

produces

precursors

a

are

convered

o

esoserone

by

n a

hormones

ecopc

o

adrena ve

androgenic

organs.

Androgens ACTH

of

ncreased.

genital In

Syndromes

can-

perpera

ssues.

Unke

gonada

androgens,

adrena

androgens

are

are

reguaed

by

ACTH.

under

nluence

Excessve

adrena

androgens

may

be

produced

beow norma because eedback nbon s nac.

e

genec

an Morphology.

Paens

w

ACTH-dependen

Cusng

dsease

auosoma

dfuse

yperpasa

o

e

adrena

corex

(Fg.

ACTH,

by

congenta

recessve

dsease

adrena

adrena

n

wc

umors,

or

n

yper pasa

enzymes

an

uncommon

(CAH).

nvoved

n

CAH

s

corso

syndrome bosyness,

sow

o

caed

16.11A).

mos

oten

21-ydroxyase,

are

deecve.

Because

cor-

Prso

producon

s

reduced,

ere

s

a

compensaor y

ncrease

n

ACTH

mary corca yperpasa s ypcay assocaed w noduar esons, reease

rom

e

puar y

a

secondary

ncreases

e

producon

o

somemes

o

wc are oten dark n appearance due o accumuaon o pouscn adrena

androgens.

he

adrena

gands

are

yperpasc,

CHAPTER

Supplemental

teristic

striae.

WF

features

eFig.

(Reproduced

(editors):

ington,

DC,

16.7

include

Atlas

with

of

American

A

patient

central

permission

Nontumor

Registry

with

obesity,

Cushing

“moon

from

Lloyd

Pathology:

of

syndrome.

facies,”

RV,

Douglas

Endocrine

Pathology,

2002.)

and

Charac-

abdominal

BR,

Diseases.

Y oung

Wash-

16

Endocrine

System

276.e1

CHAPTER

A

Endocrine

16

System

277

B

C

D

Fig.

16.11

adrenal

gland

evident.

adrenal

ing

Cushing

The

glands

from

cortical

There

mild

Department

sze.

ambguous

promnen.

I

e

genaa.

Maes

dsease

In

were

w

gland

(A)

Diffuse

section,

was

presen

in

Mayo

rom

precocous

the

by

neoplastic

its

cells

patient

grs

rsusm

pubery

(B)

solitary,

are

and

with

vacuolated

enarged

adrenal

yellow

gland

and

pigmented

(C)

and

(bottom)

thickened,

Cushing

nodular

Adrenocortical

nature.

because

necrosis

of

not

a

adrenocortical

The

Histologic

presence

seen.

(B,

a

normal

nodularity

in

whom

hyperplasia

adenoma

features

of

with

subtle

syndrome,

adenoma.

(D)

the

are

contrasted

and

of

show-

is

an

distin-

adrenal

intracytoplasmic

Courtesy

Dr.

Aidan

is

both

lipid.

Carney,

Minnesota.)

w

acne

is

circumscribed

activity

presen

the

ACTH-dependent

gland.

Rochester,

and

of

cortex

Primary

adrenal

Mitotic

Clinic,

br,

cdren,

a

adrenal

hyperplastic.

nodules

pleomorphism.

Medicine,

hyperplasia

the

from

hyperplasia

The

nuclear

of

s

cross

diffusely

nodular

pospubera

presen

a

pigmented

adenoma.

is

In

abnormal

prominent

guished

enormous

(top).

syndrome.

are

counres,

Addson

ubercuoss

and

unga

necons

are

mporan

causes

o

dsease.

gen-

as. Paens respond we o serod reamen, wc repaces e deMorphology.

cen

gucocorcods

and

suppresses

ACTH

srunken

due

ympocyc

Adrenal

Cortical

Adrenal

Addison

Insufficiency

(Addison

to

disease,

deciency

progressive

of

multiple

In

adrenocorca

adrenas,

e

corex,

e

necons,

wc

adrena

gands

conans

granuomaous

or

a

are

varabe

ger-ncome

nsuicenc y

reacons

o

e

paogen

may

be

oer

ypes

presen.

destruction

of

the

adrenal

Features.

Cnca

manesaons

become

apparen

ony

ater

cortex an

90%

o

e

gands

are

desroyed.

Paens

presen

w

weak-

hormones. ness,

Pathogenes s.

In

o

Disease)

more leads

aropy

nrae.

nlammaor y

Clncal In

auommune

o

Insufficiency o

Chronic

In

producon.

counres,

(aso

known

60%

as

o

70%

Addson

o

gasronesna

he

skn

rse

o

s

sympoms,

yperpgmened

eecroye

because

e

mbaances,

precursor

and

ypoenson.

poypepde

a

gves

cronc

dsease)

s

ACTH

aso

s

processed

o

reease

meanocye-smuang

or-

due mone, wc rses n response o e ow corso eves.

o

auommune

caed

e

adrenas,

auommune

mos

commony

poyganduar

as

syndrome.

par

One

o

a

dsorder

subype

o

s

Acute syndrome

resus

rom

oss

o

uncon

muaons

n

e

gene

In wc

conros

e

expresson

o

se

angens

n

e

ymus

con ras

e

emnaon

o

se-reacve

T

ces.

Oer

endocrne

adrena 

are

subjec

o

auommune

aack

n

afeced

paens

yrod,

parayrod,

puar y,

and

pancreas.

In

d s e as e,

nsu   c enc y

may

w c

be

a

s

c ron c

me d c a 

and

prog ress ve,

emergenc y.

c aus e

s

ad rena 

emor rage

du e

o

co agu  a on

Te

mos

d s orders .

ncude

In e

Insuficiency

Adds on

gands

common a

o

and

ac ue ence

Adrenal

AIRE,

ower-ncome

 e

s e ng

o

dss em nae d

s epss,

 s

cond on

s

reer re d

o

as

278

 e

CHAPTER

Waterou s e-Fr der c s e n

manes a on

e y

o

o

sysemc

s epss

sudden

and,

w  

are

ad rena 

sg ns

 ereore,

wo

of

the

mos

adrena 

re ae d

mos

o

and

 e

( w   c

pro du c  on )

e- re aen  ng

so ck,

bu

a

u nd ery ng

nsu  cenc y

 re a men

serod

System

a s o

or

s ress

n

ey

produce

a

Pathogeness.

up on

genes,

ACT H

(e

p a en s

Mos

ncudng

cause

o

and

ce

cnca

correcabe

conrbue

o

umors

RET,

von

NF1

ave

(e

sgncance

orm

o

es

n

e

ac

a

yperenson.

muaons

cause

Hppe-Lndau

umorgeness

was

o

n

one

o

severa

neurobromaoss),

syndrome).

dscussed

n

How

ese

Caper

onco-

and

VHL

genes

may

5

Medulla

prmar y

umors

o

e

adrena

medua

are Morphology.

peocromocyoma

her

surgcay

c aus e

o c c urs

suppress es

paragangomas).

var -

 nsu  cenc y.

Adrenal

common

Te

yp oens on

ad rena 

serod

endogenous

undery ng

s

sy mpoms

Ac ue

o

sy ndrome.

cr ss

and

common .

w  drawa 

Tumors

he

o

Endocrine

16

e

umors

are

usuay

we-dened

masses

a

com-

neurobasoma. press

e

adrena.

ey

range

rom

sma,

crcumscrbed

esons

o

arge, emorragc, cysc masses (Fg. 16.12A). ey are composed o

Pheochromocytoma

ness Pheochromocytomas

are

tumors

of

chromafn

cells

that

n catecholamine

and

other

o

poygona

or

spnde-saped

ces,

conanng

caecoamnes

produce er

granues,

surrounded

by

a

vascuar

nework

(Fg.

16.12B).

hormones. Bengn esons may sow capsuar and vascuar nvason, so e den-

hese

rare

umors

arse

rom

caecoamne-producng

ces

n ng caracersc o magnancy s dsan measass.

e

adrena

medua

(90%)

and

sympaec

ganga

(10%,

aso

A

caed

B

C

D

Fig.

16.12

Tumors

attenuated

(lower

portion).

Granules

(such

toma.

tumor

cortex

as

of

and

(B)

containing

the

The

one

tumor

showing

in

the

adrenal

medulla.

demonstrates

areas

Photomicrograph

catecholamine

the

cells

center

form

extensive

of

(A,

of

Pheochromocytoma.

demonstrating

are

this

not

visible

image),

psuedorosettes

neuronal

B)

hemorrhage.

in

even

around

differentiation.

The

characteristic

this

in

a

nests

preparation.

The

It

is

of

core

arrow

of

points

fibrillary

to

a

tumor

is

residual

cells

not

pheochromocytomas

central

The

(A)

comma-shaped

with

are

material.

neuron.

to

find

benign.

(D)

within

gland

abundant

uncommon

that

enclosed

adrenal

is

cytoplasm.

bizarre

(C)

an

seen

cells

Neuroblas-

Ganglioneuroma,

a

CHAPTER

Clncal

Features.

cromocyoma:

magnan.

may

be

bood

he

he

10%

“rue

are

majory

epsodc,

pressure,

o

en”

s

oten

exraadrena,

o

paens

presenng

assocaed

as

an

w

used

10%

are

presen

abrup

o

w

and

acycarda,

caracerze

baera,

and

yperenson

precpous

eadace,

peo-

10%

are

wc

ncrease

sweang,

n

and

remors. hese paroxysms are arbuabe o e perodc reease o ca-

ecoamnes

e

rom

ormone

e

may

umor.

cause

In

ear

severe

aure,

cases,

e

sudden

myocarda

producon

narcon,

and

do

no

c aus e

prog noss

n