Female Genital Tumours: WHO Classification of Tumours [4, 5 ed.] 9283245040, 9789283245049

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WHO C la s s ific a tio n of Tumours • 5th Edition

F e m a le G e n ita l T u m o u rs

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In t e r n a t io n a l A g e n c y f o r R e s e a rc h o n C a n c e r

World Health Organization

W HO C la s s ific a tio n of Tum ours • 5th Edition

F e m a le G e n ita l T u m o u rs

WHO Classification of Tumours Editorial Board

In t e r n a t io n a l A g e n c y f o r R e s e a rc h o n C a n c e r

MM World Health WW Organization

C o r r ig e n d a W H O C la s s ific a tio n o f T u m o u r s , 5 t h e d it io n : F e m a le G e n i t a l T u m o u r s C o rrig e n d a u p d a te d : Ju n e 2 0 2 1 ( a fte r 3 rd p r in t ru n )

S u m m a r y o f c o r r e c t io n s :

Table of contents (p. ix) T h e h ie ra rc h y o f s o m e o f th e C h a p te r 8 (T u m o u rs o f th e u te rin e ce rvix) s e c tio n title s has b e e n c o rre c te d as s h o w n , so t h a t O th e r e p ith e lia l tu m o u rs is n o lo n g e r s u b o rd in a te t o G la n d u la r tu m o u rs a n d p re c u rs o rs .

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8 Tumours of the uterine cervix

335

G la n d u la r tu m o u r s a n d p re c u rs o rs

O th e r e p ith e lia l tu m o u rs

382

C a rc in o s a rc o m a

A d e n o s q u a m o u s a n d m u c o e p id e rm o id c a rc in o m a s

335

G la n d u la r tu m o u r s a n d p re c u rs o rs

O th e r e p ith e lia l tu m o u rs C a rc in o s a rc o m a

8 Tumours of the uterine cervix

383

382

A d e n o s q u a m o u s a n d m u c o e p id e rm o id c a rc in o m a s

383

A d e n o id basal c a rc in o m a

384

A d e n o id basal c a rc in o m a

384

C a rc in o m a , u n c la s s ifia b le

386

C a rc in o m a , u n c la s s ifia b le

386

M ix e d e p ith e lia l a n d m e s e n c h y m a l tu m o u r s

M ix e d e p ith e lia l a n d m e s e n c h y m a l tu m o u r s

Updated online: O ctober 2020 Updated in print: Yes (in 2nd p rin t run), O ctober 2020

WHO classification tables (p. 1-14) T h e fo llo w in g f o o tn o te has b e e n a d d e d b e lo w each W H O c la s s ific a tio n (ICD-O c o d in g ) ta b le : S u b ty p e la b e ls a re in d e n te d . Updated online: O ctober 2020 Updated in print: Yes (in 2nd p rin t run), O ctober 2020

WHO classification of tumours of the ovary: ICD-O coding (p. 1) T h e w o rd in g o f th e ICD-O la b e l f o r th e s u b ty p e o f 8 0 4 4 /3 : sm a ll ce ll c a rc in o m a , h y p e rc a lc a e m ic ty p e , has b e e n c o rre c te d as s h o w n .

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Miscellaneous tumours

Miscellaneous tumours

8 0 4 4 /3

8 0 4 4 /3

S m all ce ll c a rc in o m a , h y p e rc a lc a e m ic ty p e

8 9 6 0 /3

W ilm s tu m o u r

S m all ce ll c a rc in o m a , h y p e rc a lc a e m ic ty p e S m all ce ll c a rc in o m a , la rg e cell v a ria n t

8 9 6 0 /3

W ilm s tu m o u r

S m all cell c a rc in o m a , la rg e cell s u b ty p e

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

WHO classification of tumours of the uterine corpus: ICD-O coding (p. 6) T h e w o rd in g o f th e la b e l f o r ICD-O c o d e 8 1 4 4 /3 has b e e n c o rre c te d as s h o w n .

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Endometrial epithelial tumours and precursors

Endometrial epithelial tumours and precursors

8 1 4 4 /3

8 1 4 4 /3

M u c in o u s c a rc in o m a , g a s tric

9 1 1 1 /3 *

M e s o n e p h ric -lik e a d e n o c a rc in o m a

8 9 8 0 /3

C a rc in o s a rc o m a NOS

M u c in o u s c a rc in o m a , in te s tin a l ty p e

9 1 1 1 /3 *

M e s o n e p h ric -lik e a d e n o c a rc in o m a

8 9 8 0 /3

C a rc in o s a rc o m a NOS

( g a s tr o in te s tin a l) - ty p e

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

WHO classification of tumours of the uterine cervix: ICD-O coding (p. 8) T h e h e a d in g O th e r e p ith e lia l tu m o u rs has b e e n a d d e d as s h o w n .

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Glandular tumours and precursors

Glandular tumours and precursors

8 3 8 0 /3

8 3 8 0 /3

E n d o m e trio id a d e n o c a rc in o m a NOS

E n d o m e trio id a d e n o c a rc in o m a NOS

8 9 8 0 /3

C a rc in o s a rc o m a NOS

8 5 6 0 /3

A d e n o s q u a m o u s c a rc in o m a

Other epithelial tumours

8 4 3 0 /3

M u c o e p id e rm o id c a rc in o m a

8 9 8 0 /3

C a rc in o s a rc o m a NOS

8 0 9 8 /3

A d e n o id basal c a rc in o m a

8 5 6 0 /3

A d e n o s q u a m o u s c a rc in o m a

8 0 2 0 /3

C a rc in o m a , u n d iffe r e n tia te d , NOS

8 4 3 0 /3

M u c o e p id e rm o id c a rc in o m a

8 0 9 8 /3

A d e n o id basal c a rc in o m a

8 0 2 0 /3

C a rc in o m a , u n d iffe r e n tia te d , NOS

Updated online: O ctober 2020 Updated in print: Yes (in 2nd p rin t run), O ctober 2020

TNM staging of tumours of the cervix uteri (p. 23-4) 2 n d p r in t ru n In th e 2n d p r in t ru n (O c to b e r 2 0 2 0 ), th e f o o tn o te te x t w a s m o d ifie d t o c la rify t h a t th e FIGO s ta g in g in fo r m a tio n p re s e n te d o n th e s e t w o pages w a s fr o m th e 2 0 0 9 FIGO p u b lic a tio n . O rig in a l t e x t (1 s t p r in t ru n )

C o rre c te d t e x t (2 n d p r in t ru n )

T he in fo r m a tio n p re s e n te d h e re has b e e n

T h e in fo r m a tio n p re s e n te d h e re has b e e n

e x c e rp te d fr o m th e 2 0 1 7 T N M c la s s ific a tio n o f

e x c e rp te d fr o m th e 2 0 1 7 T N M c la s s ific a tio n o f

m a lig n a n t tu m o u rs , e ig h th e d itio n {2 9 5 ,2 7 9 0 }.

m a lig n a n t tu m o u rs , e ig h th e d itio n {2 9 5 ,2 7 9 0 }

© 2 0 1 7 UICC.

(FIGO 2 0 0 9 ). © 2 0 1 7 UICC.

A h e lp d e sk f o r s p e c ific q u e s tio n s a b o u t th e T N M

A h e lp d e sk f o r s p e c ific q u e s tio n s a b o u t th e T N M

c la s s ific a tio n is a v a ila b le a t

c la s s ific a tio n is a v a ila b le a t

h ttp s ://w w w .u ic c .o r g /tn m - h e lp - d e s k .

h ttp s ://w w w .u ic c .o r g /tn m - h e lp - d e s k .

References cited above: 295. Brierley JD, Gospodarowicz MK, W itte k in d C, editors. TNM classification o f m alignant tum ours. 8th ed. Oxford, UK: W iley-Blackw ell; 2017. 2790. UICC [In te rn e t]. Geneva (Switzerland): Union fo r Internation al Cancer C ontrol; 2019. TNM Publications and Resources; updated 2019 Feb 4. Available fro m : h ttp s ://w w w .u ic c .o rg /re s o u rc e s /tn m /p u b lic a tio n s -re s o u rc e s . Updated online: n/a - TNM tables are cu rre n tly n o t included in W HO Classification o f Tum ours Online Updated in print: Yes (in 2nd p rin t run), O ctober 2020; superseded in 3rd p rin t run, June 2021 (see below) 3 rd p r in t ru n In th e 3 rd p r in t ru n (June 2 0 2 1 ), th e e n tir e T N M s ta g in g o f tu m o u r s o f th e c e rv ix u te ri ta b le w a s re p la c e d w ith th e re v is e d C e rv ix U te ri T N M 2 0 2 1 - p u b lis h e d o n lin e b y th e U n io n f o r In te rn a tio n a l C a n ce r C o n tro l (UICC) a t h ttp s ://w w w .u ic c .o r g /re s o u r c e s /tn m /p u b lic a tio n s - r e s o u r c e s . T h e t it le o f th e ta b le w a s also u p d a te d (to T N M s ta g in g o f g y n a e c o lo g ic a l tu m o u rs : T u m o u rs o f th e c e rv ix u te r i: 2 0 2 1 re v is io n ) in th e ta b le o f c o n te n ts (on p. v ii in th e p r in t v o lu m e ). A p rin ta b le v e rs io n o f th e re v is e d p. 2 3 - 4 is in c lu d e d a t th e e n d o f th e PDF o f th is c o rrig e n d a d o c u m e n t (h ttp s ://p u b lic a tio n s .ia r c .fr /5 9 2 ). Updated online: n/a - TNM tables are cu rre n tly n o t included in W HO Classification o f Tum ours Online Updated in prin t: Yes (in 3rd p rin t run), June 2021

High-grade serous carcinoma of the ovary (p. 46) U n d e r th e h e a d in g M a c ro s c o p ic a p p e a ra n c e , t w o s e n te n c e s ha ve b e e n d e le te d as s h o w n . B ecause th is d e le tio n re s u lte d in th e r e flo w o f tw o lin e s fr o m p. 4 7 fo r w a r d t o p. 46, th e s u b je c t in d e x e n try f o r " p 1 6 " (on p. 6 2 9 in th e p r in t v o lu m e ) has also b e e n u p d a te d a c c o rd in g ly : th e lis te d p age ra n g e " 4 6 - 4 7 " has b e e n c h a n g e d t o ju s t " 4 6 " .

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Macroscopic appearance

Macroscopic appearance

T hese tu m o u r s a re u s u a lly b ila te ra l, la rg e , and

T h e se tu m o u r s a re u s u a lly b ila te ra l, la rg e , and

e x o p h y tic , an d th e y d e m o n s tra te a s o lid and

e x o p h y tic , a n d th e y d e m o n s tra te a s o lid and

p a p illa ry g r o w th a n d flu id - fille d cysts. T h e s o lid

p a p illa ry g r o w th a n d flu id - fille d cysts. T h e s o lid

areas a re ta n t o w h ite a n d fr e q u e n tly d is p la y

a reas a re ta n t o w h ite a n d fr e q u e n tly d is p la y

e x te n s iv e n e cro sis. T h e fa llo p ia n tu b e is c o m m o n ly

e x te n s iv e n e cro sis. T h e re is c o m m o n ly .

e m b e d d e d w ith in th e o v a ria n tu m o u r a n d c a n n o t be id e n tifie d g ro ssly. A s m a ll tu m o u r n o d u le is s o m e tim e s fo u n d in th e tu b a l fim b r ia . T h e re is c o m m o n ly ... Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

High-grade serous carcinoma of the ovary (p. 47) U n d e r th e h e a d in g E s s e n tia l a n d d e s ira b le d ia g n o s tic c rite ria , an a d d itio n a l e s s e n tia l c r ite r io n has b e e n a d d e d as s h o w n .

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Essential and desirable diagnostic criteria

Essential and desirable diagnostic criteria

E sse n tia l: se ro u s tu m o u r w ith s o lid ( w ith s lit-lik e

E s s e n tia l: se ro u s tu m o u r w ith s o lid (w ith s lit-lik e

spaces), p a p illa ry , g la n d u la r, o r c r ib r ifo r m

spaces), p a p illa ry , g la n d u la r, o r c r ib r ifo r m

a rc h ite c tu re ; la rg e , m a rk e d ly a ty p ic a l n u c le i

a rc h ite c tu re ; la rg e , m a rk e d ly a ty p ic a l n u c le i

(n u c le a r size v a ria b ility o f > 3 -fo ld ); h ig h m ito tic

(n u c le a r size v a ria b ility o f > 3 -fo ld ); h ig h m ito tic

a c tiv ity .

a c tiv ity ; b o th fa llo p ia n tu b e s s h o u ld b e g ro s sly

D e s ira b le (in s e le c te d cases): W T 1 im m u n o re a c tiv ity ; m u ta tio n - ty p e p53 e x p re s s io n .

v is ib le in t h e ir e n tir e ty a n d c o n ta in n o se ro u s tu b a l in tr a e p ith e lia l c a rc in o m a o r m u c o s a l HGSC a fte r b e in g e x a m in e d in to ta l u sin g a SEE-FIM (s e c tio n in g and e x te n s iv e ly e x a m in in g th e fim b r ia te d e n d ) p ro to c o l. D e s ira b le (in s e le c te d cases): W T 1 im m u n o re a c tiv ity ; m u ta tio n - ty p e p53 e x p re s s io n .

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Small cell carcinoma of the ovary, hypercalcaemic type (p. 149) U n d e r th e h e a d in g s S u b ty p e (s ) a n d H is to p a th o lo g y (in th e fir s t p a ra g ra p h ), th e n a m e o f th e s u b ty p e o f sm a ll cell c a rc in o m a , h y p e rc a lc a e m ic ty p e , has b e e n c o rre c te d as s h o w n . T h e n a m e o f th is s u b ty p e has also b e e n c o rre c te d w ith in th e s u b je c t in d e x (o n p. 6 3 0 in th e p r in t v o lu m e ).

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Subtype(s)

Subtype(s)

S m all cell c a rc in o m a , la rg e ce ll v a ria n t

S m all ce ll c a rc in o m a , la rg e cell s u b ty p e

Histopathology

Histopathology

T u m o u r cells ty p ic a lly g ro w in sh e e ts, nests, co rd s,

T u m o u r cells ty p ic a lly g ro w in s h e e ts, nests, co rd s,

a nd tra b e c u la e ... Large cells a re p re s e n t (in v a ry in g

a n d t r a b e c u la e . Large cells a re p re s e n t (in v a ry in g

n u m b e rs ) in h a lf o f th e s e tu m o u rs , w h ic h a re

n u m b e rs ) in h a lf o f th e s e tu m o u rs , w h ic h a re

d e s ig n a te d "s m a ll cell c a rc in o m a , la rg e ce ll v a ria n t"

d e s ig n a te d "s m a ll ce ll c a rc in o m a , la rg e cell

if th e la rg e cells a re p re d o m in a n t (w h ic h is ra re ). ...

s u b ty p e " if th e la rg e cells a re p re d o m in a n t (w h ic h is ra re ). .

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

High-grade serous carcinoma of the fallopian tube (p. 219) U n d e r th e h e a d in g M a c ro s c o p ic a p p e a ra n c e , a s e n te n c e has b e e n a d d e d as s h o w n .

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Macroscopic appearance

Macroscopic appearance

T h e re is h y d ro s a lp in x w ith p a p illa ry o r s o lid

T h e re is h y d ro s a lp in x w ith p a p illa ry o r s o lid

in tra lu m in a l g r o w th a n d fu s io n o f th e fim b r ia l e n d .

in tra lu m in a l g ro w th a n d fu s io n o f th e fim b r ia l en d .

D e te c tio n o f sm a ll STICs o r c a rc in o m a s is

D e te c tio n o f sm a ll STICs o r c a rc in o m a s is

m a x im iz e d u sin g th e SEE-FIM (s e c tio n in g and

m a x im iz e d u sin g th e SEE-FIM (s e c tio n in g and

e x te n s iv e ly e x a m in in g th e fim b r ia te d e n d ) p ro to c o l

e x te n s iv e ly e x a m in in g th e fim b r ia te d e n d ) p ro to c o l

{1 7 5 3 }.

{1 7 5 3 }. S o m e tim e s th e s e tu m o u r s a re m ic ro s c o p ic a n d n o t v is ib le gro ssly.

Reference cited above: 1753. M edeiros F, M u to MG, Lee Y, e t al. The tubal fim b ria is a preferred site fo r early adenocarcinom a in w om en w ith fam ilial ovarian cancer syndrom e. Am J Surg Pathol. 2006 Feb;30(2):230-6. PMID:16434898 Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

High-grade serous carcinoma of the fallopian tube (p. 229) U n d e r th e h e a d in g E s s e n tia l a n d d e s ira b le d ia g n o s tic c rite ria , th e w o r d in g has b e e n c o rre c te d as s h o w n .

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Essential and desirable diagnostic criteria

Essential and desirable diagnostic criteria

E sse n tia l: a d o m in a n t tu b a l m ass w ith m in im a l

E s s e n tia l: th e p re s e n c e o f STIC o r a n y m u co sa l

o v a ria n o r p e rito n e a l dise a se a n d c o n c u rre n t

HGSC o r o b lite r a tio n o f p a rt o r all o f a tu b e b y th e

STIC; ...

tu m o u r m ass s ig n ifie s a p rim a ry tu b a l le s io n (see T a b le 1.01, p. 3 4 [T a b le # 1 0 9 3 1 o n lin e ]) ; ...

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Tumours of the uterine corpus: Introduction (p. 246) A t th e e n d o f th e f ir s t p a ra g ra p h , a s e n te n c e has b e e n a d d e d as s h o w n

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E n d o m e tria l c a rc in o m a is c u r r e n tly d ia g n o s e d on

E n d o m e tria l c a rc in o m a is c u r r e n tly d ia g n o s e d on

th e basis o f m o rp h o lo g y . ... T h e n e w W H O

th e basis o f m o rp h o lo g y . ... T h e n e w W H O

c la s s ific a tio n in c lu d e s n o v e l tu m o u r ty p e s , such as

c la s s ific a tio n in c lu d e s n o v e l tu m o u r ty p e s , such as

m e s o n e p h ric -lik e a d e n o c a rc in o m a a n d g a s tric -ty p e

m e s o n e p h ric -lik e a d e n o c a rc in o m a a n d g a s tric -ty p e

m u c in o u s c a rc in o m a .

m u c in o u s c a rc in o m a . E n d o m e tria l m u c in o u s c a rc in o m a is n o w re g a rd e d as a p a tte rn o f e n d o m e tr io id c a rc in o m a , a n d n o t a d is tin c t tu m o u r ty p e .

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Other endometrial carcinomas (p. 264) U n d e r th e h e a d in g ICD-O c o d in g , th e w o rd in g o f th e la b e l f o r ICD-O c o d e 8 1 4 4 /3 has b e e n c o rre c te d as show n.

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ICD-O coding

ICD-O coding

9 1 1 0 /3 M e s o n e p h ric a d e n o c a rc in o m a

9 1 1 0 /3 M e s o n e p h ric a d e n o c a rc in o m a

8 0 7 0 /3 S q u a m o u s ce ll c a rc in o m a NOS

8 0 7 0 /3 S q u a m o u s ce ll c a rc in o m a NOS

8 1 4 4 /3 M u c in o u s c a rc in o m a , in te s tin a l ty p e

8 1 4 4 /3 M u c in o u s c a rc in o m a , g a s tric

9 1 1 1 /3 M e s o n e p h ric -lik e a d e n o c a rc in o m a

( g a s tr o in te s tin a l) - ty p e 9 1 1 1 /3 M e s o n e p h ric -lik e a d e n o c a rc in o m a

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Uterine leiomyoma (p. 272) In T a b le 6 .0 2 (T a b le # 1 0 8 1 7 o n lin e ), in th e s e co n d ro w u n d e r th e T a rg e t(s ) c o lu m n h e a d in g , th e c h ro m o s o m a l lo cu s o f th e g e n e H M G A 1 has b e e n c o rre c te d as s h o w n .

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H M G A 2 (1 2 q 1 5 ) a n d H M G A 1 (6 q 21)

H M G A 2 (1 2 q 1 5 ) a n d H M G A 1 (6 p 2 1 .3 1 )

Updated online: June 2021 Updated in print: No (pending next p rin t run)

Smooth muscle tumour of uncertain malignant potential of the uterine corpus (p. 280) U n d e r th e h e a d in g H is to p a th o lo g y (in th e th ir d a n d f if t h p a ra g ra p h s ), th e e q u iv a le n t m ito tic c o u n ts p e r 10 h ig h -p o w e r fie ld s (HPF) h a ve b e e n c o rre c te d as s h o w n .

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Histopathology

Histopathology

T his is a c h a lle n g in g d ia g n o s tic a re a , a n d th e

T his is a c h a lle n g in g d ia g n o s tic a rea, a n d th e

fo llo w in g a re g e n e ra l g u id e lin e s f o r s p in d le d cell

fo llo w in g a re g e n e ra l g u id e lin e s f o r s p in d le d cell

s m o o th m u s c le tu m o u r s t o be p la ce d in th is g ro u p ,

s m o o th m u s c le tu m o u r s t o be p la c e d in th is g ro u p ,

b u t th e s e s h o u ld n o t be ta k e n as s tr ic t d ia g n o s tic

b u t th e s e s h o u ld n o t be ta k e n as s tr ic t d ia g n o s tic

c rite ria :

c rite ria :

(1) T u m o u rs w ith fo c a l/m u ltifo c a l o r d iffu s e

(1) T u m o u rs w ith fo c a l/m u ltifo c a l o r d iffu s e

n u c le a r a ty p ia , w ith 2 - 4 m ito s e s /m m 2 (e q u a tin g to

n u c le a r a ty p ia , w ith 2 - 4 m ito s e s /m m 2 (e q u a tin g to

6 - 9 m ito s e s /1 0 HPF o f 0 .5 5 m m in d ia m e te r and

5 - 9 m ito s e s / 1 0 HPF o f 0 .5 5 m m in d ia m e te r and

0 .2 4 m m 2 in are a ), .

0 .2 4 m m 2 in a re a ), .

(3) T u m o u rs la c k in g c y to lo g ic a l a ty p ia a n d tu m o u r

(3) T u m o u rs la c k in g c y to lo g ic a l a ty p ia a n d tu m o u r

cell n e cro sis, b u t w ith > 6 m ito s e s /m m 2 (e q u a tin g

ce ll n e cro sis, b u t w ith > 6 m ito s e s /m m 2 (e q u a tin g

t o > 15 m ito s e s /1 0 HPF o f 0 .5 5 m m in d ia m e te r and

t o > 15 m ito s e s /1 0 HPF o f 0 .5 5 m m in d ia m e te r an d

0 .2 4 m m 2 in are a ). .

0 .2 4 m m 2 in a re a ). .

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Uterine leiomyosarcoma (p. 284) U n d e r th e h e a d in g H is to p a th o lo g y (in th e th ir d p a ra g ra p h ), th e w o rd in g has b e e n c o rre c te d as s h o w n

Original text

Corrected text

Histopathology

Histopathology

M y x o id tu m o u r s a re o fte n p a u c ic e llu la r... The

M y x o id tu m o u r s a re o fte n p a u c ic e llu la r . The

p re s e n c e o f a n y d e g re e o f c y to lo g ic a l a ty p ia ,

p re s e n c e o f a n y s ig n ific a n t (2 + /3 + ) c y to lo g ic a l

tu m o u r cell n e cro sis, o r > 0 .4 m ito s e s /m m 2

a ty p ia , tu m o u r ce ll n e c ro s is , o r > 0 .4 m ito s e s /m m 2

(e q u a tin g t o > 1 m ito s is /1 0 HPF o f 0 .5 5 m m in

(e q u a tin g t o > 1 m ito s is /1 0 HPF o f 0 .5 5 m m in

d ia m e te r a nd 0 .2 4 m m 2 in a re a ) s h o u ld p r o m p t a

d ia m e te r a n d 0 .2 4 m m 2 in a re a ) s h o u ld p r o m p t a

d ia g n o sis o f m y x o id le io m y o s a r c o m a .

d ia g n o s is o f m y x o id le io m y o s a r c o m a .

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Low-grade endometrial stromal sarcoma (p. 288) U n d e r th e h e a d in g H is to p a th o lo g y (in th e s e co n d p a ra g ra p h ), an a d d itio n a l re fe re n c e has b e e n a d d e d as s h o w n . T his re fe re n c e has also b e e n a d d e d t o th e re fe re n c e lis t (o n p. 6 1 0 in th e p r in t v o lu m e ).

Original text

Corrected text

Histopathology

Histopathology

T u m o u rs u s u a lly s h o w d iffu s e s tro n g e x p re s s io n

T u m o u rs u s u a lly s h o w d iffu s e s tro n g e x p re s s io n

o f . T u m o u rs m a y be p o s itiv e f o r w id e -s p e c tru m

o f . T u m o u rs m a y be p o s itiv e f o r w id e -s p e c tru m

k e ra tin s { 7 5 9 } .

k e ra tin s {7 5 9 ,2 2 1 6 A } .

References cited above: 759. Farhood AI, Abram s J. Im m unohistochem istry o f end o m e tria l strom al sarcoma. Hum Pathol. 1991 M ar;22(3): 224-30. PMID:1706303 2216A. Rahimi S, Akaev I, M arani C, e t al. Im m unohistochem ical expression o f d iffe re n t subtypes o f cytokeratins by endom etrial strom al sarcoma. Appl Im m unohistochem M ol M orphol. 2019 Jul;27(6):466-70. PMID:29406332 Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Perivascular epithelioid cell tumour (PEComa) (p. 297) In T a b le 6 .05 (T a b le # 7 5 8 8 o n lin e ), th e d e n o m in a to r o f th e m ito tic c o u n t th re s h o ld has b e e n c o rre c te d in th e th r e e places it a p p e a rs , a n d th e t it le o f th e ta b le has b e e n u p d a te d t o p ro v id e a d d itio n a l in fo rm a tio n , as s h o w n .

Original text

Corrected text

Table 6.05

Table 6.05

P ro p o se d a lg o rith m s f o r s tr a tify in g th e

P ro p o s e d a lg o rith m s f o r s tra tify in g th e

b e h a v io u r o f u te rin e p e riv a s c u la r e p ith e lio id cell

b e h a v io u r o f u te rin e p e riv a s c u la r e p ith e lio id cell

tu m o u r s (PECom as); a p ro p o s a l based o n s y n th e s is

tu m o u r s (PECom as); a p ro p o s a l based o n s y n th e sis

o f in fo r m a tio n fr o m th e th r e e so u rce s c ite d b e lo w

o f in fo r m a tio n fr o m th e th r e e so u rce s c ite d b e lo w ; th e m ito tic c o u n t th re s h o ld e q u a te s t o 1 m ito s is in 5 0 h ig h -p o w e r fie ld s (HPF) o f d ia m e te r 0 .5 5 m m , a re a 0 .2 4 m m 2

General criteria > Benign

General criteria > Benign

< 5 cm , n o n - in filtr a tiv e , n o n -h ig h n u c le a r g ra d e ,

< 5 cm , n o n - in filtr a tiv e , n o n -h ig h n u c le a r g ra d e ,

m ito tic c o u n t o f < 1 m ito s is /5 0 m m 2, n o n e cro sis,

m ito tic c o u n t o f < 1 m ito s is /12 m m 2, n o n e cro sis,

n o v a s c u la r in v a s io n

n o v a s c u la r in v a s io n

Modified gynaecology-specific criteria > Uncertain malignant potential

Modified gynaecology-specific criteria > Uncertain malignant potential

< 3 o f th e fo llo w in g fe a tu re s : > 5 cm , h ig h n u c le a r

< 3 o f th e fo llo w in g fe a tu re s : > 5 cm , h ig h n u c le a r

g ra d e , m ito tic c o u n t o f > 1 m ito s is /5 0 m m 2,

g ra d e , m ito tic c o u n t o f > 1 m ito s is /12 m m 2,

n ecrosis, v a s c u la r in v a s io n

n e cro sis, v a s c u la r in v a s io n

General criteria > Malignant

General criteria > Malignant

> 2 o f th e fo llo w in g fe a tu re s : > 5 cm , in filtr a tiv e ,

> 2 o f th e fo llo w in g fe a tu re s : > 5 cm , in filtr a tiv e ,

h ig h n u c le a r g ra d e , m ito tic c o u n t o f

h ig h n u c le a r g ra d e , m ito tic c o u n t o f

> 1 m ito s is /50 m m 2, n e cro sis, v a s c u la r in v a s io n

> 1 m ito s is /12 m m 2, n e cro sis, v a s c u la r in v a s io n

Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

Chapter 8: Tumours of the uterine cervix (p. 335) O n th e c h a p te r t it le page, th e h ie ra rc h y o f th e s e c tio n title s has b e e n c o rre c te d as s h o w n , so th a t O th e r e p ith e lia l tu m o u rs is n o lo n g e r s u b o rd in a te t o G la n d u la r tu m o u rs a n d p re c u rs o rs .

Original text

Corrected text

S q u a m o u s e p ith e lia l tu m o u r s

S q u a m o u s e p ith e lia l tu m o u rs

M im ic s o f s q u a m o u s p re c u rs o r le sio n s S q u a m o u s ce ll tu m o u r s a n d p re c u rs o rs G la n d u la r tu m o u r s a n d p re c u rs o rs B enign g la n d u la r le sio n s A d e n o c a rc in o m a s O th e r e p ith e lia l tu m o u r s

M im ic s o f s q u a m o u s p re c u rs o r le sio n s S q u a m o u s cell tu m o u r s a n d p re c u rs o rs G la n d u la r tu m o u r s a n d p re c u rs o rs B enign g la n d u la r le sio n s A d e n o c a rc in o m a s O th e r e p ith e lia l tu m o u rs

M ix e d e p ith e lia l a n d m e s e n c h y m a l tu m o u r s

M ix e d e p ith e lia l a n d m e s e n c h y m a l tu m o u r s

G e rm cell tu m o u r s

G e rm ce ll tu m o u rs

Updated online: O ctober 2020 Updated in print: Yes (in 2nd p rin t run), O ctober 2020

Squamous intraepithelial lesions of the uterine cervix (p. 342) U n d e r th e h e a d in g E tio lo g y (in th e s e co n d p a ra g ra p h ), th e t e x t has b e e n c o rre c te d as s h o w n

Original text

Corrected text

Etiology

Etiology

LR-HPV ty p e s can cause b o th e x o p h y tic LSILs,

LR-HPV ty p e s can cause b o th e x o p h y tic LSILs,

k n o w n as c o n d y lo m a ta a c u m in a ta (g e n ita l w a rts ),

k n o w n as c o n d y lo m a ta a c u m in a ta (g e n ita l w a rts ),

a nd f la t LSILs; h o w e v e r, th e m a jo r ity (8 0 -9 0 % ) o f

a n d f la t LSILs; h o w e v e r, th e m a jo r ity (8 0 -9 0 % ) o f

f la t LSILs a re a ttr ib u ta b le t o HR-HPV ty p e s . A ll HR-

f la t LSILs a re a ttr ib u ta b le t o HR-HPV ty p e s . A ll HR-

H P V -a s s o c ia te d a n d ra re L R -H P V -a sso cia te d LSILs

H P V -a s s o c ia te d LSILs b e a r a risk o f p ro g re s s io n t o

b e a r a ris k o f p ro g re s s io n t o HSIL a n d m a lig n a n c y

HSIL a n d m a lig n a n c y . W h ile LR-HPV has ra re ly bee n

{9 5 2 }; th is risk is g re a te r f o r H P V 1 6 /1 8 -p o s itiv e

a s s o c ia te d w ith c a rc in o m a {9 5 2 }, in c o n tra s t, HSIL

le sio n s {2 3 2 3 }. In c o n tra s t, HSIL arises e x c lu s iv e ly in

arise s a lm o s t e x c lu s iv e ly in th e c o n te x t o f HR-HPV

th e c o n te x t o f HR-HPV in fe c tio n .

in fe c tio n .

References cited above: 952. Guimera N, Lloveras B, Lindeman J, et al. The occasional role o f low -risk hum an papillom aviruses 6, 11, 42, 44, and 70 in anogenital carcinoma defined by laser capture microdissection/PCR m ethodology: results fro m a global study. Am J Surg Pathol. 2013 Sep;37(9):1299-310. PMID:24076770 2323. 2323. R odriguez-Trujillo A, M a rti C, Angeles MA, e t al. Value o f HPV 16/18 genotyping and p16/Ki-67 dual staining to predict progression to HSIL/CIN2+ in negative cytologies fro m a colposcopy referral population. Am J Clin Pathol. 2018 Oct 1;150(5):432-40. PMID:30052715 Updated online: June 2021 Updated in prin t: Yes (in 3rd p rin t run), June 2021

WHO Classification of Tumours, 5th edition: Female Genital Tumours Corrections made in the second print run Summary of corrections: Table of contents

p. ix

8 Tumours of the uterine cervix The hierarchy of the section titles has been corrected as shown, so that “Other epithelial tumours” is no longer subordinate to “Glandular tumours and precursors”. Original text 8 Tumours of the uterine cervix

Corrected text 335

8 Tumours of the uterine cervix

Glandular tumours and precursors Other epithelial tumours Carcinosarcoma Adenosquamous and mucoepidermoid carcinomas Adenoid basal carcinoma Carcinoma, unclassifiable Mixed epithelial and mesenchymal tumours

335

Glandular tumours and precursors Other epithelial tumours Carcinosarcoma Adenosquamous and mucoepidermoid carcinomas Adenoid basal carcinoma Carcinoma, unclassifiable Mixed epithelial and mesenchymal tumours

382 383 384 386

WHO classification tables

382 383 384 386

p. 2-4, 6, 8-14

Footnotes The following footnote has been added below the WHO classification (ICD-O coding) tables: Subtype labels are indented.

WHO classification of tumours of the uterine cervix

p. 8

Glandular tumours and precursors The subheading “Other epithelial tumours" has been added as shown. Original text

Corrected text

Glandular tumours and precursors

Glandular tumours and precursors

8380/3 8980/3 8560/3 8430/3 8098/3 8020/3

8380/3

Endometrioid adenocarcinoma NOS Carcinosarcoma NOS Adenosquamous carcinoma Mucoepidermoid carcinoma Adenoid basal carcinoma Carcinoma, undifferentiated, NOS

Endometrioid adenocarcinoma NOS

Other epithelial tumours 8980/3 Carcinosarcoma NOS 8560/3 Adenosquamous carcinoma 8430/3 Mucoepidermoid carcinoma 8098/3 Adenoid basal carcinoma 8020/3 Carcinoma, undifferentiated, NOS

1

TNM staging of tumours of the cervix uteri

p. 23-4

Footnotes The footnote text has been modified to clarify that the FIGO staging information presented on these two pages is from the 2009 FIGO publication. Original text

Corrected text

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790}. ©2017 UICC.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790} (FIGO 2009). ©2017 UICC.

A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

Chapter 8: Tumours of the uterine cervix

p. 335

Title page The hierarchy of the section titles has been corrected as shown, so that “Other epithelial tumours” is no longer subordinate to “Glandular tumours and precursors”. Original text

Corrected text

Squamous epithelial tumours Mimics of squamous precursor lesions Squamous cell tumours and precursors Glandular tumours and precursors Benign glandular lesions Adenocarcinomas Other epithelial tumours Mixed epithelial and mesenchymal tumours Germ cell tumours

Squamous epithelial tumours Mimics of squamous precursor lesions Squamous cell tumours and precursors Glandular tumours and precursors Benign glandular lesions Adenocarcinomas Other epithelial tumours Mixed epithelial and mesenchymal tumours Germ cell tumours

2

© International Agency for Research on Cancer 2020 All rights reserved. Suggested citation WHO Classification of Tumours Editorial Board. Female genital tumours. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 4). https://publications.iarc.fr/592. Sales, rights, and permissions Print copies are distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland Tel.: +41 22 791 3264; Fax: +41 22 791 4857; email: [email protected]; website: https://whobluebooks.iarc.fr To purchase IARC publications in electronic format, see the IARC Publications website (https://publications.iarc.fr). Requests for permission to reproduce or translate IARC publications - whether for sale or for non-commercial distribution - should be submitted through the IARC Publications website (https://publications.iarc.fr/Rights-And-Permissions). Third-party materials If you wish to reuse material from this work that is attributed to a third party, such as figures, tables, or boxes, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. See Sources, pages 572-576. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO or contributing agencies concerning the legal status of any country, territory, city, or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO or contributing agencies in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO or contributing agencies be liable for damages arising from its use. First print run (8200 copies) Updated corrigenda can be found at https://publications.iarc.fr

IARC Library Cataloguing-in-Publication Data Names: WHO Classification of Tumours Editorial Board. Title: Female genital tumours / edited by WHO Classification of Tumours Editorial Board. Description: Fifth edition. | Lyon: International Agency for Research on Cancer, 2020. | Series: World Health Organization classification of tumours. | Includes bibliographical references and index. Identifiers: ISBN 9789283245049 (pbk.) | ISBN 9789283245056 (ebook) Subjects: MESH: Genital Neoplasms, Female. Classification: WP 15

This volume was produced with support from

The International Society of Gynecological Pathologists

The WHO classification of female genital tumours presented in this book reflects the views of the WHO Classification of Tumours Editorial Board that convened at the International Agency for Research on Cancer, Lyon, France, 7-9 October 2019.

Contents

List of abbreviations

xi

Foreword

xii

WHO classification of tumours of the female genital tract Tumours of the ovary Tumours of the peritoneum Tumours of the fallopian tube Tumours of the broad ligament and other uterine ligaments Tumours of the uterine corpus Gestational trophoblastic disease Tumours of the uterine cervix Tumours of the vagina Tumours of the vulva Neuroendocrine neoplasia Haematolymphoid proliferations and neoplasia Mesenchymal tumours of the lower genital tract Melanocytic lesions

1 3 4 5 6 7 8 9 10 11 12 13 14

TNM staging of gynaecological tumours Ovarian, fallopian tube, and primary peritoneal carcinoma Tumours of the uterus - endometrium Uterine sarcomas Gestational trophoblastic neoplasms Tumours of the cervix uteri Tumours of the vagina Tumours of the vulva

15 16 18 20 22 23 25 26

TNM staging of tumours of soft tissues

27

General introduction

29

1

31 32

Tumours of the ovary Introduction Serous tumours Benign serous tumours Serous cystadenoma, adenofibroma, and surface papilloma Borderline serous tumours Serous borderline tumour Malignant serous tumours Low-grade serous carcinoma High-grade serous carcinoma Mucinous tumours Benign mucinous tumours Mucinous cystadenoma and adenofibroma Borderline mucinous tumours Mucinous borderline tumour Malignant mucinous tumours Mucinous carcinoma Endometrioid tumours Benign endometrioid tumours Endometrioid cystadenoma and adenofibroma Borderline endometrioid tumours Endometrioid borderline tumour Malignant endometrioid tumours Endometrioid carcinoma Clear cell tumours Benign clear cell tumours Clear cell cystadenoma and adenofibroma Borderline clear cell tumours Clear cell borderline tumour

36 38 43 45

48 50 53

55 56 58

62 63

Malignant clear cell tumours Clear cell carcinoma Seromucinous tumours Benign seromucinous tumours Seromucinous cystadenoma and adenofibroma Borderline seromucinous tumours Seromucinous borderline tumour Malignant seromucinous tumours Seromucinous carcinoma Brenner tumours Benign Brenner tumours Brenner tumour Borderline Brenner tumours Borderline Brenner tumour Malignant Brenner tumours Malignant Brenner tumour Other carcinomas Mesonephric-like adenocarcinoma Undifferentiated and dedifferentiated carcinomas Carcinosarcoma Mixed carcinoma Mesenchymal tumours Endometrioid stromal sarcoma Smooth muscle tumours Ovarian myxoma Other ovarian mesenchymal tumours Mixed epithelial and mesenchymal tumours Mixed malignant epithelial and mesenchymal tumours Adenosarcoma Sex cord-stromal tumours Pure stromal tumours Ovarian fibroma Thecoma Luteinized thecoma associated with sclerosing peritonitis Sclerosing stromal tumour Microcystic stromal tumour Signet-ring stromal tumour Leydig cell tumour Steroid cell tumour Ovarian fibrosarcoma Pure sex cord tumours Adult granulosa cell tumour Juvenile granulosa cell tumour Sertoli cell tumour Sex cord tumour with annular tubules Mixed sex cord-stromal tumours Sertoli-Leydig cell tumour Sex cord-stromal tumour NOS Gynandroblastoma Germ cell tumours Mature teratoma Immature teratoma Dysgerminoma Yolk sac tumour Embryonal carcinoma Non-gestational choriocarcinoma Mixed germ cell tumour Monodermal teratomas and somatic-type tumours arising from a dermoid cyst Struma ovarii Ovarian carcinoid

65

68 69 70

71 73 75 77 79 81 83 85 87 89 90

91

93 94 95 96 97 99 100 102 104 105 107 109 111 113 116 117 119 121 123 125 127 129 131

132 134

Neuroectodermal-type tumours Monodermal cystic teratoma Somatic neoplasms arising from teratomas Germ cell-sex cord-stromal tumours Gonadoblastoma Mixed germ cell-sex cord-stromal tumour, unclassified Miscellaneous tumours Rete cystadenoma, adenoma, and adenocarcinoma Wolffian tumour Solid pseudopapillary tumour Small cell carcinoma of the ovary, hypercalcaemic type Wilms tumour Mesothelial tumours (see Ch. 3) Tumour-like lesions Follicle cyst Corpus luteum cyst Large solitary luteinized follicle cyst Hyperreactio luteinalis Pregnancy luteoma Stromal hyperplasia and hyperthecosis Fibromatosis and massive oedema Leydig cell hyperplasia Metastases

153 154 155 156 158 160 161 162 163

2

Endometriosis and related conditions Endometriosis and derived tumours

169 170

3

Tumours of the peritoneum Introduction Mesothelial tumours Adenomatoid tumour Well-differentiated papillary mesothelial tumour Mesothelioma Epithelial tumours Epithelial tumours of Mullerian type Serous borderline tumour Low-grade serous carcinoma High-grade serous carcinoma Mesenchymal tumours specific to peritoneum Smooth muscle tumours Leiomyomatosis peritonealis disseminata Miscellaneous primary tumours Desmoid fibromatosis Calcifying fibrous tumour Extragastrointestinal stromal tumour Solitary fibrous tumour Endometrioid stromal sarcoma Desmoplastic small round cell tumour Tumour-like lesions Mesothelial hyperplasia Peritoneal inclusion cysts Transitional cell metaplasia Endosalpingiosis Histiocytic nodule Ectopic decidua Splenosis Other tumour-like lesions Metastases Carcinomas and sarcomas Pseudomyxoma peritonei Gliomatosis

175 176

4

Tumours of the fallopian tube Introduction Epithelial tumours Benign serous tumours Serous adenofibroma and papilloma

136 137 138

Borderline serous tumours Serous borderline tumour Malignant epithelial tumours High-grade serous carcinoma Endometrioid carcinoma Carcinosarcoma Tumour-like lesions Paratubal cysts Tubal hyperplasia Tubo-ovarian abscess Salpingitis isthmica nodosa Metaplastic papillary lesion Placental site nodule Mucinous metaplasia Endosalpingiosis Mixed epithelial and mesenchymal tumours Adenosarcoma Germ cell tumours Teratoma

140 143 144 145 147 149 151

5

177 179 181

184 186 187

188 190 192 193 195 197 199 201 202 203 204 205 206 207 208 209 211 214 215 216

217

6

Tumours of the broad ligament and other uterine ligaments Introduction Mesenchymal and mixed tumours Leiomyoma Adenomyoma Adenosarcoma Leiomyosarcoma Other mesenchymal and mixed tumours Miscellaneous tumours Wolffian tumour Papillary cystadenoma Ependymoma Tumour-like lesions Adrenocortical remnants Tumours of the uterine corpus Introduction Endometrial epithelial tumours and precursors Precursor lesions Endometrial hyperplasia without atypia Endometrial atypical hyperplasia / endometrioid intraepithelial neoplasia Endometrial carcinomas Endometrioid carcinoma Serous carcinoma Clear cell carcinoma Undifferentiated and dedifferentiated carcinomas Mixed carcinoma Other endometrial carcinomas Carcinosarcoma Tumour-like lesions Endometrial polyp Endometrial metaplasia Arias-Stella reaction Mesenchymal tumours of the uterus Smooth muscle tumours Uterine leiomyoma Intravenous leiomyomatosis Smooth muscle tumour of uncertain malignant potential Metastasizing leiomyoma Uterine leiomyosarcoma Endometrial stromal and related tumours Endometrial stromal nodule Low-grade endometrial stromalsarcoma High-grade endometrial stromalsarcoma Undifferentiated uterine sarcoma

218 219 221 222 223 224 225 226 227 228 229 230 230 231

233 234 235 236 237 238 238 239 240 242 243 245 246

248 250 252 256 258 260 262 264 266 268 269 271

272 277 279 281 283 286 287 289 292

Miscellaneous mesenchymal tumours Uterine tumour resembling ovarian sex cord tumour Perivascular epithelioid cell tumour (PEComa) Inflammatory myofibroblastic tumour Other mesenchymal tumours of the uterus Mixed epithelial and mesenchymal tumours Adenomyoma Atypical polypoid adenomyoma Adenosarcoma Miscellaneous tumours Central primitive neuroectodermal tumour / CNS embryonal tumour Germ cell tumours 7

8

Adenosquamous and mucoepidermoid carcinomas Adenoid basal carcinoma Carcinoma, unclassifiable Mixed epithelial and mesenchymal tumours Adenomyoma Adenosarcoma Germ cell tumours

383 384 386

Tumours of the vagina Introduction Epithelial tumours Benign squamous lesions Condyloma acuminatum (see Ch. 10) Squamous papilloma Atrophy Tubulosquamous polyp Squamous cell tumours and precursors Squamous intraepithelial lesions Squamous cell carcinoma, HPV-associated Squamous cell carcinoma, HPV-independent Squamous cell carcinoma NOS Benign glandular lesions Villous adenoma Mullerian papilloma Vaginal adenosis Endocervicosis Cysts Glandular tumours Adenocarcinoma, HPV-associated Endometrioid carcinoma Clear cell carcinoma Mucinous carcinoma, gastric type Mucinous carcinoma, intestinal type Mesonephric adenocarcinoma Carcinosarcoma Other epithelial tumours Mixed tumour of the vagina Adenocarcinoma of Skene gland origin Adenosquamous carcinoma Adenoid basal carcinoma Mixed epithelial and mesenchymal tumours Adenosarcoma Miscellaneous tumours Germ cell tumours

391 392

10 Tumours of the vulva Introduction Epithelial tumours Benign squamous lesions Seborrhoeic keratosis Condyloma acuminatum Squamous cell tumours and precursors Squamous intraepithelial lesions, HPV-associated Vulvar intraepithelial neoplasia, HPV-independent Squamous cell carcinoma, HPV-associated Squamous cell carcinoma, HPV-independent Squamous cell carcinoma NOS Basal cell carcinoma Glandular tumours and cysts Mammary-type glandular lesions Papillary hidradenoma Chondroid syringoma Fibroadenoma Phyllodes tumour Adenocarcinoma of mammary gland type Bartholin gland lesions Bartholin gland cyst Hyperplasia, adenoma, and adenomyoma

419 420

294 296 298 300 301 303 305

307 308

Gestational trophoblastic disease Introduction Tumour-like lesions Non-neoplastic lesions Exaggerated placental site reaction Placental site nodule and plaque Abnormal (non-molar) villous lesions Molar pregnancies Partial hydatidiform mole Complete hydatidiform mole Invasive and metastatic hydatidiform moles Gestational trophoblastic neoplasms Epithelioid trophoblastic tumour Placental site trophoblastic tumour Gestational choriocarcinoma Mixed trophoblastic tumour

309 310

Tumours of the uterine cervix Introduction Squamous epithelial tumours Mimics of squamous precursor lesions Squamous metaplasia Atrophy Squamous cell tumours and precursors Condyloma acuminatum (see Ch. 10) Squamous intraepithelial lesions Squamous cell carcinoma, HPV-associated Squamous cell carcinoma, HPV-independent Squamous cell carcinoma NOS Glandular tumours and precursors Benign glandular lesions Endocervical polyp Mullerian papilloma Nabothian cyst Tunnel clusters Microgiandular hyperplasia Lobular endocervical glandular hyperplasia Diffuse laminar endocervical hyperplasia Mesonephric remnants and hyperplasia Arias-Stella reaction Endocervicosis Tuboendometrioid metaplasia Ectopic prostate tissue Adenocarcinomas Adenocarcinoma in situ, HPV-associated Adenocarcinoma, HPV-associated Adenocarcinoma in situ, HPV-independent Adenocarcinoma, HPV-independent, gastric type Adenocarcinoma, HPV-independent, clear cell type Adenocarcinoma, HPV-independent, mesonephric type Other adenocarcinomas Other epithelial tumours Carcinosarcoma

335 336

311 313 315 317 319 322 323 325 327 332

338 341

342 347 350 351

352 353 354 355 356 357 358 359 360 361 362 363 364 367 372 374 376 378 380 382

9

387 388 389

393 394 395 396 398 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 416 417 418

421 422 424 426 429 432 434 434

435 436 437 438 439 440 441

Bartholin gland carcinomas Other cysts Adenocarcinomas of other types Paget disease Carcinomas of sweat gland origin Adenocarcinoma of intestinal type Germ cell tumours

442 444 445 447 448 449

11 Neuroendocrine neoplasia Introduction Neuroendocrine tumour Neuroendocrine carcinoma Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Mixed neuroendocrine-non-neuroendocrine neoplasms Carcinoma admixed with neuroendocrine carcinoma

451 452 453

12 Haematolymphoid proliferations and neoplasia Introduction Reactive lymphoid hyperplasia Florid reactive lymphoid hyperplasia Lymphomas Diffuse large B-cell lymphoma Extranodal marginal zone lymphoma Follicular lymphoma Burkitt lymphoma Myeloid leukaemia Myeloid sarcoma

461 462

13 Mesenchymal tumours of the lower genital tract Introduction Adipocytic tumours Lipoma Lipoblastoma-like tumour of the vulva Liposarcoma Fibroblastic and myofibroblastic tumours Postoperative spindle cell nodule Fibroepithelial stromal polyp Prepubertal fibroma Superficial myofibroblastoma Myofibroblastoma Cellular angiofibroma Angiomyofibroblastoma Solitary fibrous tumour Dermatofibrosarcoma protuberans NTRK-rearranged spindle cell neoplasm (emerging) Vascular tumours Kaposi sarcoma Angiosarcoma Smooth muscle tumours Leiomyoma Smooth muscle tumour of uncertain malignant potential Leiomyosarcoma

477 478

455 457 459

465 467 469 471 473 474

480 481 483 485 486 488 490 491 493 495 497 498 500 502 504 506 508 509

Skeletal muscle tumours Rhabdomyoma Rhabdomyosarcoma Peripheral nerve sheath tumours Benign peripheral nerve sheathtumours Granular cell tumour Tumours of uncertain differentiation Superficial angiomyxoma Deep (aggressive) angiomyxoma Epithelioid sarcoma Alveolar soft part sarcoma Undifferentiated small round cell sarcomas Ewing sarcoma

511 512 515 517 519 520 522 524 526

14 Melanocytic lesions Naevi Acquired melanocytic naevus Congenital melanocytic naevus Blue naevus Atypical melanocytic naevus ofgenital type Dysplastic melanocytic naevus Melanoma Mucosal melanoma

527

15 Metastasis Metastasis to the lower female genital tract

539 540

16 Genetic tumour syndromes of the female genital tract BRCA1/2-assoc\a\eti hereditary breast and ovarian cancer syndrome Lynch syndrome Cowden syndrome Li-Fraumeni syndrome Peutz-Jeghers syndrome Ataxia-telangiectasia Carney complex DICER1 syndrome Ovarian dysgenesis Von Hippel-Lindau syndrome Hereditary leiomyomatosis and renal cell carcinoma Other genetic tumour syndromes

543

Contributors

564

Declaration of interests

570

IARC/WHO Committee for ICD-O

571

Sources

572

References

577

Subject index

625

Previous volumes in the series

632

528 530 532 534 535 537

544 546 548 550 552 554 555 556 558 560 561 563

List of abbreviations

3D AIDS AR CAMP Cl CIN CNS CT dMMR DNA EBV ER FGT FIGO FISH FNA GCB H&E HIV HPF HPV HR-HPV IARC ICD-11 ICD-0 ICD-O-3

three-dimensional acquired immunodeficiency syndrome androgen receptor cyclic adenosine monophosphate confidence interval cervical intraepithelial neoplasia central nervous system computed tomography mismatch repair-deficient deoxyribonucleic acid Epstein-Barr virus estrogen receptor female genital tract International Federation of Gynecology and Obstetrics fluorescence in situ hybridization fine-needle aspiration germinal-centre B cell haematoxylin and eosin human immunodeficiency virus high-power field(s) human papillomavirus high-risk human papillomavirus International Agency for Research on Cancer International Classification of Diseases, 11th revision International Classification of Diseases for Oncology International Classification of Diseases for Oncology, 3rd edition

ig ITD kb LR-HPV MRI mRNA MSI MSS N:C ratio NK cell NMDAR NOS NSE PAS PASD PCR PR RNA RT-PCR SEER Program STR TCGA TNM UICC UV VaIN VIN

immunoglobulin internal tandem duplication kilobase(s) low-risk human papillomavirus magnetic resonance imaging messenger ribonucleic acid microsatellite instability microsatellite stability nuclear-to-cytoplasmic ratio natural killer cell A/-methyl-D-aspartate receptor not otherwise specified neuron-specific enolase periodic acid-Schiff periodic acid-Schiff with diastase polymerase chain reaction progesterone receptor ribonucleic acid reverse transcriptase polymerase chain reaction Surveillance, Epidemiology, and End Results Program short tandem repeat The Cancer Genome Atlas tumour, node, metastasis Union for International Cancer Control ultraviolet vaginal intraepithelial neoplasia vulvar intraepithelial neoplasia

List of abbreviations

XI

Foreword The WHO Classification of Tumours, published as a series of books (also known as the WHO Blue Books) and now as a website (https://tumourclassification.iarc.who.int), is an essential tool for standardizing diagnostic practice worldwide. It also serves as a vehicle for the translation of cancer research into practice. The diagnostic criteria and standards that make up the classification are underpinned by evidence evaluated and debated by experts in the field. About 200 authors and editors participate in the production of each book, and they give their time freely to this task. I am very grateful for their help; it is a remarkable team effort. This fourth volume of the fifth edition of the WHO Blue Books has, like the preceding three, been led by the WHO Classification of Tumours Editorial Board, which is composed of standing members nominated by pathology organizations and expert mem­ bers selected on the basis of informed bibliometric analysis. The diagnostic process is increasingly multidisciplinary, and we are delighted that several radiology and clinical experts have joined us to address specific needs. The most conspicuous change to the format of the books in the fifth edition is that tumour types common to multiple systems are dealt with together - so there are separate chapters on neuroendocrine neoplasia, haematolymphoid proliferations and neoplasia, mesenchymal tumours, and melanocytic lesions. There is also a chapter on genetic tumour syndromes. Genetic disorders are of increasing importance to diagnosis in individual patients, and the study of these disorders has undoubtedly informed our under­ standing of tumour biology and behaviour over the past decade. We have attempted to take a more systematic approach to the multifaceted nature of tumour classification; each tumour type is described on the basis of its localization, clinical features, epidemiology, etiology, pathogenesis, histopathology, diagnostic molecular pathology, staging, and prognosis and prediction. We have also included information on macroscopic appearance and cytology, as well as essential and desirable diagnostic criteria. This standardized, modular approach makes it easier for the books to be accessible online, but it also enables us to call attention to areas in which there is little information, and where serious gaps in our knowledge remain to be addressed. The organization of the WHO Blue Books content now follows the normal progression from benign to malignant - a break with the fourth edition, but one we hope will be welcome. The volumes are still organized by anatomical site (digestive system, breast, soft tissue and bone, etc.), and each tumour type is listed within a taxonomic classification that follows the format below, which helps to structure the books in a systematic manner: • • • • •

Site; e.g. ovary Category; e.g. endometrioid tumours Family (class); e.g. malignant endometrioid tumours Type; e.g. endometrioid carcinoma Subtype; e.g. seromucinous carcinoma

The issue of whether a given tumour type represents a distinct entity rather than a subtype continues to exercise pathologists, and it is the topic of many publications in the literature. We continue to deal with this issue on a case-by-case basis, but we believe there are inherent rules that can be applied. For example, tumours in which multiple histological patterns contain shared truncal mutations are clearly of the same type, despite the differences in their appearance. Equally, genetic heterogeneity within the same tumour type may have implications for treatment. A small shift in terminology in the fifth edition is that the term “variant” in reference to a specific kind of tumour has been wholly superseded by “subtype”, in an effort to more clearly differentiate this meaning from that of “variant” in reference to a genetic alteration. The WHO Blue Books are much appreciated by pathologists and of increasing importance to practitioners of other clinical dis­ ciplines involved in cancer management, as well as to researchers. The editorial board and I certainly hope that the series will continue to meet the need for standards in diagnosis and to facilitate the translation of diagnostic research into practice worldwide. It is particularly important that cancers continue to be classified and diagnosed according to the same standards internationally so that patients can benefit from multicentre clinical trials, as well as from the results of local trials conducted on different continents.

Dr Ian A. Cree Head, WHO Classification of Tumours Group International Agency for Research on Cancer August 2020 XII

Foreword

WHO classification of tumours of the ovary Serous tumours 8441/0 Serous cystadenoma NOS 8461/0 Serous surface papilloma 9014/0 Serous adenofibroma NOS 9014/0 Serous cystadenofibroma NOS 8442/1 Serous borderline tumour NOS 8460/2 Serous borderline tumour, micropapillary variant 8460/2 Serous carcinoma, non-invasive, low grade 8460/3 Low-grade serous carcinoma 8461/3 High-grade serous carcinoma Mucinous tumours 8470/0 Mucinous 9015/0 Mucinous 8472/1 Mucinous 8480/3 Mucinous

cystadenoma NOS adenofibroma NOS borderline tumour adenocarcinoma

Endometrioid tumours 8380/0 Endometrioid cystadenoma NOS 8381/0 Endometrioid adenofibroma NOS 8380/1 Endometrioid tumour, borderline 8380/3 Endometrioid adenocarcinoma NOS 8474/3 Seromucinous carcinoma Clear cell tumours 8443/0 Clear cell cystadenoma 8313/0 Clear cell cystadenofibroma 8313/1 Clear cell borderline tumour 8310/3 Clear cell adenocarcinoma NOS Seromucinous tumours 8474/0 Seromucinous cystadenoma 9014/0 Seromucinous adenofibroma 8474/1 Seromucinous borderline tumour Brenner tumours 9000/0 Brenner tumour NOS 9000/1 Brenner tumour, borderline malignancy 9000/3 Brenner tumour, malignant Other carcinomas 9111/3* Mesonephric-like adenocarcinoma 8020/3 Carcinoma, undifferentiated, NOS 8020/3 Dedifferentiated carcinoma 8980/3 Carcinosarcoma NOS 8323/3 Mixed cell adenocarcinoma Mesenchymal tumours 8931/3 Endometrioid stromal sarcoma, low grade 8930/3 Endometrioid stromal sarcoma, high grade 8890/0 Leiomyoma NOS 8890/3 Leiomyosarcoma NOS 8897/1 Smooth muscle tumour of uncertain malignant potential 8840/0 Myxoma NOS Mixed epithelial and mesenchymal tumours 8933/3 Adenosarcoma

Sex cord-stromal tumours Pure stromal tumours 8810/0 Fibroma NOS 8810/1 Cellular fibroma 8600/0 Thecoma NOS 8601/0 Thecoma, luteinized 8602/0 Sclerosing stromal tumour 8590/0 Microcystic stromal tumour 8590/0 Signet-ring stromal tumour 8650/0 Leydig cell tumour of the ovary NOS 8670/0 Steroid cell tumour NOS 8670/3 Steroid cell tumour, malignant 8810/3 Fibrosarcoma NOS Pure sex cord tumours 8620/3 Adult granulosa cell tumour of ovary 8622/1 Granulosa cell tumour, juvenile 8640/1 Sertoli cell tumour NOS 8623/1 Sex cord tumour with annular tubules Mixed sex cord-stromal tumours 8631/1 Sertoli-Leydig cell tumour NOS 8631/0 Sertoli-Leydig cell tumour, well differentiated 8631/1 Sertoli-Leydig cell tumour, moderately differentiated 8631/3 Sertoli-Leydig cell tumour, poorly differentiated 8633/1 Sertoli-Leydig cell tumour, retiform 8590/1 Sex cord tumour NOS 8632/1 Gynandroblastoma Germ cell tumours 9080/0 Teratoma, benign 9080/3 Immature teratoma NOS 9060/3 Dysgerminoma 9071/3 Yolk sac tumour NOS 9070/3 Embryonal carcinoma NOS 9100/3 Choriocarcinoma NOS 9085/3 Mixed germ cell tumour Monodermal teratomas and somatic-type tumours arising from a dermoid cyst 9090/0 Struma ovarii NOS 9090/3 Struma ovarii, malignant 9091/1 Strumal carcinoid 9084/3 Teratoma with malignant transformation 9080/0 Cystic teratoma NOS 9084/3 Teratoma with malignant transformation Germ cell-sex cord-stromal tumours 9073/1 Gonadoblastoma Dissecting gonadoblastoma Undifferentiated gonadal tissue 8594/1 Mixed germ cell-sex cord-stromal tumour NOS Miscellaneous tumours 9110/0 Adenoma of rete ovarii 9110/3 Adenocarcinoma of rete ovarii 9110/1 Wolffian tumour 8452/1 Solid pseudopapillary tumour of ovary 8044/3 Small cell carcinoma, hypercalcaemic type Small cell carcinoma, large cell variant 8960/3 Wilms tumour

WHO classification of tumours of the ovary

Tumour-like lesions Follicle cyst Corpus luteum cyst Large solitary luteinized follicle cyst Hyperreactio luteinalis 8610/0 Pregnancy luteoma Stromal hyperplasia and hyperthecosis Fibromatosis and massive oedema Leydig cell hyperplasia Metastases to the ovary*

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-O at its meeting in June 2020.

2

WHO classification of tumours of the ovary

WHO classification of tumours of the peritoneum Mesothelial tumours 9054/0 Adenomatoid tumour NOS 9052/0 Well-differentiated papillary mesothelioma, benign 9050/3 Mesothelioma, malignant 9052/3 Epithelioid mesothelioma, malignant 9051/3 Sarcomatoid mesothelioma 9053/3 Mesothelioma, biphasic, malignant Epithelial tumours (of Mullerian type) 8442/1 Serous borderline tumour NOS 8460/3 Low-grade serous carcinoma 8461/3 High-grade serous carcinoma

Tumour-like lesions Mesothelial hyperplasia 9055/0 Peritoneal inclusion cysts Transitional cell metaplasia Endosalpingiosis Histiocytic nodule Ectopic decidua Splenosis Metastases to the peritoneum Carcinomas and sarcomas 8480/6 Pseudomyxoma peritonei Gliomatosis

Mesenchymal tumours specific to peritoneum 8890/1 Leiomyomatosis, peritonealis disseminata 8822/1 Abdominal fibromatosis 8817/0 Calcifying fibrous tumour 8936/3 Gastrointestinal stromal tumour 8815/1 Solitary fibrous tumour NOS Fat-forming (lipomatous) solitary fibrous tumour Giant cell-rich solitary fibrous tumour Dedifferentiated solitary fibrous tumour 8815/3 Solitary fibrous tumour, malignant 8931/3 Endometrioid stromal sarcoma, low grade 8930/3 Endometrioid stromal sarcoma, high grade 8806/3 Desmoplastic small round cell tumour

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; 13 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of tumours of the peritoneum

WHO classification of tumours of the fallopian tube Epithelial tumours 9014/0 Serous adenofibroma NOS 8442/1 Serous borderline tumour NOS 8461/3 High-grade serous carcinoma 8380/3 Endometrioid adenocarcinoma NOS 8980/3 Carcinosarcoma NOS

Mixed epithelial and mesenchymal tumours 8933/3 Adenosarcoma Germ cell tumours 9080/0 Mature teratoma NOS 9080/3 Immature teratoma NOS

Tumour-like lesions Paratubal cysts Tubal hyperplasia Tubo-ovarian abscess Salpingitis isthmica nodosa Metaplastic papillary lesion Placental site nodule Mucinous metaplasia Endosalpingiosis

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

4

WHO classification of tumours of the fallopian tube

WHO classification of tumours of the broad ligament and other uterine ligaments Mesenchymal and mixed tumours 8890/0 Leiomyoma NOS 8932/0 Adenomyoma NOS 8933/3 Adenosarcoma 8890/3 Leiomyosarcoma NOS

Miscellaneous tumours 9110/1 Wolffian tumour 8450/0 Papillary cystadenoma NOS 9391/3 Ependymoma NOS Tumour-like lesions Adrenocortical remnants

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; 13 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of tumours of the broad ligament and other uterine ligaments

5

WHO classification of tumours of the uterine corpus Endometrial epithelial tumours and precursors Endometrial hyperplasia without atypia Atypical hyperplasia of the endometrium 8380/2 Endometrioid adenocarcinoma NOS 8380/3 POLE-ultramutated endometrioid carcinoma Mismatch repair-deficient endometrioid carcinoma p53-mutant endometrioid carcinoma No specific molecular profile (NSMP) endometrioid carcinoma Serous carcinoma NOS 8441/3 Clear cell adenocarcinoma NOS 8310/3 Carcinoma, undifferentiated, NOS 8020/3 Mixed cell adenocarcinoma 8323/3 Mesonephric adenocarcinoma 9110/3 Squamous cell carcinoma NOS 8070/3 Mucinous carcinoma, intestinal type 8144/3 Mesonephric-like adenocarcinoma 9111/3* 8980/3 Carcinosarcoma NOS Tumour-like lesions Endometrial polyp Endometrial metaplasia Arias-Stella reaction Mesenchymal tumours specific to the uterus Leiomyoma NOS 8890/0 Lipoleiomyoma 8890/0 Leiomyoma, apoplectic 8890/0 Leiomyoma, hydropic 8890/0 Dissecting leiomyoma 8890/0 Cellular leiomyoma 8892/0 Myxoid leiomyoma 8896/0 Epithelioid leiomyoma 8891/0 8893/0 Symplastic leiomyoma 8890/1 Leiomyomatosis NOS 8890/1 Intravenous leiomyomatosis

8897/1 8891/1** 8896/1*

8898/1 8890/3 8891/3 8896/3 8930/0 8931/3 8930/3 8805/3 8590/1 8714/0 8714/3 8825/1

Smooth muscle tumour of uncertain malignant potential Epithelioid smooth muscle tumour of uncertain malignant potential Myxoid smooth muscle tumour of uncertain malignant potential Spindle smooth muscle tumour of uncertain malignant potential Metastasizing leiomyoma Leiomyosarcoma NOS Spindle leiomyosarcoma Epithelioid leiomyosarcoma Myxoid leiomyosarcoma Endometrial stromal nodule Endometrial stromal sarcoma, low grade Endometrial stromal sarcoma, high grade Undifferentiated sarcoma Uterine tumour resembling ovarian sex cord tumour Perivascular epithelioid tumour, benign Perivascular epithelioid tumour, malignant Inflammatory myofibroblastic tumour Epithelioid myofibroblastic sarcoma

Mixed epithelial and mesenchymal tumours 8932/0 Adenomyoma NOS Atypical polypoid adenomyoma 8932/0 Adenosarcoma 8933/3 Miscellaneous tumours Primitive neuroectodermal tumour NOS 9473/3 Germ cell tumour NOS 9064/3 Yolk sac tumour NOS 9071/3 Mature teratoma NOS 9080/0 Immature teratoma NOS 9080/3

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; 13 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-O at its meeting in June 2020.

6

WHO classification of tumours of the uterine corpus

WHO classification of gestational trophoblastic disease Tumour-like lesions Exaggerated placental site reaction Placental site nodule and plaque Abnormal (non-molar) villous lesions Molar pregnancies 9103/0 Partial hydatidiform mole 9100/0 Complete hydatidiform mole 9100/1 Invasive hydatidiform mole

Gestational trophoblastic neoplasms 9105/3 Trophoblastic tumour, epithelioid 9104/1 Placental site trophoblastic tumour 9100/3 Choriocarcinoma NOS 9101/3 Choriocarcinoma combined with other germ cell elements

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of gestational trophoblastic disease

WHO classification of tumours of the uterine cervix Squamous epithelial tumours Squamous metaplasia Atrophy Condyloma acuminatum 8077/0 Low-grade squamous intraepithelial lesion 8077/0 Cervical intraepithelial neoplasia, grade 1 8077/2 High-grade squamous intraepithelial lesion 8077/2 Cervical intraepithelial neoplasia, grade 2 8077/2 Cervical intraepithelial neoplasia, grade 3 8085/3 Squamous cell carcinoma, HPV-associated 8086/3 Squamous cell carcinoma, HPV-independent 8070/3 Squamous cell carcinoma NOS Glandular tumours and precursors Endocervical polyp Mullerian papilloma Nabothian cyst Tunnel clusters Microglandular hyperplasia Lobular endocervical glandular hyperplasia Diffuse laminar endocervical hyperplasia Mesonephric remnants and hyperplasia Arias-Stella reaction Endocervicosis Tuboendometrioid metaplasia Ectopic prostate tissue 8140/2 Adenocarcinoma in situ NOS 8483/2** Adenocarcinoma in situ, HPV-associated 8484/2* Adenocarcinoma in situ, HPV-independent

8140/3 8483/3* 8482/3 8310/3 9110/3

Adenocarcinoma NOS Adenocarcinoma, HPV-associated Adenocarcinoma, HPV-independent, gastric type Adenocarcinoma, HPV-independent, clear cell type Adenocarcinoma, HPV-independent, mesonephric type 8484/3* Adenocarcinoma, HPV-independent, NOS 8380/3 Endometrioid adenocarcinoma NOS 8980/3 Carcinosarcoma NOS 8560/3 Adenosquamous carcinoma 8430/3 Mucoepidermoid carcinoma 8098/3 Adenoid basal carcinoma 8020/3 Carcinoma, undifferentiated, NOS Mixed epithelial and mesenchymal tumours 8932/0 Adenomyoma NOS Mesonephric-type adenomyoma Endocervical-type adenomyoma 8933/3 Adenosarcoma Germ cell tumours 9064/3 Germ cell tumour NOS 9080/0 Mature teratoma NOS 9084/0 Dermoid cyst NOS 9071/3 Endodermal sinus tumour 9071/3 Yolk sac tumour NOS 9100/3 Choriocarcinoma NOS

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in June 2020.

8

WHO classification of tumours of the uterine cervix

WHO classification of tumours of the vagina Epithelial tumours Condyloma acuminatum 8052/0 Squamous cell papilloma NOS Vestibular micropapillomatosis Solitary vaginal papilloma Atrophy 8560/0 Tubulosquamous polyp 8077/0 Low-grade squamous intraepithelial lesion 8077/0 Vaginal intraepithelial neoplasia, grade 1 8077/2 High-grade squamous intraepithelial lesion 8077/2 Vaginal intraepithelial neoplasia, grade 2 8077/2 Vaginal intraepithelial neoplasia, grade 3 8085/3 Squamous cell carcinoma, HPV-associated 8086/3 Squamous cell carcinoma, HPV-independent 8070/3 Squamous cell carcinoma NOS 8261/0 Villous adenoma NOS 8263/0 Tubulovillous adenoma NOS Mullerian papilloma Vaginal adenosis Endocervicosis Cysts 8140/3 Adenocarcinoma NOS 8483/3** Adenocarcinoma, HPV-associated

8380/3 8310/3 8482/3 8480/3 9110/3 8980/3 8940/0 8140/3 8560/3 8098/3

Endometrioid adenocarcinoma NOS Clear cell adenocarcinoma NOS Mucinous carcinoma, gastric type Mucinous adenocarcinoma Mesonephric adenocarcinoma Carcinosarcoma NOS Mixed tumour NOS Carcinoma of Skene, Cowper, and Littre glands Adenosquamous carcinoma Adenoid basal carcinoma

Mixed epithelial and mesenchymal tumours 8933/3 Adenosarcoma Miscellaneous tumours 9064/3 Germ cell tumour NOS 9071/3 Yolk sac tumour, pre-pubertal type 9080/0 Mature teratoma NOS 9084/0 Dermoid cyst NOS

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; 13 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-O at its meeting in June 2020.

WHO classification of tumours of the vagina

WHO classification of tumours of the vulva Epithelial tumours Seborrhoeic keratosis Condyloma acuminatum 8077/0 Low-grade squamous intraepithelial lesion 8077/0 Vulvar intraepithelial neoplasia, grade 1 8077/2 High-grade squamous intraepithelial lesion 8077/2 Vulvar intraepithelial neoplasia, grade 2 8077/2 Vulvar intraepithelial neoplasia, grade 3 8071/2 Differentiated vulvar intraepithelial neoplasia (VIN) Differentiated exophytic vulvar intraepithelial lesion Vulvar acanthosis with altered differentiation 8085/3 Squamous cell carcinoma, HPV-associated 8086/3 Squamous cell carcinoma, HPV-independent 8070/3 Squamous cell carcinoma NOS 8090/3 Basal cell carcinoma NOS 8405/0 Papillary hidradenoma 8940/0 Chondroid syringoma NOS 9010/0 Fibroadenoma NOS 9020/1 Phyllodes tumour NOS 9020/0 Phyllodes tumour, benign 9020/1 Phyllodes tumour, borderline 9020/3 Phyllodes tumour, malignant 8500/3 Adenocarcinoma of anogenital mammary-like glands

Bartholin gland lesions Bartholin gland cyst 8140/0 Adenoma NOS 8932/0 Adenomyoma NOS 8070/3 Squamous cell carcinoma NOS 8200/3 Adenoid cystic carcinoma 8020/3 Carcinoma, poorly differentiated, NOS 8560/3 Adenosquamous carcinoma 8240/3 Neuroendocrine tumour NOS 8982/3 Myoepithelial carcinoma 8562/3 Epithelial-myoepithelial carcinoma 8085/3 Squamous cell carcinoma, HPV-positive 8542/3 8400/3 8401/3 8413/3 8409/3 8200/3 8144/3

Paget disease, extramammary Sweat gland adenocarcinoma Apocrine adenocarcinoma Eccrine adenocarcinoma Porocarcinoma NOS Adenoid cystic carcinoma Adenocarcinoma, intestinal type

Germ cell tumours 9064/3 Germ cell tumour NOS 9071/3 Yolk sac tumour NOS

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

10

WHO classification of tumours of the vulva

WHO classification of neuroendocrine neoplasia in the female genital tract 8240/3 8240/3 8249/3 8041/3 8013/3 8045/3 8013/3

Neuroendocrine tumour NOS Neuroendocrine tumour, grade 1 Neuroendocrine tumour, grade 2 Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Combined small cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; 13 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of neuroendocrine neoplasia in the female genital tract

11

WHO classification of haematolymphoid proliferations and neoplasia in the female genital tract 9680/3 9699/3 9690/3 9687/3

9930/3

Florid reactive lymphoid hyperplasia Diffuse large B-cell lymphoma NOS Extranodal marginal zone lymphoma of mucosaassociated lymphoid tissue Follicular lymphoma NOS Burkitt lymphoma NOS Sporadic Burkitt lymphoma Endemic Burkitt lymphoma Immunodeficiency-associated Burkitt lymphoma Myeloid sarcoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1149}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code 16 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

12

WHO classification of haematolymphoid proliferations and neoplasia in the female genital tract

WHO classification of mesenchymal tumours of the lower genital tract Skeletal muscle tumours 8905/0 Genital rhabdomyoma 8900/3 Rhabdomyosarcoma NOS 8910/3 Embryonal rhabdomyosarcoma NOS 8920/3 Alveolar rhabdomyosarcoma 8901/3 Pleomorphic rhabdomyosarcoma NOS

Adipocytic tumours 8850/0 Lipoma NOS 8881/0 Lipoblastoma-like tumour 8850/3 Liposarcoma NOS 8850/1 Atypical lipomatous tumour 8852/3 Myxoid liposarcoma 8851/3 Liposarcoma, well differentiated, NOS 8858/3 Dedifferentiated liposarcoma 8854/3 Pleomorphic liposarcoma Fibroblastic and myofibroblastic tumours Postoperative spindle cell nodule Fibroepithelial stromal polyp 8810/0 Fibroma NOS 8825/0 Myofibroblastoma 9160/0 Cellular angiofibroma 8826/0 Angiomyofibroblastoma 8815/1 Solitary fibrous tumour NOS 8815/3 Solitary fibrous tumour, malignant 8832/1 Dermatofibrosarcoma protuberans NOS 8833/1 Pigmented dermatofibrosarcoma protuberans 8832/3 Dermatofibrosarcoma protuberans, fibrosarcomatous NTRK-rearranged spindle cell neoplasm (emerging)

Peripheral nerve sheath tumours 9540/0 Neurofibroma NOS 9560/0 Schwannoma NOS 9580/0 Granular cell tumour NOS 9580/3 Granular cell tumour, malignant Tumours of uncertain differentiation 8841/0 Superficial angiomyxoma 8841/0 Aggressive angiomyxoma 8804/3 Epithelioid sarcoma Classic epithelioid sarcoma Proximal or large cell epithelioid sarcoma 9581/3 Alveolar soft part sarcoma Undifferentiated small round cell sarcomas 9364/3 Ewing sarcoma

Vascular tumours 9140/3 Kaposi sarcoma 9120/3 Angiosarcoma Smooth muscle tumours 8890/0 Leiomyoma NOS 8891/0 Epithelioid leiomyoma 8896/0 Myxoid leiomyoma 8897/1 Smooth muscle tumour of uncertain malignant potential 8890/3 Leiomyosarcoma NOS 8891/3 Epithelioid leiomyosarcoma 8896/3 Myxoid leiomyosarcoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

WHO classification of mesenchymal tumours of the lower genital tract

13

WHO classification of melanocytic lesions in the female genital tract 8720/0 8740/0 8750/0 8760/0 8761/0 8761/1 8780/0 8790/0

Naevus NOS Junctional naevus NOS Intradermal naevus Compound naevus Congenital melanocytic naevus NOS Giant pigmented naevus NOS Blue naevus NOS Cellular blue naevus

8720/0 8727/0 8720/3 8745/3 8721/3 8746/3

Atypical melanocytic naevus of genital type Dysplastic naevus Malignant melanoma NOS Desmoplastic melanoma Nodular melanoma Mucosal lentiginous melanoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1149). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; 12 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

14

WHO classification of melanocytic lesions in the female genital tract

TNM staging of gynaecological tumours Gynaecological Tumours

Introductory Notes The following sites are included: • Vulva • Vagina • Cervix uteri • Corpus uteri ° Endometrium ° Uterine sarcomas • Ovary, fallopian tube and primary peritoneal carcinoma • Gestational trophoblastic tumours Cervix uteri and corpus uteri were among the first sites to be classified by the TNM system. Originally, carcinoma of the cervix uteri was staged following the rules suggested by the Radiological Sub-Commission of the Cancer Commission of the Health Organization of The League of Nations. These rules were then adopted, with minor modifications, by the newly formed Federation Internationale de Gynecologie et d’Obstetrique (FIGO). Finally, UICC brought them into the TNM in order to correspond to the FIGO stages. FIGO, UICC, and AJCC work in close collaboration in the revision process. The classification of tumours of ovary and fallopian tube has been revised in line with the recent FIGO update.1

Histopathological Grading The definitions of the G categories apply to all carcinomas. These are: G - Histopathological Grading GX Grade of differentiation cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated or undifferentiated

Reference 1 Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet 2014; 124: 1-5.

Each site is described under the following headings: • Rules for classification with the procedures for assessing T, N, and M categories; additional methods may be used when they enhance the accuracy of appraisal before treatment • Anatomical subsites where appropriate • Definition of the regional lymph nodes • TNM clinical classification • pTNM pathological classification • Stage

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm -help-desk.

TNM staging of gynaecological tumours

15

TNM staging of ovarian, fallopian tube, and primary peritoneal carcinoma Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma (ICD-O-3 C56; IC D -0-3 C57)

The definitions of the T, N, and M categories correspond to the FIGO stages. Both systems are included for comparison.

Rules for Classification The classification applies to malignant ovarian neoplasms of both epithelial and stromal origin including those of borderline malignancy or of low malignant potential1corresponding to ‘common epithelial tumours’ of the earlier terminology. The classification also applies to carcinoma of the fallopian tubes and to carcinomas of the peritoneum (Mullerian origin). There should be histological confirmation of the disease and division of cases by histological type. The following are the procedures for assessing T, N, and M categories: T categories N categories M categories

Clinical examination, imaging, surgical exploration (laparoscopy/laparotomy) Clinical examination, imaging, surgical exploration (laparoscopy/laparotomy) Clinical examination, imaging, surgical exploration (laparoscopy/laparotomy)

TNM

F IG O

C a te g o r ie s

S ta g e s

T1c1

Surgical spill

T1c2

Capsule ruptured before surgery or tumour on ovarian or fallopian tube surface

T1c3

Malignant cells in ascites or peritoneal washings

II

Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below the pelvic brim) or primary peritoneal cancer

T2a

11A

Extension and/or implants on uterus and/or fallopian tube(s) and/or ovary(ies)

T2b

MB

Extension to other pelvic tissues, including bowel within the pelvis

III3

Tumour involves one or both ovaries or fallopian tubes or primary peritoneal carcinoma with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

T2

T3 and/or N1

N1

The FIGO stages are based on surgical staging. (TNM stages are based on clinical and/or pathological classification.)

Regional Lymph Nodes The regional lymph nodes are the hypogastric (obturator), common iliac, external iliac, lateral sacral, para-aortic, and retroperitoneal nodes.

Retroperitoneal lymph node metastasis only N1a

IIIA1 i

Lymph node metastasis not more than 10 mm in greatest dimension

N1b

IIIAlii

Lymph node metastasis more than 10 mm in greatest dimension

T3a any N

IIIA2

M icroscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without retroperitoneal lymph node, including bowel involvement

NIB

M acroscopic peritoneal metastasis beyond pelvic brim 2 cm or less in greatest dimension, including bowel involvement outside the pelvis with or without retroperitoneal nodes

me

Peritoneal metastasis beyond pelvic brim more than 2 cm in greatest dimension and/ or retroperitoneal lymph node metastasis (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of either organ)

IV

Distant metastasis (excludes peritoneal metastasis)

T3b any N

TNM Clinical Classification T - Primary Tumour TNM

F IG O

C a te g o rie s

S ta g e s

TX

^

... e mi lon

T3c any N

Primary tumour cannot be assessed

TO

No evidence of primary tumour

y«l

|

Tumour limited to one ovary or fallopian tube; capsule intact, no tumour on ovarian surface or fallopian tube surface; no malignant cells in ascites or peritoneal washings

y ^a

jg

y 1c

Tumour limited to the ovaries (one or both) or fallopian tube(s)

|£

Tumour limited to both ovaries or fallopian tubes; capsule intact, no tumour on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings Tumour limited to one or both ovaries or fallopian tubes with any of the following:

D e fin itio n

M1

M1a M1bb

IVA

Pleural effusion with positive cytology

IVB

Parenchymal metastasis and metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity)

Notes a Liver capsule metastasis is T3/stage III. b Liver parenchymal metastasis M1/stage IV.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

16

TNM staging of ovarian, fallopian tube, and primary peritoneal carcinoma

N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis N1 IIIA1 Retroperitoneal lymph node metastasis only N1a 111A1i Lymph node metastasis no more than 10 mm in greatest dimension N1b IIIAlii Lymph node metastasis more than 10 mm in greatest dimension M - Distant Metastasis MO No distant metastasis M1 Distant metastasis M1a Pleural effusion with positive cytology M1b Parenchymal metastasis and metastasis to extra­ abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity)

Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage

I IA IB IC II IIA IIB IIIA1 IIIA2 NIB MIC IV IVA IVB

T1 T1a T1b T1c T2 T2a T2b T1/2 T3a T3b T3c Any T Any T Any T

NO NO NO NO NO NO NO N1 N0,N1 N0,N1 N0,N1 Any N Any N Any N

MO MO MO MO MO MO MO MO MO MO MO M1 M1a M1b

Reference 1 Tavassoli FA, Devilee P (eds). WHO Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003.

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pNO Histological examination of a pelvic lymphadenectomy specimen will ordinarily include 10 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pNO. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

The information presented here has been excerpted from the 2017 TNM classification o f malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm -help-desk.

TNM staging of ovarian, fallopian tube, and primary peritoneal carcinoma

17

TNM staging of tumours of the uterus - endometrium Uterus - Endometrium (ICD-O-3 C54.0, 1, 3, 8, 9, C55)

The definitions of the T, N, and M categories correspond to the FIGO stages. Both systems are included for comparison.

TNM

F IG O

C a te g o r ie s

S ta g e s

III

Local and/or regional spread as specified here:

T3a

IMA

Tumour invades the serosa of the corpus uteri or adnexae (direct extension or metastasis)

T3b

NIB

Vaginal or parametrial involvement (direct extension or metastasis)

INC

Metastasis to pelvic or para-aortic lymph nodesb

N1

IIIC1

Metastasis to pelvic lymph nodes

N2

IIIC2

Metastasis to para-aortic lymph nodes with or without metastasis to pelvic lymph nodes

IV

Tumour invades bladder/bowel mucosa

T3

Rules for Classification The classification applies to endometrial carcinomas and carcinosarcomas (malignant mixed mesodermal tumours). There should be histological verification with subdivision by histological type and grading of the carcinomas. The diagnosis should be based on examination of specimens taken by endometrial biopsy. The following are the procedures for assessing T, N, and M categories: T categories N categories M categories

Physical examination and imaging including urography and cystoscopy Physical examination and imaging including urography Physical examination and imaging.

The FIGO stages are based on surgical staging. (TNM stages are based on clinical and/or pathological classification.)

Anatomical Subsites 1. Isthmus uteri (C54.0) 2. Fundus uteri (C54.3) 3. Endometrium (C54.1)

Regional Lymph Nodes The regional lymph nodes are the pelvic (hypogastric [obturator, internal iliac], common and external iliac, parametrial, and sacral) and the para-aortic nodes.

TNM Clinical Classification T - Primary Tumour TNM C a te g o rie s

F IG O S ta g e s

D e fin itio n

TX

Primary tumour cannot be assessed

TO

No evidence of primary tumour la

Tumour confined to the corpus uteri3

T1a

IAa

Tumour limited to endometrium or invading less than half of myometrium

T1b

IB

Tumour invades one half or more of myometrium

II

Tumour invades cervical stroma, but does not extend beyond the uterus

T1

T2

D e fin itio n

N1,N2

T4C

Notes a Endocervical glandular involvement only should be considered as stage I. b Positive cytology has to be reported separately without changing the stage. c The presence of bullous oedema is not sufficient evidence to classify as T4. N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis to pelvic lymph nodes N2 Regional lymph node metastasis to para-aortic lymph nodes with or without metastasis to pelvic lymph nodes M - Distant Metastasis MO No distant metastasis M1 Distant metastasis (excluding metastasis to vagina, pelvic serosa, or adnexa, including metastasis to inguinal lymph nodes, intra-abdominal lymph nodes other than para-aortic or pelvic nodes)

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pNO Histological examination of a pelvic lymphadenectomy specimen will ordinarily include 10 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pNO.

The information presented here has been excerpted from the 2017 TNM classification o f m alignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

18

TNM staging of tumours of the uterus - endometrium

Reference 1 Creasman WT, Odicino F, Maisoneuve P, Quinn MA, Beller U, Benedet JL, Heintz APM, Ngan HYS, Pecorelli S. FIGO Annual Report on the results of treatment in gynaecological cancer. Vol. 26. Carcinoma of the corpus uteri. Int J Gynecol Obstet 2006; 95 (Suppl. 1): 105-143.

pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

G Histopathological Grading For histopathological grading use G1, G2, or G3. For details see Creasman et al. 2006.1

Stage Stage 0 Stage IA Stage IB Stage II Stage MIA Stage NIB Stage NIC Stage IIIC1 Stage IIIC2 Stage IVA Stage IVB

Tis T1a T1b T2 T3a T3b T1.T2.T3 T1.T2.T3 T1.T2.T3 T4 Any T

NO NO NO NO NO NO N1,N2 N1 N2 Any N Any N

MO MO MO MO MO MO MO MO MO MO M1

The information presented here has been excerpted from the 2017 TNM classification of m alignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of tumours of the uterus - endometrium

19

TNM staging of uterine sarcomas Uterine Sarcomas (Leiomyosarcoma, Endometrial Stromal Sarcoma, Adenosarcoma) (ICD-O-3 C53, 54, 54.1, 54.2, 55)

The definitions of the T, N, and M categories correspond to the FIGO stages. Both systems are included for comparison.12

TNM

F IG O

C a te g o r ie s

S ta g e s

T3

Rules for Classification The classification applies to sarcomas except for carcinosarcoma, which is classified as carcinoma of the endometrium. There should be histological confirmation and division of cases by histological type. The following are the procedures for assessing T, N, and M categories: T categories N categories M categories

Physical examination and imaging Physical examination and imaging Physical examination and imaging

T3a

D e fin itio n

III

Tumour infiltrates abdominal tissues

IIIA

One site

NIB

More than one site

N1

INC

Metastasis to regional lymph nodes

T4

IVA

Tumour invades bladder or rectum

M1

IVB

Distant metastasis

T3b

Note Simultaneous tumours of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumours.

The FIGO stages are based on surgical staging. (TNM stages are based on clinical and/or pathological classification.) Adenosarcoma T - Primary Tumour Anatomical Subsites 1. Cervix uteri (C53) 2. Isthmus uteri (C54.0) 3. Fundus uteri (C54.3)

Histological Types of Tumours Leiomyosarcoma Endometrial stromal sarcoma Adenosarcoma

TNM

F IG O

C a te g o r ie s

S ta g e s

T1

8890/3 8930/3 8933/3

Regional Lymph Nodes The regional lymph nodes are the pelvic (hypogastric [obturator, internal iliac], common and external iliac, parametrial, and sacral) and the para-aortic nodes.

I

Tumour limited to the uterus

T1a

IA

Tumour limited to the endometrium/ endocervix

T1b

IB

Tumour invades to less than half of the myometrium

T1c

IC

Tumour invades more than half of the myometrium

II

Tumour extends beyond the uterus, within the pelvis

T2 T2a

11A

Tumour involves adnexa

T2b

MB

Tumour involves other pelvic tissues

III

Tumour involves abdominal tissues

T3a

IIIA

One site

T3b

NIB

More than one site

T3

TNM Clinical Classification Leiomyosarcoma, Endometrial Stromal Sarcoma T - Primary Tumour TNM

F IG O

C a te g o rie s

S ta g e s

T1

D e fin itio n

I

Tumour limited to the uterus

T1a

IA

Tumour 5 cm or less in greatest dimension

T1b

IB

Tumour more than 5 cm

II

Tumour extends beyond the uterus, within the pelvis

T2a

11A

Tumour involves adnexa

T2b

MB

Tumour involves other pelvic tissues

T2

D e fin itio n

N1

MIC

Metastasis to regional lymph nodes

T4

IVA

Tumour invades bladder or rectum

M1

IVB

Distant metastasis

Note Simultaneous tumours of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumours.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

20

TNM staging of uterine sarcomas

N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant Metastasis MO No distant metastasis M1 Distant metastasis (excluding adnexa, pelvic and abdominal tissues)

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

Stage - Uterine Sarcomas Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage

I IA IB IC* II IIA MB IIIA NIB NIC IVA IVB

T1 T1a T1b T1c T2 T2a T2b T3a T3b T1,T2,T3 T4 Any T

NO NO NO NO NO NO NO NO NO N1 Any N Any N

MO MO MO MO MO MO MO MO MO MO MO M1

Note * Stage IC does not apply for leiomyosarcoma and endometrial stromal sarcoma.

References 1 Prat J. FIGO staging for uterine sarcomas. Int J Gynaecol Obstet 2009; 104: 177-178. 2 FIGO Committee on Gynecologic Oncology Report. FIGO staging for uterine sarcomas. IntJ Gynaecol Obstet 2009; 104: 179.

The information presented here has been excerpted from the 2017 TNM classification o f m alignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm -help-desk.

TNM staging of uterine sarcomas

21

TNM staging of gestational trophoblastic neoplasms Gestational Trophoblastic Neoplasms (ICD-O-3 C58)

The following classification for gestational trophoblastic tumours is based on that of FIGO adopted in 1992 and updated in 2002.1 The definitions of T and M categories correspond to the FIGO stages. Both systems are included for comparison. In contrast to other sites, an N (regional lymph node) classification does not apply to these tumours. A prognostic scoring index, which is based on factors other than the anatomic extent of the disease, is used to assign cases to high-risk and low-risk categories, and these categories are used in stage grouping.

Rules for Classification The classification applies to choriocarcinoma (9100/3), invasive hydatidiform mole (9100/1), and placental site trophoblastic tumour (9104/1). Placental site tumours should be reported separately. Histological confirmation is not required if the human chorionic gonadotropin (phCG) level is abnormally elevated. History of prior chemotherapy for this disease should be noted. The following are the procedures for assessing T and M categories: Tcategories:

Clinical examination, imaging and endoscopy, and serum/urine (3hCG level M categories: Clinical examination, imaging, and assessment of serum/urine (3hCG level Risk categories: Age, type of antecedent pregnancy, interval months from index pregnancy, pretreatment serum/urine phCG, diameter of largest tumour, site of metastasis, number of metastases, and previous failed chemotherapy are integrated to provide a prognostic score that divides cases into low and high-risk categories.

TM Clinical Classification T - Primary Tumour TM

F IG O

C a te g o r ie s

S ta g e s 3

D e fin itio n

TX

Primary tumour cannot be assessed

TO

No evidence of primary tumour

T1

I

Tumour confined to uterus

T2b

II

Tumour extends to other genital structures: vagina, ovary, broad ligament, fallopian tube by metastasis or direct extension

M1a

III

Metastasis to lung(s)

M1bc

IV

Other distant metastasis

Notes a Stages I to IV are subdivided into A and B according to the prognostic score. b Genital metastasis (vagina, ovary, broad ligament, fallopian tube) is classified T2. c Any involvement of non-genital structures, whether by direct invasion or metastasis is described using the M classification.

pTM Pathological Classification The pT categories correspond to the T categories. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

Stage Stage Stage Stage Stage

I II III IV

T1 T2 Any T Any T

M0 M0 M1a M1b

Reference 1 Ngan HYS, Bender H, Benedet JL, Jones H, Montrucolli GC, Pecorelli S; FIGO Committee on Gynecologic Oncology. Gestational trophoblastic neoplasia. Int J Gynecol Obstet 2002; 77: 285-287.

The information presented here has been excerpted from the 2017 TNM classification o f m alignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

22

TNM staging of gestational trophoblastic neoplasms

TNM staging of tumours of the cervix uteri: 2021 revision Cervix Uteri (ICD-O-3 C53)

The definitions of the T, N, and M categories correspond to the Federation Internationale de Gynecologie et d ’Obstetrique (FIGO) stages. The FIGO classification has been revised (Bhatla et al. 2019).1 Both this and the AJCC v9 correspond to the 2018 FIGO Classification. The FIGO system is included for comparison.

TNM C atego ries

T1a2

F IG O S tag es

IA2

Clinical examination and imaging* Clinical examination and imaging Clinical examination and imaging

Note * Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumour size and extent, in all stages.

T ib

IB

Lesion confined to the cervix with depth of invasion greater than 5.0 mm

T ib i

IB1

Lesion 2.0 cm or less in greatest dimension

T1b2

IB2

Lesion more than 2.0 cm in greatest dimension but no more than 4.0 cm in greatest dimension

T1b3

IB3

Lesion more than 4.0 cm in greatest dimension

II

Tumour invades beyond uterus but not to pelvic wall or to lower third of vagina

T2a

IIA

Tumour without parametrial invasion

T2a1

IIA1

Lesion 4.0 cm or less in greatest dimension

T2a2

IIA2

Lesion more than 4.0 cm in greatest dimension

T2b

IIB

Tumour with parametrial invasion

III

Tumour involves lower third of vagina, or extends to pelvic wall, or causes hydronephrosis or non-functioning kidney

T3a

IIIA

Tumour involves lower third of vagina

T3b

IIIB

Tumour extends to pelvic wall, or causes hydronephrosis or non-functioning kidney

IVA

Tumour invades mucosa of the bladder or rectum, or extends beyond true pelvisc

T2

Anatomical Subsites 1. Endocervix (C53.0) 2. Exocervix (C53.1)

Regional Lymph Nodes The regional lymph nodes are the paracervical, parametrial, hypogastric (internal iliac, obturator), common and external iliac, presacral, lateral sacral nodes, and para-aortic nodes. T3

TNM Clinical Classification T - Primary Tumour TNM C ate go rie s

FIG O S tag es

e lnl lon

TX

Primary tumour cannot be assessed

TO

No evidence of primary tumour

T4

Tis

*

Ti

Carcinoma in situ (preinvasive carcinoma) |

Tumour confined to the cervix (extension to corpus should be disregarded)a

T1ab

IA

Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximal depth of 5.0 mmb

T1a1

IA1

Measured depth of stromal invasion 3.0 mm . r or less

Measured depth of stromal invasion more than 3.0 mm and not more than 5.0 mm Note: The depth of invasion should be taken from the base of the epithelium, either surface or glandular, from which it originates. The depth of invasion is defined as the measurement of the tumour from the epithelial-stromal junction of the adjacent most superficial papillae to the deepest point of invasion.

Rules for Classification The classification applies only to carcinomas. There should be histological confirmation of the disease. The following are the procedures for assessing T, N, and M categories: T categories N categories M categories

Definition

Notes * No FIGO equivalent; FIGO does not include Stage 0 (Tis). a Extension to corpus uteri should be disregarded. b Vascular space involvement, venous or lymphatic, does not affect classification. c Bullous oedema is not sufficient to classify a tumour as T4.

The information presented here is from Cervix Uteri TNM 2021 (for more information, see https://www.uicc.org/resources/tnm/publications-resources) (FIGO 2018). © 2021 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

TNM staging of tumours of the cervix uteri: 2021 revision

23

N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1* Regional lymph node metastasis to pelvic lymph nodes only N2* Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes Note * The suffix ‘mi’ is added if the lymph node metastasis is > 0.2 mm but < 2.0 mm. The suffix ‘(sn)’ is added if the metastasis is iden­ tified by sentinel node biopsy (see page 7 TNM Classification of Malignant Tumours, 8th Edition2). FIGO and AJCC add the suffix ‘a’ if the node metastasis is > 2.0 mm in size. M - Distant Metastasis M0 No distant metastasis M1 Distant metastasis (includes inguinal lymph nodes and intraperitoneal disease). It excludes metastasis to vagina, pelvic serosa, and adnexa

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pNO Histological examination of a pelvic lymphadenectomy specimen will ordinarily include 10 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pNO. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed

Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage

0 I IA IA1 IA2 I3 I31 IB2 IB3 I IA I A1 I A2 IB II I IA I IB I IC1 I IC2 IVA IVB

Tis T1 T1a T1a1 T1a2 T1b T1b1 T1b2 T1b3 T2 T2a T2a1 T2a2 T2b T3 T3a T3b TX,T0,Tis,T1,T2,T3 TX,T0,Tis,T1,T2,T3 T4 Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 Any N Any N

References 1 Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, Kehoe ST, Konishi I, Olawaiye AB, Prat J, Sankaranarayanan R, et al. Revised FIGO staging for carcinoma of the cervix uteri. Int J Gynecol Obstet 2019; 145: 129-135. doi:10.1002/ijgo.12749. Also the corrigendum. Int J Gynecol Obstet 2019; 147: 279-280. doi.org/10.1002/ ijgo.12969 2 Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th ed. Oxford, UK: WileyBlackwell; 2017.

Note * pMO and pMX are not valid categories.

The information presented here is from C ervix Uteri T N M 2021 (for more information, see https://www.uicc.org/resources/tnm/publications-resources) (FIGO 2018). © 2021 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

24

TNM staging of tumours of the cervix uteri: 2021 revision

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

TNM staging of tumours of the vagina Vagina (ICD-O-3 C52)

The definitions of the T and M categories correspond to the FIGO stages. Both systems are included for comparison.

Rules for Classification The classification applies to primary carcinomas only. Tumours present in the vagina as secondary growths from either genital or extragenital sites are excluded. A tumour that has extended to the portio and reached the external os (orifice of uterus) is classified as carcinoma of the cervix. A vaginal carcinoma occurring 5 years after successful treatment (complete response) of a carcinoma of the cervix uteri is considered a primary vaginal carcinoma. A tumour involving the vulva is classified as carcinoma of the vulva. There should be histological confirmation of the disease. The following are the procedures for assessing T, N, and M categories: Tcategories N categories M categories

Physical examination, endoscopy, and imaging Physical examination and imaging Physical examination and imaging

The FIGO stages are based on surgical staging. (TNM stages are based on clinical and/or pathological classification.)

Regional Lymph Nodes Upper two-thirds of vagina: the pelvic nodes including obturator, internal iliac (hypogastric), external iliac, and pelvic nodes, NOS. Lower third of vagina: the inguinal and femoral nodes.

TNM Clinical Classification T - Primary Tumour TN M

F IG O

C a te g o rie s

S ta g e s

N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant Metastasis MO No distant metastasis M1 Distant metastasis

TNM Pathological Classification The pT and pN categories correspond to the T and N categories. pNO FHistological examination of an inguinal lymphadenectomy specimen will ordinarily include 6 or more lymph nodes; a pelvic lymphadenectomy specimen will ordinarily include 10 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pNO. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

Stage Stage Stage Stage Stage

0 I II III

Stage IVA Stage IVB

Tis T1 T2 T3 T1,T2,T3 T4 Any T

NO NO NO NO N1 Any N Any N

MO MO MO MO MO MO M1

D e fin itio n

TX

Primary tumour cannot be assessed

TO

No evidence of primary tumour

Tis

Carcinoma in situ (preinvasive carcinoma)

T1

I

Tumour confined to vagina

T2

II

Tumour invades paravaginal tissues (paracolpium)

T3

III

Tumour extends to pelvic wall

T4

IVA

Tumour invades mucosa of bladder or rectum, or extends beyond the true pelvis*

M1

IVB

Distant metastasis

Note * The presence of bullous oedema is not sufficient evidence to classify a tumour as T4.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm -help-desk.

TNM staging of tumours of the vagina

25

TNM staging of tumours of the vulva Vulva (ICD-O-3 C51)

The definitions of the T, N, and M categories correspond to the FIGO stages.

Rules for Classification The classification applies only to primary carcinomas of the vulva. There should be histological confirmation of the disease. A carcinoma of the vulva that has extended to the vagina is classified as carcinoma of the vulva. The following are the procedures for assessing T, N, and M categories: Tcategories N categories M categories

Physical examination, endoscopy, and imaging Physical examination and imaging Physical examination and imaging

The FIGO stages are based on surgical staging. (TNM stages are based on clinical and/or pathological classification.)

Regional Lymph Nodes The regional lymph nodes are the inguinofemoral (groin) nodes.

TNM Clinical Classification T - Primary Tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour Tis Carcinoma in situ (preinvasive carcinoma), intraepithelial neoplasia grade III (VIN III) T1 Tumour confined to vulva or vulva and perineum T1a Tumour 2 cm or less in greatest dimension and with stromal invasion no greater than 1.0 mma T1b Tumour greater than 2 cm and/or with stromal invasion greater than 1 mma T2 Tumour invades any of the following structures: lower third urethra, lower third vagina, anus T3b Tumour invades any of the following perineal structures: upper 2/3 urethra, upper 2/3 vagina, bladder mucosa, rectal mucosa; or fixed to pelvic bone Notes aThe depth of invasion is defined as the measurement of the tumour from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. b T3 is not used by FIGO.

N1

N2

N3

Regional lymph node metastasis with the following features: N1a One or two lymph node metastases each less than 5 mm N1b One lymph node metastasis 5 mm or greater Regional lymph node metastasis with the following features: N2a Three or more lymph node metastases each less than 5 mm N2b Two or more lymph node metastases 5 mm or greater N2c Lymph node metastasis with extracapsular spread Fixed or ulcerated regional lymph node metastasis

M - Distant Metastasis MO No distant metastasis M1 Distant metastasis (including pelvic lymph node metastasis)

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pNO Histological examination of an inguinofemoral lymphadenectomy specimen will ordinarily include 6 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pNO. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage

0 I IA IB II IIIA NIB NIC IVA

Stage IVB

Tis T1 T1a T1b T2 T1,T2 T1,T2 T1,T2 T1,T2 T3 Any T

NO NO NO NO NO N1a,N1b N2a,N2b N2c N3 Any N Any N

MO MO MO MO MO MO MO MO MO MO M1

N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis

The information presented here has been excerpted from the 2017 TNM classification o f malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

26

TNM staging of tumours of the vulva

TNM staging of tumours of soft tissues Soft Tissues (ICD-0-3 C38.1, 2, 3, C47-49)

Rules for Classification There should be histological confirmation of the disease and division of cases by histological type and grade. The following are the procedures for assessing T, N, and M categories: T categories Physical examination and imaging N categories Physical examination and imaging M categories Physical examination and imaging

Anatomical Sites 1. Connective, subcutaneous, and other soft tissues (C49), peripheral nerves (C47) 2. Retroperitoneum (C48.0) 3. Mediastinum: anterior (C38.1); posterior (C38.2); mediastinum, NOS (C38.3)

Histological Types of Tumour The following histological types are not included: • Kaposi sarcoma • Dermatofibrosarcoma (protuberans) • Fibromatosis (desmoid tumour) • Sarcoma arising from the dura mater or brain • Angiosarcoma, an aggressive sarcoma, is excluded because its natural history is not consistent with the classification. Note Cystosarcoma phyllodes is staged as a soft tissue sarcoma of the superficial trunk.

Regional Lymph Nodes The regional lymph nodes are those appropriate to the site of the primary tumour. Regional node involvement is rare and cases in which nodal status is not assessed either clinically or pathologically could be considered NO instead of NX or pNX.

TNM Clinical Classification T - Primary Tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour Extremity and Superficial Trunk T1 Tumour 5 cm or less in greatest dimension T2 Tumour more than 5 cm but no more than 10 cm in greatest dimension T3 Tumour more than 10 cm but no more than 15 cm in greatest dimension T4 Tumour more than 15 cm in greatest dimension

Retroperitoneum T1 Tumour 5 cm or less in greatest dimension T2 Tumour more than 5 cm but no more than 10 cm in greatest dimension T3 Tumour more than 10 cm but no more than 15 cm in greatest dimension T4 Tumour more than 15 cm in greatest dimension Head and Neck T1 Tumour 2 cm or less in greatest dimension T2 Tumour more than 2 cm but no more than 4 cm in greatest dimension T3 Tumour more than 4 cm in greatest dimension T4a Tumour invades the orbit, skull base or dura, central compartment viscera, facial skeleton, and/or pterygoid muscles T4b Tumour invades the brain parenchyma, encases the carotid artery, invades prevertebral muscle or involves the central nervous system by perineural spread Thoracic and Abdominal Viscera T1 Tumour confined to a single organ T2a Tumour invades serosa or visceral peritoneum T2b Tumour with microscopic extension beyond the serosa T3 Tumour invades another organ or macroscopic extension beyond the serosa T4a Multifocal tumour involving no more than two sites in one organ T4b Multifocal tumour involving more than two sites but not more than 5 sites T4c Multifocal tumour involving more than five sites N - Regional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant Metastasis MO No distant metastasis M1 Distant metastasis

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. pM - Distant Metastasis* pM1 Distant metastasis microscopically confirmed Note * pMO and pMX are not valid categories.

The information presented here has been excerpted from the 2017 TNM classification of m alignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm -help-desk.

TNM staging of tumours of soft tissues

27

Stage - Extremity and Superficial Trunk and Retroperitoneum Stage Stage Stage Stage Stage

IA IB II MIA NIB

Stage IV

T1 T2,T3,T4 T1 T2 T3,T4 Any T Any T

NO NO NO NO NO N1* Any N

MO MO MO MO MO MO M1

G1,GX G1,GX G2.G3 G2,G3 G2,G3 Any G Any G

Low Grade Low Grade High Grade High Grade High Grade

Stage - Head and Neck and Thoracic and Abdominal Viscera There is no stage for soft tissue sarcoma of the head and neck and thoracic and abdominal viscera.

Note * AJCC classifies N1 as stage IV for extremity and superficial trunk.

The information presented here has been excerpted from the 2017 TNM classification o f malignant tumours, eighth edition {295,2790}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://w w w .uicc.org/tnm -help-desk.

28

TNM staging of tumours of soft tissues

General introduction

The classification of female genital tumours has evolved sig­ nificantly over the past decade in light of new and often key molecular discoveries that have influenced the categorization of a number of these neoplasms. Distinctive molecular altera­ tions are now known for many female genital tumours and have proved to be helpful for their correct categorization. Therefore, as in other organ systems, the morphological classification continues to advance into an integrated morphological-molec­ ular classification that will have an impact on diagnosis and treatment. One of the best-known applications of molecular pathology pertains to endometrial carcinomas: surrogate immunohistochemical markers (except for POLE) are used to stratify these tumours into four subgroups with distinctive prognoses, as defined by The Cancer Genome Atlas (TCGA) project. However, it is recommended that the molecular char­ acterization of endometrial carcinoma should be restricted to high-grade tumours, because more than two thirds of endo­ metrial carcinomas are low-stage and low-grade endometrioid carcinomas associated with an excellent prognosis and do not need molecular profiling. The classification of female genital tumours, as well as those of other organ systems, is intended for worldwide use, and there are many areas where, for various reasons, the application of immunohistochemistry or molecu­ lar pathology is limited. Additionally, standard aspects of con­ ventional pathology remain the bedrock of the interpretation and classification of female genital tract (FGT) neoplasms in routine practice, and to emphasize this point, the essential diagnostic criteria for each entity in this volume are based on these characteristics. The organization of this fifth edition of the female genital tumours volume follows the general structure of other vol­ umes in this series and differs from the prior edition in several respects. To avoid repetition, new chapters have been created to amalgamate entities that have similar morphological and molecular findings at different sites, including mesenchymal tumours of the lower FGT, metastases to the lower FGT, hae­ matopoietic neoplasms, neuroendocrine neoplasms (NENs), and associated hereditary syndromes. NENs of the FGT (with the exception of ovarian carcinoid tumours, due to their spe­ cific characteristics and germ cell origin) are now classified following the terminology of their pulmonary and pancreatic counterparts and a recently published consensus proposal initiated by the International Agency for Research on Cancer (IARC) and WHO {2292}, although studies are still needed with regard to optimal terminology in the FGT. Among the haemat­ opoietic neoplasms, emphasis is given to those entities more commonly occurring within the FGT and specifically in each organ. Terminology is the common language used by patholo­ gists and treating physicians for optimal patient care, and it should be consistently applied. Therefore, before making a change to terminology, it is important to consider the impact

Lax SF Cheung AN Oliva E

of that change. For this reason, the editorial board preferred to retain the existing, well-established terminology for several tumours. For example, in the ovary, the term “small cell car­ cinoma of hypercalcaemic type” has been retained over the proposed rhabdoid tumour terminology, because although most of these tumours are associated with SMARCA4 muta­ tions, only a minority show overt rhabdoid morphology, and it is still controversial whether they are identical to rhabdoid tumours. On the other hand, some important revisions have been made since the fourth edition of the WHO classifica­ tion. For example, serous borderline tumours with micropap­ illary architecture are now included within the broad group of serous borderline tumours, and the term “non-invasive low-grade serous carcinoma” is not recommended for them. Low-grade and high-grade serous ovarian carcinomas are considered distinct tumour types rather than a spectrum, because they have different origins, as well as different mor­ phology and molecular and genetic signatures. Among the uterine neoplasms, carcinosarcoma is now classified as an endometrial carcinoma rather than a mixed tumour, on the basis of molecular and biological similarity to high-grade endometrial carcinomas. Undifferentiated endometrial car­ cinoma, including dedifferentiated carcinoma, is considered a distinct entity supported by molecular alterations involving the SWI/SNF pathway. Minor changes include the reclas­ sification of different subtypes of endometrioid carcinoma (e.g. with squamous differentiation) as simply patterns of endometrioid carcinoma, leading to a leaner classification. Among the mesenchymal tumours, the category of smooth muscle tumours has been expanded with the new category of fumarate hydratase-deficient leiomyomas, and the cat­ egory of high-grade endometrial stromal sarcoma has been expanded to include neoplasms with novel gene fusions (in particular involving the BOOR gene), whereas the undiffer­ entiated uterine sarcoma entity has been redefined. In the category of mixed tumours of the uterus, the term “adenofi­ broma” is no longer recommended. HPV has dramatically changed the approach to epithelial tumours of the lower FGT, and this shift is reflected herein. Adenocarcinomas of the uterine cervix are now divided into HPV-associated and HPV-independent adenocarcinomas, with implications for prognosis. More importantly, recent studies have put forward a reproducible histological surro­ gate for HPV infection, allowing for such classification without HPV analysis. Squamous tumours of the lower FGT are also divided into HPV-associated and HPV-independent, because important differences in outcome exist. Squamous precur­ sor lesions throughout the lower FGT are primarily classified according to the binary Lower Anogenital Squamous Ter­ minology (LAST) standardization project proposal, but the three-tiered intraepithelial neoplasia classification can still be used. General introduction

29

Most grading systems rely on mitotic activity and necrosis. An important change in this edition of the WHO Classification of Tumours series is the conversion of mitotic count from the traditional denominator of 10 HPF to a defined area expressed in mm2. This serves to standardize the true area over which mitoses are enumerated, because different microscopes have high-power fields of different sizes. This change will also be helpful for anyone reporting using digital systems. The approx­ imate number of fields per 1 mm2 based on the field diameter and its corresponding area is presented in Table A. Finally, increased knowledge about hereditary tumour syn­ dromes has enabled us to detect carriers at an early age through counselling and genetic testing, more commonly in Lynch

syndrome but also for other rare syndromes. Lynch syndrome patients may be the best-known example, because endometrial cancer is not infrequently their first presentation. Immunohistochemistry, which can be performed in most pathology settings, is key for triaging these patients for further studies. Another exam­ ple is patients with Peutz-Jeghers syndrome, who typically have bilateral, small, and multifocal sex cord tumours with annular tubules and may have cervical gastric-type mucinous adenocar­ cinoma, typically associated with STK11 alterations. These exam­ ples illustrate the increasingly important role of pathologists in the multidisciplinary assessment of hereditary diseases. The ICD-O topographical coding for the anatomical sites cov­ ered in this volume is presented in Box A.

Approximate number of fields per 1 mm2based on the field diameter and its corresponding area

B o x A ICD-0 topographical coding for the main anatomical sites covered in this volume {817}

T a b le A

Approximate number of ., . » fields per 1 mm2

Field diameter (mm) v

Fie d area (mm2) v

0.40

0.126

8

0.41

0.132

8

0.42

0.138

7

0.43

0.145

7

0.44

0.152

7

0.45

0.159

6

0.46

0.166

6

0.47

0.173

6

0.48

0.181

6

0.49

0.188

5

0.50

0.196

5

0.51

0.204

5

0.52

0.212

5

0.53

0.221

5

0.54

0.229

4

0.55

0.237

4

’

'

C51 Vulva

C51.0 Labium majus C51.1 Labium minus C51.2 Clitoris C51.8 Overlapping lesion of vulva C51.9 Vulva NOS C52 Vagina

C52.9 Vagina NOS C53 Cervix uteri

C53.0 Endocervix C53.1 Exocervix C53.8 Overlapping lesion of cervix uteri C53.9 Cervix uteri C54 Corpus uteri

C54.0 Isthmus uteri C54.1 Endometrium C54.2 Myometrium C54.3 Fundus uteri C54.8 Overlapping lesion of corpus uteri C54.9 Corpus uteri C55 Uterus NOS

C55.9 Uterus NOS C56 Ovary

C56.9 Ovary C57 Other and unspecified female genital organs

30

0.56

0.246

4

0.57

0.255

4

0.58

0.264

4

0.59

0.273

4

0.60

0.283

4

0.61

0.292

3

0.62

0.302

3

0.63

0.312

3

0.64

0.322

3

0.65

0.332

3

0.66

0.342

3

0.67

0.352

3

0.68

0.363

3

0.69

0.374

3

General introduction

C57.0 Fallopian tube C57.1 Broad ligament C57.2 Round ligament C57.3 Parametrium C57.4 Uterine adnexa C57.7 Other specified parts of female genital organs C57.8 Overlapping lesion of female genital organs C57.9 Female genital tract NOS C58 Placenta

C58.9 Placenta

T u m o u rs o f th e o v a ry Edited by: Cheung AN, Ellenson LH, Gilks CB, Kim K-R, Kong CS, Lax SF, Longacre TA, Malpica A, McCluggage WG, Oliva E, Rabban JT, Soslow RA

Serous tumours Mucinous tumours Endometrioid tumours Clear cell tumours Seromucinous tumours Brenner tumours Other carcinomas Mesenchymal tumours Mixed epithelial and mesenchymal tumours Sex cord-stromal tumours Germ cell tumours Miscellaneous tumours Mesothelial tumours (see Chapter 3) Tumour-like lesions Metastases

McCluggage WG Lax SF Longacre TA Malpica A Soslow RA

Tumours of the ovary: Introduction

Estimated age-standardized incidence rates (World) in 2018, ovary, all ages

ASR (World) per 100 000

£ 8.1 6.75.5-6.7 3.8