Atlas of Liver Pathology [3 ed.] 9781455706266

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ATLAS OF LIVER PATHOLOGY

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ATLAS OF LIVER PATHOLOGY Third Edition

Gary C. Kanel, M.D. Professor of Clinical Pathology Keck School of Medicine University of Southern California Associate Pathologist Los Angeles County + USC Medical Center and USC University Hospital Los Angeles, California

Jacob Korula, M.D. Comprehensive Liver Disease Center St. Vincent Medical Center Los Angeles, California

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

ATLAS OF LIVER PATHOLOGY THIRD EDITION Copyright © 2011, 2005, 1992 by Saunders, an imprint of Elsevier Inc.

ISBN: 978-1-4377-0765-6

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Knowledge and best practice in this ield are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identiied, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data Kanel, Gary C. Atlas of liver pathology / Gary C. Kanel, Jacob Korula. -- 3rd ed. p. ; cm. Liver pathology Includes bibliographical references and index. ISBN 978-1-4377-0765-6 (hardcover : alk. paper) 1. Liver--Diseases--Atlases. I. Korula, Jacob. II. Title. III. Title: Liver pathology. [DNLM: 1. Liver Diseases--pathology--Atlases. 2. Biopsy--Atlases. 3. Diagnosis, Differential--Atlases. WI 17] RC846.9.K35 2011 616.3’62--dc22 2010034856

Executive Publisher: William Schmitt Senior Developmental Editor: Andrew Hall Publishing Services Manager: Patricia Tannian Senior Project Manager: Kristine Feeherty Design Direction: Steven Stave

Printed in the United States of America Last digit is the print number: 9

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To our families who support us and our colleagues who teach us much

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PREFACE Although over a decade passed between the publication of the irst and second editions of the Atlas of Liver Pathology, the rapid development in understanding the pathophysiologic concepts of diseases and identifying variations in morphologic features of these diseases necessitates a third edition over a much shorter time span. The new diagnostic tools leading to more sophisticated laboratory testing have been a hallmark in learning the etiology and pathophysiology of diseases. Where before morphologic changes were ascribed to various liver disorders without a good understanding of their signiicance, the advent of new testing procedures such as genome sequencing much better helps us understand what we see under light microscopy. An excellent example is the ongoing research in liver tumors that examines cellular signaling pathways and molecular proiling, identiies individual genes and gene groups associated with higher instances of the development of hepatocellular carcinoma in cirrhotic livers, and correlates all of the above with the morphology seen in liver biopsy specimens. The changes in the updated third edition include the use of gross images of various liver diseases with direct

correlation with the light microscopy. In addition, the total number of images has increased by approximately 50% from the second edition. What has also been added is a second section addressing speciic morphologic changes in table format and listing the various liver diseases associated with these changes. This section, which has been updated from our previous book, Liver Biopsy Evaluation, speciically aids the reader in arriving at diagnoses and differential possibilities solely on morphology, then referring the reader to the text and images of the speciic diseases in the irst part of the book. We hope that this new edition will be successful in providing pathologists, clinicians, and students a better understanding of liver pathology and disease concepts and will be a useful practical tool. The overall aim does not change from the previous editions: to offer a concise illustrative text in liver and hepatobiliary pathology. Gary Kanel, M.D. Jacob Korula, M.D. Los Angeles, California

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CONTENTS PART

I Liver and Hepatobiliary Pathology with Clinical Correlations Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter

1 2 3 4 5 6 7 8 9 10 11 12

General Aspects of the Liver and Liver Diseases 3 Viral Hepatitis 16 Cholestasis and Biliary Tract Disorders 52 Alcoholic and Non-Alcoholic Fatty Liver Diseases 71 Drug- and Toxin-Induced Liver Cell Injury 93 Vascular Disorders 134 Infectious Disorders, Non-Viral 154 Developmental, Familial, and Metabolic Disorders 194 Diseases of Hepatic Iron and Copper Metabolism 236 Neoplasms and Related Lesions 249 Transplantation 321 Miscellaneous Conditions 353

PART

II Liver Biopsy Evaluation: Morphology with Differential Diagnoses Introduction 379 Tables of Morphology 381 Appendix

Chronic Liver Diseases: Staging and Grading Systems 489

Index 495

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ATLAS OF LIVER PATHOLOGY

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PART

I LIVER AND HEPATOBILIARY PATHOLOGY WITH CLINICAL CORRELATIONS

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Chapter

1 THE NORMAL LIVER 3 Embryology 3 Gross Anatomy 3 Microanatomy 5

GENERAL ASPECTS OF THE LIVER AND LIVER DISEASES STEM CELLS 9 COMMON PIGMENTS 11 SYSTEMATIC APPROACH IN LIVER BIOPSY INTERPRETATION 12

THE NORMAL LIVER Embryology (Figs 1-1 through 1-5) 1. The hepatic primordium anlage irst appears toward the end of the third week of gestation as a hollow midline outgrowth of the endodermal epithelium (hepatic diverticulum). 2. Eventually the diverticulum enlarges (proliferation of hepatoblasts), projects cranially into the mesoderm of the septum transversum, and eventually develops into the hepatic parenchyma. 3. The proliferating endodermal cells form solid anastomosing cords, vesicles, and cribriform tubules that form luminal structures (precursor of the biliary canaliculi). 4. The hepatoblasts (progenitor cells) by way of rapid growth eventually develop into hepatic cords that initially are thickened at birth (muralium multiplex) but eventually evolve into trabeculae one cell thick (muralium simplex), with those cords adjacent to the portal mesenchyme becoming the ductal plates. These progenitor cells also can generate into both mature hepatocytes and ductules, and they can express markers of both (α-fetoprotein for liver cells and cytokeratins 7 and 19 for duct epithelium). 5. The mesoderm of the septum transversum forms the lesser omentum, falciform, coronary and triangular ligaments, and hepatic (Glisson’s) capsule. 6. The vascular network, derived from the vitelline and umbilical veins, occurs at the same time as the proliferation of the hepatoblasts, with the cords and vessels anastomosing and forming the hepatic sinusoids. 7. By the ifth week, most of the major vessels (right and left umbilical veins, transverse portal sinus, ductus venosus, portal vein) are identiied. 8. The biliary system develops from membranous infoldings occurring between the junctional complexes between individual hepatoblasts, appearing initially only as thin intercellular spaces. Bile canaliculi are irst seen at week 6, with bile synthesis occurring by week 9 and bile secretion by week 12, at which time a distinct lumen is apparent.

GENERAL CLINICAL CONSIDERATIONS OF ACUTE AND CHRONIC LIVER DISEASES 12 Acute Hepatic Injury 12 Chronic Hepatic Injury 15

9. Invasion of these double-layered tubular ductal cells into the portal mesenchyme forms an anastomosing network that is not fully formed by birth; after birth, remodeling occurs, forming the interlobular bile ducts. 10. Hematopoiesis begins in the mesoderm at approximately 6 weeks’ gestation; it is most active during the sixth and seventh months but then rapidly decreases and is usually absent by 1 month of age. 11. The perisinusoidal (Ito, stellate) cells and Kupffer cells appear by 3 months’ gestation. 12. The individual cell functions occur at different time periods during fetal development. They include synthesis of the following: a. α-Fetoprotein, which is in high quantities at birth and is initially present by 1 month gestation b. Glycogen, which is seen by 2 months, with glycogen synthesis by 3 months c. Fat, occurring at the same time as glycogen d. Hemosiderin (iron pigment), which is most evident during active hematopoiesis

Gross Anatomy (Fig. 1-6) 1. The liver in the adult takes up most of the right upper quadrant of the abdomen, measures approximately 15 to 20 cm in width, and weighs from 1200 to 1800 g, depending on the person’s overall body size. At birth, however, the liver is proportionately larger compared to the adjacent thoracic and abdominal viscera. 2. The liver anatomically has four lobes (right, left, caudate, and quadrate), with the right lobe accounting for ½ to 2⁄3 of the total liver volume; however, functionally both the right and left lobes are approximately equal in size and are divided by a line extending from the middle of the gallbladder fossa inferiorly to the inferior vena cava superiorly. 3. There are eight functional hepatic segments, each demarcated by the vascular and biliary drainage: a. Lateral divisions of the right lobe (segments VI and VII) b. Medial divisions of the right lobe (segments V and VIII) 3

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

Bare area Lesser of liver omentum Diaphragm

Thyroid Tongue Pericardial cavity Septum transversum Liver Vitelline duct

Tracheobronchial diverticulum Esophagus Stomach

Dorsal mesogastrium

Falciform ligament Gallbladder

Pancreas Duodenum

Pancreas Gallbladder

Allantois Hindgut Cloacal membrane

FIGURE 1-1 Embryonic development. The drawing to the left represents a 9-mm embryo that is approximately at the 36th day of gestation. The liver originates from the hepatic diverticulum and projects cranially into the septum transversum and caudally into the abdominal wall. The drawing to the right represents a slightly older embryo. The falciform ligament can now be seen between the liver parenchyma and the anterior abdominal wall. (From Langman J. Medical Embryology. 2nd ed. Baltimore: Williams & Wilkins, 1969, with permission.)

FIGURE 1-2 Embryonic development. The portal tract demonstrates the mesenchymal framework composed of spindle cells intermixed with a few scattered immature erythroid and myeloid precursors. Three small ductules are present at the border of the portal tract and parenchyma at the left of the ield. The adjacent periportal zone of the lobule shows prominent extramedullary hematopoiesis within the sinusoids.

c. Medial division of the left lobe (segment IV) d. Lateral divisions of the left lobe (segments II and III) e. Caudate lobe (segment I) 4. The hepatoduodenal ligament connects the liver to the superior aspect of the duodenum and supports the hilar vessels and ducts. The transverse issure divides the right lobe from the caudate lobe, and the umbilical issure, located to the left of the quadrate lobe, is bordered on the right by the gallbladder. 5. The falciform ligament, formed from the peritoneal layer and extending between the liver and the anterior abdominal wall, separates into the superior layer of the coronary ligament and the left triangular ligament; the ligamentum teres, located along the lower edge of the falciform ligament, contains the obliterated umbilical vein remnant.

FIGURE 1-3 Embryonic development. This developing ductule at the edge of the portal structure shows extension through the limiting plate, joining up with the canals of Hering that are partly lined by hepatocytes and ductules (cholangioles).

6. The portal vein, the main route of vascular drainage of the gastrointestinal tract, develops from the merger of the superior mesenteric and splenic veins, receives blood from the coronary and cystic veins, and is divided into the right and left branches. 7. The hepatic vein is composed of three major tributaries (right, middle, and left intrahepatic branches) and drains blood low from the right, left, and quadrate lobes into the inferior vena cava. The caudate lobe drains directly into the inferior vena cava. 8. The hepatic artery is a branch of the celiac artery, ascends along the hepatoduodenal ligament, and is divided into the right hepatic artery, the left hepatic artery, and the middle hepatic artery. a. The right hepatic artery is seen behind the common hepatic duct after giving rise to the cystic artery. b. The left hepatic artery passes upward and to the left in the porta hepatis. c. The middle hepatic artery feeds the quadrate lobe.

Chapter 1 / General Aspects of the Liver and Liver Diseases

FIGURE 1-4 Embryonic development. Prominent extramedullary hematopoiesis is seen within the sinusoids, with the erythroid precursors most abundant in this ield. The hepatic cords are up to two cells thick, with the individual hepatocytes showing scantier cytoplasm than seen in the fully developed liver.

FIGURE 1-5 Embryonic development. The fetal hepatocytes characteristically demonstrate abundant α-fetoprotein within the cytoplasm. (Immunoperoxidase stain for α-fetoprotein.)

9. The biliary system, which originates from the bile canaliculi, can grossly be visualized by the larger interlobular and interlobar branches. It is fed by the hepatic artery and its branches. 10. The lymphatic channels are divided into the deep and supericial branches, and the nerve supply is seen immediately adjacent to the main hepatic artery and portal vein and is divided into parasympathetic and sympathetic ibers. Many of the nerve ibers terminate on endothelial cells lining the smallest arteriolar segments and along Kupffer and stellate cells and hepatocytes.

Microanatomy (Figs 1-7 through 1-14) 1. The basic architecture includes the portal tracts, sinusoids, and outlow vessels (terminal hepatic venules and veins), all of which are evenly spaced throughout all lobes of the liver.

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2. The portal tracts are composed of the following: a. Interlobular bile ducts: Usually one and occasionally two per portal structure and seen immediately adjacent to the small hepatic artery and arteriole segments (from which they receive their blood supply) b. Hepatic arterioles: Most often singly present and drain blood into the sinusoidal network c. Portal venules: Usually a single vascular structure that provides direct communication with the sinusoids d. Fibroconnective tissue (collagen): Provides support for the major portal structures e. Cellular inlammatory cells: Composed of scanty numbers of lymphocytes, which can at times be sparsely seen in healthy livers 3. The parenchyma in the adult comprises almost 4⁄5 of the total hepatic volume and is composed predominantly of one-cell thick liver cell cords and plates with adjacent sinusoids that are lined by endothelial, Kupffer, and stellate (Ito) cells. The sinusoids then drain into the terminal hepatic venules. 4. The hepatocytes comprise approximately 2⁄3 of the total number of cells within the liver, measure 25 to 40 µm in diameter, and are arranged in one-cell thick hepatic cords and plates that have three distinct cell membrane boundaries: sinusoidal (basolateral), lateral (intercellular), and canalicular. The gap junctions represent the two adjacent liver cell membranes having a distinct 2- to 4-µm gap where there is communication between cells for transport of various components such as metabolites. Desmosomes, intermediate junctions, and tight junctions further play roles in cell membrane resilience and permeability. 5. The hepatocyte is composed of a nucleus and cytoplasm. a. The centrally located nucleus measures approximately 10 µm in diameter and contains nucleoli and clumped chromatin. The nuclear membranes have apertures (pores) that provide communication between the nucleus and cytoplasm. From one to six nucleoli may be present, their number and size in direct proportion to their degree of activity. The nucleus is usually single, although bilobed forms may be seen in elderly patients as well as in liver cells undergoing active reduplication and regeneration. In addition, variation in nuclear size can occur (nuclear anisocytosis), with enlarged nuclei in the perivenular zone (zone 3 of Rappaport) sometimes seen, especially in the elderly patient population. b. The cytoplasm comprises approximately 90% of the volume of the liver cell and contains various functional components. In addition, the overall superstructure of the cell is maintained by various ilaments, including the microilaments, microtubules, and intermediate ilaments, each with its own special functions. The various intracellular components are outlined in Table 1-1. c. Other intracellular components that can be seen on light microscopy include various pigments (lipochrome, hemosiderin, bile), lipids (macrovesicular and microvesicular fat), and glycogen (within both nuclei and cytoplasm). 6. Kupffer cells are oval to oblong sinusoidal lining cells with stellate cytoplasm that function as tissue macrophages. Originally derived from the circulation, these cells eventually attach to the sinusoidal borders and

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

Inferior vena cava

Right hepatic vein

Left and middle hepatic veins

II

VII VIII I IV

III

Right and left branches of hepatic artery

VI V

Portal vein Hepatic artery

Portal triad

Bile duct Gallbladder

FIGURE 1-6 Anatomic and functional subdivisions. The eight functional anatomic segments of the liver are demonstrated in this drawing. Each individual segment has its own blood supply and biliary drainage. The subdivisions include the right lateral (segments VI and VII) and medial (segments V and VIII) divisions, the left medial (segment IV) and lateral (segments II and III) divisions, and the caudate lobe (segment I). (From Moore KL, Dalley II AF. Clinically Oriented Anatomy. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999, with permission.)

overlie but do not form junctional complexes with the underlying endothelial lining cells. Their primary functions include phagocytosis and eventual clearance of particulate material and endotoxins, clearance of senescent erythrocytes and degenerating cellular components, sequestration of antigens, and clearance of immune complexes. 7. Endothelial cells are lattened, elongated sinusoidal cells that contain numerous cytoplasmic projections and clustered fenestrae or gaps ranging from 0.1 to 0.2 µm in diameter. These structures function by iltering the sinusoidal blood of various macromolecules by receptormediated anisocytosis, enabling certain substances such as glycoproteins direct contact with the hepatocyte, while excluding larger cellular compounds. 8. Stellate (perisinusoidal, Ito, “fat-storing”) cells, seen along the perisinusoidal liver cell recesses within the space of Disse, contain variably sized lipid droplets that have high concentrations of vitamin A (retinoyl palmitate, demonstrated by autoluorescence on frozen tissue sections). These cells synthesize extracellular matrix by way of cytokine activation and resultant transformation to myoibroblasts in response to liver injury. 9. Pit cells (liver-associated lymphocytes) are T cells distributed within the sinusoids in loose contact with the Kupffer and endothelial cells and rarely within portal tracts. They act as natural lymphocyte-activated killer

(NK) cells and are often seen in direct contact with the endothelium in response to various immunologic processes (e.g., viral hepatitis, cellular post-transplant rejection). 10. Stroma (extracellular matrix) supports the basic hepatic architectural arrangement, produces intercellular cohesion, and effects cellular differentiation. Glisson’s capsule overlies the liver and is composed of hypocellular dense collagen. Five basic types of collagen are present, with types I and III representing more than 95% of the total collagen. In addition, various noncollagenous glycoproteins that are responsible for collagen adhesion and stability include laminin, ibronectin, and elastin. The laydown of these stromal elements is often triggered by stellate cell activation in instances of liver cell injury. 11. The biliary network, whose main function is to transport bile synthesized by the hepatocyte into the gastrointestinal tract, can be subdivided into the following: a. Biliary canaliculi: Located along the intercellular spaces between the liver cells, 0.5 to 1.0 µm in diameter, lined by microvilli; sometimes dificult to see on routine histology but can be highlighted using polyclonal carcinoembryonic antigen (pCEA) and CD10 immunoperoxidase stains b. Ducts (canals) of Hering (cholangioles): Derived from liver cells at the portal tract limiting plate and have both liver cell and ductal ultrastructural and

Chapter 1 / General Aspects of the Liver and Liver Diseases

Arterial capillary emptying into para-portal sinusoid

Arterial capillary emptying into para-portal sinusoid Perisinusoidal space of Disse

Portal vein

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Periportal Limiting connective plate tissue

Central (hepatic) veins Lymph vessel

Sinusoids

Central (hepatic) veins Sublobular vein

Perisinusoidal space of Disse

Cental (hepatic) veins

Central (hepatic) veins

Intralobular cholangiole Bile canaliculi on the surface of liver plates (not frequent) Arterial capillary Inlet emptying into venules Portal intra-lobular sinusoid vein

Bile Hepatic Limiting duct artery plate

Cholangioles in portal canals

Portal tract

FIGURE 1-7 Normal hepatic architecture. This three-dimensional reconstruction of the normal hepatic architecture shows that the liver cell plates, rather than simply radiating from a terminal hepatic venule (as seen on light microscopy), are actually a labyrinth of intercommunicating plates and sinusoids. The diagram also shows the various communications of the portal structures (portal vein, bile duct, hepatic artery) with the adjacent lobule. (From Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 11th ed. West Sussex, UK: Wiley-Blackwell, 2002, with permission.)

FIGURE 1-8 Basic lobular architecture. Blood lows from the portal tract (right of the ield) into the hepatic sinusoids and leaves the lobule via the terminal hepatic (“central”) venule (left of the ield).

histochemical features; aid in communication with the portal interlobular bile ducts c. Interlobular bile ducts: 15 to 20 µm in diameter; lined by a single layer of cuboidal cells having discrete round nuclei, scanty eosinophilic cytoplasm,

and discrete basement membranes; supplied by the smaller hepatic artery branches and peribiliary plexus d. Interlobar and septal ducts: More than 100 µm in diameter; have a ibrous wall lined by a single layer of cuboidal to columnar epithelium, with the nuclei located toward the basement membrane e. Segmental ducts: Up to 800 µm in diameter; lined by columnar mucus-secreting epithelium and have a distinct ibromuscular wall; form the major hilar ducts (up to 1.5 mm in diameter) and branch into the main right and left hepatic ducts. 12. The main vascular network can be subdivided into the following: a. Portal veins: Sequentially develop interlobar, segmental, interlobular, and preterminal vein branches, with the terminal portal venules measuring approximately 20 to 30 µm in diameter and seen in the smaller triangular portal tracts b. Hepatic arteries: Accompany the portal vein, divide within the smaller portal tracts into the periportal and peribiliary plexus, and provide blood supply to the accompanying interlobular bile ducts by way of small capillaries that are layered around the ducts c. Outlow vessels (terminal hepatic venules and veins, sublobular and hepatic veins): Provide vascular drainage from the sinusoids into the inferior vena cava

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

FIGURE 1-9 Portal tract. The major components of a portal tract consist of a hepatic arteriole, portal venule, and one to two interlobular bile ducts.

FIGURE 1-12 Parenchyma. This stain of the reticulin ibers lining the hepatic sinusoids shows the orderly liver cell plates to be one cell thick. (Reticulin stain.)

FIGURE 1-10 Portal tract. Communication of a portal venule with an adjacent periportal sinusoid at the lower right of the ield is seen. The portal tract normally has some degree of collagen ibers, staining blue in this ield, supporting its major vascular and biliary components. (Trichrome stain.)

FIGURE 1-11 Parenchyma. The hepatic cords are one cell thick and are lined by both Kupffer and endothelial cells. The sinusoids drain into the terminal hepatic venule.

FIGURE 1-13 Biliary canaliculi. The immunoperoxidase stain of the CD10 surface glycoprotein CALLA (common acute lymphoblastic leukemia-associated antigen) highlights the normal biliary canaliculi, which are located at the intercellular spaces between the hepatocytes. Often these canaliculi are not apparent on routine light microscopy in a healthy liver. The polyclonal CEA immunoperoxidase stain can also demonstrate these normal canaliculi. (Immunoperoxidase stain for CD10.)

13. The space of Disse lies between the hepatocyte and the endothelial cells and forms a space often not well appreciated on routine light microscopy on biopsy material; it houses the stellate or perisinusoidal cells (Ito cells). 14. The hepatic lymph channels are derived from the space of Disse as well as from capillary leakage from the peribiliary plexus. Their main function is to drain excess proteinaceous luid from the interstitial hepatic spaces, with the majority of lymphatics leaving the liver at the porta hepatis and along Glisson’s capsule. 15. The neural network is composed of both parasympathetic and sympathetic branches, with small nerve segments sometimes seen within the larger portal tracts and toward the hepatic hilum.

Chapter 1 / General Aspects of the Liver and Liver Diseases

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PT

PT

Microcirculatory periphery

PT

ThV

3 2 1 1 2 3

ThV

“Nodal” point of Mall 3' 2' 1'

“Nodal” point of Mall

PT

FIGURE 1-14 Simple hepatic acinus and zonal arrangements. Although the hepatic lobule on routine hematoxylin and eosin–stained slides appears to have the outlow vessels located toward the center of the lobule (“central” venules), in fact the outlow vessels functionally are located at the periphery (terminal hepatic venules). This diagram denotes the location of the three hepatic zones with relationship to the portal structures and the vascular blood low. PT, Portal tract; ThV, terminal hepatic venule. (Data from Rappaport AM. The microcirculatory acinar concept of normal and pathological hepatic structure. Beitr Pathol. 1976;157:215–243; and Roskams T, Desmet VJ, Verslype C. Development, structure and function of the liver. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver. 5th ed. Elsevier, 2007.)

16. On the basis of vascular injection studies, the hepatic vascular unit (hepatic acinus) can be subdivided into three segments: a. Simple acinus: Smallest functional unit, centering around the preterminal portal venule, hepatic arteriole, and terminal bile ductules and divided into three zones (zones of Rappaport): i. Periportal (zone 1), which includes the limiting plate ii. Midzone (zone 2) iii. Perivenular (zone 3), with the terminal hepatic venule at its outer lateral margin b. Complex acinus: Derived from three adjacent simple acini that are fed by the preterminal portal vein and hepatic arterial branches c. Acinar agglomerate: Composed of four complex acini that are fed by a portal venous branch that measures 300 to 1200 µm in diameter 17. Metabolic markers (alkaline phosphatase activity) instead of morphology alone have also been used to further subclassify the architectural arrangement into primary and secondary modules based more on threedimensional arrangements of the hepatocytes and its microcirculation. 18. The various structural and functional components represent liver cell heterogeneity, with specialized liver cell

functions seen within the various parenchymal zones. These functions are manifestations of nutrient and hormonal gradients, and they relect both variations in the sinusoidal vascular perfusion and oxygen concentration gradients and variations in the expression of certain enzyme activities through gene expression. The functional heterogeneity applies not only to the hepatocytes but also to the sinusoidal and perisinusoidal spaces, Kupffer and endothelial cells, extracellular matrix, and bile duct epithelial cells. Examples are shown in Tables 1-2 and 1-3.

STEM CELLS (Fig. 1-15) 1. Primitive stem cells (“oval” cells in experimental models), located in the periportal zone near the canals of Hering, are pleural-potential in their differentiation capabilities. 2. Hepatocytes show a striking ability to regenerate (e.g., as a result of massive liver cell necrosis, after partial hepatectomy for tumor); the availability and activation of these stem cells makes regeneration possible. These cells give rise to ductular cells located at the border of the portal tracts and the parenchyma (along the ductal plate) that may differentiate into hepatocytes or ducts and that can express markers of both (α-fetoprotein for liver cells and

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

TABLE 1-1

Liver Cell Ultrastructure

TABLE 1-3

Liver Cell Functional Zonal Variations

STRUCTURE

DESCRIPTION

FUNCTION

ZONE 3 (PERIVENULAR)

ZONE 1 (PERIPORTAL)

Mitochondria

Up to 2200/liver cell; oval to oblong, ranging from 0.4–3.5 µm, with outer and inner membranes

Oxidative phosphorylation, fatty acid metabolism, urea and citric acid cycle

Glycolysis

Gluconeogenesis

Convoluted network of cisternae, saccules, tubules, vesicles; divided into rough ER (located around the nucleus) and smooth ER (meshwork of tubules that communicate with Golgi apparatus)

Rough ER: protein synthesis Smooth ER: bile acid and lipid synthesis; cytochrome P450 enhancement of drug/ toxin metabolism

40–60/cell; polarized, parallel, lattened to dilated saccules and vesicles that are 1 µm in diameter; seen most often next to the nucleus and biliary canaliculi

Bile secretion, carbohydrate integration into proteins, membrane synthesis/repair, production of secretory vacuoles for protein transport and excretion

Lysosomes

Electron-dense pleomorphic single membrane–bound vesicles, seen adjacent to biliary canaliculi; divided into primary and secondary variants

Actively involved in phagocytosis; various degradation functions of acid phosphatase, esterases, proteases, lipases

Peroxisomes (microbodies)

Round to oval, single membrane, 0.2–1.3 µm in diameter

Oxidation and degradation of numerous substrates, with formation of hydrogen peroxides; oxidation of long-chain fatty acids

Endoplasmic reticulum (ER)

Golgi apparatus

TABLE 1-2

Glycogen synthesis from glucose

Glycogen synthesis from lactate

Lipogenesis

β-Oxidation of fatty acids

Removal of ammonia from blood by glutamine

Amino acid catabolism

Detoxiication, biotransformation of the majority of drugs and toxins (cytochrome P450 enzymes)*

Urea synthesis

Ketogenesis

Cholesterol synthesis

Bile acid synthesis

Bile acid secretion

Bile salt–independent fraction of bile formation; bile acid uptake (sodium independent)

Bile salt–dependent fraction of bile formation; bile acid uptake (sodium dependent)

Glucuronidation Mixed function oxidase Increase in Kupffer cell phagocytic activity *Certain drugs and toxins (e.g., allyl formate, phosphorus) and their metabolites may cause liver cell injury in zone 1 because of different pathophysiologic mechanisms.

Liver Cell Structural Zonal Variations

ZONE 3 (PERIVENULAR)

ZONE 1 (PERIPORTAL)

Mitochondria round; less numerous and smaller; fewer inner membranes

Mitochondria oval and oblong; larger diameter, volume, and number; greater cristae area

Prominent peroxisomes

Rough endoplasmic reticulum more abundant

Bile canaliculi with fewer microvilli; smaller in diameter

Bile canaliculi with numerous microvilli; larger in diameter

Lysosomes numerous

Kupffer cells numerous

Sinusoids form parallel vessels that open into terminal hepatic venules; are wider (30 µm) and fewer in number

Sinusoids form interconnecting polygonal network; are smaller (6 µm), more tortuous, and more numerous in number

Surface area of smooth endoplasmic reticulum larger

Abundant Golgi-rich volume

Endothelial cells more numerous but smaller; increase in number of fenestrations and porosity

Endothelial cells larger; endothelial fenestrations larger but less numerous

Larger nuclear volumes

Numerous large granular lymphocytes (“pit” cells)

Increase in number of microbodies Slight increase in stellate (Ito) cells* Predominant collagen types I, III, VI *Zone distribution varies considerably depending on the nutritional state.

FIGURE 1-15 Stem cells. In instances of severe liver cell injury, hepatocytes show a striking ability to regenerate as a result of activation and proliferation of stem cells that give rise to ductular epithelium along the ductal plates located at the border of the portal tracts and parenchyma, as seen in this image of fulminant hepatitis (massive hepatic necrosis) from acute viral hepatitis.

cytokeratins 7 and 19 for ducts). The presence of numerous ductules along the borders of the portal tracts in instances of fulminant hepatitis is an example. 3. Although initial reports showed that hepatocytes and cholangioles may be derived from extrahepatic circulating stem cells of probable bone marrow origin, more recent data suggest that liver cell generation from bone marrow stem cells does not occur through a process of true differentiation but rather by cell fusion of these bone marrow stem cells with nascent mature cells in the target tissue. 4. The hepatic stellate cells, which normally play an important role in the development of hepatic ibrosis, have recently been shown to experimentally express a stem/ progenitor cell surface marker and exhibit properties of pluripotent progenitor cells, with precursor potential in the development of both endothelial cells and hepatocytes.

Chapter 1 / General Aspects of the Liver and Liver Diseases

11

COMMON PIGMENTS (Figs 1-16 through 1-19) Various pigments can be seen on liver biopsy. Following are the three most common pigments: 1. Lipochrome (lipofuscin) pigment appears as ine to coarse brown granules and is derived from an increase in lysosomal activity and intracellular condensation of various cellular remnants. It most often appears within enlarged lysosomes and is usually more frequently seen in hepatocytes located within the perivenular zone (zone 3 of Rappaport). Its presence does not denote liver disease or dysfunction; this pigment is commonly seen in the liver tissue of elderly patients. 2. Bile is present as clumped green to green-yellow globules that stain positive with Hall’s stain for bilirubin. Usually the presence of intracellular bile is also accompanied by intracanalicular bile. Most cholestatic conditions also demonstrate this pigment more commonly in the perivenular zone (zone 3 of Rappaport).

FIGURE 1-16 Lipochrome. This pigment, also referred to as “wear and tear” pigment, is inely to coarsely granular and light to dark brown; it is seen more concentrated in the hepatocytes within the perivenular zone (zone 3 of Rappaport).

FIGURE 1-18 Intracanalicular bile. Bile can be identiied within dilated canaliculi as green to green-yellow pigment in various cholestatic liver diseases associated with impairment of biliary drainage.

A

B

FIGURE 1-17 Intracellular bile. Bile pigment can be seen in various cholestatic disorders within the cytoplasm of the hepatocytes and appears as ine, irregular green to green-yellow droplets.

FIGURE 1-19 Hemosiderin. A, This coarsely granular golden brown pigment is composed of red blood cell degradation remnants. In this image, hemosiderin can be seen within all of the hepatocytes. B, Because hemosiderin pigment can sometimes resemble lipochrome pigment on routine hematoxylin and eosin staining, a positive intensely blue iron stain conirms the presence of hemosiderin. (Perl’s iron stain.)

12

Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

TABLE 1-4

Presence of Pigments and Their Characteristics BILE

HEMOSIDERIN

LIPOCHROME

Distribution

Perivenular

Periportal

Perivenular

DUBIN-JOHNSON Perivenular

Color

Yellow-green

Golden brown, retractile

Light to dark brown

Dark brown

Iron Stain

Negative

Positive

Negative

Negative

Periodic Acid—Schiff (PAS) after Diastase Resistance (DiPAS)

Occasionally positive but variable

Negative

Positive but variable

Positive but variable

Ziehl-Neelsen Acid-Fast Stain

Negative

Negative

Usually positive

Occasionally positive

FIGURE 1-20 Portal lymphocytic iniltrates. Lymphocytes can be seen expanding the portal tract. These cells in this example are not oriented toward any of the portal structures.

FIGURE 1-21 Focal necrosis. Necroinlammatory change in this ield

3. Hemosiderin pigment is coarsely granular and golden brown, is best highlighted by Perl’s iron stain, and represents red blood cell degradation remnants. This pigment, in contrast to bile or lipochrome, is irst laid down in the periportal zone (zone 1 of Rappaport). Other pigments include the lipochrome-like pigment (seen in Dubin-Johnson syndrome; Fig. 8-45B), anthracotic pigment (seen more frequently in city dwellers; Fig. 5-52), protoporphyrin (present in erythropoietic protoporphyria; Fig. 8-62), and hemozoin pigment (seen in malaria from Plasmodium falciparum infection; Fig. 7-44). Table 1-4 shows a comparison of some of the more common pigments.

morphologic features that can be seen in a variety of liver diseases. The multiple tables in Part II of this book list the various liver diseases associated with individual morphologic features.

SYSTEMATIC APPROACH IN LIVER BIOPSY INTERPRETATION

consists of a small cluster of lymphocytes and hyperplastic Kupffer cells enguling the damaged hepatocytes.

GENERAL CLINICAL CONSIDERATIONS OF ACUTE AND CHRONIC LIVER DISEASES Diseases affecting the liver present as either an acute or a chronic process, where progressive damage leads to steady deterioration in hepatic function, eventually resulting in end-stage liver disease with hepatic failure. The following are various clinical and laboratory features seen in both acute and chronic liver disease.

Acute Hepatic Injury (Figs 1-20 through 1-29) Individual morphologic changes are seldom by themselves diagnostic of any particular liver disease; however, assessing the whole complex of changes leads to a better assessment of the diagnostic possibilities. It is therefore important that the pathologist and clinician take an organized approach in reading and interpreting liver biopsy results. Even when a clinical diagnosis is known, all aspects of liver morphology should be approached in biopsy assessment so that an unexpected or additional diagnosis is not missed. Table 1-5 shows a systematic approach in liver biopsy evaluation. In addition, Figs 1-20 through 1-29 show examples of nonspeciic

1. Acute injury is manifested as hepatocellular damage with variable impairment in bile low. 2. Hepatocellular injury is characterized by elevations of serum transaminases, the degree of elevation depending on the severity or type of injury. 3. Cholestasis presents with elevation of serum bilirubin levels, approximately half of which is conjugated, with or without elevation in alkaline phosphatase activity. 4. Fatty change is sometimes seen acutely with toxin or drug exposure, or it is idiopathic (e.g., Reye’s syndrome, acute fatty liver of pregnancy). Necrosis and inlammation are

Chapter 1 / General Aspects of the Liver and Liver Diseases

13

FIGURE 1-23 Apoptosis. One form of liver cell injury (apoptosis) FIGURE 1-22 Focal necrosis. Focal necroinlammatory change of hepatocytes can also be highlighted with this stain, which accentuates the ceroid accumulations from the engulfed hepatocytes within macrophages and enlarged Kupffer cells as a coarse dark purple pigment. (DiPAS.)

shows shrunken hepatocytes that have eosinophilic cytoplasm and small pyknotic nuclei (Councilman bodies, acidophil bodies) that are eventually extruded from the liver cell plates and phagocytized by adjacent Kupffer cells.

FIGURE 1-25 Kupffer cell hyperplasia. The Kupffer cells are more FIGURE 1-24 Fatty change. Fat globules are termed macrovesicular when they are larger than the hepatocyte nuclei and microvesicular when the fat droplets are the same size or smaller than the nuclei.

numerous in this ield than normally seen, with easily recognizable plump elongated nuclei and moderate eosinophilic cytoplasm, the cells hugging the surface of the hepatic cords.

FIGURE 1-26 Nuclear anisocytosis. Variably sized liver cell nuclei can be seen. This feature more frequently occurs in the perivenular zone and in the elderly patient population.

FIGURE 1-27 Glycogenated nuclei. The “empty” nuclei of hepatocytes are in fact loaded with glycogen, which is water-soluble and removed on tissue processing, leaving the nuclei clear.

14

Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

TABLE 1-5

FIGURE 1-28 Peribiliary glands. These small clusters of benign ducts and glands are commonly seen within the walls of large hilar and extrahepatic bile ducts. The glands may be serous or mucinous and rarely can show communication with the larger duct lumen.

Basic Architecture

• Intact, distorted (bridging ibrosis, incomplete/complete septa, cirrhosis with regenerative nodules)

Portal Tracts

• Fibrosis (degree) • Inlammatory iniltrates: degree, various and predominant cell types, spillover/ periportal interface activity (“piecemeal” necrosis) • Bile ducts, ductules: number, appearance, periductal ibrosis, inlammatory cells oriented to ducts, duct loss (ductopenia) • Portal veins/venous radicles: number, size, thrombosis, inlammation (endothelialitis) • Arterioles/arteries: thickness, inlammation (arteritis) • Miscellaneous: for example, foreign particles, granulomas, tumor within vessels/ lymphatics

Parenchyma

• Cord-sinusoid pattern: intact, distorted • Necroinlammatory iniltrates: degree, predominant cell type, zonal accentuation • Fatty change: degree, macrovesicular and microvesicular, zonal distribution • Glycogenated nuclei • Mallory bodies • Pigments: bile, lipochrome, hemosiderin, others • Granulomas: epithelioid, “inlammatory” • Inclusions: nuclear, cytoplasmic • Kupffer cells: hyperplastic, hypertrophic • Sinusoids: dilation, congestion/hemorrhage, collagen deposition (zone predominance), red blood cell extravasation into hepatic cords • Tumor, other mass lesions: for example, abscess

Use of Routine and Special Stains

• Hematoxylin and eosin stain for all routine biopsies • Masson trichrome to elucidate collagen • Reticulin to evaluate maintenance of the lobular architecture and liver cell plates • Periodic acid—Schiff (PAS) after diastase digestion (DiPAS) to identify α1-antitrypsin inclusions, ceroid pigment in sinusoidal macrophages and Kupffer cells • Iron within liver/Kupffer cells, portal macrophages, duct epithelium • Orcein for copper-binding protein, hepatis B virus “ground glass” cells • Others (e.g., PAS, Gomori methenamine silver, acid fast for microorganisms; rubeanic acid, rhodanine for copper)

Use of Special Techniques

• Immunohistochemical stains (e.g., viral, tumor markers) • In situ hybridization (e.g., post-transplant Epstein-Barr virus infection)

Identiication of Artifacts

• Inappropriate, inadequate formalin ixation (discohesion, shrinkage of liver cells) • Formalin pigment precipitates • Crush artifact of liver tissue • Biopsy fragmentation (not related to severe ibrosis)

FIGURE 1-29 Surgical hepatitis. Clusters of neutrophils are evident in the perivenular zone, are frequently seen in biopsies performed intraoperatively, and are secondary to surgical manipulation in long abdominal surgical procedures. These neutrophils are also commonly seen immediately beneath Glisson’s capsule.

most often mild, and consequently serum transaminases are only slightly elevated. 5. Varying combinations of types of injury may be present. For example, fatty iniltration and cholestasis may accompany hepatocellular necrosis, seen in certain types of drug-induced injury. Clinical features of acute hepatic injury 1. Patients can be asymptomatic, or marked malaise, nausea, vomiting, and anorexia may develop, depending on the severity of the acute injury. 2. Recovery is usually heralded by the rapid return of appetite, absence of gastrointestinal symptoms, and improved energy levels. 3. Hepatic failure is characterized by the presence of encephalopathy and/or renal failure (provided renal injury is not directly induced by the agent producing the hepatic injury).

Systematic Approach in Liver Biopsy Interpretation

4. Fulminant hepatic failure, regardless of the etiology, is present when the duration from onset of injury or infection to hepatic failure is up to and including 8 weeks, whereas late-onset or subacute fulminant hepatic failure is present when the duration exceeds 8 weeks.

Chapter 1 / General Aspects of the Liver and Liver Diseases 5. Serum aminotransferases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) are moderately to markedly elevated (1000s to >10,000 IU/L) depending on the severity of the injury. The degree of transaminase elevation does not predict the outcome of the disease. An elevation in lactate dehydrogenase (LDH) suggests injury in certain conditions (e.g., ischemia, drug toxicity, or iniltrative processes). 6. Mild to moderate elevations of serum total bilirubin are usually seen but may be markedly elevated (20 to 25 mg/dL), as, for example, in the cholestatic phase of viral hepatitis. 7. Serum alkaline phosphatase is usually mildly to moderately elevated. 8. Prothrombin activity is decreased (prothrombin time prolonged) in acute hepatic injury, the severity of the abnormality directly related to the degree and extent of injury. A persistent and marked decrease in the prothrombin activity in acute hepatic injury carries a poor prognosis, with mortality often exceeding 80%.

3.

4. 5. 6.

7.

Chronic Hepatic Injury 8. 1. The injurious process continues unabated, resulting in repetitive phases of injury and repair. 2. Elevation of serum transaminases usually signiies hepatocellular injury and may vary depending on the etiology of the disease process. Elevations in alkaline phosphatase usually suggest biliary tract involvement, cholestasis, or iniltrative processes. Gamma-glutamyl transpeptidase (GGT) is nonspeciic, and elevations in GGT do not aid in speciic diagnosis except in rare clinical situations; for instance, elevations of GGT corroborate alcoholism in patients who surreptitiously drink alcohol. Elevations in serum bilirubin in hepatocellular processes suggest more serious disease and thus are of clinical value in assessing severity. 3. Collagen laid down as part of the reparative process leads to distortion of hepatic architecture, resulting in hepatic ibrosis and leading eventually to cirrhosis over a period of many years. Clinical features of chronic hepatic injury 1. Clinical features of chronic liver disease depend on the extent of progression of the liver disease. 2. Symptoms may be related to the activity of the underlying etiology. For example, in autoimmune hepatitis, fatigue, malaise, arthritis, and skin rash may relect the

9. 10. 11.

12.

15

immune disturbance. If cirrhosis is present, decompensation with ascites, hepatic encephalopathy, and/or variceal hemorrhage may occur. Patients with signiicant chronic liver disease demonstrate stigmata such as vascular spiders or spider angiomata, palmar erythema, clubbing, leukonychia (white nails), Dupuytren’s contracture, and parotid enlargement, which may not all be present in a given patient. Rarely, patients with advanced cirrhosis may not demonstrate any of these features. Gynecomastia and testicular atrophy are seen in some male patients with chronic liver disease. Abdominal wall collaterals develop in portal hypertension as the result of portal-systemic communications. Muscle wasting is due to signiicant hepatic impairment in protein synthesis, characteristically involves the face and extremities, and is usually seen in advanced liver disease. Hypoalbuminemia is usually due to decreased hepatic protein synthesis but may be due to increased proteinuria seen in conditions associated with liver disease, such as hepatitis C–related membranoproliferative nephropathy. Ascites is the intra-abdominal formation of luid exuding from the liver surface and is due to intrahepatic portal hypertension and associated impairment in renal sodium excretion. Ascites that is resistant to diuretic therapy is termed refractory ascites. Spontaneous bacterial peritonitis is infection of ascitic luid and usually occurs in patients with decompensated liver disease. Hepatic encephalopathy develops as a result of worsening hepatic function with or without portal-systemic shunting. Collaterals (varices), occurring commonly in the esophagus and stomach and rarely in the rectum or within adhesions, develop as a consequence of advanced portal hypertension. Hemorrhage from esophageal and gastric varices is a potentially fatal complication with increased mortality (≥50%) in severe liver disease. Hepatic transplantation is offered to patients with fulminant hepatic failure who are not likely to survive and for those with advanced cirrhosis and liver failure.

REFERENCES The complete reference list is available online at www. expertconsult.com.

Chapter

2

VIRAL HEPATITIS

MAJOR HEPATOTROPIC VIRUSES: A, B, δ, C, E, G, “NON-A THROUGH NON-G” 16 Acute Viral Hepatitis 16 Chronic Viral Hepatitis 27

SYSTEMIC VIRAL INFECTIONS WITH HEPATIC INVOLVEMENT 39 Epstein-Barr Virus 39 Cytomegalovirus 41 Herpes Simplex Virus 43 Human Immunodeiciency Virus and Acquired Immunodeiciency Syndrome 45

MAJOR HEPATOTROPIC VIRUSES: A, B, δ, C, E, G, “NON-A THROUGH NON-G” Acute Viral Hepatitis

6.

Typical Form (Spotty Necrosis)

7.

(Figs 2-1 through 2-13)

8.

Major morphologic features 1. All portal tracts exhibit a moderate to marked predominantly lymphocytic iniltrate. 2. Focal necrosis and apoptosis occur in all zones of all lobules, with associated hepatocytolysis and hydropic ballooning changes (lytic necrosis) of the liver cells. In early-stage disease, these changes are more prominent in the perivenular zone (zone 3 of Rappaport). 3. Variable but often prominent lymphocytic inlammatory iniltrates are seen within the lobules. 4. Phagocytosis of damaged liver cells by macrophages and Kupffer cells is present. Other features 1. The basic lobular architectural pattern (portal tracts– terminal hepatic venules–portal tracts) is maintained, although in more severe cases there may also be perivenular liver cell dropout and focal perivenular collapse of the reticulin framework (conluent necrosis; refer to discussion under “Fulminant Hepatitis”). 2. Apoptotic cells (Councilman bodies, acidophil bodies) frequently occur in all zones and consist of hepatocytes with shrunken eosinophilic cytoplasm and small pyknotic nuclei; these cells are seen either within the trabeculae or phagocytized by Kupffer cells after extrusion into the perisinusoidal space. Usually the late-stage apoptotic cells are devoid of nuclei. 3. Cholestasis may be present, often with perivenular (zone 3) accentuation. 4. Kupffer cell hyperplasia is present and is often prominent. 5. Although spillover of lymphocytes from portal tracts into the adjacent periportal zones is seen, true periportal 16

9. 10.

11.

12.

RARE SYSTEMIC VIRAL INFECTIONS WITH HEPATIC INVOLVEMENT 47 Lassa Fever 47 Yellow Fever 48 Echovirus (Enterovirus) 49

OTHER VIRUSES THAT MAY CAUSE LIVER DAMAGE 50

or interface hepatitis (“piecemeal necrosis”) is not a manifestation. The portal and lobular lymphocytes, usually T cells, can sometimes be seen attached to endothelial cells of portal and terminal hepatic venules. Portal tracts may also exhibit variable degrees of iniltration by plasma cells, macrophages, and rarely eosinophils. Although the portal inlammation commonly involves all of the portal tracts, at times there may be some variation in the degree of inlammation from one portal tract to another. Bile duct and cholangiolar proliferation can be present but is generally mild. Cytologic injury to interlobular bile ducts can occur at times but is not prominent (the exception being acute hepatitis C virus (HCV) infection; see discussion later in this chapter). With resolution: a. Residual spotty clusters of pigment-laded (ceroidladen) macrophages may be seen (tombstone lesions that are periodic acid-Schiff (PAS)-positive after diastase digestion [DiPAS]). b. Hydropic regenerative activity of liver cells occurs, with slight thickening of the liver cell plates (best appreciated on the reticulin stain) and increased mitotic activity of hepatocytes. Note that in the elderly patient population there may be some degree of impairment in liver cell regeneration; this is associated with a poorer prognosis. c. Eventually (months later) mild, nonspeciic portal and lobular inlammatory changes can occur; these usually resolve by 1 year. All types of acute hepatitis secondary to the hepatotropic viruses (A, B, δ, C, E, G, and “non-A through non-G”) basically exhibit similar morphologic features, as described previously; however, the individual subtypes may also show the following: a. Hepatitis A virus (HAV) i. Portal plasma cells may at times be prominent. ii. Inlammation and necrosis may be more prominent in the periportal than in the perivenular zones.

Chapter 2 / Viral Hepatitis

A

17

B

FIGURE 2-1 Acute viral hepatitis. A and B. These two images from the same biopsy demonstrate prominent portal lymphocytic iniltrates with some degree of “spillover” of the inlammatory cells into the adjacent periportal zone without true periportal interface inlammatory activity (“piecemeal” necrosis). Interlobular bile ducts are normal in number with occasional cholangioles present.

FIGURE 2-2 Acute viral hepatitis. The parenchyma shows variable

FIGURE 2-3 Acute viral hepatitis. Medium power shows mild

hydropic change of hepatocytes and diffuse necroinlammatory change, the inlammatory cells chiely lymphocytes. Kupffer cell hyperplasia is present.

hydropic change, spotty liver cell necrosis, and Kupffer cell hyperplasia. A mild lymphocytosis can also be seen within the sinusoids.

iii. Perivenular cholestasis may be striking in comparison with only mild lobular inflammation, mimicking a drug-induced cholestatic hepatitis versus other causes of cholestasis such as benign recurrent intrahepatic cholestasis (refer to further discussion of this liver disorder in Chapter 8). b. Hepatitis B virus (HBV) i. Lymphocytic lobular inlammation may show close contact with injured hepatocytes, with lymphocytes occasionally identiied within the cell cytoplasm (emperipolesis). c. HBV and δ i. The degree of inlammation and necrosis is often more prominent than in acute HBV infection alone. In approximately 1⁄3 of cases, a fulminant hepatitis with conluent necrosis may occur. ii. Microvesicular fatty change within liver cells has been described.

d. HCV i. Portal lymphocytic iniltrates often show lymphoid aggregate and follicle formation, occasionally with germinal centers. ii. Interlobular bile ducts may be noted within the centers of these lymphoid aggregates, with lymphocytes occasionally iniltrating beneath the duct basement membrane, associated with cytologic damage of the duct epithelium (epithelial hyperplasia, vacuolization, nuclear irregularity). iii. Although rare, granulomatous-type necrosis can be seen within the lobules, without true epithelioid granuloma formation. iv. A sinusoidal lymphocytosis may also be present. Note: The irst two described features may be a sign of impending progression to chronicity. e. Hepatitis E virus (HEV) i. Cholangiolar (ductular) proliferation may be seen, sometimes associated with bile plugs within the

18

Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

A FIGURE 2-4 Acute viral hepatitis. Moderate necroinlammatory change, the inlammatory cells chiely lymphocytes, is seen in the perivenular zone on high power. The liver cells show variable hydropic change, making it dificult to visualize the hepatic sinusoidal network.

B

FIGURE 2-5 Acute viral hepatitis. This ield demonstrates spotty necrosis with phagocytosis of the necrotic liver cells by the hypertrophic Kupffer cells. The small eosinophilic cytoplasmic droplets seen in the center of the ield represent increase in lysosomal activity within the Kupffer cells. A prominent lymphocytic iniltrate is also seen within the sinusoids and hepatic cords.

dilated cholangioles that also may be surrounded and focally iniltrated by neutrophils. ii. Acinar changes (dilated canaliculi) often containing bile can sometimes be appreciated within the lobules. iii. The degree of lobular inlammation is generally mild; however, infrequently a severe necroinlammatory process can occur, with inlammation of the portal and terminal hepatic venules reported. f. Hepatitis G virus (HGV) i. In general, the portal and lobular inlammation and the lobular necrosis are milder than what is seen with the other hepatotropic viruses. ii. There is some question whether acute HGV infection does, in fact, cause a histologically apparent acute hepatitis, with many believing it is more a passenger virus.

FIGURE 2-6 Acute viral hepatitis, apoptosis. A, Diffuse necroinlammatory changes are seen, with spotty necrosis and hypertrophic Kupffer cells. Toward the left of the ield, occasional hepatocytes show a more intense eosinophilic cytoplasm with smaller pyknotic nuclei (apoptosis). A similar but smaller cell with a lattened degenerating nucleus is seen in the bottom right. B, Higher power shows an apoptotic cell with small nuclear remnants and intensely eosinophilic cytoplasm. This cell has been extruded from the hepatic cord and is now being phagocytized within a plump Kupffer cell.

g. Other types (non-A through non-G) i. Giant cell transformation of hepatocytes has been described. ii. In some cases, paramyxovirus has been identiied within the cytoplasm by electron microscopy. iii. Viruses such as transfusion-transmitted virus (TTV) and SEN virus (SEN-V), both singlestranded circular DNA viruses, are postulated to play some part in inducing or enhancing acute hepatitis in certain patient populations; however, there is no convincing evidence to date that these viruses play any signiicant or primary role. Special stains 1. PAS after diastase digestion (DiPAS): Cytoplasmic intralysosomal granules in macrophages and Kupffer cells are prominent in areas of necrosis and in portal macrophages. 2. Reticulin: Condensation of reticulin ibers may be seen in the perivenular zones secondary to liver cell necrosis and dropout in the more severe cases.

Chapter 2 / Viral Hepatitis

19

FIGURE 2-7 Acute viral hepatitis. Cholestasis is seen within a dilated

FIGURE 2-9 Acute viral hepatitis: hepatitis B virus (HBV) + δ. The

canaliculus in the center of the ield.

necroinlammatory change is prominent, with perivenular conluent necrosis and liver cell dropout evident in the center of the ield.

FIGURE 2-8 Acute viral hepatitis: hepatitis A virus (HAV). The portal

FIGURE 2-10 Acute viral hepatitis, severe (reticulin). The perivenular (zone 3) conluent necrosis that can be seen in severe cases of acute viral hepatitis is associated with liver cell necrosis, dropout, and collapse of the reticulin framework, this latter feature highlighted with this reticulin stain. When this morphologic feature is striking, patients usually present with fulminant hepatitis.

tract shows numerous plasma cells, a feature sometimes prominent with acute HAV infection.

3. Perl’s iron: Hemosiderin may be seen in macrophages and Kupffer cells in areas of necrosis. Immunohistochemistry 1. Hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg): Surface and core antigen staining in acute viral hepatitis type B is always negative. Positive staining for either antigen in biopsies exhibiting changes of acute hepatitis is indicative of either (1) a replicative (active) phase of early chronic hepatitis B, where the portal ibrosis is minimal and easily missed, or (2) an acute non-B or drug-induced hepatitis in a patient with underlying early-stage chronic hepatitis type B. 2. Delta antigen: In acute hepatitis B with acute δ infection, liver cell nuclei exhibit variable and often prominent degrees of positive staining. Differential diagnosis 1. Drug-induced liver cell injury (e.g., isoniazid, rifampin; refer to Table 5-4): The morphologic features secondary to hepatotoxicity by certain drugs and toxins that elicit

both a portal and lobular inlammatory reaction may be similar to those seen in acute viral hepatitis; however, in some instances the degree of portal lymphocytic iniltrates may be less prominent than in classic acute viral hepatitis. In addition, scattered admixed eosinophils within the portal tracts often favor drug-induced injury. Finally, with some exceptions (e.g., the cholestatic phase of acute viral hepatitis types A and E), the degree of intralobular cholestasis in drug-induced cholestatic hepatitis usually outweighs the degree of portal and lobular inlammation. 2. Early stages of chronic viral hepatitis: Both early and relatively active stages of chronic viral liver disease may resemble the morphologic features seen in acute viral hepatitis, especially in small biopsies with few portal tracts or with only segments of portal areas for evaluation. For hepatitis type B, the presence of stainable HBV antigens (HBsAg, HBcAg) by immunohistochemical techniques in the cytoplasm and nucleus, respectively, is a useful tool in the

20

Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

diagnosis of early chronic HBV infection. Similarly, the presence of HBsAg and anti-HBc immunoglobulin G (IgG) in the absence of anti-HBc IgM in serum samples also points to chronic hepatitis type B. Of note is that the presence of distinct portal lymphoid aggregates and follicles in acute viral hepatitis type C is believed to be an indicator that the disease will most likely progress to chronicity. 3. Early stages of autoimmune hepatitis: The degree of portal and lobular inlammation in the early stages of autoimmune hepatitis may resemble that seen in acute viral hepatitis; however, the portal and lobular plasma cell component and the presence of deinite periportal interface inlammatory activity are signs suggesting an autoimmune process. In addition, most of the time, some degree of portal ibrosis may also be present in early autoimmune liver disease. This feature is best highlighted on trichrome and Sirius red stains for collagen.

4. Epstein-Barr virus (EBV), cytomegalovirus (CMV) hepatitis: Both of these viruses may produce acute hepatitis (refer to “Epstein-Barr Virus” and “Cytomegalovirus” later in this chapter), with portal lymphocytic iniltrates and diffuse lobular necroinlammatory changes. The differences from acute viral hepatitis are as follows: a. EBV and CMV tend to cause less individual liver cell damage, without the characteristic ballooning hydropic changes and apoptosis seen in typical acute viral hepatitis. b. The degree of necroinlammatory changes and elevations of the serum aminotransferases (seldom greater than 500 IU/L) are considerably less in acute EBV and CMV infections than in typical acute viral hepatitis. c. Sinusoidal lymphocytosis, although sometimes a feature present in acute viral hepatitis (particularly HCV), is usually quite prominent in EBV and CMV infection, with the lymphocytes frequently enlarged and atypical.

FIGURE 2-11 Acute viral hepatitis: hepatitis E virus (HEV). The portal tract exhibits a mild lymphocytic iniltrate. Prominent ductular (cholangiolar) proliferation and ectasia are present, and many of the ductules contain bile plugs.

FIGURE 2-13 Acute viral hepatitis, non-A through non-G. Syncytial

A

giant cell transformation is seen in a biopsy from an adult who clinically presented with signs and symptoms of an acute hepatitis. The diagnosis rests on the exclusion of other causes of acute hepatitis.

B

FIGURE 2-12 Acute viral hepatitis: hepatitis E virus (HEV). A, The parenchyma shows a mild lymphocytic iniltrate with Kupffer cell hyperplasia. Cholestasis is prominent, the hepatocytes often arranged in rosettes around the bile within the dilated biliary canaliculi. B, The canaliculi are markedly dilated and contain prominent bile plugs. In contrast to the parenchymal changes seen in the preceding igure, the hepatocytes are hydropic without liver cell necrosis or lobular inlammation.

Chapter 2 / Viral Hepatitis d. CMV often causes a granulomatous type of necrosis. The granulomas sometimes contain true epithelioid histiocytes, a feature not seen in typical acute viral hepatitis. Although acute HCV infection may rarely cause some degree of “granulomatous” necrosis, true epithelioid cells are not present. e. In the immunocompromised patient (e.g., status postchemotherapy or liver transplantation), the presence of CMV nuclear and cytoplasmic inclusions in liver cells, Kupffer cells, and/or duct epithelium is a useful marker for CMV infection. f. A positive Epstein-Barr-encoded RNA (EBER)-1 DNA probe and demonstration of speciic EBVspeciic proteins (Epstein-Barr nuclear-associated antigens) are useful markers for EBV infection in certain settings. 5. Wilson disease: Wilson disease, an autosomal recessive inherited disorder associated with increased hepatic copper deposition (see Chapter 9), may present in the early stages with an acute hepatitis picture similar to that seen in acute viral hepatitis. Conluent necrosis may be seen as well. The presence of Mallory bodies, glycogenated nuclei, increased hepatic copper (rubeanic acid and rhodanine stains on liver biopsy, copper quantiication on liver tissue), as well as low serum ceruloplasmin levels and increased urinary copper excretion are helpful indicators pointing toward a diagnosis of Wilson disease. Clinical and biologic behavior (Tables 2-1 and 2-2) 1. Acute viral hepatitis may present clinically with jaundice, but frequently it is not associated with hyperbilirubinemia (anicteric hepatitis). 2. Prodromal signs may include low-grade fever, arthralgias and myalgias, and anorexia. 3. Signiicant elevations of serum transaminases occur, are usually greater than 500 IU/L, and may at times range TABLE 2-1

4. 5.

6.

7. 8. 9. 10.

11.

21

from 1000 to 10,000 IU/L. The alkaline phosphatase is usually mildly elevated. Mild leukopenia and thrombocytopenia are also common. Children usually tend to be anicteric and asymptomatic, and adults, especially elderly individuals, may develop a more severe course. Although serum transaminases are lower in anicteric and asymptomatic forms of acute hepatitis, the degree of transaminase elevations does not correlate with outcome or prognosis. A cholestatic phase may follow acute hepatitis due to HAV and HEV infection and is characterized by jaundice and pruritus. Pruritus is sometimes intractable and may last for weeks or months. In acute hepatitis due to HAV, relapses may occur 30 to 60 days after the initial illness and mimic a biphasic hepatic disorder. The absence of gastrointestinal symptoms, improvement in prothrombin time, and improved overall sense of well-being indicate recovery. Chronic hepatitis generally occurs less frequently following acute symptomatic (icteric) hepatitis. The hepatitis D virus (HDV, δ) requires the HBV virus for both acute and chronic infection. Patients with acute HDV infection may present in two ways: a. In acute HBV and HDV coinfection, resolution of acute hepatitis B is followed by a second biphasic episode of hepatitis. This is due to suppression of HDV during the initial HBV infection. b. In acute HDV superinfection of chronic HBV infection, the ensuing hepatitis usually has a severe chronic accelerated course. The type of preexisting HBV infection may be important in determining the outcome of HDV superinfection. Active HBV viral replication (hepatitis B e antigen [HBeAg] positive, HBV DNA positive) appears more likely to be associated with a severe acute illness,

Clinical and Biologic Behavior of Hepatotropic Viruses HEPATITIS A VIRUS (HAV)

HEPATITIS B VIRUS (HBV)

HEPATITIS C VIRUS (HCV)

HEPATITIS D VIRUS (HDV)

HEPATITIS E VIRUS (HEV)

HEPATITIS G VIRUS (HGV)

Virus Type

RNA picornavirus

DNA hepadnavirus

RNA lavivirus

Defective RNA satellite

RNA calcivirus

RNA lavivirus

Genome

7.5 kb Linear, ss

3.2 kb Circular, ss/ds

9.4 kb Linear, ss

1.7 kb Circular, ss

7.6 kb Linear, ss

8.6 kb Linear, ss

Size

27 nm

42 nm Dane particle

40–60 nm

34–37 nm Associated with HBsAg

35–39 nm

50–100 nm

Incubation Period (Days)

15–45

30–150

15–160

30–180

14–60

20–140

Transmission

Fecal-oral*

Parenteral Sexual Perinatal

Parenteral (Sexual, perinatal)

Parenteral Sexual (Perinatal)

Fecal-oral

Parenteral (Sexual, perinatal)

Chronicity

None

90% newborns

65%–85%

3 mm diameter), with the disappearance of

A

B FIGURE 4-29 Alcoholic cirrhosis. This high power image shows the yellow-tan nodules to measure up to 2 mm in greatest dimension (“micronodular”). This feature is uniformly present within all of the hepatic lobes.

FIGURE 4-30 Alcoholic cirrhosis (active drinker). A, The regenerative nodule is small (“micronodular”), poorly demarcated, and contains mild macrovesicular fatty change. B, Higher power shows prominent deposition of periseptal intrasinusoidal collagen. Moderate macrovesicular fatty change is also present (trichrome).

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A

B

FIGURE 4-31 Alcoholic cirrhosis (active drinker). A, The parenchyma shows poorly demarcated nodules (pseudolobules) without appreciable regenerative change. B, Higher power demonstrates hepatic trabecular cords without any hydropic or regenerative changes. Intrasinusoidal collagen deposition in the periseptal regions is seen. These features are characteristically present in biopsies from alcoholics who are actively drinking.

FIGURE 4-33 Alcoholic cirrhosis (active drinker). The degree of FIGURE 4-32 Alcoholic cirrhosis (active drinker). Fatty change, sinusoidal collagen deposition, occasional Mallory bodies, and a lymphocytic and neutrophilic inlammatory iniltrate are seen.

A

intrasinusoidal collagen deposition can at times be striking and may diffusely involve the entire lobule (diffuse interstitial ibrosis) (trichrome).

B

FIGURE 4-34 Alcoholic cirrhosis (abstinence of alcohol intake). A, The cirrhotic liver on the trichrome stain shows sharply demarcated ibrous bands with well-developed regenerative nodules. No fatty change or sinusoidal collagen deposition is present. B, A small regenerative nodule surrounded by dense ibrous septa is seen in this example of advanced inactive alcoholic cirrhosis.

Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases

85

FIGURE 4-35 Alcoholic cirrhosis (abstinence of alcohol intake). The

FIGURE 4-36 Alcoholic cirrhosis. The sublobular vein shows ibro-

ibrous band in this example shows a mild lymphocytic iniltrate and mild bile duct proliferation. The parenchyma demonstrates hepatocytes without fatty change, the cells forming distinct cords and sinusoids without an inlammatory iniltrate or sinusoidal collagen deposition.

intimal thickening (phlebosclerosis) with mild lymphocytic iniltrates within the intima (lymphocytic phlebitis). The sclerosis at times can be striking, with total occlusion of the entire lumen (trichrome).

fat, sinusoidal collagen, and Mallory bodies by 3 to 6 months of abstinence. The ibrous septa between these nodules may eventually become quite thin when the alcoholic stops drinking and the cirrhosis is at an early stage. Prominent sclerosis is seen involving the terminal hepatic venules and veins that are entrapped within the ibrous bands. In addition, intraluminal sclerosis of the terminal hepatic and sublobular veins is evident. Cholestasis may be present in the advanced stages. Diffuse interstitial ibrosis may be seen in the active alcoholic, with intrasinusoidal collagenosis involving virtually all of the sinusoids, without regenerative changes of the hepatocytes. As the cirrhosis progresses, the ibrous septa become exceptionally wide in the active alcoholic, with the dense scars most evident at the junction of the right and left hepatic lobes. Hepatocellular carcinoma (HCC) may be seen as a secondary change in anywhere from 4% to 10% of patients with advanced disease, usually occurring in patients who have stopped drinking and hence survived longer than the active alcoholic. Those patients with co-existing chronic HCV are at a higher risk of developing HCC as well.

in some instances the regenerative nodules in NASH can be well-demarcated as opposed to the poorly formed nodules in the active alcoholic. NASH also is associated with the presence of glycogenated nuclei, a feature less commonly seen in the alcoholic. Wilson disease: Fat, sinusoidal collagen deposition, Mallory bodies, and cirrhosis may be seen in Wilson disease. Special stains for copper (rubeanic acid, rhodanine) and copper-binding protein (orcein) show strong staining in Wilson disease, as does hepatic tissue copper quantitation. Chronic viral hepatitis secondary to HCV: Chronic hepatitis C is associated with variable degrees of fat and sinusoidal collagen deposition, but the degree seen is typically much less than in the active alcoholic. In addition, Mallory bodies are not features in chronic HCV infection. Of note is that it is not uncommon for chronic alcoholics with liver disease to also be HCV positive, hence serologic assessment is important in the differential diagnosis. Drug-induced liver injury: Certain drugs can cause fat, variable sinusoidal collagen deposition, and in some instances Mallory bodies (e.g., amiodarone; refer to Tables 5-6, Fatty Change, and 5-8, Mallory Bodies). Clinical correlation is important in the differential. Indian childhood cirrhosis: This liver disease is associated with a micronodular cirrhosis, sinusoidal collagenosis, and numerous Mallory bodies. This disorder, however, develops in infancy, with liver failure and death by 2 years of age. α1-Antitrypsin deiciency: In the adult, a well-established cirrhosis may occur in this hepatic disorder, with variable degrees of fat and rarely Mallory bodies identiied. The presence of α1-antitrypsin globules in the periseptal hepatocytes on DiPAS stain and conirmed on immunoperoxidase stain is diagnostic; however, of note is that in the heterozygous states (PiMZ), patients may have inclusions without liver disease. Therefore, when cirrhosis and α1-antitrypsin inclusions are seen in a patient with a long history of alcohol abuse, phenotyping is essential to better deine the etiology of the cirrhosis (refer to the section under α1-Antitrypsin Deiciency in Chapter 8).

6.

7. 8.

9.

10.

Special stains 1. Masson trichrome: The sinusoidal collagen deposition and ibrous bands are best appreciated. 2. Perl’s iron : Increase in stainable iron is sometimes apparent within periseptal hepatocytes. Immunohistochemistry 1. Ubiquitin, pancytokeratin: These stains are useful in conirming the presence of Mallory bodies in the active alcoholic. Differential diagnosis 1. Non-alcoholic steatohepatitis (cirrhotic stage) (NASH): This liver disease in the cirrhotic stage can mimic alcoholic cirrhosis. Usually the degree of fat in NASH at this stage is signiicantly less than in the active alcoholic. In addition,

2.

3.

4.

5.

6.

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

Clinical and biologic behavior 1. Alcoholic liver disease is the most common cause of cirrhosis in the Western world and accounts for 38% to 50% of all cirrhosis related deaths. 2. The common clinical presentation of the alcoholic with cirrhosis in the decompensated state, with or without concomitant alcoholic hepatitis, includes jaundice, ascites, debilitation, impotence/amenorrhea, loss of skeletal muscle mass, and other features related to alcohol itself (e.g., delirium tremens, pancreatitis, polyneuritis, and gastritis with hemorrhage). Patients often present with signs of chronic liver disease such as vascular spiders and palmar erythema. Visible collateral veins on the abdominal wall indicate portal hypertension. Ankle edema occurs when hypoalbuminemia develops. 3. Splenomegaly is seen in only 30% of patients with alcoholic cirrhosis. 4. Unless there is superimposed alcoholic hepatitis, laboratory tests reveal mild to moderate elevations of serum AST, generally below 100 IU, with normal ALT. Selective serum immunoglobulin A (polymeric IgA) is usually elevated in alcoholic cirrhosis, but not in cirrhosis of other etiologies. 5. In early stages of cirrhosis, the liver is almost always enlarged, sometimes achieving weights of over 3000 g. In advanced stages, the liver is of normal size or is slightly small (900 g). 6. Dense sclerosis is typically seen in areas between the gallbladder bed and hepatic vein outlow to the inferior vena cava, an area demarcating the vascular boundary between the true median portions of the right and left lobes and hence more sensitive to ischemia. 7. Regenerative changes present as proliferating hydropicappearing hepatocytes with sharp, distinct nuclear and cytoplasmic membranes. Mitoses are not typically seen. The sinusoids appear to be poorly deined and almost always compressed, and inlammatory changes and Kupffer cell hyperplasia are not present. These regenerative changes in the cirrhotic liver can be quite variable from one nodule to another, and are more prominent away from the dense sclerotic regions. 8. The nodules in the active drinker are generally between 1 to 4 mm in diameter; in the patient who abstains from alcohol for months to years, however, the nodules can become larger (1.5 cm or more), grossly mimicking cirrhosis from chronic viral hepatitis. 9. If drinking continues, the nodules are always small, as there is constant subdivision of enlarging regenerative nodules by sinusoidal ibrogenesis. In addition, there is inhibition, to varying degrees, of regeneration of liver cells by alcohol itself. 10. Alcohol can induce ibrogenesis without overt episodes of acute liver disease, as approximately 40% of cases irst present clinically in the cirrhotic stage. 11. In 30% of patients, biopsy shows appreciable amounts of fat, while in 20% there is some degree of Mallory body deposition. 12. Hepatic arteries and the arterial bed are increased in size in cirrhotics, with an increase in communication between the hepatic arterial and portal venous systems. 13. Decompensation is precipitated by heavy drinking (superimposed acute liver disease), as well as by gastrointestinal hemorrhage, infection, or other causes of stress to the liver.

14. Hepatocellular carcinoma occurs in approximately 4% to 6% of all alcoholic cirrhotics and is more common in those who have abstained from drinking for a number of years. The average age of the alcoholic who has stopped drinking and develops hepatocellular carcinoma is 60 years, 10 years older than the alcoholic who continues to drink and dies of consequences of cirrhosis without hepatocellular carcinoma. Treatment and prognosis 1. Once the patient has reached the cirrhotic stage, abstinence from drinking does not signiicantly decrease complications from the consequences of portal hypertension. 2. Management of complications is similar regardless of the etiology of the cirrhosis. 3. Controlled trials of propylthiouracil and colchicine in ambulatory cirrhotics showed some beneit in survival in those who received therapy despite continued drinking, although these drugs are rarely used in the clinical situation. 4. One year survival: after onset of ascites, 35%; after onset of gastrointestinal hemorrhage, 28% to 55%. The 5-year survival after portal-systemic shunt: 50% at 2 years, 25% at 5 years. 5. Liver transplantation should be offered in individuals who have demonstrated abstinence or completed a rehabilitation program. The survival of these patients after transplant is similar to those patients with cirrhosis of other etiologies. Patients with alcoholic hepatitis, however, have a 50% recidivism rate.

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) Non-Alcoholic Fatty Liver (NAFL) (Fig. 4-37) Major morphologic features 1. Variable degrees of predominantly macrovesicular fatty change are seen and are sometimes quite prominent, usually with no distinct zonal distribution pattern. 2. Portal and/or perivenular ibrosis is not present. Other features 1. Occasional glycogenated nuclei of hepatocytes are present, and sometimes appear concentrated in the periportal zones. 2. Some degree of microvesicular fat can also be seen but is generally uncommon. 3. No lobular necroinlammatory or ballooning changes are present, and there is no evidence of Mallory body formation. 4. Portal tracts show a mild lymphocytic iniltrate, but more often are devoid of inlammatory cells. Special stains 1. Masson trichrome: This stain conirms the absence of portal, periportal and perivenular ibrosis. Differential diagnosis 1. Other causes of fatty liver: Numerous liver diseases (e.g., chronic viral hepatitis due to HCV infection, acute fatty liver of pregnancy) are associated with variable degrees

Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases

FIGURE 4-37 Non-alcoholic fatty liver. Most of the hepatocytes in this ield show a macrovesicular fatty change. No liver cell ballooning, liver cell necrosis, or lobular inlammation is seen. The terminal hepatic venule at the top of the ield is normal, without perivenular ibrosis.

of fat. Most of the patients with those liver diseases have abnormal liver tests and various clinical signs and symptoms pointing to those disorders, while patients with simple non-alcoholic fatty livers, although sometimes obese, have no speciic signs of liver disease and have normal liver tests. Clinical and biologic behavior 1. Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and liver ibrosis. It is commonly associated with metabolic syndromes such as obesity, type 2 diabetes and dyslipidemia. The exact pathogenesis of this condition is not known. 2. Patients are usually asymptomatic with normal liver tests, or may have mild transaminitis. 3. Some patients may go on to develop inlammation and ibrosis (steatohepatitis), although it is not possible to predict which patient population is most affected. 4. A number of interesting pathophysiologic concepts are involved in understanding non-alcoholic fatty liver disease that can eventually target the basis for treatment. a. The current proposed hypothesis for non-alcoholic fatty liver is a “two-hit” model, where the irst hit is lipid accumulation in the liver (seen in simple fatty liver, both in alcoholic and non-alcoholic diseases), with inlammation and ibrogenesis (steatohepatitis) the second hit. b. In obesity, excess energy intake leads to increase in fat storage cells with failure to adapt to proliferation and differentiation. Hypertrophic fat cells are under considerable metabolic stress, particularly the endoplasmic reticulum (ER), which usually adapts to increased protein and triglyceride synthesis. In states of nutrient excess, the ER is overwhelmed and the unfolded protein response is activated, triggering insulin resistance through a number of mechanisms. Dysfunctional adipose tissue impairs glucose and lipid homeostasis by free fatty acid-induced ectopic fat deposition and

87

lipotoxicity and by release of fat derived cytokines. These effects on glucose and lipid homeostasis lead to systemic inlammation and insulin resistance. Activation of intracellular inlammatory pathways leads to eventual cellular collapse and apoptosis. c. Lipotoxicity results from the effects of excessive free fatty acids (FFA) on tissues. FFA inhibits muscle insulin signal transduction, causing insulin resistance and the accumulation of intramyocellular lipid. Similar changes are noted in the myocardium affecting function. d. Adipokines have numerous functions related to the role of adipose tissue in non-alcoholic fatty liver disease, and include hormones that are involve in glucose homeostasis, insulin regulation, and lipid and lipoprotein metabolism. Investigation of two of the hormones, leptin and adiponectin, have provided some experimental insights into non-alcoholic steatohepatits, although their exact role in insulin resistance is not exactly clear. In insulin resistance, adipocyte lipolysis leads to increased plasma FFA levels, increased hepatic uptake of FFA, as well as increased de novo lipogenesis, all leading to increased hepatic steatosis. This in turn leads to intracellular oxidative stress, ER stress and lipid peroxidation. e. Recent evidence suggests that these events activate c-jun N-terminal kinases ( JNK 1 and JNK 2). JNK perpetuates insulin resistance by altering normal insulin signaling through the insulin receptor substrates IRS1 and IRS2. Activation of JNK also by proinlammatory cytokines through tumor necrosis factor (TNFα) may accelerate intracellular injury by activating transcription of NFκB, activator protein 1 (AP-1), and Fas ligand, all of which contribute to apoptosis and hepatocyte injury. This injury promotes activation of macrophages and hepatic stellate cells through transforming growth factor (TGFβ), leading to ibrosis. Since not all patients with steatosis develop inlammation and ibrosis, the precise mechanisms still must be elucidated. Treatment and prognosis 1. There is no speciic treatment for fatty liver. Weight loss and exercise will usually lead to disappearance of fat. 2. In the patient with simple non-alcoholic fatty liver, progression to cirrhosis will not occur.

Non-Alcoholic Steatohepatitis (NASH) (Figs. 4-38 through 4-46) Major morphologic features 1. A predominantly macrovesicular fatty change is present, usually involving over 75% of the hepatocytes, with no distinct zonal distribution pattern. 2. Sinusoidal collagen deposition is present to variable degrees and is most often accentuated in the perivenular zones, with intraluminal ibrosis of the terminal hepatic venules often apparent. 3. Perivenular liver cell ballooning, sometimes associated with Mallory body formation, is present in the more active

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

A

B

FIGURE 4-38 Non-alcoholic steatohepatitis. A, The trichrome stain shows abundant sinusoidal collagen involving the terminal hepatic venule and extending into the adjacent parenchyma. B, The perivenular zone on H&E stain shows prominent intrasinusoidal collagen deposition with liver cell ballooning, Mallory body formation, and a moderate predominantly neutrophilic iniltrate.

FIGURE 4-39 Non-alcoholic steatohepatitis. The hepatocytes are hydropic, with some containing Mallory bodies. A mild predominantly lymphocytic iniltrate is seen. Sinusoidal collagen deposition is prominent.

FIGURE 4-40 Non-alcoholic steatohepatitis. Moderate macrovesicular fatty change is seen with a moderate predominantly neutrophilic iniltrate.

FIGURE 4-41 Non-alcoholic steatohepatitis. High-power shows

FIGURE 4-42 Non-alcoholic steatohepatitis. Numerous glycoge-

numerous Mallory bodies with a neutrophilic iniltrate surrounding some of the cells.

nated nuclei of hepatocytes are seen. Moderate macrovesicular fat is also present.

Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases

89

stages of the disease, often associated with a neutrophilic or a mixed lymphocytic and neutrophilic inlammatory iniltrate.

FIGURE 4-43 Non-alcoholic steatohepatitis. Both macrovesicular and microvesicular “foamy” change of hepatocytes is present.

FIGURE 4-44 Non-alcoholic steatohepatitis. An epithelioid granuloma is present within the lobule in this patient who underwent jejunoileal bypass surgery for morbid obesity.

A

Other features 1. Variable degrees of periportal ibrosis are also present, with eventual progression to a micronodular cirrhosis in a large minority of cases. In the cirrhotic stage, the degree of fat is often less prominent than in early stage disease. 2. In markedly active disease, the Mallory bodies may extend into the midzones but are seldom seen diffusely within the lobules. In cirrhotic livers, the Mallory bodies when present may be more apparent in the periseptal regions but often are scattered within the regenerative nodules. 3. Microvesicular fat may also be seen. 4. Glycogenated nuclei of hepatocytes are often present and predominate in the periportal liver cells. 5. Rarely megamitochondria of hepatocytes may be present. 6. Portal tracts show variable degrees of lymphocytic iniltration, with some degree of periportal interface inlammatory activity also apparent in some cases. Although occasional neutrophils may be seen, they are uncommon. 7. The terminal hepatic venules may sometimes be associated with endothelial inlammation (endothelialitis), although this feature is uncommon. 8. The regenerative nodules in the cirrhotic stage may be well-formed or poorly formed. 9. Non-caseating granulomas have been reported in patients after bypass surgery for morbid obesity. Special stains 1. Masson trichrome: The portal, periportal and perivenular ibrosis seen in non-alcoholic steatohepatitis are best enhanced with this stain. In addition, the megamitochondria can often best be seen and stain red. 2. Perl’s iron: A usually mild degree of stainable iron can be seen in periportal hepatocytes.

B

FIGURE 4-45 Non-alcoholic steatohepatitis, cirrhotic stage. A and B. Both low- and medium-power images show a well-established cirrhosis, with the regenerative nodules small (“micronodular”). Mild periseptal sinusoidal collagen deposition can be seen in the higher power image. The amount of fat is only mild in this example, as it is not uncommon for the degree of fatty change to decrease by the time the liver is cirrhotic (trichrome).

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TABLE 4-2

FIGURE 4-46 Non-alcoholic steatohepatitis, cirrhotic stage. The regenerative nodules are small and rather well-circumscribed (“micronodular”). Moderate fatty change is present.

TABLE 4-1

Morphologic Comparison of Alcoholic Liver Diseases versus Non-Alcoholic Steatohepatitis ALCOHOLIC LIVER DISEASE

NON-ALCOHOLIC STEATOHEPATITIS

Mallory bodies

Abundant

Present but less common

Lobular inlammation

Usually neutrophils

Neutrophils, or mixed neutrophils and lymphocytes

Portal inlammation

Mixed lymphocytes and neutrophils

Predominantly lymphocytes

Periportal interface inlammation

Usually absent

Usually present to variable degrees

Glycogenated nuclei

Infrequent

Present, often numerous

Ductular (cholangiolar) reaction

Present, sometimes prominent

Infrequent

Megamitochondria

Round, usually perivenular

Round to spindly, perivenular or random

Fat

Usually abundant, with perivenular zonal predilection; macrovesicular or microvesicular

Usually abundant, perivenular or scattered with no zonal predominance; usually macrovesicular, can be microvesicular

Cholestasis

Often seen in active disease

Uncommon

Perivenular sinusoidal ibrosis

Common

Present to a lesser extent

Veno-occlusive changes

Common

Infrequent

Histologic Staging and Grading Systems for Non-Alcoholic Steatohepatitis

Perisinusoidal/pericellular ibrosis (0–4) Necroinlammatory changes (0–3)

Brunt, et al (1999)

Fibrosis (0–4) Steatosis (0–3) Portal, lobular inlammation (0–3) Liver cell injury (0–2)

Kleiner, et al (2005)

Portal ibrosis (0–6) Lobular inlammation, Mallory bodies, ballooning (0–3) Perisinusoidal ibrosis (0–3) Fatty change (0–4)

Mendler, et al (2005)

Fatty liver alone and with lobular inlammation, ballooning, Mallory bodies, ibrosis (0–4)

Matteoni, et al (1999)

Immunohistochemistry 1. Ubiquitin, pancytokeratin: The Mallory bodies, which represent intermediate ilaments, stain strongly positive. Histologic disease grading and staging 1. Various morphologic approaches are now in use in qualitatively assessing the stage (ibrosis) and grade (inlammatory activity) of the liver disease. Four systems are listed in the Table 4-1 (refer to Appendix Tables D through G for a more detailed description). Differential diagnosis 1. Alcoholic liver disease: Both alcoholic liver disease in an active drinker and non-alcoholic steatohepatitis have similar morphologic features. In the most active stages of the disease (e.g., alcoholic hepatitis), the distinction between the two disorders is more apparent, but in only mildly active disease, often the clinical history and correlation with laboratory tests may be most important for distinction. Table 4-2 lists the various morphologic changes in both disorders for comparison.

2. Other disorders that can mimic both alcoholic and non-alcoholic fatty liver disease: Numerous disease entities cause fatty change often with co-existent lobular inlammation (steatohepatitis). Additionally, Mallory bodies have been described in over two dozen disorders. Table 4-3 lists the various diseases that should be included in the differential, with both alcoholic hepatitis and non-alcoholic fatty liver disease also included in this table for comparison. History and laboratory data are then essential in making the correct diagnosis. Clinical and biologic behavior 1. Nonalcoholic steatohepatitis (NASH) is a condition of hepatic fat accumulation associated with lobular inlammation. The diagnosis can only be made after careful exclusion of alcohol use in patients as well as drug induced steatosis caused by corticosteroids, estrogens, tamoxifen, and others. Associated conditions include type 2 diabetes mellitus and hyperlipidemia. Although initial reports suggest a female preponderance, there are data to indicate that there is no sex predilection for this disease. NASH is considered within a spectrum of fat related disorders of the liver collectively called non-alcoholic fatty liver disease (NAFLD). 2. The prevalence of NAFLD in the general population is not known. It is estimated to be 10% to 24%, but increases (57% to 74%) in obese persons. Patients with steatosis alone have a benign clinical course over a 10- to 15-year period, whereas 23% of patients with NASH progress to cirrhosis over the same time period.

Chapter 4 / Alcoholic and Non-Alcoholic Fatty Liver Diseases

TABLE 4-3

Liver Disorders Morphologically Resembling Alcoholic and NonAlcoholic Fatty Liver Disease

DISORDER

MALLORY BODIES

SINUSOIDAL COLLAGEN

FAT

Alcoholic hepatitis

+++

+++

+++

Non-alcoholic steatohepatitis (NASH)

+/++

++

+++

Gastric stapling, gastric or jejunoileal bypass

++

++

+++

Indian childhood cirrhosis

+++

++

–

Wilson disease

+/++

+

+

Chronic hepatitis C

–

+

+/++

• Extrahepatic biliary atresia • Large extrahepatic bile duct obstruction • Primary biliary cirrhosis • Primary sclerosing cholangitis

+ +

– –

– –

++ +/++

– –

– – –

5.

Chronic cholestasis

Weber-Christian disease

+

–

Abetalipoproteinemia

+

–

–

Tyrosinemia

–

+/++

+/++

Glycogen storage disease 1a

+/++

–

+ ++

Galactosemia

–

+/++

α1-antitrypsin deiciency

+

–

–

Kwashiorkor

+

–

+++

Post-intestinal resection

+

–

–

Radiation

+

+

–

Asbestosis

+

–

–

Hyperalimentation (TPN)

–

++

+

+ + +/++

– – +

+ +/++ +

+ +

– –

– –

+ + +/– ++ + ++ + +/–

– – ++ + − ++ − ++

++ – + + + + + +

6.

7.

Tumors • Focal nodular hyperplasia • Liver cell adenoma • Hepatocellular carcinoma Drugs • Perhexiline maleate • Diethylaminoethoxyhexestrol • Glucocorticoids • Griseofulvin • Methotrexate • Nifedipine • Tamoxifen • Amiodarone • Estrogens • Vitamin A

8.

Frequency in liver biopsies: +++, common; ++, occasional; +, rare.

3. NAFLD is the most common cause for asymptomatic elevation of serum transaminases and for referral to hepatologist. Elevations in ALT and AST are usually mild and frequently less that 100 U/L. Serum bilirubin is normal, alkaline phosphatase and γ-glutamy transpeptidase activities are mildly or variably elevated, and hepatic synthetic function is preserved. 4. There are no speciic diagnostic tests for this disease. A number of composite tests have been evaluated that provide a greater or lower probability of diagnosis. A computerized calculation of alcoholic liver disease/NAFLD index uses a weighted multivariate model and logistic

9.

91

regression analysis of mean corpuscular volume, AST and ALT values, height, weight, and sex to generate a score. A score >0 (the higher the “+” score the greater the probability) favors alcoholic liver disease, and a score 100, the AST:ALT ratio is usually ≤1 in most but not all non-cirrhotic patients with NASH, a useful clue in differentiating NASH from active alcoholic liver disease, where the ratio in the latter is usually >1. On physical examination hepatomegaly is frequently present, although the accuracy of the clinical indings is often in doubt because of the dificulty in palpating the liver in an obese individual. In patients with cirrhosis, splenomegaly may be present. Hepatocellular carcinoma may develop rarely. Ultrasound scan shows hepatomegaly and increased echotexture consistent with fatty change or ibrosis. On CT scan, indings of diffuse low density of the liver compared to the spleen density are diagnostic of fatty change. The diagnosis can be conirmed on liver biopsy where the disease can be staged by semi-quantifying steatosis, inlammation, necrosis, and ibrosis. There are no satisfactory noninvasive tests for assessing the degree of ibrosis, but several have been proposed. Cytokeratin 18 (CK18) is a major intermediate ilament protein in hepatocytes and is cleaved mainly by caspase 3 in the apoptosis cascade. Higher CK18 fragments are seen in NASH, although 25% of suspected NASH patients with elevated CK18 levels have normal histology. The NAFLD score, utilizing BMI, AST/ALT ratio, glucose level, platelet count and albumin level, showed that a low cut off score had low probability of advanced ibrosis, whereas a high cutoff indicated signiicant ibrosis. The BARD score is a weighted sum of BMI >28 (1 point), AST/ALT >0.8 (2 points) and diabetes (1 point); scores of 2 to 4 had odds ratio predicting advanced ibrosis. The inclusion of age in the Fibrotest model (using three serum markers for matrix turnover) was considered to predict advanced ibrosis. The clinical utility of all these indirect measurements of ibrosis and their relative beneit will be validated in larger cohorts of patients with NAFLD and NASH. NAFLD and NASH were also seen in patients’ statuspost jejunoileal bypass, a surgical procedure for producing signiicant and rapid weight loss in the morbidly obese patient. The gastrointestinal tract is shortened by anastomosing the proximal 14 inches of jejunum to the distal 4 inches of ileum, whereby patients may lose anywhere from 65 to 127 lbs during the irst 5 months after surgery. Although most patients may just have a fatty liver on biopsy, up to 12% may develop liver disease characteristic of NASH. This procedure is not currently performed. The pathophysiologic concepts for NASH are reviewed under the discussion above for Non-Alcoholic Fatty Liver (NAFL).

Treatment and prognosis 1. There is no speciic treatment for this condition. Weight loss and an exercise program will usually lead to disappearance of fat, particularly loss of visceral fat and improvement in histology.

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2. Treatment trials with ursodeoxycholic acid and vitamin E have been tried with no conclusive results regarding beneit. Taurine, considered to function as a lipotrophic factor, improves mobilization of fat and was found to reduce hepatic fat on ultrasound in a small group of children treated with oral supplements. Betaine, a precursor of S-adenosylmethionine and a hepatoprotective factor, was associated with improvement in liver tests and histology after 1 year of treatment in a small pilot study. In a recent study, the thiazolidinedione drug piaglitazone was shown in a randomized controlled study to decrease serum ALT, improve insulin sensitivity, and histology; however patients on this medication developed increase in weight. Two other studies with this type of drug showed equivocal results. The use of metformin in NAFLD patients who were not diabetic was shown in a meta-analysis to decrease serum transaminases and improve histology. Other drugs, namely silimarin, pentoxyfylline, omega 3

fatty acids, SAMe, exenitide, and recombinant leptin and endocannabinoid receptor antagonists are currently in preliminary stages of clinical trials. 3. In patients with cirrhosis progressing to liver failure, liver transplantation may be performed. Recurrent disease in the graft can occur. 4. In patients who acquire the liver disease after bypass surgery, liver biopsy should be performed. If histopathologic changes typical for this lesion are noted and other etiologies excluded, early takedown of the bypass may prevent the development of cirrhosis.

REFERENCES The complete reference list is available online at www. expertconsult.com.

Chapter

5

DRUG- AND TOXININDUCED LIVER CELL INJURY

CLASSIFICATION 93 Basic Mechanisms of Disease 93 Predominant Morphologic Features 93

HEPATOCELLULAR NECROSIS WITH MINIMAL TO ABSENT INFLAMMATION 93 Acetaminophen 93 Cocaine 95

HEPATOCELLULAR NECROSIS WITH INFLAMMATION 98 Isoniazid 98 Phenytoin 100 Halogenated Hydrocarbons (Halothane) 101 Nitrofurantoin 102

LOBULAR CONFLUENT NECROSIS WITH INFLAMMATION 103 Troglitazone 104 Niacin (Nicotinic Acid) 105 Sertraline 106

FATTY CHANGE 106

CHOLESTASIS WITH INFLAMMATION 117 Ketoconazole 117 Clarithromycin 119 Bupropion 119

BILE DUCTS: INFLAMMATION AND INJURY 119

Tetracycline 106 Mushrooms 108 Sulfasalazine 110 Vitamin A 110

Chlorpromazine 120 Allopurinol 121

VASCULAR 122

GRANULOMAS 111 Sulfonamides and Derivatives 111 Mineral Oil 113

MALLORY BODIES 113 Amiodarone 113

CHOLESTASIS, SIMPLE 115 Oral Contraceptives 115 Methyltestosterone 116

Busulfan (Conditioning Regimen for Bone Marrow Transplants) 122

FIBROSIS 123 Methotrexate 123

NEOPLASMS AND RELATED LESIONS 125 MISCELLANEOUS DRUG-INDUCED LESIONS 125

CLASSIFICATION

Predominant Morphologic Features

Basic Mechanisms of Disease

1. Table 5-2 lists the various histologic features associated with drug-induced and toxic liver cell injury, with examples. 2. It is important to note that the majority of drugs and toxins that produce an idiosyncratic hypersensitivity reaction often cause various morphologic changes.

1. Drug- and toxin-induced liver cell injury is among the most common causes of abnormal liver tests in humans. 2. In one series, up to 10% of patients with transaminitis suggestive of acute hepatitis were found to have drug or toxin-induced liver injury, with the incidence signiicantly rising in patients over age 50. 3. The overall incidence in hospitalized patients is 1.4%, with the incidence increasing to 2% to 5% in hospitalized patients with jaundice. 4. Additionally, up to 50% of cases of acute hepatic failure, and from 20% to 50% of cases of non-viral chronic hepatitis, are due to drug or toxin-induced liver damage. 5. The range of histologic changes is numerous, and can be subdivided into intrinsic and idiosyncratic injury. 6. The reproducibility of morphologic injury, the relationship to dosage, and the time frame from the time of ingestion or exposure and the liver test abnormalities all play a part in the pathophysiologic disease mechanisms (see Table 5-1, Intrinsic versus idiosyncratic drug and toxin induced liver injury).

HEPATOCELLULAR NECROSIS WITH MINIMAL TO ABSENT INFLAMMATION (Table 5-3, Figs. 5-1 through 5-6)

Acetaminophen (Figs. 5-1 through 5-4) Major morphologic features 1. Coagulative-type necrosis of hepatocytes, manifested by slightly shrunken liver cells with intensely eosinophilic cytoplasm and small pyknotic hyperchromatic nuclei, is present involving predominantly the perivenular zone 93

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TABLE 5-1

Intrinsic versus Idiosyncratic Drug- and Toxin-Induced Liver Injury INTRINSIC INJURY

IDIOSYNCRATIC INJURY

DIRECT

INDIRECT (TOXIC METABOLIC BYPRODUCTS)

IMMUNOLOGIC (HYPERSENSITIVITY)

METABOLIC (TOXIC METABOLITES)

Reproducible in Animal Models

+

+

−

−

Dose Relationship

+

+

−

−

Temporal Relationship

+

+

−

−

Speciic Reproducible Morphologic Changes

+

+

−

−

Unpredictable Morphologic Features

−

−

+

+

Main Clinical Presentation

Severe injury, hepatic failure

Severe injury, hepatic failure

Fever, eosinophilia, transaminitis

Transaminitis (liver failure in more severe cases)

Mortality

High

High

Variable

Variable

Examples

Carbon tetrachloride Phosphorus

Acetaminophen Cocaine

Phenytoin, chlorpromazine

Isoniazid, troglitazone

(zone 3 of Rappaport), this change most prominent 4 to 6 days after drug ingestion. 2. The perivenular necrosis usually involves all of the hepatocytes in that zone (“conluent necrosis”), with corresponding collapse of the perivenular reticulin framework (best seen 6 to 10 days after ingestion), and with marked midzonal and periportal hepatocellular regeneration (manifested by two cell–thick hepatic cords, clear “hydropic” liver cell cytoplasm with distinct nuclear outlines, and prominent nuclear chromatin). Other features 1. Portal tracts are normal in size and appearance, without an inlammatory iniltrate or bile duct changes. 2. Lobular inlammation is absent; however, phagocytosis of necrotic hepatocytes by mononuclear and Kupffer cells is prominent in the areas of liver damage and lobular collapse. 3. In the more severe cases, the conluent necrosis can extend into the mid-zones and even periportal zones. 5. Cholestasis is quite rare. 6. All lobules throughout the liver are uniformly involved. Special stains 1. PAS after diastase digestion (DiPAS): The DiPAS-positive lysosomal granules in macrophages and Kupffer cells in the perivenular areas of necrosis are highlighted with this stain. 2. Reticulin: The perivenular lobular collapse that is seen 6 to 10 days after drug ingestion is emphasized. Differential diagnosis 1. Ischemic necrosis (poor vascular perfusion): Eosinophilic coagulative-type necrosis in the perivenular regions may occur in severe hypoxia and histologically resembles acetaminophen hepatotoxicity. Predisposing factors for ischemia (e.g., heart failure), a history of acetaminophen ingestion, and early acetaminophen blood levels are helpful in establishing the diagnosis. 2. Acute viral hepatitis: Both acetaminophen-induced hepatotoxicity and acute viral hepatitis may clinically present in a similar manner, and plasma drug levels are not

helpful unless performed within the irst 16 hours after ingestion. Serum aminotransferase activities are markedly elevated, sometimes reaching levels >10,000 IU/L, in acetaminophen hepatotoxicity, this level seldom seen in typical acute viral hepatitis. Serum lactic dehydrogenase (LDH) levels are usually much higher in drug-induced and ischemic-related injury than in viral hepatitis. Biopsy is usually not necessary for diagnosis unless the possibility of viral hepatitis and the subsequent risk of chronic hepatitis need exclusion, since acetaminophen liver injury does not lead to chronic liver disease. Other features seen in acute viral hepatitis, such as marked portal lymphocytic iniltrates, prominent Kupffer cell hyperplasia, and diffuse spotty lobular necrosis and inlammation, are not features of acetaminophen toxicity. Clinical and biologic behavior 1. Acetaminophen is normally metabolized in the liver by sulfation and glucuronidation, with 10,000 U/L. Other complications that may be seen in cocaineinduced injury, such as rhabdomyolysis, are not features seen in acute viral hepatitis. Although cocaine-induced injury may exhibit portal lymphocytic iniltrates, the numbers of lymphocytes within a portal tract are less than that seen in acute viral hepatitis. Other morphologic features seen in acute viral hepatitis, such as diffuse spotty necroinlammatory changes and prominent Kupffer cell hyperplasia, are not features seen in cocaine-induced liver cell injury. Clinical and biologic behavior 1. Cocaine, a popular drug due to its tremendous stimulant and euphoriant effects, is a member of the tropane family of alkaloids and is found in the South American tea-like leaves of Erythroxylon coca. 2. The drug can be administered in a number of ways, including chewing the leaves and smoking the free base. Nasal and intravenous routes are used as well. 3. The rapid absorption of the free base by the abundant pulmonary alveolar surface area results in striking effects that occur within seconds.

Chapter 5 / Drug- and Toxin-Induced Liver Cell Injury

FIGURE 5-2 Hepatocellular necrosis with minimal to absent inlammation: Acetaminophen. The portal tract shows only minimal lymphocytic iniltrates with normal bile ducts.

97

FIGURE 5-4 Hepatocellular necrosis with minimal to absent inlammation: Acetaminophen. This biopsy was taken approximately 10 days after the initial onset of abnormal liver tests, and shows loss of the damaged hepatocytes with collapse of the reticulin framework in the perivenular zone. Enlarged Kupffer cells in this area are seen which have phagocytized the necrotic liver cells. The hepatocytes towards the left of the ield are hydropic due to liver cell regeneration but are not inlamed.

FIGURE 5-3 Hepatocellular necrosis with minimal to absent inlammation: Acetaminophen. The perivenular hepatocytes to the left of the ield are slightly smaller, with eosinophilic cytoplasm and pyknotic nuclei, compared to the undamaged liver cells towards the right of the ield. No appreciable inlammatory iniltrate is seen.

4. The major route of metabolism (90%) is by hydrolysis, with urinary excretion of the metabolites ecgonine methyl ester, benzoylecgonine, small amounts of ecgonine, and unmetabolized cocaine. 5. Approximately 10% of cocaine undergoes N-demethylation in hepatocytes by the cytochrome P450 mixed function oxidase system, forming norcocaine, a metabolite that elicits signiicant liver cell damage when injected intraperitoneally into mice. The metabolites can be identiied in the urine 24 to 60 hours after use. Further enzymatic breakdown to N-hydroxynorcocaine and norcocaine occurs, with eventual oxidation to the nitrosonium ion, the latter highly reactive with glutathione. Nitrosonium ion also serves as a catalyst for the conversion of alcohols, amines, and hydroxide ions to aldehydes, ketones, and hydrogen peroxide which cause lipid peroxidation and damage of liver cell membranes.

FIGURE 5-5 Hepatocellular necrosis with minimal to absent inlammation: Ferrous sulfate. Iron infrequently can be associated with a periportal necrosis.

6. Experimentally, cocaine was found to induce liver cell damage in both the periportal and perivenular zones in animals, and are relections on induction and inhibition of the cytochrome P450 oxidase system and the different patterns of localization of various cytochrome P450 isoenzymes. 7. After taking cocaine, patients may present with tachycardia, diaphoresis, and disorientation. Serious complications include seizures, psychoses, hallucinations, strokes, dysrhythmias, myocardial infarction, and rhabdomyolysis. 8. Laboratory tests include striking elevations of the aminotransferase activities, sometimes over 10,000 IU/L, with associated marked increase in the LDH and CPK levels. 9. In the more severe cases, renal failure may also occur. 10. The diagnosis rests on the history and positive toxicology screen for cocaine.

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A

B

FIGURE 5-6 Hepatocellular necrosis with minimal to absent inflammation: Cocaine. Different zonal damage can be seen with cocaineinduced liver cell injury in the same liver, as this autopsy specimen demonstrates. A, The portal tract shows bile duct and cholangiolar proliferation but little inflammatory infiltrate. The periportal hepatocytes show a striking coagulative necrosis. B, In the same specimen but a different field, the periportal hepatocytes are spared damage, while the adjacent midzonal hepatocytes show extensive necrosis.

11. The mechanism by which cocaine causes liver injury relates to production of highly reactive metabolites, with peroxidation, free radical formation, and covalent binding to liver proteins. Glutathione is important in preventing the accumulation of peroxides and superoxide radicals, but other factors also play a role. Treatment and prognosis 1. There are no speciic antidotes and recovery is usual, provided comorbid cardiac or cerebrovascular disease is not associated, and patients do not have underlying chronic liver disease; however, the latter is sometimes apparent, since patients who abuse cocaine also often have a higher incidence than the general population of chronic viral hepatitis. 2. In the rare cases of liver failure, liver transplantation is not recommended because of the involvement of other organ systems in an individual with active drug or substance abuse.

HEPATOCELLULAR NECROSIS WITH INFLAMMATION (Table 5-4, Figs. 5-7 through 5-11)

Isoniazid

TABLE 5-4

Hepatocellular Necrosis with Inlammation

α-Methyldopa Aspirin Benzarone Bupropion Carbutamide Chaparral Chlorpromazine Clarithromycin Clometacin Dantrolene Dapsone Diclofenac Dideoxyinosine Dihydralazine Disuliram Ethanol Etretinate

Fenoibrate Germander Halogenated hydrocarbons Herbalife nutritional supplements Ibuprofen Indomethacin Isoniazid Jin Bu Huan Ketoconazole Lisinopril Methotrexate Minocycline Naproxen Niacin Nifedipine Nitrofurantoin Olmesartan Oxacillin Oxaprozin Oxyphenisatin

Papaverine Para-aminosalicylic acid Pemoline Perhexiline maleate Phenylbutazone Phenytoin Pirprofen Propylthiouracil Rifampin Sertraline Sulfadoxine Sulfasalazine Sulfonamides Suloctidil Telithromycin Ticrynafen Toxic oil (rapeseed) Trazodone Troglitazone

Entries listed in bold italics indicate well-documented examples of toxicity. (Data from Kanel GC: Histopathology of drug-induced liver disease. In: Kaplowitz N, DeLeve LD (eds): Drug-Induced Liver Disease, 2nd ed, pp 237-289. New York: Informa Healthcare, 2007.)

Major morphologic features 1. Diffuse lobular necrosis with apoptosis, hydropic change of hepatocytes, and predominantly a lymphocytic lobular inlammatory iniltrate are present involving all zones. 2. Portal tracts exhibit a moderate lymphocytic iniltrate, with the bile ducts unremarkable.

3. Fulminant hepatitis, with conluent submassive and massive hepatic necrosis, has been described but is infrequent. 4. Endophlebitis has been described involving the terminal hepatic venules. 5. Periportal interface inlammatory activity has been reported but is extremely uncommon. 6. Mild macrovesicular fatty change and granuloma formation have been described.

Other features 1. Cholestasis may be seen, but is infrequent. 2. Slight periportal accentuation of the inlammatory iniltrates may sometimes occur.

Differential diagnosis 1. Acute viral hepatitis: Prominent lobular inlammation and necrosis as well as portal lymphocytic iniltrates are seen in both conditions. The degree of portal

(Figs. 5-7, 5-14)

Chapter 5 / Drug- and Toxin-Induced Liver Cell Injury

A

99

B

FIGURE 5-7 Hepatocellular necrosis with inlammation: Isoniazid. A, The portal tract exhibits a moderate lymphocytic iniltrate. B, The parenchyma shows hydropic and necroinlammatory changes diffusely throughout the lobule. The majority of the pigment is lipochrome, although some degree of intracellular bile is also present.

A

B

FIGURE 5-8 Hepatocellular necrosis with inlammation: Phenytoin. A, The portal tract exhibits a mixed inlammatory iniltrate consisting of lymphocytes and numerous eosinophils. B, The parenchyma shows mild focal necrosis with lymphocytic iniltration. Mild sinusoidal lymphocytosis is also apparent.

FIGURE 5-9 Hepatocellular necrosis with inlammation: Phenytoin. The hepatocytes show inely granular eosinophilic intracytoplasmic inclusions resembling the “ground-glass” cells often seen in chronic hepatitis due to HBV infection, that diagnosis having been excluded in this patient on phenytoin.

inlammation in isoniazid-induced liver cell injury is usually not as marked as that seen in acute viral hepatitis, although that is not always the case when compared to a mild acute viral hepatitis. Periportal accentuation of the liver cell injury in isoniazid-induced liver cell damage may be a helpful although an uncommon clue. Clinical correlation and assessment of the serum viral serologic markers is imperative in arriving at the correct diagnosis. 2. Early and active stages of chronic viral hepatitis: In the early stages of chronic viral hepatitis, the degree of portal ibrosis may be quite minimal. Additionally, in active stage disease of chronic viral hepatitis, sometimes the lobular inlammation can be diffuse, these features therefore mimicking the histology associated with both acute viral hepatitis as well as acute druginduced injury as seen with isoniazid. The presence of periportal interface inlammatory activity in chronic hepatitis can be a helpful clue in differentiation. Correlation with the hepatitis serologic markers is most important.

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A FIGURE 5-11 Hepatocellular necrosis with inlammation: Nitrofurantoin. The lobule shows variable hydropic change, focal necrosis with lymphocytic iniltration, and Kupffer cell hyperplasia.

B FIGURE 5-10 Hepatocellular necrosis with inlammation: Halogenated hydrocarbons (halothane). A, The portal tract shows a marked lymphocytic iniltrate with mild bile duct proliferation. B, The lobule shows marked liver cell necrosis and dropout with a prominent lymphocytic iniltrate, this feature most prominent in the perivenular and midzones.

Clinical and biologic behavior 1. The incidence of acute hepatitis secondary to isoniazid (INH) is 0.1% to 1.0% of all patients receiving the drug. In those over 35 years of age the incidence is 2% to 3%; however, anywhere from 10% to 20% of patients receiving INH may have some degree of aminotransferase elevations. 2. INH is metabolized through both the indirect and direct pathways: a. Indirect: INH is acetylated to acetyl isoniazid which is then hydrolyzed to monoacetyl hydrazine and isonicotinic acid. b. Direct: INH is hydrolyzed by isoniazid hydrolase to isonicotinic acid and hydrazine. In both pathways the isonicotinic acid is conjugated with glycine and excreted by the kidneys. The conversion, however, of the monoacetyl hydrazine to electrophilic intermediates by the P450 mixed function oxidase system may be responsible in part for the liver cell injury. In addition, phenobarbital and other enzyme inducers of the cytochrome P450 system may enhance the hepatotoxicity.

3. INH hepatotoxicity clinically occurs in two patterns: a. Subacute hepatic injury, occurring in 12% to 20% of recipients with an average of 3 months of drug use, associated with asymptomatic elevations (three- to four-fold) of serum aminotransferases which resolve when the medication is discontinued. b. Overt hepatic injury, resembling viral hepatitis, with onset 2 to 11 months (rarely longer) after continued ingestion. 4. There is little documented evidence for cirrhosis developing as a sequel to INH-induced liver injury. Treatment and prognosis 1. Treatment is supportive, with prompt recognition of toxicity and withdrawal of the drug resulting in resolution in the vast majority of cases. 2. Older patients and those receiving continued therapy despite symptoms have an increased risk of severe hepatitis and hepatic failure, with an overall mortality rate of 10% in those presenting with jaundice. Liver transplantation should be considered for patients with liver failure.

Phenytoin (Figs. 5-8 and 5-9) Major morphologic features 1. Lobular necrosis and apoptosis with lymphocytic inlammatory iniltrates are diffusely present throughout all zones. 2. Portal lymphocytic iniltrates with occasional eosinophils may be seen. Other features 1. The lobular inlammation may present with a “mononucleosis-type” pattern, with increased numbers of slightly atypical circulating lymphocytes seen within the sinusoids.

Chapter 5 / Drug- and Toxin-Induced Liver Cell Injury

2. Conluent lobular necrosis has been reported but is uncommon. 3. Poorly formed granulomas may rarely be seen within the lobules. 4. In some instances the lobular inlammation may be mild, with the hepatocytes exhibiting an eosinophilic “groundglass” cytoplasmic appearance. 5. In rare instances, bile ducts may be surrounded and iniltrated by lymphocytes, with eventual duct destruction and duct depletion (ductopenia). 6. Vasculitis involving the small hepatic artery branches has been reported. Special stains 1. Orcein, aldehyde fuchsin, Victoria blue: Although the “ground glass” type of cells are uncommonly seen in phenytoin-induced injury, when present these stains differentiate those cells from similarly appearing hepatocytes often present in chronic HBV infection (all three stains negative for phenytoin-induced injury and positive for chronic HBV infection). Immunohistochemistry 1. HBsAg: The “ground glass” type of cells sometimes seen in phenytoin-induced injury stain negatively, but show positive cytoplasmic staining for chronic HBV infection. Differential diagnosis 1. Acute viral hepatitis: Phenytoin-induced liver cell injury may exhibit variable numbers of eosinophils within the portal tracts, this feature not characteristic of acute viral hepatitis. In addition, the degree of lobular inlammation is generally mild compared to the classic acute viral hepatitis secondary to the hepatotropic viruses; however, mild forms of acute viral hepatitis may be morphologically indistinguishable from phenytoin-induced injury, hence clinical and serologic correlation is most important. 2. Cytomegalovirus (CMV), Epstein-Barr virus (EBV) infections: The presence of a “mononucleosis” type of lobular pattern (atypical lymphocytes lining up within sinusoids) is seen in both CMV and EBV infection in the immunocompetent patient. Portal eosinophils are not characteristic of CMV or EBV infection, however. 3. Chronic viral hepatitis due to HBV infection: The “ground glass” type of cells seen in chronic viral hepatitis secondary to HBV infection are quite similar on hematoxylin-eosin stain as those infrequently seen in phenytoin-induced injury. Special histochemical and immunohistochemical stains are helpful in the differential diagnosis (see descriptions of Special stains and Immunohistochemistry in this section). Clinical and biologic behavior 1. The overall incidence of phenytoin-induced hepatotoxicity is 5 mg/dl, frequently in the unconjugated form. Overt jaundice is quite uncommon. Serum aminotransferase elevations are mild in one-third of the cases, and alkaline phosphatase values are usually normal. In severe heart failure, however, prominent anoxic change in perivenular regions due to a low cardiac output state results in moderate to marked (may be greater than 1000 IU/L) elevations of serum aminotransferase activities, moderate hyperbilirubinemia and signiicant increase in the prothrombin time. In chronic right-sided heart failure, persistent increased venous pressure may cause phlebosclerosis of the medium and large hepatic venous structures. Long-term congestion leading to “cardiac” cirrhosis takes many years to develop and is not a true cirrhosis, as regenerative nodules do not form. In cardiac failure, ascites can occur without portal hypertension and is due to elevation in both free and wedged hepatic venous pressures. Once cardiac cirrhosis develops, portal hypertension may ensue. Esophageal varices may occur in some patients, although bleeding from varices is rare. Acute congestive cardiac failure usually results from congenital, ischemic, or valvular heart diseases, or cardiomyopathy. In patients with presumed liver disease, alcoholic cardiomyopathy and iron overload need consideration. The hepatic changes seen in congestive heart failure are part of two pathophysiologic mechanisms termed ischemic hepatopathy. a. Hepatic venous congestion or stasis leads to interference in hepatic blood low and consequent impairment in oxygen delivery to the hepatocytes. b. Decreased hepatic perfusion and hypoxemia, caused usually by acute hypotension or low cardiac output states, lead to liver cell ischemic necrosis.

The end result in both mechanisms is coagulative ischemic necrosis of the hepatocytes, with the liver cells in the perivenular zone most susceptible to injury. In severe congestive cardiac failure, both of the above mechanisms may be operative. Treatment and prognosis 1. Adequate treatment of heart failure will result in resolution of hepatic abnormalities. 2. Mortality is frequently related to severe heart failure rather than hepatic failure.

Hepatic Vein Thrombosis (Budd-Chiari Syndrome) (Figs. 6-7 through 6-13) Major morphologic features Acute 1. Severe sinusoidal dilatation, congestion, and acute hemorrhage occur in the perivenular zones. 2. Red blood cells in the perivenular zones can be seen within the space of Disse, partially or totally replacing damaged hepatocytes that have undergone anoxic ischemic necrosis (red blood cell–trabecular lesion). Chronic 1. Prominent intraluminal and perivenular ibrosis of the terminal hepatic venules may develop over time. Other features 1. Variable degrees of acute changes, ranging from only mild sinusoidal dilatation to marked hemorrhagic necrosis, may occasionally be present within different lobules in the same liver biopsy specimen. 2. Mild degrees of macrovesicular and some microvesicular fatty change may be present in viable hepatocytes. 3. Cholestasis may occur but is unusual. 4. Portal and parenchymal inlammatory changes are minimal to absent, with the bile ducts unremarkable.

FIGURE 6-6 Venous congestion, micronodular cirrhosis. With time the portal tracts within the nodules in cardiac cirrhosis become ibrotic, with eventual bridging ibrosis and resultant formation of a micronodular cirrhosis (trichrome).

FIGURE 6-7 Budd-Chiari syndrome, acute. The perivenular and midzones show striking acute hemorrhage.

Chapter 6 / Vascular Disorders

137

FIGURE 6-9 Acute Budd-Chiari syndrome. The perivenular zone FIGURE 6-8 Acute Budd-Chiari syndrome. The perivenular liver cells show coagulative ischemic necrosis. Dilated sinusoids are present.

shows striking sinusoidal dilatation. The red blood cells on this lowpower image are mostly located within the hepatic cords and not within the sinusoids (red blood cell–trabecular lesion).

FIGURE 6-10 Acute Budd-Chiari syndrome. High-power image of a perivenular zone shows absence of many of the liver cells within the hepatic cords, with their replacement by red blood cells. Viable hepatocytes can be seen merging with these areas of liver cell dropout at the lower left of the ield. The sinusoids are open.

FIGURE 6-11 Acute Budd-Chiari syndrome. This low-power image

FIGURE 6-12 Chronic Budd-Chiari syndrome. The hepatic vein branch shows virtual total luminal occlusion by relatively dense ibrous tissue with multiple small foci of revascularization.

FIGURE 6-13 Chronic Budd-Chiari syndrome. The perivenular zone shows ibrosis that extends into the midzonal sinusoids. The adjacent liver cells are small and somewhat atrophic.

shows a totally occluded sublobular vein branch with revascularization, this lesion responsible for the perivenular changes noted in Fig. 6-10 (trichrome).

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5. In long-term outlow obstruction, sinusoidal dilatation may not be present when collateral channels shunting blood proximal to the obstruction are established. 6. Sublobular and hepatic veins often exhibit variable degrees of organizing thrombosis with recanalization. 7. Secondary portal vein thrombosis can occur, leading to variable degrees of portal ibrosis, sometimes forming indiscrete septa between portal tracts and terminal hepatic venules (venoportal cirrhosis). 8. Perivenular bridging ibrosis may lead to a “nodule” with a normal to only slightly ibrotic centrally located portal tract (reversed lobulation or cardiac cirrhosis). In longterm cases, portal-perivenular ibrosis may eventually occur leading to micronodular cirrhosis. 9. The caudate lobe outlow vessel that drains separately into the inferior vena cava is occasionally spared, resulting in hypertrophy and enlargement of the caudate lobe. 10. A thin ibrous web forming a valve-like membrane located at the border of the hepatic veins and the inferior vena cave can be present to variable degrees, causing thrombosis and organization, sometimes with calciications. Note: The red blood cell–trabecular lesion, also seen in chronic hepatic venous outlow obstruction, may be dificult to identify when severe sinusoidal congestion and perivenular hemorrhage are also present. Special stains 1. Masson trichrome: The collagen within the sinusoids and space of Disse in the chronic phase are best demonstrated. 2. Phosphotungstic acid hematoxylin (PTAH): Fibrin can be identiied within the recently thrombosed sublobular and hepatic veins. Differential diagnosis The Budd-Chiari syndrome is associated with various conditions causing hepatic venous outlow obstruction, these disorders summarized in Table 6-1. 1. Vascular congestion secondary to heart failure: Hepatic morphology in both the acute and chronic Budd-Chiari syndrome may resemble that seen in right-sided congestive heart failure. The distinctive red blood cell–trabecular

TABLE 6-1

Various Causes of Hepatic Venous Outlow Obstruction

HEPATIC VEIN THROMBOSIS Agnogenic myeloid metaplasia Drugs (e.g., dacarbazine, estrogens, oral contraceptives) Late term pregnancy Leukemias Paroxysmal nocturnal hemoglobinuria Polycythemia vera Primary coagulation defects (e.g., dysibrinogenemia, anti-thrombin III deiciency, protein S and C deiciency, lupus anti-coagulant) Thrombocytopenia purpura (idiopathic, thrombotic) Vasculitis

HEPATIC VEIN OUTFLOW OBSTRUCTION (NONTHROMBOTIC) Cirrhosis (alcoholic, viral) Congestive heart failure (rightsided) Constrictive pericarditis Membranous obstruction of inferior vena cava Various space-occupying lesions: primary and metastatic hepatic tumors, hematomas, cavernous hemangiomas, large cysts (e.g., hydatid), abscesses

lesion is characteristic of the Budd-Chiari syndrome and may also be seen in left-sided heart failure without hypotension, but is not seen in congestive right-sided heart failure. In addition, perivenular hemorrhage is less common in heart failure. 2. Drug-induced injury: Certain drugs may be associated with hepatic vein thrombosis and include dacarbazine, estrogens, and even ethanol (see Table 5-12). A history of drug use and time frame of symptoms and onset of abnormal liver tests are important for correlation. The intraluminal ibrosis and vascular occlusion of the small terminal hepatic venules (veno-occlusive disease, VOD) caused by certain drugs (e.g., busulfan) is not seen in the Budd-Chiari syndrome, which generally involves larger vessels. Secondary intraluminal ibrosis of these small venules, however, sometimes occurs in the BuddChiari syndrome; in these instances, however, the larger vessels are also involved, this latter feature not present in VOD. 3. Cirrhosis of alcoholic or viral etiology: Advanced cases of the Budd-Chiari syndrome may show micronodular cirrhosis, which is sometimes dificult to differentiate from inactive advanced cirrhosis of other etiologies. The nodules in these instances exhibit minimal regenerative activity, without signiicant septal or parenchymal inlammatory iniltrates. In addition, sinusoidal dilatation is often seen within the nodules. The cardiac cirrhosis or reverse lobulation also seen in the earlier stages of the chronic Budd-Chiari syndrome is characterized by centrally placed normal-sized portal tracts within the nodules, this inding not seen in a true cirrhosis of other etiologies. 4. Immediately adjacent to space occupying lesions: Both primary and metastatic tumors as well as certain nonneoplastic mass lesions (e.g., abscesses) may cause sinusoidal dilatation and congestion of the immediately adjacent hepatic parenchyma due to obstruction of the sinusoidal outlow. Less commonly obstruction to biliary drainage can lead to cholestasis and an acute cholangitis as well. Imaging will conirm the presence of the hepatic mass. Note: The cardiac cirrhosis that may be seen in long-term Budd-Chiari syndrome is not a true cirrhosis, as in fact the architectural arrangement of portal tracts and terminal hepatic venules is not disrupted. Clinical and biologic behavior 1. The Budd-Chiari syndrome is a clinicopathologic disorder caused by obstruction of the hepatic venous outlow at any site from the terminal hepatic veins to the entry of the major hepatic veins into the inferior vena cava. 2. The incidence of hepatic venous outlow obstruction is variable. In Western countries, it is estimated that about one case per year is seen in large acute care facilities. The two most common causes are membranous obstruction of the large hepatic veins immediately superior to their entrance into the inferior vena cava (South Africa, Japan, India), and complete ibrous obliteration of major hepatic veins or ostia (44% in one series, and the most common cause over the years at the Los Angeles County-USC Liver Unit).

Chapter 6 / Vascular Disorders

3. The occlusion of the hepatic veins or ostia can range from partial to complete thrombosis and/or ibrous obliteration, depending on the clinical presentation and acuity of the occlusion. 4. Membranous obstruction of the vena cava (MOVC), where the obstruction occurs at any site that extends from the conluence of the hepatic veins into the inferior vena cava to the entry of the inferior vena cava into the right atrium, is commonly seen in Asia and Southern Africa, and is usually long standing. In fact, hepatocellular carcinoma was shown to be associated with almost 50% of cases of membranous obstruction in a South African series. 5. Other causes of hepatic vein thrombosis and outlow obstruction (Table 6-1) include hematologic abnormalities (myeloproliferative disorders, polycythemia vera, paroxysmal nocturnal hemoglobinuria), neoplasms (primary and metastatic), abscess formation, trauma, pregnancy, and various drugs (e.g., oral contraceptives). 6. Clinical manifestations depend on the type and acuteness of the obstruction, and vary from a vague illness and mild abdominal distress of weeks to months duration, to acute abdominal pain, hepatomegaly, ascites, and hepatic failure. The characteristic visible dilatation of the lumbar veins posteriorly provides a clinical clue to the diagnosis. 7. Clinically apparent portal hypertension is present in all patients that survive long enough for collateral circulation between the portal and systemic circulations to develop. The most important collaterals that may lead to massive gastrointestinal hemorrhage are through the coronary and left gastroepiploic veins, forming gastric and esophageal varices. 8. The drainage of the caudate lobe is often spared, resulting in marked enlargement secondary to a compensatory hyperplasia, and can be identiied in technetium 99m sulfur colloid and computed tomography (CT) scans. 9. Laboratory data shows variable degrees of aminotransferase elevations and hyperbilirubinemia, depending on the severity of the disease. In chronic disease, laboratory tests are similar to that seen in cirrhosis. 10. The red blood cells seen within the hepatic trabeculae are secondary to perivenular ischemia and increased sinusoidal pressure from the outlow obstruction, establishing an extrasinusoidal circulatory plexus for these extravasated red cells. It is presumed that sinusoidal blood lows coaxially with the terminal hepatic veins in an attempt to bypass the hepatic vein occlusion. Treatment and prognosis 1. Extensive hepatic vein thrombus formation may lead to death within weeks to months after irst symptoms. In chronic disease, survival is similar to those cases of cirrhosis of uncertain etiology (e.g., cryptogenic). 2. In acute Budd-Chiari syndrome, thrombolytic agents have been tried with variable success. 3. In severe acute portal hypertension and hepatic congestion, decompression with side-to-side portacaval surgical shunts or transjugular intrahepatic shunts, provided patency of a hepatic vein is preserved, can be lifesaving. 4. Transplantation is also an effective treatment; however, in the postoperative period, anticoagulant therapy is necessary to avoid thrombosis of the graft vascular anastomosis.

139

Veno-Occlusive Disease (VOD) (Sinusoidal Obstruction Syndrome) (Figs. 6-14 and 6-15) Major morphologic features Acute 1. Subintimal acute hemorrhage and edema, and intraluminal ibrin deposition involving the terminal hepatic vessels 500 g, and often >1000 g). 5. Angiography has demonstrated distortion and sudden diminution of the diameter of intrahepatic portal vein radicals with occasional complete cutoff of the channels,

TABLE 6-4

Other Causes of Vascular DisOrders

DISEASE

HISTOLOGY

Kawasaki disease

• Acute cholangitis with bile duct damage occurs. • Vasculitis may be seen involving the main hepatic artery branches.

CLINICAL/LABORATORY PARAMETERS • Also termed “mucocutaneous lymph node syndrome,” the disorder is characterized by arteritis, with cardiac complications developing in 22% of patients. • Hepatosplenomegaly may be present. • Hydrops of the gallbladder may develop, presenting with biliary colic, elevated serum transaminases, and increased serum bilirubin. • Acute cholangitis may clinically develop, and aneurysms of the hepatic artery have also been described.

REFERENCES The complete reference list is available online at www. expertconsult.com.

Chapter

7

INFECTIOUS DISORDERS, NON-VIRAL

BACTERIA 154 Reactive Changes and Pyogenic (Abscess) 154 Brucellosis 156 Salmonellosis 158

SPIROCHETES 160 Syphilis 160

MYCOBACTERIUM 163 Tuberculosis 163 Mycobacterium Avium Complex (MAC) 165 Leprosy 166

RICKETTSIA 167 Q Fever 167 Rocky Mountain Spotted Fever 169

FUNGI 170 Histoplasmosis 170 Coccidioidomycoses 172 Cryptococcosis 173 Candidiasis 175

OTHER NON-VIRAL INFECTIOUS DISORDERS THAT MAY CAUSE LIVER DAMAGE 189

PARASITES 176 Amebiasis 176 Malaria 178 Leishmaniasis 179

BACTERIA Reactive Changes and Pyogenic (Abscess) (Figs. 7-1 through 7-4) Major morphologic features 1. Portal tracts are expanded by variable degrees of edema and a mixed inlammatory iniltrate consisting of lymphocytes and neutrophils, these inlammatory cells not directly oriented towards any particular portal structure. 2. The ductules (cholangioles) may be dilated and sometimes contain inspissated bile plugs, these cholangioles usually surrounded and partially iniltrated by neutrophils (acute cholangiolitis). 3. Variable but usually mild necroinlammatory change and mild predominantly macrovesicular fatty change are seen, the inlammatory component consisting predominantly of neutrophils with some mononuclear cells. 4. In more severe cases associated with clinically apparent sepsis: a. Dilatation and proliferation of the interlobular bile ducts as well as the cholangioles may be seen, the neutrophils sometimes surrounding and iniltrating into the duct wall and lumen (acute cholangitis). b. Perivenular cholestasis may be present and sometimes may be marked. c. Microabscesses may occur within the portal tracts and parenchyma. In untreated cases, enlarged pyogenic abscesses from coalescence of smaller microabscesses may also develop. 154

Echinococcosis (Hydatid Cyst) 180 Clonorchiasis 183 Visceral Larva Migrans 184 Toxoplasmosis 186 Schistomosiasis 187

Other features 1. Necrotizing granulomas may be seen in some instances, depending on the microorganisms infecting the liver (e.g., chronic granulomatous disease secondary to staphylococcal infection). 2. Hepatocytes show variable degrees of hydropic change; however, there is maintenance of an intact cord-sinusoid pattern. 3. Increase in circulating sinusoidal leukocytes associated with an elevated peripheral white blood cell count is common. Special stains 1. Gram stain: Purely reactive changes of the liver in instances of sepsis would not demonstrate microorganisms; however, organisms may sometimes be seen when there is direct hepatic involvement. In addition, smears from aspirated specimens may more readily demonstrate microorganisms on gram stain than tissue sections from routinely processed biopsy or autopsy material. 2. Periodic-acid Schiff (PAS): When an abscess is present, this stain is useful in differentiating pyogenic from amebic abscesses, as the latter often exhibit positive cytoplasmic staining of E. histolytica located along the abscess wall (Table 7-1). Aspiration cytology 1. White to cream colored malodorous aspirated material containing abundant numbers of neutrophils is seen when the abscesses are secondary to bacteria. Identiication of gram-positive and/or -negative microorganisms is common and conirms the diagnosis.

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A

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B

FIGURE 7-1 Reactive and pyogenic. A, The small portal tract at the right of the ield shows a mild mixed inlammatory iniltrate consisting of lymphocytes and neutrophils. There is patchy necrosis within the parenchyma, the inlammatory iniltrate composed chiely of neutrophils. B, A portal tract on medium power shows a mild mixed inlammatory iniltrate with scattered neutrophils located along the ductules.

A

B

FIGURE 7-2 Reactive and pyogenic. A, The perivenular and midzones show prominent hydropic ballooning change of the hepatocytes and iniltration by numerous neutrophils. B, High-power shows the hydropic liver cells to be surrounded and iniltrated by neutrophils, with microabscess formation. The occasional round distinct eosinophilic extracellular inclusions represent an incidental inding of globular amyloid.

FIGURE 7-3 Reactive and pyogenic. Proliferating and ectatic cholangioles contain bile plugs. Neutrophils can also be seen surrounding these ductules.

FIGURE 7-4 Reactive and pyogenic. Neutrophils and mononuclear cells can be seen hugging up against and iniltrating beneath the endothelium of a terminal hepatic venule (endothelialitis) in this example of a biopsy from a patient with an intra-abdominal infection.

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TABLE 7-1

Amebic versus Pyogenic Abscesses AMEBIC

PYOGENIC

Jaundice

Rare

Common

Number

Usually single

Single or multiple

Associated acute cholangitis

Absent (organisms enter via portal venous circulation)

May occur (organisms enter via biliary tract)

Inlammatory changes

Scanty to absent

Neutrophils prominent

Contents

Thick, yellow-brown, pasty; inlammatory cells few; trophozoites sometimes demonstrated on PAS stain of smears

White-yellow pus, malodorous; neutrophils common; organisms often seen on gram stain

Amebic serology

Positive

Negative (unless previous exposure)

Abscess cultures for bacteria

Usually sterile; occasionally positive cultures suggest superinfection

Positive in up to 80% of cases

2. Non-odorous brown to red aspirated material demonstrating few inlammatory cells points towards a diagnosis of amebiasis, which must be conirmed by serology, examination of stool specimens, and response to therapy. Differential diagnosis 1. Acute viral hepatitis: Portal inlammatory changes are predominantly lymphocytic without a neutrophilic response in acute viral hepatitis. In addition, the focal necrosis, hydropic change, mononuclear inlammatory iniltrates, and disruption of the cord-sinusoid pattern typical of acute viral hepatitis is usually minimal in reactive changes due to bacterial infections. Lastly, microabscesses seen in cases of severe sepsis are not present in acute viral hepatitis. 2. Extrahepatic biliary tract obstruction: Perivenular cholestasis, bile duct dilatation and proliferation, and acute cholangitis and cholangiolitis are features of extrahepatic bile duct obstruction, but may also be seen in instances of severe bacterial sepsis with hepatic involvement. Usually the interlobular bile ducts are less affected in sepsis, but that is not the case when ascending cholangitis occurs. Correlation with cultures and imaging indings of the biliary tree may be necessary for distinction. 3. Amebic versus pyogenic abscesses: Abscesses formed by bacteria and E. histolytica may attain huge sizes, with Table 7-1 comparing the pertinent differential characteristics. Clinical and biologic behavior 1. Pyogenic abscesses are uncommon, the true incidence is unknown, and prevalence in autopsy series range from 0.3% to 1.5%. Abscesses are solitary in 60% to 70% of cases, and involve the right lobe in 95% of cases. 2. The most frequent symptoms in both reactive and pyogenic infections of the liver are malaise, anorexia, right upper quadrant abdominal pain and fever. 3. Diabetic patients are at increased risk. In some patients with diabetes, fever may be the only symptom, since pain may be absent due to autonomic neuropathy.

4. Hepatomegaly is the most common physical inding. In addition, one-third of patients with a liver abscess become jaundiced. 5. Serum aminotransferases are only minimally elevated in the majority of cases, although alkaline phosphatase is often elevated. Serum albumin is decreased and levels below 2 g/dl carry a poor prognosis. Anemia and leukocytosis with a left-shift are frequent indings. 6. Neutrophilic reaction around ducts and cholangioles may itself cause an obstructive process at the lobular level and be in part responsible for cholestasis and jaundice. 7. The causes of pyogenic abscesses include ascending cholangitis from biliary tract obstruction, blunt and penetrating trauma of the liver, or direct extension from adjacent organs (e.g., gallbladder). Spread from an intestinal focus (e.g., appendix, diverticulae) through the portal circulation may occur in approximately 10% of cases but may be as high as 46% in the older patient population. In a signiicant number of patients, no obvious etiology is found. 8. In published series, abscess cultures show that 50% are due to gram-negative organisms (Klebsiella pneumoniae being the most common in diabetics), 25% are due to gram-positive organisms, 10% are secondary to anaerobic organisms, and in 15% the cultures are sterile. Treatment and prognosis 1. The priority in management of hepatic abscesses is to use speciic antibiotics to which the organism(s) are susceptible based on the culture of the aspirated material, unless this is known from blood culture. Although the speciic duration of therapy is not clear, the current standard is to treat pyogenic abscesses for approximately 6 weeks. 2. Larger abscesses are drained with pigtail catheters placed under ultrasound or computed tomography (CT) guidance. Rarely, surgery (open or laparoscopic) is indicated for drainage. 3. The prognosis is related to the severity of the infection, the susceptibility of the organisms to the antibiotic regimen, the ability to offer continued antibiotic therapy without complications, and the presence of comorbid disease states (e.g., immunosuppressed patient, multiorgan failure, malnutrition).

Brucellosis (Figs. 7-5 and 7-6) Major morphologic features 1. Well to poorly formed granulomas composed predominantly of lymphocytes, macrophages, Kupffer cells and occasional epithelioid cells are present and scattered throughout the parenchyma, with no distinct zonal distribution pattern. 2. Kupffer cell hyperplasia and hypertrophy is uniformly present. Other features 1. Multinucleated giant cells may rarely be seen within the granulomas. 2. Granulomas may undergo a central ibrinoid necrosis in long-term cases. Caseous necrosis (coin lesions) may also be seen in the larger granulomas.

Chapter 7 / Infectious Disorders, Non-Viral

FIGURE 7-5 Brucellosis. A granuloma composed of numerous plump histiocytes and scattered lymphocytes is seen within the parenchyma.

FIGURE 7-6 Brucellosis. Kupffer cell hyperplasia and hypertrophy are present.

3. In later stages the granulomas may undergo healing with ibrosis. Occasionally microcalciications within the granulomas may also be seen. 4. Focal necrosis, apoptosis, hydropic change, and hepatocytolysis without granuloma formation also occur within the lobules. 5. Portal tracts show mild lymphocytic iniltrates with occasional neutrophils. Bile ducts are unremarkable 6. Abscess formation (usually microabscesses) may occur in severe cases (B. suis infection). Special stains 1. Gram: The gram-negative coccobacillary microorganisms can rarely be identiied within enlarged Kupffer cells and macrophages. 2. Acid-fast (AFB), Gomori methenamine silver (GMS), periodic-acid Sciff (PAS): These special stains are useful to rule out acid fast bacilli and fungi as causes of the granulomatous response.

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Differential diagnosis 1. Other causes of hepatic granulomas (see Chapter 12 for discussion of granulomatous liver disease): a. Salmonella typhi (typhoid fever), Francisella tularensis (tularemia): Both of these infectious conditions also may produce not only granulomas but also hypertrophic Kupffer cells. Culture is necessary for diagnosis. b. Mycobacterium, fungi (e.g., coccidioidomycosis, blastomycosis): These microorganisms elicit well-deined and often large epithelioid granulomas, frequently with accompanying multinucleated giant cells. The granulomas associated with brucellosis are usually but not always less well-demarcated, with multinucleated giant cells uncommon. Special stains and cultures are warranted for diagnosis. c. Epstein-Barr, CMV hepatitis: Both of these viral infectious processes may show granulomatous necrosis, sometimes with multinucleated giant cells. In addition, Kupffer cell hyperplasia is often prominent. A marked portal and sinusoidal iniltrate of atypical lymphocytes is characteristic of these disorders and is not seen in brucellosis. d. Alcoholic liver disease: Lipogranulomas that are often seen in alcoholic liver disease are small and poorly demarcated; however, they also contain macrophages filled with fat, this feature not seen in brucellosis. e. Sarcoidosis: The granulomas seen in sarcoidosis are epithelioid in nature and oftentimes show coalescence with septate division into smaller granulomas, this feature not present in brucellosis. f. Drug-induced liver injury: Certain drugs (e.g., sulfasalazine; see Table 5-7) may elicit a granulomatous necrosis, the granulomas usually small, poorly formed, and rarely exhibiting multinucleated giant cells. Microorganisms are not present within these granulomas in drug-induced injury. Clinical history with correlation of the time frame of when the drug was initiated and the onset of liver test abnormalities is necessary for distinction. Clinical and biologic behavior 1. Brucella is a gram-negative coccoid-shaped obligate parasite capable of invading all tissues, and contracted by humans from close contact with infected cattle, goats, sheep, and swine. Non-pasteurized dairy products such as cheese are a minor source of contamination. 2. Four species are capable of infection in humans and have the following features: a. B. abortus: Mild, self-limited; severe complications rare. b. B. suis: Destructive suppurative disease that may go on to chronicity. c. B. melitensis: Most virulent, with severe acute infection and highest mortality. d. B. canis (dogs, mainly Beagles): Rare in humans, but may produce a mild disease. 3. Infection predominantly occurs in men 20 to 50 years of age, and most often in workers in slaughter houses and in farmers.

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4. Acute disease: An incubation period of 5 to 14 days is followed by bacteremia and resultant chills, fever and generalized lymphadenopathy. Splenomegaly occurs in the majority of cases, with hepatomegaly in approximately one-third of cases. A tender liver is occasionally present. Jaundice and hepatic abscess formation may occur, but are rare. 5. Chronic disease: In a small percent of patients, chronic illness develops following acute infection, lasting months to years, with fatigue, vague pains, and intermittent fever. Splenomegaly is the main physical inding. Although cirrhosis has been described, it is questionable as to its direct association with the infection. 6. Laboratory indings are of minimal value, with only slight elevation of aminotransferase activities. Brucella agglutinin tests (Rose Bengal and Wright) are sensitive and speciic when titers of greater than 1:160 are present. Blood cultures or cultures from tissue (bone marrow, liver, lymph nodes) are also helpful for a more deinitive diagnosis. 7. Pathophysiology: Experimental formation of hepatic granulomas has been shown in mice and guinea pigs. After intravenous injection of bacilli, prominent Kupffer cell reaction occurs within 3 hours. Within 6 hours these cells contain abundant numbers of organisms, and by 24 hours neutrophils also contain bacilli. By 5 days, aggregates of epithelioid-type macrophages and large Kupffer cells collect in dilated sinusoids, forming granulomas; some fuse, with the larger ones exhibiting central necrosis. After 1 year, the granulomas most often disappear. Treatment and prognosis 1. The current treatment of acute and chronic brucellosis is a combination of high intravenous doses of rifampicin and oral minocycline which result in a 100% response rate and a relapse rate of 2% to 8%. 2. In untreated patients, mortality is 3% to 5%, and deaths are most often associated with endocarditis. Treated patients have a mortality of less than 1%, with complications occurring in 1% to 2% of patients. 3. Liver failure is not a feature of Brucella infection

Salmonellosis (Typhoid Fever) (Figs. 7-7 through 7-12) Major morphologic features 1. Focal necrosis with aggregated clusters of Kupffer cells, lymphocytes, and macrophages within the parenchyma is seen (granulomatous necrosis, inlammatory nodule, “typhoid nodule”). 2. Kupffer cells are diffusely hyperplastic and hypertrophic. Other features 1. Portal tracts exhibit a moderate to marked lymphocytic iniltrate. 2. Bile ducts usually show only mild reduplication; however, in rare instances neutrophils can be seen surrounding and iniltrating into the duct lumen (acute cholangitis). 3. The larger granulomas may exhibit central necrosis, although this feature is uncommon.

FIGURE 7-7 Salmonellosis. The portal tract exhibits expansion by a prominent predominantly lymphocytic iniltrate. The adjacent sinusoids show Kupffer cell hyperplasia and iniltration by mononuclear inlammatory cells.

FIGURE 7-8 Salmonellosis. Higher power of the portal tract shows the numerous lymphocytes. The interlobular bile duct is unremarkable.

4. The granulomas are usually diffusely seen within the lobules but in some instances may have a perivenular (zone 3) accentuation. 5. Sinusoidal lymphocytosis is often present. 6. Microvesicular fatty change may be present, but when seen is mild. 7. Kupffer cells may exhibit erythrophagocytosis. 8. Cholestasis is relatively uncommon. 9. Endothelialitis of portal, terminal hepatic, or sublobular veins has been described, the inlammatory cells usually lymphocytic. Special stains 1. Gram: The gram-negative microorganisms may be identiied within the enlarged Kupffer cells. 2. Acid-fast (AFB), Gomori methenamine silver (GMS), periodic-acid Sciff (PAS): These special stains are useful to rule out microorganisms such as acid fast bacilli and fungi as causes of the granulomatous response.

Chapter 7 / Infectious Disorders, Non-Viral

A

159

B

FIGURE 7-9 Salmonellosis. A, An aggregate of lymphocytes and histiocytes with a few scattered nuclear remnants forming an ill-deined granuloma (typhoid nodule) is seen adjacent to the portal tract. B, High-power view of a different granuloma shows it to be composed predominantly of plump histiocytes with occasional lymphocytes. A few entrapped hepatocytes are also seen amongst the histiocytes.

FIGURE 7-10 Salmonellosis. Focal necrosis is seen within the lobule.

FIGURE 7-11 Salmonellosis. The Kupffer cells are both hyperplastic and hypertrophic, with plump eosinophilic cytoplasm. A mild lymphocytic iniltrate is also seen predominantly within the sinusoids.

FIGURE 7-12 Salmonellosis. Hypertrophic Kupffer cells, most notably the one in the center of the ield, contain a few phagocytized red blood cells (erythrophagocytosis).

Differential diagnosis 1. Acute viral hepatitis: The prominent portal lymphocytic iniltrates and associated lobular necrosis and Kupffer cell reaction are in many ways similar to those seen in mild stages of acute viral hepatitis. Usually the hepatocytes in acute viral hepatitis have variable degrees of hydropic change, a feature not seen in salmonellosis. Granulomatous necrosis is not a characteristic feature of acute viral hepatitis. In addition, the marked enlargement (hypertrophy) of the Kupffer cells in salmonellosis is striking compared to the Kupffer cell changes seen in acute viral hepatitis. 2. Cytomegalovirus (CMV), Epstein-Barr virus (EBV) infections (immunocompetent patients): Liver biopsy pathology in both acute CMV and EBV are histologically similar to that seen in salmonellosis, with prominent portal lymphocytic iniltrates, patchy lobular necrosis, and Kupffer cell reaction. In addition, granulomatous necrosis can also occur in EBV and especially CMV

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infections. Viral inclusions are also not features seen in the immunocompetent patient with CMV hepatitis. Therefore the differential diagnosis distinguishing between these processes and salmonellosis can be dificult. The diagnosis often rests on viral serologies and cultures of the blood and tissue (when available). A hint is that the markedly hypertrophic Kupffer cells seen in salmonellosis are not features identiied in CMV and EBV infections. 3. Drug-induced injury (e.g., isoniazid; see Table 5-4): Numerous drugs can show features of portal and lobular inlammation that mimic both acute viral hepatitis as well as salmonellosis. Additionally, small granulomatous clusters similar to those seen in salmonellosis can also be associated with certain drugs (see Table 5-7). Correlation with hepatitis serologies and cultures, as well as the time frame of initiation of drug use and the onset of abnormal liver tests, is essential in arriving at the correct diagnosis. 4. Infections secondary to other microorganisms: Certain bacteria such as Brucella may evoke a granulomatous necrosis resembling the inlammatory nodule of salmonellosis, and may also show prominence of the hypertrophic Kupffer cells. Cultures and the clinical setting are necessary in these instances for diagnosis. Clinical and biologic behavior 1. Salmonellae are gram-negative anaerogenic bacteria with a worldwide distribution, S. typhi responsible for typhoid fever, and S. paratyphi for paratyphoid infection. Worldwide there are 17 million new cases and 600,000 deaths annually. The annual incidence is 198/100,000 with higher morbidity in children. The case fatality rate is 10% but is reduced to 1% with treatment. 2. The organisms are the most common etiologic agent responsible for food poisoning (the most common being S. typhimurium). Reservoirs have been isolated from virtually all domestic animals, with humans developing illness after ingestion of contaminated food products. 3. In S. typhi infection, humans are the only natural reservoir, and spread occurs from one infected individual to another via food, water, or contact. 4. In typhoid fever, the incubation period is 7 to 14 days. Although asymptomatic infection is most common, a small proportion of patients will develop fever, headache, and abdominal pain, with one-third having cough, and one-half nausea, vomiting, and diarrhea. 5. Hepatomegaly will develop in one-third of the cases of typhoid fever, but jaundice is infrequent (0.4% to 7% in various series). 6. Laboratory tests are not useful for diagnosis of liver disease, with only nonspeciic elevations of serum aminotransferase levels and rarely bilirubin occurring. 7. Serologic testing (Widal test) is not helpful in early diagnosis. Increased antibody titers to somatic (O) antigen (>1:80) is seen in the convalescent stage but has an overall sensitivity of 70%. In anamnestic reactions, increase in antibody titers to the lagellar (H) antigen is seen. 8. The diagnosis is made by culture, with the blood positive 90% of the time during the irst week, and stools (85%) and urine (25%) positive during the third and fourth weeks.

9. Biliary tract disease may be involved, rarely with acute cholangitis. Cholelithiasis and choledocholithiasis predispose to bacterial growth. A chronic carrier state may develop leading to prolonged excretion of microorganisms in the stool (positive stool cultures for >1 year). Carriers have an increased incidence of gallbladder carcinoma. 10. Complications may occur in up to 10% to 15% of patients, with gastrointestinal bleeding, perforation and typhoid encephalopathy the most serious. Bleeding from small intestinal ulcers can occur as well but is clinically signiicant in only 2% of cases. Other complications include myocarditis, bone marrow suppression, and localized infection (e.g., arthritis, meningitis). Treatment and prognosis 1. Treatment is effective with luoroquinolones. Chloramphenicol, amoxicillin, and trimethoprim-sulfamethoxazole are appropriate choices when luoroquinolones is unavailable, although resistance to these antibiotics has been reported. 2. Vaccination is only of temporary beneit. 3. Mortality from untreated cases is very rare and occurs in regions with little access to antibiotics. 4. Relapse occurs in 5% to 10% of untreated cases, but symptoms are usually mild. A chronic carrier state occurs in 1% to 3% of cases with the gallbladder as the focus of infection. In these cases, cholecystectomy is recommended.

SPIROCHETES Syphilis (Figs. 7-13 through 7-17) Major morphologic features Congenital 1. Diffuse lobular necroinlammatory change is present; the inlammatory iniltrates are chiely lymphocytic, sometimes forming medium-sized necrotic lesions. 2. Numerous multinucleated syncytial hepatocytes (neonatal giant cell hepatitis) are seen. 3. Many spirochetes, demonstrated by the Warthin-Starry reaction, are present and are most prominent within the areas of necrosis. Secondary 1. Epithelioid granulomas are present and sometimes numerous. 2. A lymphocytic vasculitis may be seen involving the small arteries, arterioles, venules, and veins, these vessels sometimes exhibiting slightly thickened walls. Tertiary (latent) 1. Gumma formation occurs, demonstrated as single or multiple epithelioid granulomas with central necrosis resembling caseation, with an accompanying plasma cell and lymphocytic iniltrate. 2. Obliterative endarteritis in small vessels adjacent to the gumma is present. Other features Congenital 1. Small epithelioid granulomas may be present within the parenchyma.

Chapter 7 / Infectious Disorders, Non-Viral

FIGURE 7-13 Syphilis, secondary. The portal tract shows a mild lymphocytic iniltrate with rare neutrophils.

161

FIGURE 7-15 Syphilis, secondary. A granuloma composed of epithelioid cells and a multinucleated giant cell is seen adjacent to the terminal hepatic venule.

2. Gummas may undergo severe ibrosis, with resultant deep and relatively dense scar formation, forming broad bands and “potato-like” nodules (hepar lobatum). 3. In some instances amyloid deposition may be seen. Special stains 1. Warthin-Starry: This silver stain demonstrates the helically coiled Treponema microorganisms which have regular spirals around the axis. The numbers seen vary: a. Congenital: Organisms are easily seen within vascular structures, ibroconnective tissue, and focally within the areas of lobular necroinlammatory change. b. Secondary: Organisms are dificult to identify but may be present in areas of necrosis in approximately 50% of the cases. c. Tertiary: Organisms are scanty to absent. FIGURE 7-14 Syphilis, secondary. The parenchyma shows focal granulomatous-type necrosis, the inlammatory iniltrate consisting of lymphocytes and histiocytes.

2. Portal and interstitial collagen deposition may be seen as the disease progresses. Secondary 1. Portal lymphocytic and neutrophilic iniltrates may be seen. 2. Acute cholangitis and associated portal edema may at times occur. 3. Focal lobular necrosis and hepatocytolysis are present, these features sometimes granulomatous in appearance, with iniltration of the lobules by lymphocytes, eosinophils, and neutrophils. 4. Variable but often prominent Kupffer cell hyperplasia is present. 5. Cholestasis may be seen but is infrequent. 6. Microorganisms may be demonstrated but are not frequently seen. Tertiary (latent) 1. Gummas may rarely undergo microcalciications.

Immunohistochemistry 1. Antigenic determinants of Treponema pallidum may be demonstrated and are most abundant in the neonatal (congenital) variant disease. Differential diagnosis 1. Neonatal giant cell hepatitis: Congenital syphilis often exhibits diffuse necroinlammatory change with prominent numbers of syncytial giant cells. Microorganisms are numerous and easily demonstrated with the WarthinStarry reaction in congenital syphilis. 2. Granulomatous lesions of other etiologies (see Chapter 12 for discussion of Granulomatous liver disease): Granulomas associated with a variety of liver diseases may be morphologically similar to those seen in secondary syphilis. Special stains for microorganisms are helpful but unfortunately are often negative. The presence of other morphologic features such as vasculitis can lean towards a diagnosis of syphilis. 3. Other causes of vasculitis: Various conditions such as Epstein-Barr virus (EBV) infection, sarcoidosis, bacterial infections (e.g., salmonellosis, schistosomiasis), and non-infectious inlammatory processes (e.g., rheumatoid arthritis, polyarteritis nodosa) may also demonstrate inlammation involving arteries, portal veins, and outlow

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A

B

FIGURE 7-16 Syphilis, secondary. A, The sublobular vein shows a prominent mononuclear inlammatory iniltrate along the endothelium (vasculitis). B, Higher power shows the inlammatory cells to be chiely lymphocytes with scattered neutrophils and rare eosinophils.

5.

6.

FIGURE 7-17 Syphilis, congenital. This silver stain shows numerous helically coiled Treponema microorganisms having regular spirals around the long axis. The microorganisms are commonly seen in congenital syphilis but more dificult to identify in the secondary and tertiary stages of the disease. (Warthin-Starry reaction).

7. vessels. Other histologic parameters and associated clinical history and laboratory data for each of these disorders help in reaching the correct diagnosis. Clinical and biologic behavior 1. Syphilis is a highly infectious venereal disease caused by the obligate anaerobe spirochete Treponema pallidum. Other Treponema species are normally present in the oral cavity (T. macrodentium, T. ovale) and genital region (T. refringens), while pathologic species include T. pertenue (“yaws,” a tropical disease), and T. carateum (“pinta,” a chronic skin disease). 2. Syphilis is most prevalent in the sexually active population in their early 20s. An increased risk of human immunodeiciency virus infection is seen in individuals infected with syphilis. 3. Hepatic involvement can occur at any stage of the disease. Ten percent of patients in the secondary stage (hepatosplenomegaly, anemia, generalized lymphadenopathy, skin rash) have some degree of hepatic damage. Jaundice

8.

9.

may be present, with moderate elevations of aminotransferases and alkaline phosphatase values. This is the stage where most liver biopsies are performed. Women acquiring syphilis in the 3rd trimester of pregnancy may transmit the infection to the fetus. Abortions and stillbirths are common, and although the infant may appear normal at birth, weeks to years later liver disease will become clinically manifest. The microorganisms penetrate intact mucous membranes as well as defects in keratinized epithelium, forming a chancre (primary stage), which heals within 4 to 6 weeks. The secondary stage develops weeks to months later, followed by a latent period during which two-thirds of the patients become spontaneously cured or remain asymptomatic. In the remaining one-third, the tertiary stage will develop with gumma formation, aortic aneurysms, tabes dorsalis, and hepar lobatum, the latter a deeply scarred liver secondary to multiple ibrosed gumma that is often associated with ascites and varices. Note that in the past this lesion was erroneously confused with true cirrhosis. The Budd-Chiari syndrome has been described when gumma forms immediately adjacent to the inferior vena cava and causes compression to hepatic venous outlow. The diagnosis is made by non-treponemal and treponemal serologic tests and darkield microscopy. The VDRL and RPR (rapid plasma reagin) are low-cost non-treponemal screening tests that have lower sensitivity and speciicity compared to the treponemal antigen tests. The Treponema pallidum antibody tests are more speciic, the most common being the Treponema pallidum microhemagglutination test (MHA-TP) and the luorescent treponemal antibody adsorption test (FTA-ABS). The availability of newer recombinant antigens (Tp0453, Tp092, and TP0257) in an ELISA test may provide an alternative and less expensive diagnostic test. Darkield microscopy: Organisms can be identiied on smears of moist lesions and chancre sores and appear as thin 6- to 15-µm × 0.2-µm tightly wound, corkscrewshaped structures, with 4 to 14 uniform rigid spirals exhibiting backward, forward, or corkscrew rotation about a long, sometimes slightly lexed, axis.

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Treatment and prognosis 1. Penicillin is effective standard treatment, and benzathine penicillin (long-acting) is used commonly for all infections except in tertiary syphilis and neurosyphilis, where high dose intravenous penicillin G is administered for 2 weeks. 2. Other drugs such as doxycycline, tetracycline, and azithromycin have been offered, but are less effective. 3. Decreased survival is seen in individuals with untreated secondary and tertiary syphilis, especially in those patients with cardiac, neurologic, and hepatic disease.

MYCOBACTERIUM Tuberculosis (Figs. 7-18 through 7-21)

FIGURE 7-18 Tuberculosis. An epithelioid granuloma composed of lymphocytes, epithelioid histiocytes, and multinucleated giant cells, is seen within a portal tract.

Major morphologic features 1. Well-demarcated granulomas are present in both the portal tracts and parenchyma, the granulomas composed of lymphocytes, numerous enlarged histiocytes (“epithelioid” cells), and often multinucleated Langhans giant cells (epithelioid granulomas). 2. Central caseous necrosis of larger granulomas may be seen, indicative of active growth of the bacilli (acid-fast stain often positive). Other features 1. The granulomas are often small, without caseation, with the acid-fast stain in these cases usually negative. 2. The granulomas in some cases tend to be more prominent within the portal tracts. 3. Focal liver cell necrosis and hepatocytolysis with associated mild to moderate Kupffer cell hyperplasia is often seen away from the granulomas. 4. Variable degrees of macrovesicular fatty change with no distinct zonal distribution pattern are occasionally seen; however, in cases of chronically ill patients, periportal fatty change is more common. 5. Cholestasis is relatively uncommon. 6. In severe acute cases, a mixed portal lymphocytic and neutrophilic iniltrate may be seen, often with associated bile duct damage and acute cholangitis. 7. Enlarged solitary granulomas with central caseation rarely can form and measure up to a few cm. in diameter (tuberculoma). 8. In immunocompromised patients, the granulomas may be composed of histiocytes with or without central necrosis, without epithelioid or multinucleated giant cells, and characteristically contain abundant microorganisms on acid-fast stain. 9. Portal ibrosis may sometimes be present, often due to portal granulomas that with time may become sclerosed, these types of granulomas sometimes exhibiting microcalciications. 10. An uncommon form in the neonate whereby transmission occurs from the infected placenta by way of the umbilical vein shows numerous small caseating granulomas in the liver parenchyma with little inlammatory reaction.

FIGURE 7-19 Tuberculosis. This epithelioid granuloma in the periportal zone shows caseation with multinucleated giant cell formation.

Special stains 1. Acid-fast (Ziehl-Neelsen carbolfuchsin): The rod-shaped bacilli ranging in size from 0.8 µm to 5 µm in length stain deep red-purple, and are most often seen in larger granulomas that exhibit caseous necrosis. When these organisms are identiied, usually only a small number are seen within a granuloma; however, in immunocompromised patients the bacilli are often numerous. Differential diagnosis 1. Sarcoidosis: The granulomas seen in sarcoidosis characteristically exhibit ibrous septate divisions, a feature not typical of tuberculosis. Sarcoidosis usually exhibits a greater inlammatory (usually lymphocytic) reaction in the portal tracts and parenchyma, and in some cases is associated with duct depletion. Although a central type of necrosis may rarely be identiied in sarcoid granulomas, acid-fast stain is always negative. In addition, asteroid and Schaumann bodies that are occasionally present in sarcoid granulomas are not seen in tuberculosis.

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A

B

FIGURE 7-20 Tuberculosis. A, The granuloma contains plump epithelioid histiocytes and three multinucleated giant cells. B, This granuloma shows a centrally located multinucleated giant cell with numerous adjacent epithelioid histiocytes and scattered lymphocytes.

TABLE 7-2

Tuberculosis and the Incidence of Hepatic Involvement*

TYPE OF INFECTION

PERCENTAGE OF CASES WITH HEPATIC INVOLVEMENT

Primary acute pulmonary

~75

Miliary

95

Chronic pulmonary

25

Tuberculoma (aggregates of granulomas forming grossly visible abscesses)

Rare

Cholangitis (secondary to ruptured caseous granulomas within the intrahepatic biliary system)

Rare

*USC series.

FIGURE 7-21 Bacillus Calmette-Guérin (BCG) immune response. The granuloma in the periportal zone is composed of lymphocytes, epithelioid cells, and numerous multinucleated giant cells. BCG, an immunostimulant derived from Mycobacterium bovis, elicits this type of granulomatous response morphologically similar to that seen in tuberculosis. Microorganisms are not present within these granulomas.

2. Granulomatous reaction to other infectious agents: Tuberculosis has well-deined epithelioid granulomas, while granulomas associated with infection by other microorganisms (e.g., Q fever) tend to be ill-deined. Fungi (e.g., Candida albicans, Coccidioides immitus) within granulomas may frequently be demonstrated by special stains (PAS, methenamine silver). Caseous necrosis, when present, is typical but not diagnostic of tuberculosis (can rarely be seen in sarcoidosis). 3. Drug-induced granulomatous reaction (e.g., allopurinol, phenylbutazone; see Table 5-7): Certain drugs may elicit a granulomatous response. Usually the granulomas are most noted in the lobules and are usually small and poorly deined, with multinucleated giant cells and epithelioid cells infrequent. No microorganisms are seen on special stains. In addition, upon cessation of the drug, the granulomas with time will resolve.

Clinical and biologic behavior 1. Tuberculosis ranks among the top 10 causes of death worldwide. Every year, 8 million people develop active disease and about 2 million die of the disease. 2. All Mycobacterium have the following characteristics: a. The organisms resist decolorization with acid-alcohol (“acid-fast”) after staining with carbolfuchsin. b. The growth rates are relatively slow. c. The organisms are obligate aerobes. d. A granulomatous inlammatory reaction occurs. 3. Of all causes of granulomatous involvement of the liver, tuberculosis (M. tuberculosis) is the second most common (26.6% at the University of Southern California Liver Unit [USC]), the most common being sarcoidosis (28.3%). 4. Within 1 year of exposure, 3% to 5% of patients will develop clinical disease, while the remaining are asymptomatic with a positive skin test. Five percent of these will develop clinically active tuberculosis at a later time, and these cases are responsible for 95% of new cases per year 5. The disease presents as pulmonary disease in 84% of the cases, while the incidence of hepatic involvement is presented in Table 7-2. 6. In only 1% of granulomas on liver biopsy can caseous necrosis be demonstrated. AFB positive staining is also relatively uncommon unless caseation is seen, and culture is positive in approximately 10% of cases.

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A

165

B

FIGURE 7-22 Mycobacterium avium complex (M. intracellulare). These images are from a patient with the acquired immunodeiciency syndrome. A, The granuloma is well-demarcated and composed almost entirely of plump histiocytes without multinucleated giant cell formation. B, Acid fast stain shows these granulomas to be illed with the microorganisms.

7. Signiicant hepatic dysfunction is seldom present, with hepatomegaly (50% of cases) and splenomegaly (25% to 40%) usually the only physical signs of liver disease. Biopsy is usually performed during workup for fever of undetermined origin, or for investigation of possible dissemination of pulmonary disease. 8. Laboratory values show elevation of alkaline phosphatase in 75% of cases with hepatic involvement. Aminotransferase elevations are variable but usually low. 9. Infection of the fetus may occur by way of the umbilical cord from an infected mother, the lesions often occurring in the porta hepatis as well as the parenchyma. 10. Bacillus Calmette-Guérin (BCG), an immunostimulant derived from a strain of M. bovis and used to vaccinate against tuberculosis in certain populations at high risk of infection, evokes a virtually identical granulomatous response in the liver. 11. The detection of mycobacterial DNA using polymerase chain reaction has allowed rapid diagnosis by a sensitive test, but correction for inhibitors and DNA contamination limits widespread use of this test in clinical practice. 12. Mechanism of infection and resultant granulomatous response: The organisms (beaded rods 1 to 4 µm long) are spread through the air, the smaller droplets (1:512) or rising IgG titer during convalescence (from negative to >1:128). The role of polymerase chain reaction in diagnosis is not clear. Treatment and prognosis 1. Doxycycline is the treatment of choice and should be instituted for a 7-day period as soon as the disease is clinically suspected. Other agents to which the organism is susceptible are tetracycline and chloramphenicol. 2. Recovery is usual provided the diagnosis is made early and the severe form of the disease does not occur. The mortality in treated patients is approximately 3%, while in untreated cases the mortality may reach up to 25% of patients.

FUNGI Histoplasmosis (Figs. 7-31 through 7-33)

FIGURE 7-31 Histoplasmosis. The intracytoplasmic microorganisms with a surrounding retracted clear space (“halo” appearance) are present within this aggregated cluster of histiocytes and Kupffer cells.

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A

171

B

FIGURE 7-32 Histoplasmosis. A, This biopsy from a liver transplant recipient shows a portal tract containing a medium-sized granuloma composed of histiocytes and scattered lymphocytes. B, This Gomori-methenamine silver (GMS) stain from the same biopsy identiies the positively staining yeast forms within the granuloma.

4. An inlammatory reaction in immunocompromised patients may be minimal to absent, with abundant numbers of microorganisms present in hypertrophic Kupffer cells. Special stains 1. Periodic-acid Schiff (PAS), Gomori methenamine silver: These stains demonstrate the thin-walled round to oval and occasionally budding yeast forms of the organism. The “halo” effect seen on hematoxylin and eosin stain does not stain, enhancing the presence of the yeast.

FIGURE 7-33 Histoplasmosis. This biopsy from a patient with the acquired immunodeiciency syndrome shows numerous yeast forms within enlarged Kupffer cells. (GMS)

Major morphologic features 1. Intracytoplasmic encapsulated yeast forms 2 to 5 µm in diameter with retracted clear spaces (“halo”) are present within histiocytes, Kupffer cells, and portal macrophages in active lesions. 2. Granulomas are seen within the parenchyma and consist of histiocytes and lymphocytes with occasional epithelioid cells. Multinucleated giant cells may be present but are uncommon. 3. Fibrotic, calciied, and rarely ossiied granulomas may be seen with resolution of the infection. Other features 1. Larger granulomas measuring from 1 to 3 mm in diameter may exhibit central necrosis with variable ibrosis, microcalciications, and surrounding granulation tissue. 2. In rare instances the granulomas may contain Schaumann (laminated concretions of calcium and protein) and asteroid (stellate-shaped inclusions) bodies. 3. Portal tracts either are normal or exhibit a mild lymphocytic iniltrate with mild bile duct proliferation.

Differential diagnosis 1. Tuberculosis: Central caseous necrosis may occur in tuberculosis and histoplasmosis; however, multinucleated Langhans giant cells characteristic of tuberculosis are not common in histoplasmosis. Identiication of microorganisms by special stains and culture are diagnostic. 2. Sarcoidosis: Schaumann and asteroid bodies are characteristic, although not diagnostic, of sarcoid granulomas, and rarely have been described in histoplasmosis. The septate granulomas characteristic of sarcoidosis are not seen in histoplasmosis. Identiication and culture of the organisms are essential. 3. Leishmaniasis: Leishmania donovani are small intracytoplasmic parasites 2 to 3 µm in diameter and are present within Kupffer cells in infected livers. Although resembling Histoplasma capsulatum, this organism does not stain with PAS or methenamine silver stains. Clinical and biologic behavior 1. Histoplasmosis is a world-wide disease caused by the dimorphic fungus Histoplasma capsulatum. 2. The disease is highly endemic in the Ohio and Mississippi river valleys, and in Guatemala, Mexico, Venezuela, and Peru. 3. The main carriers are birds, especially chickens, with spores present in bird droppings. Inhalation of the spores with development of yeast forms in the lung results in respiratory infection. Spread of the organism through the blood and lymphatics may then lead to dissemination and hepatic involvement.

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4. The organisms are 2 to 5 µm in diameter and reside in macrophages and Kupffer cells. On blood smears or aspirated material, the organisms have a basophilic cytoplasm which shows retraction from one side of a thin but rigid wall, giving a crescent or halo appearance. 5. Histoplasmosis is asymptomatic 90% of the time, or presents as only a mild lu-like illness, resolving without complications. Depending on the host immune status and the number of infecting organisms, this infection may present as an acute pulmonary illness, and in less than 1% of cases may disseminate or become chronic. 6. Laboratory tests are nonspeciic and show only mild elevations of serum aminotransferases and alkaline phosphatase values. 7. In the disseminated form usually seen in immunocompromised or suppressed hosts, hepatosplenomegaly is almost always present. In chronic forms, hepatomegaly is seen in approximately one-half and splenomegaly in onethird of the cases. 8. Culture of the organism is the gold standard but requires a lengthy incubation period, with fungal staining less sensitive. Testing for Histoplasma antigen and antibody provides a more rapid diagnosis but is less sensitive and speciic. Treatment and prognosis 1. Antifungal treatment with intravenous amphotericin B (preferably the newer lipid formulations) is recommended for acute severe or chronic infection. In moderate infection, itraconazole is effective. 2. Disseminated infection is associated with high infectious inoculums, is treated with amphotericin and oral itraconazole over the long term after control of the acute infection, and is associated with high mortality, particularly in immunosuppressed patients (HIV infection and post-transplant).

Coccidioidomycoses

FIGURE 7-34 Coccidioidomycosis. Numerous multinucleated giant cells are seen within a ibrotic portal tract, many of the giant cells containing microorganisms.

Special stains 1. Periodic-acid Schiff (PAS), Gomori methenamine silver: These stains demonstrate the thick wall of the spherules as well as the thin walls of the endospores. Differential diagnosis 1. Tuberculosis, sarcoidosis: Granulomas from many causes may morphologically be quite similar on hematoxylineosin stain. Central caseous necrosis that is often seen in active tuberculosis is not a feature of coccidioidomycosis. In addition, subdivision of granulomas by ibrous septa is often present in the granulomas of sarcoidosis but are not seen in coccidioidomycosis. Special stains for identiication of the microorganisms may be necessary for diagnosis. 2. Blastomycosis: The small immature spherules of Coccidioides may resemble the yeast forms of Blastomyces dermitiditis. Blastomyces has a characteristic budding pattern and lacks the presence of large spherules seen in Coccidioides infection.

(Figs. 7-34 through 7-37) Major morphologic features 1. Epithelioid granulomas with prominent multinucleated giant cells are seen within the lobules, and contain spherules that are characterized by the following: a. 20 to 200 µm in diameter with a wall 2 µm thick. b. Filled with either endospores 2 to 5 µm in diameter or granular eosinophilic material. Other features 1. The spherules may rupture, with endospores present immediately outside empty and often distorted spherules. 2. Smaller immature spherules 10 to 20 µm in diameter may also be present. 3. Granulomas may coalesce. 4. Granulomas may undergo some degree of ibrosis during resolution, with microcalciications reported but uncommon. 5. Portal tracts are normal or exhibit only a mild lymphocytic iniltrate with mild bile duct reduplication.

Clinical and biologic behavior 1. Coccidiodes immitis usually causes a benign, asymptomatic self-limited pulmonary infection, with no hepatic involvement. 2. The organism is endemic in the southwestern United States, northern Mexico, and Central and South America. 3. Five percent of the patients develop severe pulmonary injury, often with cavitation. Less than 1% develop disseminated infection with multiple organ-system involvement. 4. Conditions related to the severity of the illness: a. Degree of intensity of exposure to the organisms. b. The infection is more frequent in blacks and in people native to Mexico and the Philippines. c. More frequent in immunocompromised patients (e.g., AIDS). d. More severe in pregnant women. 5. Hepatic involvement is usually present in disseminated infection; however, there are only mild serum aminotransferase elevations consistent with minimal hepatic dysfunction.

Chapter 7 / Infectious Disorders, Non-Viral

A

173

B

FIGURE 7-35 Coccidioidomycosis. A and B, These two images show the multinucleated giant cells to contain large spherules that range in size from 80 to 100 µm. The wall of the spherules is distinct and approximately 2 µm thick.

FIGURE 7-36 Coccidioidomycosis. A cluster of spherules, many containing endospores, is seen. Scattered lymphocytes and histiocytes are also present amongst the spherules.

6. Peritonitis presenting with ascites and fever has been reported, and at laparoscopy small white nodules similar to and often confused with Mycobacterium tuberculosis can be seen on the parietal peritoneum. 7. The diagnosis is made by positive serologic tests. Coccidioidal IgM is detected in early infection using immunodiffusion or enzyme linked immunoassay, and in chronic infection coccidioidal IgG by complement ixation is detected. Coccidioidal antibody can be tested in body luids in disseminated infection provided serum antibody levels are elevated. Histologic conirmation is indicated prior to commencing therapy. Recent attempts to identify the organism by polymerase chain reaction seem promising. Treatment and prognosis 1. The standard treatment is with intravenous amphotericin B. Therapy with itraconazole has been offered in less severe cases, while voriconazole has been effective in meningeal infection.

FIGURE 7-37 Coccidioidomycosis. Four spherules are seen, the largest almost entirely illed by endospores. The empty spherule has partially ruptured, with scattered small endospores present within the ield as well. These endospores may in some instances be confused with the non-budding yeast forms of Blastomyces dermatitidis (GMS).

2. Mortality is high in clinically manifest acute, chronic, and disseminated infections, especially in untreated cases, in immunosuppressed patients (HIV and posttransplant) and in those individuals treated for hematologic malignancies.

Cryptococcosis (Figs. 7-38 through 7-40) Major morphologic feature 1. Variably sized spherical budding yeast 5 to 20 µm in diameter are seen, are surrounded by a thick mucoid capsule, and are present usually within portal macrophages but may also occur within hyperplastic Kupffer cells.

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Other features 1. Occasional pseudohyphae may also be demonstrated, and non-encapsulated yeast forms also occur. 2. Rarely a granulomatous response with multinucleated giant cell formation may be present. 3. An accompanying lobular inlammation is usually quite minimal. 4. Portal tracts otherwise are unremarkable or exhibit a mild lymphocytic iniltrate. Bile ducts are uninvolved. Special stains 1. Periodic-acid Schiff (PAS), Gomori methenamine silver: The microorganisms are highlighted, with the variability in the size of the yeast a characteristic feature. 2. Mucicarmine: This stain highlights the thick mucoid capsule. FIGURE 7-38 Cryptococcosis. Multiple round to oval variably sized yeast forms 5 to 20 µm in diameter are seen within the portal tract. The clear space surrounding these organisms represents the thick mucoid capsule. Note that the inlammatory iniltrates amongst the microorganisms is sparse.

FIGURE 7-39 Cryptococcosis. The yeast are highlighted, with the considerable variability in the sizes of the organisms characteristic for cryptococcosis (GMS).

FIGURE 7-40 Cryptococcosis. The pink staining mucoid capsules are seen surrounding the yeast (Mucicarmine).

Differential diagnosis 1. Candida and other fungal yeast forms: The variability of the size and shape of Cryptococcus neoformans is quite characteristic and is not seen to this degree in Candida infection. In addition, the yeast forms of Candida albicans are smaller. Most importantly, the mucoid capsule of Cryptococcus is diagnostic and not found in Candida or other mycotic infections. Clinical and biologic behavior 1. Cryptococcosis is an indolent infection caused by the yeast-like fungus Cryptococcus neoformans. 2. The organism is world-wide and is especially seen in soil enriched by pigeon droppings. 3. Humans acquire the infection through inhalation of aerosolized spores. At irst the infection is asymptomatic, but hematogenous spread occurs to the central nervous system, skin, bone, subcutaneous tissue, mucosa of the mouth, nose, and larynx, and less commonly to the liver, lymph nodes, and spleen. 4. Central nervous system involvement such as meningoencephalitis is common, possibly due to the absence of complement and soluble anticryptococcal factors in the cerebrospinal luid that are, however, present in the serum. 5. Patients with meningoencephalitis present with fever and headache, while those with pulmonary involvement develop chest pain and cough in a minority of cases. Approximately 10% of patents also have papular centrally ulcerated skin lesions. 6. Infection is a common complication in immunocompromised patients, especially in those with the acquired immunodeiciency syndrome. Patients who have undergone solid organ transplantation, those on steroid therapy, and certain patients with sarcoidosis are also at high risk of infection. 7. The polysaccharide capsule plays an essential role in the virulence of the organism in that it inhibits phagocytosis, impairs leukocyte migration, and induces T-suppressor cell activity. 8. The microorganisms can be demonstrated by the India Ink preparation, whereby a drop of India Ink admixed with a drop of sediment from centrifuged CSF luid highlights the presence of the encapsulated yeast forms in approximately one-half of the cases.

Chapter 7 / Infectious Disorders, Non-Viral 9. The hepatic signs and symptoms are non-speciic, with only rare examples of hepatitis and liver failure. Although the liver grossly is usually unremarkable, at times small focal lesions can be seen when there is coalescence of the clusters of microorganism. Treatment and prognosis 1. Initial treatment to control symptoms with intravenous amphotericin B, followed by luconazole, is the approach in those with the acquired immunodeiciency syndrome. 2. In patients that are not immunocompromised, cure with amphotericin B is more effective. 3. In patients with meningoencephalitis the outcome is poor in non-treated patients. Hepatic involvement itself does not alter the prognosis.

Candidiasis (Fig. 7-41) Major morphologic features 1. Granulomas develop that most often are composed of clusters of neutrophils with occasional histiocytes and lymphocytes, with multinucleated giant cells and epithelioid histiocytes uncommon. 2. At times variably sized abscesses can occur. 3. Pseudohyphae and budding yeast forms are usually visible. Other features 1. The granulomas are usually small; however, in some cases, especially in the immunocompromised patient, the granulomas can coalesce and acquire large sizes that often contain necrotic hepatocytes with scattered identiiable microorganisms. 2. The portal tracts are normal or exhibit a mild lymphocytic iniltrate with mild bile duct reduplication. Special stains 1. Periodic-acid Schiff (PAS), Gomori methenamine silver: These stains highlight the pseudohyphae and budding yeast forms.

A

175

Differential diagnosis 1. Bacterial infections: Various bacteria can elicit microabscesses within the hepatic parenchyma. Usually these are quite small and the organisms themselves are seldom identiied on gram stain; however, the abscesses seen in candidiasis are usually much larger and more easily demonstrate the pseudohyphae and yeast forms on hematoxylin-eosin as well as special stains. The larger abscesses with considerable central necrosis may at times be more dificult in that the microorganisms are not as abundant throughout the abscess, necessitating careful inspection of numerous tissue sections; however, it is not infrequent in the immunocompromised patient for the organisms to be extremely abundant even in the larger abscesses. 2. Cytomegalovirus: CMV infection in patients after liver transplantation is often associated with microabscess formation. Usually but not always, characteristic CMV nuclear and sometimes cytoplasmic inclusions can be demonstrated within the hepatocytes, Kupffer cells and/ or macrophages within the microabscess. Note: It is important that abundant clusters of neutrophils from biopsies taken at the time of laparotomy are not misinterpreted as microabscesses, as neutrophils are frequently seen secondary to surgical manipulation (for more about “surgical hepatitis,” see Fig. 1-29). A useful clue is that in these instances the neutrophils tend to be accentuated in the perivenular zone and immediately beneath Glisson’s capsule, with the adjacent hepatocytes uninvolved. Clinical and biologic behavior 1. Candida are fungi that exist predominantly in unicellular form. Of the 150 species of Candida, only 10 have pathogenic signiicance for infections in humans. Although Candida albicans is the most common pathogen, increasingly other species, such as Candida tropicalis, Candida krusei, and Candida glabrata, have been observed in isolates from patients, particularly in critical care settings. 2. The microorganisms are small oval budding yeast (4 to 6 µm in diameter) and pseudohyphae forms that are ubiquitous and one of the most common nosocomial pathogens.

B

FIGURE 7-41 Candidiasis. A, Coagulative-type necrosis is seen containing scattered neutrophils and degenerating cells. B, This periodic-acid Schiff (PAS) stain conirms the presence of numerous budding yeast forms and pseudohyphae.

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3. Candidiasis involving the liver is a well-recognized infectious process in immunocompromised patients receiving chemotherapy for various malignancies, steroids for various conditions such as autoimmune liver disease, patients with post-transplantation status, and patients with AIDS. Dissemination from mucocutaneous sites throughout the body by hematogenous spread has been well documented. Hepatosplenic candidiasis is a complication of disseminated infection and is probably recognized more frequently because of increased awareness of the infection and improved scanning modalities to diagnosis the infection. Infection may occur involving the chorioretina and heart valves in heroin addicts, and vaginitis from local overgrowth of the organisms after suppression of bacterial lora from antibiotic use also may occur. 4. The disease can run many forms, with oral and vaginal mucosal involvement, cutaneous lesions, urinary tract infections, endocarditis, disseminated disease, and involvement of prosthetic implants and infected intravenous lines. With hepatic involvement, the clinical presentation includes fever with moderate increases in the serum aminotransferases and alkaline phosphatase values, and rarely hyperbilirubinemia. 5. Hepatic candidiasis also typically occurs in patients who have hematologic malignancies and are receiving induction therapy or bone marrow transplantation. These patients have prolonged periods of neutropenia, have received multiple courses of broad spectrum antibiotics, and have indwelling catheters where the nidus of infection occurs. 6. On ultrasound, the oftentimes multiple hepatic lesions are observed as discrete hypoechoic lesions with a central echogenic focus (“bulls eye” lesion). CT scan shows hypodense lesions. 7. The diagnosis is conirmed by needle aspiration with culture, with characteristic pseudohyphae and budding yeast forms seen from tissue taken from the abscesses. The presence of Candida in blood culture in the setting of liver test derangements and scan abnormalities may be diagnostic. Thrombocytopenia or coagulopathy may preclude liver aspiration, however.

A

Treatment and prognosis 1. The treatment of candidiasis is dificult. In milder infections, therapy with luconazole is effective. In severe infections, prolonged therapy with amphotericin or the newer lipid formulations may be beneicial. The newer agents voriconazole and caspofungin provide additional options for treatment. 2. The prognosis depends on the underlying comorbid condition and the potential to recover from the infection; however, when immunosuppression is marked, recovery may be dificult with a poor overall prognosis.

PARASITES Amebiasis (Figs. 7-42 and 7-43) Major morphologic features 1. A cyst (abscess) is present and is composed of the following: a. Fibrous wall with granulation tissue formation. b. Peripherally located hepatocytes immediately beneath the ibrous wall, these liver cells undergoing coagulative necrosis. c. Central amorphous eosinophilic debris (lysed liver cells) with few if any admixed inlammatory cells. d. Trophozoites identiied at the edge of the cyst wall, these microorganisms having the following characteristics: i. Round to oval, 15 to 30 (range 10 to 60) µm in diameter. ii. Single eccentric nucleus with single karyosome and ine chromatin granules, the nucleus approximately one-ifth the size of the organism. iii. Eosinophilic refractile cytoplasm often containing phagocytized debris and red blood cells. iv. Surrounding clear space (halo) if the organisms are viable.

B

FIGURE 7-42 Amebiasis. A, Abundant eosinophilic debris secondary to lysis of hepatocytes is present from this hepatic lesion that was visualized on imaging. Scattered nuclear remnants of the degenerating cells are seen. B, Medium power from the same example demonstrates within empty clear spaces numerous degenerating trophozoites that are round to oval and measure up approximately 50 µm in diameter. An occasional small spherical nucleus can also be seen in some of the microorganisms.

Chapter 7 / Infectious Disorders, Non-Viral Other features 1. The earliest change shows focal necrosis with small neutrophilic aggregates within the lobules, with trophozoites within the sinusoidal spaces. 2. Variable degrees of sinusoidal ibrosis may be seen within the compressed lobules adjacent to the abscess wall. 3. Cholestasis may be present, but is relatively uncommon, and when seen is usually secondary to compression and obstruction of the medium sized to large intrahepatic bile ducts by large abscesses. 4. Macrovesicular fatty change may be present within the lobules distant to the abscess. 5. With time dense ibrous scarring of the abscess wall may occur. 6. Prominent neutrophilic iniltration within abscesses may sometimes be seen and is indicative of bacterial superinfection. Special stains 1. Periodic-acid Schiff (PAS): Strong positive cytoplasmic staining of the trophozoites is present. 2. Gridley: The organisms stain blue-green. Aspiration cytology 1. The gross identiication of “anchovy” chocolate colored non-foul–smelling paste-like material (bacterial culturenegative) is characteristic. 2. The contents may be cream-colored due to a combination of necrotic cells, bile, fat, red blood cells, and neutrophils (secondary bacterial superinfection). 3. The characteristics of the trophozoites on smears are similar to those seen on hematoxylin-eosin stained preparations (see previous description). Differential diagnosis 1. Amebic versus pyogenic abscesses (see Table 7-1). 2. Necrotic tumor masses: Tumor forming enlarged hepatic masses that have undergone ischemic necrosis may appear histologically similar to the necrotic hepatocytes in amebic abscesses. Identiication of the microorganisms is diagnostic. Unfortunately, in amebiasis the trophozoites are usually absent in the necrotic regions distant from the ibrous capsule. In addition, in aspirated material trophozoites are identiied in only 20% to 50% of cases. Necrotic tumor may at times demonstrate a neutrophilic

FIGURE 7-43 Amebiasis. Three trophozoites are seen under high power from a large amebic abscess.

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iniltrate, a inding not typically seen in amebic abscesses unless there is bacterial superinfection. Examination of other tissue sections of the mass lesion for viable tumor, or for tissue containing trophozoites, is often necessary. 3. Ischemic (coagulative) necrosis secondary to hypotension or vascular thrombosis: Although the histology in coagulative necrosis from hypoxia resembles that seen in amebiasis, only infrequently is a large well-formed discrete lesion or mass identiied associated with ischemia. Coagulative necrosis may be seen in cirrhotic nodules secondary to severe hypotension (e.g., in instances of bleeding esophageal varices); however, these nodules are small, the injury is usually multifocal, and the presence of cirrhosis easily differentiates those nodules from an amebic abscess. Clinical and biologic behavior 1. Entameba histolytica is a microaerophilic protozoa present predominantly in the tropic and subtropical regions as an intestinal parasite, with prevalence ranging from 5% to 50% compared to 1% to 3% in industrialized countries. 2. In the United States, the disease is found more commonly in the homosexual population, immigrants, refugees, and foreign travelers (Mexico). 3. The predominant clinical manifestation of amebic infection is colitis, often with typical lask-shaped ulcerations. The most common extra-intestinal manifestation is hepatic abscess, occurring predominantly in men 40 to 60 years of age. 4. Access of the parasites into the portal venous system from the intestine leads to hepatic involvement. Although most organisms initially do not lodge in the sinusoids, with time, sinusoidal thrombosis traps the ameba, which then invade the hepatic cords, release cytotoxins, and destroy liver cells. 5. Abscesses are usually single, range from 8 to 12 cm in diameter, and affect the right lobe approximately 70% of the time. 6. The clinical onset of hepatomegaly and right upper quadrant tenderness is gradual. Fever is usually present, and abdominal tenderness is sometimes referred to the shoulder when the abscess is adjacent to the diaphragm. About one-half of patients presenting with hepatic abscess have no clinical symptoms of intestinal disease. 7. Laboratory tests reveal elevations in serum aminotransferase (20,000) is present in about 50% of patients but without eosinophilia. Decreases in serum albumin occur but prothrombin time is usually normal. Amebic serology using the indirect hemagglutination test is positive in 95% of cases with a 78% to 94% sensitivity. The dot ELISA test is sensitive and speciic and can be performed with minimal equipment. Elevated amebic serology may be present for several months after treatment. 8. With response to therapy, resolution occurs by shrinkage of the abscess with eventual complete obliteration or stellate scar formation; however, in some patients the abscess cavity may persist for months and even years. 9. Complications include systemic dissemination leading to pulmonary or cerebral abscesses, rupture into the pleural, pericardial, or peritoneal cavities, and fulminant infection. Hepatic failure is rare.

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Treatment and prognosis 1. Metronidazole is effective treatment. To clinically distinguish pyogenic abscess from amebic, while awaiting serologic conirmation, response to a therapeutic trial with chloroquine is helpful. Treatment of intestinal cysts with iodoquinol after treatment of the liver abscess is worthwhile. 2. Drainage of the abscess is rarely necessary except in cases where abscesses with high propensity to rupture into pleura, pericardium, or peritoneum are identiied. Aspiration for culture is performed only if a pyogenic abscess is suspected. Secondary bacterial infection of amebic abscesses is rare. 3. Mortality is increased if rupture into the pericardium or peritoneum occurs, especially if the disease is unrecognized and untreated.

Malaria (Figs. 7-44 and 7-45)

FIGURE 7-44 Malaria. The hyperplastic and hypertrophic Kupffer cells are loaded with a dark brown to black granular pigment (hemozoin, derived from the breakdown of hemoglobin by Plasmodium falciparum). This pigment can be differentiated from hemosiderin by its negative staining with the Prussian blue reaction for iron.

Major morphologic features 1. Malarial hemozoin pigment (dark brown to grey-black, granular and birefringent) is present within hypertrophic and hyperplastic Kupffer cells and, in later stages, portal macrophages. 2. The parasites (ring forms of Plasmodium falciparum) consist of faint clear round to oval rings with a hematoxylin-staining dot (nucleus) and may be identiied within erythrocytes that often are present hugging up against the sinusoidal border; however, the organisms may be masked when abundant hemozoin pigment is present. Other features 1. In acute stages, sinusoidal congestion can be marked. In addition, focal areas of perivenular coagulative (ischemic) necrosis may occur due to vascular compromise from the adherent red blood cells containing the microorganisms. 2. In resolving cases, hemozoin pigment may be present only in portal macrophages, with the pigment slowly disappearing with time. 3. Variable degrees of hemosiderin are often present in Kupffer cells (secondary to hemolysis of red blood cells). 4. Hemosiderin may also be present in hepatocytes, predominantly periportal, in long-term infections (secondary to anemia). 5. Variable but usually mild macrovesicular fatty change may be seen. 6. Portal iniltrates consisting of lymphocytes and scanty numbers of histiocytes and plasma cells are usually present. 7. Portal stellate ibrosis has been described in long-term infection, but cirrhosis does not occur. 8. Tropical splenomegaly syndrome (hyperimmune reaction) may occur, manifested by: a. Marked portal lymphocytic iniltrates. b. Mild portal ibrosis. c. Marked Kupffer cell hyperplasia, with scanty to absent hemozoin pigment. d. Numerous lymphocytes clustering or lining in a single ile pattern within the sinusoids.

FIGURE 7-45 Malaria. Parasitized red blood cells demonstrating the hemozoin pigment are seen within small capillaries surrounding this large interlobar bile duct.

Special stains 1. Prussian blue: Hemozoin does not stain for iron in routine sections, and is therefore useful to differentiate from hemosiderin. Of note, however, is that hemosiderin is often seen within the Kupffer cells as well due to hemolysis. Differential diagnosis 1. Disorders associated with marked hemosiderin deposition in Kupffer cells: Patients with chronic hemolytic disorders (e.g., thalassemia major) or those having received multiple blood transfusions may accumulate considerable amounts of hemosiderin within Kupffer cells and portal macrophages. Hemozoin is brown-black, birefringent, and negative on Prussian blue stain for iron, while hemosiderin is golden-brown and stains positively with Prussian blue. Both pigments are often present, however, within the same Kupffer cells in malaria.

Chapter 7 / Infectious Disorders, Non-Viral 2. Schistosomiasis: Schistosomal pigment resembles hemozoin on H&E stain, and is also negative with the Prussian blue stain for iron. These pigments are different ultrastructurally and biochemically. Liver biopsy will also exhibit differentiating morphologic features of schistosomiasis, such as portal ibrosis, granuloma formation, and Schistosoma ova. 3. Acute viral hepatitis, infectious mononucleosis (Epstein-Barr, cytomegalovirus infections), lymphocytic leukemia: Chronic immune stimulation directed to the parasite (tropical splenomegaly syndrome) results in a prominent lymphocytic iniltrate involving the portal tracts and sinusoids and often resembles infectious mononucleosis or even lymphocytic leukemia. In some instances, acute viral hepatitis due to HCV infection may also demonstrate a sinusoidal lymphocytosis as well. Clinical and laboratory data, serology, and detection of antibodies to malarial antigens may be necessary for diagnosis. 4. Anthracotic pigment: Black anthracotic (anthracite) pigment (see Fig. 5-52) may be seen in the liver in instances when thoracic lymph nodes containing this pigment rupture into adjacent pulmonary veins. The pigment then becomes phagocytized by Kupffer cells, becomes stored predominantly within portal macrophages, and morphologically resembles hemozoin. This type of pigment, however, is dark black and particulate. In addition, unlike anthracotic pigment, hemozoin is birefringent. 5. Erythropoietic protoporphyria: The pigment protoporphyrin (see Fig. 8-62) within Kupffer cells and macrophages seen in erythropoietic protoporphyria is in some ways similar to the hemozoin pigment seen in malaria. Protoporphyrin, however, is dark red-brown, birefringent (demonstration of Maltese cross under polarized light), and present within hepatocytes and biliary canaliculi as well, features not seen in malaria. In addition, the protoporphyrin is intensely red on autoluorescence. Clinical and biologic behavior 1. Malaria caused by the Plasmodium species is the most common parasitic infection worldwide, with over 100 million cases per year, and 1 million deaths in Africa alone per year. 2. Malaria is mainly found in tropical and subtropical regions, and is most prevalent in sub-Saharan Africa and in South America, Haiti, and Southeast Asia. In the United States, malaria is seen predominantly in refugees and travelers, or in military personnel who served in endemic areas. 3. Infection is spread through the insect vector Anopheles mosquito, leading to: a. Inoculation of sporozoite into the blood. b. Rapid invasion into the hepatocyte with proliferation (exoerythrocytic stage). c. Development asexually (schizogony), releasing merozoites which invade red blood cells (erythrocytic stage). d. Rupture of red blood cells with release of merozoites (febrile stage), followed by invasion of other red cells cyclically. e. Some merozoites differentiating into gametocytes (gametogony) that are ingested by the mosquito, undergo sexual development into sporozoites, and infect the human host at inoculation, thus completing the cycle.

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f. Small dormant forms (hypnozoites: e.g., P. ovale, P. vivax) present within hepatocytes and capable of initiating nuclear division and perpetuating the exoerythrocytic state. Four species infect humans: P. falciparum and P. malariae that have no hepatic forms after initial exoerythrocytic stage, and P. ovale and P. vivax that maintain hepatic and red blood cell forms and are responsible for relapses months to years after apparent resolution of the infection. P. falciparum is responsible for most fatalities, with adherence to postcapillary venules in the liver, brain and other organs, causing severe cerebral dysfunction (cerebral malaria), ischemic necrosis within the liver (predominantly perivenular zone) and kidneys (acute tubular necrosis), and massive hemolysis with marked hemoglobinuria and renal failure (blackwater fever). Patients present with cyclical symptoms of high fever (red blood cell hemolysis and release of parasites, toxins and pyrogens), nausea, vomiting and headache, followed by sweats with defervescence, occurring every 72 hours for P. vivax, P. ovale, and P. malariae, and 48 hours (less consistent) with P. falciparum. Hepatomegaly and splenomegaly almost always are present, sometimes with abdominal pain. Jaundice may be present. Serum aminotransferase activities are three to four times normal and are higher when ischemic necrosis is prominent. Serum bilirubin is mildly elevated and is predominantly in the unconjugated form. Hemozoin pigment, an iron porphyrin protein complex derived from anaerobic glucose metabolism and hemoglobin breakdown by the parasite, is commonly identiied in Kupffer cells due to hemolysis and erythrophagocytosis of parasitized red blood cells. Because of hemolysis, hemosiderin to some degree is usually present as well in Kupffer cells and periportal hepatocytes (increased iron absorption in the chronically anemic state).

Treatment and prognosis 1. Chemoprophylaxis using agents such as chloroquine, primaquine, and meloquine in persons traveling to endemic areas is effective but not completely reliable. Pyrimethamine-sulfadoxine can be used in areas where the malaria is chloroquine resistant. 2. Many anti-malarial drugs, such as chloroquine, quinine, and quinidine, are available for use in those patients already infected and symptomatic. 3. Increased mortality occurs in P. falciparum infections secondary to hemolysis and/or vascular occlusion by parasitized red blood cells. The cause of death is not due to hepatic disease.

Leishmaniasis (Figs. 7-46 and 7-47) Major morphologic features 1. The 2- to 5-µm intracellular, non-lagellated, oval-shaped parasites (amastigotes) having basophilic nuclei are seen within hypertrophic and hyperplastic Kupffer cells, portal histiocytes, and less commonly within endothelial cells and hepatocytes.

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Differential diagnoses 1. Other causes of hepatic granulomas: The presence of the parasite within the Kupffer cells and clusters of portal and lobular histiocytes is uncommon but quite helpful in diagnosis. Aspirates of splenic tissue demonstrating the characteristic amastigotes is diagnostic. (Refer to the discussion of Granulomatous Liver Disease in Chapter 12.)

FIGURE 7-46 Leishmaniasis (splenic aspirate). The 2 to 5 µm intracellular non-lagellated oval-shaped parasites (amastigotes) having basophilic nuclei are seen within these macrophages and free within the aspirate.

FIGURE 7-47 Leishmaniasis. The hepatic granuloma is composed of plump histiocytes and scattered lymphocytes. Microorganisms are not usually present within these granulomas.

2. Histiocytic clusters as well as epithelioid granulomas may also occur within the parenchyma, the histiocytes rarely exhibiting the parasite. Other features 1. The more characteristic paranuclear slightly perpendicular rod-shaped kinetoplast may be seen within the Kupffer cells at times. 2. Mild portal and sinusoidal lymphocytic and plasma cell iniltrates, and variable lobular mononuclear inlammation, may also be seen. 3. Diffuse sinusoidal collagen deposition may occur in longterm infection. 4. Mild macrovesicular fatty change may be seen. 5. Cholestasis is infrequent, but can be seen in severe and sometimes fatal cases of infection, where necrotizing granulomas containing the parasite may develop. 6. Fibrin ring granulomas and ischemic necrosis have been reported. Special stains 1. Giemsa: The parasite can best be seen within macrophages in splenic aspirate material.

Clinical and biologic behavior 1. Leishmaniasis is a spectrum of diseases caused by the protozoa Leishmania spp. of the Trypanosomatidae family. About 12 million persons worldwide are infected, and increasingly infections in patients with HIV and organ transplants have been reported. Hepatic involvement occurs in visceral leishmaniasis (also called Kala Azar) due to generalized infection of the reticuloendothelial system. 2. There are four species of Leishmania: L. donovani (Indian subcontinent and parts of Africa and South America), L. infantum/chagasi and L. tropica (Middle East, central Asia, and sub-Saharan Africa) and L. amazonis (parts of Brazil). 3. Leishmania spp. are diploid protozoa with dimorphic life cycles and are transmitted from the bites of female phlebotomine sand lies where the organisms develop in the digestive tract of the sand ly as promastigotes. When the lies attempt to feed, they regurgitate the parasite’s lagellated promastigote stage into the skin of mammalian hosts. These promastigotes attach to receptors on macrophages, are phagocytized, and transform into the nonlagellated amastigote stage, leading to a local reaction and presenting as the cutaneous form. The release of the non-lagellated amastigotes and infection of new macrophages then leads to infection of the reticuloendothelial system that explains the presentation of lymphadenopathy, hepatosplenomegaly, and bone marrow suppression. 4. The clinical manifestations vary depending on the complex interactions of the genetically determined host cell mediated immunity, parasite invasiveness, tropism and pathogenicity. Patients usually present with fever, lymphadenopathy, anemia, abdominal distension caused by enlargement of the liver and spleen (the latter often massive), and failure to thrive. In more advanced states, jaundice and ascites can mimic cirrhosis and portal hypertension. Rarely varices (grade 2) have been observed. 5. Tests reveal mild to moderate increases in serum transaminases, hypoalbuminemia, and pancytopenia. Hyperbilirubinemia is seen in more advanced disease and may resemble cholestatic hepatitis. Fulminant presentation has been reported in children. Liver biopsy and bone marrow examination are useful in the diagnosis. Treatment and prognosis 1. Pentavalent antimony drugs are commonly used for treatment and are less expensive; however, toxicity in over 30% is a limitation. 2. Liposomal amphotericin B is the preferred treatment, especially in organ transplant recipients.

Echinococcosis (Hydatid Cyst) (Figs. 7-48 through 7-53)

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FIGURE 7-48 Echinococcosis (hydatid cyst). A, Low-power shows the daughter cyst to be composed of numerous semicircular acellular laminated membranes. B, The laminated membrane in this ield is lined by a germinal layer with attached dead and calciied protoscolices and calciied remnants (hydatid sand).

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FIGURE 7-49 Echinococcosis (hydatid cyst). Both of these images show protoscolices. A, These three protoscolices are taken from an aspirate of a cyst. B, This viable protoscolex demonstrating a semicircle of hooklets is present within the lumen of a vascular channel, one mode of systemic spread of the microorganisms from ruptured cysts.

FIGURE 7-50 Echinococcosis (hydatid cyst). This aspirated material shows numerous hooklets and eosinophilic markedly degenerating cellular debris (hydatid sand).

FIGURE 7-51 Echinococcosis (hydatid cyst). The laminated membrane shows invagination through the outer cyst wall. Eventual rupture is an unfortunate complication when cyst wall invasion occurs.

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FIGURE 7-52 Echinococcosis (hydatid cyst). The outer cyst wall is

FIGURE 7-53 Echinococcosis (hydatid cyst). The parenchyma just

composed of acellular hyalinized ibrous tissue with focal calciications. A rim of chronic inlammatory cells is seen at the outer aspect of the cyst wall.

outside of the cyst wall shows a mixed inlammatory iniltrate consisting of lymphocytes, plasma cells, and numerous eosinophils.

Major morphologic features 1. Unilocular (E. granulosus) cysts (up to 30 cm in diameter) exhibit the following: a. An outer layer of acellular dense hyalinized and often calciied ibrous tissue with overlying granulation tissue (ibroblasts, lymphocytes, plasma cells, eosinophils) that merges into the bordering hepatic parenchyma. b. Underlying endogenous thin-walled, bulb-like daughter cysts composed of an ivory white acellular laminated membrane up to 1 mm thick, lined by a nucleated germinal membrane (or brood capsules). c. Protoscolices (ovoid structures 100 µm in diameter with two circles of refractile hooklets and a sucker) attached to the laminated membrane. 2. Alveolar multilocular cysts (E. multilocularis) are characterized by: a. Daughter cysts outside of a poorly formed large cyst wall. b. Irregular fragmented laminated membranes with absence of a germinal layer. c. Prominent granulomatous reaction to membranes with iniltration by numerous eosinophils and neutrophils, with microcalciications often apparent.

Aspiration cytology 1. Although generally contraindicated due to the risk of intra-peritoneal seeding of protoscolices, in some limited series no sequelae were observed, with quick diagnosis established when aspirated luid shows hyalinized membrane segments and protoscolices.

Other features 1. Amorphous eosinophilic and often calciied granular sediment (“hydatid sand”) may be seen within the cyst, representing in part degenerating protoscolices and debris. 2. Collapsed cysts exhibit irregular folds of the laminated membranes, with remnants of the protoscolices such as hooklets sometimes apparent. 3. Cyst rupture may incite a granulomatous reaction with numerous eosinophils, multinucleated giant cells, and secondary acute cholangitis. Sclerosing cholangitis has also been reported. Special stains 1. Von Kossa: Black calcium granules are often present in the outer cyst wall and granular sediment.

Differential diagnosis 1. Amebic abscess: The various layers of the capsule, with the inner brood capsules containing protoscolices, are diagnostic for Echinococcus infection. The ibrous wall, amorphous eosinophilic coagulative-type necrosis within the cyst, absence of inlammatory changes, and presence of amebic trophozoites at the edge of the cyst, are diagnostic of an amebic abscess. 2. Biliary cysts: Both simple and multiloculated biliary cysts can reach large size and mimic hydatid cysts. Biliary cystadenomas are also multiloculated with a distinct ibrous wall. These cysts, however, are lined by biliary epithelium, with or without a stromal framework, and are distinct from the hydatid cysts with the laminated and germinal membranes and daughter cysts. Clinical and biologic behavior 1. Echinococcus is a cestode (tapeworm) causing hepatic cyst formation in humans. E. granulosus is predominantly present in North Africa, Spain, Greece, the Middle East, Australia, New Zealand, and southern South American countries, while E. multilocularis predominates in Alaska, Canada, Russia, and Central America. 2. The common host is the dog, where the eggs are shed in the stools and ingested by humans (contaminated raw plants, soil, fur of dogs). The larvae are freed into the duodenum and migrate through the mesenteric veins into the liver. 60% are retained in the sinusoids, while the rest continue into the inferior vena cava, 20% then retained in the lungs and 20% in other organs via the systemic circulation. 3. The disorder presents as an enlarging, often palpable hepatic tumor mass (may be larger than 20 cm in diameter), 80% forming in the right lobe and usually single.

Chapter 7 / Infectious Disorders, Non-Viral 4. Infection is often asymptomatic. When symptoms occur, the liver is most often involved (liver 63%, lung 23%, kidney 3%, bone 2%, brain 1%). 5. The capsule and scolices of E. granulosus and E. multilocularis are quite similar. Large cysts of E. granulosus form endogenous daughter cysts, while E. multilocularis form exogenous cysts with growth and clinical behavior much like that in invasive metastatic carcinomas. 6. Encysted hepatic larvae form a characteristic lining of germinal and laminated zones. Proliferating brood capsules containing scolices form their own cyst lining (daughter cysts), eventually rupturing and forming “hydatid sand” (capsules, scolices). Degeneration of cysts and parasites leave a calciied amorphous debris. 7. Cysts forming just beneath Glisson’s capsule may become pedunculated, with invasion of the diaphragm into the pleural cavity. Peritoneal, pleural, or pericardial rupture may result in an anaphylactic reaction, with delirium, syncope and marked eosinophilia. 8. Complications include biliary obstruction from compression of large intrahepatic ducts especially when the cyst is situated at the porta hepatis, cholangitis due to rupture into the biliary tract, secondary infection, and anaphylaxis from ruptured cyst contents. 9. The appearance of cystic lesions with septations and calciications on CT scans are virtually diagnostic. On abdominal radiographs, sharply deined cysts and daughter cysts with calciication are seen 50% of the time. Serologic testing is positive in 90% of cases. Treatment and prognosis 1. The ideal therapy is complete surgical resection if the cyst is solitary and accessible to the surgeon. Pretreatment with albendazole is necessary prior to cystectomy. In addition, aspiration of the cyst for diagnostic purposes should be performed only after pre-treatment with albendazole. 2. If surgically unresectable, parasiticidal therapy prior to marsupialization is preferable and may be the only option. 3. In E. multilocularis, surgery is usually dificult due to multiloculations and exogenous daughter cyst formation. Parasiticidals may be offered. 4. Prognosis is usually good, patients often living for years, with eventual calciication of the cyst. The prognosis is also good when the cyst is surgically accessible for removal. The prognosis is worse with infected and ruptured cysts. With E. multilocularis, the majority of patients will die if untreated.

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FIGURE 7-54 Clonorchiasis. A main hepatic duct contains the parasite Clonorchis sinensis (liver luke). Numerous glandular structures can be seen within the duct wall even at low power.

FIGURE 7-55 Clonorchiasis. High-power shows within the organism numerous eggs that measure up to 30 µm in length and are secreted directly into the biliary passages.

Clonorchiasis (Figs. 7-54 through 7-56) Major morphologic features 1. The liver luke Clonorchis sinensis, measuring anywhere from 12 to 20 mm by 3 to 5 mm, is seen within the extrahepatic and large intrahepatic bile ducts. 2. Marked adenomatous proliferation of small peribiliary glands, often with goblet cell metaplasia and increased mucin production, are seen immediately surrounding the larger ducts.

FIGURE 7-56 Clonorchiasis. The duct wall shows prominent hyperplasia of the peribiliary glands (adenomatous hyperplasia).

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Other features 1. The liver luke is characterized by a ventral sucker, a loosely coiled intestinal ceca, deeply lobed testes with a poorly developed ejaculatory duct, a lobate ovary with a loosely coiled uterus, and numerous yellow-brown eggs measuring 29 by 16 µm. 2. Variable degrees of inlammatory iniltrates consisting of lymphocytes, plasma cells and numerous eosinophils are often seen surrounding the large duct walls. 3. Biliary cysts may form including or distal to the luke, the cysts containing clear bile. 4. Intrahepatic biliary sludge and stones may be seen, sometimes accompanied by dead worms. 5. Segmental duct dilatation (up to 6 mm in diameter) may occur, with thickened walls and worms within the duct lumen. 6. Ducts may become superinfected by colonic bacteria (E. coli), with evidence of acute cholangitis, leading to abscess formation. 7. Portal tracts with variable degrees of ibrosis, bile duct proliferation, periductal ibrosis and edema, and mild inlammatory iniltrates may be seen distally due to secondary biliary tract obstruction. Acute cholangitis and intralobular cholestasis may also at times be seen. 8. Multifocal intrahepatic cholangiocarcinoma is a rare complication. Aspiration cytology 1. Clear mucoid luid containing parasites may be present in the aspirated cysts. Differential diagnosis 1. Mechanical bile duct obstruction of other causes: Cholestasis, bile duct proliferation and dilatation, and acute cholangitis are changes that can be seen in both Clonorchis infection and large bile duct obstruction due to more frequent conditions such as choledocholithiasis and biliary strictures. The presence of a large duct in the biopsy exhibiting adenomatous hyperplasia and prominent numbers of eosinophils suggests parasitic infection. The presence of the liver luke is diagnostic. 2. Recurrent pyogenic cholangiohepatitis: Acute cholangitis and abscess formation may occur in Clonorchis infection, and are typical indings in recurrent pyogenic cholangiohepatitis (RPC) (refer to discussion of this disorder in Chapter 3). Clonorchiasis is felt to be one of the etiologic factors in the development of RPC; however, about 50% of those cases of RPC do not have Clonorchis infection. Therefore, identiication of the typical large-duct adenomatous lesions, and the parasite if possible, are essential for a diagnosis of clonorchiasis. Clinical and biologic behavior 1. Clonorchis (Opisthorchis) sinensis (oriental liver luke) is a common infection of humans in the Far East. In some regions such as Hong Kong, the parasite is present in up to 80% of persons in the 51- to 60-year-old age group. 2. The oblong (20 mm in length) parasite rests in major intrahepatic ducts. Although usually asymptomatic, severe infection may cause problems of mechanical bile duct obstruction, and is associated 50% of the time with recurrent pyogenic cholangiohepatitis.

3. Patients present with recurrent attacks of fever, abdominal pain and jaundice lasting 1 to 2 weeks. As the disease progresses, intervals between attacks shorten. Serum bilirubin, alkaline phosphatase and the peripheral white cell count are signiicantly elevated, with only mild to moderate elevations of serum aminotransferases. 4. The enlarged liver may reveal cysts beneath Glisson’s capsule that are gray-white to pale blue (dilated ducts containing adult worms and clear bile). 5. The natural hosts are humans, but other hosts include dogs, cats, and hogs. The eggs pass through feces into fresh water, are ingested by snails (intermediate host), and after development in the gut, larvae eventually leave the snails and penetrate the scales of fish, forming cysts. The worm develops from ingested cysts when raw or poorly cooked fish are eaten, and travels to the biliary tree via the ampulla of Vater, where it matures. 6. Gallstones sometimes contain dead parasites, eggs, and inlammatory products producing an amorphous greenbrown material (“biliary mud”). 7. Liver damage and bile duct injury occurs not only by obstructive change, but also by (a) direct mechanical injury to ducts from parasite suckers, and (b) chemical stimulants from metabolic byproducts of the parasite. 8. Complications include mechanical bile duct obstruction, often with intrahepatic gallstones, cholangitis, and abscess formation. In addition, cholangiocarcinoma may develop in a small percentage of patients (in large part most likely due to chronic irritation of the bile ducts). Treatment and prognosis 1. Praziquantel is the treatment of choice. Bacterial infections are treated appropriately with systemic antibiotics, while abscesses should be promptly drained. 2. The prognosis is generally good, as the majority of infections can be adequately managed.

Visceral Larva Migrans (Figs. 7-57 through 7-61) Major morphologic features 1. A granulomatous necroinlammatory reaction is seen, the granulomas composed of lymphocytes, plasma cells, numerous eosinophils, and occasional multinucleated giant cells, with prominent central ibrinoid necrosis often containing degenerating eosinophils and neutrophils. 2. In rare instances a segment of the larva Toxocara canis (300 by 20 µm) may be seen within the granulomas. Other features 1. The borders of the granulomas often exhibit palisading ibroblasts. 2. The granulomas often coalesce and appear as large multifocal mass lesions on imaging. 3. Charcot-Leyden spindle-shaped crystals that develop from degranulated eosinophils can also at times be seen.

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FIGURE 7-57 Visceral larva migrans. A and B, These two low-power images demonstrate granulomatous inlammatory lesions characterized by extensive central ibrinoid necrosis and surrounding palisading ibroblasts and inlammatory cells.

FIGURE 7-58 Visceral larva migrans. Higher power shows the prominence of the palisading ibroblasts. The marked outer inlammatory iniltrate consists of lymphocytes, neutrophils and numerous eosinophils.

FIGURE 7-60 Visceral larva migrans. High-power view of the stroma surrounding the granulomas shows striking numbers of eosinophils.

Differential diagnosis 1. Granulomatous necrosis secondary to other etiologies: Granulomas exhibiting central ibrinoid necrosis can be seen in other infectious (e.g., tuberculosis) and non-infectious (e.g., sarcoidosis) etiologies (refer to the discussion of Granulomatous Liver Disease in Chapter 12). In some instances, eosinophils may also be frequent (e.g., other parasitic infestations such as schistosomiasis). The demonstration of speciic microorganisms for each particular infectious disease entity, as well as serologic titers and culture studies, are helpful in making the distinctions. In the non-infectious causes, appropriate clinical and laboratory information is critical.

FIGURE 7-59 Visceral larva migrans. A smaller granuloma with central ibrinoid necrosis is seen.

Clinical and biologic behavior 1. Visceral larva migrans is a condition caused by Toxocara canis, a helminthic parasite that has a life cycle similar to Ascariasis. 2. The eggs mature in contaminated soil (pica) and usually infect dogs and cats. The passed eggs are then ingested by humans, with the larvae penetrating the intestinal mucosa and migrating to the liver, brain, eyes, and lungs.

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FIGURE 7-61 Visceral larva migrans. These (A) low- and (B) high-power images from a large necrotizing granuloma show abundant numbers of eosinophils. Charcot-Leyden crystals derived from degranulated eosinophils are also present.

3. The larvae eventually die, eliciting a prominent eosinophilic granulomatous response. 4. Patients present with fever, abdominal pain, ocular involvement, and diarrhea. 5. Children tend to have more severe disease with failure to thrive, weight loss and hepatomegaly. 6. Leukocytosis with eosinophilia and hyperglobulinemia is prominent, with only mild luctuations of the serum aminotransferase activities and bilirubin values. 7. Scanning of the liver by ultrasound reveals multiple hypoechoic nodules. On CT scans, low density lesions are seen, with ring shaped enhancement during the contrast phase. On magnetic resonance imaging, high signal intensity lesions are seen during the T2-weighted imaging, and low signal intensity is seen during T1-weighted imaging. 8. The diagnosis can be suggested when aspiration biopsy of the lesions demonstrates inlammatory cells with a predominance of eosinophils. Identiication of part of the larva on biopsy or aspirate can be helpful but is quite uncommon. 9. Serologic tests using the larval antigen and enzyme immunoassays are positive in over 85% of the infected patients. Treatment and prognosis 1. Treatment with antihelminthic drugs such as thiabendazole or albendazole is effective. A course of steroid therapy in combination with antihelminthic drugs may be necessary when the infestation occurs in the eye and central nervous system, or for severe pneumonia. 2. Recovery is usual and mortality is low if the infestation is diagnosed and treated promptly.

Toxoplasmosis

FIGURE 7-62 Toxoplasmosis. A cyst in the center of the ield containing numerous pyriform zoites is seen in this liver biopsy from a patient with the acquired immunodeiciency syndrome.

nucleus, a central karyosome, and numerous organelles), with or without an accompanying granulomatous reaction. These cysts are more frequently present in the immunocompromised patients. 2. Mild focal necroinlammatory change, mild fatty change, and rarely cholestasis may be seen, with the microorganism often dificult to demonstrate in the immunocompetent patients. Other features 1. The parasites may also be seen as free tachyzoites adjacent to the cysts. 2. Epithelioid granulomas have been described. 3. In the neonate, hepatitis may occur, with variable numbers of syncytial giant cells and parasites within the sinusoidal lining cells.

(Fig. 7-62) Major morphologic features 1. Characteristic small cysts are seen within liver cells, the cysts containing many zoites (the intracellular pyriform parasite 3 to 6 µm in diameter having a spheroid to oval

Special stains 1. Gomori methenamine silver (GMS): This silver stain highlights the cyst wall. 2. Periodic-acid Schiff (PAS): The pinpoint zoites stain positively.

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Differential diagnosis 1. Granulomatous necrosis secondary to other etiologies. The granulomas seen in toxoplasmosis are small and microscopic, with the microorganisms characteristic. Special stains can also help distinguish toxoplasmosis from other forms of infectious granulomatous hepatitis. (Refer to the discussion of Granulomatous Liver Disease in Chapter 12.) Clinical and biologic behavior 1. Toxoplasmosis is caused by infection with the obligate intracellular sporozoan parasite Toxoplasma gondii, has a worldwide distribution, but is more prevalent in areas having a warm moist climate. 2. The parasite infects humans when cysts containing the merozoites are ingested in uncooked or mostly raw meats, by transplacental passage of trophozoites from acutely infected pregnant women to the fetus, and less commonly by exposure to cat feces. 3. The organisms then invade the intestinal mucosa, multiply intracellularly with the production of trophozoites, and then disseminate throughout the body. 4. Asymptomatic infection occurs in most immunocompetent adults, whereby the acute infection is terminated by both humoral and cellular immune reactions. Symptoms may occur in approximately 15% of infected patients, and is manifested by cervical or generalized lymphadenopathy. 5. Headache, fever, malaise, sore throat, and a rash may also occur. 6. In the immunodeicient patient, particularly in those patients with the acquired immunodeiciency syndrome, chronic disseminated infection occurs in up to one-third of patients, with CNS manifestations frequent. 7. Hepatitis is uncommon, with only mild increases in the bilirubin and aminotransferases; however, congenital infection, occurring when a previously uninfected woman is acutely infected during pregnancy, may cause hepatosplenomegaly, jaundice, purpura, chorioretinitis, seizures, hydrocephalus, and intracerebral calciications in the newborn. 8. Toxoplasma antibody IgM is most useful in conirming the acute infection and can be performed using ELISA. Serologic tests using direct agglutination, indirect immunoluorescence and complement ixation will demonstrate antibodies but will not help distinguish acute from prior exposure. Diagnosis also rests on identiication of the microorganism on tissue biopsy. Treatment and prognosis 1. Infection in the normal host is most often self-limited, with treatment directed to symptoms. 2. In the immunocompromised patient, in pregnant women, and in those with disseminated infection, pyrimethamine and sulfadiazine are administered and are synergistic in their effectiveness. Improvement occurs in the majority of patients, although relapses are frequent.

Schistomosiasis (Figs. 7-63 through 7-65)

FIGURE 7-63 Schistosomiasis. This low-power image shows extensive ibrosis with bridging between portal tracts, without regenerative nodule formation (trichrome).

Major morphologic features 1. In the early acute phase, live and viable Schistosoma ova (eggs) appear within portal venous radicals and elicit a prominent eosinophilic granulomatous reaction (“eosinophilic abscess”) with scattered lymphocytes, histiocytes, ibrin, and less commonly multinucleated giant cells surrounding the ova. Intermixed Charcot-Leyden crystals may also be seen. 2. The granulomas early on develop a characteristic perigranulomatous lamellar ibrous reaction (“pipe-stem lesion”). With time this ibrosis obliterates the granulomas. 3. Within a few weeks after hepatic involvement, the eggs degenerate and die, becoming empty shells that often calcify, and may be numerous within the portal tracts and portal venous radicals, these dead ova usually devoid of a surrounding inlammatory reaction. 4. Variable degrees of portal and periportal ibrosis eventually develop in the chronic phase, without progression to cirrhosis. Other features 1. Inlammation of the portal veins and venules may subsequently occur (“endophlebitis”), often with thrombosis, vascular occlusion, subintimal ibrosis, and ibrous obliteration of the lumen, with eventual decrease in the numbers of portal venous radicals. 2. A grey-black pigment (resembling hemozoin) may be seen within the ova, within macrophages located within the granulomas, and within Kupffer cells and portal macrophages. 3. Proliferation of intrahepatic arterioles may sometimes be appreciated. 4. Nerve trunks may appear hypertrophic in large ibrotic portal regions near the hilum. 5. Adult worms may sometimes be seen within the portal vein radicals in larger wedge biopsy specimens. Special stains 1. Acid-fast (Ziehl-Neelsen carbolfuchsin): All Schistosoma species except hematobium stain positively. 2. Prussian blue: Schistosome pigment does not pick up this stain for iron, and hence this stain is useful in differentiating the pigment from hemosiderin.

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B FIGURE 7-64 Schistosomiasis. A and B, Numerous dead and partially calciied ova are seen within the ibrotic portal tracts.

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B

FIGURE 7-65 Schistosomiasis. A, A granuloma containing a viable ovum in its center is present. Eventually a lamellar ibrosis will surround the granuloma, forming a typical pipe-stem lesion. B, High power demonstrates the ova surrounded by lymphocytes and histiocytes.

Aspiration cytology 1. Eggs are not generally present within the hepatic lobules, and aspiration is usually not contributory; however, when seen, speciic identiication can be diagnostic: a. S. mansoni: Elliptical, 148 µm in length, very prominent lateral spine. b. S. japonicum: Spherical, 91 µm in length, small lateral spine (often dificult to identify). c. S. hematobium: Elliptical, 152 µm in length, terminal spine. Differential diagnosis 1. Granulomatous lesions of other etiologies: Most granulomatous disorders do not exhibit the characteristic ibrous “pipe-stem” lesion seen with schistosomiasis. Sarcoidosis, however, may exhibit a segmental ibrosis of larger granulomas, the older granulomas eventually becoming totally sclerosed. Granulomas within the parenchyma are unusual for schistosomiasis, while quite common in sarcoidosis. The presence of a centrally located viable ova is diagnostic for schistosomiasis, as are the more frequently seen calciied ova; however, at times special stains may be

necessary for determining the etiology of granulomas due to other infectious agents (e.g., fungi, mycobacterium). (See Chapter 12 for discussion of Granulomatous Liver Disease.) 2. Non-cirrhotic portal ibrosis: There are multiple causes of portal hypertension arising in ibrotic but non-cirrhotic livers, Schistosomiasis being one example. If a liver biopsy does not contain ova or typical granulomas, it may dificult to differentiate from other etiologies (refer to Chapter 6 for the discussion of Non-cirrhotic portal ibrosis). A more detailed clinical evaluation may then be necessary for appropriate diagnosis. Clinical and biologic behavior 1. Three species of the nematode Schistosoma infect humans: a. S. mansoni is seen in tropical and subtropical Africa, the Middle East, Central and South America, and the Caribbean. b. S. japonicum is present in the Far East. c. S. hematobium is prevalent in Africa and the Indian Ocean islands.

Chapter 7 / Infectious Disorders, Non-Viral 2. Schistosoma mansoni and S. japonicum settle in the portal venous system and are responsible for the most common cause of portal hypertension throughout the world. S. hematobium settles in the vesicular venous plexus, causing urinary bladder disease and very seldom liver disease. 3. In acute schistosomiasis (Katayama syndrome), patients present with fever, chills, hepatomegaly, lymphadenopathy, and marked eosinophilia (serum sickness). The liver exhibits an acute inlammatory reaction, with granulomas uncommon on biopsy. 4. A small subset of patients may go on to develop chronic disease, where a marked portal granulomatous and ibrogenic reaction to the eggs leads to presinusoidal portal hypertension. 5. Patients may present with melena, hematemesis from esophageal variceal bleeding, hepatosplenomegaly (the spleen averaging 1000 g), ascites, and rarely jaundice. Features of chronic liver disease such as spiders, gynecomastia, and testicular atrophy are rare and may occur if liver disease from another etiology is also present. 6. Alkaline phosphatase is mildly elevated, but serum aminotransferase activities and bilirubin are usually normal. 7. Man contracts the parasite through bathing or wading in contaminated waters. The intermediate host is the snail, where the fork-tailed cercariae develop, leave the snail, and infect humans by direct skin contact or invasion of mucous membranes after ingestion.

TABLE 7-3

189

8. The organisms migrate through the lymphatics and venules into the venous circulation, through the heart and lungs, and eventually terminate in the intrahepatic portal venous radicles. The larvae mature into the adult male and female worms and migrate into the mesenteric veins. Ovulation occurs (S. mansoni 300 eggs/day, S. japonicum 3500 eggs/day), with some of these eggs retained in the portal veins, eliciting the acute response. 9. The number of eggs in the feces often directly correlates with the degree of hepatic ibrosis in long-term infection. 10. Diagnosis is made by serology and identiication of ova in feces or on biopsy. Treatment and prognosis 1. Patients with acute or chronic schistosomiasis are treated with praziqantal. Mortality from the liver disease is uncommon, since hepatic function is well preserved. 2. Once ibrosis develops, however, reversal of complications secondary to the portal hypertension such as uncontrolled variceal hemorrhage is not likely, even after treatment.

OTHER NON-VIRAL INFECTIOUS DISORDERS THAT MAY CAUSE LIVER DAMAGE Table 7-3

Other Non-Viral Infectious Disorders That May Cause Liver Damage

DISEASE

HISTOLOGY

CLINICAL/LABORATORY PARAMETERS

Actinomycosis (Actinomyces israelii)

• Microabscesses are present that may coalesce. • A surrounding ibrinoid reaction may be seen at the periphery of the abscesses, resembling granuloma formation. • Branching hyphae may be seen in and amongst a neutrophilic iniltrate and appear as radiating gram-positive bacilli.

• These branched, gram-positive, ilamentous 1 µm–wide beaded organisms are considered prokaryotic bacteria and form entire granules in tissue that range in size from 30 to 3000 µm in diameter. • The organisms gain access through breaks in skin or mucosa and cause chronic suppuration with draining sinuses and istulae. • Portal seeding contributes to the development of hepatic disease, characterized by hyperbilirubinemia, elevated alkaline phosphatase activity, and mild increase in serum transaminase. • Hypoalbuminia is common in severe disease.

Ascariasis (Ascaris lumbricoides)

• An eosinophilic and neutrophilic granulomatous reaction to small larvae and eggs is present. • Acute cholangitis with numerous eosinophils, and abscess formation may occur as a complication of the worm migrating within the biliary tree. • Intrahepatic biliary calculi in large ducts may be seen as a response to trapped dead worms, with resultant secondary duct damage and adenomatous proliferation of biliary epithelium.

• This intestinal helminthic infestation occurs by ingesting infected cysts that are digested in the small intestine, releasing larva that enter the portal circulation and lymphatics, eventually reaching the lungs through the thoracic duct where an eosinophilic reaction develops. • The larvae migrate through the tracheobronchial tree to be swallowed into the esophageal lumen and ultimately end up in the small intestine as mature roundworms. • Reactions to the larvae in the liver can occur during the migratory process; however, the major clinical impact develops when these adult helminths migrate up the biliary tract, whereby patients present with fever, biliary colic, cholangitis (jaundice; leukocytosis; increases in serum alkaline phosphatase, transaminases, and bilirubin) and bile duct obstruction. • In unrecognized and untreated cases, abscesses and pylephlebitis can occur.

Aspergillosis (Aspergillus lavus and fumigatus)

• Hyphae (3–6-µm septate branching) can be demonstrated within vessels, leading to thrombosis and infarction of hepatocytes. • Hemorrhagic necrosis may be seen within the lobules.

• The liver is involved in disseminated aspergillus infections when patients are severely immunosuppressed (e.g., high-dose corticosteroid therapy for autoimmune disease, chemotherapy, organ transplantation). • Patients may become seriously ill, with fever unresponsive to antibiotics, pulmonary iniltrates, elevated alkaline phosphatase and hyperbilrubinemia. • The diagnosis is made by isolation of this fungus on cultures and biopsies. Continued

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TABLE 7-3

Other Non-Viral Infectious Disorders That May Cause Liver Damage—cont’d

DISEASE

HISTOLOGY

CLINICAL/LABORATORY PARAMETERS

Babesiosis (Babesia species)

• Focal coagulative necrosis is present within the lobules with little inlammatory iniltrate. • Hypertrophic Kupffer cells containing ring-shaped parasites that look similar to malaria but without pigment are also seen.

• Transmitted by the bite of Ixodes ticks, infection occurs usually during the summer months; patients with prior splenectomy are at increased risk. • Clinical signs and symptoms relate to proliferation of the organism in red blood cells with eventual rupture of these erythrocytes. • Patients present with fever, myalgia, sweats and headache. Mild hepatosplenomegaly and elevations of serum transaminases, alkaline phosphatase and bilirubin may be noted. • The infection by B. microti is mild and self-limited; however, infection by B. divergens results in fever, jaundice, anemia, renal failure, hemoglobinuria, marked leukocytosis, elevation of serum transaminases and bilirubin, and has a high mortality. • The immunoluorescent antibody titer of ≥1:64 with demonstration by light microscopy of the organism in erythrocytes is diagnostic.

Blastomycosis (North American) (Blastomyces dermatitidis)

• Microabscesses and epithelioid granulomas can develop within the parenchyma. • 6–15-µm budding yeast forms with thick refractile cell walls are seen within the granulomas.

• This fungus present in the soil is acquired by inhalation of conidia with eventual localization within the lungs. • Chronic pulmonary infection may be noted, with involvement of skin, bones, genitourinary tract, and liver in disseminated disease. • An increased incidence in patients with AIDS is recognized. • Enzyme immunoassays are not sensitive for diagnosis, with detection of organism in tissue samples preferred.

Borreliosis (relapsing fever, Borrelia species)

• Focal necrosis with hemorrhage is seen in the perivenular and midzonal regions. • Increase in sinusoidal lymphocytes and neutrophils is present. • Kupffer cell hypertrophy with erythrophagocytosis is often seen. • Organisms (spirochetes 10–20 µm demonstrated by the Warthin-Starry reaction) are present free within the sinusoids.

• This infection is caused by spirochetes of the genus Borrelia, a gram-negative organism transmitted by lice and ticks, with sporadic occurrences. • During acute infection that is characterized by fever, headache, sore throat, and myalgia, spirochetes are isolated from blood culture; in the non-febrile phase, organisms may be found in the liver, spleen, bone marrow, and central nervous system. • In severe infections, miliary abscesses are found in the spleen, with perisplenitis. • Infection may also involve the lungs, myocardium and kidneys; rarely DIC develops. • In tick and louse borne diseases respectively, hepatomegaly (17% and 65%), splenomegaly (37% and 72%), and jaundice (7% and 38%) are observed. • Serologic tests are somewhat helpful in chronic disease, with presence of agglutinins to Proteus OX-K (interpret cautiously in scrub typhus endemic areas).

Boutonneuse fever (Rickettsia conorii)

• Focal necrosis and lymphocytic iniltration within the lobules is seen. • Granulomatous necrosis may also be identiied. • Immunoperoxidase stain demonstrates rickettsial antigen in endothelial cells lining the sinusoids.

• This disease, also termed Mediterranean spotted fever, is caused by Rickettsii conorii and is usually seen in Tunisia and other countries bordering the Mediterranean and Black seas. • It is transmitted by tick bite, causing a raised maculopapular eschar. • Local lymphadenopathy and fever are frequent. • Hepatomegaly and mildly abnormal serum aminotransferases may occur. • Diagnosis is conirmed by complement ixation test.

Capillariasis (Capillaria hepatica)

• A granulomatous response to adult worms and numerous eggs, the granulomas containing prominent numbers of eosinophils, is present within the lobules.

• This nematode is found in the small intestine; humans are infected by ingesting larvae that reside in muscles of fresh water ish. • Patients present with abdominal pain, diarrhea, and protein-losing enteropathy. • Liver involvement is rare and may be due to ectopic localization.

Cat-scratch disease (Aipia felis)

• Microabscesses with granulomatous borders may be seen. • Extracellular clumps of bacillary organisms (demonstrated with the Warthin-Starry reaction) may be seen at the edge of the abscesses.

• Caused by a gram-negative bacillus, the vast majority of cases occur by contact with cats, often by way of cat scratch or bite. • Skin lesions and regional lymphadenopathy are the commonest manifestation in the non-HIV infected population, with children developing the infection more often than adults. • Rarely, encephalopathy, lytic bone necrosis, and pneumonitis may develop. • Hepatic involvement is seen most often with systemic infection in the immunocompromised patient.

Cryptosporidiosis (Cryptosporidium parvum)

• The small 1- to 2-µm diameter organisms are seen adherent to the luminal surface of large to medium-sized bile ducts that may show variable inlammation, ibrosis, and duct epithelial hyperplasia. • Rarely the organisms can be demonstrated involving smaller interlobular ducts. • These smaller ducts may show periductal sclerosis; in some cases, ductopenia can occur.

• This small protozoan organism is found in the small intestine and has a predilection for infecting biliary epithelial cells. • Approximately 20% of cases of HIV-associated cholangiopathy were detected to have cryptosporidium on biopsy. • Patients may present with right upper quadrant pain, elevated alkaline phosphatase, and sometimes hyperbilirubinemia. • Ultrasound may demonstrate dilated bile ducts. • Endoscopic retrograde cholangiopancreatography has the advantage of permitting biopsies for diagnosis, with sphincterotomy to relieve symptoms.

Chapter 7 / Infectious Disorders, Non-Viral

TABLE 7-3

191

Other Non-Viral Infectious Disorders That May Cause Liver Damage—cont’d

DISEASE

HISTOLOGY

CLINICAL/LABORATORY PARAMETERS

Enterobiasis (Enterobius [oxyuris] vermicularis)

• Up to 1 cm round granulomatous nodules composed predominantly of acellular eosinophilic debris are present. • The nodules exhibit extensive eosinophilic necrosis with central usually degenerating triangular worms that are sometimes surrounded by eggs. • A mixed inlammatory granulomatous iniltrate including eosinophils is present at the periphery of the nodules.

• The most cosmopolitan of all nematodes, this pinworm affects mainly children who present with perianal pruritus. • The worm resides in the lumen of the cecum and colon, and may be linked to appendicitis. • Ectopic localization of the worms has been noted in the peritoneal cavity, fallopian tubes and rarely in the liver, forming mass lesions.

Fascioliasis (Fasciola hepatica)

• Yellow surface nodules are present that are 5 to 20 mm in diameter. • A track containing the leaf-like worms with surrounding eosinophils and variable tissue necrosis is present, eventually leading to subcapsular scar formation. • Segmental duct dilatation with a centrally located worm may occur, associated with duct erosion and prominent reactive adenomatous duct hyperplasia. • Large necrotic granulomas can develop around trapped eggs. • Acute cholangitis may also occur, with eosinophils prominent. • Portal ibrosis occurs without progression to cirrhosis.

• The life cycle of this trematode is similar to that of Clonorchis sinensis except that the cercaria released from the snail (intermediate host) attaches to aquatic plants (like watercress), with infection of humans occurring by drinking contaminated water or ingesting these plants. • The metacercariae released in the duodenum migrate to the biliary ducts and produce inlammation and obstruction of the biliary radicles, presenting as biliary colic, hepatomegaly with acute cholangitis, formation of strictures and pigmented stones, and abscesses. • During attacks of acute cholangitis, the presence of eosinophilia should raise this diagnostic possibility in endemic areas. • Diagnosis is made by demonstrating the characteristic biliary tract abnormalities on scanning modalities or at cholangiography.

Leptospirosis (Weil’s disease, Leptospira icterohaemorrhagica)

• Cholestasis with variable chronic inlammatory iniltration is seen within the lobules, associated with scattered acidophil body formation • Kupffer cell hyperplasia and hypertrophy with erythrophagocytosis is seen. • Organisms (spirochetes 10–20 µm, demonstrated by the Warthin-Starry reaction) are seen within Kupffer and endothelial cells.

• These gram-negative spirochetal bacteria are shed in the urine of rodents, infrequently in pigs, dogs and cattle, and are acquired by humans when swimming in contaminated water or exposure to excrements of animals. • After an incubation period of 7 to 10 days, a biphasic illness develops with fever, photophobia, headache, myalgia, sweating, prostration, epistaxis, and lymphadenopathy. • Delirium, hemolysis, renal failure, anemia, thrombocytopenia, myocarditis, pericarditis, and hepatitis may follow. • Splenomegaly is noted frequently. • Leukocytosis, hyperbilirubinemia (partly caused by hemolysis), and moderate increases in serum transaminases and alkaline phosphatase are observed. • Blood cultures are positive if obtained within the irst 7 to 10 days; the organism may be identiied in alkaline urine by dark-ield microscopy. • Mortality approaches 40% in severe cases, but death is not from liver failure.

Listeriosis (Listeria monocytogenes)

• Microabscess formation may be seen within the lobules. • Granulomatous-type necrosis may be present. • Organisms (bacilli) are often present and abundant within the abscesses.

• This infection caused by Listeria monocytogenes is acquired from contaminated food or drink, particularly from cold storage of uncooked foods such as milk, milk products, and soft cheeses. • Bacteremia accounts for fever, headache, chills, and myalgia. • Meningitis, endocarditis, pericarditis, skin rash, peritonitis, osteomyelitis, and liver involvement are seen in severe cases. • Hepatosplenomegaly and moderate elevation in transaminases and alkaline phosphatase may occur. • Jaundice is rare except in severe infections. • Positive blood cultures obtained early in the course of the infection conirms the diagnosis.

Lyme disease (Borrelia burgdorferi)

• Lobular necroinlammatory change is present with variable liver cell ballooning. • Lymphocytes and neutrophils can be seen to variable degrees within the sinusoids. • Microvesicular fatty change is present. • Organisms (spirochetes 10–20 µm, demonstrated by the Warthin-Starry reaction) are seen within the sinusoids and hepatocytes.

• This tick-borne spirochetal infection is caused by gram-negative Borrelia burgdorferi and presents as a brief acute illness with skin rash, arthritis, cardiac and CNS symptoms • The initial skin lesion (erythema migrans) at the site of the tick bite develops within 8 to 9 days; the late-phase illness lasts weeks to months, with musculoskeletal and cardiac symptoms. • Liver involvement is minor, with hepatomegaly and only mild derangement of liver tests.

Continued

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TABLE 7-3

Other Non-Viral Infectious Disorders That May Cause Liver Damage—cont’d

DISEASE

HISTOLOGY

CLINICAL/LABORATORY PARAMETERS

Melioidosis (Pseudomonas pseudomallei)

• Variably sized abscesses are present in acute infection. • Necrotizing granulomas may be seen within the lobules in chronic infection.

• Caused by a gram-negative unencapsulated non-sporulating organism Pseudomonas pseudomallei, the infection is endemic to Southeast Asia, tropical Australia and other tropical countries. • Most infections are subclinical. • In patients with chronic infection, 80% have concurrent diseases such as diabetes mellitus, malnutrition, obesity, chronic renal failure, and connective tissue diseases. • The course of infection in these patients is characterized by recurring suppuration, mimicking tuberculosis or fungal infections. • The most serious disseminated disease involves lungs, liver and spleen, with high grade fever, headache, myalgia, diarrhea, hepatosplenomegaly and shock. • Cultures of blood, urine, sputum, and pus are diagnostic. • In chronic infections, serology (IgG immunoluorescent antibody titer of ≥1:10) has a sensitivity of 90%.

Microsporidiosis (Enterocytozoon, Encephalitozoon species)

• Small oval intracellular refractile spores in the cytoplasm of duct epithelium are present and are best seen on toluidine blue stain. • In patients with the acquired immunodeiciency syndrome, duct sclerosis and eventual depletion (ductopenia) may occur.

• This obligate intracellular gram-negative protozoan parasite is recognized as a cause of opportunistic infection in patients with AIDS and organ transplants. • Ingestion of spores from contaminated food and drink reach the small intestine and are internalized by phagocytosis by macrophages, allowing schizogony to occur by binary ission. • Patients present with diarrhea, weight loss, anemia, and involvement of the biliary tract. • Parasites can be detected in the stool or on biopsy. • Serologic tests are not reliable.

Nocardiosis (Nocardia asteroides and brasiliensis)

• Microabscesses are present and may sometimes coalesce, producing larger abscesses. • A surrounding ibrinoid granulomatous reaction may be seen at the periphery of the abscesses. • Organisms may be seen within neutrophils and appear as gram-positive beaded bacilli that are weakly AFBpositive and best seen with the Grocott silver stain.

• The skin and subcutaneous tissues are involved primarily by the formation of abscesses and draining sinuses. • Involvement of the lungs with cavitary lesions resemble tuberculosis. • In immunocompromised patients (usually with N. asteroides) other organs, such as the liver, spleen, kidneys, and brain, may be involved.

Paracoccidioidomycosis (South American blastomycosis, Paracoccidioides brasiliensis)

• Epithelioid granulomas are seen predominantly within portal tracts. • 5–60-µm budding yeast forms can be seen within the granulomas. • Portal ibrosis may be seen without progression to cirrhosis.

• Infection is recognized in rural areas of Mexico and South America. • Humans are infected by inhalation of conidia that are present within the soil. • Two patterns of involvement may occur: reticuloendothelial, with hepatosplenomegaly (juvenile form), and respiratory (adult form). • Disseminated disease involves the skin, lymph nodes, oropharynx, liver, spleen, and adrenal glands.

Penicilliosis (Penicillium marneffei)

• Epithelioid granulomas may be present within the parenchyma. • A diffuse form may also be seen, with yeast forms (5 × 2 µm non-budding) seen within hypertrophic Kupffer cells and histiocytes.

• This infection, caused by molds (hyalophyphomycosis), is prevalent in Southeast Asia and is increasingly seen in patients with AIDS and those receiving cancer chemotherapy. • The majority (75%) of patients develop a variety of skin lesions ranging from umbilicated papules mistaken for molluscum contagiosum, ecthymiform lesions, folliculitis, subcutaneous nodules, and morbilliform eruptions. • The liver and spleen are involved in disseminated disease.

Pentastomiasis (Armillifer [Porocephalus] armillatus)

• Fibrotic, calciied, and rarely non–epithelial-lined cystic nodules 5 to 10 mm in diameter enclosing dead parasites are present. • A surrounding granulomatous response may occur.

• This larva, referred to as tongue worm, is present in rodents and herbivorous animals that ingest eggs, with the deposition of larvae into the animal muscles and other organs. • Humans are infected by drinking water contaminated by these eggs, or by consuming raw tissues of herbivorous hosts. • Encysted larvae are found in the mesentery, lung, liver, and peritoneal cavity.

Pneumocystis carinii infection

• Focally widened sinusoids with patchy liver cell necrosis but little inlammation are present in patients with the acquired immunodeiciency syndrome. • Focal areas of frothy eosinophilic material containing small pale cysts with a few basophilic dots on hematoxylin and eosin stain are seen; the organism is best demonstrated as oval- or cup-shaped, folded cysts 4 to 6 µm in diameter using the GMS stain.

• Pneumocystis is a eukaryotic microbe with morphologic features similar to fungi but is neither true fungi nor protozoa. • The ubiquitous organism is acquired by the airborne route. • Fever, nonproductive cough, and shortness of breath are characteristic. • Slight increase in serum aminotransferases may be present with liver involvement. • Lymph nodes, heart, pancreas, liver, spleen, brain, thyroid, and kidneys may be involved in disseminated disease (usually in patients with low CD4 counts) with multiorgan failure and death often occurring.

Chapter 7 / Infectious Disorders, Non-Viral

TABLE 7-3

193

Other Non-Viral Infectious Disorders That May Cause Liver Damage—cont’d

DISEASE

HISTOLOGY

CLINICAL/LABORATORY PARAMETERS

Strongyloidiasis (Strongyloides stercoralis)

• Larvae (600 × 16 µm) are present in small portal veins and sinusoids, with or without an inlammatory reaction. • When inlammation is present, a granulomatous response with multinucleated giant cells and eosinophils is seen.

• This female nematode, called threadworm, is endemic worldwide. • The adult parasite hatches eggs in the small intestinal mucosa from which rhabditiform larva hatch. • These then pass into the feces where they mature to ilariform larvae that have the propensity to penetrate skin and infect barefoot humans. • These larvae migrate to the lungs from the peripheral circulation, penetrate the alveoli, and escape into the tracheobronchial tree where they migrate cephalad and eventually enter the small intestine after being swallowed. • The skin (site of entry), pulmonary (migration), and gastrointestinal tracts are the main targets of infection. • In disseminated disease, seen in immunosuppressed individuals, pneumonitis, septicemia, ulcerative enteritis and colitis, meningitis, peritonitis, and hepatic involvement can be seen, referred to as hyperinfection syndrome, with mortality exceeding 50%.

Toxic shock syndrome

• Perivenular cholestasis is present, with variable lobular acute and chronic inlammatory iniltration. • Acute cholangitis, with variable portal neutrophilic iniltration may be seen. • Microvesicular fatty change is present. • Pylephlebitis of portal veins and arteritis have been described.

• Toxic shock syndrome is caused by staphylococcal exotoxin and develops in women who used sanitary towels contaminated with the toxin. • Salient indings include hyperbilirubinemia, mild elevations of serum transaminases, mild to moderate increase in alkaline phosphatase activity, increased serum bile salt concentrations, and hypoalbuminemia.

Whipple’s disease

• Foamy macrophages that are DiPASpositive are often seen within portal tracts • The sickle-type bacilli have been described within these macrophages as well as within hypertrophic Kupffer cells. • Epithelioid granulomas have also been described.

• This uncommon bacterial infection (Tropheryma whippelii, Whipple’s bacilli) of the small intestine is associated with marked iniltration of the intestinal mucosa by foamy macrophages. • The liver is usually involved, with good hepatic function.

Zygomycosis (Mucor species)

• Necrotizing granulomas up to 1 cm in diameter are present, with prominent coagulative necrosis containing hyphae.

• Numerous fungi, including Mucor species, contribute to this ubiquitous disease, which is seen more frequently in diabetics and patients on immunosuppressive therapy. • Inhalation of spores infects sinuses and the lower respiratory tract. • Infection of surgical and other wounds allows the organism to travel across tissue planes with invasion of blood vessels. • The liver is involved in disseminated disease, with hepatic injury often secondary to vascular involvement with resultant ischemia.

REFERENCES The complete reference list is available online at www. expertconsult.com.

Chapter

8

DEVELOPMENTAL, FAMILIAL, AND METABOLIC DISORDERS

NEONATAL HEPATITIS 194 BILIARY ATRESIA 196 Extrahepatic 196 Intrahepatic 198

INHERITED CHOLESTATIC DISORDERS 200 Progressive Familial Intrahepatic Cholestasis (Byler Syndrome) 200 Benign Recurrent Intrahepatic Cholestasis 202

FIBROCYSTIC DISEASES 202 Biliary Microhamartoma 202 Peribiliary Cysts 203 Choledochal Cyst 204 Solitary Unilocular (Nonparasitic) Cyst 205 Polycystic Disease 206 Perinatal (Infantile Type) 206

Congenital Hepatic Fibrosis (Juvenile/ Adult Type) 207 Caroli Disease 209 Adult Polycystic Disease 210

CYSTIC FIBROSIS 212 ALPHA-1 ANTITRYPSIN DEFICIENCY 214 HEREDITARY HYPERBILIRUBINEMIAS 217 Gilbert Syndrome 217 Dubin-Johnson Syndrome 218

DISORDERS OF AMINO ACID METABOLISM 220 Hereditary Tyrosinemia 220

STORAGE DISORDERS 221

MITOCHONDRIAL FATTY ACID OXIDATION DISORDERS 226 Medium-Chain Acyl CoA Dehydrogenase Deiciency 226

PORPHYRIAS 226 Porphyria Cutanea Tarda 227 Erythropoietic Protoporphyria 228

SICKLE CELL ANEMIA 230 OTHER DEVELOPMENTAL, FAMILIAL AND METABOLIC DISORDERS THAT MAY CAUSE LIVER DAMAGE 231

Glycogen Storage Diseases 221 Gaucher Disease 222

NEONATAL HEPATITIS (Figs. 8-1 through 8-3) Major morphologic features 1. Syncytial giant cell transformation of hepatocytes is seen in almost all cases, the individual cells often containing anywhere from 4 to >50 nuclei. 2. Variable associated necroinlammatory changes, apoptosis, and Kupffer cell hyperplasia are seen. 3. Portal tracts are normal in size, with mild to moderate predominantly lymphocytic iniltrates. Other features 1. Although the giant cells are typically accentuated in the perivenular zone, these cells may be present throughout the lobules in severe cases. 2. The giant cells oftentimes have ill-deined cytoplasmic borders, with a suggestion of fusion of adjacent hepatocytes. 3. The giant cells often have hydropic to granular eosinophilic cytoplasm, and may contain fat, glycogen, bile or hemosiderin, and remnants of cell membranes. 4. Neutrophils are rarely identiied surrounding the giant cells, and are usually seen in association with cell injury. 5. Cholestasis with pseudoglandular formation of hepatocytes is often present. 194

Niemann-Pick Disease 223 Myoclonus Epilepsy (Lafora Disease) 225

6. Sinusoidal collagen deposition may be present to some degree around the larger multinucleated giant cells. 7. Interlobular bile ducts are normal to slightly increased in number. 8. Severe conluent liver cell necrosis can also occur at times, dependent on the etiology of the hepatitis (e.g., may be seen in some instances of viral hepatitis). 9. Extramedullary hematopoiesis may be seen to variable degrees and is subject to the age of the infant. Additionally the numbers of giant cells inversely correlate with the age of the patient, with giant cells infrequent after 1 year of age. 10. Depending on the etiology (e.g., α1-antitrypsin deiciency), ibrosis and cirrhosis may also occur; however, in the “idiopathic” form, cirrhosis is not a characteristic feature. Special stains 1. Perl’s iron: Hemosiderin is often seen within the involved hepatocytes. 2. Masson trichrome: The sinusoidal collagen deposition is enhanced with this stain. Differential diagnosis Other conditions associated with neonatal hepatitis: Many liver disorders are associated with neonatal hepatitis, the majority also exhibiting variable degrees of syncytial giant cell

Chapter 8 / Developmental, Familial, and Metabolic Disorders 195

transformation of hepatocytes. Table 8-1 lists these various disorders. More often than not there is no deinite cause (“idiopathic”); however, the three liver diseases listed below are more frequent and oftentimes problematic disorders that must often be considered: 1. Extrahepatic biliary atresia (EBA): This is one of the more common disorders that elicits syncytial giant cell transformation. Within the irst 3 months of life, there is marked bile duct and ductular proliferation in EBA. The portal tracts during this time period are usually normal in size to mildly ibrotic; thereafter, the ibrosis becomes more prominent, with biliary cirrhosis described as early as 6 months after birth, ibrosis not a feature in neonatal giant cell hepatitis. Very early in EBA, however, morphologic features differentiating it from neonatal giant cell hepatitis may be quite minimal, diagnosis then resting on the absence of extrahepatic bile ducts on Rose Bengal I131 or HIDA scans in EBA. 2. Intrahepatic biliary atresia: Syncytial giant cells often occur in this disease in the perivenular zone; however,

FIGURE 8-1 Neonatal giant cell hepatitis. Many of the hepatocytes are markedly enlarged and show prominent multinucleation (syncytial giant cell transformation).

A

interlobular bile ducts are decreased to absent in these cases, but present to slightly increased in neonatal giant cell hepatitis. Unfortunately, in the very early stages of intrahepatic biliary atresia, interlobular bile ducts may still be seen. In these instances, the marked elevation of the alkaline phosphatase activity, serum cholesterol (500 to 1000 mg/dL), and bile acids (predominantly cholic acid) seen in intrahepatic biliary atresia but not in neonatal giant cell hepatitis may be helpful in diagnosis. 3. α1-Antitrypsin deiciency: This disorder in the infant is often associated with syncytial giant cell transformation, but also may show loss of the interlobular bile ducts. Biliary ibrosis may be present, depending on the time of biopsy. α1-Antitrypsin cytoplasmic inclusions in periportal hepatocytes are the key inding, but may be quite small and exceptionally dificult to identify within the irst 10 weeks of life. Serum α1-antitrypsin levels with phenotyping are necessary for a deinitive diagnosis, as heterozygotes (PiMZ, overall incidence 3%) do not develop chronic liver disease. In addition, immunoperoxidase stains would be helpful in identifying the small inclusions as well (see discussion of α1-antitrypsin deiciency later in this chapter for a more detailed description of this disorder). Clinical and biologic behavior 1. Neonatal giant cell hepatitis is generally deined as any condition in the neonate with conjugated hyperbilirubinemia, a patent and normal extrahepatic and intrahepatic biliary tree, and morphologic hepatic features of chronic inlammation and syncytial giant cell transformation of hepatocytes. 2. Numerous conditions are associated with this clinicopathologic disorder and are listed in Table 8-1. Of note is that frequently there are speciic morphologic features (e.g., duct loss in paucity of duct syndrome, abundant hepatic iron in perinatal hemochromatosis) in many of these disorders that distinguish them from neonatal giant cell hepatitis. 3. Although extrahepatic biliary atresia and choledochal cysts commonly produce giant cell change, many investigators omit these disorders when deining neonatal hepatitis. Nonetheless, they are almost always considered in the differential diagnosis.

B

FIGURE 8-2 Neonatal giant cell hepatitis. A and B, High power demonstrates, in these two images of hepatocytes with marked syncytial giant cell change, many of the liver cells containing over 50 nuclei on serial sectioning. The golden-brown pigment represents hemosiderin.

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4. Giant cell transformation is a result of mitotic inhibition and/or fusion of adjacent liver cells. This inding is rather nonspeciic in the neonate with inlammatory, cholestatic, and numerous congenital and metabolic disorders; however, giant cell change is much rarer in children and adults. When seen in the older age groups, the giant cells are relatively scanty and smaller, usually containing not more than 4 nuclei.

BILIARY ATRESIA Extrahepatic (Figs. 8-4 through 8-7)

Treatment and prognosis 1. The overall prognosis is relatively good, with resolution of the hepatitis. 2. Careful follow-up is important to exclude homozygous α1-antitrypsin deiciency, biliary atresia, or rare hepatic disorders such as progressive familial intrahepatic cholestasis that warrant speciic therapies.

Major morphologic features 1. Marked interlobular bile duct and ductular (cholangiolar) proliferation and dilatation with portal edema are seen. 2. Cholestasis is present and is most prominent in the perivenular zone (zone 3 of Rappaport), with mild associated lobular inlammation. 3. Portal ibrosis of biliary type occurs, with eventual bridging ibrosis and progression to secondary biliary cirrhosis.

FIGURE 8-3 Neonatal giant cell hepatitis. The portal tract shows only a mild lymphocytic iniltrate. Interlobular bile ducts are present and are unremarkable, an important feature in that a variety of neonatal liver diseases associated with duct loss (e.g., paucity of duct syndrome) also often show syncytial giant cells.

Other features 1. Three types of duct abnormalities are seen at the hepatic hilum (porta hepatis) and extrahepatic biliary tree: a. Type 1: Absence of ducts. b. Type 2: Small irregularly shaped elliptical duct lumen (diameter 300 µm in diameter with focal necrosis of the epithelial lining. c. Type 3: Ducts described in type 2 above, with addition proliferating ductules within the ibroconnective stroma. 2. Portal tracts exhibit variable degrees of lymphocytic and occasional neutrophilic iniltrates, with prominence and hyperplasia of the hepatic arterioles. 3. Multinucleated giant cell transformation of hepatocytes is seen in approximately 15% to 25% of cases and is accentuated in the perivenular zones. 4. Bile plugs often occur within the proliferating dilated cholangioles. 5. Extramedullary hematopoiesis may be present.

TABLE 8-1

Various Diseases Associated with Neonatal Hepatitis*

Infectious causes

Adenovirus Bacteria Congenital syphilis Coxsackie virus Cytomegalovirus Echovirus Herpesvirus Human herpesvirus 6 Paramyxovirus Rubella Toxoplasmosis Treponema Viral hepatitis B and C

Metabolic disorders

α1-Antitrypsin deiciency Cystic ibrosis Galactosemia Gaucher disease Hereditary fructose intolerance Niemann Pick disease Perinatal hemochromatosis Tyrosinemia Wolman disease Zellweger syndrome

Structural abnormalities

Biliary atresia, extrahepatic Biliary atresia, intrahepatic (paucity of ducts) • Alagille syndrome • Progressive familial intrahepatic cholestasis Biliary hypoplasia Caroli disease Choledochal cyst Spontaneous perforation of extrahepatic bile ducts

Miscellaneous

Budd-Chiari syndrome Hyperalimentation “Idiopathic”

*Data from Portmann BC, Roberts EA: Developmental abnormalities and liver disease in childhood. In: Burt AD, Portmann BC, Ferrell LD (eds): MacSween’s Pathology of the Liver, 5th ed, pp 147-197. London: Churchill-Livingstone, 2007.

Chapter 8 / Developmental, Familial, and Metabolic Disorders 197

6. As the disease progresses: a. Xanthomatous appearance of clusters of hepatocytes and Kupffer cells occurs. b. Bile lakes, bile infarcts, and/or Mallory bodies are seen and are most often present in the periportal and periseptal zones. c. Increase in copper and copper-binding protein is identified within periportal and periseptal hepatocytes. d. In the cirrhotic stage, although bile duct proliferation is usually present, considerable cytologic atypia of the interlobular bile ducts with duct loss (ductopenia) may occur with time. Special stains 1. A number of stains are useful in demonstrating the increased copper and copper-binding protein in periportal and periseptal hepatocytes seen in this disorder: a. Orcein (copper-binding protein): Brown-black granules. b. Rhodanine (copper): Brown-red granules. c. Rubeanic acid (copper): Green-black granules.

A

2. Van Gieson: Green-staining bile in perivenular hepatocytes and occasionally within dilated cholangioles can be seen and is accentuated with this stain. Differential diagnosis 1. Other causes of cholestasis with neonatal hepatitis: Up to 25% of cases of extrahepatic biliary atresia exhibit some degree of syncytial giant cell transformation of hepatocytes, and may be dificult to differentiate from neonatal hepatitis from other causes (see Table 8-1). Interlobular bile ducts and cholangiolar proliferation is marked in extrahepatic biliary atresia. Additionally, portal biliary ibrosis along with imaging indings (HIDA scan) of extrahepatic biliary disease help conirm the diagnosis of extrahepatic biliary atresia. Clinical and biologic behavior 1. Extrahepatic biliary atresia is the most common cause of protracted cholestasis in infants, accounts for almost 50% of all cases of neonatal cholestasis with an overall incidence of 1/8000 to 1/20,000 live births, and is four to

B

FIGURE 8-4 Extrahepatic biliary atresia. A, The architecture is disrupted due to severe bridging ibrosis approaching an early biliary cirrhosis. B, The portal tracts and ibrous bands demonstrate striking proliferation of the interlobular bile ducts and cholangioles (trichrome).

FIGURE 8-5 Extrahepatic biliary atresia. The bile ducts show not only proliferation but ectasia of the lumen. Scattered lymphocytes and neutrophils are seen within the ibrous matrix of the portal tract.

FIGURE 8-6 Extrahepatic biliary atresia. The parenchyma shows hepatocytes undergoing syncytial giant cell transformation.

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FIGURE 8-7 Extrahepatic biliary atresia. Cholestasis is seen predominantly within the dilated canaliculi.

2. 3. 4.

5.

6.

7.

8.

ive times more common in Southeast and East Asia with predominance in Asian females. Jaundice is not present at birth, but develops 1 to 3 weeks later, with dark urine and acholic stools. Pruritus and xanthoma formation are rare. Hepatomegaly is common. Splenomegaly is initially mild but becomes progressively more pronounced as hepatic ibrosis sets in. Elevation of conjugated serum bilirubin and marked increase in the alkaline phosphatase and 5´-nucleotidase values occurs; serum aminotransferases, however, are only slightly elevated. Associated anomalies are present 15% to 30% of the time, and include polysplenia syndrome and trisomy 21. An increased incidence of viral infection (CMV, rubella, varicella) is also present. Extrahepatic biliary atresia usually presents with complete involvement of the entire extrahepatic biliary system in 75% to 85% of the cases, with the rest of the cases exhibiting partial atresia or hypoplasia. Although originally felt to be congenital, considerable evidence indicates that it is probably an acquired disorder: a. It is exceptionally rare in premature infants and stillbirths. b. Reports of dizygotic and monozygotic twins have shown one to have atresia, the other a normal biliary tract. c. An increased association with continuing portal inlammatory iniltrates and gradually diminishing ducts (obstructive, obliterative cholangiopathy) occurs. d. Possible association with viral infection (reovirus-3) is postulated. The diagnosis using Rose Bengal I131 or HIDA scan is highly sensitive in over 97% of cases. Liver biopsy 60% to 95% of the time is diagnostic, although dificulty occurs in very early stage disease.

Treatment and prognosis 1. A partial but intact common bile duct is corrected by a Roux-en-Y anastomosis; however, this is seen in only a small percentage of cases.

2. An absent common duct (75% to 85% of cases) is corrected with hepatoportoenterostomy (Kasai procedure), anastomosing the jejunal loop to the porta hepatis. Some derive long-term beneit, although the majority still have poor biliary drainage leading to biliary ibrosis. This temporizing procedure allows survival for eventual hepatic transplantation. 3. A good prognosis is achieved when the duct size at the hilum is >150 µm in diameter (correctable type). When ducts are 20 g parenchymal iron storage (>10,000 µg/g dry weight, with liver biopsy showing ibrosis or cirrhosis). 5. The age-related iron accumulation led to the concept of calculating the hepatic iron index (HII) (hepatic iron concentration in liver biopsy specimens in micromoles per gram dry weight divided by the age of the patient in years). HII of >1.9 effectively distinguishes the homozygous state from heterozygous and nonhereditary causes of iron overload; however, the accumulation can be variable and exceptions can occur in 8% to 50% of individuals with hereditary hemochromatosis. 6. The gene defect is a G to A missense mutation (C282Y) leading to the substitution of tyrosine for cysteine at the 282 amino acid position of the protein product of the HFE gene located on the short arm of chromosome 6 (6p). Another mutation (H63D) in which aspartic acid is substituted for histidine at position 63 has also been associated as a cofactor in this disease. The homozygous state, in which both alleles of chromosome 6 possess the C282Y mutation, and the compound heterozygous state with C282Y on one chromosome and H63D in the other, are the predominant genetic abnormalities for hereditary hemochromatosis. Rarely, hemochromatosis not related to the HFE gene (non HFE) has been reported in small ethnic clusters. The pathogenesis of hemochromatosis is likely related to a deiciency or dysregulation of hepcidin, a circulating hormone produced

7.

8.

9.

10.

11.

12.

241

by the liver that regulates body iron balance; however, the relationship of hepcidin to the HFE protein is not clear. Patients with cirrhosis present with hepatomegaly and portal hypertension or bleeding esophageal varices, while asymptomatic patients are identiied by abnormal elevations of serum transaminases. Liver test abnormalities are usually unimpressive even in the cirrhotic stage. Serum albumin is often normal, serum transaminases are normal or slightly elevated, alkaline phosphatase is elevated in about 20% of cases, and prothrombin time is prolonged only in about 25% of patients with advanced disease. The diagnosis of hereditary hemochromatosis is made with indirect tests initially. Transferrin saturation is derived by dividing the serum iron by the total iron binding capacity. The sensitivity and speciicity of this test is 92% and 93% respectively, and the positive predictive value is 86% when fasting transferrin saturation exceeds 50% for women and 60% for men. Serum ferritin is not speciic and can be raised in inlammatory conditions (e.g., chronic viral hepatitis C); however, combined with transferrin saturation, ferritin has a predictive value of 97%. In established hereditary hemochromatosis, ferritin levels of >1000 ng/ml predict hepatic ibrosis. Initial screening for fasting transferrin saturation can be performed on those where iron overload is suspected as well as irst-degree relatives of hereditary hemochromatosis patients. If elevated, genotypic testing for C282Y and H63D will identify those who are at risk of liver disease and hepatocellular carcinoma and require treatment. Liver biopsy is recommended for all homozygous patients who have clinical evidence of liver disease, the biopsy useful to stage the severity of liver disease and to determine prognosis. At the time of biopsy a small piece of tissue should be submitted for quantitative iron measurement and to determine the hepatic iron index. Other factors such as increase in dietary iron (from dietary supplements, iron leached from cooking vessels used in certain cultures), increase in parenteral iron (hemolysis, transfusions) or decrease in normal iron losses (menopause, hysterectomy) can hasten the presentation of the disease, while conditions that cause increased iron losses (bleeding) can delay the manifestations of disease. Alcohol increases iron absorption and vitamin C accelerates the mobilization of iron. The mechanism by which iron causes injury is considered to be from free radical and prooxidant-related injury.

Treatment and prognosis 1. Phlebotomy is the standard and mainstay of therapy for this condition and can prevent cirrhosis and hepatocellular carcinoma if offered before cirrhosis develops. Phlebotomy should be stopped when ferritin levels fall below 50 ng/ml. Ferritin values should be tested every 12 phlebotomies. Hematocrit levels should not be allowed to fall below 20% of baseline. In patients without hereditary hemochromatosis, however, hematocrit will drop quickly with phlebotomy and can be used as an indirect test to exclude hemochromatosis.

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TABLE 9-3

Copper Distribution Total body copper (100 mg)*

⇓ Liver 20 mg

⇓ Red blood cells, plasma 10 mg (ceruloplasmin, 4.3 mg)

⇓ Brain 20 mg

⇓ Muscle 35 mg

⇓ Connective tissue 10 mg

⇓ Kidney 5 mg

*Data from Hamza I, Gitlin JD: Copper metabolism and the liver. In: Arias IM, Boyer JL, Chisari FV, et al (eds): The Liver: Biology and Pathobiology, 4th ed, pp 331-343. Philadelphia: Lippincott Williams & Wilkins, 2001.

2. Iron chelation with desferoxamine (20 to 40 mg/kg body weight) is not effective in hereditary hemochromatosis but is offered in secondary iron overload. 3. Treatment of diabetes, cardiomyopathy and congestive heart failure should follow standard guidelines. Cardiac arrhythmias may cause sudden death. The lower survival rate following liver transplantation in these patients is most likely related to cardiac events. 4. Once cirrhosis develops, phlebotomy is not effective in reversing the process. Vitamin C supplements and alcohol should be avoided during treatment. 5. Management strategy for cirrhosis includes treatment of complications. In end stage liver disease and hepatocellular carcinoma, liver transplantation should be considered.

COPPER STORAGE DISORDERS (Table 9-3)

Basic Copper Metabolism 1. Absorption: a. The daily body requirement of copper is approximately 2.5 mg. b. The copper is absorbed predominantly in the duodenum and is then loosely bound to albumin and histidine. 2. Hepatic uptake, storage and excretion: a. Copper then undergoes reduction to the cuprous form and is then transported into the liver cells by the transmembrane transporters hCtr1 and hCtr2. b. Copper taken up by the liver is irmly bound to the α2-globulin ceruloplasmin, and then released into the plasma, the end result being: i. Six percent loosely bound. ii. Eighty percent to 95% irmly bound. iii. Trace amounts free and dialyzable. c. Copper is stored in the liver as hepatocuprein (copperbinding protein) with binding to metallothionein, with little (if any) copper present in the free form. d. The main excretory pathway is by way of the biliary system. 3. Copper is a component of various proteins and enzyme systems, and plays an important role in the following: electron transfer reactions of speciic cuproenzymes, formation of neurotransmitters, pigment production, iron homeostasis, and peptide biosynthesis. Two enzymes that play a critical role include: a. Ceruloplasmin: This serum glycoprotein contains >95% of the plasma copper, is synthesized in the liver, and is secreted into the blood. Copper is incorporated into

TABLE 9-4

Disorders Associated with Increased Hepatic and Plasma Copper

HEPATOCYTES

PLASMA

• α1-Antitrypsin deiciency (neonate) • Chronic long-term biliary tract obstruction (e.g., strictures) • Cystic ibrosis • Drugs causing chronic cholestasis (e.g., chlorpromazine) • Exposure to sprays containing copper sulphate (vineyard workers) • Hyperalimentation (TPN) • Indian childhood cirrhosis • Paucity of ducts syndrome • Primary biliary cirrhosis • Primary sclerosing cholangitis • Progressive familial intrahepatic cholestasis • Wilson disease

• Acute and chronic infections • Acute biliary tract obstruction • Leukemia, lymphoma (Hodgkin’s) • Oral contraceptives • Pregnancy • Rheumatoid arthritis • Thyrotoxicosis • Wilson disease

this protein in the Golgi apparatus, where each protein molecule contains six copper atoms. Ceruloplasmin also plays a role in the mobilization and release of iron from storage sites. b. Superoxide dismutase: Copper chaperones play a role in this enzyme function, which protects red blood cells, liver and brain by catalytically scavenging the toxic free radical superoxide (O2–) generated during aerobic metabolism.

Conditions Associated with Elevated Copper Levels (Table 9-4)

Wilson Disease (Figures 9-10 through 9-18) Major morphologic features 1. Precirrhotic stage a. Mild macrovesicular and occasionally microvesicular fatty change is seen, with no distinct zonal distribution pattern. b. Glycogenated liver cell nuclei and increase in lipochrome pigment are present, both predominantly periportal in location. c. Portal ibrosis with variable degrees of intrasinusoidal collagen deposition is present.

Chapter 9 / Diseases of Hepatic Iron and Copper Metabolism

FIGURE 9-10 Wilson disease. Thin strands of sinusoidal ibrosis are highlighted on this stain for collagen. Fatty change is also present (Trichrome).

A

243

FIGURE 9-11 Wilson disease. Numerous glycogenated nuclei of hepatocytes are seen.

B

FIGURE 9-12 Wilson disease. A and B, Fatty change and a predominantly intracanalicular cholestasis are present in these two images.

FIGURE 9-14 Wilson disease. Large intracytoplasmic clear spaces FIGURE 9-13 Wilson disease. Mallory bodies are present in hepatocytes, these cells partially surrounded by neutrophils in this example.

containing clumped eosinophilic material represent enlarged vacuolated lysosomes. Mallory bodies are also seen in some of the hepatocytes.

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d. Copper is demonstrated either diffusely or predominantly in periportal hepatocytes (rubeanic acid, rhodanine stains) in approximately 40% of cases, with all lobules equally affected. 2. Cirrhotic stage a. Bridging ibrosis with eventual macronodular or mixed macro- and micronodular cirrhosis occurs. b. Macrovesicular and occasional microvesicular fatty change is present in up to 80% of cases, with cholestasis (65%) and Mallory bodies (40%) also identiied. c. Copper is demonstrable in hepatocytes (rubeanic acid, rhodanine stains), usually periseptal in location, with the distribution irregular from one regenerative nodule to another. FIGURE 9-15 Wilson disease. Prominent giant lysosomes, intracellular bile, and mild fatty change are present.

FIGURE 9-16 Wilson disease. Extensive liver cell dropout with lobular collapse (conluent necrosis) is present in this example of a young patient with Wilson disease who developed fulminant hepatic failure. Residual trapped hydropic hepatocytes are seen.

FIGURE 9-17 Wilson disease. A well-established micronodular cirrhosis is present (Trichrome).

Other features 1. In both the precirrhotic and cirrhotic stages, focal necrosis and mononuclear lobular inlammatory iniltrates are present to variable degrees, with syncytial giant cells of hepatocytes occasionally demonstrated in the more active stages of the disease. 2. Variable degrees of portal and periportal interface inlammatory activity are present, the inlammatory cells chiely lymphocytes with occasional plasma cells. 3. Liver cell nuclei exhibit variable but sometimes marked nuclear anisocytosis and dysplasia, with some of the cells exhibiting prominent eosinophilia of the cytoplasm (oncocytic, oxyphilic change). 4. The lipochrome pigment, present predominantly in periportal and periseptal hepatocytes, may be composed of large clumped and often vacuolated granules. 5. Kupffer cells may contain hemosiderin (due to hemolytic episodes) or small amounts of copper (secondary to liver cell necrosis and phagocytosis). 6. In patients clinically presenting with fulminant hepatic failure, the necroinlammatory change with apoptosis is usually diffuse, oftentimes with conluent bridging (submassive) necrosis, cholestasis, and marked cholangiolar proliferation. In addition, small vacuolated “clear” spaces with irregularly shaped eosinophilic structures (lysosomes) may also be seen in liver cells. Special stains 1. PAS after diastase digestion (DiPAS): Lysosomes which are prominently found in hepatocytes in cases of fulminant hepatitis stain positively. 2. Rubeanic acid, rhodanine: Copper stains a granular black-green (rubeanic) or red (rhodanine), and is most prominent in periportal and periseptal hepatocytes. Stainable copper may also be identiied in Kupffer cells and portal macrophages in instances of a severe hepatitis. 3. Orcein, Victoria blue: These stains identify copper-binding protein, not copper, within the periportal and periseptal hepatocytes, and appears coarsely granular black-brown (orcein) or purple (Victoria blue). 4. Prussian blue: Hemosiderin may be present in Kupffer cells secondary to hemolytic episodes and can best be demonstrated with this stain for iron. In addition, over time this pigment can also be present and sometimes may be prominent in hepatocytes as well.

Chapter 9 / Diseases of Hepatic Iron and Copper Metabolism

A

B

C

D

245

FIGURE 9-18 Wilson disease. Various stains are useful in demonstrating pigments that are increased in the liver in Wilson disease, the pigment usually prominent in the periportal or periseptal hepatocytes. In most cases the pigment is most abundant in the advanced stages of the disease, with the exception of copper itself, which is most concentrated in the early stages. These stains include rubeanic acid (A) and rhodanine (B) for copper, orcein (C) for copper-binding protein, and Perl’s iron (D) for hemosiderin.

Hepatic copper quantitation A concentration of hepatic copper greater than 250 µg/g dry weight is diagnostic for Wilson disease. Note that the degree of stainable copper seen in the cirrhotic stage may be misleading, as copper frequently is irregularly distributed from one regenerative nodule to the next. The hepatic tissue copper quantitation, however, is diagnostic. Differential diagnosis 1. The morphologic changes seen in Wilson disease are not diagnostic and represent a spectrum of changes. Correlation of these features in conjunction with the clinical and laboratory tests, hepatic copper stains, and hepatic copper quantitation are necessary for a deinitive clinicopathologic diagnosis. Some useful clues in the differential are included in Table 9-5. Clinical and biologic behavior 1. Wilson disease (hepatolenticular degeneration) is a genetically transmitted hepatic disorder manifested by abnormal copper deposits principally in the liver and brain but eventually also involving other organ systems.

2. The incidence of the homozygous disease is about 1 per 30,000, with a slight male preponderance. The disease has a worldwide prevalence, with a higher incidence noted in communities where consanguinity is common. 3. Patients with Wilson disease have a defective gene on chromosome 13, designated as ATP7B, that encodes a metal-transporting P-type adenosine triphosphatase which is mainly expressed in hepatocytes and functions in the transmembrane transport of copper in hepatocytes. Absent or reduced ATP7B protein leads to decreased hepatocellular excretion of copper into bile. Failure to incorporate ceruloplasmin is a consequence of loss of functional ATP7B protein. The low levels of ceruloplasmin seen in Wilson disease are due to the decreased half life of apoceruloplasmin (ceruloplasmin protein produced and secreted without copper). There are over 60 mutations, most being point mutations resulting in amino acid substitutions. 4. Copper accumulates in the liver during childhood, thus presentation of the disease in children is always hepatic. After the liver becomes saturated, the copper is then deposited in the brain (chiely the basal ganglia), with

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TABLE 9-5

Differential Diagnosis of Wilson Disease

Wilson disease

MALLORY BODIES

SINUSOIDAL FIBROSIS

STAINABLE COPPER AND COPPER-BINDING PROTEIN

FAT

GLYCOGENATED NUCLEI

+

++

++

+

+

+/–

+/–

+/–

–

–

+

+

++

–

–

+/-

+

+/++

–

–

–

+

++

–

– –

Chronic cholestatic disorders Mechanical bile duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Paucity of duct syndrome

–

–

+

–

Indian childhood cirrhosis

Drugs (e.g., chlorpromazine)

++

++

++

–

–

Alcoholic liver disease (active drinker)

++

++

–

++

–

Chronic hepatitis (HCV) Non-alcoholic steatohepatitis

–

+

–

+

+/–

+/++

+/++

–

++

++

+, Occasional; ++, common.

5.

6.

7.

8.

9.

the patient presenting with neuropsychiatric symptoms in the second and third decades. Although these particular neurologic manifestations of Wilson disease almost never occur after the fourth decade, liver involvement is always present. Hepatic disease alone has been rarely reported in the ifth decade. The liver disease presents as chronic hepatitis (sometimes clinically mimicking autoimmune hepatitis); however, in about 45% of cases, patients may be asymptomatic. Rarely, acute liver failure may occur associated with acute severe (Coombs-negative) hemolysis, renal failure, and resultant high mortality unless the patient is transplanted. Cirrhosis with time eventually occurs with or without manifestations of portal hypertension. Hepatocellular carcinoma is rare. Mild to moderate increases in serum transaminases are common and are associated with mild increases in serum bilirubin; however, in patients with fulminant disease and hemolysis, the serum bilirubin can exceed 20 mg/dL. Serum uric acid is generally low and sometimes low levels of serum alkaline phosphatase can be seen. The ophthalmic manifestations include the following: a. Kayser-Fleischer rings: a granular copper protein complex deposited in the Descemet’s membrane of the cornea and appearing as a greenish brown or graybrown ring at the periphery of the cornea (97% of patients), identiied best by slit lamp examination of the eye. b. “Sunlower” cataracts: deposition of copper protein complex in the posterior lens capsule, with demonstration of a frond-like appearance. No signiicant visual defects occur as a consequence. The neurologic manifestations include rigidity, tremors, gait abnormalities, and choreiform movements. In addition, neuropsychiatric symptoms often occur as well. Other organ involvement includes the kidneys presenting with renal tubular defects, red blood cells causing hemolysis, skeletal abnormalities, endocrine dysfunction affecting the pituitary gland, gonads and parathyroid glands, and cardiac disease presenting with arrhythmias and electrocardiographic abnormalities.

10. Diagnostic tests and copper studies include the following: a. The serum ceruloplasmin level is less than 20 mg/dL (normal 20 to 50 mg/dL) in 95% of patients; however, in advanced cirrhosis or fulminant hepatitis due to other causes, low ceruloplasmin levels can be seen secondary to impaired protein synthetic function. Elevated ceruloplasmin values are seen in acute inlammatory conditions, malignancy, pregnancy, and estrogen therapy. In addition, approximately 5% of patients with Wilson disease may have normal values. b. Serum copper levels are usually low (normal values from 80 to 120 µg/dL) because of the low ceruloplasmin levels. The unbound (free) copper levels are normally 25 µg/dL. c. Twenty-four-hour urinary excretion of copper is increased, with levels >100 µg/dL (normal 250 µg/g dry weight (normal 27 µg/g dry weight) is noted in patients with Wilson disease, which in conjunction with other morphologic changes and the clinical setting is diagnostic. Of note, however, is that elevated levels can also be see in other cholestatic diseases such as primary biliary cirrhosis (441 µg/g), extrahepatic biliary obstruction (128 µg/g) and biliary atresia. Low hepatic copper levels can also be seen in patients who received chelation therapy. Measurement of copper in liver biopsy specimens from patients with advanced disease is not considered useful in certain instances because of the variable distribution of copper in the liver in cirrhosis, plus the fact that in the cirrhotic stage the biopsy used for copper determination may be composed predominantly of ibrous tissue and not hepatocytes. Treatment and prognosis 1. Wilson disease is uniformly fatal without treatment. Although low copper diet is recommended, signiicant reductions in copper levels in affected organs occur only with chelation therapy. 2. The current and generally successful standard of therapy is 1 g of D-penicillamine (250 mg four times, maximum

Chapter 9 / Diseases of Hepatic Iron and Copper Metabolism

A

247

B

FIGURE 9-19 Indian childhood cirrhosis. A, Small ill-deined regenerative nodules are present, with thin ibrous bands and prominent periseptal sinusoidal collagen deposition. The hepatocytes show considerable hydropic change. B, Higher power shows that many of the hepatocytes contain Mallory bodies.

dose 20 mg/kg/day, reduce by 25% when stable) daily and indeinitely, if side effects and toxicity do not preclude continued therapy. Trietene is a general chelator and is offered to patients who are intolerant to D-penicillamine (20 mg/kg/day, reduce by 25% when stable). 3. The use of zinc at doses of 150 to 200 mg three times daily is useful to maintain negative copper balance once adequate chelation is achieved with D-penicillamine and as adjunctive therapy. Primary therapy with zinc is not effective. Tetrathiomolybdate is a chelator that also blocks intestinal copper absorption but is in the experimental drug stage. 4. In patients with fulminant hepatic failure and hemolysis, hemoiltration is beneicial in reducing copper levels and stabilizing the patient while awaiting liver transplantation. 5. In patients with fulminant liver failure, end-stage cirrhosis with complications, patients who decompensate following cessation of chelation therapy, and patients with neurologic complications unresponsive to therapy, liver transplantation is usually curative.

Indian Childhood Cirrhosis (Figures 9-19 and 9-20) Major morphologic features 1. Extensive portal, perivenular, and diffuse interstitial ibrosis is seen, with eventual development of micronodular cirrhosis. 2. Mallory bodies are present in many of the hepatocytes. Other features 1. Hepatocytes exhibit variable degrees of hydropic ballooning change, with focal necrosis, hepatocytolysis, and mild lymphocytic and occasional neutrophilic lobular iniltrates present. 2. Portal tracts exhibit mild to moderate predominantly lymphocytic iniltrates with occasional histiocytes, rare plasma cells, and mild bile duct proliferation. 3. Cholestasis may be present but is uncommon.

FIGURE 9-20 Indian childhood cirrhosis. Increase in coarsely granular black pigment representing copper-binding protein is present in virtually all of the hepatocytes (orcein).

4. Fat may be present in the early stages of the disease but usually is absent in the more advanced stages. 5. Mallory bodies are not present in the early stages of the disease. 6. Liver cells may at times be multinucleated (syncytial change), with two to three nuclei per cell; however, prominent giant cell transformation is not present. 7. The micronodules in the cirrhotic stage are poorly deined, with scanty to absent regenerative change of the hepatocytes. Special stains 1. Orcein, Victoria blue: These stains identify the marked increase in copper-binding protein (not copper) which appears coarsely granular and black-brown (orcein) or purple (Victoria blue). Although this stainable protein is accentuated in the periseptal hepatocytes, it may at times be diffuse and involve most of the liver cells.

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2. Rubeanic acid, rhodanine: The increase in copper stains green-black (rubeanic) or red (rhodanine) and is most prominent in periseptal hepatocytes, although at times it may be diffuse. 3. Masson trichrome: The prominent portal and diffuse interstitial ibrosis is enhanced. Differential diagnosis 1. α1-Antitrypsin deiciency: Portal and to some degree sinusoidal ibrosis, occasional Mallory bodies, and eventual biliary cirrhosis can be seen in infants with α1-antitrypsin deiciency. Atypical duct formation, decrease in ducts, and α1-antitrypsin inclusions conirmed by immunoperoxidase stain are characteristic of this disorder, these features not seen in Indian childhood cirrhosis. 2. Other causes of cirrhosis in infancy and childhood: Rare metabolic defects (e.g., tyrosinemia, cystinosis, galactosemia, fructosemia, glycogen storage diseases III and IV) may be associated with cirrhosis in infancy and childhood. Indian childhood cirrhosis is distinctive, however, in being conined, with a few exceptions, to the Indian subcontinent (a similar type of cirrhosis has been reported in the United States). In addition, excluding Wilson disease, abundant Mallory bodies and increase in stainable copper and copper-binding protein are present only in Indian childhood cirrhosis. 3. Alcoholic hepatitis: This type of acute alcoholic liver disease may morphologically resemble Indian childhood cirrhosis, although fat is more abundant in the alcoholic; however, Indian childhood cirrhosis is not seen in the adult population. Clinical and biologic behavior 1. Indian childhood cirrhosis is a rapidly progressive liver disease found most often in children in India, usually of the Brahmin class, and often has a familial predilection. There are case reports of similar disorders in the United States. 2. The clinical presentation is at 2 years of age (range 6 months to 5 years), and generally presents in three clinical stages. The irst stage has an insidious onset and is characterized by

irritability, anorexia, failure to thrive, gastrointestinal abnormalities, and hepatomegaly. This is followed in the second stage by jaundice, marked hepatosplenomegaly, portal hypertension with ascites, and susceptibility to infections. The inal stage is characterized by increasing jaundice, gastrointestinal bleeding, infections, edema, encephalopathy, and death from liver failure. Neurologic abnormalities related to copper deposition in the brain are not seen in this disease. 3. Laboratory abnormalities are those seen in decompensated liver disease and are not unique to Indian childhood cirrhosis. Serum alpha-fetoprotein levels are elevated but not caused by hepatocellular carcinoma. Aminoaciduria may suggest renal tubular acidosis. Serum immunoglobulins are markedly elevated, serum complement is low, and smooth muscle antibody may be positive in 45% of cases. 4. The liver in Indian childhood cirrhosis has the highest copper levels with average values of 1400 µg/g dry weight and reported values as high as 4788 µg/g dry weight. Ceruloplasmin levels are normal or raised, unlike that seen in Wilson disease. The hepatobiliary excretion of copper is not well studied in this disorder. 5. A defect in copper metabolism may play a part in the pathogenesis; however, a striking observation is that copper toxicosis develops in children ingesting milk boiled in copper cooking vessels and may be acquired from the leaching of copper from these vessels. Altering the practice of boiling milk in copper utensils has substantially reduced the incidence of this disease in Indian children. Treatment and prognosis 1. Avoidance of copper in the diet, and treatment with D-penicillamine (20 mg/kg/day) in children before the onset of cirrhosis and complications results in improved survival and reduction in mortality. 2. In children with advanced disease, liver transplantation is lifesaving.

REFERENCES The complete reference list is available online at www. expertconsult.com.

Chapter

10

NEOPLASMS AND RELATED LESIONS

PRIMARY NEOPLASMS, BENIGN 249 Epithelial Benign Tumors 249 Liver Cell Adenoma 249 Bile Duct Adenoma 254 Hepatobiliary Cystadenoma 256 Mesenchymal Benign Tumors 258 Cavernous Hemangioma 258 Infantile Hemangioendothelioma 260 Angiomyolipoma 262 Mesenchymal Hamartoma 263 Rare Benign Mesenchymal Tumors 265 Miscellaneous Benign Tumors 266

PRIMARY NEOPLASMS, MALIGNANT 266 Basic Pathophysiologic Concepts 266 Epithelial Malignant Tumors 267 Hepatocellular Carcinoma 267 Common Patterns 267 Fibrolamellar Hepatocellular Carcinoma 278

Cholangiocarcinoma 281 Hepatoblastoma 288 Mesenchymal Malignant Tumors 290 Angiosarcoma 290 Epithelioid Hemangioendothelioma 293 Rare Mesenchymal Malignant Tumors 295 Miscellaneous Malignant Tumors 298

METASTATIC NEOPLASMS 308 TUMOR-LIKE LESIONS 311 Focal Nodular Hyperplasia 311 Regenerative Lesions 314 Inlammatory Pseudotumor 317 Focal Fatty Change 320

HEMATOPOIETIC DISEASES 299 Hodgkin’s Lymphoma 299 Non-Hodgkin’s Lymphoma 301 Leukemia, Myeloproliferative Disorders 303 Langerhans Cell Histiocytosis 305 Plasma Cell, Lymphoplasma Cell Dyscrasias 306

PRIMARY NEOPLASMS, BENIGN Epithelial Benign Tumors Liver Cell Adenoma (Figs. 10-1 through 10-15) Major morphologic features 1. Uniform arrangement of cytologically benign hepatocytes is present that form trabecular cords no more than two cells thick. Other features 1. The cords are often closely arranged, with the normal cord-sinusoid pattern at times not apparent due to variable hydropic change of the hepatocytes; however, the normalsized cords can best be conirmed by the reticulin stain. 2. The tumor cells are generally larger than the adjacent non-neoplastic hepatocytes. 3. The tumor cells may have an eosinophilic granular cytoplasm, and may contain fat, glycogen, bile, and lipochrome-like pigment. 4. Mallory bodies and in rare instances epithelioid granulomas may also occur. 5. Small acinar structures and pseudogland formation may occur, but are infrequent (usually associated with anabolic steroid usage). 6. Extramedullary hematopoiesis may rarely be seen within the sinusoids.

7. Bile ducts are not seen within the tumor; however, focal microscopic segments of bile ductules can sometimes be identiied and is usually associated with variable but often prominent sinusoidal dilatation (telangiectatic variant). 8. Sinusoids may be focally dilated and congested, sometimes forming hemorrhagic cysts (pelioid pattern). 9. Endothelial lining cells are present along the trabecular cords. Kupffer and stellate cells are also present, although usually not readily noticeable. 10. Variously sized thin-walled vascular structures and small arterioles within the tumor are seen. In addition, thick walled small and medium-sized arteries are often present at the periphery of the tumor and often show variable degrees of ibrointimal thickening. 11. Although a capsule is infrequently seen in the smaller lesions, a thin ibrous capsule is often present in the larger lesions. 12. Areas of hemorrhage and necrosis may focally occur to various degrees in up to 20% of cases, with ibrous scars often containing pigmented histiocytes in areas of previous necrosis, the pigment usually hemosiderin but may at times be condensed lipochrome-like pigment. Rarely microcalciications may also occur in these areas. 13. When the tumor is identiied beneath Glisson’s capsule, there is almost always a rim of normal liver (often compressed or atrophic) between the tumor and the capsule. 14. Atypical pleomorphic cells with distorted hyperchromatic nuclei and abundant cytoplasm (dysplastic cells) may infrequently be seen, these cells sometimes containing Mallory bodies. Transformation to hepatocellular 249

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carcinoma, with micro-invasion into the adjacent nonneoplastic liver, has been described in these lesions but is uncommon. Note: Although the rate of malignant transformation to hepatocellular carcinoma is uncommon, positive nuclear immunostaining of the liver cell adenoma tumor cells for β-catenin has been shown to be a risk factor in malignant transformation.

FIGURE 10-1 Liver cell adenoma. This nonencapsulated tumor in a patient on oral contraceptives demonstrates an ill-deined nodularity. Focal areas of acute hemorrhage are also present. (Ishak KG, et al: Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

Special stains 1. Reticulin: In cases where the tumor cells are hydropic and the sinusoids are dificult to identify, this stain aids in the conirmation of normal-sized hepatic cords no more than two cells thick. 2. Perl’s iron: Hemosiderin pigment in areas of previous necrosis is conirmed. In addition, the nonstaining of pigment also can be suggestive of lipochrome pigment, and is helpful in ruling out hepatocellular carcinoma (which virtually never contains lipochrome pigment). Immunohistochemistry 1. HepPar 1, polyclonal carcinoembryonic antigen (pCEA): In instances where there is any doubt of the hepatocellular origin of the tumor cell, especially in small

FIGURE 10-2 Liver cell adenoma. Two tumor nodules with extensive acute hemorrhage are present. This tumor is from a patient with glycogen storage disease type I. (Ishak KG, et al: Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

A

B FIGURE 10-3 Liver cell adenoma. The well-circumscribed encapsulated and partially pedunculated tumor has a thin surrounding ibrous capsule. Focal acute hemorrhage is also present.

FIGURE 10-4 Liver cell adenoma. A, The hepatic cords are lined by endothelial cells, with the individual hepatocytes showing no cytologic abnormalities. B, The hepatic cords are one to two cells thick, conirmed on this reticulin stain.

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FIGURE 10-5 Liver cell adenoma. Benign hepatocytes are seen with variable but mild hydropic change. Numerous vascular channels are present.

251

FIGURE 10-6 Liver cell adenoma. The adenoma is to the right of the ield, with the tumor cells showing moderate fatty and hydropic changes. No ibrous capsule is seen between the tumor and nontumor liver, although the border is nonetheless distinct.

FIGURE 10-8 Liver cell adenoma. The cytologically benign tumor FIGURE 10-7 Liver cell adenoma. Bile is seen within the dilated biliary canaliculi. Finely granular intracytoplasmic bile is also present.

cells form trabecular cords one cell thick. Many of the hepatocytes also contain some degree of lipochrome pigment.

FIGURE 10-10 Liver cell adenoma. Mallory bodies are present within FIGURE 10-9 Liver cell adenoma. An epithelioid granuloma is present. Some of the surrounding tumor cells also contain macrovesicular fat.

these hydropic tumor cells. A mixed inlammatory iniltrate consisting predominantly of lymphocytes with occasional neutrophils is also present. Note also that the hepatocytes show nuclear irregularity and dysplasia, a feature often seen in association with Mallory body deposition.

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FIGURE 10-11 Liver cell adenoma. A ibrous scar with acute hemorrhage is seen. The adjacent hepatocytes within the adenoma demonstrate macrovesicular fat.

FIGURE 10-13 Liver cell adenoma. Low power shows focal areas of prominent sinusoidal dilatation. A few small portal-like structures towards the left of the ield containing small vessels and a few ductules are also present. Although the term “telangiectatic focal nodular hyperplasia” has often been applied to this type of tumor, in fact molecular studies have shown these tumors to be liver cell adenomas.

adenoma should not lead the pathologist to errantly diagnose hepatocellular carcinoma. A re-biopsy with more ample tissue to assess would be the appropriate next step. 5. Lysozyme: Kupffer cells lining the trabecular cords stain positively.

FIGURE 10-12 Liver cell adenoma. A sclerotic small hepatic artery is present within the outer ibrous capsule of the tumor. Non-tumor liver is present at the left of the ield.

biopsy specimens, the diffuse strong cytoplasmic staining of the tumor cells with HepPar1 and the staining of biliary canaliculi with pCEA conirm the liver cell origin. 2. Glypican-3: This heparin sulfate proteoglycan shows positive both membranous and cytoplasmic staining of tumor cells in the majority of cases of hepatocellular carcinoma, but shows negative staining in liver cell adenomas. 3. Proliferative cell nuclear antigen (PCNA), Ki-67: These stains are helpful in differentiating liver cell adenomas from well-differentiated hepatocellular carcinomas. PCNA and Ki-67 stain the nuclei in many tumor cells in hepatocellular carcinoma, but show very little staining or are negative with liver cell adenomas. 4. CD34: The CD34, which stains activated endothelial cells, shows diffuse positive staining in hepatocellular carcinoma but is negative or shows only focal staining in liver cell adenomas. Of importance in the use of this stain is that if the biopsy only includes a very small segment of an otherwise larger tumor, positive endothelial staining in this tumor that otherwise meets the criteria for a liver cell

Aspiration cytology 1. Tumor cells are generally but not always larger than normal hepatocytes, with the cytoplasm eosinophilic to hydropic. 2. A normal nuclear:cytoplasmic ratio is seen. 3. The nuclei are relatively small with uniform nuclear chromatin. 4. Nucleoli are not prominent. 5. Mitoses are exceptionally rare, and cytoplasmic inclusion bodies (with the exception of Mallory bodies) are absent. 6. Nuclear pleomorphism may rarely be seen in the dysplastic tumor nodules, but are usually associated with abundant cytoplasm (normal nuclear:cytoplasmic ratio). Differential diagnosis 1. Well-differentiated hepatocellular carcinoma: Liver cell adenomas and well-differentiated hepatocellular carcinomas may morphologically appear quite similar, especially in needle biopsy specimens or ine needle aspirates. Table 10-1 compares the histologic features of the two liver tumors. 2. Focal nodular hyperplasia: This more common benign hepatic lesion, with ductules and ibrous septa radiating from a centrally placed scar, is grossly and morphologically quite distinctive; however, areas away from the scar appear similar to liver cell adenomas. Additionally, secondary scars can form in liver cell adenomas due to intra-tumor hemorrhage. Comparison of the two lesions is present in Table 10-2. 3. Nodular regenerative hyperplasia (NRH): This entity consists of a liver with multiple small well-delineated white nodules ≤1 cm in diameter which morphologically resemble liver cell adenoma as well as regenerative nodules seen

Chapter 10 / Neoplasms and Related Lesions

A

253

B

FIGURE 10-14 Liver cell adenoma with transformation to hepatocellular carcinoma. A, The tumor is composed of variably sized irregular bulging tan-yellow lesions, with one nodule exhibiting acute hemorrhage. A ibrous pseudocapsule can be seen surrounding much of the tumor. B, This low-power image from a tissue section taken from the same liver shows iniltration of the tumor into the adjacent non-tumor liver, this invasion one of the features of the malignant transformation of the adenoma.

TABLE 10-1

FIGURE 10-15 Liver cell adenoma with transformation to hepatocellular carcinoma. The parenchyma shows the presence of thickened hepatic cords characteristic of well-differentiated hepatocellular carcinoma. Overtly benign tumor was also present elsewhere in the same lesion, this then being an example of focal malignant transformation.

in cirrhosis. This lesion has been described in Felty’s syndrome, congestive heart failure, subacute bacterial endocarditis, and is not uncommon after liver transplantation. Portal hypertension may also be associated when NRH is present. Although liver cell adenomas at times may be multiple (adenomatosis), seldom are numerous small 55% of lesions

Angiography

Looping centripetal blood low; hypervascular or hypovascular

Centrifugal blood low; hypervascular with dense capillary blushing

Computed tomography (CT)

Absence of scar

Stellate central scar, hypodense arterial phase, then hyperdense

Magnetic resonance imaging (MRI)

Hemorrhage seen as hyperintense areas on T1- and T2-weighted images; hypointense foci corresponding to hyperintense areas on T2 represent necrosis; no accumulation of gadolinium contrast

Homogeneously hypervascular after intravenous gadolinium, with a hypointense central area

RADIOLOGY

*May rarely see small foci of ductules associated with sinusoidal dilatation (“telangiectatic” type).

4. On laboratory tests slight elevation of serum aminotransferases is seen in 50% of cases, and less than 20% have elevated alkaline phosphatase values. Importantly, the α-fetoprotein is not elevated. 5. The tumors tend to occur several years after ingesting the contraceptives mestranol or ethinyl estradiol, the risk markedly increasing after 5 years. 6. Classiication of the etiology is as follows: a. Estrogenic origin: oral contraceptives, steroid therapy (vast majority of cases). b. Androgenic origin. c. Spontaneous. d. Associated with other conditions: Glycogen storage disease type 1A, galactosemia, tyrosinemia, diabetes mellitus, hemosiderosis.

7. Androgenic-related tumors are seen in association with 17α-alkylated compounds used in the treatment of Fanconi’s anemia. 8. The spontaneous type occurs at any age, the incidence equal for men and women. 9. Gross features of resected tumors often aid in the diagnosis: a. Usually solitary (80% of case) ranging from 5 to 20 cm in diameter, but can at times be multiple (adenomatosis). b. Well-circumscribed and encapsulated (75% of cases). c. Yellow-brown to red in areas of hemorrhage and pelioid changes. d. Predominance in the right lobe. e. Located just beneath Glisson’s capsule, with a thin rim of normal liver separating the capsule from the tumor. 10. During pregnancy, the incidence of hemorrhage and necrosis is markedly increased in adenomas related to oral contraceptives. 11. Regression of lesions may occur upon discontinuance of oral contraceptives. Spontaneous regression may also occur. 12. An adenoma can rarely progress to hepatocellular carcinoma; however, this malignancy is observed more frequently in adolescents with untreated glycogen storage disease type 1A. In addition, capsular invasion is the determining factor in diagnosis. Of importance is that vascular and lymphatic invasion and metastases are not reported features. Treatment and prognosis 1. Withdrawal of oral contraceptives is indicated, with close follow-up using scanning modalities to assess regression. 2. In asymptomatic cases, the decision to surgically resect depends on the size and location of the tumor. The rare possibility of progression to hepatocellular carcinoma also favors resection. 3. Surgery is the treatment of choice for symptomatic tumors. Rupture and intraperitoneal hemorrhage are likely with large tumors, and even hepatic lobectomy should be considered. Hepatic artery ligation or embolization may be performed in large unresectable hemorrhagic tumors. 4. Prognosis is excellent when resection is complete.

Bile Duct Adenoma (Peribiliary Gland Hamartoma) (Figs. 10-16 through 10-19) Major morphologic features 1. Proliferation of well-differentiated cytologically benign bile ducts is present within a thin ibroconnective tissue stroma, the lesion sharply demarcated from the adjacent hepatic parenchyma. Other features 1. The duct structures show small nuclei without nucleoli, and form one cell thick tubules as well as glandular and acinar structures, all having a basement membrane and exhibiting variable degrees of dilatation and branching.

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255

FIGURE 10-18 Bile duct adenoma. In this example the glands are more compacted but are cytologically benign. (Courtesy Milton Kiyabu, Lancaster, CA.) FIGURE 10-16 Bile duct adenoma. This low-power image demonstrates a well-demarcated subcapsular lesion composed of many small glands.

FIGURE 10-19 Bile duct adenoma. The border of the tumor and nonFIGURE 10-17 Bile duct adenoma. High power shows well-differentiated glands with a mild interstitial ibrosis.

2. A mild lymphocytic iniltrate with occasional but rare neutrophils may be seen within the ibroconnective stroma, and is most characteristically present at the border of the lesion. 3. A ibrous capsule is not present. 4. Small portal tracts are sometimes present within the bile duct adenoma, with the interlobular bile duct component of these portal structures slightly smaller than the tumor ductular cells. 5. In rare instances the epithelium and lumen of the glands may contain mucin. 6. Microcalciications and epithelioid granulomas have been described. Special stains 1. Masson trichrome: This stain conirms the presence of interstitial collagen. 2. Mucicarmine, Alcian blue: The presence of mucin within the glandular epithelium can be conirmed.

tumor liver demonstrates a lymphocytic iniltrate, a common feature in these lesions compared to its absence in cholangiocarcinoma.

Immunohistochemistry 1. AE1/AE3, CK7, CK19, Epithelial membrane antigen (EMA): These stains conirm the epithelial nature of the glands. Differential diagnosis 1. Well-differentiated cholangiocarcinoma, metastatic adenocarcinoma: Both of these lesions when small may in some ways resemble bile duct adenomas. Table 10-3 compares the various features distinguishing between these different hepatic tumors. 2. Biliary microhamartoma (von Meyenburg complex): These structures consist of moderately dilated and in part branching ductules, the lumen often containing bile, and are usually located within portal tracts, these features not present in bile duct adenomas. These complexes may be multiple, and unlike adenomas are often associated with ibrocystic liver diseases (e.g., choledochal cyst, Caroli disease, polycystic disease, congenital hepatic ibrosis).

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TABLE 10-3

Bile Duct Adenoma versus Cholangiocarcinoma and Metastatic Adenocarcinoma BILE DUCT ADENOMA

CHOLANGIOCARCINOMA

METASTATIC ADENOCARCINOMA

Tumor size, number

1–10 mm, rarely up to 2 cm, usually solitary

Greater than 2 cm, solitary or multiple

Usually >2 cm, most often multiple

Growth pattern

Noninvasive

Invasion into hepatic trabeculae and sinusoids

Invasion into sinusoids

Compression of adjacent liver

Infrequent

Often

Often

Necrosis

No

Occasional

Often

Fibrous stroma

Variable

Abundant

Variable

Pleomorphism of nuclei, cytoplasm; increase in mitoses

Absent

Present

Present

Centrally placed portal tracts

Occasional

Extremely rare

Absent

Clinical and biologic behavior 1. Also termed peribiliary gland hamartoma, bile duct adenomas are rare (seen in 6 out of 97,000 consecutive autopsies in series at the University of South California [USC]) asymptomatic irm gray-white lesions found incidentally at surgery or autopsy. 2. The tumor is present slightly more frequently in women and is seen in all age groups. 3. The lesions are usually solitary (83% of cases), well demarcated, and present immediately beneath Glisson’s capsule (95%). The size ranges from 1 to 10 mm (93%), rarely up to 2 cm in diameter. 4. The tumor follows a benign course. Although there are rare case reports of malignant transformation, it is possible that the original small lesions were well-differentiated cholangiocarcinomas rather than bile duct adenomas. The small lesions rarely exhibit enough atypia for concern, especially since in virtually all surgical cases the entire lesion had been resected. 5. Bile duct adenomas may represent a reactive process to focal hepatic injury or could represent a developmental anomaly rather than a true neoplasm.

FIGURE 10-20 Hepatobiliary cystadenoma. The tumor is composed of a multiloculated cyst, some of the locules empty with others showing papillary projections. (From Ishak KG, et al. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

Treatment and prognosis 1. If the diagnosis is established by an adequate ultrasound or computed tomography (CT)-guided needle biopsy, no treatment is necessary. If malignancy cannot be excluded in larger lesions, surgical resection may be indicated.

Hepatobiliary Cystadenoma (Figs. 10-20 through 10-24) Major morphologic changes 1. The multiloculated cyst is characterized by: a. A lining of columnar, cuboidal to lattened nonciliated epithelial cells. b. A middle layer of cellular spindle cells (mesenchymal stroma), sometimes associated with adjacent intermixed smooth muscle, fat, scattered lymphocytes and neutrophils, small vessels, and neural elements (seen in more than 75% of cases and only in females). c. An outer layer of dense collagen, this layer sharply delineating the cyst from the adjacent hepatic parenchyma.

FIGURE 10-21 Hepatobiliary cystadenoma. This low-power image demonstrates a well-demarcated cyst with inner projection of the wall and septum formation, causing the multiloculation seen on gross inspection and imaging.

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A

257

B

FIGURE 10-22 Hepatobiliary cystadenoma. A, The cyst wall is lined by single-layered cuboidal duct epithelium. Immediately adjacent to the epithelium are highly cellular spindle-shaped cells (mesenchymal stroma). B, The cyst lining in this example shows benign duct epithelium but with absence of an underlying stromal component.

8. Dysplastic epithelium may be seen, with malignant transformation to biliary cystadenocarcinoma in the mucinous tumors occurring as a known complication. Special stains 1. Mucicarmine, alcian blue: These stains confirm the presence of mucin in the epithelial cells and cyst contents. 2. Von Kossa: The microcalciications can be highlighted.

FIGURE 10-23 Hepatobiliary cystadenoma. Dense calciication is seen along the cyst wall.

Other features 1. The cells comprising the epithelial lining are usually mucinous in type but may be serous, and are sometimes sloughed from the cyst wall. 2. The lining may be smooth or exhibit undulations of the wall, with polypoid projections or infoldings of the epithelial lining into the underlying stroma. 3. Focal intestinal metaplasia of the cyst epithelial wall may occur. 4. Stromal hemorrhage, foamy histiocytes, and cholesterol clefts may be seen within the cyst wall in instances of cyst rupture. 5. Microcalciications may sometimes occur. 6. The adjacent liver may show atrophic hepatic cords with sinusoidal dilatation due to obstruction of the vascular outlow by the cyst. 7. Cholestasis can be seen due to biliary tract obstruction from larger cysts or cysts that originate from the large intrahepatic ducts.

Immunohistochemistry 1. CK7, CK19, AE1/AE3, CA 19-9: The cyst lining stains strongly positive, conirming the ductal nature. 2. Chromogranin: Positive staining of the epithelial cells can be seen in approximately 10% of cases. 3. Muscle-speciic actin, vimentin: Positive staining with these two antibodies is seen within the stromal component. Aspiration cytology 1. The cysts contain mucinous and rarely serous gelatinous luid with benign columnar to cuboidal mucin-secreting epithelial cells. 2. Nuclear atypia and proliferation of papillary projections suggests possible malignancy. Differential diagnosis 1. Simple and multiple cysts: These cystic lesions are lined by simple cuboidal or columnar duct epithelium and surrounded by ibroconnective tissue without an associated spindle-shaped mesenchymal stroma. In addition, these simple cysts are unilocular, while cystadenomas are multiloculated. 2. Intrahepatic biliary ectasia and cyst formation (Caroli disease): Although ducts can be markedly ectatic and cystic in Caroli disease, the multifocality of the duct lesions, the prominent cholestasis, and the characteristic imaging seen on endoscopic retrograde cholangiopancreatography (ERCP) in Caroli disease helps in the diagnosis. 3. Ecchinococcal (hydatid) cysts: These lesions are also multilocular and may exhibit calciications on imaging; however,

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A

B

FIGURE 10-24 Hepatobiliary cystadenoma with malignant transformation. A and B, Progression to a well-differentiated cholangiocarcinoma may occur in these cysts and is seen in these two examples.

inspection of the cyst demonstrates a characteristic laminated hyalinized capsule with an inner germinal membrane and daughter cysts containing Echinococcus protoscolices. 4. Biliary cystadenocarcinoma: These malignant tumors arise from choledochal cysts and from malignant transformation of the cystadenomas. This neoplasm exhibits a papillary growth into the cyst lumen, with direct iniltration into the adjacent hepatic stroma. Clinical and biologic behavior 1. Cystadenomas are benign intrahepatic multiloculated cystic tumors categorized as with (CMS) or without (COMS) mesenchymal stroma. 2. The vast majority of patients (96%) are females, usually white (89%), with the disease occurring at any age (average 45 years). 3. Over 50% of the patients present with an abdominal mass and/or abdominal pain. 4. Laboratory tests are nonspeciic, with occasionally mildly elevated aminotransferases. Serum alkaline phosphatase and bilirubin may become elevated with large lesions obstructing the biliary tract. 5. Typical gross indings show the tumor to be multilocular, ranging in size from 2.5 to 28 cm in diameter. The lesions are seen slightly more frequently in the left lobe, and rarely have been seen in the extrahepatic biliary tree. The cyst inner lining is smooth to trabeculated, with the cyst contents usually clear or opalescent. 6. Malignant transformation, characterized grossly by solid inner protruding masses, may occur in up to onequarter of the cases of CMS, some tumors exhibiting transition zones between the benign and malignant regions. Treatment and prognosis 1. Surgical resection when complete is curative. 2. In large nonresectable tumors, marsupialization can be performed. 3. Involvement of large intrahepatic or extrahepatic ducts may make surgical resection dificult. Relief of obstruction with stenting (endoscopic, surgical) may then be offered.

FIGURE 10-25 Cavernous hemangioma. The well demarcated subcapsular lesion shows variable degrees of ibrosis intermixed with abundant red blood cells.

Mesenchymal Benign Tumors Vascular Benign Tumors Cavernous hemangioma (Figs. 10-25 through 10-29) Major morphologic features 1. Large dilated communicating blood-illed spaces lined by single layered endothelial cells are characteristic. 2. Relatively thick and hypocellular ibrous septa between the vascular channels are present. Other features 1. The lesion is well-demarcated from the adjacent liver, and is often located immediately beneath Glisson’s capsule. 2. Large “feeding” vessels may be present at the edges of the lesion.

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259

FIGURE 10-26 Cavernous hemangioma. This low-power image demonstrates a hemangioma with a central ibrous scar and numerous peripheral dilated and congested vascular channels.

FIGURE 10-27 Cavernous hemangioma. Numerous dilated congested vascular spaces are seen. A small portal tract with a lymphocytic iniltrate is seen in the adjacent non-tumor liver at a corner of the ield.

A

B

FIGURE 10-28 Cavernous hemangioma. A and B, These two images demonstrate the relatively loose nature of the collagen comprising the ibrous bands between the vascular channels. Endothelial cells can be seen lining these vascular spaces.

A

B

FIGURE 10-29 Cavernous hemangioma. A, The ibrous bands can at times be quite thick with the vascular spaces small and irregular. B, With time the vascular tumor can undergo total sclerosis, sometimes exhibiting focal areas of calciication.

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3. Large thick walled vessels may be seen between the vascular spaces, representing hepatic venous outlow. Thrombosis of these vessels may lead to coagulative ischemic necrosis and ibrin deposition within the vascular spaces; resultant ibrous obliteration of these spaces with central ibrous scarring can then eventually be seen. 4. Older lesions may exhibit hyalinization of the septa with remnants of the obliterated spaces; foci of calciication can also occur.

4. 5.

Immunohistochemistry 1. Factor VII-related antigen, CD31, CD34: Endothelial cells are conirmed by positive cytoplasmic staining with these markers. Aspiration cytology 1. Aspiration reveals considerable blood, benign spindle (endothelial) cells, ibroconnective tissue with minimal to absent inlammatory iniltration, and rare calcium deposits. Note: Although aspiration generally is contraindicated, the lesion may not be suspected when it is partially or totally sclerotic and is then sometimes confused with a primary or metastatic solid tumor. Differential diagnosis 1. Angiosarcoma: Angiosarcoma may present as a solitary lesion. The majority of these patients are ill, while patients with cavernous hemangiomas are generally asymptomatic or may have only mild or vague abdominal pain or back discomfort. Biopsies are generally not recommended in either lesion due to the risk of hemorrhage. Thin needle aspiration may be performed, with demonstration of overtly malignant endothelial cells in angiosarcoma. 2. Peliosis hepatis: These lesions are multiple, quite small (from less than 1 mm to 1 cm in diameter, very rarely larger), illed with blood, but do not exhibit septa, and usually do not have lining of the vascular spaces by endothelial cells. 3. Infantile hemangioendothelioma: This morphologically benign vascular neoplasm is predominantly capillary in nature and is not seen in adults. 4. Angiomyolipoma: These lesions may be small incidental indings, or larger (up to 20 cm in diameter), and are sometimes associated with renal angiomyolipomas. The tumor itself is composed of a mixture of benign vascular spaces, smooth muscle, fat, and hematopoietic elements, and is therefore distinctly different from cavernous hemangiomas. Clinical and biologic behavior 1. Cavernous hemangioma is the most common benign hepatic neoplasm, its overall incidence ranging from 0.4% to 19.0% (1% from USC experience of 91,000 consecutive autopsies). It is also the most common site for hemangioma formation in the abdomen. 2. There is a female predominance (6:1) in patients under 40. Hormonal stimulation plays a role in their development, as the lesions may enlarge during pregnancy, with hemangiomas also forming in the skin and gingiva. In the elderly, the lesion is more common in men (2:1). 3. The vast majority of patients are asymptomatic, the lesion in these instances usually less than 4 cm in diameter.

6.

7.

8.

Symptomatic hemangiomas present with abdominal discomfort or back pain, and sometimes pain due to compression of adjacent viscera. Sudden pain is usually secondary to the rare occurrence of tumor thrombosis or spontaneous rupture and hemorrhage into the abdominal cavity (larger lesions). Liver tests are usually normal. Ninety percent are solitary, the majority under 5 cm in diameter (may even be a few millimeters), but multiple lesions in both the right and left lobes may often occur. Although usually the location is immediately beneath Glisson’s capsule, they may occur anywhere within the parenchyma. Exceptionally large tumors may also be seen, ranging from 10 to 30 cm in diameter (“giant” hemangiomas); however, malignant transformation to angiosarcoma does not occur. The tumors are usually red to red purple, with dilated “cavernous” vascular features. The older lesions often become gray-white and irm due to ibrosis which begins centrally. Involution may occur, and focal calciication may become apparent on radiographs. The neonate with this lesion may develop severe complications of heart failure secondary to arteriovenous shunting, as well as rupture and coagulopathy, and must therefore be promptly diagnosed and treated. Rarely hemangiomas with shunting has been reported in adults. The diagnosis is made in typical large lesions by ultrasound where the lesions are hyperechoic, the CT scan shows a corresponding low-density lesion with delayed peripheral contrast enhancement, and the T-2 weighted image on magnetic resonance imaging (MRI) demonstrates a bright signal referred to as the “light bulb” sign. Smaller lesions or those with thrombosis or ibrosis may not demonstrate these features.

Treatment and prognosis 1. The majority of lesions are asymptomatic and incidentally discovered on ultrasound or CT scans performed for workup of other disorders, or incidentally seen at surgery. No treatment is necessary for these small lesions. 2. Although larger lesions are at risk of spontaneous rupture, this is extremely rare and surgery is not usually required. Large symptomatic lesions should be considered for resection if surgically accessible. Rarely, liver transplantation has been performed where the liver is virtually replaced by the hemangioma. 3. When the lesion is nonresectable due to location, size, and number, radiation therapy has been tried but is not generally recommended. 4. Overall the prognosis is excellent, with no treatment in the vast majority of cases. The prognosis is also excellent in cases necessitating resection, without recurrence over long-term follow-up. Infantile hemangioendothelioma (Figs. 10-30 through 10-33) Major morphologic features 1. Numerous small intercommunicating vascular channels lined by a single layer of cytologically benign lattened to plump endothelial cells are present.

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Other features 1. The center of the lesions may have cavernous spaces in the majority of cases, sometimes with thrombosis, infarction, and variable ibrosis. The periphery of these lesions may also exhibit some degree of these cavernous changes, although the more typical small vascular spaces are usually seen. 2. The tumor periphery is usually well-demarcated, although vascular sinusoidal extension into the adjacent parenchyma encircling entrapped hepatocytes occurs in a minority of cases. 3. Small bile ductules are often scattered and entrapped throughout the tumor. 4. Extramedullary hematopoiesis is often seen. 5. Myxoid changes and microcalciications have also been described. Special stains 1. Reticulin: This stain highlights the proliferating vascular structures.

FIGURE 10-30 Infantile hemangioendothelioma. The tumor crosssection is mottled yellow-red to tan, with focal areas of calciications. (From Ishak KG, et al. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

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Immunohistochemistry 1. Factor VIII–related antigen, CD31, CD34: Endothelial cells are conirmed by positive cytoplasmic staining with these markers. Aspiration cytology 1. Aspiration is contraindicated due to possible bleeding; however, in unsuspected lesions the presence of abundant red blood cells and numerous cytologically benign endothelial cells in an infant is suggestive of the diagnosis. Differential diagnosis 1. Cavernous hemangioma: Both lesions may have virtually identical cavernous changes, but the peripherally located capillary vascular spaces seen in infantile hemangioendotheliomas are not features of cavernous hemangiomas. 2. Angiosarcoma: Iniltration of endothelial cells within sinusoids at the periphery of the lesion can be a worrisome feature of infantile hemangioendothelioma, as this type of growth pattern characteristically occurs in angiosarcoma. The endothelial cells in infantile hemangioendothelioma are cytologically bland and single layered, while the endothelial cells in angiosarcoma are pleomorphic and oftentimes multilayered. Note: Previously there were two subdivisions of infantile hemangioendotheliomas. The type 1 lesion was that described above, while the type 2 lesion exhibited pleomorphic multilayered cells with papillary projections, solid growth patterns, and mitoses. This latter pattern is now considered an angiosarcoma. Of note is that malignant transformation of infantile hemangioendothelioma to angiosarcoma has been reported. Clinical and biologic behavior 1. Infantile hemangioendotheliomas resemble the capillary hemangiomas seen in the skin, and represents 12% of all primary hepatic neoplasms in the infant. 2. The tumors are twice as common in females. Approximately 50% are discovered incidentally at surgery or autopsy.

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FIGURE 10-31 Infantile hemangioendothelioma. A and B,These medium- and high-power images demonstrate numerous small vascular channels lined by plump endothelial cells.

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FIGURE 10-34 Angiomyolipoma. Two tumor nodules are well-cirFIGURE 10-32 Infantile hemangioendothelioma. The vascular spaces here are dilated and overall have a cavernous-type appearance.

cumscribed and uniformly light yellow. (From Ishak KG, et al. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

3. Mortality may be up to 70% due to high-output heart failure, although a recent series suggests a lower mortality. Other complications include hepatic failure and hemorrhage. 4. Liver transplantation is an option if liver failure develops.

Angiomyolipoma (Figs. 10-34 through 10-36) Major morphologic features 1. A mixture of benign thick-walled tortuous vascular spaces, capillaries, smooth muscle, fat and hematopoietic elements are characteristic. FIGURE 10-33 Infantile hemangioendothelioma. In some areas a loose ibroconnective stroma can be seen between the vascular spaces, resembling a cavernous hemangioma.

3. Symptomatic patients present during the irst 6 months of life with hepatomegaly and often with an abdominal mass. Approximately 25% have severe high-outlow congestive heart failure (arteriovenous hepatic shunting). Cutaneous hemangiomas are present in 19% to 87% of these cases as well. 4. The tumor mass may be solitary or consist of multiple red-purple nodules involving both lobes. The nodules may appear gray in areas of ibrosis. 5. Spontaneous involution is common; however, malignant transformation with metastasis has been described. Treatment and prognosis 1. When the tumor is solitary, or when multiple but conined to a focal hepatic segment, surgical resection is recommended, as probability of cure is very high. 2. Hepatic artery ligation and radiation are considered for large nonresectable lesions.

Other features 1. The smooth muscle elements may be spindle-shaped or have a plump “epithelioid”-type appearance, with the cytoplasm usually eosinophilic but sometimes partially clear. 2. A trabecular growth pattern may also at times be present. 3. Pleomorphic cells having large nuclei with prominent nucleoli and abundant clear cytoplasm may occur. 4. Melanin pigment within the smooth muscle cells can at times be present. 5. Foamy histiocytes can be present and contain abundant fat. 6. Microcalciications may be seen. Special stains 1. Periodic-acid Schiff (PAS): Positive staining for glycogen (best seen on frozen sections of fresh or formalin-ixed material) can be appreciated within the cytoplasm of the epithelioid-type cellular component. 2. Oil Red O: On frozen section specimens the foamy histiocytes demonstrate the presence of neutral triglycerides. 3. Fontana: This stain conirms that the pigment within the tumor cells represents melanin. 4. Von Kossa: The microcalciications can be highlighted.

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FIGURE 10-35 Angiomyolipoma. These (A) medium- and (B) high-power images demonstrate numerous plump eosinophilic smooth muscle cells with interposed fat and scattered small vessels.

Clinical and biologic behavior 1. This rare benign tumor is usually seen in the adult population (age range from 24 to 70 years) with no sex predilection. 2. The majority present with abdominal discomfort, fever, and an abdominal mass. Liver tests are usually normal, and there are no serum tumor markers. 3. The tumor usually presents as a single mass, occurs most often in the right lobe, and varies in size from less than 1 cm to >20 cm in diameter (“giant angiomyolipoma”). 4. Imaging studies show a hyperechoic lesion on ultrasound, with a hypervascular component on angiographic studies. 5. Malignant transformation does not occur. FIGURE 10-36 Angiomyolipoma. Calciications within the tumor are seen.

Immunoperoxidase 1. Smooth muscle actin, HMB-45, vimentin: Positive focal staining can be seen in the smooth muscle cells. Differential diagnosis 1. Primary spindle cell neoplasms (e.g., leiomyoma, ibroma, leiomyosarcoma, ibrosarcoma). The spindle cell nature of the angiomyolipoma can on small biopsy material hint at the diagnosis of a well-differentiated either benign or malignant spindle cell tumor. A helpful clue is that the smooth muscle cells in angiomylolipomas stain positively for HMB-45, while the spindle cells in leiomyomas and leiomyosarcomas do not stain. Observation of other features such as plump epithelioid cells, fat and small vessels leads to the correct diagnosis. The absence of mitotic activity also distinguishes an angiomyolipoma from a malignant process. 2. Hepatocellular carcinoma: The uncommon spindle cell variant of hepatocellular carcinoma can be suspected when large pleomorphic smooth muscle cells predominate on biopsy specimens. Absence of staining for cytoplasmic polyclonal CEA along with the presence of staining for smooth muscle actin supports the diagnosis of angiomyolipoma.

Treatment and prognosis 1. Resection of the lesion is considered when the tumor is large and symptomatic.

Mesenchymal Hamartoma (Figs. 10-37 through 10-40) Major morphologic features 1. Random and disorganized arrangements of loose often stellate myxoid mesenchyme that contains variable numbers of bile ducts, hepatocytes, clusters of thin-walled vessels, and variable-sized cysts usually with no deinite lining are present. Other features 1. The ducts may at times be surrounded by either a loose myxoid stroma or dense collagen ibers and have atypical or distorted features. 2. Although usually the cysts show no deinite epithelial lining, in the older patient population cuboidal epithelium lining the cysts has been seen. 3. Extramedullary hematopoiesis may be seen in most cases and most often occurs towards the periphery of the lesions.

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FIGURE 10-39 Mesenchymal hamartoma. Numerous small vascular and cystic spaces are seen intermixed with a mild lymphocytic iniltrate. A few scattered ductules are present as well.

FIGURE 10-37 Mesenchymal hamartoma. The tumor is large, taking up the entire right lobe, and is composed of red-brown soft tissue containing variably sized hemorrhagic cysts.

FIGURE 10-40 Mesenchymal hamartoma. Bile ductules are seen within a ibroconnective tissue matrix adjacent to a large cyst.

hemangioendotheliomas when compared to mesenchymal hamartomas. FIGURE 10-38 Mesenchymal hamartoma. The stromal matrix has a myxoid appearance with stellate-type cells and scattered benign ducts.

4. Variable numbers of lymphocytes and plasma cells may be seen within the tumor matrix. 5. “Satellite” lesions may occur and are secondary to extension and growth of the vascular mesenchyme that compresses the intervening hepatic lobules, causing secondary liver cell atrophy. Differential diagnosis 1. Infantile hemangioendothelioma: The infantile hemangioendothelioma is also composed of numerous small vessels, sometimes with a myxoid stroma; however, the cystic structures seen in mesenchymal hamartomas are not components of these hemangioendotheliomas. In addition, the bile ductules are much less prominent in the infantile

Clinical and biologic behavior 1. These benign mesenchymal tumors occur most often within the irst few years of life, with up to 75% by 2 years of age. Rarely case reports have been described of these tumors in the elderly, however. 2. These tumors occur slightly more frequently in males. 3. The patients often clinically present with an enlarging non-tender abdomen that may rapidly increase in size. Although usually the patient is asymptomatic, respiratory distress and congestive heart failure have been reported. 4. The lesions are seen as both multicystic and solid on ultrasound, CT scans, and MRI, with variations in size of the septa often present. 5. The tumors occur usually in the right lobe, and in a minority of cases may be pedunculated. They range in size from a few centimeters to up to 30 cm in greatest dimension and contain in over 85% of cases cysts that vary from pinpoint to up to 21 cm in diameter, the cysts

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FIGURE 10-41 Chondroma. These (A) low- and (B) high-power images show a well-demarcated tumor composed of mature cartilage. Viableappearing chondrocytes are noted best on the higher power. (Courtesy Charles Alpers and the late Rodger Haggitt, University of Washington Medical Center, Seattle, WA, and John Craig, Pasadena, CA.)

containing clear to amber-yellow luid or gelatinous substances. The cysts may have a smooth or sometimes ragged lining. Hemorrhage and necrosis may rarely occur. Treatment and prognosis 1. Surgical resection is indicated, although the large size and location of the tumors may make resection sometimes dificult. Partial resection and drainage may then be an option. 2. The overall survival rate is quite good (approximately 90%), with mortality and morbidity usually related to postoperative complications.

Rare Benign Mesenchymal Tumors Chondroma (Fig. 10-41) 1. Chondroma is a very rare tumor, with only one case report in the literature (demonstrated in these accompanying images). 2. The tumor that was described occurred in a 44-yearold woman, was multilobulated, and took up almost the entire right lobe, measuring 16 cm in greatest dimension. 3. Microscopically the lesion was well demarcated from the adjacent liver parenchyma and was composed of mature cartilaginous tissue with scattered viable chondrocyte-type cells, without an accompanying inlammatory component. 4. In the case report, the patient had a history of a mixed parotid gland tumor, and the possibility of the hepatic lesion representing a metastatic lesion was unlikely but could not be entirely excluded. Lipoma (Fig. 10-42) 1. Hepatic lipomas are very rare lesions that usually occur in middle-aged males and are found incidentally. 2. Approximately 10% of patients with renal angiomyolipomas may also have these hepatic lesions (either lipoma or angiomyolipoma).

FIGURE 10-42 Lipoma. The well-demarcated tumor is composed entirely of mature fat.

3. The tumors more often involve the right lobe and are usually solitary and well-circumscribed round to oval yellow to yellow-tan lesions. 4. The tumors are usually nonencapsulated and range in size from 1 to 20 cm in greatest dimension. 5. Microscopically the tumor is composed entirely of mature fat, sometimes associated with calciications and rarely ossiications. Tumor necrosis can also occur at times. 6. The etiology is not clear; however, many feel that the lesions may not be true neoplasms but instead are secondary to adhesions of colonic appendix epiploic to the hepatic surface (“pseudolipoma”). Lymphangioma (Fig. 10-43) 1. This uncommon benign tumor may occur at any age, is twice as common in females, and often involves multiple organ systems including the kidneys, spleen, lymph nodes, and bone.

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FIGURE 10-43 Lymphangioma. Numerous dilated lymphatic spaces containing an amorphous acellular eosinophilic material representing lymph are seen. (Courtesy John Craig, Pasadena, CA.)

2. The tumor is seen more often in females and presents as an abdominal mass. 3. Associated conditions include anencephaly, trisomy 13, and ovarian teratomas. 4. The tumor may be quite large (up to 20 cm in greatest dimension), may occur in either lobe, and varies from soft to irm and cystic. 5. Microscopically all three germ cell line components are present, and most often include gastrointestinal mucosa, smooth muscle, respiratory epithelium with cartilage, fat, bone, and nerve elements. Less frequently pancreatic tissue, teeth and hair have been reported. 6. In some cases, part of the tumor has features of hepatoblastoma, whereby the lesion is then termed “teratoid hepatoblastoma.” 7. Resection is often curative, although high mortality and morbidity may occur with the larger tumors. 8. The pathogenesis is not certain, although origin from ectopic primordial germ cells is proposed.

PRIMARY NEOPLASMS, MALIGNANT 2. Patients can be asymptomatic or present with an enlarged liver and spleen with abdominal swelling. Symptoms related to organ compression from the tumor may also occur. Imaging shows a hypodense lesion in the liver, and sometimes lytic bone lesions occur. 3. The tumor on gross inspection shows a multicystic mass, the cysts containing clear, proteinaceous or chylous luid. The tumors can be solitary or multiple. Diffuse involvement of the liver (lymphangiomatosis) has also been reported. 4. Microscopically, variably-sized cyst-like (lymphatic) spaces are seen that are illed with an amorphous acellular eosinophilic material representing lymph. These cystic spaces are lined by a single layer of lattened cells that are conirmed as endothelium by positive immunoperoxidase staining for the endothelial markers CD31 and CD34. The cystic lymphatic spaces can be associated with atrophy of the adjacent hepatocytes due to compression. Rarely papillary projections have been reported. The dilated lymphatic channels can sometimes have an adjacent loose ibroconnective stroma. 5. The differential diagnosis includes mesenchymal hamartoma, which in part shows proliferation of vascular structures; however, the hamartomas also show scattered bile ducts, a feature not seen in lymphangiomas. 6. Treatment relates to symptoms, with a guarded prognosis when other viscera and bone (with fractures) is involved. Tumor resection may be considered when the lesion is localized. One case reported tumor recurrence 19 years after liver transplantation for lymphangiomatosis.

Miscellaneous Benign Tumors Teratoma (Fig. 10-44) 1. Teratomas are rare tumors that most often occur at birth or in very early childhood, although rare cases in the adult have been reported.

Basic Pathophysiologic Concepts Various factors are involved in the oncogenesis and progression of malignant liver tumors, some of which are listed in Table 10-4. A summary of some of the pathophysiologic concepts are listed below: 1. In chronic hepatitis and cirrhosis, the repeated cell division and turnover increases the rate of possible mutations and limits the time frame for chromosomal repair. The inlammation seen in chronic hepatitis can generate reactive oxygen species (e.g., nitric oxide, hydroxy radicals) that have mutagenic effects. 2. Tumor suppressor genes (e.g., p53, pRb) normally arrest cell cycles. In hepatocellular carcinoma, this regulatory process is inhibited, resulting in progressive and uncontrolled cell division. 3. Speciic abnormalities such as allelic deletions and regional chromosomal losses and gains have been detected in malignant hepatic tumors. 4. Telomeres, normally seen at chromosomal ends, are known to shorten over time with increased cell cycles and eventually lead to cell aging, block of cell division, and eventual cell death. It has recently been shown that telomeres are often markedly shorter in tumor cells in mTERC–/– mice as well as in man compared to non-neoplastic tissue. Telomere shortening has also recently been linked to speciic alterations of chromosome 8 in human hepatocellular carcinoma. Human telomerase reverse transcriptase (hTERT]), felt to be essential for telomerase activity and tumor cell growth, is increased in bile duct adenocarcinomas. 5. Aberrant DNA methylation of certain genes (e.g., p16, E-cadherin) can lead to early genetic events in the development of hepatocellular carcinoma. 6. Growth factors such as insulin-like growth factor (IGF-2) and transforming growth factor (TGF-α) can be overexpressed, resulting in uncontrolled cell division. These growth factors can also stimulate the expression of vascular endothelial growth factor (VEGF) which is critical in tumor angiogenesis.

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FIGURE 10-44 Teratoma. These (A) low- and (B) high-power images show mature cartilage, developing osteoid, a cyst lined by ciliated respiratory epithelium, and scattered gastrointestinal glands. (Courtesy John Craig, Pasadena, CA.)

TABLE 10-4

Hepatobiliary Neoplasia: Basic Pathophysiologic Concepts

• Cirrhosis with increased cellular (hepatocytes, ductules) turnover • Chronic inlammation (chronic viral or biliary tract diseases) with generation of cytokines, reactive oxygen species • Tumor suppressor gene (p53 and pRb) inactivation • Telomerase activation • Structural chromosomal alterations (deletions, losses, gains) • Oncogenes (c-myc, c-erbB-2), growth factor overexpression

• Angiogenesis signaling • Aberrant DNA methylation • Speciic hepatotropic virus-related (hepatocellular carcinoma): HBX gene HBV-encoded X antigen (HBxAg) HBV-DNA integration HCV core protein • Bile acids and COX-2 overexpression (cholangiocarcinoma)

7. Recent advances in complementary oligonucleotide microarray proile techniques have shown groups, subgroups, and individual genes (gene signatures) that are associated with hepatocellular carcinoma in cirrhotic patients and hence can identify those patients at higher risk. 8. Various viral markers, such as HBx gene, HBV-encoded X antigen (HBxAg), HBV-DNA integration, and HCV core protein have shown correlations with the development of hepatocellular carcinoma. 9. With cholangiocarcinoma, a major component in tumor development rests upon duct injury, usually by an inlammatory process, with reparative and proliferative changes. Alterations of the balance between damage and repair can lead to malignant transformation by generation of cytokines, which then cause ductules to express the inducible form of nitric oxide synthase (iNOS). Both primary sclerosing cholangitis, a precursor lesion of cholangiocarcinoma, and cholangiocarcinoma itself express iNOS. 10. Cytokines such as interleukin 6 (IL-6) are at high levels in cholangiocarcinoma and enhance tumor growth via a mitogen-activated protein kinase signaling pathway.

FIGURE 10-45 Hepatocellular carcinoma. The liver shows a coarsely nodular cirrhosis secondary to chronic hepatitis HBV infection. The lateral left lobe shows three large bulging tumor lesions with adjacent acute hemorrhage, the nodules representing multifocal hepatocellular carcinoma.

11. Bile acids contribute to the development of cholangiocarcinoma by generating production of the enzyme cyclooxygenase (COX)-2 which can inhibit apoptosis, enhance angiogenesis, and enhance cell proliferation. 12. A number of molecules (e.g., aspartyl-hydroxylase, the receptor tyrosine kinases c-erB-2 and c-met) have been shown to be overexpressed and contribute to the formation of cholangiocarcinoma.

Epithelial Malignant Tumors Hepatocellular Carcinoma Common patterns (trabecular, acinar, ductular) (Figs. 10-45 through 10-79) Major morphologic features 1. The tumor cells have morphologic features of hepatocyte origin and exhibit the following: a. Round to oval and sometimes irregular shaped hyperchromatic nuclei with prominent nucleoli.

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FIGURE 10-46 Hepatocellular carcinoma. This distinct tan-brown tumor mass is located within the lateral left lobe.

FIGURE 10-47 Hepatocellular carcinoma. The single tumor mass located in the right lobe has a central scar and is intensely green due to prominent synthesis of bile by the tumor cells. (From Kanel GC. Liver, gallbladder, and extrahepatic bile ducts. In: Alison MR (ed): The Cancer Handbook, 2nd ed. London: John Wiley & Sons, 2007, with permission.)

FIGURE 10-48 Hepatocellular carcinoma. Both the right and left lobes are replaced by variably sized and variably colored tumor masses.

FIGURE 10-50 Hepatocellular carcinoma. The tumor cells have eosinophilic cytoplasm and increase in the nuclear:cytoplasmic ratio, with the formation of trabecular cords up to six cells thick lined by lattened endothelial cells.

FIGURE 10-49 Hepatocellular carcinoma. Cut section from a micronodular cirrhotic liver secondary to chronic alcoholism shows two tan-gray lesions located within small regenerative nodules and represent hepatocellular carcinoma in situ.

FIGURE 10-51 Hepatocellular carcinoma. High-power shows tumor cells with eosinophilic to clear cytoplasm and round to irregular nuclei with prominent nucleoli, the tumor cells forming trabecular cords ranging from six to more than eight cells thick lined by endothelial cells.

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A FIGURE 10-52 Hepatocellular carcinoma. Thickened hepatic trabeculae are seen in these tumor cells having basophilic cytoplasm. A mitotic igure is noted in a tumor cell towards the left of the ield.

B FIGURE 10-54 Hepatocellular carcinoma. A and B, Both images show the tumor forming pseudoglands, with bile also present within the glandular lumen in B. FIGURE 10-53 Hepatocellular carcinoma. This stain conirms the presence of hepatic cords more than two cells thick, these thickened cords an essential feature of trabecular hepatocellular carcinoma (reticulin stain).

b. Eosinophilic, granular or hydropic cytoplasm with distinct cell borders, the cytoplasm appearing scanty to abundant. c. Increase in the nuclear:cytoplasmic ratio. 2. The tumor cells most commonly form trabecular cords greater than two cells thick, these cords lined by endothelial cells (trabecular variant). Other features 1. The tumor cells and their growth patterns have various characteristics: a. Macrovesicular and microvesicular fat is not uncommon, and intracytoplasmic and intracanalicular bile and rarely lipochrome-like pigment may also be seen. b. Radial acinar and pseudoglandular arrangements of neoplastic hepatocytes may occur around centrally maintained canaliculi (12% of cases), the lumen frequently markedly dilated and containing bile. c. Duct-like structures may be focally present (5% to 10% of cases), often within a ibrous stroma.

FIGURE 10-55 Hepatocellular carcinoma. The slightly thickened hepatic cord towards the center of the ield contains a bile plug. In addition, some of the tumor cells also contain Mallory bodies within the cytoplasm.

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FIGURE 10-56 Hepatocellular carcinoma. A and B, These images show the presence of Mallory bodies within tumor cells, a useful clue for less well differentiated tumors of a hepatocellular origin.

2. 3.

4. FIGURE 10-57 Hepatocellular carcinoma. The tumor is forming trabeculae ranging from 15 to 20 cells thick (macrotrabeculae).

d. Mallory bodies may be seen (4% to 12% of cases), and glycogenated nuclei may rarely occur. e. Papillary projections of the tumor may occur. f. Distinct cytoplasmic eosinophilic inclusions (hyaline globules) and rarely ground glass–like cells composed of proteins normally synthesized in the hepatocytes (α1antitrypsin, α-fetoprotein, ibrinogen, albumin) may be seen. These ground glass cells very rarely may be associated with syntheses of HBsAg (conirmed by immunoperoxidase stain). g. Tumor cells may show considerable compression of the sinusoids and appear as sheets (compact pattern). Additionally, exceptionally thickened trabeculae greater than 10 cells thick may be formed (macrotrabecular pattern). h. Accumulation of eosinophilic secretory material within markedly dilated acinar structures may be seen (adenoid pattern). i. Cords and nests of small- to medium-sized neoplastic hepatocytes surrounded by dense, hyalinized, and relatively avascular collagen may occur (sclerosing or scirrhous pattern).

5. 6.

7.

8. 9.

j. Highly vascularized lesions may show markedly dilated and congested microscopic and in some cases macroscopic hemorrhagic cysts (pelioid pattern). k. In less well-differentiated tumors, the trabecular arrangement may show the tumor plates to be only one cell thick; however, these cells cytologically are malignant, usually with absence of reticulin ibers along the tumor plates. Mitoses are often present and may occasionally be atypical (tri-polar); however, mitoses may be uncommon in well-differentiated tumors. Abundant small vascular channels are often present within the tumor. Larger vessels may exhibit thrombosis, with resultant ischemic necrosis and hemorrhage of the supplied tumor. Larger lesions may exhibit pseudocapsules (compressed adjacent reticulin ibers) or true ibrous capsules. Although an inlammatory component within the tumor is infrequent, at times a lymphocytic and rarely a neutrophilic iniltrate can be seen. The growth of the tumor merges into the adjacent non-neoplastic trabeculae, not sinusoids. Larger lesions tend to bulge into the adjacent liver with resultant compression and atrophy of non-neoplastic hepatocytes, with associated sinusoidal dilatation and congestion. Tumor thrombi may be present in the portal and hepatic venous channels in from one-ifth to one-third of cases in autopsy series, as well as microscopically within lymphatic channels in portal tracts and ibrous septa. Intraarterial and intraductal growth patterns may occur but are infrequent. Extramedullary hematopoiesis, microcalciications (especially in areas of tumor necrosis) and rarely ossiication and epithelioid granuloma formation can occur. Less common variants include: a. Clear cell: The cytoplasm is either hydropic or contains abundant amounts of glycogen, these cells having a cobblestone-like growth pattern. b. Spindle cell: A sarcomatous type of growth is present.

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FIGURE 10-58 Hepatocellular carcinoma. A and B, Both images show tumor cells containing macrovesicular fat. The interstitial ibrosis between the thickened trabeculae is highlighted in the trichrome stain for collagen (B).

FIGURE 10-59 Hepatocellular carcinoma. Numerous lymphocytes

FIGURE 10-60 Hepatocellular carcinoma. All of the tumor cells

surrounding groups of tumor cells are seen. Rare lymphocytes can also be seen iniltrating into the tumor cell cytoplasm itself.

contain distinct cytoplasmic inclusions that resemble the “ground glass” cells seen in chronic viral hepatitis due to HBV infection; however, the inclusions in this example stain negatively for the HBsAg immunoperoxidase marker.

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FIGURE 10-61 Hepatocellular carcinoma. A, The well-differentiated tumor cells have eosinophilic inclusions resembling the “ground glass cells” often seen in chronic HBV infection. B, These same tumor cells exhibit strong cytoplasmic staining for HBsAg by immunoperoxidase stain. Of note is that although the patient did have chronic HBV infection, this staining characteristic of tumor cells is uncommon.

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FIGURE 10-62 Hepatocellular carcinoma. All of the tumor cells have a clear cytoplasm secondary to abundant glycogen deposition (clear cell changes).

FIGURE 10-63 Hepatocellular carcinoma. Some of the tumor cell nuclei are markedly pleomorphic, with the cytoplasm generally clear.

FIGURE 10-64 Hepatocellular carcinoma. The tumor cell in the cen-

FIGURE 10-65 Hepatocellular carcinoma. This low-power image

ter of the ield is multinucleated (giant cell changes).

shows numerous enlarged spaces, some illed with red blood cells (pelioid type).

FIGURE 10-66 Hepatocellular carcinoma. Infrequently epithelioid granulomas can occur in these tumors. Although in some instances a granulomatous hepatitis may be occurring in the adjacent nontumor liver with the tumor secondarily involved, in other examples the granulomas may be conined to the tumor itself.

FIGURE 10-67 Hepatocellular carcinoma. This poorly differentiated tumor shows sheets of small cells with scanty cytoplasm. Positive immunoperoxidase markers are necessary to be sure of the hepatocellular origin of these neoplasms.

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FIGURE 10-68 Hepatocellular carcinoma. New bone formation (osteoid) is seen within the interstitium.

FIGURE 10-71 Hepatocellular carcinoma. In situ hepatocellular carci-

FIGURE 10-69 Hepatocellular carcinoma. The tumor is composed of spindle cells (sarcomatoid type), and can at times be confused with a primary sarcoma. Although not seen in this ield, merging of these spindle cells with thickened hepatic cords was present, a helpful clue in the diagnosis of this variant.

FIGURE 10-72 Hepatocellular carcinoma. Lymphatic invasion is pres-

noma is seen arising from the adjacent nonmalignant hepatic cords.

ent. Note that the tumor forms thickened cords with focal multinucleation.

c. Giant cell: Large multinucleated and often markedly anaplastic tumor cells can occur in small clusters or be diffuse. d. Anaplastic: The tumor cells are pleomorphic and appear in sheets, without any particular differentiation. Note: The neoplasms are often complex, and not infrequently are composed of a mixture of morphologic variants and growth patterns. Cirrhosis is present in 60% to 90% of cases. Additionally, it is not uncommon for the non-tumor liver to exhibit within the regenerative nodules various morphologic characteristics, some of which are preneoplastic (e.g., large and small cell dysplasia, see the discussion of Macroregenerative nodules within this chapter).

FIGURE 10-70 Hepatocellular carcinoma. The thickened trabeculae show focal coagulative necrosis with microcalciications.

Special stains 1. Reticulin: The presence of hepatic cords greater than two cells thick can best be appreciated with this stain. In addition, decrease to absent reticulin staining among the tumor sheets and along single tumor cell plates also supports a diagnosis of hepatocellular carcinoma.

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FIGURE 10-73 Hepatocellular carcinoma. A, A ine needle aspirate of a distinct tumor mass reveals clusters of malignant cells having round nuclei, prominent nucleoli, and scanty cytoplasm. B, The cell block from the same aspirate shows classic hepatocellular carcinoma with thickened cords and intracanalicular bile.

FIGURE 10-74 Hepatocellular carcinoma. Glypican-3, a heparin sulfate proteoglycan, shows strong positive cytoplasmic staining of tumor cells in this example (immunoperoxidase stain for glycipan-3).

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FIGURE 10-75 Hepatocellular carcinoma. The tumor shows strong diffuse cytoplasmic staining for Hep Par 1, a very useful cytoplasmic marker for hepatocellular origin rather than malignancy, as both benign and malignant liver cell tumors stain positively (immunoperoxidase stain for Hep Par 1).

B

FIGURE 10-76 Hepatocellular carcinoma. The polyclonal CEA (pCEA) may stain either the canaliculi (A) or the cytoplasm (B) in hepatocellular carcinoma. Of note is that canalicular staining is also seen in normal liver and benign tumors, hence this staining pattern is most helpful in designating overtly malignant tumors as having a hepatocellular origin. Cytoplasmic staining, however, is not seen in normal liver or benign tumors, and hence is a marker for malignancy (immunoperoxidase stain for pCEA).

Chapter 10 / Neoplasms and Related Lesions

A

275

B

FIGURE 10-77 Hepatocellular carcinoma. A, The tumor cells contain abundant α-fetoprotein. Positive staining with this marker is seen in only a minority of cases. B, The CD31, a marker for endothelial cells, helps conirm the presence of thickened hepatic cords (immunoperoxidase).

A

B

FIGURE 10-78 Combined hepatocellular-cholangiocarcinoma. These images are from the same tumor. A, Classic thickened hepatic cords are present, the tumor cells containing both bile and Mallory bodies (hepatocellular carcinoma). B, Distinct glands are seen (cholangiocarcinoma).

2. PAS after diastase digestion (DiPAS): Distinct eosinophilic intracytoplasmic globules may be positive, and may represent α1-antitrypsin (conirmed on immunoperoxidase stains), a helpful marker for hepatocellular carcinoma. 3. Van Gieson: Intracytoplasmic or intracanalicular pigment in tumor cells or acini can be conirmed as bile by variable degrees of green staining (dependent on the amount of biliverdin).

FIGURE 10-79 Combined hepatocellular-cholangiocarcinoma. This image shows changes of both a moderately differentiated hepatocellular carcinoma (right of the ield) and iniltrating cholangiocarcinoma (left of the ield) in tissue taken from a single hepatic mass lesion.

Immunohistochemistry (Table 10-5) 1. Polyclonal carcinoembryonic antigen (pCEA): This biliary glycoprotein stains the biliary canaliculi and is diagnostic for hepatocellular carcinoma, staining positively in up to 70% of cases. Cytoplasmic staining can also occasionally be seen. Note that monoclonal CEA rarely (20 ng/ml as cutoff ) have a sensitivity of 41% to 65% and speciicity of 80% to 94%. Lectin binding of AFP (AFP L3) has similar sensitivity (37%) and speciicity (93%). Des-γ-carboxy prothrombin (DCP) has been shown to have a sensitivity of 56% and a speciicity of 77%. Other conditions associated with elevated AFP levels include acute fulminant viral hepatitis due to HBV infection (in those most likely to survive), pregnancy, fetal distress, gastric carcinoma with or without hepatic metastases, pancreatic carcinoma, embryonal tumors (yolk sac, teratocarcinoma, endodermal sinus tumors), cholangiocarcinoma (reported in Japanese series), and chronic hepatitis (occasionally elevated to values of 75%) hepatic replacement by tumor. 6. Liver tests reveal normal or minimally increased serum aminotransferases; in contrast, marked increase in alkaline phosphatase and lactate dehydrogenase activities provide clues to metastatic hepatic involvement. Increase in serum bilirubin occurs only when the liver is diffusely iniltrated or when obstruction of the bile ducts occurs. 7. Although serum α-fetoprotein values >500 ng/ml in patients with mass lesions in the liver are virtually diagnostic of hepatocellular carcinoma, certain metastatic tumors may rarely produce markedly elevated α-fetoprotein levels (gastric, testicular, yolk sac, embryonal tumors). 8. Multiple nodules in the liver are seen in 90% of cases. Single massive nodules and iniltrative lesions can also be present. 9. When the liver is involved, unguided needle biopsies are positive for tumor 40% to 75% of the time. The yield is increased when the biopsy or aspirate is ultrasoundguided, multiple biopsies are taken, or biopsies are performed during peritoneoscopy. 10. It is felt by some that cirrhotic livers are a less favorable site for metastatic disease, although studies by others show this to be incorrect. 11. Tables 10-9 and 10-10 list the frequencies of nonhematopoietic malignant tumors metastatic to the liver.

TABLE 10-9

Frequency of Various Metastatic Tumors to the Liver (Total 1051 Autopsies)

PRIMARY

LIVER AS METASTATIC SITE (% OF TOTAL CASES)

Bile duct

1.0

Bladder

2.4

Breast

20.7

Cervix

9.2

Colon

3.3

Esophagus

2.0

Gallbladder

1.7

Kidney

2.0

Lung

5.5

Ovary

2.4

Pancreas

6.0

Pharynx

2.2

Prostate

3.4

Rectum

11.4

Skin (body) Stomach

1.9 11.9

Testes

1.8

Thyroid

1.0

Uterus

3.2

Data from DiSibio G, French SW: Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med 2008;132:931-939.

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311

Treatment and prognosis 1. Localized metastatic lesions may be surgically resected in conjunction with removal of the primary tumor and absence of metastases to other organs. In diffuse metastatic lesions, surgery is not recommended. 2. Arterial ligation, embolism, and intra-arterial chemotherapy can be tried but generally have not been effective. 3. When metastatic liver tumors produce bile duct obstruction, palliative stenting by endoscopy or by surgical choledochojejunostomy provides only temporary beneit. 4. The overall prognosis is generally poor, death usually occurring 6 to 12 months after diagnosis. Some tumors such as neuroblastomas and carcinoids carry a better prognosis. FIGURE 10-156 Focal nodular hyperplasia (reticulin stain). Low power emphasizes the radiating central scar with this stain.

TUMOR-LIKE LESIONS Focal Nodular Hyperplasia (Figs. 10-155 through 10-162)

TABLE 10-10

PRIMARY SITE

Metastatic Tumors to the Liver Los Angeles County–University of Southern California Autopsy Series PERCENTAGE OF TOTAL NUMBER OF MALIGNANCIES IN SERIES

PERCENTAGE WITH HEPATIC METASTASES

Lung

24.9

41.8

Prostate

12.1

12.6

Colon

11.8

56.0

Breast

8.0

53.2

Pancreas

6.5

70.4

Stomach

5.8

44.0

Kidney

5.2

23.9

Cervix

3.9

31.7

A

B FIGURE 10-157 Focal nodular hyperplasia. A, A ibrous septum FIGURE 10-155 Focal nodular hyperplasia. The tumor has a central radiating scar and is light yellow. (Ishak KG, et al. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 31, 3rd series. Washington, DC: Armed Forces Institute of Pathology, 1999, with permission from the AFIP.)

is seen in the center of the tumor nodule and contains numerous dilated vascular spaces and a mild lymphocytic iniltrate. B, A higherpower image reveals numerous duct-like structures at the border of the septum. Scattered lymphocytes are also seen. The adjacent hepatocytes show some hydropic change but are cytologically benign.

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A

B

FIGURE 10-158 Focal nodular hyperplasia. A and B, These two images show different examples of the duct-like structures seen at the border of the ibrous septum. Variable degrees of lymphocytic iniltration in and among the ductules are common. This morphologic feature in a mass lesion is virtually diagnostic of focal nodular hyperplasia.

FIGURE 10-160 Focal nodular hyperplasia. This immunoperoxidase FIGURE 10-159 Focal nodular hyperplasia. High-power view of the ductules shows some irregularity in the nuclear size. In some instances, ectasia of the ductules can be seen.

A

cytokeratin stain shows intense positive staining of the ductules. This stain is useful in instances when the ductules are not that well deined (immunoperoxidase stain for CK7).

B

FIGURE 10-161 Focal nodular hyperplasia. A, The hepatocytes are cytologically benign, with the hepatic cords one to two cells thick. B, Fatty change of the hepatocytes can occasionally be seen.

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313

Aspiration cytology 1. Round nuclei without prominent nucleoli, and relatively abundant eosinophilic to clear cytoplasm are characteristically seen. 2. Fibrous tissue with cytologically benign ductules may also be seen, but are sometimes not obvious. Note: The hepatocytes of liver cell adenomas have identical cytologic features, and a well-differentiated hepatocellular carcinoma in some instances cannot be ruled out on cytologic grounds alone, necessitating directed core biopsy.

FIGURE 10-162 Focal nodular hyperplasia. The central feeding vessels characteristically show variable but often prominent intimal and myointimal thickening. This cross-section shows striking hyperplasia of the smooth muscle with marked stenosis of the vessel lumen.

Major morphologic features 1. Characteristic central radiating ibrous septa subdividing the mass lesion into multiple segments are seen. 2. The radiating scars exhibit a lymphocytic iniltrate with numerous small vascular channels (arteries and veins). 3. Proliferating irregularly shaped ductules are present at the border of the ibrous septa and the parenchyma, these ductules composed of lattened epithelial cells with illdeined or no distinct lumen. True interlobular bile ducts are absent. 4. The hepatocytes are cytologically benign, usually with an eosinophilic, but sometimes clear hydropic cytoplasm, forming normal-sized (one to two cells thick) trabecular cords lined by endothelial and Kupffer cells. Additionally these hepatocytes are sometimes larger than the hepatocytes in the non-tumor liver. Other features 1. Hepatocytes may sometimes contain fat, glycogen, and lipochrome pigment. Bile is very rarely seen. 2. Mallory bodies and extramedullary hematopoiesis have also been described but are uncommon. 3. Larger arteries in the central portion of the scar are present with irregular intimal and myointimal thickening. 4. Microcalciications may be present but are uncommon, and rupture with hemorrhage can occur but is infrequent. 5. Increase in both copper and copper-binding protein within the hepatocytes has been described but is not common. 6. A surrounding ibrous capsule is not characteristic. Special stains 1. Reticulin: This stain highlights the normal-sized hepatic cords in instances where the hydropic change of the hepatocytes makes the sinusoidal spaces dificult to evaluate. 2. Rubeanic acid, rhodanine: The increase in copper can be seen as green-black and dark red granules, respectively, within the liver cells. 3. Orcein: The increase in copper-binding protein can be highlighted.

Differential diagnosis 1. Liver cell adenoma: Radiating ibrous septa and ductules are not seen in liver cell adenomas. If the biopsy only shows hepatocytes, however, distinction between the two entities may not be possible on morphologic grounds alone. Morphologic and radiologic features distinguishing between the two lesions are listed in this chapter in Table 10-2. Of note is that in the “telangiectatic” type of liver cell adenoma, rare ductules can be seen; however, the degree of ductule formation is mild and focal, and central radiating septa is not a feature of this liver cell adenoma variant. 2. Well-differentiated hepatocellular carcinoma: If a biopsy of a mass lesion exhibits only hepatocytes without ibrous septa, the features of a well-differentiated hepatocellular carcinoma (prominent nucleoli, cords greater than two cells thick, mitoses, tumor cells within vascular channels) assist in differentiating between the two lesions. 3. Fibrolamellar hepatocellular carcinoma: Fibrous septa and occasionally a central radiating scar may be seen in ibrolamellar hepatocellular carcinoma, and on gross inspection both focal nodular hyperplasia and ibrolamellar hepatocellular carcinoma may at times be similar. Ductules are not present, however, in ibrolamellar hepatocellular carcinoma. The ibrosis in ibrolamellar hepatocellular carcinoma also shows marked hypocellularity and is laid down in a parallel fashion, unlike the central ibrous septa in focal nodular hyperplasia. Fibrolamellar hepatocellular carcinoma is also characterized by cells with prominent eosinophilic cytoplasm that often exhibits distinct cytoplasmic inclusions (pale bodies), these inclusions not seen in focal nodular hyperplasia. Clinical and biologic behavior 1. Focal nodular hyperplasia is a mass lesion that is not a true neoplasm, but rather a result of enhanced arterial blood low, vascular thrombosis with secondary myointimal proliferation, and liver cell atrophy (hypoperfusion) with consequent regeneration of adjacent hepatocytes. 2. Most patients are women. Although the majority of patients are between 20 and 39 years of age, case reports range between 14 months to 74 years. 3. This lesion is found incidentally on liver scans (ultrasound or CT) or at surgery. Patients are usually asymptomatic and only about 25% of patients have vague abdominal pain or fullness related to the presence of a hepatic mass. About 67% are found in the right lobe of the liver. In the childhood form, one series suggests a left lobe predominance in about 60% of cases.

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4. Serum aminotransferases and alkaline phosphatase are normal in over 80% of cases. The α-fetoprotein is not elevated. 5. The lesions are usually solitary, light tan, sometimes bulging from the surface, range in size from 2 to 15 cm, and are characterized by a central radiating ibrous scar. The lesions are usually found immediately beneath Glisson’s capsule. There is no statistical relationship between the incidence of focal nodular hyperplasia and the use of oral contraceptives. 6. Malignant transformation has not been reported. Treatment and prognosis 1. Complications such as rupture are rare. Treatment is relatively conservative. 2. Small lesions incidentally discovered at surgery may be totally resected, especially those that are pedunculated. 3. Some feel oral contraceptives should be avoided due to possible hemorrhage of the lesion.

a. Normal (without liver cell dysplasia): Cytologically benign hepatocytes having the same histologic changes seen in the other regenerative nodules throughout the liver. b. Small cell dysplasia: Small round to oval nuclei with inconspicuous nucleoli and scanty eosinophilic cytoplasm are seen. These are precancerous lesions that have a high proliferative rate, low rate of apoptosis, and lack E-cadherin expression. c. Large cell dysplasia: Large hyperchromatic often pleomorphic nuclei with abundant eosinophilic cytoplasm are present. Although these features are more often seen in cirrhotic livers with hepatocellular carcinoma than those without the tumor, these cells do not contain genetic alterations that are present in tumors but instead show the senescent p16 marker, implying that

REGENERATIVE LESIONS Macroregenerative Nodules Typical variant without dysplasia Dysplastic variants (low and high grade) (Figs. 10-163 through 10-166) Major morphologic changes 1. Macroregenerative nodules are regenerative nodules within a cirrhotic liver that measure at least 8 mm in diameter but may be as large as 5 to 6 cm in diameter (up to 10 cm described). 2. The hepatocytes within the nodules have varying histologic features and microscopically are classiied as either normal or having small cell and/or large cell dysplasia:

FIGURE 10-163 Macroregenerative nodule. This low-power image demonstrates a 2-cm nodule composed of hydropic hepatocytes (lower left) that on high power shows no atypia or dysplastic changes. The thickness of the hepatic cords can sometimes be dificult to assess in these types of nodules, whereby a reticulin stain will conirm that the cords are indeed one to two cells thick. The ibrous band representative of the cirrhotic liver is present towards the center of the ield. Note that the hepatocytes in the adjacent regenerative nodule are eosinophilic, with the normal cord-sinusoid pattern apparent.

FIGURE 10-164 Macroregenerative dysplastic nodule. The hepatocytes are enlarged and hydropic, with the nuclei round to oval, some exhibiting prominent nucleoli (large cell dysplasia). Some of the cells contain Mallory bodies.

FIGURE 10-165 Macroregenerative dysplastic nodule. Many of the hepatocytes are small, with hyperchromatic nuclei and increase in the nuclear:cytoplasmic ratio (small cell dysplasia) compared to the liver cells in the lower left of the ield. A reticulin stain showed no cord thickening involving these smaller cells.

Chapter 10 / Neoplasms and Related Lesions

these cells themselves do not have the tendency for malignant transformation. 3. The nodules are also classiied overall as either morphologically normal (macroregenerative nodules without dysplasia) or having low-grade or high-grade dysplasia (see Table 10-11). Other features 1. Variable degrees of fatty change, bile, and hydropic and regenerative changes of the liver cells are seen. 2. Mallory bodies may be present, and when seen are more often associated with the dysplastic variants (low or high grade). 3. “Reconstituted” small portal structures within the larger nodules may often occur. 4. Bulging irregular regeneration of groups of liver cells within the larger nodules themselves is not uncommon, often appearing as a “nodule within a nodule.” Special stains 1. Reticulin: This stain best shows normal-sized hepatic cords no more than 2 cells thick, conirming the benign nature of these nodules. In addition, the intensity of the staining is also helpful, with strong diffuse staining seen in dysplastic nodules, but with decreased to absent staining seen in well-differentiated hepatocellular carcinomas. 2. Prussian blue: Although some degree of staining for iron may occur in the large regenerative nodules, the presence of large or small cell dysplasia within the larger macroregenerative nodules is often associated with minimal to absent staining. This decrease in staining is best appreciated where the corresponding non-tumor liver shows increased iron staining patterns (e.g., chronic viral hepatitis C, hereditary hemochromatosis); of note, however, is that absent iron staining of these nodules is also a feature of hepatocellular carcinoma, hence other morphologic features to distinguish between dysplastic

FIGURE 10-166 Macroregenerative dysplastic nodule. The nodule in the upper left of the ield shows the hepatic cords to be one to two cells thick; however, the degree of reticulin staining is decreased in this high-grade dysplastic nodule which is worrisome for malignancy when compared to the adjacent small cirrhotic nodule with strong reticulin staining that showed no dysplasia on H&E stain (reticulin).

315

nodules and hepatocellular carcinoma must be assessed (see Table 10-11). Differential diagnosis 1. Well-differentiated hepatocellular carcinoma: The macroregenerative nodules with high-grade dysplasia can be very worrisome for hepatocellular carcinoma, which, in fact, can arise within these nodules themselves. Table 10-11 shows the important differential characteristics between dysplastic nodules and hepatocellular carcinoma. 2. Liver cell adenoma: The regenerative nodules without dysplasia or only low-grade dysplasia have all the morphologic changes that may be seen in liver cell adenomas. Liver cell adenomas almost always arise in non-cirrhotic livers in otherwise healthy young women, while the macroregenerative nodules arise in cirrhotic livers and are seen equally in men and women. Clinical and biologic behavior 1. Macroregenerative nodules are distinct mass lesions greater than 8 mm in diameter that arise from cirrhotic livers. 2. Symptoms are attributable to the underlying chronic liver disease, the lesion evoking interest because the presence of a mass raises the concern about associated hepatocellular carcinoma. In these patients, this lesion may also be identiied on screening ultrasonography for hepatocellular carcinoma or as a mass lesion on laparoscopy or surgery.

TABLE 10-11

Comparison of Morphologic Features in Dysplastic Nodules and Early Hepatocellular Carcinoma LOW-GRADE DYSPLASTIC NODULE

HIGH-GRADE DYSPLASTIC NODULE

EARLY HEPATOCELLULAR CARCINOMA

Clone-like populations

Present

Present

Present

Liver cell plates >3 cells thick

Absent

Absent

Present

Mitotic activity >5/10 high-power ield

Absent

Absent

Sometimes present (welldifferentiated) Present (moderately differentiated)

Increase nuclear: cytoplasmic ratio

Absent

Absent to present

Present

Nuclear hyperchromasia

Absent

Present

Present

Irregularity of nucleus

Absent

Mild

Moderate

Pseudoglands

Absent

May be present

May be present

Reticulin framework

Normal

Normal; may be decreased

Normal, decreased to absent

Stromal, vascular invasion

Absent

Absent

Present

MORPHOLOGIC FEATURE

Data from Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis 2005;25:133-142; Wanless I. Liver biopsy in the diagnosis of hepatocellular carcinoma. Clin Liver Dis 2005;9:281-285.

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3. Macroregenerative nodules may be single or multiple and may vary in size from 1 to 12 cm. Necrosis in these lesions is not seen except when there is hypotension or shock related to a terminal event. 4. This lesion is considered to be related to marked regenerative stimuli in response to the chronic necroinlammatory processes that led to cirrhosis. Of major importance is the malignant potential of the nodules that histologically show dysplasia. Note: Large nodular lesions can also be seen following acute severe hepatic injury such as recovery from submassive hepatic necrosis (“postnecrotic regenerative nodules,” hepar lobatum); however, of importance is that after full recovery, the “lesions” usually disappear due to total regeneration of the entire liver. In addition, these particular lesions have no malignant potential. Treatment and prognosis 1. There is no speciic treatment. Complications of cirrhosis are managed as appropriate. 2. Resection of these nodules is not recommended unless the degree of dysplasia is worrisome for possible malignant transformation.

FIGURE 10-168 Nodular regenerative hyperplasia. Multiple foci of hydropic hepatocytes are present and represent the nodules that are distinctly present on gross examination (see Figure 10-167). The portal tracts at the borders of these nodules are normal in size to only slightly ibrotic. No ibrous septa are present (trichrome).

Nodular Regenerative Hyperplasia Partial Nodular Transformation (Figs. 10-167 through 10-171) Major morphologic changes 1. Cytologically benign hepatocytes are present in non-cirrhotic livers and form small regenerative nodules composed of irregularly aligned hepatic trabeculae. Other features 1. Nodular regenerative hyperplasia a. The nodules range in size from 0.1 to 1.0 cm in diameter, with the larger nodules on low and high power exhibiting rather sharp outlines from the adjacent hepatic parenchyma. Fibrous capsules surrounding these lesion are not present.

A

B

FIGURE 10-167 Nodular regenerative hyperplasia. This segment of liver shows numerous irregularly shaped but small nodules that on supericial inspection appear similar to cirrhotic nodules; however, no ibrous septa are present surrounding these nodules.

FIGURE 10-169 Nodular regenerative hyperplasia. A, This highpower trichrome stain shows a normal-sized portal tract and adjacent hydropic hepatocytes, the latter forming a regenerative nodule. B, The H&E stain of the same ield shows the portal tract to contain a single normal interlobular bile duct and only minimal lymphocytic iniltrates. The adjacent regenerative hepatocytes are hydropic, without necrosis or inlammation.

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317

i. Thrombosis and recanalization of intrahepatic portal veins may occur. 2. Partial nodular transformation a. Fibrosis may occur at the periphery of the larger nodules that may be up to 4 cm in diameter, these nodules always centered at the hepatic hilum. b. Sinusoidal dilatation of the nodules may be present. c. Portal tracts within the nodules may occur and are normal in size without any inlammatory iniltrates or abnormal bile ducts. d. Portal vein thrombosis may occur adjacent to these hilar nodules.

FIGURE 10-170 Nodular regenerative hyperplasia. This stain highlights the liver cell regeneration, with the liver cell cords measuring up to two cells thick. Note also the compression of the hepatic cords immediately adjacent to the regenerating nodule (reticulin).

Special stains 1. Reticulin: This stain highlights these nodules by demonstrating the compression of the adjacent sinusoids. In addition the two-cell–thick liver cell plates in nodular regenerative hyperplasia and partial nodular transformation are best appreciated. Differential diagnosis 1. Multiple liver cell adenomas (hepatocellular adenomatosis): Nodular regenerative hyperplasia occurs as multiple small nodules that usually uniformly involve a single lobe or both hepatic lobes, while there is an irregular distribution of the nodules with the adenomas. The nodules in nodular regenerative hyperplasia are almost always 500 to 2000 IU/L), serum bilirubin remains elevated and coagulopathy is persistent. The mental status is impaired with inability to extubate the patient from the ventilator, and renal function deteriorates with low urinary output, progressing to renal failure requiring hemodialysis. Hypothermia, hypoglycemia, metabolic and lactic acidosis, and elevations of serum lactate dehydrogenase are observed which collectively support the diagnosis of acute graft failure. These abnormalities are observed immediately and within the irst week following liver transplant. 3. Ultrasound of the liver demonstrates no obstruction of the bile duct or thrombosis of the portal vein and hepatic artery 4. Acute graft failure may result from technically inadequate revascularization but is commonly associated with donor characteristics of obesity, antemortem hypoxia and hypotension, and hepatic steatosis. In general, when the degree of fat in the implanted liver exceeds 60% of the liver cell volume, the incidence of graft failure substantially rises. In implantation of liver segments from living-related donors, however, graft nonfunction can occur when the degree of fat is substantially less than with cadaveric livers. Preservation factors such as prolonged warm or cold ischemia times may also play a part in the cause of graft failure. Treatment and prognosis 1. Treatment is supportive. Recovery is indicated by normalization of mental and renal function with improvement in liver tests and restoration of bile to normal color and consistency. 2. Milder forms of graft failure referred to as initial poor function may be treated with infusion of prostaglandin E1. The exact mechanism of action is not known. 3. If recovery of graft function does not occur, mortality is 100% unless retransplantation occurs, which must be performed expeditiously.

325

FIGURE 11-8 Hyperacute (humoral) rejection. The small hepatic artery shows a recent intraluminal ibrin thrombus. A mild lymphocytic inlammatory iniltrate is seen surrounding the vessel. (Courtesy AJ Demetris, University of Pittsburgh Medical Center.)

FIGURE 11-9 Hyperacute (humoral) rejection. The small artery branches within this portal tract show IgM deposition along the vessel walls (immunoperoxidase stain for IgM). (Courtesy AJ Demetris, University of Pittsburgh Medical Center.)

REJECTION 1. Liver allograft rejection is mediated by the immune response of the recipient to allogeneic antigens expressed by the donor liver. Multiple immunologic mechanisms participate in the alloimmune reaction. 2. Clinically there are three types of rejection: a. Hyperacute (humoral) rejection, which is relatively uncommon. b. Acute (cellular) rejection, commonly occurring during the irst few months after transplantation. c. Chronic (ductopenic) rejection, a manifestation of bile duct loss.

Hyperacute (Humoral) Rejection

FIGURE 11-10 Hyperacute (humoral) rejection. Extensive coagula-

(Figs. 11-8 through 11-10)

tive necrosis and hepatic infarction is seen secondary to intravascular thrombosis and occlusion of the small hepatic artery branches.

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Major morphologic features 1. Coagulative necrosis and acute hemorrhage are present, most prominent within the perivenular and midzones but often involving the entire lobule. Other features 1. Fibrin deposition with neutrophils and platelet aggregates are seen in the very early stages within the sinusoids, hepatic arterioles, and portal venules. 2. Numerous neutrophils may be seen in the sinusoids adjacent to resultant ischemic necrosis as the disease progresses. 3. Cholestasis is often present and is most accentuated amidst the adjacent viable liver cells. 4. The viable hepatocytes can show variable hydropic ballooning change 5. Necrotizing endothelial damage and denudation occurs predominantly involving medium-sized (>120 µm in diameter) arteries, with neutrophilic iniltration, ibrin thrombi and partial vascular occlusion occurring. Fibrin thrombi may also be seen within portal venules and terminal hepatic venules and veins. Special stains 1. Phosphotungstic-acid-hematoxylin (PTAH): The ibrin thrombi within vessels can best be appreciated. Immunohistochemistry 1. IgM, IgG, C1q, C3, C4, C4d, ibrinogen: Deposits in arteries, veins and portal capillaries may be identiied. Differential diagnosis 1. Ischemic necrosis secondary to severe hypotension, hepatic artery thrombosis: Coagulative ischemic changes within the lobules due to poor perfusion from various causes such as hypotension and hepatic artery occlusion are similar to those seen in hyperacute rejection. The presence of small vessel thrombosis with immunoglobulin deposition is characteristic of hyperacute rejection. The clinical setting without associated hypotension is also characteristic. In addition, with hepatic artery thrombosis, panlobular ischemic necrosis with hepatic infarction rather than a zonal necrosis is common. 2. Primary nonfunction: Severe perivenular and midzonal coagulative necrosis is seen in both primary nonfunction and hyperacute humoral rejection. The absence of primary vascular involvement favors primary nonfunction. Clinical and biologic behavior 1. Hyperacute (humoral) rejection is an infrequent complication that occurs within hours or days following liver transplantation. 2. It is mediated by preformed recipient antibodies that bind to allogeneic epitopes on donor endothelial cells. These preformed antibodies recognize both carbohydrate and peptide components of glycosylated proteins on the endothelial cells. Binding of immunoglobulins results in a cascade of events that include complement activation, induction of endothelial cell expression of adhesion molecules for neutrophil binding, activation of the coagulation cascade, and production of vasoactive peptides. These events destroy sinusoidal endothelial cells, obstruct blood

low and culminate in hemorrhagic necrosis of hepatocytes leading to liver failure. 3. The diagnosis rests on early graft failure with no other distinctive explanation, consistent microscopic features by both light and immunoluorescence, the presence of a presensitized state in the recipient, and the presence of preformed donor-speciic antibodies in the recipient. 4. Since preformed antibodies are frequently seen in the recipient, it is surprising that hyperacute rejection is not more frequent. This may be due to the fact that there is a dual blood supply to the liver (via the hepatic artery and portal vein). In addition, the antibodies directed toward HLA class I antigens on the endothelium of the donor liver may be neutralized by high circulating soluble HLA class I antigens immediately after reperfusion. 5. The clinical course of these patients after transplant is manifest by poor graft function, encephalopathy and renal failure. Serum transaminases and serum bilirubin levels are markedly elevated, prothrombin time is prolonged and serum albumin is decreased. Treatment and prognosis 1. Retransplantation is the only option and is life saving.

Acute (Cellular) Rejection (Figs. 11-11 through 11-15) Major morphologic features The following triad of histologic changes may be seen to variable degrees, depending on the severity of the rejection: 1. Mixed portal inlammatory iniltrates a. Activated lymphocytes (immunocytes, immunoblasts), eosinophils, occasional plasma cells, histiocytes, and neutrophils are present and are usually conined to the portal tracts (except in severe cases, where periportal spillover may occur). 2. Venous endothelial inlammation (endothelialitis) a. Lymphocytes and immunocytes attach to the endothelium of portal and terminal hepatic venules, involving part or all of the intravascular luminal lining. b. Subendothelial iniltration of these mononuclear cells is often seen. In severe rejection, the inlammatory cells also involve the perivenular sinusoids and may be associated with perivenular ischemic necrosis of hepatocytes. c. Arterioles may be involved in severe cases. 3. Nonsuppurative cholangitis, destructive or nondestructive a. Interlobular bile ducts are surrounded and invaded by lymphocytes, immunocytes and neutrophils, with the biliary epithelium showing variable cytoplasmic vacuolization and nuclear pyknosis, dependent on the rejection severity. Other features 1. Cholestasis, mild mononuclear inlammatory iniltrates, and rare apoptosis may be present within the lobules. 2. When perivenular necrosis and lobular collapse are present in severe cases, sinusoidal congestion with acute hemorrhage may occur. In addition, red blood cells may be seen iniltrating into the hepatic cords (red blood cell extravasation).

Chapter 11 / Transplantation

A

327

B

FIGURE 11-11 Acute (cellular) rejection. These (A) low- and (B) high-power images show a portal tract with a marked mixed inlammatory iniltrate consisting of lymphocytes, immunoblasts, and numerous eosinophils. Lymphocytes and immunoblasts can be seen hugging up against and iniltrating beneath the endothelium of the portal venule (endothelialitis). An interlobular bile duct, best seen at the left of the ield on the higher-power image, is surrounded and iniltrated by some lymphocytes and neutrophils.

grades individually the degree of portal inlammation, duct damage, and endothelial inlammation, each on a scale of 0 through 3, with a total score ranging from 0 (no rejection) to 9 (severe rejection). For example, a biopsy showing portal rejection iniltrates involving only a minority of portal tracts, with the portal iniltrate mostly lymphocytic (score = 1), bile duct damage involving a minority of ducts (score = 1), and endothelial damage involving only some portal venules (score = 1), would be graded as mild (RAI = 3 of 9). Table 11-3 outlines the criteria in acute rejection grading.

FIGURE 11-12 Acute (cellular) rejection. The portal tract shows a striking iniltration by eosinophils. Interlobular bile ducts show cytologic atypia and are surrounded and focally iniltrated by inlammatory cells.

3. In some cases perivenular inlammation with endothelialitis may occur in the absence of corresponding portal tract changes of rejection. Note: The above histologic changes are characteristic indings of acute rejection in the early post-transplant setting (weeks to months); however, acute rejection in allografts over one year post-transplant may in fact show only mild nonspeciic changes, such as mild portal and lobular inlammation, and may histologically resemble a chronic hepatitislike reaction. In these instances, other causes such as disease recurrence, drug-induced injury, and superinfection must be ruled out before a diagnosis of possible rejection can be made; unfortunately, in some instances this exclusion process may not conidently be possible. Grading of acute rejection (Banff Criteria) Liver allograft pathology for acute cellular rejection is graded by use of the Banff scoring system, and is subdivided into the global assessment of mild to severe rejection, followed by a numerical score (rejection activity index, RAI). This score

Differential diagnosis 1. Acute viral hepatitis (hepatotropic viruses): Patients may clinically present with an acute hepatitis-like picture, with moderately or markedly elevated aminotransferases. Biopsy in acute rejection does not exhibit the degree of liver cell injury and lobular inlammation seen in acute viral hepatitis. In addition, in acute viral hepatitis the portal inlammation is chiely lymphocytic and not mixed, without appreciable duct injury and with absence of vascular inlammation. 2. CMV hepatitis: Portal lymphocytic iniltrates are seen in CMV hepatitis without a mixed inlammatory iniltrate, the latter a characteristic inding for acute rejection. In addition, nuclear and/or cytoplasmic CMV inclusions, which are often associated with microabscess formation in the transplant setting, are characteristic for CMV hepatitis and not a feature of acute rejection. These viral inclusions can also be seen within Kupffer cells and portal bile duct epithelium, and can be conirmed as CMV by immunoperoxidase stains as well. 3. Epstein Barr Virus (EBV) infection: Also termed posttransplant lymphoproliferative disorder, this infectious process is characterized by a marked portal iniltrate by atypical lymphocytes, the iniltrate also seen within the lobules and sinusoids. A mixed inlammatory iniltrate characteristic of acute rejection is not present. The diagnosis of EBV infection can be conirmed by in situ hybridization (demonstration of the EBER-1 gene), which shows positive staining within portal lymphocytes.

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A

B

FIGURE 11-13 Acute (cellular) rejection. The portal tract in these (A) low- and (B) high-power images shows a marked mixed inlammatory iniltrate with numerous eosinophils. Lymphocytes are seen hugging up against the endothelium of the portal venule. The interlobular bile duct shows mild hydropic change, with a few lymphocytes beneath the duct basement membrane.

A

B

FIGURE 11-14 Acute (cellular) rejection. A and B,The interlobular bile ducts in these two images show considerable cytologic distortion, with irregularly arranged nuclei and inlammatory cells abutting up against and focally iniltrating into the duct walls. The portal tract shows a prominent mixed inlammatory iniltrate including numerous immunoblasts.

FIGURE 11-15 Acute (cellular) rejection. The terminal hepatic venule shows numerous lymphocytes up against and iniltrating through the disrupted endothelium (endothelialitis). The inlammation has also extended into the perivenular zone, with damage and focal dropout of hepatocytes.

4. Drug toxicity: Patients on post-transplant immunosuppressive treatment may exhibit variable degrees of liver cell necrosis and occasionally cholestasis not attributable to the more common causes such as rejection, biliary strictures or recurrent disease. Destructive inlammatory duct lesions and endothelial inlammation, features characteristic of acute rejection, are rarely seen in druginduced injury. 5. Native liver disease recurrence: Transplanted livers may often develop portal and lobular inlammation that represent recurrent disease (e.g., chronic viral hepatitis). The portal inlammation in recurrent viral hepatitis is chiely lymphocytic, usually without appreciable duct injury and without endothelialitis. Although certain recurrent diseases may show a mixed portal iniltrate as well as duct injury (e.g., portal lymphocytes, plasma cells and eosinophils, nonsuppurative cholangitis in recurrent primary biliary cirrhosis), endothelialitis is not a feature of disease recurrence, although recurrent HCV can at time show mild focal perivenular inlammation. In addition, the

Chapter 11 / Transplantation

TABLE 11-3

329

Grading of acute allograft rejection GLOBAL ASSESSMENT

SUBJECTIVE GRADE

CRITERIA

Indeterminate (borderline, insuficient for a diagnosis of acute rejection)

Portal inlammatory iniltrates that fail to meet the criteria for the diagnosis of acute rejection

Mild

Rejection iniltrates in a minority of the triads that are mild and conined to the portal spaces

Moderate

Rejection iniltrates expanding most or all of the portal tracts

Severe

As above, with spillover of inlammatory cells into the periportal areas, with moderate to severe perivenular inlammation that extends into the hepatic parenchyma and is associated with perivenular liver cell necrosis REJECTION ACTIVITY INDEX (RAI)

PORTAL INFLAMMATION 1

Mostly lymphocytic inlammation involving but not expanding a minority of the portal triads

2

Expansion of most or all of the portal tracts by a mixed inlammatory iniltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils

3

Marked expansion of most or all of the portal tracts by a mixed iniltrate containing numerous immunoblasts and eosinophils, with spillover of the cells into the periportal region

BILE DUCT INFLAMMATION/DAMAGE 1

A minority of the ducts are surrounded and iniltrated by inlammatory cells and show only mild reactive changes (e.g., increased nuclear/cytoplasmic ratio)

2

Most or all of the ducts are iniltrated by inlammatory cells; more than an occasional duct shows degenerative changes (nuclear pleomorphism, disordered polarity, cytoplasmic vacuolization)

3

As above, with most or all of the ducts showing degenerative changes or focal luminal disruption

VENOUS ENDOTHELIAL INFLAMMATION 1

Subendothelial lymphocytic iniltration involving a minority of the portal and/or hepatic venules

2

Subendothelial lymphocytic iniltration involving most or all of the portal and/or hepatic venules

3

As above, with moderate to severe perivenular inlammation that extends into the perivenular regions, associated with perivenular liver cell necrosis

From Demetris AJ, Batts KP, Dhillon AP, et al: Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658-663.

presence of granulomas, seen in many cases of recurrent primary biliary cirrhosis, is not a feature of acute rejection. Recurrent disease can also be conirmed in disorders where immunoperoxidase markers are available (e.g., recurrent HBV infection with nuclear and cytoplasmic staining for the hepatitis B core and surface antigens, respectively). 6. Other causes of perivenular inlammation (central perivenulitis): A number of inlammatory processes besides acute cellular rejection may cause a perivenular inlammation and include ischemia (preservation injury, vascular occlusion), chronic ductopenic rejection, recurrent viral hepatitis (especially HCV), autoimmune hepatitis, EBV infection, veno-occlusive disease, secondary syphilis, and certain drugs (e.g., azathioprine, busulfan). Clinical correlation is then necessary in consideration of these possibilities. Note: Concurrent post-transplant disorders (e.g., acute rejection in a patient with recurrent viral hepatitis) unfortunately may be seen, making deinitive pathologic diagnoses sometimes quite dificult. Correlation with laboratory tests including hepatitis and autoimmune serologies, imaging, timeframe post-transplant, and clinical presentations are therefore quite important in arriving at the best possibilities in biopsy signouts. Clinical and biologic behavior 1. Despite induction immunosuppressive therapy, about 40% to 60% of recipients will experience one or more acute rejection episodes, usually encountered early in the postoperative period.

2. Patients may present with fever, right upper quadrant and back pain, anorexia, ascites, and decreased bile output and bile pigment (from drainage catheter). 3. Elevations in serum transaminases, bilirubin and alkaline phosphatase activity occur, with variable levels depending on the severity. Bilirubin levels may be normal early in the course of acute rejection. 4. The diagnosis is made by exclusion of bile leak, biliary strictures with duct dilatation, and thrombosis of the hepatic artery on ultrasound examination. Liver biopsy conirms the diagnosis and grades the severity of acute rejection, but may not be necessary in the early postoperative period. 5. The “vanishing bile duct syndrome,” an irreversible type of acute rejection that occurs in a small percentage of patients, presents within the irst 100 days of transplant and is characterized by spiking fever, lethargy, jaundice, pruritus, dark urine, light stools, and ascites. The patient rapidly deteriorates, necessitating retransplantation. The speed of deterioration is somewhat unique for this type of rejection, the morphologic changes revealing marked destruction of the interlobular bile ducts (see Chronic [ductopenic] rejection). 6. Extrahepatic complications of acute rejection serious enough to be life threatening or necessitate retransplantation include pulmonary infections, disseminated intravascular coagulation, bile leaks or stricture at the site of the duct-to-duct anastomosis, intra-abdominal abscess formation or peritonitis, renal failure, wound complications, and cardiac and neurologic abnormalities.

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7. There are three stages in the pathophysiologic mechanisms of acute cellular rejection*: a. Presentation of allograft antigens to the host: Allograft antigens are recognized by the host T cells via interaction of the T-cell receptor (TCR) and particularly the CD4 antigen on the surface of the host lymphocytes with the MHC molecules expressed on the surface of the graft cells. This interaction involves many components that include adhesive molecules (promote strong adhesion between graft cells and binding T-cells) and co-stimulatory cells (e.g., CD28 and B7 that are necessary for T-cell activation). b. T-cell activation and cytokine release: Once there is binding of the T-cell receptor with the MHC antigens, a cascade of intracellular signaling occurs with production and release of cytokines (e.g., interleukins, interferon, monocyte chemotactic protein) that have a variety of pro-inlammatory effects including the generation of cytotoxic T lymphocytes, activation of macrophages, and up-regulation of co-stimulatory cells. c. Effector mechanisms in cell-mediated injury: The cytotoxic T lymphocyte then mediate cell damage, with a mixed population of CD4 and CD8 lymphocytes seen in varying proportions, the CD8 responsible for damage to bile duct epithelium, endothelial cells, and to some extent the hepatocytes in the perivenular zone. The CD8 T-cell– mediated damage occurs by way of two pathways: i. Synthesis and secretion of cytolytic granules (perforin, granzymes, granulysin): After T-cell binding with the target cell, these granules are released and fuse with the cell membrane, causing membrane pores, further inlux of the cytolytic proteins, and activation of caspases with resultant apoptosis of the target cell. ii. Expression of Fas ligand (FasL): The ligand binds to the Fas, located on the surface of the hepatocytes, bile ducts, and endothelial target cells, which is *Hubscher SG, Portmann BC. Transplantation pathology. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver. 5th ed. London: Churchill-Livingstone; 2007: 815-879.

A

enhanced by cytokines released from the activated T cells, resulting in the cleaving and disassembly of the cellular structure with eventual cell death. Treatment and prognosis 1. Standard treatment of acute cellular rejection is an intravenous bolus dose of corticosteroids (usually 1 g in proven moderate or severe cases) and rapid tapering of dosage over a few days with maintenance of adequate levels of other immunosuppressive drugs such as tacrolimus, cyclosporine, or sirolimus. 2. In milder forms, increase in dose of immunosuppressive drugs and corticosteroids (without the bolus and taper regimen) is tried. 3. The response to treatment is generally good with resolution of injury and improvement in liver tests. Less frequently, treatment with monoclonal antibody or antilymphocyte globulin (OKT3) is necessary.

Chronic (Ductopenic) Rejection (Figs. 11-16 through 11-21) Major morphologic features 1. Interlobular bile ducts show considerable cytologic atypia including irregularly spaced hyperchromatic and pyknotic nuclei, and lattened to irregular eosinophilic cytoplasm, without inlammatory cells oriented to the ducts (early reversible stage). 2. Eventually the bile ducts become depleted in the majority of portal tracts (advanced irreversible stage). 3. Subendothelial intraluminal foam cells develop within small and medium-sized hepatic arteries (obliterative vasculopathy). Other features 1. Although small interlobular bile ducts are usually involved, medium-sized and larger ducts can also be affected, best appreciated in explanted livers (obtained from retransplant). 2. With time depletion of hepatic arterioles may also occur.

B

FIGURE 11-16 Chronic (ductopenic) rejection (early). Both images show interlobular bile ducts in the early stage of chronic rejection. A, The duct epithelium is markedly eosinophilic, with cytoplasmic damage and focal detachment from the duct basement membrane. There is marked distortion and irregularity of the nuclei. B, The interlobular bile duct shows considerable nuclear irregularity, with focal loss of nuclei and considerable cytoplasmic damage and loss. Note also that there is only a mild portal inlammatory iniltrate in both examples, without these inlammatory cells oriented to the damaged ducts.

Chapter 11 / Transplantation

A

331

B

FIGURE 11-17 Chronic (ductopenic) rejection (late). A and B, Both portal tracts show total loss of the interlobular bile ducts, with scanty to absent portal lymphocytic iniltrates. Small arterioles are seen; however, in some instances of late chronic rejection there also may be a decrease in arterioles.

A

B

FIGURE 11-18 Chronic (ductopenic) rejection. A and B, Both images show small hepatic arteries almost totally occluded by foamy histiocytes (obliterative vasculopathy).

A

B

FIGURE 11-19 Chronic (ductopenic) rejection. A, The lumen of this hepatic artery segment is almost totally occluded by foamy histiocytes (obliterative vasculopathy). B, This medium-sized hepatic artery shows iniltration by foamy histiocytes. Prominent ibrointimal thickening of the intima is also present.

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Part I / Liver and Hepatobiliary Pathology with Clinical Correlations

FIGURE 11-20 Chronic (ductopenic) rejection. Perivenular ibrosis

FIGURE 11-21 Chronic (ductopenic) rejection. Clusters of foamy his-

and cholestasis is present.

tiocytes are often present scattered within the hepatic lobule.

3. Perivenular ballooning of hepatocytes is often seen, with associated cholestasis. In severe cases the cholestasis may become diffuse. 4. Fibrosis and sclerosis of portal and terminal hepatic venules, with variable perivenular ibrosis, may occur. 5. Occasionally a bridging ibrosis may be seen between terminal hepatic venules. Biliary cirrhosis has been reported but is quite uncommon. 6. Variable lymphocytic iniltrates can also be seen within the intima in affected vessels. 7. Aggregates of foam cells can be identiied within the sinusoids. 8. With time the foam cells in the arteries are replaced by intraluminal myoibroblasts (ibromyointimal proliferation) with considerable intraluminal narrowing. 9. Portal tracts show only a mild lymphocytic iniltrate. When duct loss is complete, portal tracts become devoid of inlammatory cells. Note: Both duct loss and obliterative vasculopathy are components of chronic rejection, and it is likely that duct loss in many cases may be due to duct ischemia secondary to the vasculopathy; however, studies have shown that duct loss can occur without evidence of vasculopathy in 14% of cases, and vasculopathy can be seen without evidence of duct loss in 15% of cases.

of these liver diseases may eventually progress to a biliary cirrhosis. Adenovirus infection in the pediatric population can also rarely be associated with duct injury and eventual duct loss; however, characteristic nuclear inclusions (smudge cells) are also present with this infection, and rarely a severe conluent parenchymal necrosis may also occur. Chronic rejection, however, is associated with mild portal ibrosis, with occasional bridging ibrosis seen between terminal hepatic venules, without cirrhosis (rare cases reported) or signiicant lobular inlammation or necrosis. In addition, portal inlammation diminishes as duct loss develops, with most portal tracts showing virtually no portal inlammation at the time of late stage chronic rejection. 2. Drug-induced liver injury (e.g., chlorpromazine, chlorpropamide; see Table 5-11): Certain drugs are associated with bile duct injury and ductopenia. Correlation with the timeframe of initiation of the drug and the onset of abnormal liver tests is important. In drug-induced duct injury, after the drug is discontinued, the vast majority of cases will show eventual resolution of the duct damage; if the etiology is chronic rejection, however, duct damage will persist with eventual bile duct loss. 3. Bile duct ischemia from hepatic artery thrombosis: Bile duct ischemia with eventual bile duct loss can also occur in partial or total hepatic artery occlusion from hepatic artery thrombosis. The liver injury in this setting is acute and severe due to coexisting ischemic necrosis of the parenchyma, and arteriography conirms the appropriate diagnosis.

Grading of chronic rejection (Banff criteria) 1. Liver allograft pathology for chronic ductopenic rejection is graded by use of the Banff scoring system and is subdivided into early and late chronic rejection. Unlike acute rejection, no numerical scoring system is used. A summary of the criteria are listed in Table 11-4. Differential diagnosis 1. Recurrent and infectious disorders associated with duct loss: A number of recurrent liver diseases post-transplant are associated with ductopenia (e.g., primary biliary cirrhosis and primary sclerosing cholangitis). These conditions are associated with prominent portal lymphocytic iniltrates and in some instances (e.g., primary biliary cirrhosis) numerous portal plasma cells, with the majority having some degree of portal ibrosis as well. In addition, many

Clinical and biologic behavior 1. Chronic rejection is usually seen within a few weeks to 6 months, and in rare instances many years post-transplant, and is characterized by the unrelenting and gradual loss of bile ducts associated with progressive foamy arteriopathy. 2. Chronic rejection was seen in 11.3% cases in earlier studies, but now the rate is 1.3% and will continue to decrease secondary to improvement in immunosuppressive drugs and improved extra-corporeal graft preservation. 3. Chronic rejection occurs in two ways: a. Acute rejection that does not respond to anti-rejection medications, with persistent duct damage and eventual duct loss.

Chapter 11 / Transplantation

TABLE 11-4

333

Grading of Chronic Allograft Rejection

HISTOPATHOLOGIC STRUCTURES

EARLY CHRONIC REJECTION

LATE CHRONIC REJECTION

Small bile ducts (50% of portal tracts • Mural ibrosis and inlammation of large bile ducts

Terminal hepatic venules, perivenular zone hepatocytes

• Mild perivenular ibrosis • Mild perivenular necrosis, liver cell swelling and dropout

• Severe perivenular ibrosis with focal central-tocentral bridging • Hepatocyte swelling and dropout with cholestasis

Hepatic artery/arterioles

• Mild subintimal, adventitial and focal medial foam cell accumulation • Occasional loss of small portal hepatic artery/arterioles involving 25% of portal tracts

Other

• “Transition” hepatitis with spotty necrosis

• Sinusoidal foam cell deposition • Marked cholestasis

Eosinophilic transformation of the cytoplasm Increased nuclear: cytoplasmic ratio Nuclear hyperchromasia Uneven nuclear spacing Ducts only partially lined by biliary epithelial cells Bile duct loss in 50% of liver cells involved) or modest (≤50% of liver cells involved). In addition, the table shows whether the fatty change that is present is predominantly macrovesicular or microvesicular, or whether both types are equally present. Although many of the liver diseases that contain fat have associated inlammation (e.g., neutrophils in alcoholic hepatitis, lymphocytes in chronic viral hepatitis due to HCV infection), this table relates only to the fatty change itself. (Figs. II-33 through II-35, and Table II-12)

FIGURE II-33 Fatty change. Alcoholic fatty liver.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-34 Fatty change. Alcoholic foamy degeneration.

FIGURE II-35 Fatty change. Non-alcoholic steatohepatitis.

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TABLE II-12

Fatty Change MACROVESICULAR

MICROVESICULAR

CHAPTER

FATTY CHANGE, PROMINENT (>50%) Abetalipoproteinemia

++

Acute alcoholic fatty liver (steatosis) with or without cholestasis

++

Acute fatty liver of pregnancy

+

++

12

Alcoholic hepatitis

++

+

4

Alcoholic fatty liver

++

Alcoholic foamy degeneration

+

++

4

Alpers disease

+

8 4

4 ++

8

+

++

8

++

+

8

Hereditary fructose intolerance

++

+

8

Homocystinuria

++ ++

12

Cholesterol ester storage disease Drug-induced (see Table 5-6) Galactosemia

5

Kwashiorkor (early stage)

8

Kwashiorkor (later stage)

++

Long chain acyl-CoA dehydrogenase deiciency

++

+

8

Medium chain acyl-CoA dehydrogenase deiciency

+

++

8

Non-alcoholic fatty liver

++

Non-alcoholic steatohepatitis

++

+

4

Perivenular alcoholic ibrosis

++ ++

12 12

Reye syndrome

12

4 4

Reye syndrome (recovery)

+

++

Systemic carnitine deiciency

++

+

Weber-Christian disease

++

Wolman disease

+

8 12

++

8

FATTY CHANGE, MODERATE (≤50%) Acute viral hepatitis, HBV and δ Allograft, recurrent viral hepatitis type B and type C (steatoviral)

++

2

++

11

α1-Antitrypsin deiciency

++

8

Amebiasis

++

7

Chronic granulomatous disease of childhood

++

8

Chronic viral hepatitis, HBV and δ

++

2

Chronic viral hepatitis, HCV

++

Cystic ibrosis

++

2 8

Cytomegalovirus

++

2, 11

Epstein-Barr virus

++

2, 11

Gilbert syndrome

++

8

Glycogen storage disease I

++

8

Glycogen storage disease II

++

8

Glycogen storage disease VI

++

8

Graft versus host disease

++

11

Hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome

++

12

Hepatic venous outlow obstruction (Budd-Chiari syndrome), acute

++

+

6

Hepatic venous outlow obstruction (Budd-Chiari syndrome), chronic

++

+

6

Hereditary hemochromatosis

++

Hereditary tyrosinemia

++

Human immunodeiciency virus (HIV)

++

9 8 +

2

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-12

Fatty Change—cont’d MACROVESICULAR

Hyperalimentation (TPN), adult

MICROVESICULAR

++

Hyperpyrexia and heat stroke

CHAPTER 12

++

12

Hyperthyroidism

++

12

Inlammatory bowel disease: ulcerative colitis, Crohn’s disease

++

12

Leishmaniasis

++

Lyme disease

7 ++

7

Malaria

++

7

Mannosidosis

++

8

Marasmus

++

12

Nonspeciic reactive hepatitis

++

12

Polymyalgia rheumatica

++

12

Porphyria cutanea tarda

++

8

Primary sclerosing cholangitis

++

3

Q fever

++

7

Reactive changes, bacterial infections

++

7

Rheumatoid arthritis

++

12

Rocky Mountain spotted fever

++

7

Rubeola

++

Salmonellosis

2 ++

7

Sickle cell anemia

++

8

Systemic lupus erythematosus

++

12

Toxic shock syndrome

++

Toxoplasmosis

++

Tuberculosis

++

Wilson disease

++

Yellow fever + occasional type seen; ++ predominant type seen.

7 7 7

+

9

++

2

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Granulomas Granulomas are loosely deined as collections of inlammatory cells. Epithelioid granulomas are well-demarcated and are composed of variable numbers of lymphocytes, occasional plasma cells, and prominent numbers of activated macrophages which have round to indented clear nuclei and abundant eosinophilic cytoplasm (epithelioid cells). Multinucleated giant cells are sometimes seen. Inlammatory granulomas are usually smaller than the epithelioid type and are composed of a mixed inlammatory iniltrate consisting of lymphocytes, macrophages, and occasional plasma cells, neutrophils and eosinophils. These granulomas may or may not be poorly demarcated. Although occasional multinucleated giant cells can be seen, they are much less frequent than in the epithelioid granulomas. A combination of both epithelioid and inlammatory granulomas may be seen within the same biopsy specimen. Granulomas may occur anywhere within the liver. Although in some instances they may be more prominent within the portal tracts (e.g., primary biliary cirrhosis), in other disorders they are seen more commonly within the lobules (e.g., drug-induced injury); however, many liver disorders such as sarcoidosis may demonstrate granulomas within the portal tracts and lobules. Some granulomas have unusual histologic features very characteristic of one disease entity (e.g., schistosomiasis with pipestem granuloma having a central schistosome ovum). Special stains may at times be helpful (e.g., AFB or PAS in Mycobacterium avium-intracellulare infection), although in immunocompetent patients, granulomas secondary to an infectious process (especially mycobacteria) are more often negative on special stains. In addition, some liver diseases may exhibit granulomas that coalesce (e.g., sarcoidosis), forming distinct mass lesions that may be visualized on imaging. (Figs. II-36 through II-38, and Table II-13)

FIGURE II-36 Granulomas. Primary biliary cirrhosis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-37 Granulomas. Drug-induced (sulfasalazine).

FIGURE II-38 Granulomas. Inlammatory bowel disease (Crohn’s).

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TABLE II-13

Granulomas EPITHELIOID

INFLAMMATORY

CHAPTER

Actinomycosis

+

7

Acute alcoholic fatty liver with or without cholestasis

+ (Lipogranuloma)

4

Acute viral hepatitis, HCV

+

2

Alcoholic fatty liver

+ (Lipogranuloma)

4

Alcoholic hepatitis

+ (Lipogranuloma)

4

Ascariasis

+

Blastomycosis

+

Boutonneuse fever Brucellosis

+

Candidiasis

+

Capillariasis Cat-scratch disease Chronic granulomatous disease of childhood

7 7

+

7

+

7

+ + (Necrotizing)

+

7 8

+

Cryptococcosis Cytomegalovirus

+ +

+

Churg-Strauss syndrome Coccidioidomycoses

7 7

6 7

+

7

+

2, 11

Drug-induced (see Table 5-7)

5

Echinococcosis (hydatid cyst)

+

Enterobiasis

+

7 7

Eosinophilic gastroenteritis

+

+

12

Epstein-Barr virus

+

+

2, 11

Farber lipogranulomatosis

+

8

Fascioliasis

+

7

Foreign body giant cell reaction*

+

Histoplasmosis

+

+

7

Human immunodeiciency virus (HIV)

+

+

2

Idiopathic granulomatous hepatitis

+

Inlammatory bowel disease: Crohn’s disease

+

Leishmaniasis

+

+ (Fibrin-ring)

7

Leprosy

+

–

12 12 +

7

Listeriosis

+

7

Melioidosis

+ (Necrotizing)

Mucolipidoses type II

+

Mycobacterium avium complex (MAC)

+

Neoplasms, tumor-like lesions: +

• Hodgkin’s lymphoma (in adjacent non-tumor liver)

+

• Fibrolamellar hepatocellular carcinoma

+

• Inlammatory pseudotumor

+

• Langerhans cell histiocytosis

+ (Histiocytes) +

Nocardiosis Non-alcoholic steatohepatitis (s/p bypass surgery)

7 10

• Hepatocellular carcinoma

• Liver cell adenoma

7 8

+ +

Non-alcoholic steatohepatitis

+ (Lipogranuloma)

Nonspeciic reactive hepatitis

+

Paracoccidioidomycosis

+

Penicilliosis

+

7 4 4 12 7 7

Pentastomiasis

+

7

Polyarteritis nodosa

+ (Necrotizing)

12

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-13

Granulomas—cont’d EPITHELIOID

Polymyalgia rheumatica Primary biliary cirrhosis

INFLAMMATORY +

+

CHAPTER 12 3

Q fever

+

+

7

Reactive changes, bacterial infections

+

+

7

Rheumatoid arthritis

+

12

Salmonellosis

+

Sarcoidosis

+

7 12

Schistosomiasis

+

+

7

Strongyloidiasis

+

+

7

+

7

Syphilis, congenital

+

Syphilis, secondary

+

Syphilis, tertiary (gumma)

+

Systemic lupus erythematosus

7 7 +

12

Toxoplasmosis

+

+

7

Tuberculosis

+

+ (Immunocompromised)

7

Visceral larva migrans

+

+

Whipple disease

+

Zygomycosis *Foreign

7 7

+ (Necrotizing)

7

body giant cell granulomas are most frequently seen in patients who have had previous hepatobiliary surgery; although IV drug users may have polarizable talc-like injectant within portal tracts, this foreign material seldom elicits a giant cell reaction.

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Inclusions: Hepatocytes Inclusions within liver cells may be subdivided into nuclear and cytoplasmic. The inclusions may be seen as single well-demarcated round cytoplasmic globules (e.g., megamitochondria in alcoholic fatty liver) or may be numerous within the same cell (e.g., α1-antitrypsin globules in periportal hepatocytes). Inclusions may also diffusely involve the cytoplasm and have a inely granular to smooth appearance (“ground glass-like”). Special stains can at times be helpful in classifying the etiology of the inclusions (e.g., orcein or immunoperoxidase stains identifying the HBsAg particles of the ground glass cells in chronic HBV infection). Glycogenated nuclei are enlarged liver cell nuclei that are clear on hematoxylin-eosin stain, the glycogen best demonstrated on PAS stain using frozen section material, glycogen being water soluble. Although hepatocytes containing these nuclei tend to be periportal, in some liver diseases such as Wilson disease they may be focal or diffuse. A Mallory body is a speciic type of cytoplasmic inclusion that is discussed and demonstrated in a separate table (Table II-19). (Figs. II-39 through II-42, and Table II-14)

FIGURE II-39 Inclusions, hepatocytes (nuclear). Glycogenated nuclei (diabetic patient).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-40 Inclusions, hepatocytes (nuclear). Herpes simplex virus.

FIGURE II-41 Inclusions, hepatocytes (cytoplasmic). Chronic viral hepatitis (HBV infection, ground-glass cells).

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FIGURE II-42 Inclusions, hepatocytes (cytoplasmic). Alcoholic liver disease, megamitochrondria (trichrome stain).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-14

Inclusions: Hepatocytes VIRAL

GLYCOGENATED

CHAPTER

INCLUSIONS, NUCLEAR Adenovirus

+

2

α1-antitrypsin deiciency

+

8

Chronic viral hepatitis, HCV

+

2

Cytomegalovirus (immunocompromised, allograft)*

+

2, 11

Glycogen storage diseases I, III, VI

+

8

Hereditary hemochromatosis

+

9

Herpes simplex virus

+ (Cowdry A, B)

2, 11

Herpes zoster

+

2

Non-alcoholic fatty liver

+

Non-alcoholic steatohepatitis

+

Parvovirus (B19 virus)

+

Porphyria cutanea tarda Rubeola Yellow fever

4 2

+ +

Wilson disease

4

8 2

+ + TYPE OF INCLUSIONS

9 2 CHAPTER

INCLUSIONS, CYTOPLASMIC Acute alcoholic fatty liver with or without cholestasis

Megamitochondria

4

Acute fatty liver of pregnancy

Megamitochondria

12

Alcoholic fatty liver

Megamitochondria

4

Alcoholic foamy degeneration

Megamitochondria

4

Alcoholic hepatitis

Megamitochondria

4

α1-Antichymotrypsin deiciency

Periportal eosinophilic DiPAS+ globules (α1-chymotrypsin)

8

α1-Antitrypsin deiciency

Periportal eosinophilic DiPAS+ globules (α1-antitrypsin)

8

Chronic viral hepatitis, HBV (with or without δ)

Ground glass cells (HBsAg)

2

Cytomegalovirus (immunocompromised, allograft)*

Cytoplasmic inclusions

2, 11

Drug-induced (see Table 5-15)

Cytoplasmic inclusions, “ground glass–like” cells

5

Fibrinogen storage disease

Eosinophilic globules (ibrinogen); intracytoplasmic globules (C3, C4 complements)

8

Glycogen storage disease IV

Eosinophilic DiPAS-positive globules (amylopectin)

8

Hypoxic injury secondary to hypotension

Eosinophilic hyaline globules within perivenular liver cells

6

Lafora disease

Periportal eosinophilic globules (branched polyglucosan)

8

Mannosidosis

PAS negative vacuoles

8

Non-alcoholic steatohepatitis

Megamitochondria

4

Perivenular alcoholic ibrosis

Megamitochondria

4

Porphyria cutanea tarda

Needle-shaped, birefringent

8

Reye syndrome

Distorted mitochondria

12

Rubeola

Eosinophilic globules

2

Venous congestion secondary to rightsided heart failure

Eosinophilic hyaline globules within perivenular hepatocytes

6

*Inclusions

also can be seen in bile duct epithelium, Kupffer cells, and hepatocytes.

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Inclusions: Kupffer Cells, Portal Macrophages The Kupffer cell is the hepatic component of the mononuclear phagocyte, whereby blood monocytes originating from bone marrow macrophage stem cells are deposited along the sinusoids of the liver as well as in other organs such as the spleen and lungs. These cells can be activated by certain stimuli and function as a host defense against bacteria, parasites, viruses and tumor cells, and also function in clearing endotoxins from the circulation. Activation of Kupffer cells may also induce liver cell injury by the release of cytokines and proteases. Kupffer cells can be seen as hyperplastic in a wide variety of inlammatory conditions in the liver (e.g., acute viral hepatitis), and in that way are not diagnostically helpful and not included in this table; however, certain liver diseases may demonstrate characteristic distinct deposits within Kupffer cells and occasionally within portal macrophages. For instance, the striated wrinkled cytoplasmic inclusions within markedly enlarged Kupffer cells are virtually diagnostic of Gaucher disease. Of note is that the sinusoidal endothelial cells can also at times exhibit some degree of phagocytic function and most often cannot be distinguished from Kupffer cells on routine hematoxylin-eosin stain. (Figs. II-43 and II-44, and Table II-15)

FIGURE II-43 Inclusions, Kupffer cells. Salmonellosis (erythrophagocytosis).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-44 Inclusions, Kupffer cells. Infection-associated hemophagocytic syndrome (erythrophagocytosis).

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TABLE II-15

Inclusions: Kupffer Cells, Portal Macrophages INCLUSIONS

CHAPTER

Amyloidosis (globular type)

Globules (portal macrophages)

Babesiosis

Ring-shaped parasites

12 7

Borreliosis (relapsing fever)

Erythrophagocytosis

7

Brucellosis

Gram negative coccobacilli

7

Cholesterol ester storage disease

Birefringent cholesterol ester crystals

8

Chronic viral hepatitis

Polarizable particulate material (injectant)*

2

Cryptococcosis

Encapsulated yeast forms

7

Cystinosis

Hexagonal cylindrical birefringent crystals

8

Drug-induced (see Table 5-15)

5

Erythropoietic protoporphyria

Red-yellow birefringent Maltese cross crystals (protoporphyrin)

8

Fabry disease

Birefringent granular crystals

8

Gangliosidosis, GM1 (types 1 and 2)

Vacuolated inely lipid-laden

8

Gangliosidosis, GM2 (Sandhoff )

PAS-positive, Luxol-fast blue-positive granules

8

Gaucher disease

Striated wrinkled cytoplasm

8

Histoplasmosis

Intracytoplasmic encapsulated yeast (“halo” forms)

7

Human immunodeiciency virus (HIV)

Erythrophagocytosis

2

Infection-associated (reactive) hemophagocytic syndrome

Erythrophagocytosis

12

Leishmaniasis

Oval to rod-shaped parasites

7

Leptospirosis (Weil disease)

Erythrophagocytosis

7

Malaria

Ring-shaped parasites; hemozoin pigment

7

Metachromatic leukodystrophy†

Large foamy portal macrophages with metachromatic granules

8

Mucolipidoses types I, II, III, IV

Lipid-laden foamy cytoplasm

8

Mucopolysaccharidoses types I, II, III, IV, VI, VII

Vacuolated cytoplasm

8

Niemann-Pick disease

Foamy vacuolated cytoplasm

8

Penicilliosis

Non-budding yeast

7

Rocky Mountain spotted fever

Erythrophagocytosis

7

Salmonellosis

Erythrophagocytosis; organisms (gram stain)

7

Sickle cell anemia

Sickled red blood cells in Kupffer cells; erythrophagocytosis

8

Systemic mastocytosis

Mast cells within portal tracts, sinusoids

12

Tangier disease

Foamy cytoplasm; needle-shaped birefringent cholesterol crystals

8

Whipple disease

Foamy DiPAS-positive cytoplasm (containing sickle-type bacilli)

7

Wolman disease

Foamy DiPAS-positive cytoplasm; birefringent cholesterol ester crystals

8

*Injectant †Granules

is usually extracellular within portal tracts but may sometimes be seen within portal macrophages and Kupffer cells. also seen in bile duct epithelium and less commonly in Kupffer cells and hepatocytes.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Lobular Necrosis with Inlammation One of the most frequent morphologic features seen in liver biopsy material is the lobular inlammatory iniltrate with corresponding liver cell injury and necrosis (necroinlammatory change). This table is subdivided as to the type of inlammatory cells predominantly involved (lymphocytes versus neutrophils) and whether or not cholestasis is a frequent associated occurrence. In all the listed conditions, a portal inlammatory iniltrate is also present, and may be predominantly lymphocytic, neutrophilic, or mixed. The PAS stain after diastase digestion (DiPAS) is often helpful in determining the degree of necroinlammatory change, as the areas of focal necrosis often demonstrate increased lysosomal activity within Kupffer cells and histiocytes, these cells DiPAS positive. Granulomas represent speciic types of inlammation and are dealt within a separate table (Table II-13); however, some liver diseases that characteristically cause granuloma formation may also be associated with variable lobular necrosis and inlammation as well (e.g., sarcoidosis, cytomegalovirus) and are also listed in this present table. (Figs. II-45 through II-47, and Table II-16)

FIGURE II-45 Lobular necrosis with inlammation. Acute viral hepatitis (lymphocytes).

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FIGURE II-46 Lobular necrosis with inlammation. Drug-induced (lymphocytes, cholestasis; chlorpromazine).

FIGURE II-47 Lobular necrosis with inlammation. Alcoholic hepatitis (neutrophils).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-16

Lobular Necrosis with Inlammation INFLAMMATORY CELLS LYMPHOCYTES

NEUTROPHILS

CHOLESTASIS

CHAPTER

Acute alcoholic fatty liver with or without cholestasis

+

•

4

Acute viral hepatitis, fulminant

++

•

2

Acute viral hepatitis, typical type

++

•

2

Alcoholic foamy degeneration

+

•

4

•

4

•

11

•

11

•

11

•

11

Alcoholic hepatitis Allograft, acute (cellular) rejection

++ +

Allograft, acute graft failure (primary nonfunction) Allograft, chronic (ductopenic) rejection

+ +

Allograft, hyperacute (humoral) rejection

+

Allograft, preservation (harvesting, reperfusion) injury

+

•

11

Allograft, recurrent viral hepatitis type B and type C (ibrosing cholestatic hepatitis)

+

•

11

Alpers disease

+

8

α1-Antitrypsin deiciency (adult)

+

8

α1-Antitrypsin deiciency (neonate)

+/++

Amebiasis (early stage)

•

8

+

7

Autoimmune hepatitis (untreated)

++

•

12

Benign recurrent intrahepatic cholestasis

+

•

8

Biliary atresia, extrahepatic*

+

•

8

Borreliosis

+

7

Boutonneuse fever

+

7

Brucellosis

+

7

Caroli disease

+/++

•

8

Choledochal cyst (associated bile duct obstruction)

+/++

•

8

Chronic viral hepatitis, typical type

+

Chronic viral hepatitis (reactivation)

++

Coronavirus

++

Cystic ibrosis

+

Cystic ibrosis (rupture of cholangioles)

2

+

Cytomegalovirus (allograft)

+

Down syndrome

+

2

•

8

•

8

2 +

Cytomegalovirus

•

2 + (Clusters)

11 8

Drug-induced (see Tables 5-4, 5-10)

5

Epstein-Barr virus

+

Erythropoietic protoporphyria

+

Extrahepatic bile duct obstruction, early and mid stages†

+

2, 11

+/++

•

8

•

3

Continued

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TABLE II-16

Lobular Necrosis with Inlammation—cont’d INFLAMMATORY CELLS LYMPHOCYTES

Extrahepatic bile duct obstruction, late stage†

NEUTROPHILS

+

CHOLESTASIS

CHAPTER

•

3

•

11

Graft versus host disease

+/++

Group B coxsackie

+

Hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome

+

12

Hereditary hemochromatosis

+

9

Hereditary hemochromatosis (neonate)

++

•

9

Hereditary tyrosinemia

+

•

8

Human herpes virus-6 (HHV)

+

Human immunodeiciency virus (HIV)

+

Hyperthyroidism

+

Idiopathic adulthood ductopenia

+

+

•

2

2 •

2 12

• +

3

Indian childhood cirrhosis

+

Inlammatory bowel disease: Crohn’s disease

+

12

9

Inlammatory bowel disease: Ulcerative colitis

+

12

Leishmaniasis

+

•

Leptospirosis (Weil disease)

+

•

Lyme disease

+

7 7 7

Neonatal hepatitis

++

Niemann-Pick disease (neonate)

+

Nonspeciic reactive hepatitis

+

Parvovirus (B19 virus)

+/++

Perivenular alcoholic ibrosis

+

4

Polymyalgia rheumatica

+

12

Porphyria cutanea tarda

+

Primary biliary cirrhosis*

+

•

3

Primary sclerosing cholangitis†

+

•

3

Pyogenic abscess

+

+

Reactive changes, bacterial infections

+

8 8 12

•

2

8

++

Q fever

• •

•

7 7

+

•

7

++

•

3

+

•

7

Rubella

+/++

•

2

Rubeola

+

Salmonellosis

+

Sarcoidosis

+/++

Recurrent pyogenic cholangiohepatitis Rocky Mountain spotted fever

Syphilis, congenital

++

Syphilis, secondary

+

Systemic lupus erythematosus

+

Toxic shock syndrome

+

2 7 •

12

•

7

•

12

•

7

7 +

+

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-16

Lobular Necrosis with Inlammation—cont’d INFLAMMATORY CELLS LYMPHOCYTES

Toxoplasmosis

+

Tuberculosis

+

Weber-Christian disease

+

Wilson disease

+/++

Yellow fever

+

Zellweger syndrome

+

*Cholestasis

NEUTROPHILS

•

CHAPTER 7 7

+

is seen only in late-stage disease. lakes and bile infarcts also may occur. + mild inlammation; ++ moderate/severe inlammation; • cholestasis often present. †Bile

CHOLESTASIS

12 •

9 2

•

8

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Lobular Conluent Necrosis with Inlammation Certain liver diseases may be associated with lobular inlammation and necrosis that is severe, and may become conluent, with extensive liver cell dropout and associated lobular collapse of the reticulin framework. The inlammatory iniltrates are usually mononuclear (e.g., lymphocytes in acute viral hepatitis, lymphocytes and plasma cells in autoimmune hepatitis), and the necrosis sometimes may be associated with a zonal distribution pattern (e.g., perivenular conluent necrosis in severe acute viral hepatitis); however, at other times the necrosis may involve the entire lobule (panacinar necrosis in fulminant hepatitis). If the patient does survives the acute insult, there usually is complete resolution of the liver disease, with the hepatic lobules and liver tests resolving to normal within 6 months; however, in instances where bridging necrosis (merging together of the perivenular and periportal necrosis) occur, ibrosis can take the place of the sites of injury and remain afterwards. (Figs. II-48 and II-49, and Table II-17)

FIGURE II-48 Lobular conluent necrosis (panacinar) with inlammation. Fulminant viral hepatitis (HBV).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-49 Lobular conluent necrosis (perivenular) with inlammation. Autoimmune hepatitis.

TABLE II-17

Lobular Conluent Necrosis with Inlammation CHAPTER

Acute viral hepatitis, fulminant

2

Allograft, acute (cellular) rejection

11

Allograft, acute graft failure (primary nonfunction)

11

Allograft, hyperacute (humoral) rejection

11

Allograft, preservation (harvesting, reperfusion) injury (severe)

11

Alper disease Autoimmune hepatitis Chronic viral hepatitis (reactivation) Drug-induced (see Table 5-5) Graft versus host disease

8 12 2 5 11

Hereditary hemochromatosis (neonatal)

9

Wilson disease (fulminant)

9

Yellow fever

2

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Lobular Necrosis with Minimal to Absent Inlammation Although inlammation is a frequent inding associated with liver cell necrosis, in some liver diseases the degree of inlammation is minimal to absent. The liver cell necrosis may at times be patchy with no distinct zonal distribution pattern, or diffuse, involving most or all of the hepatic lobule. In many instances the associated liver diseases have some degree of vascular compromise. For example, in liver transplant patients, hyperacute (humoral) rejection is associated with sinusoidal red blood cell sludging and severe necrotizing endothelial damage of small arteries and arterioles, the end result being severe ischemic (coagulative) necrosis of hepatocytes due to poor vascular perfusion. Similarly, vasculitis in non-transplant patients (e.g., rheumatoid arthritis, systemic lupus erythematosus) may be associated with vascular thrombosis and liver cell ischemia. It must be noted that a neutrophilic iniltrate may be seen as a secondary response to ischemic necrosis. Interestingly, certain viral infections (e.g., adenovirus, herpesvirus) elicit only a minimal inlammatory response when compared to acute viral hepatitis from the more common hepatotropic viruses. (Figs. II-50 through II-52, and Table II-18)

FIGURE II-50 Lobular necrosis with minimal to absent inlammation. Drug-induced (acetaminophen).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-51 Lobular necrosis with minimal to absent inlammation. Herpes simplex virus infection.

FIGURE II-52 Lobular necrosis with minimal to absent inlammation. Hypoxic injury secondary to hypotension.

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TABLE II-18

Lobular Necrosis with Minimal to Absent Inlammation PATCHY

CONFLUENT

CHAPTER

Adenovirus

+

2

Allograft, hepatic artery thrombosis

+

11

Amebiasis

+

7

Aspergillosis

+

7

Churg-Strauss syndrome

+

6

Cirrhosis of any cause (secondary to ischemia from severe hypotension associated with bleeding esophageal varices)

+

6

Babesiosis

Dengue fever

+

7

+

2

Drug-induced (see Table 5-3) Ebola virus

5 +

2

Echovirus

+

+

2

Hepatic venous outlow obstruction (Budd-Chiari syndrome), acute

+

6

+

2, 11

Herpes simplex virus Herpes zoster

+

+

2

Hyperpyrexia and heat stroke

+

12

Hypoxic injury secondary to left-sided heart failure without hypotension (RBC lesion)

+

6

Hypoxic injury secondary to hypotension Lassa fever

+

Malaria Marburg virus

+

Pneumocystis carinii infection

+

+

6

+

2

+

7

+

2 7

Polyarteritis nodosa

+

12

Rheumatoid arthritis

+

12

Sickle cell anemia

+

8

Spontaneous rupture in pregnancy

+

12

Systemic lupus erythematosus (secondary to arteritis)

+

12

Toxemia of pregnancy

+

12

Veno-occlusive disease (VOD)

+

6

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Mallory Bodies Mallory bodies are intracytoplasmic inclusions within hepatocytes and have a characteristic eosinophilic “ropey” appearance on hematoxylin-eosin stain. These inclusions are composed in part of various polypeptides and cytokeratins, and result from damage of the intermediate ilaments in the liver cell cytoplasm due most frequently to chronic alcohol usage. The aggregates and ilaments can be divided into three ultrastructural variants, and can appear as parallel arrays (types I and II), as randomly oriented ilaments (type II), or as amorphous and granular material (type III) (see Figure 4-21). On trichrome stain these inclusions may stain either dark blue or red, and can also easily be conirmed on immunoperoxidase stains for ubiquitin and cytokeratin. In some instances neutrophils can be seen abutting against the cell membranes of hepatocytes containing Mallory bodies (“satellitosis”), these neutrophils occasionally iniltrating into the liver cell cytoplasm itself. Mallory bodies are a sign of irreversible liver cell injury, but the deposits may be seen in liver cell cytoplasm for extended periods of time. For instance, in a patient with alcoholic hepatitis who abstains from drinking, the Mallory bodies may still be identiied up to four months and very rarely up to 6 months after abstinence. Mallory bodies are present in a number of chronic cholestatic conditions as well, and their deposition can be caused by numerous drugs and toxins. Mallory bodies are also identiied in certain primary liver cell neoplasms and may be a helpful clue in differentiating these tumors from metastatic lesions. (Figs. II-53 through II-56, and Table II-19)

FIGURE II-53 Mallory bodies. Alcoholic hepatitis.

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FIGURE II-54 Mallory bodies. Primary biliary cirrhosis.

FIGURE II-55 Mallory bodies. Primary sclerosing cholangitis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-56 Mallory bodies. Hepatocellular carcinoma.

TABLE II-19

Mallory Bodies OCCURRENCE

CHAPTER

Abetalipoproteinemia

+

Alcoholic cirrhosis (active drinker)

++/+++

8 4

Alcoholic hepatitis

+++

4

α1-Antitrypsin deiciency

+

8

Biliary atresia, extrahepatic

+

8

+

3

Drug-induced (see Table 5-8) Extrahepatic bile duct obstruction, early to mid stage

5

Extrahepatic bile duct obstruction, late stage

+

3

Focal nodular hyperplasia

+

10

Glycogen storage disease Ia

+/++

8

Hepatocellular carcinoma, common patterns

+/++

10

Hyperalimentation (TPN), adults

+

12

Indian childhood cirrhosis

+++

Kwashiorkor

+

12

Liver cell adenoma

+

10

Perivenular alcoholic ibrosis

+

4

Primary biliary cirrhosis

++

3

Primary sclerosing cholangitis

++

3

Non-alcoholic steatohepatitis

++

4

Weber-Christian disease

+

12

Wilson disease

+/++

+++ common; ++ occasional; + rare.

9

9

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Space Occupying (Noncystic) Lesions, Benign Discrete mass lesions visualized on ultrasound, computed tomography, or magnetic resonance imaging may on ine needle aspirate yield only cytologically benign hepatocytes, duct epithelium, vascular channels, and/or inlammatory cells. Most often imaging can conidently estimate the likelihood of the benign nature of these lesions; however, many times a conirmatory tissue diagnosis is necessary. For example, focal nodular hyperplasia and oftentimes ibrolamellar hepatocellular carcinoma have characteristic centrally radiating scars on gross examination and imaging. It is imperative that the physician performing the biopsy is conident that the biopsy was indeed from the lesion, as certainly a misdiagnosis could be drastic (e.g., diagnosing “liver cell adenoma” when the ine-needle aspiration (FNA) missed the mass lesion and consisted only of benign hepatocytes, when repeat biopsy at a later time demonstrated hepatocellular carcinoma). (Figs. II-57 through II-59, and Table II-20)

FIGURE II-57 Space occupying (noncystic) lesions, benign. Liver cell adenoma.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-58 Space occupying (noncystic) lesions, benign. Bile duct adenoma.

FIGURE II-59 Space occupying (noncystic) lesions, benign. Focal nodular hyperplasia.

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TABLE II-20

Space Occupying (Noncystic) Lesions, Benign CHAPTER

Allograft, Epstein-Barr virus (PTLD) Amebiasis

11 7

Angiomyolipoma

10

Bile duct adenoma

10

Candidiasis Cavernous hemangioma

7 10

Cirrhosis (viral, alcoholic) with macroregenerative dysplastic nodules

2, 4

Cirrhosis (viral, alcoholic) with macroregenerative nodules, typical without dysplasia

2, 4

Drug-induced (see Table 5-14)

5

Enterobiasis

7

Fascioliasis

7

Focal fatty change

10

Focal nodular hyperplasia

10

Galactosemia (macroregenerative nodules)

8

Hepatobiliary cystadenoma

10

Infantile hemangioendothelioma

10

Inlammatory pseudotumor

10

Liver cell adenoma

10

Lymphangioma

10

Mesenchymal hamartoma

10

Nodular regenerative hyperplasia

10

Partial nodular transformation

10

Pyogenic abscess

7

Sarcoidosis

12

Tuberculosis

7

Visceral larva migrans

7

Zygomycosis

7

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Space Occupying (Noncystic) Lesions, Malignant When discrete mass lesions reveal malignant cells on biopsy or aspirate, the diagnosis may be straightforward. For example, thickened hepatic cords lined by endothelial cells are characteristic of hepatocellular carcinoma of trabecular type, while acellular ibrous bands laid down in a parallel fashion and interspersed between malignant hepatocytes having abundant eosinophilic cytoplasm is characteristic of ibrolamellar hepatocellular carcinoma. The diagnosis becomes more dificult when dealing with adenocarcinomas and poorly differentiated malignant neoplasms, where statistically metastatic disease is much more frequent than primary neoplasms (excluding tumors in the pediatric population). In these instances, the patient’s history of any known non-hepatic primary malignant neoplasm, and comparison of the histology of that tumor, if available, with the histology of the biopsy of the hepatic lesion, is most essential. Additionally, immunohistochemical staining can be most helpful as well (e.g., demonstrating estrogen receptor markers in metastatic breast carcinomas). (Figs. II-60 and II-61, and Table II-21)

FIGURE II-60 Space occupying (noncystic) lesions, malignant. Hepatocellular carcinoma.

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FIGURE II-61 Space occupying (noncystic) lesions, malignant. Cholangiocarcinoma.

TABLE II-21

Space Occupying (Noncystic) Lesions, Malignant CHAPTER

Allograft, Epstein-Barr virus (PTLD-lymphoma)

11

Angiosarcoma

10

Biliary cystadenocarcinoma

10

Cholangiocarcinoma

10

Embryonal rhabdomyosarcoma

10

Embryonal sarcoma

10

Epithelioid hemangioendothelioma

10

Drug-induced (see Table 5-14)

5

Fibrolamellar hepatocellular carcinoma

10

Fibrosarcoma

10

Glycogen storage disease Ia (hepatocellular carcinoma)

8, 10

Hepatoblastoma

10

Hepatocellular carcinoma (all patterns)

10

Langerhans cell histiocytosis*

10

Leiomyosarcoma

10

Leukemia*

10

Lymphoma, Hodgkin’s*

10

Lymphoma, non-Hodgkin’s*

10

Metastatic*

10

Multiple myeloma*

10

Myeloproliferative disorders*

10

Squamous cell carcinoma

10

Waldenstrom’s macroglobulinemia*

10

Yolk sac tumor

10

*Tumors

may be iniltrative and/or present as a mass (space-occupying) lesion.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Pigments The most common pigments seen in the liver are lipochrome, hemosiderin, and bile. Bile in liver biopsies is discussed in Table II-8 (Cholestasis, Simple) and Table II-16 (Lobular Necrosis with Inlammation) under the column for concomitant cholestasis. Lipochrome, which overall is the most common pigment seen in hepatocytes, is also known as the “wear and tear” pigment, and is more prominent in the perivenular and midzonal hepatocytes in the middle-aged to elderly population. This pigment is generally not associated with liver disease, although a similar type of pigment is seen in the Dubin Johnson syndrome. Hemosiderin may be seen within hepatocytes associated with increase in iron absorption (e.g., hereditary hemochromatosis) or within Kupffer cells and portal macrophages in disorders associated with hemolytic anemias (e.g., hereditary spherocytosis). Very often, pigment is seen in both liver cells and Kupffer cells. Copper cannot be visualized on hematoxylin-eosin stain, but requires special stains, either directly staining the copper (rubeanic acid, rhodanine) or copper-binding protein (orcein). This pigment on special stains is seen predominantly within the liver cell cytoplasm. Hemosiderin, copper, and copper-binding protein are irst deposited within periportal hepatocytes, but can diffusely involve virtually all liver cells in advanced disease. Table II-22B also lists less common pigments, their presence alone sometimes diagnostic of the liver disease (e.g., dark-brown autoluorescent pigment [protoporphyrin] within hepatocytes, bile duct epithelium and Kupffer cells in erythropoietic protoporphyria). (Figs. II-62 through II-65, and Tables II-22A and II-22B)

FIGURE II-62 Pigments. Bile, intracanalicular (extrahepatic bile duct obstruction).

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-63 Pigments. Bile, intracytoplasmic (extrahepatic bile duct obstruction).

FIGURE II-64 Pigments. Lipochrome-like (Dubin-Johnson syndrome).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-65 Pigments. Hemosiderin (hemochromatosis, top; with iron stain, bottom).

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-22A

Pigments HEPATOCYTES

KUPFFER CELLS/PORTAL MACROPHAGES

CHAPTER

HEMOSIDERIN Acute viral hepatitis Alcoholic cirrhosis

+

2

++

9

+

Anemias secondary to abnormal hemoglobins,* hemolysis†

4

Anemias secondary to chronic infection

+

+

9

Anemias secondary to ineffective erythropoiesis‡

+

+

9

Chronic viral hepatitis, HCV

+

2

Cystic ibrosis

+/++

8

Down syndrome

+/++

8

Drug-induced (see Table 5-15)

5

Epstein-Barr virus

+

Erythropoietic protoporphyria

+

Galactosemia

+/++

2, 11 8 8

Gaucher disease

+

8

Graft versus host disease

+

11

+

++

9

Hereditary hemochromatosis

++

+

9

Hereditary tyrosinemia

+

Hyperalimentation (TPN), adults

+

+

12

+

12

Hemosiderosis (secondary iron overload)

Infection-associated (reactive) hemophagocytic syndrome Inspissated bile syndrome Leukemia

+

8

+

3

++

10 10

Lymphoma

+

++

Malaria

+

++

7

Myeloproliferative disorders

+

+

10

Neonatal hepatitis

+/++

8

Non-alcoholic steatohepatitis

+

4

Porphyria cutanea tarda

+/++

Sickle cell anemia

+

++

8

Wilson disease

+

+

9

Zellweger syndrome

+

+

8

8

COPPER, COPPER-BINDING PROTEIN α1-Antitrypsin deiciency (neonate)

+

8

Biliary atresia, extrahepatic

++

8

Congenital hepatic ibrosis

+

8

Cystic ibrosis

+

8

Extrahepatic bile duct obstruction, late stage

+

3

Fibrolamellar hepatocellular carcinoma

+

10

Focal nodular hyperplasia

+

10

Galactosemia

+

8

Graft versus host disease

+

11

Hereditary fructose intolerance

+

8

Hyperalimentation (TPN), adults

+

12

Idiopathic adulthood ductopenia

++

3

Indian childhood cirrhosis

++

9

Paucity of ducts syndrome, nonsyndromatic

++

8

Paucity of ducts syndrome, syndromatic (Alagille syndrome)

++

8

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-22A

Pigments—cont’d HEPATOCYTES

KUPFFER CELLS/PORTAL MACROPHAGES

CHAPTER

Primary biliary cirrhosis (late stage)

++

3

Primary sclerosing cholangitis (late stage)

++

3

Progressive familial intrahepatic cholestasis (Byler syndrome)

++

8

Wilson disease

++

9

*Sickle

cell anemia, homozygous β-thalassemia. spherocytosis, glucose-6-phosphate dehydrogenase deiciency, pyruvate kinase deiciency. megaloblastic. + present; ++ present and often abundant. †Hereditary

‡Sideroblastic,

TABLE II-22B

Pigments, Other Material LOCATION TYPE

HEPATOCYTES

KUPFFER CELLS/PORTAL MACROPHAGES ++

CHAPTER

Angiosarcoma

Thorotrast (in non-tumor)

Chronic granulomatous disease of childhood

Lipochrome

Chronic viral hepatitis (IV drug users)

IV particulate material*

+/++

2

Cystinosis

Cystine

++

8

+

10 8

Drug-induced (see Table 5-15)

5

Dubin-Johnson syndrome

Lipochrome-like

++

Erythropoietic protoporphyria

Protoporphyrin†

++

Focal nodular hyperplasia

Lipochrome

+

8 ++

8 10

Gilbert syndrome

Lipochrome

+

8

Hepatoblastoma

Melanin

+

10

Liver cell adenoma

Lipochrome

+

Malaria

Hemozoin

Niemann-Pick disease

Lipochrome-like

+

8

Porphyria cutanea tarda

Lipochrome

+

8

Schistosomiasis

Hemozoin-like

Wilson disease

Lipochrome

10 ++

++ +

*More often seen free within portal tracts. †Also seen in bile canaliculi, interlobular bile ducts, and portal tracts. + present; ++ present and often abundant.

7

7 9

451

452

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Portal Lymphocytes One of the most frequent features seen in liver biopsy material is variable portal lymphocytic iniltrates. At times this represents a response to systemic disease and is not associated with abnormal liver laboratory tests. In speciic hepatic disorders, the iniltrate may be present to various degrees in a vast array of liver diseases (e.g., viral, non-viral infectious disorders, biliary tract, and metabolic diseases). Therefore, clinical and laboratory correlation is most essential for accurate biopsy interpretation. A more important inding associated with portal lymphocytic iniltrates is spillover of inlammatory cells into the adjacent periportal zones, surrounding individual and small group of hepatocytes, and termed periportal interface inlammatory activity (piecemeal necrosis by older terminology). The presence of periportal activity does hint at the development of portal ibrosis and eventual cirrhosis with time (e.g., chronic viral hepatitis); however, its presence to a minor degree does not always signal progressive disease. The degree of portal lymphocytic iniltrates (e.g., only scattered lymphocytes versus marked lymphocytic aggregates) is not emphasized in this table, as oftentimes any liver disease showing portal lymphocytes can have mild or marked iniltrates at any point in time, or even considerable variability from one portal tract to another in the same biopsy specimen; however, the liver diseases that can be associated with periportal activity are noted with an asterisk, as prominent periportal activity is an associated feature in disease progression if this activity cannot be held in check by therapy (e.g., interferon in chronic viral hepatitis, steroids in autoimmune hepatitis). (Figs. II-66 through II-69, and Table II-23)

FIGURE II-66 Portal lymphocytes. Chronic viral hepatitis (HCV infection).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-67 Portal lymphocytes. Primary biliary cirrhosis (germinal center formation).

FIGURE II-68 Portal lymphocytes. Autoimmune hepatitis (periportal activity).

453

454

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-69 Portal lymphocytes. Chronic viral hepatitis (HCV infection, periportal activity).

TABLE II-23

Portal Lymphocytes CHAPTER

Acute alcoholic fatty liver with or without cholestasis

4

Acute viral hepatitis, typical type*

2

Alcoholic cirrhosis

4

Allograft, acute (cellular) rejection*

11

Alper disease*

8

α1-Antichymotrypsin deiciency*

8

Autoimmune hepatitis, typical type*

12

Benign recurrent intrahepatic cholestasis

8

Biliary atresia, extrahepatic

8

Brucellosis

7

Caroli disease

8

Chronic granulomatous disease of childhood

8

Chronic viral hepatitis*

2

Cytomegalovirus

2, 11

Echovirus

2

Epstein-Barr virus

2, 11

Erythropoietic protoporphyria*

8

Extrahepatic bile duct obstruction, late stage

3

Graft versus host disease

11

Group B coxsackie

2

Hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome

12

Herpes simplex virus

2, 11

Human herpes virus-6 (HHV)

2

Hypereosinophilic syndrome*

12

Idiopathic adulthood ductopenia

3

Indian childhood cirrhosis

9

Inlammatory bowel disease: Crohn’s disease

12

Inlammatory bowel disease: Ulcerative colitis*

12

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-23

Portal Lymphocytes—cont’d CHAPTER

Inspissated bile syndrome

3

Lassa fever

2

Leishmaniasis

7

Leprosy

7

Leukemia, lymphocytic

10

Lymphoma, Hodgkin’s and non-Hodgkin’s

10

Neonatal hepatitis

8

Non-alcoholic steatohepatitis*

4

Nonspeciic reactive hepatitis

12

Parvovirus (B19 virus)

2

Paucity of ducts syndrome, nonsyndromatic

8

Paucity of ducts syndrome, syndromatic (Alagille syndrome)

8

Perivenular alcoholic ibrosis

4

Polymyalgia rheumatica

12

Porphyria cutanea tarda

8

Primary biliary cirrhosis*

3

Primary sclerosing cholangitis*

3

Q fever

7

Rheumatoid arthritis

12

Rocky Mountain spotted fever

7

Rubeola

2

Salmonellosis Sarcoidosis*

7 12

Syphilis, secondary

7

Tuberculosis

7

Visceral larva migrans

7

Wilson disease*

9

Yellow fever

2

*Associated

periportal interface inlammatory activity in active stages of the disease.

455

456

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Portal Neutrophils Neutrophils within portal tracts are most frequently seen in biliary tract obstruction, with the neutrophils oriented towards the interlobular bile ducts (acute cholangitis). Although acute cholangitis may clinically be suspected, sometimes that feature is not seen on biopsy, as acute cholangitis frequently does not involve all portal tracts equally, and may not be represented in a small biopsy specimen. In these cases it is not infrequent to see some degree of scattered portal neutrophils. Some liver diseases (e.g., bacterial sepsis) may exhibit portal neutrophils away from duct epithelium and have no clinical or radiologic evidence of bile duct obstruction. Additionally, in some instances of acute cellular rejection, neutrophils can be seen either scattered within the portal tracts or attacking interlobular bile ducts in the absence of biliary tract obstruction or stricture. This table lists disorders where portal neutrophils may be seen without deinite bile duct orientation. Note that many of these diseases (e.g., extrahepatic biliary tract obstruction) may also exhibit acute cholangitis when multiple tissue sections are examined. (Figs. II-70 and II-71, and Table II-24)

FIGURE II-70 Portal neutrophils. Alcoholic hepatitis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-71 Portal neutrophils. Extrahepatic bile duct obstruction.

TABLE II-24

Portal Neutrophils CHAPTER

Alcoholic hepatitis

++

4

Allograft, acute (cellular) rejection

+

11

Ascariasis

++

7

Autoimmune hepatitis, typical type

+

12

Biliary atresia, extrahepatic

+

8

Brucellosis

+

7

Caroli disease

+/++

8

Choledochal cyst (associated bile duct obstruction)

+/++

8

Churg-Strauss syndrome

+

6

Cystic ibrosis

+

8

Extrahepatic bile duct obstruction, early stage

++

3

Extrahepatic bile duct obstruction, early to mid stage

+/++

3

Group B coxsackie

+

2

Hepatic vein phlebitis

++

6

Hyperalimentation (TPN), infants

+

12

Inspissated bile syndrome

+

3

Polyarteritis nodosa

+

6

Primary biliary cirrhosis

+

3

Primary sclerosing cholangitis

+

3

Pylephlebitis

++

6

Pyogenic abscess

++

7

Reactive changes, bacterial infections

++

7

Recurrent pyogenic cholangiohepatitis

++

3

Rocky Mountain spotted fever

+

7

Syphilis, secondary

+

7

Toxic shock syndrome

+

7

Tuberculosis (severe)

+

7

+ present; ++ present and often abundant.

457

458

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Portal Plasma Cells Autoimmune hepatitis characteristically shows striking plasma cell iniltrates within the portal tracts and parenchyma in untreated patients; however, other liver diseases where autoreactivity may play a role (e.g., virus-induced) also may demonstrate numerous portal plasma cells. It is not unusual, for instance, to see a prominent plasma cell iniltrate in chronic viral hepatitis from hepatitis B virus infection. The plasma cells may be seen diffusely within the portal regions, but often occur as localized clusters at the periphery of the portal tracts. In instances where this iniltrate is striking and seen in the absence of a lobular hepatitis, a plasma cell dyscrasia becomes a worrisome possibility. Additionally, in many instances of post-transplant lymphoproliferative disorders (PTLD), a portal lymphoplasmacellular iniltrate may be prominent. In these instances, immunoperoxidase studies (e.g., B and T cells, κ and λ light chains) are essential in determining whether the iniltrates are polyclonal or monoclonal. (Figs. II-72 and II-73, and Table II-25)

FIGURE II-72 Portal plasma cells. Autoimmune hepatitis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-73 Portal plasma cells. Acute viral hepatitis (HAV).

TABLE II-25

Portal Plasma Cells CHAPTER

Acute fatty liver of pregnancy

+

Acute viral hepatitis, HAV

+/++

12

Acute viral hepatitis, typical type

+

2

Allograft, acute (cellular) rejection

+

11

Autoimmune hepatitis, typical type

++

12

Chronic granulomatous disease of childhood

+

8

Chronic viral hepatitis, HBV

+/++

2

Chronic viral hepatitis, HBV and δ

+/++

2

Chronic viral hepatitis, typical type

+

2

Echinococcosis (hydatid cyst)

+

7

Epstein-Barr virus

+/++

Hodgkin’s lymphoma

+

2

2, 11 10

Human immunodeiciency virus (HIV) (HIV-associated cholangiopathy)

+

2

Leishmaniasis

+

7

Multiple myeloma

++

10

Primary biliary cirrhosis

++

3

Primary sclerosing cholangitis

+

3

Q fever

+

7

Visceral larva migrans

++

7

Waldenstrom’s macroglobulinemia

++

10

Wilson disease

+

9

+ present; ++ present and often abundant.

459

460

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Portal Eosinophils Although the most common causes of increased portal eosinophils seen on liver biopsy are parasitic infestations and drug-induced hypersensitivity reactions, other liver diseases such as primary biliary cirrhosis may be noted to contain increased numbers of portal eosinophils as well. Usually the eosinophils are scattered within the portal tracts, although sometimes they are oriented to speciic portal structures (e.g., small- and medium-sized hepatic arteries in polyarteritis nodosa). Lobular iniltration can also be seen and is usually located within the sinusoids, especially when there is an associated eosinophilia. Of note is that whenever a liver disease such as acute and chronic viral hepatitis is associated with a prominent portal inlammatory iniltrate, eosinophils may occasionally be seen; however, in most cases the eosinophils are generally few in number and not considered for inclusion in this table. (Figs. II-74 through II-76, and Table II-26)

FIGURE II-74 Portal eosinophils. Drug-induced (chlorpropamide).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-75 Portal eosinophils. Allograft, acute (cellular) rejection.

FIGURE II-76 Portal eosinophils. Visceral larva migrans.

461

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-26

Portal Eosinophils CHAPTER

Acute fatty liver of pregnancy

+

12

Allograft, acute (cellular) rejection

+/++

11

Ascariasis

++

7

Capillariasis

++

7

Churg-Strauss syndrome

+

6

Clonorchiasis*

+/++

7

Echinococcosis (hydatid cyst)

++

7

Enterobiasis

++

7

Eosinophilic gastroenteritis

++

12

Epstein-Barr virus (EBV)

+

2, 11

Fascioliasis

++

7

Hodgkin’s lymphoma

+

10

Hypereosinophilic syndrome

++

12

Polyarteritis nodosa

+

6

Primary biliary cirrhosis

+/++

3

Primary sclerosing cholangitis

+

3

Recurrent pyogenic cholangiohepatitis†

+/++

3

Schistosomiasis (early)

++

7

Strongyloidiasis

++

7

Visceral larva migrans

++

7

*Large

interlobar and hilar ducts involved. associated with clonorchiasis. + present; ++ present and often abundant. †When

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Portal Fibrosis The majority of chronic liver diseases that demonstrate portal ibrosis may eventually lead to cirrhosis, deined as ibrous bands with regenerative nodule formation. Dependent on their size, the nodules are termed micronodular (≤3 mm in diameter) or macronodular (>3mm in diameter). Not infrequently some of the macronodules may subdivide into micronodules as the disease becomes advanced, hence both macro- and micronodules (“mixed” pattern) may be seen in the same liver. When cirrhosis is due to a disorder such as primary biliary cirrhosis, the nodules often tend to have a geographic pattern, with the ibrous bands exhibiting collagen laid down in a parallel fashion around the nodules. This type of cirrhosis is termed biliary, these nodules usually but not always small and “micronodular” in size. This table in part lists the various causes of cirrhosis. The list, however, is not broken down into macronodular versus micronodular, as there is a tremendous degree of overlap in the size of the regenerative nodules in many liver diseases. For example, it is often said in the literature that cirrhosis secondary to chronic hepatitis from HBV infection is macronodular, yet autopsy indings have clearly shown that the nodules can be small (micronodular), especially in the advanced stages of the disease. Similarly, the patient with alcoholic cirrhosis who has stopped drinking is said to eventually develop a macronodular cirrhosis; however, in examining explanted livers from alcoholics who have abstained, the nodules may still be micronodular, or the pattern may be mixed. This table also lists the chronic liver diseases that characteristically exhibit some degree of portal ibrosis that does not progress to cirrhosis with time. The value of listing these disorders in this table separately is that if a liver disease such as “idiopathic portal hypertension” is clinically suspected, but a well-established cirrhosis is seen on biopsy, then that disease can be eliminated in the differential diagnosis. (Figs. II-77 through II-79, and Table II-27)

FIGURE II-77 Portal ibrosis. Chronic viral hepatitis, bridging ibrosis (trichrome stain).

463

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-78 Portal ibrosis. Chronic viral hepatitis, cirrhosis (mixed macronodules and micronodules) (trichrome stain).

FIGURE II-79 Portal ibrosis. Paucity of duct syndrome, cirrhosis (adult, biliary type) (trichrome stain).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-27

Portal Fibrosis CHAPTER

DISEASES ASSOCIATED WITH PROGRESSION TO CIRRHOSIS Abetalipoproteinemia

8

Alcoholic cirrhosis

4

Alpers disease

8

α1-Antichymotrypsin deiciency

8

α1-Antitrypsin deiciency

8

Autoimmune hepatitis, typical type*

12

Biliary atresia, extrahepatic†

8

Chronic granulomatous disease of childhood (hepar lobatum)

8

Chronic viral hepatitis, typical type

2

Cystic ibrosis†

8

Drug-induced (see Table 5-13)

5

Erythropoietic protoporphyria

8

Extrahepatic bile duct obstruction, late stage†

3

Fibrinogen storage disease

8

Galactosemia

8

Gaucher disease

8

Glycogen storage disease III, IV, VI

8

Graft versus host disease†

11

Hepatic venous outlow obstruction (Budd-Chiari syndrome), chronic‡

6

Hereditary fructose intolerance

8

Hereditary hemochromatosis

9

Hereditary tyrosinemia

8

Hyperalimentation (TPN), adults

12

Hyperalimentation (TPN), infants†

12

Idiopathic adulthood ductopenia†

3

Indian childhood cirrhosis

9

Inlammatory bowel disease: Ulcerative colitis

12

Langerhans cell histiocytosis (associated primary sclerosing cholangitis)†

3, 10

Long-chain acyl-CoA dehydrogenase deiciency

8

Mucopolysaccharidoses, types I, II, III, IV, VI, VII

8

Non-alcoholic steatohepatitis

4

Paucity of ducts syndrome, nonsyndromatic†

8

Porphyria cutanea tarda§

8

Primary biliary cirrhosis†

3

Primary sclerosing

cholangitis†

3

Progressive familial intrahepatic cholestasis (Byler syndrome)†

8

Sarcoidosis

12

Syphilis, tertiary (hepar lobatum)

7

Tangier disease

8

Veno-occlusive disease (VOD), chronic‡

6

Venous congestion secondary to right-sided heart failure, chronic†

6

Wilson disease

9

Wolman disease

8

Zellweger syndrome DISEASES THAT DO NOT PROGRESS TO CIRRHOSIS

8

Allograft, chronic (ductopenic) rejection║

11

Caroli disease

8

Cholesterol ester storage disease║

8

Congenital hepatic ibrosis

8

Cystinosis

8

Cytomegalovirus

2, 11

Drug-induced (see Table 5-13)

5 Continued

465

466

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-27

Portal Fibrosis—cont’d CHAPTER

Fascioliasis

7

Glycogen storage disease VIII

8

Glycogen storage disease IX

8

Hereditary hemorrhagic telangiectasia (OWR)║

6

Homocystinuria

8

Hypereosinophilic syndrome

12

Lafora disease

8

Malaria

7

Medium chain acyl-CoA dehydrogenase deiciency

8

Niemann-Pick disease║

8

Non-cirrhotic portal ibrosis (IPH)

6

Paracoccidioidomycosis

7

Paucity of ducts syndrome, syndromatic (Alagille syndrome)

3

Polycystic disease, perinatal (infantile) form

8

Schistosomiasis

7

Syphilis, congenital

7

Systemic carnitine deiciency

8

Tuberculosis

7

*Biliary

in type when associated with autoimmune cholangitis. †Biliary type. ‡Cardiac type. §May be related to coexisting chronic HCV or alcoholic cirrhosis. ║Rare cases of cirrhosis reported.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Sinusoids: Fibrosis Sinusoidal collagen deposition may be present either as delicate ibrous strands which may or may not have a zonal distribution, or as striking and often diffuse interstitial bands involving virtually all of the sinusoids in all zones. The strands of collagen may be quite thin and dificult to visualize on hematoxylin-eosin stain alone, but can be best seen on trichrome or Sirius Red stains. Usually the collagen is irst laid down beneath the endothelial and Kupffer cells within the space of Disse. Often the collagen may encircle the individual hepatocytes (pericellular). In instances where the sinusoidal collagen deposition is prominent (e.g., alcoholic hepatitis), signs of portal hypertension such as ascites and esophageal varices may be present in a non-cirrhotic liver due to impediment of blood low through these vascular spaces. Associated intraluminal sclerosis of the terminal hepatic venules may also be seen in some liver diseases in association with intrasinusoidal collagen deposition, these diseases listed in Table II-35, Vessels (Excluding Sinusoids): Thrombosis, Occlusion. It is important to differentiate true sinusoidal collagen from collapse and condensation of the reticulin framework seen in severe hepatitis, as the trichrome stain will show in both a blue staining of the sinusoidal spaces. A helpful clue is that mature type 1 collagen stains a more intense blue on trichrome stain, while collapsed reticulin ibers stain a pale light blue. The Sirius Red stain is most useful in making this differentiation as well, as the Sirius Red stains mature collagen and not collapsed reticulin ibers. (Figs. II-80 through II-82, and Table II-28)

FIGURE II-80 Sinusoids, ibrosis. Perivenular alcoholic ibrosis.

467

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-81 Sinusoids, ibrosis. Alcoholic hepatitis (trichrome stain).

FIGURE II-82 Sinusoids, ibrosis. Non-alcoholic steatohepatitis (trichrome stain).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-28

Sinusoids: Fibrosis CHAPTER

Alcoholic cirrhosis (active drinker)

++

4

Alcoholic foamy degeneration

+

4

Alcoholic hepatitis

++

4

Allograft, chronic (ductopenic) rejection

+

11

Allograft, recurrent viral hepatitis type B and type C (ibrosing cholestatic hepatitis)

++

11

Cholesterol ester storage disease

+

8

Chronic viral hepatitis, HCV

+

2

Cystic ibrosis

+

8

Cytomegalovirus (neonate)

+

2

Down syndrome

++

8

Erythropoietic protoporphyria

+

8

Gangliosidosis, GM2

+

8

Gaucher disease

+

8

Hereditary fructose intolerance

++

8

Hereditary tyrosinemia

++

8

Hyperalimentation (TPN), adults

+

12

Hyperalimentation (TPN), infants

+/++

12

Indian childhood cirrhosis

++

9

Lafora disease

+

8

Leishmaniasis (long-term infection)

++

7

Mannosidosis

+

8

Mucopolysaccharidoses types I, II, III, IV, VI, VII

++

8

Neonatal hepatitis

+

8

Non-alcoholic steatohepatitis

+/++

4

Non-cirrhotic portal ibrosis

+

6

Paucity of ducts syndrome, nonsyndromatic

++

8

Perivenular alcoholic ibrosis

++

4

Schistomosiasis

+

7

Sickle cell anemia

+

8

Syphilis, congenital

++

7

Veno-occlusive disease (VOD), chronic

+

6

Venous congestion secondary to right-sided heart failure, chronic

+/++

6

Wilson disease

+

9

Wolman disease

+

8

Zellweger syndrome

+

8

+ present; ++ present and often abundant.

469

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Sinusoids: Dilatation, Congestion, Hemorrhage The most common causes of sinusoidal dilatation and congestion relate to impairment of hepatic venous outlow from the liver. In these instances, the histologic changes are most prominent in the perivenular and midzones (zones 3 and 2 respectively), although in severe instances the changes can be diffuse and involve all zones. Generally, dilatation and congestion involve all lobules throughout the liver, although focal hepatic involvement is characteristic adjacent to mass lesions. In addition, occlusion of one of the major hepatic vein segments and not the others can show focal changes as well. When the congestion is severe, in conjunction with prominent vascular compromise (poor intrahepatic blood low), perivenular ischemic necrosis and eventual liver cell dropout may occur, with resultant hemorrhage. The red blood cell-trabecular lesion represents red blood cell extravasation occurring initially beneath the Kupffer and endothelial cells within the space of Disse, eventually replacing liver cells that have become atrophic or have dropped out due to ischemic injury. The sinusoids often remain open to variable degrees. It is often associated with acute hepatic venous outlow obstruction (acute Budd-Chiari syndrome), but may also be seen in instances of poor arterial blood low in the absence of hypotension. It also may be seen within the irst few days to weeks after liver transplantation where liver cell dropout in the absence of hypotension may occur due to preservation injury. The red blood cell-trabecular lesion is seen most frequently within the perivenular zone (zone 3), although in severe cases the mid zone (zone 2) may also be involved. The liver diseases listed in this table that are also associated with this lesion are noted with asterisks. (Figs. II-83 through II-85, and Table II-29)

FIGURE II-83 Sinusoids, dilatation, congestion, hemorrhage. Venous congestion secondary to right-sided heart failure.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-84 Sinusoids, dilatation, congestion, hemorrhage. Allograft, preservation (harvesting) injury.

FIGURE II-85 Sinusoids, dilatation, congestion, hemorrhage. Hepatic venous outlow obstruction (Budd-Chiari syndrome), acute (red blood cell extravasation).

471

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Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-29

Sinusoids: Dilatation, Congestion, Hemorrhage DILATATION, CONGESTION

Acute fatty liver of pregnancy Allograft, acute (cellular) rejection (severe)

+*

HEMORRHAGE

CHAPTER

+

12

+

11

+

11

+

11

+

11

Aspergillosis

+

7

Borreliosis

+

Allograft, acute graft failure (primary nonfunction) Allograft, hyperacute (humoral) rejection Allograft, preservation (harvesting, reperfusion) injury

+*

Drug-induced (see Table 5-12)

7 5

Echovirus

+

2

Group B coxsackie

+

2

Hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome

+

12

+

6

Hepatic venous outlow obstruction (Budd-Chiari syndrome), acute

+*

Hepatic venous outlow obstruction (Budd-Chiari syndrome), chronic

+

Hereditary hemorrhagic telangiectasia (OWR)

+

Herpes simplex virus Hypereosinophilic syndrome

6 6 +

+

2, 11 12

Hyperthyroidism

+

12

Hypoxic injury secondary to left-sided heart failure without hypotension (RBC lesion)

+*

6

Infection-associated (reactive) hemophagocytic syndrome

+

12

Leukemia

+

10

Light chain disease

+

12

Malaria

+

7

Marasmus

+

12

Myeloproliferative disorders

+*

10

Peliosis hepatic

+

6

Pneumocystis carinii infection

+

Rheumatoid arthritis

+

Rocky Mountain spotted fever

+

Sickle cell anemia

+

Spontaneous rupture in pregnancy

7 +

8 +

Systemic lupus erythematosus

+

Toxemia of pregnancy

+

+

Veno-occlusive disease (VOD), acute

+*

+

Veno-occlusive disease (VOD), chronic

+

Venous congestion secondary to right-sided heart failure, acute

+†

Venous congestion secondary to right-sided heart failure, chronic

+

*Red

12 7 12 12 12 6 6

+

6 6

blood cells may be seen iniltrating into the hepatic cords, with the sinusoids remaining open (“red blood cell–trabecular lesion”). †Red blood cell trabecular lesion may occur in association with constrictive pericarditis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Sinusoids: Peliotic Lesions Peliosis is a cystic space that is illed with red blood cells and is distributed randomly within the hepatic parenchyma. It is formed either secondary to intrinsic weakness of the reticulin ibers, or by focal liver cell dropout. These lesions initially do not have an endothelial lining, but endothelialization may in time occur. In some instances a thin collagenous rim or ibrin strands can be seen along the cyst lining. The lesion is usually microscopic, although in some instances peliotic lesions can reach up to two cm in diameter (e.g., associated with acquired immunodeiciency syndrome) and be visualized on imaging. Although peliosis hepatis and angioproliferative lesions are well described hepatic vascular entities, peliotic lesions also at times can be seen in other disorders such as primary benign and malignant hepatic neoplasms due to variable vascular drainage of the tumors. (Figs. II-86 and II-87, and Table II-30)

FIGURE II-86 Sinusoids, peliotic lesions. Peliosis hepatic.

473

474

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-87 Sinusoids, peliotic lesions. Liver cell adenoma.

TABLE II-30

Sinusoids: Peliotic Lesions CHAPTER

Angiosarcoma Drug-induced (see Table 5-12) Fibrolamellar hepatocellular carcinoma Glycogen storage disease Ia

10 5 10 8

Hepatocellular carcinoma, common patterns

10

Hodgkin’s lymphoma

10

Human immunodeiciency virus (HIV)

2

Leukemia, hairy cell

10

Light chain disease

12

Liver cell adenoma

10

Marasmus

12

Non-Hodgkin’s lymphoma

10

Peliosis hepatic Systemic lupus erythematosus Veno-occlusive disease (VOD), chronic Waldenstrom’s macroglobulinemia

6 12 6 10

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Sinusoids: Circulating Cells Increased circulating cells within the sinusoids are usually associated with a high peripheral white blood cell count. Neutrophils predominate in disorders such as sepsis, but also may be seen in certain primary liver diseases such as alcoholic hepatitis. Lymphocytes can be increased in certain viral-induced disorders, such as Epstein-Barr or cytomegalovirus infections, and parallel the degree of atypical lymphocytosis seen in the peripheral blood. In many instances, variable degrees of lobular inlammation and necrosis (e.g., EBV infection) may also be seen, usually associated with a portal inlammatory iniltrate. Additionally, immature circulating cells can be observed associated with certain types of leukemia (e.g., chronic myelogenous leukemia). (Figs. II-88 through II-91, and Table II-31)

FIGURE II-88 Sinusoids, circulating cells. Alcoholic hepatitis (neutrophils).

475

476

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-89 Sinusoids, circulating cells. Epstein-Barr virus infection (lymphocytes).

FIGURE II-90 Sinusoids, circulating cells. Lymphoma (non-Hodgkin’s).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-91 Sinusoids, circulating cells. Leukemia (chronic myelogenous).

TABLE II-31

Sinusoids: Circulating Cells CHAPTER

Acute viral hepatitis, HCV

L

2

Alcoholic hepatitis

N

4

Allograft, acute (cellular) rejection (severe)

L

11

Borreliosis (relapsing fever)

L, N

7

Chronic viral hepatitis, HCV

L

2

Cytomegalovirus

L

2, 11

Epstein-Barr virus

L

2, 11

Hypoxic injury secondary to hypotension

Hyaline droplets*

6

Hypoxic injury secondary to left-sided heart failure without hypotension (RBC lesion)

Hyaline droplets*

6

Leishmaniasis

L

7

Leukemia, chronic lymphocytic

L

10

Leukemia, chronic myelogenous

N

10

Lyme disease

L, N

7

Malaria (tropical splenomegaly syndrome)

L

7

Non-Hodgkin’s lymphoma

L

10

Nonspeciic reactive hepatitis

L

12

Pyogenic abscess

N

7

Reactive changes, bacterial infections

N

7

Rheumatoid arthritis

L

12

Rocky Mountain spotted fever

L

7

Salmonellosis

L

7

“Surgical” hepatitis

N

1

Venous congestion secondary to right-sided heart failure, acute

Hyaline droplets*

6

Venous congestion secondary to right-sided heart failure, chronic

Hyaline droplets*

6

*The

hyaline droplets are seen within the sinusoids but are most likely adherent to the endothelium, as these droplets are not actually observed in the peripheral blood. L, lymphocytes; N, neutrophils.

477

478

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Sinusoids: Extramedullary Hematopoiesis Although extramedullary hematopoiesis within the liver is most commonly seen in biopsies from neonates, it is also seen in various primary hematologic disorders that replace the bone marrow such as myeloproliferative disease, and may also occur in certain neoplasms such as hepatoblastoma. In addition, extramedullary hematopoiesis is also associated with various malignancies metastatic to the bone. Usually the hematologic precursors are seen clustered within the sinusoids but may less frequently occur to some degree within the portal tracts. It must be kept in mind that identiication of a single megakaryocyte with no evidence of myeloid or erythroid precursors may rarely be encountered in an otherwise “normal” liver where there is no clinical evidence of hematopoietic abnormalities or metastatic disease. (Figs. II-92 and II-93, and Table II-32)

FIGURE II-92 Sinusoids, extramedullary hematopoiesis. Bone marrow replacement by chronic myelogenous leukemia.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-93 Sinusoids, extramedullary hematopoiesis. Paucity of duct syndrome (normoblasts).

TABLE II-32

Sinusoids: Extramedullary Hematopoiesis CHAPTER

α1-Antitrypsin deiciency (neonate)

8

Angiosarcoma (non-neoplastic liver)

10

Biliary atresia, extrahepatic Bone marrow replacement by leukemia Down syndrome

8 10 8

Embryonal sarcoma

10

Focal nodular hyperplasia

10

Galactosemia

8

Hepatoblastoma

10

Hepatocellular carcinoma, common patterns

10

Hereditary tyrosinemia

8

Infantile hemangioendothelioma

10

Leukemia

10

Liver cell adenoma

10

Malignant tumors metastatic to bone

10

Mesenchymal hamartoma

10

Multiple myeloma

10

Myeloproliferative disorders

10

Neonatal hepatitis Nodular regenerative hyperplasia Paucity of ducts syndrome, nonsyndromatic

8 10 8

Paucity of ducts syndrome, syndromatic (Alagille syndrome)

8

Sickle cell anemia

8

479

480

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Syncytial Giant Cells Syncytial giant cells (giant cell transformation) represent multinucleated hepatocytes. These cells are enlarged, have anywhere from 4 to over 50 nuclei, and have an eosinophilic to slightly granular and sometimes hydropic cytoplasm. These cells are most commonly seen in the neonate in a variety of liver diseases, and may involve all zones or tend to have a perivenular (zone 3) accentuation. In the adult the presence of these cells is less frequent, and when present they tend to be smaller and have fewer nuclei than those seen in the neonate. These giant cells infrequently can be seen in poorly differentiated primary hepatic malignancies. Syncytial giant cells occur due to inhibition of mitotic activity from viruses, drugs, or various inherited disorders, and may also occur due to dissolution of liver cell membranes. These syncytial giant cells should not be confused with multinucleated giant cells (fusion of activated macrophages forming “epithelioid” cells) seen in granulomas. (Figs. II-94 through II-96, and Table II-33)

FIGURE II-94 Syncytial giant cells. Autoimmune hepatitis.

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-95 Syncytial giant cells. Neonatal (giant cell) hepatitis.

FIGURE II-96 Syncytial giant cells. Hepatocellular carcinoma.

481

482

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-33

Syncytial Giant Cells CHAPTER

Acute viral hepatitis, non-A through non-G

2

Adenovirus infection (neonate)

2

α1-Antitrypsin deiciency (neonate)

8

Autoimmune hepatitis, typical type

12

Biliary atresia, extrahepatic

8

Chronic viral hepatitis, non-A through non-G

2

Cystic ibrosis (neonate)

8

Cytomegalovirus (neonate)

2

Galactosemia

8

Hepatocellular carcinoma, giant cell variant

10

Hereditary fructose intolerance (neonate)

8

Hereditary hemochromatosis (neonate)

9

Herpes simplex virus

2, 11

Human herpes virus-6 (HHV)

2

Hyperalimentation (TPN), infants

12

Indian childhood cirrhosis

9

Intrahepatic cholestasis of pregnancy

12

Neonatal hepatitis

8

Niemann-Pick disease (neonate)

8

Parvovirus (B19 virus)

2

Paucity of ducts syndrome, nonsyndromatic

8

Paucity of ducts syndrome, syndromatic (Alagille syndrome)

8

Progressive familial intrahepatic cholestasis (Byler syndrome)

8

Rubella

2

Rubeola

2

Syphilis, congenital

7

Toxoplasmosis (neonate)

7

Wilson disease

9

Yellow fever

2

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Vessels (Excluding Sinusoids): Inlammation It is unusual to see inlammation of small arteries or arterioles in a biopsy specimen from a patient with systemic vasculitis, as the medium-sized and larger vessels are more characteristically involved. The changes of vasculitis are more frequently seen by the pathologist when the biopsy has been taken toward the hepatic hilum during laparotomy, where larger vessels are then available for evaluation, or from explanted liver specimens. In some instances, when the vasculitis is severe and associated with partial or total occlusion of the lumen, the distal smaller arteries and arterioles may be indirectly involved, with the interlobular bile ducts often then undergoing ischemic changes due to impaired blood supply and oxygen depletion, the ducts being directly fed by these branching smaller hepatic artery segments. Secondary changes within the hepatic lobules also occur due to the hypoxemia, with resultant oftentimes severe coagulative ischemic necrosis. The inlammatory cells involving the arteries and arterioles are often mixed, including eosinophils, lymphocytes, and often neutrophils, sometimes associated with ibrin deposition. Dependent on the etiology of the vasculitis, immunoperoxidase stains may demonstrate immunoglobulins (e.g., IgM, C4d deposits in hyperacute humoral allograft rejection). Inlammation of portal, terminal hepatic and sublobular veins is usually mononuclear or mixed, with eosinophils less common; in instances of abdominal sepsis, however, neutrophils are usually present and may be prominent. (Figs. II-97 and II-98, and Table II-34)

FIGURE II-97 Vessels (excluding sinusoids), inlammation. Allograft, acute (cellular) rejection (terminal hepatic venule).

483

484

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-98 Vessels (excluding sinusoids), inlammation. Autoimmune hepatitis (terminal hepatic venule).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-34

Vessels (Excluding Sinusoids): Inlammation ARTERIES/ARTERIOLES

Acute viral hepatitis, typical type

PORTAL, TERMINAL HEPATIC VENULES; SUBLOBULAR AND HEPATIC VEINS

CHAPTER

+

2

+

11

Allograft, acute (cellular) rejection

+

Allograft, chronic (ductopenic) rejection

+

11

Allograft, hepatic artery thrombosis

+

11

Allograft, hyperacute (humoral) rejection

+

11

Allograft, obliterative vasculopathy

+

11

Autoimmune hepatitis, typical type Churg-Strauss syndrome

+ +

12 6

Drug-induced (see Table 5-12)

5

Epstein-Barr virus

+

2, 11

Graft versus host disease

+

11

+

6

Hepatic vein phlebitis Hereditary hemorrhagic telangiectasia (OWR)

+

6

Idiopathic granulomatous hepatitis

+

12

Inlammatory bowel disease: Crohn’s disease

+

12

Inlammatory bowel disease: Ulcerative colitis

+

12

+

4

+

4

Pylephlebitis

+

6

Recurrent pyogenic cholangiohepatitis

+

3

Kawasaki disease

+

Non-alcoholic steatohepatitis Perivenular alcoholic ibrosis Polyarteritis nodosa

6

+

6

Rheumatoid arthritis

+

12

Rocky Mountain spotted fever

+

7

Salmonellosis

+

7

Sarcoidosis

+

12

+

7

Schistosomiasis Syphilis, secondary

+

+

Syphilis, tertiary

+

7

Systemic lupus erythematosus

+

12

Toxic shock syndrome

+

+

7

7

485

486

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

Vessels (Excluding Sinusoids): Thrombosis, Occlusion This table includes disorders where the vascular occlusion is acute and secondary to thrombosis of the hepatic outlow vessels (e.g., acute Budd-Chiari syndrome), or chronic where signiicant luminal sclerosis of the terminal hepatic venules and veins with associated perivenular ibrosis may be present (e.g., chronic right-sided heart failure). Secondary hepatic injury in the acute phase consists of perivenular and sometimes midzonal sinusoidal congestion, acute hemorrhage, and liver cell ischemia. In addition, extravasated red blood cells may at times be seen within the space of Disse. In chronic longterm hepatic venous outlow obstruction, eventual bridging ibrosis between terminal hepatic veins may occur, leading to a “cardiac” cirrhosis (“reverse lobulation,” with sparing of centrally located portal tracts). Partial or complete occlusion of hepatic artery segments by foam cells or ibrointimal proliferation without a true vasculitis (obliterative vasculopathy) can be seen in the liver allograft in chronic ductopenic rejection, resulting in variable ischemic changes to the perivenular hepatocytes with associated perivenular ibrosis. Veno-occlusive change refers to sclerosis of the small terminal hepatic venules, with relative sparing of the larger outlow vessels, and may be seen secondarily in certain liver diseases (e.g., acute and chronic alcoholic liver disease) or as a primary condition (veno-occlusive disease). (Figs. II-99 and II-100, and Table II-35)

FIGURE II-99 Vessels (excluding sinusoids), thrombosis, occlusion. Alcoholic hepatitis (total sclerosis of a terminal hepatic venule).

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

FIGURE II-100 Vessels (excluding sinusoids), thrombosis, occlusion. Bacterial sepsis (sublobular vein).

487

488

Part II / Liver Biopsy Evaluation: Morphology with Differential Diagnoses

TABLE II-35

Vessels (Excluding Sinusoids): Thrombosis, Occlusion CHAPTER

THROMBOSIS/FIBROUS THICKENING/FIBROUS OBLITERATION (TERMINAL HEPATIC VENULES, SUBLOBULAR AND HEPATIC VEINS) Alcoholic cirrhosis

4

Alcoholic hepatitis

4

Allograft, chronic (ductopenic) rejection

11

Allograft, hepatic artery thrombosis

11

Allograft, obliterative vasculopathy

11

Aspergillosis

7

Churg-Strauss syndrome

6

Congenital hepatic ibrosis

8

Drug-induced (see Table 5-12)

5

Echovirus

2

Hepatic vein phlebitis

6

Hepatic venous outlow obstruction (Budd-Chiari syndrome), acute

6

Hepatic venous outlow obstruction (Budd-Chiari syndrome), chronic

6

Hypothyroidism

12

Idiopathic granulomatous hepatitis

12

Myeloproliferative disorders (secondary hepatic vein thrombosis)

6, 10

Nodular regenerative hyperplasia (adjacent intrahepatic portal venule thrombosis)

10

Non-cirrhotic portal ibrosis (IPH)

6

Polyarteritis nodosa

6

Pylephlebitis

6

Schistosomiasis

7

Sickle cell anemia

8

Toxemia of pregnancy

12

Venous congestion secondary to right-sided heart failure, chronic

6

VENO-OCCLUSIVE CHANGES Alcoholic cirrhosis

4

Alcoholic hepatitis

4

Drug-induced (see Table 5-12)

5

Graft versus host disease

11

Non-alcoholic steatohepatitis

4

Perivenular alcoholic ibrosis

4

Veno-occlusive disease (VOD), acute

6

Veno-occlusive disease (VOD), chronic

6

REFERENCES The complete reference list is available online at www.expertconsult.com.

Appendix

CHRONIC LIVER DISEASES: STAGING AND GRADING SYSTEMS TABLE A

Chronic Hepatitis: Staging and Grading NECROINFLAMMATORY SCORE (0–18)

FIBROSIS SCORE (0–6)

PERIPORTAL OR PERISEPTAL INTERFACE (“PIECEMEAL” NECROSIS)

CONFLUENT NECROSIS

FOCAL (SPOTTY) LYTIC NECROSIS, APOPTOSIS, FOCAL INFLAMMATION

0: No ibrosis

0: Absent

0: Absent

0: Absent

0: None

1: Fibrous expansion of some portal areas, with or without short ibrous septa

1: Mild (focal, few portal areas)

1: Focal conluent necrosis

1: One focus or less per 10× objective

1: Mild, some or all portal areas

2: Fibrous expansion of most portal areas, with or without short ibrous septa

2: Mild to moderate (focal, most portal areas)

2: Zone 3 necrosis in some areas

2: Two to four foci per 10× objective

2: Moderate, some or all portal areas

3: Fibrous expansion of most portal areas, with occasional portal-portal bridging

3: Moderate (continuous around 50% of portal tracts or septa)

4: Zone 3 necrosis with occasional portal-central bridging

4: More than 10 foci per 10× objective

4: Marked, all portal areas

5: Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis)

5: Zone 3 necrosis with multiple portal-central bridging

6: Cirrhosis, probable or deinite

6: Panacinar or multiacinar necrosis

PORTAL INFLAMMATION

From Ishak K, Baptista A, Bianchi L, et al: Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-699.

489

Appendix / Chronic Liver Diseases: Staging and Grading Systems

490

TABLE B

Chronic Hepatitis—Staging and Grading

STAGE

DESCRIPTION

CRITERIA

0

No ibrosis

Normal connective tissue

1

Portal ibrosis

Fibrous portal expansion

2

Periportal ibrosis

Periportal or rare portal-portal septa

3

Septal ibrosis

Fibrous septa with architectural distortion; no obvious cirrhosis

4

Cirrhosis

Cirrhosis

GRADE

DESCRIPTION

LYMPHOCYTIC PIECEMEAL NECROSIS*

LOBULAR INFLAMMATION AND NECROSIS*

0

Portal inlammation only; no activity

None

None

1

Minimal

Minimal, patchy

Minimal, occasional spotty necrosis

2

Mild

Mild, involving some or all portal tracts

Mild, little hepatocellular change

3

Moderate

Moderate, involving all portal tracts

Moderate, with noticeable hepatocellular change

4

Severe

Severe, may have bridging ibrosis

Severe, with prominent diffuse hepatocellular damage

*When discrepancy exists between piecemeal necrosis and lobular necrosis, the more severe lesion should determine the grade. From Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417.

TABLE C

METAVIR Cooperative Study Group

FIBROSIS 0 1 2 3 4

No ibrosis Stellate enlargement of portal tracts without septa formation Enlargement of portal tracts with rare septa formation Numerous septa without cirrhosis Cirrhosis

ACTIVITY Piecemeal necrosis 0 = Absent 1 = Focal alteration of the periportal plate in some portal tracts 2 = Diffuse alteration of the periportal plate in some portal tracts or focal lesions around all portal tracts 3 = Diffuse alteration of the periportal plate in all portal tracts

Focal lobular necrosis 0 = Less than one necroinlammatory foci per lobule 1 = At least one necroinlammatory foci per lobule 2 = Several necroinlammatory foci per lobule or conluent or bridging necrosis

0

0 1 2

0 1 2

1

0 1 2

1 1 2

2

0 1 2

2 2 3

3

0, 1, 2

3

Total activity

Data from Bedossa P, Poynard T for the METAVIR Cooperative Study Group: An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996;24:289-293; and The French METAVIR Cooperative Study Group: Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994;20:15-20.

Appendix / Chronic Liver Diseases: Staging and Grading Systems

TABLE D

Non-Alcoholic Steatohepatitis: Grading and Staging

TABLE E

NASH Clinical Research Network Scoring System*

GRADE

PARAMETERS

HISTOLOGY PARAMETERS

Grade 1, mild

• Steatosis (predominantly macrovesicular) involving up to 66% of biopsy • Occasional minimal zone 3 ballooning • Scattered rare lobular neutrophils ± intraacinar lymphocytes with 33%, may be >66%) • Zone 3 ballooning present • Intra-acinar neutrophils ± intra-acinar lymphocytes, may be associated with zone 3 pericellular ibrosis, with 2–4 foci per 20× ield • Portal and intra-acinar chronic inlammation, mild to moderate

491

DEFINITIONS

SCORE

66%

0 1 2 3

Location (predominant distribution pattern)

Zone 3 Zone 1 Azonal Panacinar

0 1 2 3

Microscopic steatosis (contiguous patches)

Absent Present

0 1

Fibrosis

None Perisinusoidal or periportal Mild, zone 3, perisinusoidal Moderate, zone 3, perisinusoidal Portal/periportal Perisinusoidal and portal/ periportal Bridging ibrosis Cirrhosis

Lobular inlammation*

No foci 4 foci per 200× ield

0 1 2 3

• Steatosis (>33% to >66%) • Marked zone 3 ballooning • Intra-acinar neutrophils ± intra-acinar lymphocytes, with >4 foci per 20× ield • Portal and intra-acinar chronic inlammation, mild to moderate

0 1 1A 1B 1C 2 3 4

STAGE

PARAMETERS

Stage 1

Zone 3 perisinusoidal/pericellular ibrosis; focally or extensively present

Stage 2

Zone 3 perisinusoidal/pericellular ibrosis with focal or extensive periportal ibrosis

Microgranuloma

Stage 3

Zone 3 perisinusoidal/pericellular ibrosis and portal ibrosis with focal or extensive bridging ibrosis with septa

Absent Present

0 1

Large lipogranuloma

Absent Present

0 1

Stage 4

Extensive bridging ibrosis with cirrhosis

Portal inlammation

None to minimal Greater than minimal

0 1

Liver cell ballooning*

None Few balloon cells Many cells/prominent ballooning

0 1 2

Acidophil bodies, Pigmented macrophages, Megamitochondria, Mallory bodies, Glycogenated nuclei (each scored individually)

None to rare Many

0 1

Diagnostic classiication

Not steatohepatitis Possible/borderline Deinite steatohepatitis

0 1 2

From Brunt EM, Janney CG, Di Bisceglie AM, et al: Nonalcoholic steatohepatitis: a proposal for grading and staging of histological lesions. Am J Gastroenterol 1999;94:2467-2474.

*Activity score determined by adding scores of steatosis, lobular inlammation, and ballooning (0–8). From Kleiner DE, et al: Design and validation of a histological scoring system for non-alcoholic fatty liver disease. Hepatology 2005;41:1313-1321.

Appendix / Chronic Liver Diseases: Staging and Grading Systems

492

TABLE F

Non-Alcoholic Fatty Liver Disease Scoring System

Portal Fibrosis 0 1 2 3 4 5 6

No ibrosis Fibrous expansion of some portal areas, with or without short ibrous septa Fibrous expansion of most portal areas, with or without short ibrous septa Fibrous expansion of most portal areas, with occasional portal-portal (P-P) and/or portal-central (P-C) bridging Fibrous expansion of portal areas with marked bridging (P-P as well as P-C) Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis) Cirrhosis, probable or deinite Lobular Inlammation and necrosis Mallory bodies Hepatocyte ballooning (each scored individually 0–3)*

Perisinusoidal ibrosis (0–3)*

Fatty change (0–4)

0

Absent

Absent

Absent

1

Focal involvement of some lobules

Perivenular and/or periportal involvement of some lobules

66% liver cells involved

*Activity score based on summary of four subscores of lobular inlammation and necrosis, Mallory bodies, hepatocyte ballooning, and perisinusoidal ibrosis. The degree of fat is excluded from the activity score. From Mendler MH, Kanel G, Govindarajan S: Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease. Liver Int 2005;25:294-304.

TABLE G

Nonalcoholic Fatty Liver Disease Scoring System

Type 1

Fatty liver alone

Type 2

Fat accumulation and lobular inlammation

Type 3

Fat accumulation and ballooning degeneration

Type 4

Fat accumulation, ballooning degeneration, either Mallory bodies or ibrosis

From Matteoni CA, Younossi ZM, Gramlich T, et al: Nonalcoholic fatty liver disease: a spectrum of clinical and pathologic severity. Gastroenterology 1999;116:1413-1419.

Appendix / Chronic Liver Diseases: Staging and Grading Systems

TABLE H

Autoimmune Hepatitis Scoring System

PARAMETER

FEATURE

Sex

Male Female

SCORE 0 +2

Alkaline phosphatase:AST (or ALT) ratio

3.0

+2 0 –2

Serum globulins or IgG above normal

>2.0 1.5–2.0 1.0–1.5 1:80 1:80 1:40 15 10–15 >17 12–17

Alvarez F, et al: International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatology 1999;31:929-938.

493

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INDEX

A abscess formation characterization of, 381 common patterns of, 382f conditions associated with, 383t acetaminophen absorption, 94–95 hepatocellular necrosis from clinical/biologic behavior of, 94–95 differential diagnosis for, 94 features of, 93–94 prognosis for, 95 special stains for, 94 treatment for, 95 metabolism, 94 acid-fast (AFB) brucellosis, 157 salmonellosis, 158 sarcoidosis, 355 acinar agglomerate, 9 acinus, complex, 9 acinus, simple, 9 acute (cellular) rejection clinical/biologic behavior of, 329–330 common patterns of, 327f differential diagnosis of, 327–329 features of, 326–327 grading of, 327, 329t post-transplant-associated autoimmune hepatitis versus, 349 HBV/HCV versus, 345 PBC versus, 347 PLTD versus, 341 prognosis for, 330 treatment for, 330 acute alcoholic fatty liver disease common patterns of, 76f VOD versus, 140 with or without cholestasis clinical/biologic behavior of, 77 differential diagnosis for, 76–77 features of, 76 prognosis for, 77 special stains for, 76 treatment for, 77 acute fatty liver pregnancy-associated clinical/biologic behavior of, 366 common patterns of, 365f differential diagnosis for, 365–366 features of, 364–365 prognosis for, 366 stains for, 365 tetracycline-induced fatty change versus, 108 treatment for, 366

acute graft failure clinical/biologic behavior of, 324–325 common patterns of, 324f differential diagnosis of, 324 features of, 324 hepatic artery thrombosis versus, 334 prognosis for, 324–325 transplant rejection versus, 326 treatment for, 324–325 acute hepatic injury clinical features of, 14–15 manifestation of, 12–15 acute hepatitis autoimmune hepatitis versus, 360 common patterns of, 361f sarcoidosis versus, 356 acute lymphocytic leukemia (ALL), 304 acquired immunodeiciency syndrome (AIDS) clinical/biologic behavior of, 46–47 differential diagnosis for, 46 features of, 45–46 immunohistochemistry for, 46 prognosis for, 47 stains, 46 treatment for, 47 adenocarcinoma congenital hepatic ibrosis versus, 208 metastatic congenital hepatic ibrosis versus, 208 HCC versus, 277 hepatocellular carcinoma versus, 286 liver cell adenoma versus, 255 adenovirus infection histology/clinical parameters, 50t–51t post-transplant CMV versus, 264 adult polycystic disease aspiration cytology for, 211 clinical/biologic behavior of, 211–212 common patterns of, 211f differential diagnosis for, 211 features of, 210 prognosis for, 212 treatment for, 212 AFD. See alcoholic foamy degeneration; alcoholic foamy degeneration (AFD) Alagille’s syndrome, 200 alcian blue cystic ibrosis, 213 epithelioid hemangioendothelioma, 294 hepatobiliary cystadenoma, 257 liver cell adenoma, 255 alcoholic cirrhosis Budd-Chiari syndrome versus, 138 clinical/biological behavior of, 86 common patterns of, 83f–85f differential diagnosis for, 85

alcoholic cirrhosis (Continued) features of, 83–85 immunohistochemistry for, 85 prognosis for, 86 special stains for, 85 treatment for, 86 alcoholic fatty liver disease clinical/biologic behavior of, 72–74 common patterns of, 72f–75f differential diagnosis for, 71 disorders morphologically resembling, 91t features of, 71 MCAD versus, 226 prognosis for, 74 stains for, 71 treatment for, 74 alcoholic foamy degeneration (AFD) common patterns of, 81f–82f features of, 82 special stains for, 82 tetracycline-induced fatty change versus, 108 alcoholic hepatitis amiodarone-induced Mallory bodies versus, 114 bile duct obstruction versus, 55 busulfan-induced vascular occlusion versus, 123 clinical/biologic behavior of, 80–82 common patterns of, 77f–80f differential diagnosis for, 80, 82 features of, 77–80 immunohistochemistry for, 80 Indian childhood cirrhosis versus, 203 leukemia versus, 304 myeloproliferative disorders versus, 304 prognosis for, 81, 83 special stains for, 80 treatment for, 81, 83 alcoholic liver disease brucellosis versus, 157 fatty change versus, 109–110 methotrexate-induced ibrosis versus, 125 mineral oil-induced granulomas versus, 113 NASH versus, 90 non-cirrhotic portal ibrosis versus, 152–153 porphyria cutanea tarda versus, 227 post-transplant clinical/biologic behavior, 350 common patterns for, 349f differential diagnosis, 349 features of, 349 prognosis for, 350 stains for, 349 treatment for, 350 VOD versus, 140 ALL. See acute lymphocytic leukemia (ALL) allografts, 144, 147

Page numbers followed by f or t indicate igures and tables, respectively.

495

496

Index

allopuriono bile duct injury from clinical/biologic behavior of, 122 differential diagnosis for, 121–122 features of, 121 prognosis for, 122 stains for, 121 treatment for, 122 alpha-1 antitrypsin deiciency alcoholic cirrhosis versus, 85 Byler syndrome versus, 201 cirrhotic stage adult, 202 neonatal, 202–203 clinical/biologic behavior of, 216–217 common patterns of, 215f differential diagnosis for, 216 features of, 214 immunohistochemistry for, 216 Indian childhood cirrhosis versus, 203 intrahepatic biliary atresia versus, 200 myoclonus epilepsy versus, 225 neonatal hepatitis versus, 195 prognosis for, 217 stains for, 216 treatment for, 217 alpha-heavy chain disease, 307–308, 307f–308f amebiasis aspiration cytology for, 177 clinical/biologic behavior of, 177 common patterns of, 176f–177f differential diagnosis for, 177 morphologic features of, 176–177 prognosis for, 177 stains for, 177 treatment for, 177 amiodarone clinical/biologic behavior of, 114–115 differential diagnosis for, 114 electron microscopy, 114 features of, 113–114 immunohistochemistry for, 114 stains for, 114 treatment for, 115 amyloidosis aspiration cytology, 363 clinical/biologic behavior, 364 common features of, 362f–363f differential diagnosis for, 363–364 features of, 361–363 luorescence for, 363 immunohistochemistry for, 363 prognosis for, 364 stains for, 363 treatment for, 364 anabolic steroids, 126f–127f anatomy, gross, 3–5 angiomyolipoma cavernous hemangioma versus, 260 clinical/biologic behavior of, 263 common patterns of, 262f–263f differential diagnosis for, 263 features of, 262 prognosis for, 263 stains for, 262–263 treatment for, 263 angioproliferative lesion, 149f–150f angiosarcoma aspiration cytology for, 292 cavernous hemangioma versus, 260 clinical/biologic behavior of, 293 common patterns of, 291f–292f

angiosarcoma (Continued) differential diagnosis for, 292–293 epithelioid hemangioendothelioma versus, 295 features of, 290–292 immunohistochemistry for, 292 infantile hemangioendothelioma versus, 261 prognosis for, 293 stains for, 292 treatment for, 293 anthracite pigments, 128f anthracotic pigments, 179 aspiration cytology amebiasis versus, 177 echinococcosis, 182 sarcoidosis, 363 schistomosiasis, 188 aspiration cytology for, 276 adult polycystic disease, 211 cavernous hemangioma, 260 epithelioid hemangioendothelioma, 294 ibrolamellar HCC versus, 279 liver cell adenoma, 252 metastatic neoplasms, 310 solitary unilocular cysts, 206 autoimmune hepatitis bile duct obstruction versus, 55 chronic viral hepatitis versus, 36 clinical/biologic behavior, 360–361 common patterns of, 358f–359f differential diagnosis, 360 early stage, 20 features of, 26, 357–359 histologic grading/staging, 360 nirofurantoin-induced hepatocyte damage versus, 102 overlap variants of, 359–360 post-transplant clinical/biologic behavior of, 349 common patterns of, 350f differential diagnosis for, 349 features of, 348 prognosis for, 349 stains for, 349 treatment for, 349 prognosis for, 361 sarcoidosis versus, 356 stains for, 360 treatment for, 361 troglitazone-induced hepatocyte damage, 104

B Bacillus Calmette-Guerin (BCG), 164f bacterial infections candidiasis versus, 175 post-transplant clinical/biologic behavior of, 337 common patterns of, 336f differential diagnosis, 336–337 features of, 336 prognosis for, 337 stains for, 336 treatment for, 337 bacterial sepsis leukemia versus, 304 mushroom-induced fatty change versus, 109 myeloproliferative disorders versus, 304 prevention injury versus, 323 sulfasalazine-induced change versus, 110 Banff scoring system, 327, 332 Bartonella benselae, 150 BCG. See Bacillus Calmette-Guerin (BCG) benign hepatic mass lesion, 276–277

benign recurrent intrahepatic cholestasis (BRIC) clinical/biologic behavior of, 202 differential diagnosis for, 202 features of, 202 stains for, 202 bile acids, 267 bile duct adenoma cholangiocarcinoma versus, 286 common patterns of, 255f congenital hepatic ibrosis versus, 208 differential diagnosis for, 255 features of, 254–255 immunohistochemistry for, 255 prognosis for, 256 stains for, 255 treatment for, 256 bile duct injury allopurionol-induced clinical/biologic behavior of, 122 differential diagnosis for, 121–122 features of, 121 prognosis for, 122 special stains for, 121 treatment for, 122 chlorpromazine-induced clinical/biologic behavior of, 120 differential diagnosis for, 120 features of, 120 prognosis for, 120 treatment for, 120 bile duct ischemia, 332, 336 bile duct loss, developmental, 62 bile duct obstruction. See extrahepatic (mechanical) bile duct obstruction bile duct strictures clinical/biologic behavior of, 334 common patterns of, 333f–334f differential diagnosis of, 333–334 morphologic features, 333 prognosis for, 334 treatment for, 334 bile ducts cytologic atypia in characterization of, 396 common patterns of, 396f–398f conditions associated with, 399t ductopenia in characterization of, 396 common patterns of, 396f–398f conditions associated with, 399t large tumors in, 287 lymphocyte inlammation of characterization of, 387 common patterns of, 387f–388f conditions associated with, 381 neutrophil inlammation of characterization of, 384 common patterns of, 384f–385f conditions associated with, 386t periductal ibrosis in characterization of, 393 common patterns of, 393f–394f conditions associated with, 395t reduplication/ectasia in characterization of, 390 common patterns of, 390f–391f conditions associated with, 392t bile infarcts causes, 58 deined, 52 identiication, 53 bile lakes deined, 52 formation, 58 identiication, 53

Index

bile pigment, 11, 11f biliary atresia extrahepatic clinical/biologic behavior of, 197–198 common patterns of, 197f differential diagnosis for, 197 features of, 196–197 prognosis for, 198 stains for, 197 treatment for, 198 intrahepatic common patterns of, 199f differential diagnosis for, 200 features of, 198 prognosis for, 200 stains for, 200 treatment for, 200 biliary canaliculi, 6, 8f biliary cirrhosis, 213 biliary microhamartoma clinical/biologic behavior of, 203 common patterns of, 207f congenital hepatic ibrosis versus, 208 differential diagnosis for, 203 features of, 202–203 perinatal polycystic disease versus, 207 prognosis for, 203 treatment for, 203 biliary system cysts in, 182 cystadenoma in, 206 development, 3 divisions, 6–7 fetal, 5 function, 6–7 inlammatory bowel disease-associated, 357 biopsy evaluation, 12, 379–381 black anthracotic pigment, 179 blastomycosis, 172 bone-marrow transplantation common patterns of, 122f hepatic changes following, 351f clinical/biologic behavior of, 352 common patterns of, 351f differential diagnosis for, 352 features of, 351–352 prognosis for, 352 stains for, 352 treatment for, 352 hepatic changes from, 351–352 BRIC. See benign recurrent intrahepatic cholestasis (BRIC) brucellosis clinical/biologic behavior of, 157–158 common patterns of, 157f differential diagnosis for, 157 features of, 156–157 prognosis for, 158 special stains for, 157 treatment for, 158 Budd-Chiari syndrome busulfan-induced vascular occlusion versus, 123 clinical/biologic behavior of, 138–139 common patterns of, 136f–137f differential diagnosis for, 138 features of, 136–138 prognosis for, 139 red blood cell-trabecular lesion versus, 143 special stains for, 138 treatment for, 139 VOD versus, 140

busulfan vascular occlusion from clinical/biologic behavior of, 123 differential diagnosis for, 123 features of, 122–123 prognosis for, 123 stains for, 123 treatment for, 123 Byler syndrome. See progressive familial intrahepatic cholestasis

C calciication characterization of, 400 common patterns of, 400f conditions associated with, 388f calcium deposits, 400 candidiasis clinical/biologic behavior of, 175–176 common patterns of, 175f cryptococcosis versus, 174 differential diagnosis for, 175 features of, 175 prognosis for, 176 stains for, 175 treatment for, 176 Caroli disease clinical/biologic behavior of, 210 common patterns of, 210f differential diagnosis for, 210 hepatobiliary cystadenoma versus, 257 morphologic features, 209 prognosis for, 210 solitary unilocular cysts versus, 206 treatment for, 210 cavernous hemangioma angiosarcoma versus, 292 aspiration cytology for, 260 clinical/biologic behavior of, 260 common patterns of, 258f–259f differential diagnosis for, 260 features of, 258–260 immunohistochemistry for, 260 infantile hemangioendothelioma versus, 261 prognosis for, 260 treatment for, 260 CD10, 275 CD31, 276 CFTR gene, 214 chlorpromazine bile duct injury from clinical/biologic behavior of, 120 differential diagnosis for, 120 features of, 120 prognosis for, 120 treatment for, 120 cholangiocarcinoma aspiration cytology for, 286 characterization, 267 clinical/biologic behavior of, 286–287 common patterns of, 281f–285f congenital hepatic ibrosis versus, 208 differential diagnosis for, 286 epithelioid hemangioendothelioma versus, 295 features of, 283–285 ibrolamellar HCC versus, 280–281 HCC versus, 277 immunohistochemistry for, 285–286 metastatic neoplasms versus, 310 prognosis for, 287 stains for, 285 treatment for, 287 well-differentiated, 255

cholangiohepatitis recurrent pyogenic bile duct obstruction, 57 Caroli disease versus, 210 clonorchiasis versus, 184 differential diagnosis for, 68–69 features of, 68–70 cholangitis acute, 145, 384 autoimmune, 55 ibroobliterative, 64 lorid nonsuppurative destructive, 58 fulminant hepatitis-associated, 24 primary sclerosing autoimmune hepatitis versus, 360 bile duct obstruction versus, 55 biliary cirrhosis versus, 60 chronic viral hepatitis versus, 36 clinical/biologic behavior of, 69 differential diagnosis for, 66–67 features of, 64 prognosis for, 68, 70 stains for, 64–66 treatment for, 68, 70 viral hepatitis versus, 36 secondary sclerosing, 68–69 choledochal cysts common patterns of, 205f differential diagnosis for, 204 features of, 204 hyperalimentation versus, 368 prognosis for, 205 treatment for, 205 cholestasis benign recurrent intrahepatic clinical/biologic behavior of, 202 differential diagnosis for, 202 features of, 202 stains for, 202 characterization, 12 conditions associated with, 404t fulminant hepatitis-associated, 25 hyperalimentation versus, 368 methyltestosterone-induced clinical/biologic behavior of, 116 differential diagnosis for, 116 features of, 116 prognosis for, 117 special stains for, 116 treatment for, 117 oral contraceptive-induced, 116 progressive familial intrahepatic clinical/biologic behavior of, 201 differential diagnosis for, 201 morphologic changes, 200–201 prognosis for, 201 stains for, 201 treatment for, 201 with duct injury, 121f cholestasis with inlammation bupropion-induced, 118f chlorpomazine-induced, 118f clarithromycin-induced clinical/biologic behavior of, 119 common patterns of, 118f differential diagnosis for, 119 features of, 119 prognosis for, 119 special stains for, 119 treatment for, 119 ketoconazole-induced clinical/biologic behavior of, 117 common patterns of, 118f features of, 117 prognosis for, 117

497

498

Index

cholestasis with inlammation (Continued) stains for, 117 treatment for, 117 niacin-induced, 118f cholestasis, simple characterization of, 402 common patterns of, 402f–403f oral contraceptive-induced clinical/biologic behavior of, 115 differential diagnosis for, 115 features of, 115 special stains for, 115 treatment for, 116 cholesterol ester storage disease, 108 chondroma, 265, 265f chronic (ductopenic) rejection clinical/biologic behavior of, 332–333 common patterns of, 330f–332f differential diagnosis of, 332 features of, 330–332 grading of, 332 post-transplant PBC versus, 347 chronic liver diseases. See speciic conditions chronic lymphocytic leukemia, 40, 43 Churg-Strauss syndrome characterization, 147–148 common patterns of, 147f cirrhosis. See also specific types clarithromycin characterization of, 119 cholestasis with inlammation from clinical/biologic behavior of, 119 differential diagnosis for, 119 features of, 119 prognosis for, 119 special stains for, 119 treatment for, 119 clonorchiasis aspiration cytology for, 184 clinical/biologic behavior of, 184 common patterns of, 183f differential diagnosis for, 184 features of, 183–184 prognosis for, 184 treatment for, 184 CMV. See cytomegalovirus (CMV) coagulative necrosis, 371 cocaine effects of, 96 fatty change from, 108f hepatocellular necrosis from clinical/biologic behavior of, 96–98 differential diagnosis for, 96 features of, 95–96 prognosis for, 98 special stains for, 96 treatment for, 98 zonal damage, 98f metabolism, 97 coccidioidomycoses clinical/biologic behavior of, 172–173 common patterns of, 172f–173f differential diagnosis for, 172 features of, 172 prognosis for, 173 stains for, 172 treatment for, 173 collagen. See ibroconnective tissue colloidal iron, 225 complex acinus, 9 conluent (submassive) hepatic necrosis, 24 conluent necrosis, 24 congenital hepatic ibrosis clinical/biologic behavior of, 209 common patterns of, 208f

congenital hepatic ibrosis (Continued) cystic cirrhosis versus, 214 differential diagnosis for, 208 features of, 207–208 perinatal polycystic disease versus, 207 prognosis for, 209 stains for, 208 treatment for, 209 congo red, 363 congo red after trypsin, 363 copper basic metabolism, 242 hepatic quantitation, 245 copper storage disorders characterization of, 242 Indian childhood cirrhosis, 247–248 Wilson disease, 242–247 coronary ligament, 4 coronavirus, 50t–51t covalently closed circular DNA, 36 Cowdry type A, 44 Cowdry type B, 44 coxiella burnetii, 169 coxsackie virus, 49, 50t–51t cryptococcosis clinical/biologic behavior of, 174–175 common patterns of, 174f differential diagnosis for, 174 features of, 173–174 prognosis for, 175 stains for, 174 treatment for, 175 cystic dilation of intrahepatic ducts. See Caroli disease cystic ibrosis clinical/biologic behavior of, 213–214 common patterns of, 212f–213f congenital hepatic ibrosis versus, 208 differential diagnosis for, 213 features of, 212–213 hereditary tyrosinemia versus, 220 prognosis for, 214 stains for, 213 treatment for, 214 cystic lesions characterization of, 405 common patterns of, 405f conditions associated with, 406t cysts biliary, 182 choledochal common patterns of, 205f differential diagnosis for, 204 features of, 204 hyperalimentation versus, 368 prognosis for, 205 treatment for, 205 ecchinococcal, 257–258 intrahepatic duct-associated, 206 multilocular hepatic, 204 multiple, 257 multiple simple, 211 peribiliary clinical/biologic behavior of, 204 common patterns of, 204f differential diagnosis for, 204 features of, 203 prognosis for, 204 treatment for, 204 simple, 257 simple hepatic, 204 simple hepatic biliary, 149 solitary unilocular aspiration cytology for, 206 clinical/biologic behavior of, 206

cysts (Continued) common patterns of, 205f differential diagnosis for, 206 features of, 205–206 prognosis for, 206 treatment for, 206 cytochrome P450, 95 cytokeratins, 276 cytologic atypia bile duct-associated characterization of, 396 common patterns of, 396f–398f conditions associated with, 399t cytomegalovirus (CMV) acute (cellular) rejection versus, 256 bacterial/fungul infections versus, 336–337 brucellosis versus, 157 candidiasis versus, 175 clinical/biologic behavior of, 43 common patterns of, 41f–42f differential diagnosis for, 43 early stage, 20–21 EBV versus, 40 features of, 41–43 HIV-associated, 47 immunohistochemistry for, 43 phenytoin-induced liver cell injury versus, 101 post-transplant clinical/biologic behavior of, 265 common patterns of, 261f–262f differential diagnosis of, 264–265 features of, 263–264 immunohistochemistry for, 264 prognosis for, 265–266 treatment for, 265–266 prognosis for, 43 salmonellosis versus, 159–160 treatment for, 43 cytoplasm, 5

D de novo liver disease, 350–351 decreased arterial blood low, 141–143 deibrotide, 140 delta antigens, 19, 35 dengue fever, 50t–51t diagnostic lesions characterization of, 407 common patterns of, 407f–410f conditions associated with, 391f diffuse papillomatosis, 287 DiPAS. See PAS after diastase digestion drug-induced granulomatous reaction, 164 drug-induced inclusions, 363 drug-induced liver cell injury alcoholic cirrhosis versus, 85 alcoholic fatty liver disease versus, 71 alpha-1 antitrypsin deiciency versus, 216 bile duct, 119–122 bile duct obstruction versus, 56 BRIC versus, 202 brucellosis versus, 157 Budd-Chiari syndrome versus, 138 cholestasis with inlammation versus, 117–119 cholestasis, simple, 115–117 chronic transplant rejection versus, 332 chronic viral hepatitis versus, 36 classiication, 93 CMV versus, 43 Epstein-Barr virus versus, 40 fatty change, 48 features of, 93 ibrosis, 123–125 fulminant hepatitis versus, 26 granulomas, 41–42

Index

drug-induced liver cell injury (Continued) hepatocellular necrosis, 93–98 hepatocellular necrosis from, 98–103 herpes virus versus, 44–45 myoclonus epilepsy versus, 225 lobular conluent necrosis, 103–106 Mallory bodies, 113–115 morphologic variants, 95t histologic changes, 129t–133t neoplasms, 125 perivenular alcoholic ibrosis versus, 75 portal vein thrombosis versus, 142 primary biliary cirrhosis versus, 62 salmonellosis versus, 160 steatosis versus, 77 vascular conditions and, 122–123 viral hepatitis versus, 19 Dubin-Johnson syndrome clinical/biologic behavior of, 220 prognosis for, 220 treatment for, 220 Gilbert syndrome versus, 217–218 ductal plate development, 3 ductopenia bile duct-associated characterization of, 396 common patterns of, 396f–398f conditions associated with, 399t HIV-associated, 46 idiopathic adult-onset, 62 ducts of Hering, 6–7

E Ebola virus, 50t–51t EBV. See Epstein-Barr virus (EBV) echinococcosis aspiration cytology for, 182 clinical/biologic behavior of, 182–183 common patterns of, 181f–182f differential diagnosis for, 182 ecchinococcal cysts, 257 – 258 features of, 182 prognosis for, 183 stains for, 182 treatment for, 183 echovirus clinical/biologic behavior of, 49–50 common patterns of, 49f differential diagnosis for, 49 features of, 49 prognosis for, 50 treatment for, 50 eclampsia. See pregnancy embryology developmental, 4f normal liver, 3 embryonal rhabdomyosarcoma, 295–296, 295f embryonal sarcoma, 297–298, 297f endodermal cells, 3 endothelial cells, 6 endothelialitis, 39 Entameba histolytic, 177 enterovirus. See echovirus eosinophils portal characterization of, 460 common patterns of, 460f–461f conditions associated with, 462t epithelial tumors benign bile duct adenoma, 254–256 hepatobiliary cystadenoma, 256–258 liver cell adenoma, 249–254 malignant cholangiocarcinoma, 281–290

epithelial tumors (Continued) ibrolamellar hepatocellular carcinoma, 278 hepatocellular carcinoma, 267–281 epithelioid hemangioendothelioma angiosarcoma versus, 292 aspiration cytology for, 294 clinical/bilogic behavior of, 295 common patterns of, 294f–295f differential diagnosis for, 295 features of, 293–294 immunohistochemistry for, 294 prognosis for, 295 stains for, 294 treatment for, 295 epitheloid granulomas, 418 EPM2A gene, 225 EPM2B gene, 225 Epstein-Barr virus (EBV) acute (cellular) rejection versus, 256 brucellosis versus, 157 clinical/biologic behavior of, 41 CMV versus, 43 common patterns of, 39f–40f differential diagnosis for, 40–41 early stage, 20–21 features of, 39–40 Hodgkin lymphoma versus, 300 immunohistochemistry for, 40 malaria versus, 179 molecular hybridization techniques, 40 non-Hodgkin lymphoma versus, 302 phenytoin-induced liver cell injury versus, 101 prognosis for, 41 salmonellosis versus, 159–160 treatment for, 41 erythropoietic protoporphyria autoluorescence, 229 clinical/biologic behavior of, 229–230 common patterns of, 229f differential diagnosis for, 229 features of, 228 prognosis for, 230 stains for, 228 treatment for, 230 ethanol metabolism, 72f extracellular deposits common patterns of, 412f–413f conditions associated with, 413t evaluation of, 412 extracellular matrix. See stroma extrahepatic (mechanical) bile duct obstruction benign recurrent intrahepatic cholestasis versus, 202 bile duct injury versus, 120–122 biliary microhamartoma versus, 203 Caroli disease versus, 210 cholestasis versus, 115–116 cholestasis with inlammation versus, 117, 119 clinical/biologic behavior of, 57–58, 67–68 clonorchiasis versus, 184 common patterns of, 53f–58f, 203f cystic ibrosis versus, 212–214 differential diagnosis for, 55–57 early stage, 52 early to mid-stage, 52–53 early, BRIC versus, 202 features of, 54 fulminant hepatitis, 26–27 hyperalimentation versus, 368 late stage, 54–58 post-transplant infections versus, 336 prevention injury versus, 323 primary biliary cirrhosis versus, 60 prognosis for, 58

499

PSC versus, 66 pyogenic abscess versus, 156 reactive changes versus, 156 recurrent pyogenic cholangiohepatitis versus, 68 stains, 55 treatment for, 58 extrahepatic biliary atresia (EBA) Byler syndrome versus, 201 Caroli disease versus, 209–210 hyperalimentation versus, 368 intrahepatic biliary atresia versus, 200 neonatal hepatitis versus, 195 extramedullary hematopoiesis common patterns of, 5f embryonic, 3 sinusoid-associated characterization of, 478 common patterns of, 478f–479f conditions associated with, 479t

F falciform ligament, 4 familiar hypoibrinogenemia, 216, 225 fat, embryonic, 3 fat, microvesicular, 71 fatty change characterization of, 414 cocaine-induced, 108f common patterns of, 414f–415f, 419f conditions associated with, 416t–417t focal, 320, 320f mushroom-induced clinical/biologic behavior of, 109 common patterns of, 109f differential diagnosis for, 108–109 features of, 108 prognosis for, 109 treatment for, 109 sulfasalazine-induced clinical/biologic behavior of, 110 common patterns of, 110f differential diagnosis for, 110 features of, 110 tetracycline-induced, 107f autoluorescence, 108 clinical/biologic behavior of, 108 common patterns of, 107f differential diagnosis for, 108 features of, 106 prognosis for, 108 special stains for, 106–107 treatment for, 108 types of, 107t vitamin A-induced autoluorescence, 111 clinical/biologic behavior of, 111 common patterns of, 110f differential diagnosis for, 111 features of, 110–111 prognosis for, 111 stains for, 111 treatment for, 111 fatty change, macrovesicular, 13f fatty liver disease. See alcoholic fatty liver disease; non-alcoholic fatty liver disease FCH. See ibrosing cholestatic hepatitis (FCH) feathery degeneration, 16 feulgen reactions, 44, 339 ibrin, 363 ibroconnective tissue formation of, 74 function of, 5 sarcoidosis and, 363

500

Index

ibrocystic diseases biliary microhamartoma, 202–203 choledochal cysts, 204–205 peribiliary cysts, 203–204 solitary unilocular cysts, 205–206 ibrolamellar hepatocellular carcinoma, 278–279 ibroma, 318–319 ibro-obliterative cholangitis, 64 ibrosarcoma, 296, 296f ibrosing cholestatic hepatitis (FCH), 346 ibrosis. See also cystic ibrosis bridging, 33f congenital hepatic clinical/biologic behavior of, 209 common patterns of, 208f differential diagnosis for, 208 features of, 207–208 prognosis for, 209 treatment for, 209 methotrexate-induced clinical/biologic behavior of, 125 common patterns of, 124f differential diagnosis for, 125 features of, 123, 125 prognosis for, 125 stains for, 125 treatment for, 125 portal characterization of, 463 common patterns of, 463f–464f conditions associated with, 465t–466t reactive, 318 secondary to other causes, 151, 153 sinusoids characterization of, 467 common patterns of, 467f–468f conditions associated with, 469t FIC-1 gene, 202 lorid nonsuppurative destructive cholangitis, 58 focal fatty change, 320, 320f focal nodular hyperplasia aspiration cytology for, 313 clinical/biologic behavior, 313–314 common patterns of, 311f–313f differential diagnosis for, 313 features of, 313 ibrolamellar HCC versus, 280 liver cell adenoma versus, 252 prognosis for, 314 stains for, 313 treatment for, 314 Fontana-Masson, 219, 289 fulminant hepatitis acute viral, 119 characterization, 23f clarithromycin-induced, 119 clinical/biologic behavior of, 27 common patterns of, 23f–26f differential diagnosis for, 26–27 features of, 24–25 immunohistochemistry for, 26 prognosis for, 27 special stains for, 25–26 subtypes, 24 treatment for, 27 fumarylacetoacetate hydrolase (FAH) deiciency, 221 fungal infections post-transplant clinical/biologic behavior of, 337 differential diagnosis, 336–337 features of, 336 prognosis for, 337 treatment for, 337

G Gaucher disease clinical/biologic behavior of, 223 common patterns of, 223f differential diagnosis for, 223 enzyme histochemistry, 222 features of, 222 immunohistochemistry for, 222 prognosis for, 223 stains for, 222 treatment for, 223 Gilbert syndrome differential diagnosis for, 217–218 features of, 217 prognosis for, 218 treatment for, 218 glycogen storage disorders clinical/biologic behavior of, 222 differential diagnosis for, 222 features of, 221–222 myoclonus epilepsy versus, 225 prognosis for, 222 stains for, 222 treatment for, 222 glycogen, embryonic, 3 glycogenated nuclei, 13f, 422 glypican-3, 252, 275 gold pigments, 129f Gomori methenamine silver (GMS) brucellosis, 157 cryptococcosis versus, 174 leprosy versus, 167 salmonellosis, 158 sarcoidosis, 355 toxoplasmosis, 186 grading and staging autoimmune hepatitis, 360, 493t chronic hepatitis, 489t–490t chronic viral hepatitis, 35 METAVIR, 490t NALD, 492t NASH, 90, 491t graft versus host disease (GVHD) clinical/biologic behavior of, 352 common patterns of, 351f differential diagnosis for, 352 features of, 351–352 prognosis for, 352 stains for, 352 treatment for, 352 gram stains brucellosis, 157 pyogenic abscess, 154 reactive changes, 154 salmonellosis, 158 granulomas characterization of, 418 chlorpromazine-induced, 112f common patterns of, 418f–419f conditions associated with, 420t–421t deined, 41 epitheloid, 418 MAC versus, 165–166 mineral oil-induced clinical/biologic behavior of, 113 common patterns of, 112f differential diagnosis for, 113 features of, 113 prognosis for, 113 treatment for, 113 noncaseating epithelioid, 59 post-transplant CMV versus, 264 sulfasalazine-induced, 112f sulfonamide-induced

granulomas (Continued) clinical/biologic behavior of, 112–113 common patterns of, 112f differential diagnosis for, 112 features of, 112 prognosis for, 113 treatment for, 113 granulomatous lesions schistomosiasis versus, 188 spirochetes versus, 161 tuberculosis versus, 164 granulomatous liver disease characterization of, 353–356 epithelioid type, 353 inlammatory type, 353 sarcoidosis, 353–356 visceral larva migrans versus, 185 granulomatous necrosis toxoplasmosis versus, 187 visceral larva migrans versus, 185 gridley, 177 ground-glass cells, 34, 363 GVHD. See graft versus host disease (GVHD)

H HAART (highly active anti-retroviral therapy), 47 halogenated hydrocarbons. See halothane halothane hepatocellular necrosis with inlammation from clinical/biologic behavior of, 102 features of, 101 prognosis for, 102 special stains for, 102 treatment for, 102 HAV. See hepatitis A virus (HAV) HBV. See hepatitis B virus (HBV) HCC. See hepatocellular carcinoma (HCC) HCV. See hepatitis C virus (HCV) heart failure left-sided, without hypotension, 143–144 long-term right-sided, 75, 140 right-sided, venous congestion secondary to, 134–136 heat stroke. See hyperpyrexia hemangioendothelioma. See infantile hemangioendothelioma hemangioma, 292 hematopoiesis. See extramedullary hematopoiesis hematopoietic diseases alpha-heavy chain disease, 307–308 Hodgkin’s lymphoma, 299–301 Langerhans cell histocytosis, 305–306 leukemia, 303–305 lymphoplasma cell dyscrasias, 306 myeloproliferative disorders, 303–305 non-Hodgkin lymphoma, 301–303 plasma cell, 306 Waldenstrom’s macroglobulinemia, 306–307 hemochromatosis. See hereditary hemochromatosis hemosiderine pigment, 3, 11f, 12, 178 hemosiderosis clinical/biologic behavior of, 238 differential diagnosis for, 238 features of, 238 prognosis for, 238 stains for, 238 treatment for, 238 hepatic vein thrombosis. See acute Budd-Chiari syndrome hepatitis chronic viral, 220–221 reactivation of, 30 staging and grading, 383t surgical, 14f

Index

hepatitis A virus (HAV), 16–17, 23 hepatitis B virus (HBV) antigens, 19 chronic clinical/biologic behavior of, 36–37 features of, 34 myoclonus epilepsy versus, 225 phenytoin-induced liver cell injury versus, 101 prognosis for, 38 serovirologic patterns of, 37 treatment for, 38 common patterns of, 29f–31f early stage, 19–20 features of, 17, 34 HIV-associated, 47 immunohistochemistry for, 35 post-transplant clinical/biologic behavior, 345–346 common patterns, 343f–344f differential diagnosis for, 345 morphologic features, 342–343 prognosis for, 346 stains for, 343 treatment for, 346 hepatitis C virus (HCV) chronic clinical/biologic behavior of, 37–38 features of, 34 prognosis for, 38–39 treatment for, 38–39 viral hepatitis secondary to, 85, 111 clinical/biologic behavior of, 22–23 common patterns of, 32f features of, 17 HIV-associated, 47 immunohistochemistry for, 35 porphyria cutanea tarda versus, 227 post-transplant clinical/biologic behavior of, 345–346 common patterns, 343f–345f differential diagnosis for, 345 morphologic features, 342–343 prognosis for, 346 stains for, 343 treatment for, 346 hepatitis D virus (HDV) chronic clinical/biologic behavior of, 38 prognosis for, 39 treatment for, 39 hepatitis E virus (HEV) chronic, 35 clinical/biologic behavior of, 23 common patterns of, 20f features of, 17–18 hepatitis G virus (HGV), 18, 35 hepatobiliary cystadenoma aspiration cytology for, 257 clinical/biologic behavior of, 258 common patterns of, 256f–258f differential diagnosis for, 257–258 features of, 256–257 immunohistochemistry, 257 prognosis for, 258 stains for, 257 treatment for, 258 hepatoblastoma aspiration cytology for, 290 clinical/biologic behavior of, 290 common patterns of, 288f–289f differential diagnosis for, 290 features of, 288–289 immunohistochemistry for, 290 prognosis for, 290

hepatoblastoma (Continued) stains for, 289–290 treatment for, 290 hepatoblasts, 3 hepatocellular adenomatosis, 317 hepatocellular carcinoma (HCC) alcoholic cirrhosis associated, 85 angiomyolipoma versus, 263 aspiration cytology for, 276 cholangiocarcinoma versus, 286 clinical/biologic behavior of, 277–278 common patterns of, 268f–275f differential diagnosis for, 276–277 etiologic factors, 277t extensive sclerosis-associate, 295 features of, 267, 269–273 ibrolamellar, 278 hepatoblastoma versus, 289 immunohistochemistry for, 275–276 macroregenerative nodules versus, 315 metastatic neoplasms versus, 310 stains for, 273–275 trabecular variant of, 280 tumor grading, 276 well-differentiated, 252 hepatocellular necrosis acetaminophen-induced clinical/biologic behavior of, 94–95 common patterns of, 96f–97f differential diagnosis for, 94 features of, 93–94 prognosis for, 95 special stains for, 94 treatment for, 95 cocaine-induced clinical/biologic behavior of, 96–98 common patterns of, 98f differential diagnosis for, 96 features of, 95–96 prognosis for, 98 special stains for, 96 treatment for, 98 zonal damage, 98f ferrous sulfate-induced, 97f with minimal to absent inlammation acetaminophen-induced, 93–95 cocaine-induced, 95–98 perivenular zones, 96t hepatocellular necrosis with inlammation halothane-induced clinical/biologic behavior of, 102 common patterns of, 100f features of, 101 prognosis for, 102 special stains for, 101 treatment for, 102 isoniazid-induced clinical/biologic behavior of, 100 common patterns of, 99f differential diagnosis for, 98–99 features of, 98 prognosis for, 100 treatment for, 100 nitrofurantoin-induced clinical/biologic behavior of, 103 differential diagnosis for, 102 features of, 102 special stains for, 102 phenytoin-induced clinical/biologic behavior of, 101 differential diagnosis for, 101 features of, 100–101 prognosis for, 101 special stains for, 101 treatment for, 101

501

hepatocytes composition, 5 drug-induced lesions, 128t feathery degeneration, 16 fetal, 5f giant cell transformation, 35 inclusions characterization of, 422 common patterns of, 422f–424f conditions associated with, 425t nucleus of, 5 regeneration, 9–10 size, 5 ultra structure, 10t zone variations, 10t hepatoduodenal ligament, 4 hepatolenticular degeneration. See Wilson disease hepatolithiasis, 69 hepatoportal sclerosis. See non-cirrhotic portal ibrosis hereditary hemochromatosis aspiration cytology for, 238 clinical/biologic behavior of, 239–241 common patterns of, 239f–240f differential diagnosis for, 239 features of, 238 Gilbert syndrome versus, 218 prognosis for, 241–242 stains for, 238 treatment for, 241–242 hereditary hemorrhagic telangiectasia, 152 hereditary hyperbilirubinemias characterization of, 218t Dubin-Johnson syndrome, 218–220 Gilbert syndrome, 217–218 hereditary tyrosinemia clinical/biologic behavior of, 221 common patterns of, 220f differential diagnosis for, 220–221 features of, 220 prognosis for, 221 stains for, 220 treatment for, 221 herpes simplex virus (HSV) clinical/biologic behavior of, 45 common patterns of, 44f features of, 43–44 immunohistochemistry for, 44 intranuclear inclusions, 44 post-transplant clinical/biologic behavior, 46 common patterns of, 30f differential diagnosis for, 45 immunohistochemistry for, 45–47 morphologic features, 45 prognosis for, 46 stains for, 45 treatment for, 46 prognosis for, 45 stains, 44 treatment for, 45 herpes zoster virus, 50t–51t HEV. See hepatitis E virus (HEV) HGV. See hepatitis G virus (HGV) hilar lesions, 287 histoplasmosis clinical/biologic behavior of, 171–172 common patterns of, 171f differential diagnosis for, 171 features of, 171 prognosis for, 172 stains for, 171 treatment for, 172 HIV. See human immunodeiciency virus (HIV)

502

Index

HLA gene, 228 Hodgkin’s lymphoma aspiration cytology for, 300 clinical/biologic behavior of, 301 common patterns of, 299f–300f differential diagnosis for, 300 EBV versus, 40–41 features of, 300 immunohistochemistry for, 300 primary biliary cirrhosis versus, 62 prognosis for, 301 treatment for, 301 HSV. See herpes simplex virus (HSV) human herpesvirus-6, 50t–51t human immunodeiciency virus (HIV). See AIDS clinical/biologic behavior of, 46–47 common patterns of, 45f, 149f differential diagnosis for, 46 features of, 45–46 immunohistochemistry for, 46 infections, 45t neoplasms, 45t prognosis for, 47 stains, 46 treatment for, 47 hydatid cyst. See echinococcosis hyperacute (humoral) rejection acute graft failure versus, 324 clinical/biologic behavior of, 326 differential diagnosis of, 326 features of, 326 hepatic artery thrombosis versus, 334 immunohistochemistry for, 326 stains for, 326 hyperalimentation clinical/biologic behavior, 368 common patterns of, 367f differential diagnosis, 368 features of, 367–368 prognosis for, 368 stains for, 368 treatment for, 368 hyperbilirubinemias. See hereditary hyperbilirubinemias hyperpyrexia common patterns of, 370f differential diagnosis for, 371 features of, 370–371 prognosis for, 371 tetracycline-induced fatty change versus, 108 treatment for, 371 hypoibrinogenemia, familiar, 216, 225 hypotension hypoxic injury secondary to, 142f hypoxic injury without, 144f ischemia secondary to, 49 ishemic necrosis secondary to, 177 hypoxic injury differential diagnosis for, 143–144 secondary to hypotension clinical/biologic behavior of, 143 common patterns of, 142f differential diagnosis for, 140 features of, 142 prognosis for, 143 special stains for, 142 treatment for, 143 secondary to left-sided heart failure without hypotension clinical/biologic behavior of, 144 features of, 143 prognosis for, 144 special stains for, 143 treatment for, 144 without hypotension, 144f

I idiopathic adult-onset ductopenia, 62 idiopathic portal hypertension, 151. See also non-cirrhotic portal ibrosis immunohistochemistry alpha-1 antitrypsin deiciency, 216 angiosarcoma, 292 epithelioid hemangioendothelioma, 294 ibrolamellar HCC versus, 279 Gaucher disease, 222 hepatobiliary cystadenoma, 257 inlammatory pseudotumor, 318 Langerhans cell histocytosis, 306 liver cell adenoma, 250–252 metastatic neoplasms, 310 polyarteritis nodosa versus, 147 post-transplant CMV, 264 post-transplant HBV/HCV, 343 post-transplant HSV, 339 sarcoidosis, 363 transplant rejection, 326 inclusions hepatocytes characterization of, 422 common patterns of, 128f, 422f–424f conditions associated with, 425t Kupffer cell characterization of, 426 common patterns of, 426f–427f conditions associated with, 428t procainamide, 128f Indian childhood cirrhosis alcoholic cirrhosis versus, 85 clinical/biologic behavior of, 248 differential diagnosis for, 248 features of, 247 prognosis for, 248 stains for, 247–248 treatment for, 248 infantile hemangioendothelioma cavernous hemangioma versus, 260 common patterns of, 261f–262f aspiration cytology for, 261 clinical/biologic behavior of, 261–262 differential diagnosis for, 261 immunohistochemistry for, 261 prognosis for, 262 treatment for, 262 features of, 260–261 stains for, 261 infectioon-associated (reactive) hemophagocytic syndrome, 40 clinical/biologic behavior of, 369–370 common features of, 369f differential diagnosis, 369 features of, 368–369 prognosis for, 370 stains for, 369 treatment for, 370 infectious disorders. See non-viral infections disorders infectious mononucleosis, 179 inlammatory bowel disease common patterns of, 357f hepatic dysfunction in biliary tract disorders and, 357 chronic hepatitis and, 357 cirrhosis and, 357 nonspeciic reactive changes, 356–357 mushroom-induced fatty change versus, 109 reactive change in, 357, 357f

inlammatory lesions of hepatic artery. See vasculitis inlammatory lesions, portal/hepatic veins pylephlebitis clinical/biologic features of, 146 differential diagnosis for, 145 features of, 144–145 prognosis for, 146 treatment for, 146 inlammatory pseudotumor, 319f common patterns of, 318f–319f features of, 317–318 immunohistochemistry for, 318 interlobular and septal ducts, 7 interlobular bile ducts characterization of, 5 formation of, 3 size of, 7 intrahepatic biliary atresia (EBA), 195, 201 iron colloidal, 225 location of, 237t metabolism, 236 overload (See hemosiderosis) pigments. (See hemosiderin) stainable hepatic, 239 iron storage disorders basic iron metabolism, 236 hereditary hemochromatosis, 238–239 secondary iron overload, 236–238 ischemic necrosis acetaminophen-induced hepatocellular necrosis versus, 94 amebiasis versus, 177 cocaine-induced hepatocellular necrosis versus, 96 polyarteritis nodosa versus, 146 transplant rejection versus, 326 isoniazid hepatocellular necrosis with inlammation from clinical/biologic behavior of, 100 differential diagnosis for, 98–99 features of, 98 prognosis for, 100 treatment for, 100 Ito cells, 3

J JAG1, 200

K Kaposi sarcoma, 47 Kayser-Fleischer rings, 246 ketoconazole characterization of, 117 cholestasis with inlammation from clinical/biologic behavior of, 117 features of, 117 prognosis for, 117 stains for, 117 treatment for, 117 Kupffer cells characterization, 5–6 drug-induced lesions, 128t embryonic, 3 focal necrosis, 12f hemosiderin deposition in, 178 hyperplasia, 13f, 157f inclusions characterization of, 426 common patterns of, 426f–427f conditions associated with, 428t kwashiorkor, 108–109

Index

L LaFora disease alpha-1 antitrypsin deiciency versus, 216 clinical/biologic behavior of, 225–226 differential diagnosis for, 225 features of, 225 prognosis for, 226 stains for, 225 treatment for, 226 Langerhans cell histocytosis clinical/biologic behavior of, 306 common patterns of, 305f features of, 305–306 immunohistochemistry for, 306 prognosis for, 306 stains for, 306 treatment for, 306 Lassa fever clinical/biologic behavior of, 48 common patterns of, 47f differential diagnosis for, 48 electron microscopy, 47 features of, 47 prognosis for, 48 treatment for, 48 leiomyosarcoma, 296–297, 296f leishmaniasis clinical/biologic behavior of, 180 common patterns of, 180f differential diagnosis for, 180 features of, 179–180 histoplasmosis versus, 171 prognosis for, 180 stains for, 180 treatment for, 180 leprosy clinical/biologic behavior of, 167 common patterns of, 166f differential diagnosis for, 167 features of, 166 prognosis for, 167 stains for, 167 treatment for, 167 leukemia clinical/biologic behavior of, 304–305 common patterns of, 303f–304f differential diagnosis for, 304 features of, 303–304 immunohistochemistry for, 304 prognosis for, 305 stains for, 304 treatment for, 305 lipochrome pigment common patterns of, 11, 11f Dubin-Johnson syndrome and, 219 Gilbert syndrome and, 218 lipogranulomas, 71 lipomas characterization, 265 common patterns of, 265f mesenchymal benign tumors, 265 liver cell adenoma aspiration cytology for, 252 clinical/biologic behavior of, 253–254 common patterns of, 250f–252f differential diagnosis for, 252–253 features of, 249–250 ibrolamellar HCC versus, 280 immunohistochemistry for, 250–252 macroregenerative nodules versus, 315 multiple (See hepatocellular adenomatosis) prognosis for, 254 stains for, 250 treatment for, 254

lobular conluent necrosis niacin-induced features of, 105 prognosis for, 106 special stains for, 105 treatment for, 106 sertraline-induced differential diagnosis for, 106 features of, 106 special stains for, 106 troglitazone-induced clinical/biologic behavior of, 104–105 differential diagnosis for, 104 features of, 104 prognosis for, 105 special stains for, 104 treatment for, 105 with inlammation characterization of, 429, 434 common patterns of, 429f–430f, 434f–435f conditions associated with, 431t–433t, 435t with minimal/absent inlammation characterization of, 436 common patterns of, 436f–437f conditions associated with, 438t lymphangioma characterization, 265–266 common patterns of, 266f lymphatic channels, 5 lymphocytes liver-associated (See pit cells) portal characterization of, 452 common patterns of, 452f–454f conditions associated with, 454t–455t portal, depletion, 46 lymphocytic leukemia chronic CMV versus, 43 EBV versus, 40 malaria versus, 179 lymphoma. See Hodgkin’s lymphoma; nonHodgkin’s lymphoma lymphoplasma cell dyscrasias, 306 lymphoproliferative disorder (PLTD) post-transplant clinical/biologic behavior of, 273–275 common patterns of, 263f–264f differential diagnosis for, 269–273 immunohistochemistry for, 267–269 molecular techniques for, 267–269 morphologic features, 267, 340 prognosis for, 275–276 treatment for, 275–276

M macroglobulinemia. See alpha-heavy chain disease macroregenerative nodules clinical/biologic behavior of, 315–316 common patterns of, 314f–315f differential diagnosis for, 315 features of, 314–315 prognosis for, 316 stains for, 315 treatment for, 316 macrovesicular fat, 71, 414 malaria clinical/biologic behavior of, 179 common patterns of, 178f differential diagnosis for, 178–179 features of, 178 prognosis for, 179 stains for, 178 treatment for, 179

503

Mallory bodies alcoholic hepatitis-associated, 78f–79f amiodarone-induced clinical/biologic behavior of, 114–115 common patterns of, 114f differential diagnosis for, 114 electron microscopy, 114 features of, 113–114 immunohistochemistry for, 114 prognosis for, 115 special stains for, 114 treatment for, 115 characterization of, 81, 439 common patterns of, 439f–440f conditions associated with, 441t Wilson disease-associated, 26 malnutrition, severe, 71 Marburg virus, 50t–51t Masson trichrome alcoholic hepatitis, 80 alcoholic liver disease, 71 angiosarcoma, 292 biliary ibrosis, 60 Budd-Chiari syndrome, 138 chronic HBV, 35 epithelioid hemangioendothelioma, 294 ibrolamellar HCC versus, 279 ibrosis, 125 fulminant hepatitis, 25–26 Gaucher disease, 222 glycogen storage disorders, 222 hepatocellular necrosis with inlammation, 102 hereditary tyrosinemia, 220 hyperalimentation, 368 Indian childhood cirrhosis, 248 inlammatory pseudotumor, 318 liver cell adenoma, 255 NAFL, 86 NASH, 89 neonatal hepatitis, 194 Osler-Weber-Rendu disease, 151 perivenular alcoholic ibrosis, 75 post-transplant autoimmune hepatitis, 349 post-transplant HBV/HCV, 343 post-transplant PBC, 347 PSC, 35–36 sarcoidosis, 355, 363 steatosis, 76 venous congestion, 134 VOD, 80 MCAD. See medium-chain acyl CoA dehydrogenase (MCAD) medium-chain acyl CoA dehydrogenase (MCAD) clinical/biologic behavior of, 226 differential diagnosis for, 226 features of, 226 prognosis for, 226 treatment for, 226 megamitochondria, 216 mesenchymal hamartoma clinical/biologic behavior of, 264–265 common patterns of, 264f differential diagnosis for, 264 features of, 263–264 prognosis for, 265 treatment for, 265 mesenchymal tumors benign angiomyolipoma, 262–263 chondroma, 265 common patterns of, 263f infantile hemangioendothelioma, 260

504

Index

mesenchymal tumors (Continued) lipomas, 265 lymphangioma, 265–266 malignant angiosarcoma, 290 embryonal sarcoma, 297–298 embryonic rhabdomyosarcoma, 295–296 epithelioid hemangioendothelioma, 293 ibrosarcoma, 296 leiomyosarcoma, 296–297 pheochromocytoma, 298 squamous cell carcinoma, 298–299 yolk sac tumor, 299 mesoderm, 3 metabolism copper, 242 ethanol, 72f iron, 236 methotrexate characterization of, 125 ibrosis from clinical/biologic behavior of, 125 common patterns of, 124f differential diagnosis for, 125 features of, 123, 125 prognosis for, 125 stains for, 125 treatment for, 125 methyltestosterone cholestasis from clinical/biologic behavior of, 116 differential diagnosis for, 116 features of, 116 prognosis for, 117 special stains for, 116 treatment for, 117 microabscess, 264 microanatomy, 5, 6f microvesicular fat, 71, 414 mineral oil granulomas from clinical/biologic behavior of, 113 differential diagnosis for, 113 features of, 113 prognosis for, 113 treatment for, 113 monospot test, 41 mucicarmine cholangiocarcinoma, 285 cryptococcosis versus, 174 cystic ibrosis, 213 hepatobiliary cystadenoma, 257 hepatoblastoma, 289 liver cell adenoma, 255 mucoviscoidosis. See cystic ibrosis multiple myeloma. See Waldenstrom’s macroglobulinemia mushrooms fatty change from clinical/biologic behavior of, 109 differential diagnosis for, 108–109 features of, 108 prognosis for, 109 treatment for, 109 mycobacterium avium complex (MAC) clinical/biologic behavior of, 166 common patterns of, 165f differential diagnosis for, 165–166 features of, 165 Langerhans cell histocytosis versus, 306 leprosy versus, 167 prognosis for, 166 stains for, 165 treatment for, 166

myeloproliferative disorders clinical/biologic behavior of, 304–305 common patterns of, 262f differential diagnosis for, 304 features of, 303–304 immunohistochemistry for, 304 prognosis for, 305 stains for, 304 treatment for, 305 myoclonus epilepsy. See LaFora disease

N NASH. See non-alcoholic steatohepatitis (NASH) native liver disease recurrence, 256 neonatal hepatitis clinical/biologic behavior of, 195–196 common patterns of, 195f–196f differential diagnosis for, 194–195, 196t extrahepatic biliary atresia, 196–198 features of, 194 intrahepatic biliary atresia, 198–200 prognosis for, 196 spirochetes versus, 161 stains for, 194 treatment for, 196 neoplasms clinical/biologic behavior of, 310, 310t drug-induced, 125 metastatic aspiration cytology for, 310 common patterns of, 127f, 308f–309f differential diagnosis for, 310 features of, 308 immunohistochemistry for, 310 prognosis for, 311 stains for, 308–310 treatment for, 311 primary benign common patterns of, 126f–127f epithelial, 249 mesenchymal, 258 miscellaneous, 266 teratoma, 266 primary malignant hepatoblastoma, 288–290 mesenchymal, 290 pathophysiologic concepts, 266–267 neural network, 8 neutrophils bile duct inlammation by, 384 portal characterization of, 456 common patterns of, 456f–457f conditions associated with, 457t niacin lobular conluent necrosis from features of, 105 prognosis for, 106 special stains for, 105 treatment for, 106 use of, 105 Niemann-Pick disease clinical/biologic behavior of, 224–225 common patterns of, 224f differential diagnosis for, 224 features of, 224 prognosis for, 225 stains for, 224 treatment for, 225 nitrofurantoin hepatocellular necrosis with inlammation from clinical/biologic behavior of, 103 differential diagnosis for, 102 features of, 102 special stains for, 102

nodular regenerative hyperplasia (NRH) clinical/biologic behavior of, 317 common patterns of, 316f–317f differential diagnosis for of, 317 liver cell adenoma versus, 252–253 morphologic features, 316–317 prognosis for, 317 stains for, 317 treatment for, 317 non-alcoholic fatty liver disease (NAFLD) clinical/biologic behavior of, 87 common patterns of, 87f differential diagnosis for, 86–87 disorders morphologically resembling, 91t fatty change versus, 86–87, 111 features of, 86 glycogen storage disorders versus, 222 grading and staging, 492t NASH and, 90–91 porphyria cutanea tarda versus, 227 prognosis for, 87 special stains for, 86 treatment for, 87 non-alcoholic steatohepatitis (NASH) alcoholic cirrhosis versus, 85 alcoholic fatty liver disease versus, 71 alcoholic hepatitis versus, 80 amiodarone-induced Mallory bodies versus, 114 busulfan-induced vascular occlusion versus, 123 clinical/biologic behavior of, 90–91 common patterns of, 88f–90f differential diagnosis for, 90 fatty change versus, 90, 110 features of, 87–89 grading and staging, 90, 491t grading/staging, 90 immunohistochemistry for, 90 methotrexate-induced ibrosis versus, 125 perivenular alcoholic ibrosis versus, 75 prognosis for, 91–92 special stains for, 89 steatosis versus, 76 tetracycline-induced fatty change versus, 108 treatment for, 91–92 VOD versus, 140 non-caseating granulomas, 167 non-cirrhotic portal ibrosis clinical/biologic behavior of, 153 common patterns of, 151f–152f differential diagnosis for, 152–153 features of, 151–153 prognosis for, 153 schistomosiasis versus, 188 special stains for, 152 treatment for, 153 non-Hodgkin’s lymphoma aspiration cytology for, 302 clinical/biologic behavior of, 302 common patterns of, 301f differential diagnosis for, 302 features of, 301–302 immunohistochemistry for, 302 prognosis for, 303 stains for, 302 treatment for, 303 non-viral infectious disorders amebiasis, 176–178 brucellosis, 156–158 candidiasis, 175–176 clonorchiasis, 183–184 coccidioidomycoses, 172–173 cryptococcosis, 173 echinococcosis, 180–183 histoplasmosis, 170–172

Index

non-viral infectious disorders (Continued) leishmaniasis, 179–180 leprosy, 166–167 liver damage risk from, 189t–193t MAC, 165–166 malaria, 178–179 Q fever, 167–169 reactive changes, 154–156 Rocky Mountain spotted fever, 169–170 salmonellosis, 158–160 schistomosiasis, 187–189 syphilis, 160–163 toxoplasmosis, 186–187 tuberculosis, 163–165 visceral larva migrans, 184–186 non-caseating epithelioid granulomas, 59 NRH. See nodular regenerative hyperplasia (NRH)

O oil red O acute foamy degeneration (ADF) diagnosis with, 81–83 Niemann-Pick disease, 224 Reye syndrome, 372 tetracycline-induced fatty change with, 106–107 oral contraceptives cholestasis from clinical/biologic behavior of, 115 differential diagnosis for, 115 features of, 115 prognosis for, 116 special stains for, 115 treatment for, 116 neoplasms from, 126f orcein alpha-1 antitrypsin deiciency, 216 autoimmune hepatitis versus, 360 bile duct obstruction diagnosis with, 55 biliary ibrosis diagnosis with, 60 Byler syndrome, 201 congenital hepatic ibrosis, 208 cystic ibrosis, 213 ibrolamellar HCC versus, 279 fulminant hepatitis diagnosis with, 25–26 hepatocellular necrosis with inlammation diagnosis with, 101 hyperalimentation, 368 Indian childhood cirrhosis, 247 intrahepatic biliary atresia, 200 Langerhans cell histocytosis, 306 post-transplant PBC, 347 PSC diagnosis with, 35 Wilson’s disease, 201 Osler-Weber-Rendu disease (OWR) clinical/biologic behavior of, 151 common patterns of, 150f differential diagnosis for, 151 features of, 150–151 prognosis for, 151 special stains for, 151 treatment for, 151 ossiication, 388f, 400 outlow vessels, 7

P pale bodies, 363 panacinar (massive) hepatic necrosis, 24 partial nodular transformation. See nodular regenerative hyperplasia parvovirus (B19), 50t–51t

PAS after diastase digestion (DiPAS) acute foamy degeneration (ADF), 82 alpha-1 antitrypsin deiciency, 216 bile duct obstruction, 55 characterization, 18 cholangiocarcinoma, 285 cystic ibrosis, 213 Dubin-Johnson syndrome, 219 epithelioid hemangioendothelioma, 294 ibrolamellar HCC versus, 279 fulminant hepatitis, 25 Gaucher disease, 222 glycogen storage disorders, 222 hepatocellular carcinoma, 275 hepatocellular necrosis, 94, 96 steatosis, 76 tetracycline-induced fatty change, 107 Wilson’s disease, 201 passive congestion, 231 paucity of duct syndrome. See intrahepatic biliary atresia PBC. See primary biliary cirrhosis peliosis hepatis cavernous hemangioma versus, 260 clinical/biologic behavior of, 150 common patterns of, 148f differential diagnosis for, 149 features of, 148–149 prognosis for, 150 special stains, 149 treatment for, 150 peliotic lesions sinusoid-associated characterization of, 473 common patterns of, 473f–474f conditions associated with, 474t peribiliary cysts clinical/biologic behavior of, 204 common patterns of, 204f differential diagnosis for, 204 features of, 203 prognosis for, 204 treatment for, 204 peribiliary gland hamartoma. See bile duct adenoma peribiliary glands, 14f periductal ibrosis bile duct-associated characterization of, 393 common patterns of, 393f–394f conditions associated with, 395t periodic-acid Schiff (PAS) amebiasis versus, 177 brucellosis, 157 candidiasis versus, 175 coccidioidomycoses versus, 172 cryptococcosis versus, 174 histoplasmosis versus, 171 Mycobacterium-avium complex (MAC), 165 myoclonus epilepsy, 225 Niemann-Pick disease, 224 pyogenic abscess, 154 reactive changes, 154 salmonellosis, 158 sarcoidosis, 363 toxoplasmosis, 186 periportal inclusions, 363 perivenular alcoholic ibrosis clinical/biologic behavior of, 75 differential diagnosis for, 75 features of, 74–75 prognosis for, 75 special stains for, 75 treatment for, 75 perivenular inclusions, 363

505

Perl’s iron acute viral hepatitis, 19 hyperalimentation, 368 liver cell adenoma, 250 NASH diagnosis with, 89 neonatal hepatitis, 194 phenytoin hepatocellular necrosis with inlammation from clinical/biologic behavior of, 101 differential diagnosis for, 101 features of, 100–101 prognosis for, 101 special stains for, 101 treatment for, 101 pheochromocytoma, 298, 298f phosphotungstic acid hematoxylin (PTAH) Budd-Chiari syndrome, 138 hepatoblastoma, 289 peliosis hepatis, 140 polyarteritis nodosa, 146 Q fever versus, 169 Rocky Mountain spotted fever versus, 170 toxemia of pregnancy, 366 transplant rejection, 289 VOD, 140 pigments anthracite, 128f characterization of, 447 common patterns of, 447f–449f drug-induced lesions, 128t gold, 129f thorotrast, 129f types of, 11–12 pit cells, 6 plasma cell disorders, 306 plasma cells portal characterization of, 458 common patterns of, 458f–459f conditions associated with, 459t Plasmodium spp, 179 PLTD. See post-transplant lymphoproliferative disorder (PLTD) polyarteritis nodosa clinical/biologic behavior of, 147 common patterns of, 147f differential diagnosis for, 146–147 features of, 146 prognosis for, 148 stains for, 146 treatment for, 148 polyclonal carcinoembryonic antigen (pCEA), 275 polycystic diseases adult, 210–212 Caroli disease, 209–210 congenital hepatic ibrosis, 207–209 peribiliary cysts versus, 204 perinatal, 206–207 poor vascular perfusion. See ischemic necrosis porphyria cutanea tarda autoluorescence, 227 clinical/biologic behavior of, 227–228 common patterns of, 228f differential diagnosis for, 227 features of, 227 prognosis for, 228 stains for, 227 treatment for, 228 porphyrias characterization of, 226 erythropoietic protoporphyria, 228–230

506

Index

portal eosinophils characterization of, 460 common patterns of, 460f–461f conditions associated with, 462t portal ibrosis characterization of, 463 common patterns of, 463f–464f conditions associated with, 465t–466t portal lymphocytes characterization of, 452 common patterns of, 452f–454f conditions associated with, 454t–455t portal neutrophils characterization of, 456 common patterns of, 456f–457f conditions associated with, 457t portal plasma cells characterization of, 458 common patterns of, 458f–459f conditions associated with, 459t portal tracts common patterns of, 8f fulminant hepatitis-associated, 24 lymphocyte expansion, 12f portal vein thrombosis causes of, 142t characterization of, 141 common patterns of, 141f portal veins, 4, 7 portal venules, 5 post-transplant lymphoproliferative disorder. See Epstein-Barr virus (EBV) pregnancy acute fatty liver during, 108 clinical/biologic behavior of, 366 common patterns of, 365f differential diagnosis for, 365–366 features of, 364–365 prognosis for, 366 stains for, 365 tetracycline-induced fatty change versus, 367 treatment for, 366 toxemia during clinical/biologic behavior of, 367 common patterns of, 366f–367f differential diagnosis, 366 features of, 366 herpes virus versus, 44 morphologic features, 366 stains for, 366 treatment for, 367 preservation harvesting/reperfusion injury clinical/biologic behavior of, 323–324 common patterns of, 323f differential diagnosis for, 323 features of, 322–323 pathology, 322t primary biliary cirrhosis (PBC) autoimmune hepatitis versus, 360 bile duct injury versus allopurionol-induced, 120 ketoconazole-induced, 120 bile duct obstruction versus, 55 chronic viral hepatitis versus, 36 clinical/biologic behavior of, 63–64 common patterns of, 59f–63f differential diagnosis for, 60–62 features of, 58–64 overlap syndrome, 36 post-transplant clinical/biologic behavior of, 347 common patterns, 346f differential diagnosis for, 347 features of, 347

primary biliary cirrhosis (PBC) (Continued) prognosis for, 347 strains for, 347 treatment for, 347 prognosis for, 64 stains, 60 treatment for, 64 primary nonfunction. See acute graft failure primary sclerosing cholangitis (PSC) allopurional-induced bile duct injury versus, 122 bile duct obstruction versus, 55 biliary cirrhosis versus, 60 chronic viral hepatitis versus, 36 clinical/biologic behavior of, 69 common patterns of, 64f–67f differential diagnosis for, 66–67 features of, 64 ketoconazole-induced bile duct injury versus, 120 post-transplant clinical/biologic behavior of, 348 common patterns for, 347f differential diagnosis for, 348 features of, 348 prognosis for, 348 stains for, 348 treatment for, 348 prognosis for, 68, 70 recurrent pyogenic cholangiohepatitis versus, 69 stains, 64–66 treatment for, 68, 70 viral hepatitis versus, 36 primitive stem cells, 9 procainamide inclusions, 128f progenitor cells, 3 progressive familial intrahepatic cholestasis clinical/biologic behavior of, 201 common patterns of, 201f differential diagnosis for, 201 morphologic changes, 200–201 prognosis for, 201 stains for, 201 treatment for, 201 Prussian blue erythropoietic protoporphyria, 228 Gaucher disease, 222 GVHD, 352 hemosiderosis, 238 macroregenerative nodules, 315 malaria, 178 reactive hemophagocytic syndrome, 369 schistomosiasis, 187 Wilson’s disease, 201 PSC. See primary sclerosing cholangitis pseudolymphoma, 302 pylephlebitis bile duct obstruction versus, 56 clinical/biologic features of, 146 common patterns of, 145f differential diagnosis for, 145 features of, 144–145 hepatic vein, 145f polyarteritis nodosa versus, 146 prognosis for, 146 treatment for, 146 pyogenic abscess aspiration cytology for, 154–156 clinical/biologic behavior of, 156 common patterns of, 155f differential diagnosis for, 156 features of, 154 prognosis for, 156 stains for, 154 treatment for, 156

Q Q fever clinical/biologic behavior of, 169 common patterns of, 168f differential diagnosis for, 169 features of, 167 prognosis for, 169 stains for, 169 treatment for, 169

R reactive changes aspiration cytology for, 154–156 clinical/biologic behavior of, 156 common patterns of, 155f differential diagnosis for, 156 features of, 154 inlammatory bowel disease-associated, 357, 357f prognosis for, 156 stains for, 154 treatment for, 156 recurrent pyogenic cholangiohepatitis (RPC) bile duct obstruction versus, 57 common patterns of, 69f differential diagnosis for, 68–69 features of, 68–70 red blood cell-trabecular lesion, 138 rejection clinical/biologic behavior of, 326 differential diagnosis of, 326 features of, 326 immunohistochemistry for, 326 stains for, 326 types of, 325–333 reticulin stain angiosarcoma, 292 autoimmune hepatitis versus, 360 characterization, 18 for HBV, 26 for hepatocellular necrosis acetaminophen-induced, 94 cocaine-induced, 94 halothane-induced, 102 for lobular conluent necrosis sertraline-induced, 106 troglitazone-induced, 104 for perivenular alcoholic ibrosis, 75 hepatocellular carcinoma, 273 hereditary tyrosinemia, 220 infantile hemangioendothelioma, 261 liver cell adenoma, 250 macroregenerative nodules, 315 nodular regenerative hyperplasia, 317 Reye syndrome, 12–14 clinical/biologic behavior of, 372 common patterns of, 371f differential diagnosis for, 372 features of, 371–372 prognosis for, 372 special stains for, 372 tetracycline-induced fatty change versus, 108 treatment for, 372 rhodanine bile duct obstruction, 55 biliary ibrosis, 60 Byler syndrome, 201 hyperalimentation, 368 Indian childhood cirrhosis, 248 intrahepatic biliary atresia, 200 Langerhans cell histocytosis, 306 post-transplant PBC, 347 PSC, 35 Wilson’s disease, 201

Index

Rocky Mountain spotted fever clinical/biologic behavior of, 170 common patterns of, 169f differential diagnosis for, 170 features of, 169–170 prognosis for, 170 stains for, 170 treatment for, 170 RPC. See recurrent pyogenic cholangiohepatitis (RPC) rubeanic acid bile duct obstruction, 55 biliary ibrosis, 60 Byler syndrome, 201 hyperalimentation, 368 Indian childhood cirrhosis, 248 intrahepatic biliary atresia, 200 ketoconazole-induced bile duct injury, 120 Langerhans cell histocytosis, 306 post-transplant PBC, 347 PSC, 35 Wilson’s disease, 201 rubella, 50t–51t rubeola, 50t–51t

S salmonellosis brucellosis versus, 157 clinical/biologic behavior of, 160 common features of, 159f common patterns of, 158f–159f differential diagnosis for, 159–160 features of, 158 prognosis for, 160 special stains for, 158 treatment for, 160 sarcoidosis brucellosis versus, 157 clinical/biologic behavior of, 356 coccidioidomycoses versus, 172 common patterns of, 354f–355f differential diagnosis for, 356 features of, 353, 355 histoplasmosis versus, 171 Hodgkin’s lymphoma versus, 300 leishmaniasis versus, 275–276 primary biliary cirrhosis versus, 62 prognosis for, 356 stains for, 355 treatment for, 356 tuberculosis versus, 163 schistomosiasis clinical/biologic behavior of, 188–189 common patterns of, 187f–188f differential diagnosis for, 188 features of, 187 malaria versus, 179 non-cirrhotic portal ibrosis versus, 152 prognosis for, 189 stains for, 187 treatment for, 188–189 secondary iron overload. See hemosiderosis secondary sclerosing cholangitis, 68–69 segmental ducts, 7 SEN virus, 18 sepsis. See also bacterial sepsis alcoholic fatty liver disease versus, 71 benign recurrent intrahepatic cholestasis (BRIC), 202 bile duct obstruction versus, 55 cholestasis versus, 115–116

sertraline lobular conluent necrosis from differential diagnosis for, 106 features of, 106 special stains for, 106 sickle cell anemia clinical/biologic behavior of, 231 common patterns of, 230f differential diagnosis for, 230–231 features of, 230 prognosis for, 231 stains for, 230 treatment for, 231 simple acinus, 9 simple hepatic cysts, 149, 204, 257 sinusoidal obstruction syndrome. See veno-occlusive disease sinusoids circulating cells in characterization of, 475 common patterns of, 475f–477f conditions associated with, 477t conditions associated with, 479t congestion in characterization of, 470 common patterns of, 470f–471f conditions associated with0, 472t dilatation in characterization of, 470 common patterns of, 470f–471f conditions associated with, 472t extramedullary hematopoiesis in, 478, 478f–479f ibrosis in characterization of, 467 common patterns of, 467f–468f conditions associated with, 469t hemorrhage in characterization of, 470 common patterns of, 470f–471f conditions associated with, 472t peliotic lesions in characterization of, 473 common patterns of, 473f conditions associated with, 474t sirius red, 25–26, 363 solitary unilocular cysts aspiration cytology for, 206 clinical/biologic behavior of, 206 common patterns of, 205f differential diagnosis for, 206 features of, 205–206 prognosis for, 206 treatment for, 206 space occupying lesions benign, 442 common patterns of, 442f–443f conditions associated with, 444t malignant characterization of, 445 common patterns of, 445f–446f conditions associated with, 446t space of Disse, 8 spindle cell neoplasms, 263, 319 squamous cell carcinoma, 298–299, 298f stellate cells characterization, 6 embryonic, 3 regeneration, 10 stem cells, 9, 11–12 Stevens-Johnson syndrome, 113 storage disorders characterization of, 221t Gaucher disease, 222–223 glycogen, 221–222

507

storage disorders (Continued) myoclonus epilepsy, 225–226 Niemann-Pick disease, 223–225 Sudan black, 106–107, 372 sulfasalazine fatty change from clinical/biologic behavior of, 110 differential diagnosis for, 110 features of, 110 sulfonamide granulomas from clinical/biologic behavior of, 112–113 differential diagnosis for, 112 features of, 112 prognosis for, 113 treatment for, 113 sunlower cataracts, 246 surgical hepatitis, 14f syncytial giant cells characterization of, 480 common patterns of, 480f–481f conditions associated with, 482t hepatitis-associated alpha-1 antitrypsin deiciency versus, 216 hepatocytes transformation by, 35 hyperalimentation versus, 368 neonatal, 161 syphilis congenital, 162f differential diagnosis for, 161 features of, 160–161 prognosis for, 163 secondary, 161f–162f stains for, 161 treatment for, 163

T telomeres, 266 teratoma, 266 tetracycline fatty change from autoluorescence, 108 clinical/biologic behavior of, 108 differential diagnosis for, 108 features of, 106 prognosis for, 108 special stains for, 106–107 treatment for, 108 thiazolidinediones, 104 thorotrast pigments, 129f thrombosis. See vascular thrombosis toxemia pregnancy-associated clinical/biologic behavior of, 367 common patterns of, 366f–367f differential diagnosis, 366 features of, 366 herpes virus versus, 44 morphologic features, 366 stains for, 366 treatment for, 367 toxic shock syndrome, 55 toxin-induced liver cell injury bile duct, 119–122 cholestasis with inlammation, 117–119 cholestasis, simple, 115–117 classiication, 93 fatty change, 48 features of, 93 ibrosis, 123–125 granulomas, 41–42 hepatocellular necrosis from, 93–103 lobular conluent necrosis, 103–106 Mallory bodies, 113–115 morphologic variants, 95t

508

Index

toxin-induced liver cell injury (Continued) neoplasms, 125 vascular conditions and, 122–123 toxoplasmosis clinical/biologic behavior of, 187 common patterns of, 186f differential diagnosis for, 186 features of, 186 prognosis for, 187 stains for, 186 treatment for, 187 transfusion-transmitted virus (TTV), 18 transplantation. See also bone-marrow transplantation acute (cellular) rejection, 326–330 acute graft failure, 324–325 chronic (ductopenic) rejection, 330–333 complications following, 333–336 hyperacute (humoral) rejection, 321 opportunistic infections following, 336–339 pathologic change timeframe, 321–322 preservation injury, 322–324 recipients, 322t recurrent disease of, 342–350 rejection overview, 325–333 transverse issure, 4 troglitazone lobular conluent necrosis from clinical/biologic behavior of, 104–105 differential diagnosis for, 104 features of, 104 prognosis for, 105 special stains for, 104 treatment for, 105 metabolism, 105 tropical splenomegaly syndrome, 179 TTV. See transfusion-transmitted virus (TTV) tuberculosis clinical/biologic behavior of, 164–165 coccidioidomycoses versus, 172 common patterns of, 163f–164f differential diagnosis for, 163–164 features of, 163 hepatic involvement incidence, 164t prognosis for, 165–166 stains for, 163 treatment for, 165–166 tumor suppressor genes, 266 tyrosinemia. See hereditary tyrosinemia

U umbilical issure, 4 uridine diphosphoglucoronyl transferase (UDPGT), 218

V vaculitis, 56–57 van Gieson contraceptive-induced cholestasis, 115 allopurionol-induced bile duct injury, 121 bile duct obstruction, 55 Byler syndrome, 201 clarithromycin-induced cholestasis, 119 hepatocellular carcinoma, 275 intrahepatic biliary atresia, 200 ketoconazole-induced bile duct injury, 120 ketoconazole-induced cholestasis, 117 methyltestosterone-induced cholestasis, 116 varicella zoster, 44, 339 vascular disorders Budd-Chiari syndrome, 136–139 congestion secondary to heart failure, 138 congestion, common patterns of, 135f–136f hypoxic injury secondary to hypotension, 141–143

vascular disorders (Continued) inlammation characterization of, 483 common patterns of, 483f–484f conditions associated with, 485t non-cirrhotic portal ibrosis, 151 occlusion characterization of, 486 common patterns of, 486f–487f conditions associated with, 488t Osler-Weber-Rendu disease, 150–151 peliosis hepatis, 148–150 perfusion, 102 portal vein thrombosis, 141 pylephlebitis, 144–146 red blood cell-trabecular lesion, 143–144 vasculitis, 146–153 venous congestion secondary to right-side heart failure, 134–136 venous outlow obstruction, 134–136 VOD, 139–141 vascular endothelial growth factor (VEGF), 266 vascular network, 3 vascular occlusion busulfan-induced clinical/biologic behavior of, 123 differential diagnosis for, 123 features of, 122–123 prognosis for, 123 special stains for, 123 treatment for, 123 drug-induced liver cell injury and, 122–123 toxin-induced cell injury and, 122–123 vascular thrombosis characterization of, 486 common patterns of, 486f–487f conditions associated with, 488t necrotic tumor mass versus, 177 vasculitis causes, 45 polyarteritis nodosa clinical/biologic behavior of, 147 differential diagnosis for, 146–147 features of, 146 prognosis for, 148 stains for, 146 treatment for, 148 spirochetes versus, 161–162 toxemia of pregnancy versus, 366 veno-occlusive disease (VOD) characterization, 123 clinical/biologic behavior of, 140 common patterns of, 139f congestion and dilatation of, 149 differential diagnosis for, 140 features of, 139–140 perivenular alcoholic ibrosis versus, 75 prognosis for, 140–141 red blood cell-trabecular lesion versus, 143 special stains for, 140 treatment for, 140–141 venous outlow obstruction hepatic vein thrombosis, 136–139 secondary to right-sided heart failure, 134–136 clinical/biologic behavior of, 134–136 differential diagnosis for, 134 features of, 134 prognosis for, 136 special stains, 134 treatment for, 136 VOD, 139–141

Verhoeff ’s elastic tissue, 146, 151 Verhoeff ’s Van Gieson fulminant hepatitis, 25–26 non-cirrhotic portal ibrosis, 152 perivenular alcoholic ibrosis, 75 Victoria blue, 101, 201 viral hepatitis, 341, 356 viral hepatitis, acute acetaminophen-induced hepatocyte damage versus, 94 acute (cellular) rejection versus, 327 cholestasis with inlammation versus, 117 chronic viral hepatitis versus, 35–36 clinical/biologic behavior of, 19 CMV versus, 43 cocaine-induced liver hepatocyte damage versus, 96 common patterns of, 17f–19f differential diagnosis for, 19–21 early and active stages of, 99 EBV versus, 40 echovirus versus, 49 features of, 16–18 immunohistochemistry for, 19 isoniazid-induced hepatocyte damage versus, 98–99 Lassa fever versus, 48 malaria versus, 179 nitrofurantoin-induced hepatocyte damage versus, 102 phenytoin-induced liver cell injury versus, 101 prognosis for, 23 pyogenic abscess versus, 156 salmonellosis versus, 24 sertraline-induced liver hepatocyte damage versus, 106 sickle cell anemia versus, 230–231 special stains, 18–19 treatment for, 23 troglitazone-induced hepatocyte damage versus, 104 yellow fever versus, 48 viral hepatitis, chronic briding ibrosis in common patterns of, 33f cirrhosis with, 26, 34f clinical/biologic behavior of, 36–38 common patterns of, 27f–29f differential diagnosis for, 35–36 features of, 27–35 hereditary tyrosinemia versus, 220 histologic staging/grading, 35 immunohistochemistry for, 35 IV drug abuse-associated, 33f methotrexate-induced ibrosis versus, 125 nirofurantoin-induced hepatocyte damage versus, 102 phenytoin-induced liver cell injury versus, 101 primary biliary cirrhosis versus, 60–62 PSC versus, 66 severe ibrosis with, 26 special stains for, 35 stains for, 35 visceral larva migrans clinical/biologic behavior of, 185–186 common patterns of, 185f differential diagnosis for, 185 eosinophils in, 186f features of, 184 prognosis for, 186 treatment for, 186

Index

vitamin A fatty change from autoluorescence, 111 clinical/biologic behavior of, 111 differential diagnosis for, 111 features of, 110–111 prognosis for, 111 special stains for, 111 treatment for, 111 VOD. See veno-occlusive disease (VOD) von Kossa, 182, 257 von Meyenburg complex. See biliary microhamartoma

W Waldenstrom’s macroglobulinemia clinical/biologic behavior of, 307 common patterns of, 307f differential diagnosis for, 307 features of, 306 immunohistochemistry for, 307 prognosis for, 307

Waldenstrom’s macroglobulinemia (Continued) stains for, 306 treatment for, 307 Warthin-Starry, 140, 161 Wilson disease acute viral hepatitis versus, 21 alcoholic cirrhosis versus, 85 chronic viral hepatitis versus, 36 clinical/biologic behavior of, 245–246 common patterns of, 243f–245f differential diagnosis for, 245, 246t features of, 242–244 fulminant hepatitis versus, 26 hepatic copper quantitation, 245 prognosis for, 246–247 stains for, 244 treatment for, 246–247 troglitazone-induced hepatocyte damage, 104 Wolman disease tetracycline-induced fatty change versus, 108

Y yeast forms, 174 yellow fever clinical/biologic behavior of, 49 common patterns of, 48f differential diagnosis for, 48–49 features of, 48 immunohistochemistry for, 48 prognosis for, 49 treatment for, 49 yolk sac tumor, 299, 299f

Z Ziehl-Neelsen carbolfuchsin Dubin-Johnson syndrome, 219 leprosy versus, 167 MAC, 165 schistomosiasis, 187 tuberculosis versus, 163

509

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