Color Atlas of Pediatric Pathology [1 ed.] 1933864575, 9781933864570

Pediatric pathology has been a recognised sup-specialty of pathology for almost two decades. Today pathology training pr

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Color Atlas of Pediatric Pathology [1 ed.]
 1933864575, 9781933864570

Table of contents :
Color Atlas of Pediatric Pathology
Title page
Copyright
Dedication
Contents
Preface
Contributors
1. Placenta
Inflammatory Lesions
Maternal Vascular Lesions
Fetal Vascular Lesions
Developmental Abnormalities
Extrinsic Process
Multiple Pregnancy
References
2.Congenital Malformation Syndromes
Introduction
Terminology and Definitions
Chromosomal Abnormalities
Disruptions
Fusion Defects
Growth Defects
Deformations
Association
Suggested
Readings
3. Infections
Viral Infections
Bacterial Infections
Fungal Infections
Protozoal Infections
Metazoal Infections
Artifacts Resembling Infections
4. The Skin
Introduction
Skin Biopsy: When, Why and How
Genodermatoses
Noninfectious Acquired Vesiculobullous Diseases
Noninfectious Papulosquamos Dermatoses
Infectious Diseases
Noninfectious Neutrophilic Dermatoses
Noninfectious Granulomatous Dermatoses
Noninfectious Panniculitis
Vasculitis
Systemic Diseases with Prominent Cutaneous Manifestations
Cysts, Neoplasms, and Hamartomas
Melanocytic Proliferations
Hematopoietic Proliferations
5. Soft Tissue Lesions
Fibrous Lesions
Myogenic Lesions
Neural Lesions
Fatty Lesions
Vascular Lesions
Fibrohistiocytic Lesions
Lesions of Indeterminate Histogenesis
6. Bone and Joints
Introduction
Nonneoplastic Bone Diseases
Bone Tumors and Tumorlike Conditions
Joint Disorders
Bibliography
7. The Heart
Structural Cardiovascular Diseases
Infectious and Inflammatory Cardiovascular Diseases
Metabolic Disorders
Conduction System Abnormalities
Cardiac Tumors
Heart Transplant Pathology
Bibliography
8. The Lung and Mediastinum
Tracheoesophageal Fistula and Esophageal Atresia
Bronchogenic Cyst
Extralobar Pulmonary Sequestration
Intralobar Pulmonary Sequestration
Pulmonary Hypoplasia
Infantile Lobar Emphysema
Congenital Pulmonary Lymphangiectasis
Congenital Pulmonary Airway Malformation
Alveolar Capillary Dysplasia
Peripheral Cysts
Hyaline Membrane Disease, Bronchopulmonary Dysplasia, and Chronic Lung Disease of the Premature
Congenital Surfactant Deficiency
Interstitial Pulmonary Emphysema
Idiopathic Pulmonary Hemosiderosis
Myofibroblastic Tumor
Juvenile Squamous Papillomas
Pleuropulmonary Blastoma
Cystic Fibrosis
Asthma
Diaphragmatic Hernia and Diaphragmatic Eventration
Suggested Readings
9. The Kidney
Introduction
Developmental Defects
Cystic Diseases
Glomerular Diseases
Tubulointerstitial and Vascular Diseases
Kidney Transplant Pathology
Renal Neoplasms
Suggested Readings
10. Female and Male Reproductive Systems
Normal Development of Reproductive Structures
Specific Reproductive Tract Anomalies
Disorders of Sex Development
Inflammatory Disorders
Gonadal Tumors
References
11. Gastrointestinal Tract
Esophageal Duplication/Enteric Cyst/Other Gastrointestinal Duplications
Tracheoesophageal Fistula with or without Esophageal Atresia
Reflux Esophagitis/Barrett Esophagus
Eosinophilic Esophagitis
Hypertrophic Pyloric Stenosis
Omphalocele
Gastroschisis
Malrotation
Intestinal Atresia and Stenosis
Meckel Diverticulum and Other Vitelline Duct Anomalies
Meconium and Meconium Abnormalities
Hirschsprung Disease
Intussusception
Celiac Disease
Intestinal Lymphangiectasia
Neonatal Necrotizing Enterocolitis
Ulcerative Colitis
Crohn Disease
Bacterial Diarrhea
Gastrointestinal Tumors
Additional Readings
12. Liver, Biliary Tract, and Pancreas
Liver and Biliary Tract
Pancreas
References
13. Thyroid, Parathyroid, and Adrenal Glands
Thyroid Gland
Parathyroid Glands
Adrenal Gland
References
14. Bone Marrow, Lymph Nodes, and Thymus
Introduction
Bone Marrow
Lymph Nodes
Spleen
Thymus
References
Bibliography
15. Central Nervous System and Neuromuscular Disease
Developmental Abnormalities
Perinatal Injuries
Neoplasms of the Nervous System
Neuromuscular Diseases
Bibliography
Index

Citation preview

of Pediatric Pathology

Aliya N. Husain, MD • J. Thomas Stocker, MD

The Color Atlas of Pediatric Pathology covers the broad range of pediatric diseases that a pathologist will likely encounter and is written by well-known leaders in this field. Coverage includes both frequent and less commonly seen cases, and each discussion presents a concise summary of the salient features of the disease along with expertly selected, high-quality color images. The Color Atlas of Pediatric Pathology is a practical working resource for every pathologist who sees pediatric cases as well as the pathology trainee. The atlas features approximately 1,100 high-quality images as well as important staging and prognostic (including molecular) parameters. Features of the Color Atlas of Pediatric Pathology include:  omprehensive coverage of both common and uncommon diseases in pediatric C surgical pathology n Chapters presented by a recognized expert n Practical presentations: concise text highlights diagnostic features making the atlas an outstanding resource for the practitioner n

n

1,100 full-color images

A Look Inside the Book 10. Female and Male Reproductive Systems 11. Gastrointestinal Tract 12. Liver, Biliary Tract, and Pancreas 13. Thyroid, Parathyroid, and Adrenal Glands 14. Bone Marrow, Lymph Nodes, Spleen, and Thymus 15. Central Nervous System and Neuromuscular Diseases

About the Editors Aliya N. Husain, MD, Professor of Pathology, University of Chicago, Chicago, Illinois J. Thomas Stocker, MD, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Pathology, Bethesda, Maryland Recommended Shelving Category:

Pathology 11 W. 42nd Street New York, NY 10036 www.demosmedpub.com Cover Design: Joe Tenerelli

Husain Stocker

1. Placenta 2. Congenital Malformation Syndromes 3. Infections 4. The Skin 5. Soft Tissue Lesions 6. Bone and Joints 7. The Heart 8. The Lung and Mediastinum 9. The Kidney

Color Atlas of Pediatric Pathology

Color Atlas

Color Atlas of Pediatric Pathology Aliya N. Husain J. Thomas Stocker

Color Atlas of

Pediatric Pathology

Color Atlas of

Pediatric Pathology

EDITORS

Aliya N. Husain, MD Professor of Pathology university of Chicago Chicago, Illinois

J. Thomas Stocker, MD uniformed Services university of the Health Sciences F. edward Hébert School of Medicine Department of Pathology Bethesda, Maryland

NEW YORK

Acquisitions Editor: Richard Winters Cover design: Joe Tenerelli Compositor: Absolute Service, Inc. Visit our website at www.demosmedpub.com © 2011 Demos Medical Publishing, LLC. All rights reserved. ISBN 978-1-933864-57-0 eISBN 978-1-935281-40-5 This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Library of Congress Cataloging-in-Publication Data Color atlas of pediatric pathology / editors, Aliya N. Husain, J. Thomas Stocker. p. ; cm. Includes bibliographical references and index. ISBN 978-1-933864-57-0 1. Pediatric pathology—Atlases. I. Husain, Aliya N. II. Stocker, J. Thomas. [DNLM: 1. Pathologic Processes—Atlases. 2. Pediatrics—Atlases. WS 17] RJ49.C65 2011 618.92’007—dc22 2010052842 11 12 13 14 5 4 3 2 1 Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. For details, please contact: Special Sales Department Demos Medical Publishing 11 W. 42nd Street, 15th Floor, New York, NY 10036 Phone: 800–532–8663 or 212–683–0072; Fax: 212–941–7842 E-mail: [email protected] Printed in the United States of America by Bang Printing

For my family, Shaghil, Ameena, Ayesha, and Omar: Balancing work and home would not be possible without your understanding, support, and encouragement. Aliya N. Husain

Contents Preface

ix

Contributors

xi

1. PlaCenTa

1

raymond W. redline

2. ConGeniTal MalForMaTion syndroMes

29

nicole A. Cipriani and Aliya n. Husain

3. inFeCTions

43

David M. Parham

4. The sKin

57

Vijaya B. reddy

5. soFT Tissue lesions

79

Zhongxin Yu and David M. Parham

6. Bone and JoinTs

103

Karen S. thompson

7. The hearT

123

Bahig M. Shehata and Charlotte K. Steelman

8. The lunG and MediasTinuM

147

J. thomas Stocker and Aliya n. Husain

9. The Kidney

177

Anthony Chang, neeraja Kambham, and elizabeth J. Perlman

10. FeMale and Male reProduCTive sysTeMs

207

Michael K. Fritsch and elizabeth J. Perlman

11. GasTroinTesTinal TraCT

235

J. thomas Stocker, Haresh Mani, and John Hart

12. liver, Biliary TraCT, and PanCreas

265

Haresh Mani and J. thomas Stocker

vii

viii 

Contents

13. Thyroid, ParaThyroid, and adrenal Glands

319

John Hicks

14. Bone Marrow, lyMPh nodes, sPleen, and ThyMus

373

Andrea M. Sheehan

15. CenTral nervous sysTeM and neuroMusCular disease Peter Pytel Index

419

401

Preface Pediatric pathology is distinct from adult pathology in many ways: types of diseases, genetic and molecular defects, therapies (including side effects and long-term complications), and outcomes. This is not only because of congenital malformations but also because infections and tumors that affect children are not the same as those seen in adults. One example is Wilms tumor, which is relatively common in children but exceedingly rare in adults, with diagnostic and staging parameters distinct from adult renal tumors, and a cure rate of over 95%. Thus, pediatric pathology has been a boarded subspecialty in the United States and Canada since 1991. The majority of pediatric pathologists work in children’s hospitals; however, more than half of the pediatric cases are being seen by “general pathologists” in various practice settings. Thus, there continues to be a need for all pathologists to keep current in their diagnostic skills and knowledge of pediatric pathology and this atlas has been written with those residents, fellows, and general pathologists in mind. It is meant to serve as a handy reference for people who see pediatric cases infrequently and may have no special expertise in the subject. It cannot replace a comprehensive textbook; rather it should be used in addition to one. For years, one of us (JTS) had wanted to use his extensive collection of photographs to illustrate an atlas of pediatric pathology. You may wonder why such a book is needed in this age of “Google pictures.” We think there is considerable value to the student as well as the practicing pathologist to see illustrations selected by “experts,” such as the chapter authors in this book. In addition, the accompanying text concisely summarizes the pertinent features of each disease. Thus, rather than sifting through the thousands of items brought up in nanoseconds by any of the search engines, one can turn to an atlas such as this when faced with an uncommon or rare diagnostic specimen. The Color Atlas of Pediatric Pathology is organized in a traditional manner with each chapter devoted to a specific organ system. The authors for each chapter were chosen for their knowledge, and were asked to cover common as well as selected uncommon diseases that every pathologist would need to know about. Because this is an atlas, the focus is on illustrations with supporting text; only selected references are given. This book brings together the experience and expertise from many institutions, which add to its value. As with any multi-author book, there is some variation in how each chapter is written and illustrated. We hope our readers will find the Color Atlas of Pediatric Pathology to be a valuable resource in their diagnoses of pediatric cases.

Acknowledgments: Pictures are from the teaching collections of several pathologists and university hospitals; many are thanks to the diligence of past residents and fellows who are unnamed but not forgotten.

ix

Contributors Anthony Chang, MD Associate Professor of Pathology University of Chicago Medical Center Chicago, Illinois Nicole A. Cipriani, MD Department of Pathology University of Chicago Medical Center Chicago, Illinois Michael K. Fritsch, MD, PhD Associate Professor of Pathology Northwestern University Feinberg School of Medicine Children’s Memorial Hospital Chicago, Illinois John Hart, MD Professor of Pathology The University of Chicago Medical Center Chicago, Illinois John Hicks, MD, DDS, MS, PhD Professor of Pathology Texas Children’s Hospital and Baylor College of Medicine Houston, Texas Aliya N. Husain, MD Professor of Pathology University of Chicago Chicago, Illinois Neeraja Kambham, MD Associate Professor of Pathology Co-Director, Renal Pathology Laboratory Stanford University Medical Center Stanford, California Haresh Mani, MD Assistant Professor of Pathology Penn State Milton S. Hershey Medical Center and Penn State College of Medicine Hershey, Pennsylvania

David M. Parham, Pediatric MD Professor Department of Pathology University of Oklahoma Health Science Center Oklahoma City, Oklahoma Elizabeth J. Perlman, MD Head, Pathology and Laboratory Medicine Arthur C. King Professor of Pathology and Laboratory Medicine Professor of Pathology Northwestern University Feinberg School of Medicine Children’s Memorial Hospital Chicago, Illinois Peter Pytel, MD Department of Pathology University of Chicago Medical Center Chicago, Illinois Vijaya B. Reddy, MD Professor of Pathology Rush University Medical Center Chicago, Illinois Raymond W. Redline, MD Department of Pathology Case Western Reserve University Cleveland, Ohio Andrea M. Sheehan, MD Assistant Professor of Pathology and Immunology Assistant Professor of Pediatrics, Section of Hematology-Oncology Texas Children’s Hospital and Baylor College of Medicine Houston, Texas Bahig M. Shehata, MD Professor of Pathology and Pediatrics Emory University School of Medicine Department of Pathology Children’s Healthcare of Atlanta Atlanta, Georgia

xi

xii 

Contributors

Charlotte K. Steelman, BS Emory University School of Medicine Children’s Healthcare of Atlanta Atlanta, Georgia

J. Thomas Stocker, MD Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine Department of Pathology Bethesda, Maryland

Karen S. Thompson, MD Associate Professor of Pathology John A. Burns School of Medicine, University of Hawaii Pediatric Pathologist, Pan Pacific Pathologists, LLC Kapiolani Medical Center for Women and Children Honolulu, Hawaii Zhongxin Yu, MD Assistant Professor Department of Pathology University of Oklahoma Health Science Center Oklahoma City, Oklahoma

1

Placenta raymond W. redline

n

INFLAMMATORY LESIONS Infectious Acute Chorioamnionitis Intervillositis Placentitis (TORCH) Idiopathic Villitis of Unknown Etiology Chronic Deciduitis

n

MATERNAL VASCULAR LESIONS Obstructive Decidual Arteriopathies Acute Atherosis Mural Hypertrophy Villous Changes Consistent With Maternal Malperfusion Villous Infarct Perivillous Fibrin Deposition Disruptive Abruptio Placentae Marginal Abruption (Acute Peripheral Separation) Chronic Abruption (Chronic Peripheral Separation)

n

FETAL VASCULAR LESIONS Obstructive Fetal Thrombotic Vasculopathy Changes Consistent With Chronic Partial/Intermittent Umbilical Cord Occlusion Disruptive Intervillous Thrombi (Fetomaternal Hemorrhages) Fetal Vessel Rupture

n

DEVELOPMENTAL ABNORMALITIES Villous Architecture Distal Villous Hypoplasia Distal Villous Immaturity Villous Vasculature Villous Chorangiosis Chorangioma

n

EXTRINSIC PROCESS Meconium Exposure (Fetal Stool Within the Amniotic Fluid) Recent: Less Than 6 Hours (Membranes) Prolonged: 6–12 Hours or More (Chorionic Plate and/or Umbilical Cord) Meconium-Associated Vascular Necrosis Increased Circulating Fetal Nucleated Red Blood Cells Normoblastemia Erythroblastosis

n

MULTIPLE PREGNANCY Dichorionic Twin Placentas Monochorionic Twin Placenta

inFlaMMaTory lesions n inFeCTious ACUte CHorIoAMnIonItIs (neutrophilic Inflammation of the Placental Membranes) Prevalence/gestational age: The prevalence of acute chorioamnionitis (ACA) ranges from 60% at less than 24 weeks to less than 10% term (1). ACA is also a common cause of late first and second trimester loss. Etiology: ACA is usually an ascending infection caused by organisms resident in the vagina (2). In some cases, the membranes may be seeded hematogenously during periods of transient bacteremia. Spread from contiguous pelvic infections has also been proposed. Causative organisms include bacteria, mycoplasma, or fungi. Many cases are polymicrobial, but infections causing serious complications for the mother or fetus usually involve more virulent organisms such as gram-negative bacilli, group B streptococci, and Staphylococcus aureus. Clinical presentation: ACA may present with preterm labor, preterm premature rupture of membranes, maternal fever, maternal/fetal tachycardia, uteri and tenderness, or a foul-smelling discharge. However, the majority of cases are clinically silent.

1

2 

Placenta

Figure 1.1  Early acute subchorionitis (maternal stage 1) (H&E; 310). Neutrophils are limited to fibrin below the chorionic plate.

Figure 1.2  Acute chorioamnionitis (maternal stage 2) (H&E; 320). Neutrophils infiltrate both chorion and amnion.

Pathology

Gross: Cloudiness or opacity may be seen on the fetal surface, particularly surrounding the major chorionic vessels. In severe cases, a yellow-green discoloration may be noted. Marginal abruption (discussed later) often accompanies ACA in premature deliveries. Microscopic: The neutrophilic inf lammatory response to microorganisms in the membranes and amniotic f luid comes from both the mother and fetus (2). Early (stage 1) maternal ACA is limited to neutrophils in the subchorionic fibrin and/or the decidual–chorionic interface of the membranes (early acute subchorionitis, Figure 1.1). Intermediate (stage 2) maternal ACA affects both chorion and amnion (Figure 1.2), whereas in late (stage 3) ACA, the inf lammatory response causes amnion necrosis, neutrophil karyorrhexis, and eosinophilic thickening of the amniotic epithelial basement membrane (necrotizing chorioamnionitis, Figure 1.3). In early (stage 1) fetal responses, neutrophils are seen in the walls of the umbilical vein and/or chorionic plate vessels. In intermediate (stage 2) fetal responses, the walls of the umbilical artery are infiltrated. Late (stage 3) fetal responses are characterized by organizing arcs of neutrophils and neutrophilic debris surrounding vessels in the umbilical cord (subnecrotizing funisitis, Figure 1.4). A histologically severe fetal

Figure 1.3  Necrotizing chorioamnionitis (maternal stage 3) (H&E; 320). Amniotic epithelium is necrotic with a thick eosinophilic basement membrane. Some neutrophils show ­karyorrhexis.

Figure 1.4  Subnecrotizing funisitis (fetal stage 3) (H&E; 34). A band of neutrophils and neutrophilic debris are seen in the umbilical cord stroma surrounding the umbilical vein.

INFLAMMATORY LESIONS 

Figure 1.5  Severe chorionic vasculitis (fetal grade 2) (H&E; 310). A near confluent neutrophilic infiltrate occupies the amniotic aspect of a major chorionic vessel accompanying by medial degeneration and endothelial activation.

Figure 1.6  Peripheral funisitis (Candida albicans) (H&E; 34). Triangular neutrophilic microabscesses are noted on the umbilical cord surface.

acute inf lammatory response is associated with an increased risk of brain injury (Figure 1.5) (3). Subacute (chronic) maternal responses manifest as a mixed neutrophil-macrophage infiltrate in the chorionic plate with polarization of inf lammation to the amniotic surface, while the corresponding fetal responses consist of calcification and/or neovascularization in the umbilical cord stroma (4). Fungal infections, usually caused by Candida albicans, have a specific histologic picture characterized by microabscesses on the surface of the umbilical cord (Figure 1.6) (5). Special studies: Histochemical stains for bacteria (Gram, Steiner, and Giemsa) may be useful in some cases of membrane infection. Gömöri methenamine silver (GMS) stain for fungi is indicated only in the presence of umbilical cord microabscesses. Placental cultures play little or no role in either pathologic diagnosis or clinical management. Differential diagnosis: Conditions to be distinguished from ACA include chronic deciduitis and decidual necrosis of the membranes and other fetal vasculitides (Table 1.1).

Intervillositis (Acute or Chronic Inflammatory Response in the Intervillous Space) Prevalence/gestational age: Intervillositis is rare in the developed world. However, it is the second most common inflammatory process affecting placentas in areas with a high prevalence of Plasmodium falciparum malaria (6). Etiology: There are several distinct patterns of intervillositis (7). Acute intervillositis with intervillous abscess formation is most commonly seen with Listeria monocytogenes infection. ­Campylobacter fetus and other rare bacteria may also elicit this response. Acute villitis with foci of intervillositis is seen with fetal septicemia, particularly when caused by gram-negative bacilli. Acute intervillositis with small foci of acute villitis may occur in maternal septicemia, particularly with group A streptococci. Chronic intervillositis with increased perivillous fibrin deposition (PVF) is the pattern associated with P. falciparum malaria. Clinical presentation: Listeria infections most commonly occur during local food born epidemics (8). Fetal septicemia is often clinically silent, but maternal septicemia can be associated with septic shock and multiorgan failure. Malarial infection of the placenta is particularly common in primiparous females traveling to endemic regions from areas of low prevalence. Human immunodeficiency virus (HIV) coinfection increases the risk of placental malarial infection.

3

4 

Placenta

Table 1.1  Differential Diagnosis of Placental Findings FINDING

LESION

PRIMARY CHARACTERISTICS

HELPFUL ASSOCIATED FINDINGS

Solid/ cystic gross lesions

Villous infarct

Wedge-shaped, abutting BP, granular, necrotic debris, separation between villi lost

Small placenta, findings c/w MMP, FGR or hypertension

PVF plaque

Often transmural, smooth, villi embedded in fibrin, separation between villi maintained Spherical, smooth, firm, usually marginal or subchorionic (capillary vascular lesion) Spherical, smooth, soft, tanred, laminated hematoma, surrounded by villi Area of decreased placental thickness, fibrin coats stem villi and surfaces of BP and CP Extravillous trophoblastlined cyst within a decidual septum, clear-bloody fluid content Villi with lymphocytes in stroma, agglutinated by fibrin

No other pregnancy or placental abnormalities

Chorangioma

Intervillous thrombus

Placental atrophy

Septal cyst

Villous agglutin­ation

Avascular villi

VUE

Uterine abnormality, low implantation, abnormal placental shape

No other pregnancy or placental abnormalities

FGR, abnormal fetal monitoring, prior pregnancy loss, decidual plasma cells Small placenta, villous infarct(s), FGR or hypertension

Massive PVF deposition

Villi  trophoblast necrosis agglutinated by fibrinoid matrix and extravillous trophoblast Intermediate to large segments of villous tree with hyalinized AV (average  15 AV per slide) Widely scattered small foci of AV (2–10 AV per focus) VUE with small to large areas of hyalinized AV, and stem villous arteritis/periarteritis

FGR, fetal monitoring abnormalities, recurrent pregnancy loss

Changes 2° to fetal death

Diffuse AV, varying stages, affecting entire placenta

Villous hemosiderin, fibromuscular sclerosis of large fetal vessels

Massive PVF deposition

Fibrinoid matrix completely surrounds ­distal villi  embedded ­trophoblast

FGR, fetal monitoring abnormalities, recurrent pregnancy loss

VUE with perivillous fibrin

Fibrin completely surrounds chronically inflamed distal villi  chronic intervillositis, no embedded trophoblast

FGR, abnormal fetal monitoring, prior pregnancy loss, decidual plasma cells

Fetal thrombotic vasculopathy

VUE with obliterative fetal vasculopathy

Inflammation, membranes

Fetomaternal hemorrhage (small to large)

Findings consistent with MMP Villi with increased syncytial knots agglutinated by direct contact

Findings consistent with UCO

Perivillous fibrin

Preeclampsia, multiple pregnancy

Pathologic UC abnormalities, neonatal coagulopathy/thrombosis

Pathologic UC abnormalities, intimal fibrin cushions, large vessel ectasia FGR, fetal monitoring abnormalities, neonatal encephalopathy

Findings consistent with MMP Eccentric aggregates of fibrin focally attached to villi and/ or incorporated into villous stroma

Small placenta, villous infarct(s), FGR or hypertension

Placental atrophy

Area of decreased placental thickness, fibrin coats stem villi and surfaces of BP and CP

Uterine abnormality, low implantation, abnormal placental shape

ACA

Neutrophils in amnion plus chorion or diffusely lining choriodecidual interface

Must have abundant neutrophils in fibrin below CP (Continued)

INFLAMMATORY LESIONS 

5

Table 1.1  Differential Diagnosis of Placental Findings (Continued) FINDING

LESION

PRIMARY CHARACTERISTICS

HELPFUL ASSOCIATED FINDINGS

Inflammation, membranes (cont.)

Chronic deciduitis

Small lymphocytes and/or plasma cells in decidua capsularis

VUE, preterm labor, some cases of pre­ eclampsia/FGR

Laminar necrosis

Focal neutrophilic debris with a background of ischemic necrosis in choriodecidua

Small placenta, findings c/w MMP, FGR or hypertension

ACA with acute fetal vasculitis

Neutrophils ( eosinophils) in wall of chorionic or umbilical vessels facing the amniotic cavity

Chorioamnionitis, maternal response in membranes and/or subchorionic fibrin

Prolonged meconium exposure

Rare neutrophils in wall of umbilical and/or chorionic veins

Long umbilical cord, large fetus, oligohydramnios, variable decelerations

VUE with obliterative fetal vasculopathy

Small lymphocytes surrounding and/or ­invading chorionic or stem villous vessels

Distal chronic villitis, extensive avascular villi

T-cell/eosinophil vasculitis

Eosinophils and lymphocytes within the walls of chorionic or stem villous vessels facing away from amniotic cavity

Possible relation to later childhood atopy

Meconium

Fine red-brown pigment in markedly vacuolated macrophages

Green discoloration of membranes and fetal surface, amnion edema/necrosis

Hemosiderin

Crystalline golden brown refractile pigment within and outside macrophages

Iron-stain positive in 2/3 of cases, old marginal blood clot, circumvallation, greenbrown discoloration

Inflammation, fetal vessels

Pigment, membranes

Abbreviations: ACA, acute chorioamnionitis; AV, avascular villi; BP, basal plate; CP, chorionic plate; FGR, fetal growth restriction; MMP, maternal ­malperfusion; PVF, perivillous fibrin; UCO, umbilical cord occlusion; VUE, villitis of unknown etiology.

Pathology

Gross: Placentas with acute intervillositis may have irregular pale firm “septic infarcts” on the cut section. Chronic intervillositis can be associated with nonspecific consolidation of the villous parenchyma. Microscopic: Acute intervillositis is characterized by maternal neutrophils in the intervillous space with occasional involvement of contiguous villi (Figure 1.7). Patchy intervillous fibrin often accompanies this pattern. Chronic intervillositis shows a predominance of intervillous monocyte/macrophages with abundant PVF. In malaria infections, areas of trophoblast necrosis and hemozoin pigment deposition are also prominent (9). Special studies: Histochemical stains or microorganisms (Gram, silver impregnation stains, Giemsa) may be helpful in distinguishing the etiology of infection.

Placentitis (TORCH) (Multifocal Placental Chronic Inflammation) Prevalence/gestational age: TORCH is an acronym for fetoplacental infections caused by ­Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses (HSV). O stands for “other” organisms, the most common of which are varicella-zoster virus (VZV), Epstein-Barr virus, Trypanosoma cruzi, and Treponema pallidum (syphilis). In the United States, infections caused by organisms other than CMV and T. pallidum are rare (10). All TORCH infections are most commonly detected in second- and early third-trimester placentas.

6 

Placenta

Figure 1.7  Acute intervillositis (Listeria monocytogenes) (H&E; 310). Confluent neutrophils in the intervillous space surround and invade distal villi.

Figure 1.8  Chronic placentitis (cytomegalovirus), plasma cell villitis (H&E; 340). Small lymphocytes and plasma cells infiltrate the fibrotic villous stroma.

Etiology: TORCH infections usually occur following primary infection of the mother (11). Risk of infection is increased with coexisting sexually transmitted diseases, HIV infection, or other immune deficiencies. Clinical presentation: Clinical features common to all TORCH infections include fetal pneumonitis, cytopenias, and growth restriction (7). CMV infections specifically target the brain and liver; syphilis targets the GI tract, liver, pancreas, and skin; and HSV targets the liver, adrenals, and lung. Toxoplasmosis shows trophism for the brain and retina. VZV may cause skin rashes and/or limb reduction defects with a “zosterlike” dermatomal distribution. TORCH infections acquired early in pregnancy often result in fetal death or spontaneous abortion. Later infections are associated with symptomatic disease at the time of birth. Pathology

Gross: Placentitis caused by HSV and VZV is generally associated with a small firm placenta. Placentas with syphilis and toxoplasmosis are often large and edematous. Placentas with CMV infection may show either pattern. Microscopic: Infectious placentitis is distinguished from idiopathic villitis (see discussion that follows) by a generally mild lymphohistiocytic infiltrate affecting most or all distal villi. CMV infection should be strongly suspected whenever plasma cells are seen in the villous stroma (Figure 1.8). Prominent involvement of fetal blood vessels with hemosiderin deposition and the presence of viral inclusions are other typical features (Figure 1.9). Placental syphilis often shows stem villous arteritis and necrotizing umbilical periphlebitis in addition to the nonspecific lymphohistiocytic villous infiltrate. HSV and VZV infections lead to villous necrosis, fibrosis, and mineralization and can spread to the placental membranes. Toxoplasmosis is characterized by a focal nonspecific villitis, often with granulomatous features. Diagnostic toxoplasma cysts may be seen in the umbilical cord stroma. Special studies: Microbial proteins and DNA may be detected by immunohistochemistry or polymerase chain reaction (PCR). Mouse inoculation studies continue to be diagnostically useful in areas with a high prevalence of toxoplasmosis (12). Other

Granulomatous deciduitis: Rare patients with disseminated or abdominal Mycobacteria tuberculosis infections may show diffuse decidual necrosis, with poorly formed decidual granulomas (13). However, most cases of granulomatous deciduitis are idiopathic. Intervillous organisms (schistosomiasis, coccidiomycosis, cryptococcosis): Placental infections associated with noncandidal fungi and circulating parasites are usually confined to the intervillous space, where an inconspicuous inflammatory infiltrate and fibrin surround diagnostic organisms (14).

INFLAMMATORY LESIONS 

Figure 1.9  Chronic placentitis (cytomegalovirus), viral inclusion (H&E; 360). A villous stromal cell has a large central eosinophilic nuclear inclusion with surrounding halo plus multiple smaller basophilic cytoplasmic inclusions.

Figure 1.10  Villitis of unknown etiology, high grade (patchy/diffuse) (H&E; 310). A focus of more than 10 affected villi shows a diffuse stromal infiltrate of small lymphocytes.

n IDIOPATHIC Villitis of Unknown Etiology (Patchy Chronic Lymphocytic Infiltrate in Villous Stroma) Prevalence/gestational age: Chronic villous inflammation not associated with recognizable microorganisms (villitis of unknown etiology [VUE]) is observed in 5% to 10% of all term placentas (15). Occasional studies report prevalences of up to 20%, if cases with a single isolated focus are accepted. VUE is rare in placentas at less than 34 weeks of gestation. Etiology: VUE occurs following entry of maternal T cells into the fetal villous stroma, where they react to fetal antigens presented by stromal macrophages (16). CD8 T cells predominate over CD4 T cells (17). VUE is associated with significant systemic maternal and fetal inflammatory cytokine and chemokine responses (18). It is more frequent in multiparous females and in ovum donation pregnancies, consistent with the hypothesis that repeated or novel antigen exposure plays an important role in promoting cellular inflammation. Clinical presentation: VUE is associated with fetal growth restriction (FGR), abnormal fetal monitoring patterns, neonatal encephalopathy, and recurrent reproductive failure. Basal VUE is associated with late preterm delivery and an increased prevalence of genitourinary infections (19). Pathology

Gross: Placentas with VUE are somewhat small for gestation and occasionally contain ill-­defined areas of parenchymal consolidation. Microscopic: VUE is characterized by lymphocytic inflammation of the villous stroma with or without accompanying macrophages or histiocytic giant cells (Figure 1.10) (7). Other types of inflammatory cells are rarely seen. It can be distinguished from chronic placentitis caused by TORCH infections by the focal or patchy nature of the villous infiltrate (rarely exceeding 25%). Low-grade VUE has been defined as containing clusters of less than 10 contiguous inflamed villi (focal: confined to one slide; multifocal: affecting multiple slides). High-grade VUE contains foci of more than 10 villi (patchy: less than 10% of total villi affected; diffuse: 10% or more). VUE with chronic perivasculitis/vasculitis affecting proximal villous or chorionic vessels can lead to downstream avascular villi (discussed later), a process referred to as obliterative fetal vasculopathy (Figure 1.11). VUE with an exclusively basal distribution is termed basal villitis (Figure 1.12). Special studies: Special studies, as detailed in the preceding discussion, may rarely be required to exclude a TORCH infection.

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Placenta

Figure 1.11  Villitis of unknown etiology with obliterative fetal vasculopathy (H&E; 310). Stem villi show lymphocytic vasculitis with fetal vascular stenosis.

Figure 1.12  Basal villitis of unknown etiology (H&E; 320). A dense lymphocytic decidual infiltrate with accompanying fibrin spreads into anchoring and adjacent villi in the basal plate.

Differential diagnosis: Villous agglutination and PVF, sometimes seen in VUE, should be distinguished from agglutination and intervillous fibrin deposition seen with MMP, massive perivillous fibrinoid deposition, and areas of placental atrophy (Table 1.1).

Chronic Deciduitis (Lymphocytic Infiltration of the Endometrium) Prevalence/gestational age: Prevalence ranges from 13% at 23 weeks of gestation to 3% at term (7). This pattern may occasionally be associated with recurrent fetal losses before 23 weeks. Etiology: Chronic deciduitis is a local inflammatory response to antigens in the endometrium, often with formation of antibodies secreting plasma cells. Possible stimuli include microorganisms associated with chronic endometritis in nonpregnant women, retained placental tissue from previous pregnancies, fetal antigens expressed on extravillous trophoblast, or maternal autoantigens. Clinical presentation: Chronic deciduitis often accompanies ACA, VUE, or maternal vascular disease associated with antiphospholipid antibodies. Isolated chronic deciduitis has itself been proposed as an uncommon cause of premature labor and delivery (20). Pathology

Gross: No findings. Microscopic: Chronic deciduitis has been defined as either patchy/diffuse lymphocytic inflammation or the presence of any plasma cells in the basal and/or membranous decidua (Figure 1.13) (21). Special studies: Plasma cell endometritis and positive endometrial cultures often coexist in patients after premature deliveries (22). Differential diagnosis: Conditions to be distinguished from chronic deciduitis include ACA with acute deciduitis and laminar necrosis of the membranes (see Table 1.1, p. 4). Other

Chronic histiocytic intervillositis: Diffuse infiltration of the intervillous space by CD68-positive macrophages without clinical pathologic evidence of malaria infection is a rare but important cause of recurrent reproductive failure (23). The presence of coexisting villitis excludes this diagnosis.

MATERNAL VASCULAR LESIONS 

Figure 1.13  Chronic deciduitis, lymphoplasmacytic (H&E; 340). Small lymphocytes and plasma cells infiltrate decidualized endometrium.

Chronic periarteritis: Nonspecific lymphocytic infiltrates in the perivascular connective tissue surrounding maternal arterioles in the decidua are a distinct finding in some cases of maternal vascular disease (7). Eosinophil/T-cell vasculitis: Mural infiltration of large fetal arteries in the chorionic plate and/or stem villi by T lymphocytes and eosinophils is a recently described pattern of unclear etiology and clinical significance (24). Unlike fetal vasculitis in ACA, the infiltrate typically involves the vessel wall on the side away from the amniotic cavity and may be associated with recent fetal thrombosis (see Table 1.1, p. 4). Anecdotal cases associated with adverse outcomes, including a long-term risk of atopic/ allergic disease, have yet to be verified in larger studies.

MATERNAL VASCULAR LESIONS n OBSTRUCTIVE Decidual Arteriopathies Acute Atherosis (Fibrinoid Necrosis of Maternal Uterine Arteries and Arterioles) Prevalence/gestational age: Acute atherosis is found in approximately 1 of 6 cases preeclampsia and is more frequent in severe and/or early preeclampsia (25). Increased sampling of the marginal and membranous areas of the placenta can increase detection. Acute atherosis is not seen before 18 weeks gestation. Etiology: Fibrinoid degeneration and medial necrosis of the arterial wall are believed to occur secondary to acute endothelial damage caused by circulating antiangiogenic factors in preeclampsia. Local factors must also play a role because preeclampsia causes systemic endothelial damage, yet only muscularized arteries in the uterus and placenta show atherosis. Amongst the factors associated with endothelial damage are sflt-1, sENG, and angiotensin receptor autoantibodies (26, 27). Excessive amounts of circulating oxidized lipoproteins may contribute to the formation of foam cells within areas of fibrinoid necrosis (28). Clinical presentation: Most placentas with acute atherosis are associated with preeclampsia. However, occasional placentas from cases of diabetes mellitus, FGR, or antiphospholipid antibody syndrome will be affected in the absence of maternal hypertension.

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Placenta

Figure 1.14  Decidual arteriopathy, acute atherosis (H&E; 310). Decidual arterioles are dilated with fibrinoid degeneration of the muscular media, focal foamy macrophages, and ill-­defined endothelial activation and early adjacent coagulation.

Pathology

Microscopic: The arterial wall in acute atherosis shows red-blue glassy degeneration of the muscular wall with scattered intramural foamy macrophages (Figure 1.14) (29). Affected vessels may be lined by activated endothelial cells and sometimes show mural thrombi. Arteries are often markedly dilated and can show coexistent mural hypertrophy (see succeeding discussion).

Mural Hypertrophy (Medial Hypertrophy of Maternal Arterioles) Prevalence/gestational age: Mural hypertrophy of decidual arterioles and may be seen in the placentas of some women with chronic hypertension, diabetes, or preeclampsia. Etiology: Mural hypertrophy is increased in women with angiotensinogen T235 mutations and essential hypertension (30). The lesion is believed to be a consequence of defective nontrophoblast related remodeling of spiral arteries in very early pregnancy. Clinical presentation: In addition to hypertension and diabetes, women with recurrent spontaneous abortion and autoimmune abnormalities sometimes show marked hypertrophy in specimens from early pregnancy. Pathology

Microscopic: Mural hypertrophy is diagnosed when the thickness of the arteriolar smooth muscle wall exceeds two-thirds of the total diameter (Figure 1.15). The lesion may be seen with or without acute atherosis in preeclampsia (29). Smooth muscle hypertrophy tends to be more prominent with chronic hypertension; excessive extracellular matrix more prominent with diabetes. Cases associated with recurrent spontaneous abortion often show an associated ­periarteritis.

Villous Changes Consistent With Maternal Malperfusion (Increased Syncytial Knots, Intervillous Fibrin, Villous Agglutination) Prevalence/gestational age: Changes consistent with maternal malperfusion (MMP) are observed in up to 10% to 15% of third trimester placentas (31). These findings are rare before 24 weeks. Etiology: Villous changes are the result of aberrant maternal perfusion. Perfusion failure leads to reduced bulk flow, local stasis, decreased transit time, and episodes of ischemia/reperfusion leading to oxidative injury and increased turnover of villous trophoblast (32). The underlying etiology of MMP is failure of trophoblast-dependent remodeling of the uterine arterial system in the first and second trimesters of pregnancy.

MATERNAL VASCULAR LESIONS 

Figure 1.15  Decidual arteriopathy, mural hypertrophy (H&E; 320). Decidual arterioles show medial hypertrophy exceeding two-thirds of the total diameter.

Figure 1.16  Findings consistent with maternal malperfusion (H&E; 34). Distal villi show excessive numbers of syncytial knots and focal agglutination in the presence of ill-defined aggregates of intervillous fibrin.

Clinical presentation: MMP is the most common cause of FGR and an important cause of idiopathic preterm delivery (33). It is commonly seen in association with preeclampsia, especially in preterm placentas, and is a nonspecific finding in some chromosomal abnormalities. Pathology

Gross: Placentas with villous changes consistent with MMP are often small with an increased fetoplacental weight ratio and can show other gross changes of maternal vascular disease including infarcts and abruption (discussed later). A thin umbilical cord (decreased hydration of Wharton’s jelly) may be observed reflecting fetal volume depletion secondary to reduced maternal perfusion. Microscopic: Maternal large vessel obstruction results in an increase in villous trophoblast turnover (increased syncytial knots), circulatory stasis (patchy areas of intervillous fibrin deposition), and foci of villous trophoblast necrosis (villous agglutination) (Figure 1.16) (29). Patchy areas of ischemic necrosis in the decidua (laminar necrosis) may also be seen indicative of abnormal flow in smaller vessels not communicating with the intervillous space (34). Differential diagnosis: Intervillous fibrin needs to be distinguished from perivillous fibrin in VUE, massive PFV, and placental atrophy. Villous agglutination may mimic aggregated villi in VUE or perivillous fibrin plaques (see Table 1.1, p. 4).

Villous Infarct (Ischemic Necrosis of Villous Parenchyma Caused by Cessation of Maternal Blood Flow) Prevalence/gestational age: Approximately 10% to 20% of third trimester placentas contain one or more villous infarcts (35). Marginal infarcts of less than 3-cm diameter are considered normal by some authors (36). Multiple infarcts at term and any infarct in a premature infant are indicative of significant underlying maternal vascular disease. Etiology: Villous infarcts occur in two situations: obstruction of major uterine arteries by thrombosis or abnormal remodeling and separation of the placenta from its underlying blood supply caused by retroplacental hemorrhage (discussed later). Clinical presentation: Infarcts are associated with FGR, preeclampsia, idiopathic preterm labor or membrane rupture, and maternal systemic diseases such as chronic hypertension, diabetes, and autoimmune disease, especially when associated with antiphospholipid antibodies (37).

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Placenta

Figure 1.17  Villous infarct (H&E; 34). A large contiguous segment of villous parenchyma shows collapse of the intervillous space and ischemic necrosis of villous trophoblast.

Figure 1.18  Massive perivillous fibrinoid deposition (“maternal floor infarction”) (H&E; 34). Anastomosing bands of perivillous fibrin and fibrinoid surround and entrap large portions of the distal villous tree.

Pathology

Gross: Villous infarcts are firm, granular, wedge-shaped lesions abutting the basal plate. Infarcts of less than 1- to 2-day duration are dark red. Those that are more remote, pale yellow. Centrally hemorrhagic villous infarcts need to be distinguished from intervillous thrombi (IVT) by microscopy. Microscopic: The hallmarks of villous infarction are collapse of the intervillous space with widespread agglutination of villi and evidence of ischemic necrosis in the trophoblastic layer (karyorrhectic debris and loss of nuclear basophilia) (Figure 1.17). Differential diagnosis: Lesions that may mimic infarcts on gross or microscopic exam include marginal villous atrophy, perivillous plaques, chorangiomas, IVT, and hemorrhagic septal cysts (see Table 1.1, p. 4).

Perivillous Fibrin Deposition (Fibrin and Fibrinoid Matrix Enveloping Distal Villi) Prevalence/gestational age: Localized plaques of PVF are observed in 13% of term placentas (35). Massive PVF deposition, also sometimes known as “maternal floor infarction,” is a rare placental lesion usually presenting in the late second and early third trimester (38). However, it may also be seen at other stages of pregnancy and is an important cause of recurrent first trimester loss. Etiology: Massive PVF deposition is an idiopathic process, sometimes associated with autoimmune disorders (particularly antiphospholipid antibody syndrome), hypertension, and, in a single case report, fetal long-chain 3-hyroxyacyl-coenzyme A dehydrogense (LCHAD) deficiency (39). Reported recurrence risks of more than 50% are most consistent with a maternal, nongenetic etiology. However, the lesion can be discordant in twin pregnancies, suggesting some component of fetal susceptibility (40). Histologic findings including focal villous trophoblast necrosis, patchy intervillous fibrin, and abundant trophoblast embedded in extracellular matrix suggest a sequence of trophoblast injury followed by metaplasia to an extravillous phenotype with subsequent matrix secretion. Spread might occur via a positive feedback loop. The pathogenesis of PVF plaques is also uncertain and may involve local changes in blood flow with secondary secretion of matrix. Clinical presentation: Massive PVF deposition is associated with severe FGR, stillbirth, preterm delivery, fetal brain injury, and recurrent reproductive failure. One case report documented rapid development over a 3-week period in association with accelerating maternal hypertension (40). Localized PVF plaques have no known clinical significance (41).

MATERNAL VASCULAR LESIONS 

Pathology

Gross: Diagnosis of massive PVF deposition requires documentation of consolidation affecting at least 20% of the villous parenchyma and/or thickening of 50% of the basal plate. The majority of placentas are small for gestational age, although occasional placentas may be enlarged secondary to the volume of extracellular matrix. PVF plaques are grossly indistinguishable from villous infarcts. Microscopic: Massive PVF deposition is characterized by an admixture of extracellular matrix and fibrin that completely surrounds large zones of distal villi with preservation of the space between villi (lack of villous agglutination) (Figure 1.18). In some cases, the entire placenta may be “marbled” by anastomosing bands of degenerating villi surrounded by whorls of fibrin with foci of ischemic cellular debris. PVF plaques show similar features but are localized with sharply demarcated ­borders. Differential diagnosis: Massive PVF deposition must be distinguished from intervillous fibrin with MMP, PFV with VUE, and placental atrophy. PVF plaques must be differentiated from other localized lesions such as chorangiomas, villous infarcts, and IVT (see Table 1.1, p. 4).

n DISRUPTIVE Abruptio Placentae (Central Retroplacental Hemorrhage Secondary to Maternal Arterial Rupture) Prevalence/gestational age: Estimates of the prevalence and gestational age range of abruptio placentae are unreliable because of overlap with marginal abruption in the clinical literature (42). Bona fide abruptio placentae occurs most commonly after 30 weeks of gestation in women with hypertensive disorders. Etiology: Abruptio placentae represents rupture of one or more spiral arteries. There are three recognized causes of rupture: (a) weakening of the arterial wall by acute atherosis, (b) ischemia-reperfusion injury secondary to vasoactive drugs (cocaine or nicotine), and (c) shear stress secondary to trauma or hard physical labor (43, 44). Clinical presentation: The classic signs of abruptio placentae are vaginal bleeding, fetal distress, and abdominal pain/rigidity. Common associations include hypertensive crisis or eclamptic seizures. Pathology

Gross: Abruptio placentae is characterized by retroplacental hemorrhage with indentation of or rupture through the basal plate. This generally occurs in the central portion of the placenta. Occasionally, no hemorrhage is noted and the basal plate either is normal or shows only a concave depression left by the clotted blood. Microscopic: Histologic features indicative of arterial hemorrhage include intradecidual spread, retromembranous extension, and dissection into the villous parenchyma (basal intervillous thrombus) (Figure 1.19). Premature placentas often show acute villous stromal hemorrhage. Retroplacental hemorrhages present for 6 or more hours prior to delivery have changes indicative of overlying recent villous infarction.

Marginal Abruption (Acute Peripheral Separation) (Peripheral Retroplacental Hemorrhage Secondary to Recent Marginal Venous Rupture) Prevalence/gestational age: Marginal abruptions most commonly occur before 30 weeks of gestation and are important causes of preterm delivery and second trimester abortion (45). Prevalence ranges from 30% at 24 weeks to 5% at term (unpublished data). Etiology: Marginal abruptions occur because of rupture of maternal venous sinuses at the periphery of the placenta. Two factors play an important role in rupture: (1) changes in uterine geometry occurring with rupture of membranes or expansion of the lower uterine segment and (2) weakening of decidual tissue supporting the venous wall caused by ACA or laminar necrosis.

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Placenta

Figure 1.19  Findings consistent with subacute abruptio placentae (H&E; 34). Retroplacental hemorrhage has dissected through the basal plate (basal intervillous ­thrombus), where it is adjacent to villi showing recent villous infarction.

Figure 1.20  Marginal abruption (acute peripheral separation) (H&E; 34). A large recent retroplacental hematoma disrupts the decidua adjacent to the placental margin.

Clinical presentation: Marginal abruptions are associated with premature labor, vaginal bleeding, and precipitous delivery. Pathology

Gross: Marginal abruptions are characterized by a wedge-shaped retroplacental hematoma at the periphery of the placental disc. They may sometimes extend centrally or behind the placental membranes. Microscopic: Marginal sections show a poorly organized blood clot adjacent to congested or ruptured decidual veins, often with extensive tissue necrosis and/or ACA (Figure 1.20).

Chronic Abruption (Chronic Peripheral Separation) (Placental Changes Secondary to Remote and/or Recurrent Marginal Venous Rupture) Prevalence/gestational age: Chronic abruption is most common between 32 and 36 weeks (affecting approximately 10% of placentas at that gestation; unpublished data) but may be seen at any stage of pregnancy. Etiology: Chronic abruptions develop when marginal abruptions do not progress to delivery (46). They often begin as subchorionic hemorrhages in the first trimester (47). Hemorrhage may push the membrane insertion away from the margin of the placenta, resulting in circumvallation. Clinical presentation: Chronic abruptions can be associated with abnormal vaginal bleeding in all three trimesters. They may also be detected as subchorionic hemorrhages by early ultrasound. In many cases, they are clinically silent. Other clinical associations include oligohydramnios, preterm delivery, and an increased risk of chronic lung disease in premature infants (48, 49). Chronic abruption has been associated with cerebral palsy in term infants (50, 51). Pathology

Gross: Placentas with chronic abruption may show circumvallate membrane insertion, old marginal blood clots, and green/brown discoloration of the fetal surface (7). Microscopic: Sections from areas with circumvallation or old marginal hematoma show a pale red, loosely organized blood clot with adjacent hemosiderin in the chorionic plate (Figure 1.21). In some cases, blood enters the amniotic cavity resulting in diffuse chorioamniotic hemosiderosis. Differential diagnosis: Hemosiderin pigment must be distinguished from meconium pigment (see Table 1.1, p. 4).

FETAL VASCULAR LESIONS 

Figure 1.21  Chorioamniotic hemosiderosis consistent with chronic abruption (chronic peripheral separation) (H&E; 340). Golden brown refractile hemosiderin pigment is seen free and in macrophages in the membranous amnion and chorion.

FETAL VASCULAR LESIONS n OBSTRUCTIVE Fetal Thrombotic Vasculopathy (Large Contiguous Areas of Avascular Villi and/or Villi With Stromal–Vascular Karyorrhexis Secondary to Reduced Fetal Blood Flow) Prevalence/gestational age: Fetal thrombotic vasculopathy (FTV) is most common in term and nearterm placentas. Prevalence is 2% amongst placentas of 36 weeks or more submitted to pathology (31). Lesser numbers of affected villi may be seen in placentas of all gestational ages. Etiology: Extensive avascular villi in FTV occur because of thrombotic occlusion of the chorionic plate or major stem villous vessels (52). Predisposing factors include clinical cord entanglement, pathologic umbilical cord abnormalities, and to a lesser extent, thrombophilic conditions such as antiphospholipid antibody syndrome, mutations involving clotting factors, and antiplatelet antibodies (53, 54). Diabetic mothers may also be at increased risk. Clinical presentation: Antenatal findings include decreased fetal movement, nonreassuring fetal monitoring, and oligohydramnios. Affected infants are at risk for neonatal encephalopathy, cerebral palsy, thrombocytopenia, disseminated intravascular coagulation, major vessel thrombi, and severe liver disease (51, 53, 55–57). Pathology

Gross: Placentas with FTV often contain ill-defined areas of villous pallor and firmness conforming to the distribution of villous trees supplied by the occluded vessels. Dilatation, congestion, and frank thrombi within these vessels may be apparent on the chorionic plate. Microscopic: An average of more than 15 affected villi per section of villous parenchyma is required for the diagnosis of FTV (58). The two categories of villous abnormalities in FTV are (a) hyalinized avascular villi (Figure 1.22) and (b) villi with stromal–vascular karyorrhexis (previously termed hemorrhagic endovasculitis) (Figure 1.23). Organized thrombi in major fetal vessels are identified in onethird to two-thirds of cases. Vessels between thrombi and affected distal villi show progressive luminal occlusion (fibromuscular sclerosis) which may be diagnostically useful. Differential diagnosis: Avascular villi and villi with stromal–vascular karyorrhexis are also seen focally in VUE with obliterative fetal vasculopathy and, diffusely, after fetal death (see Table 1.1, p. 4).

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Figure 1.22  Fetal thrombotic vasculopathy: large­intermediate foci of avascular villi (H&E; 310). A large group of contiguous proximal and distal vascular villi with stromal hyalinization are seen.

Figure 1.23  Fetal thrombotic vasculopathy: villous stromal–vascular karyorrhexis (“hemorrhagic endovasculitis”) (H&E; 320). Distal villi with karyorrhectic debris and fragmented red blood cells in the stroma.

Changes Consistent With Chronic Partial/Intermittent Umbilical Cord Occlusion (Scattered Small Foci of Avascular Villi, Intimal Fibrin Cushions in Large Fetal Veins, Ectasia of Large Fetal Veins) Prevalence/gestational age: Changes consistent with chronic partial/intermittent umbilical cord occlusion (UCO) may be observed with clinical umbilical cord entanglements and pathologic umbilical cord abnormalities (53). Cord entanglements, the most common of which is nuchal cord, are observed at delivery in 30% of pregnancies. Persistent cord entanglement, present in multiple sonographic examinations, is observed in 6% of pregnancies (59). Various types of pathologic umbilical cord abnormalities occur in approximately 10% of term placentas. Etiology: Histologic changes consistent with chronic partial/intermittent UCO develop over a period of days to weeks prior to delivery (58). This sequence is associated with increased pressure in large chorionic and stem villous veins resulting in intimal fibrin cushions and vascular ectasia (60, 61). Circulatory stasis in the most distal branches of the villous tree leads to the formation of scattered small clusters of avascular villi. More severe prolonged stasis causes thrombosis and FTV as described previously. Clinical presentation: In addition to clinical cord entanglements, affected pregnancies usually show severe variable decelerations by fetal monitoring. Other risks include stillbirth and a “partial/prolonged asphyxia” pattern of postnatal brain injury (31, 61). Pathology

Gross: Pathologic umbilical cord abnormalities associated with chronic partial/intermittent UCO include marginal or membranous insertion with a potential for vessel torsion, excessively long or hypercoiled umbilical cords with altered flow, and decreased Wharton’s jelly (thin umbilical cord) with an increased risk for vascular compression. Microscopic: Large veins in the chorionic plate and major stem veins near the umbilical cord insertion may show vascular ectasia (.43 diameter of adjacent veins) (61). Plaques of organizing subendothelial fibrin may be seen in major fetal vessels (intimal fibrin cushions). Scattered small foci (2 to 10) of avascular villi or villi with villous stromal–vascular karyorrhexis are usually concentrated near the basal plate (Figure 1.24).

FETAL VASCULAR LESIONS 

Figure 1.24  Scattered small foci of avascular villi suggestive of chronic partial/intermittent umbilical cord obstruction (H&E; 320). A small cluster of hyalinized avascular villi is surrounded by normally vascularized villi.

Figure 1.25  Intervillous thrombus (H&E; 32). A focally laminated spherical hematoma compresses adjacent villi.

n DISRUPTIVE Intervillous Thrombi (Fetomaternal Hemorrhages) (Parenchymal Hematomas Surrounded by Villi) Prevalence/gestational age: IVT can be found in most thoroughly sectioned term placentas. The prevalence of fetomaternal hemorrhage as determined by the presence of fetal red blood cells in the maternal circulation ranges from 75% for small clinically insignificant hemorrhages to one in 1,146 pregnancies for hemorrhages of greater than 80 mL (62). Etiology: Fetomaternal hemorrhages arise from small breaks in the distal villous tree. The corresponding morphologic lesion is believed to be the IVT, demonstrated by Kaplan to contain fetal red blood cells (63). The maximum diameter and total number of IVT have been correlated with the magnitude of fetomaternal hemorrhage (64). Clinical presentation: Significant fetomaternal hemorrhages are associated with decreased fetal movement, sinusoidal fetal heart rate, neonatal encephalopathy, cerebral palsy, and in utero fetal demise (IUFD). They may also present as a transfusion reaction in cases of ABO incompatibility, in which case Kleihauer-Betke or flow cytometric testing may be falsely negative (see discussion that follows). Pathology

Gross: IVT are spherical, smooth, tan red, and often laminated hematomas completely surrounded by villi. Microscopic: Expansile IVT compress surrounding villi (Figure 1.25). They are surrounded by, at most, a thin rim of surrounding infarcted villous tissue. Special studies: Significant fetomaternal hemorrhages are detectable in maternal blood by KleihauerBetke testing or flow cytometry for fetal hemoglobin. Differential diagnosis: Lesions to be distinguished from IVT are villous infarcts or septal cysts with secondary hemorrhage (see Table 1.1, p. 4).

Fetal Vessel Rupture (Transection of Major Umbilical or Chorionic Vessels) Prevalence/gestational age: Rupture of major fetal vessels is extremely rare and can occur at any gestational age.

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Etiology: Intramembranous fetal vessels, usually associated with membranous insertion of the umbilical cord or accessory lobes, may become torn during membrane rupture or at parturition (ruptured vasa previa) (7). Less common causes of fetal vessel rupture include parenchymal tears caused by placenta previa or abruptio placentae, rupture of major chorionic (subamniotic hemorrhage) or umbilical cord vessels (umbilical stromal hemorrhage) secondary to excessive tension on the umbilical cord, and prior invasive antenatal testing (amniocentesis or percutaneous fetal blood sampling). Clinical presentation: Consequences of major vessel rupture include fetal distress, hypovolemia, and fetal death. Pathology

Gross/microscopic: Disrupted membranous vessels, large subamniotic hemorrhages, umbilical cord hemorrhage, and parenchymal tears are nonspecific findings that suggest fetal hemorrhage only when corroborated by additional data such as severe anemia or hypovolemia. Findings of a local hematoma or hemosiderin deposition at or near the umbilical cord insertion site are other supportive findings. Special studies: Vaginal bleeding secondary to ruptured vasa previa may be detected by the Apt test (65).

DEVELOPMENTAL ABNORMALITIES n VILLOUS ARCHITECTURE Distal Villous Hypoplasia (Diminished Growth and Arborization of the Distal Villous Tree) Prevalence/gestational age: Distal villous hypoplasia, also known as “terminal villous deficiency,” is an extreme form of MMP that usually presents in the late second or early third trimester. Etiology: Dysregulation of the normal sequence of maternal arterial remodeling in early pregnancy leads to severe and longstanding MMP, resulting in a fetal adaptive response characterized by chronically reduced perfusion of the placenta and other organs not directly required for fetal viability (i.e., heart and brain) (66, 67). Clinical presentation: Distal villous hypoplasia is associated with severe FGR, oligohydramnios, abnormal biophysical profile, and abnormal pulse flow Doppler testing. Affected cases are at high risk for fetal death. Indicated preterm delivery may be life saving. Pathology

Gross: Placentas are usually extremely small with decreased chorionic plate diameter and placental weight (68). Fetoplacental weight ratio is markedly elevated. Parenchymal thickness is not generally reduced. Microscopic: The villous tree shows a decrease in the number of distal relative to proximal stem villi (29). Long, thin, and nonbranching immature intermediate villi surrounded by clusters of syncytial knots are typically noted (Figure 1.26). There are a decreased number of fetal arterioles and those remaining may show medial hypertrophy (69).

Distal Villous Immaturity (Excessive Distal Villous Growth With Persistence of Abundant Villous Stroma and Immature Fetal Vessels) Prevalence/gestational age: Distal villous immaturity, also known as “placental maturation defect,” is predominantly recognized in term or near-term placentas (prevalence 2%) (31). It is most commonly associated with maternal diabetes. Occasional examples in preterm infants may be associated with malformations or chromosomal abnormalities. Etiology: Distal villous immaturity in placentas from infants of diabetic mothers is believed to be the consequence of excessive maternal glucose leading to the release of fetal insulin and other growth factors

DEVELOPMENTAL ABNORMALITIES 

Figure 1.26  Distal villous hypoplasia (“terminal villous deficiency”) (H&E; 34). Sparse elongated nonbranching distal villi with scattered syncytial knots.

Figure 1.27  Distal villous immaturity (decreased vasculosyncytial membranes) (H&E; 310). Numerous enlarged distal villi with excessive villous stromal cellularity and a predominance of central capillaries with deficient vasculosyncytial membrane formation.

that promote excessive placental growth at the expense of villous maturation (70). Maternal obesity or excessive pregnancy weight gain can result in similar changes. Clinical presentation: Clinical conditions associated with distal villous immaturity in term pregnancies include fetoplacental overgrowth syndromes (e.g., Beckwith-Wiedmann syndrome), impaired maternal glucose tolerance, delayed pulmonary maturation, and sudden unexpected fetal death (71–74). FGR may be seen in premature infants. Pathology

Gross: Placentas are usually large for gestational age in term infants. Placental weight for preterm infants is variable. Microscopic: Distal villous immaturity is characterized by an increased number of enlarged distal villi with an excessive number of stromal cells and villous macrophages (Figure 1.27) (7). Capillaries tend to be central with a decrease in vasculosyncytial membranes (areas where syncytiotrophoblast and fetal endothelium merge to promote gas exchange).

n VILLOUS VASCULATURE Villous Chorangiosis (Hypercapillarization of Distal Chorionic Villi) Prevalence/gestational age: Villous chorangiosis is most frequently observed in term and near-term placentas. Prevalence amongst term placentas submitted to pathology is 12% (31). Etiology: Chorangiosis may be a component of generalized distal villous immaturity as seen in maternal diabetes and fetoplacental overgrowth syndromes (mentioned earlier). In these conditions, growth factors may directly promote hypervascularization. Other causal factors relate to chronically decreased oxygen availability in the intervillous space and include maternal anemia or smoking and pregnancies occurring at high altitudes or in areas of excessive air ­pollution (75, 76). Clinical presentation: Chorangiosis has no specific association with adverse outcomes. Rather, it is an adaptive response that often accompanies other placental patterns of injury. Pathology

Gross: Chorangiosis is more frequent in large placentas.

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Microscopic: More than 10 capillary cross sections should be observed in at least 10 villi in several different areas of the placenta (“rule of tens”) (77). However, the diagnosis cannot be made with confidence unless at least 15 to 20 capillaries are seen in some distal villi (Figure 1.28) (78).

Chorangioma (Benign Capillary Vascular Tumor Within Proximal Villi) Prevalence/gestational age: Chorangiomas are most common in near-term placentas. Overall prevalence is less than 1% (79). Etiology: Chorangiomas are benign vascular tumors, possibly related to infantile hemangiomas with which they share clinical risk factors (see discussion that follows). A genetic component is suspected as these lesions may recur in subsequent pregnancies and may be associated with vascular lesions in other fetal organs (80, 81). Clinical presentation: Risk factors for chorangioma include preeclampsia, FGR, and multiple gestations. Large chorangiomas may also cause FGR (82). Other complications include nonimmune hydrops fetalis or disseminated intravascular coagulation (83, 84). Unusual cases with extremely large numbers of chorangiomas have been associated with recurrent intrauterine fetal death (79). Pathology

Gross: Chorangiomas are spherical firm nodules with a smooth cut surface. They are usually located at the placental margin or underneath the chorionic plate (78). Occasionally they spread out over several adjacent stem villi (localized chorangiomatosis). Microscopic: Chorangiomas are composed of an anastomosing capillary vascular network with prominent surrounding pericytes (Figure 1.29). Intervening areas show a variable amount of connective tissue that can sometimes predominate masking the vascular nature of the lesion. Occasionally, infarction can lead to obliteration of the vascular architecture. Almost half of chorangioma are associated with peripheral nonspecific trophoblastic hyperplasia, which may be the result of excessive local growth factor release (85). Occasional chorangiomas have excessive endothelial mitotic activity (atypical cellular chorangioma) without any adverse clinical sequela (86). Differential diagnosis: Chorangiomas must be distinguished from other firm nodular lesions such as villous infarcts, PVF plaques, and IVT (see Table 1.1, p. 4).

Figure 1.28  Villous chorangiosis (H&E; 320). Hypercapillarization of distal villi with capillary cross sections exceeding 15 per villus.

Figure 1.29  Chorangioma (H&E; 310). Capillary hemangioma composed of endothelial-lined channels with prominent surrounding pericytes arising in the stroma of a proximal stem villus, with mild nonspecific surrounding trophoblast hyperplasia.

EXTRINSIC PROCESS 

EXTRINSIC PROCESS n MECONIUM EXPOSURE (FETAL STOOL WITHIN THE AMNIOTIC FLUID) Prevalence/gestational age: Release of meconium into the amniotic fluid complicates 10% to 15% of term pregnancies (87, 88). Passage of meconium is extremely uncommon before 34 weeks. Meconium associated vascular necrosis is a rare lesion affecting 3% of term placentas submitted to pathology (31, 89). Etiology: Fetal stool is released into amniotic fluid as a direct response to decreased intestinal perfusion via a vagally mediated response to sudden changes in cardiac output (diving reflex). The most common cause is reduced venous return caused by transient UCO. Meconium contains caustic agents including bile acids, which can cause vasospasm, tissue necrosis, and cellular apoptosis after prolonged exposure (90–92). Clinical presentation: Meconium release is commonly associated with variable decelerations on fetal monitoring and clinical cord entanglement at the time of delivery. Antenatal diagnosis of prolonged meconium exposure is problematic in the absence of membrane rupture. Meconium associated vascular necrosis is most commonly seen in the scenario of intact membranes, decreased amniotic fluid, and meconium exposure of greater than 12 hours duration (unpublished data).

Recent: Less Than 6 Hours (Membranes) Gross: The membranes and fetal surface are usually either green-stained or flecked with particulate meconium. Microscopic: Pigment laden macrophages with marked cytoplasmic vacuolation may be observed in all three layers of the membrane (Figure 1.30). Amnion shows toxic effects including connective tissue edema, dehiscence of epithelial cells, and areas of cellular necrosis. Differential diagnosis: Meconium pigment must be distinguished from hemosiderin pigment (see Table 1.1, p. 4).

Prolonged: 6–12 Hours or More (Chorionic Plate and/or Umbilical Cord) Gross: The membranes and chorionic plate show deep-green staining that persists after stripping the amnion from the chorion. The surface of the umbilical cord is often green-stained.

Figure 1.30  Membrane meconium (recent exposure) (H&E; 340). Vacuolated macrophages containing ill-defined granular red-brown pigment. Amniotic epithelium shows degenerative change.

Figure 1.31  Chorionic plate meconium (prolonged exposure) (H&E; 360). Abundant vacuolated pigment-laden macrophages in the dense fibrous connective tissue of the chorionic plate.

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Microscopic: Abundant pigment-laden macrophages are seen in the dense fibrous stroma of the chorionic plate (Figure 1.31). Macrophages may also be observed in the wall of large chorionic plate vessels. There is often extensive perivascular condensation of the loose connective tissue of Wharton’s jelly, occasionally accompanied by pigment laden macrophages. Differential diagnosis: Occasional neutrophils in the walls of umbilical and chorionic veins may occur with prolonged meconium exposure and should be distinguished from a fetal inflammatory response associated with ACA (see Table 1.1, p. 4) (90).

Meconium-Associated Vascular Necrosis Gross: No findings. Microscopic: Eosinophilic apoptotic bodies with pyknotic nuclei are seen at the periphery of the vascular smooth muscle in the umbilical cord and chorionic plate (Figure 1.32) (92, 93). Adjacent myocytes may show early degenerative changes such as intensely eosinophilic cytoplasm.

n INCREASED CIRCULATING FETAL NUCLEATED RED BLOOD CELLS Normoblastemia Prevalence/gestational age: Nucleated red blood cells (NRBC) are abnormal in the fetal circulation after 20 weeks gestation. Normoblastemia is observed in approximately 1% to 2% of placentas submitted to pathology and is most common at term (94). Etiology: Prolonged severe fetal hypoxia and selected cytokines such as erythropoietin and IL-6 stimulate intramedullary and extramedullary erythropoiesis and promote the release of immature red blood cells into the peripheral circulation (95–97). Clinical presentation: Normoblastemia is associated with abnormal fetal monitoring, decreased fetal movement, neonatal encephalopathy, and chronic partial/intermittent UCO (98). It is more common in placentas with subacute/chronic lesions with duration of more than 6 to 12 hours (99). Pathology

Gross: No findings.

Figure 1.32  Meconium-associated vascular necrosis (H&E; 320). Numerous peripheral vascular smooth muscle cells showing cytoplasmic eosinophilia and nuclear pyknosis. Adjacent vacuolated pigment-laden macrophages are seen in the vascular wall.

Figure 1.33  Increased circulating fetal NRBC (normoblastemia) (H&E; 340). Normoblasts with circular hyperchromatic nuclei and scant glassy eosinophilic cytoplasm are noted in some villous capillaries.

MULTIPLE PREGNANCY 

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Figure 1.34  Increased circulating fetal NRBC (erythroblastosis) (H&E; 340). All capillaries show numerous red blood cell precursors including erythroblasts. Villous stroma is edematous and there is a distinctive artifactual dehiscence of the thickened villous trophoblast layer from the villous stroma.

Microscopic: Neonatal normoblastemia (.2,000/mm3) may be diagnosed when an average of one or more NRBC is observed per high-powered (340) field of placental parenchyma (Figure 1.33) (99). A qualitative impression of their presence can be obtained by scanning cross sections of large fetal vessels at low power (310).

Erythroblastosis Prevalence/gestational age: Hydrops fetalis (fetal congestive heart failure) may be separated into immune and nonimmune subcategories. All cases of immune hydrops and many cases of nonimmune hydrops are associated with erythroblastosis (markedly increased NRBC with circulating erythroblasts). Etiology: Erythroblastosis has the same pathogenesis as normoblastemia. However, the decrease in fetal oxygen at sites of erythropoiesis is more severe and prolonged. Most cases are associated with fetal anemia. Severe anemia with erythroblastosis leads to high-output cardiac failure. Clinical presentation: The differential diagnosis of chronic fetal anemia includes blood group incompatibility, parvovirus infection, inherited red blood cell defects, and massive fetomaternal hemorrhage (100–102). Pathology

Gross: Placentas with erythroblastosis are often enlarged, pale, and friable on cut section. They may have IVT, either as a cause of fetomaternal hemorrhage or as a consequence of increased villous friability. Microscopic: Most villous capillaries contain clusters of normoblasts. More immature forms including erythroblasts are easily identified (Figure 1.34). Parvovirus B19 nuclear inclusions should be searched for. In cases of hydrops, the distal villi show variable amounts of stromal edema and a thick cellular layer of villous trophoblast that often shows artifactual dehiscence from the stroma.

MULTIPLE PREGNANCY n DICHORIONIC TWIN PLACENTAS Prevalence/gestational age: Dichorionic twin placentas may result from either implantation of multiple fertilized eggs (dizygotic) or early dichotomous separation of a single fertilized egg (monozygotic) (7). The prevalence of dizygotic twinning varies with ethnic origin and is increased in patients undergoing artificial reproductive technologies (ARTs) (103). Etiology: Dizygotic twinning occurs secondary to either polyovulation or the introduction of multiple fertilized eggs during ART. The etiology of monozygotic twinning is poorly understood.

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Clinical presentation: Multiple gestation is associated with an increased incidence of preterm delivery, breech presentation, FGR of one or both twins, and neurodevelopmental abnormalities. Pathology

Gross: The critical factor in properly identifying dichorionic twins is assessment of the dividing membrane. Gross findings of membrane opacity and three membrane layers are indicative of dichorionic gestation. After evaluation of the dividing membrane, fused dichorionic twin placentas should be separately weighed and assessed for abnormalities, such as abnormal umbilical cord insertion site. Plaquelike thickenings in the membranes of either singleton or multiple placentas may represent early missed abortion of additional gestational sacs (“vanishing twins”/fetus papyraceous). Microscopic: Histologic sections of the dividing membrane show two fused chorions in the center flanked by amnions (Figure 1.35).

n MONOCHORIONIC TWIN PLACENTA Prevalence/gestational age: Monochorionic twin placentas are almost invariably monozygous. Monozygotic twinning occurs in 3.5/1,000 pregnancies and is also mildly increased with ART (7). Rare cases of dizygotic twins with monochorionic placentas have been reported in ART patients (104). Etiology: Monochorionic placentas result from cleavage of the inner cell mass after establishment of the trophectoderm. Early separation results in a diamniotic monochorionic placenta. Later separation results in a monoamniotic monochorionic placenta or, in extreme cases, single forked umbilical cord or conjoined twins. Clinical presentation: Monochorionic twin placentas suffer from the same clinical problems as dichorionic placentas (see preceding discussion), but have additional complications related to their partially shared fetal circulation. Chronic twin–twin transfusion syndrome develops because of the presence of deep arteriovenous anastomoses without counterbalancing interarterial anastomoses on the chorionic plate (105). This pattern leads to a marked discrepancy in circulating blood volumes and, subsequently, rate of fetal growth. Reduced growth may also be accentuated by markedly reduced maternal perfusion of the smaller (“trapped”) twin. Acute twin–twin transfusion most commonly develops after the death of one of twins leading to a sudden shift of blood from the survivor to the dead twin and resulting in severe hypoperfusion and brain injury in more than 50% of cases (106). Transfusion syndrome may also occur after spontaneous or laser ablation of critical anastomotic connections, resulting in circulatory imbalance (107).

Figure 1.35  Dividing membrane, dichorionic twin placentas (H&E; 320). Two amnions (epithelium and basement membrane) and fibrous connective tissue flank a fused chorionic bilayer of epithelioid extravillous trophoblast.

Figure 1.36.  Dividing membrane, monochorionic twin placenta (H&E; 320). Two amnions are fused without intervening chorion. Wisps of basophilic mucin represent hyaluronate that normally connects the amnion to the chorion.

REFERENCES 

Pathology

Gross: There is no dividing membrane in monoamniotic twin placentas. Inspection of the dividing membrane in diamniotic monochorionic twins reveals translucency and only two layers. Description of the fetal vasculature should include (a) estimation of the percentage of the chorionic surface occupied by each twin, (b) the presence or absence of artery–artery surface anastomoses, and (c) the results of injection studies using either air or dye to demonstrate deep arterial venous anastomoses. Microscopic: Histologic sections of the dividing membrane show two fused amnions without intervening chorion (Figure 1.36). Areas of avascular villi may be seen in patients undergoing laser ablation therapy for chronic twin–twin transfusion syndrome (108).

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80. Maymon R, Hermann G, Reish O, et al. Chorioangioma and its severe infantile sequelae: case report. Prenat Diagn. 2003;23:976–980. 81. Mulliken JB, Bischoff J, Kozakewich HP. Multifocal rapidly involuting congenital hemangioma: a link to chorangioma. Am J Med Genet A. 2007;143A:3038–3046. 82. Mucitelli DR, Charles EZ, Kraus FT. Chorioangiomas of intermediate size and intrauterine growth retardation. Pathol Res Pract. 1990;186:455–458. 83. Jones EEM, Rivers RPA, Taghizadeh A. Disseminated intravascular coagulation and fetal hydrops in a newborn infant in association with a chorangioma of placenta. Pediatrics. 1972;50:901–905. 84. Tonkin IL, Setzer ES, Ermocilla R. Placental chorangioma: a rare cause of congestive heart failure and hydrops fetalis in the newborn. Am J Roentgenol. 1980;134:181–183. 85. Khong TY. Chorangioma with trophoblastic proliferation. Virchows Arch. 2000;436:167–171. 86. Mesia AF, Mo P, Ylagan LR. Atypical cellular chorangioma. Arch Pathol Lab Med. 1999;123:536–538. 87. Miller FC, Sacks DA, Yeh SY, et al. Significance of meconium during labor. Am J Obstet Gynecol. 1975;122:573–579. 88. Rossi EM, Philipson EH, Williams TG, et al. Meconium aspiration syndrome: intrapartum and neonatal attributes. Am J Obstet Gynecol. 1989;161:106–110. 89. Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta and poor pregnancy outcome. Obstet Gynecol. 1992;79:760–766. 90. Burgess AM, Hutchins GM. Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases. Pathol Res Pract. 1996;192:1121–1128. 91. Holcberg G, Huleihel M, Katz M, et al. Vasoconstrictive activity of meconium stained amniotic fluid in the human placental vasculature. Eur J Obstet Gynecol Reprod Biol. 1999;87:147–150. 92. King EL, Redline RW, Smith SD, et al. Myocytes of chorionic vessels from placentas with meconium associated vascular necrosis exhibit apoptotic markers. Hum Pathol. 2004;35:412–417. 93. Altshuler G, Hyde S. Meconium-induced vasocontraction: a potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome. J Child Neurol. 1989;4:137–142. 94. Hermansen MC. Nucleated red blood cells in the fetus and newborn. Arch Dis Child Fetal Neonatal Ed. 2001;84:F211–F215. 95. Minior V, Levine B, Guller S, et al. Antenatal fetal hypoxemia gradually increases fetal nucleated red blood cells in a rat model. Am J Obstet Gynecol. 2004;191:S168. 96. Ferber A, Fridel Z, Weissmann-Brenner A, et al. Are elevated fetal nucleated red blood cell counts an indirect reflection of enhanced erythropoietin activity? Am J Obstet Gynecol. 2004;190:1473–1475. 97. Ferber A, Minior VK, Bornstein E, et al. Fetal “nonreassuring status” is associated with elevation of nucleated red blood cell counts and interleukin-6. Am J Obstet Gynecol. 2005;192:1427–1429. 98. Phelan JP, Korst LM, Ahn MO, et al. Neonatal nucleated red blood cell and lymphocyte counts in fetal brain injury. Obstet Gynecol. 1998;91:485–489. 99. Redline RW. Elevated circulating fetal nucleated red blood cells and placental pathology in term infants who develop cerebral palsy. Hum Pathol. 2008;39:1378–1384. 100. Machin GA. Hydrops revisited: literature review of 1,414 cases published in the 1980s. Am J Med Genet. 1989;34:366–390. 101. Morey AL, Keeling JW, Porter HJ, et al. Clinical and histopathological features of parvovirus B19 infection in the human fetus. Br J Obstet Gynaecol. 1992;99:566–574. 102. Roberts DJ, Nadel A, Lage J, et al. An unusual variant of congenital dyserythropoietic anaemia with mild maternal and lethal fetal disease. Br J Haematol. 1993;84:549–551. 103. Reynolds MA, Schieve LA, Martin JA, et al. Trends in multiple births conceived using assisted reproductive technology, United States, 1997–2000. Pediatrics. 2003;111:1159–1162. 104. Souter VL, Kapur RP, Nyholt DR, et al. A report of dizygous monochorionic twins. N Engl J Med. 2003;349:154–158. 105. Wee LY, Fisk NM. The twin-twin transfusion syndrome. Semin Neonatol. 2002;7:187–202. 106. Dembinski J, Haverkamp F, Maara H, et al. Neurodevelopmental outcome after intrauterine red cell transfusion for parvovirus B19-induced fetal hydrops. Bjog. 2002;109:1232–1234. 107. van den Wijngaard JP, van Gemert MJ, Lopriore E, et al. Case report: twin-to-twin transfusion syndrome resulting from placental collateral artery development. Placenta. 2008;29:220–223. 108. De Paepe ME, Friedman RM, Poch M, et al. Placental findings after laser ablation of communicating vessels in twin-to-twin transfusion syndrome. Pediatr Dev Pathol. 2004;7:159–165.

2

Congenital Malformation Syndromes nicole A. Cipriani Aliya n. Husain

n

n

INTRODUCTION Gross Examination and Organ Dissection Intact Specimen Fragmented Specimen Radiology Cytogenetics TERMINOLOGY AND DEFINITIONS

n

CHROMOSOMAL ABNORMALITIES Turner Syndrome Trisomy 21 Trisomy 18 Trisomy 13

n

DISRUPTIONS Amniotic Band Sequence

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FUSION DEFECTS Conjoined Twins Sirenomelia Failures of Closure

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GROWTH DEFECTS Macrosomia/Microsomia/ Organomegaly

n

DEFORMATIONS Potter Syndrome Potter Sequence and Prune Belly Sequence

n

ASSOCIATION VATER/VACTERL

inTroduCTion There exists a wide array of congenital malformations, and a detailed description of the entire spectrum of anomalies is beyond the scope of this atlas. Instead, our intent is to illustrate common gross defects encountered in both surgical and autopsy specimens. As prenatal evaluation becomes more sophisticated and accurate, pathologists are receiving elective abortions at earlier gestational ages. Pathologic diagnosis often requires use of the following techniques, depending on the clinical setting and specimen received.

n Gross eXaMinaTion and orGan disseCTion Intact specimen Examination should be performed in a standard manner (see suggested reading), including weights, measurements, and gross photographs.

fragmented specimen When pregnancy is electively terminated for a malformation, knowledge of the clinical diagnosis is integral. One can direct examination of the fetal parts to areas expected to be abnormal, and often the disease can be confirmed (Figure 2.1A–D). On the other hand, there are some cases in which prenatal diagnosis is unknown, and although abnormalities are grossly identified (Figure 2.1E), the exact diagnosis remains unclear. In these cases, ancillary techniques are very helpful.

radiology Any specimen showing gross evidence of bony malformation should be x-rayed.

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Cytogenetics If blood or tissue has not already been obtained by the clinician for chromosomal analysis, fresh, grossly viable tissue should be placed in an appropriate medium in a clean but not necessarily sterile manner. Figure 2.1  Fragmented specimens. Illustrated here are electively terminated twin fetuses at 19 weeks of gestation (A), both with deformed long bones and blue sclera (inset) consistent with prenatal diagnosis of osteogenesis imperfecta. X-rays of the fetal parts demonstrate fractured radius and ulna (B), bowed and fractured femur (C), and bowed tibia (D). Contrarily, the prenatal diagnosis of this 21-week-gestation singleton is unknown (E), but multiple gross anomalies are identified.

1A

1E

1B

1C

1D

TERMINOLOGY AND DEFINITIONS TERM

DEFINITION

Malformation

Defect of organs or body parts caused by an intrinsically abnormal developmental process (not formed, partially formed, malformed)

Syndrome

Pattern of anomalies occurring together that have a ­presumed common etiology but unrelated formal ­pathogenesis

Sequence

Pattern of anomalies occurring together that have a known common etiology and a related formal ­pathogenesis (a ­single developmental defect causes a cascade of ­subsequent abnormalities)

Disruption (secondary malformation)

Defect of organs or body parts caused by breakdown of or interference with originally normal development

Deformation

Abnormal form, shape, or position of body parts caused by mechanical forces

Dysplasia

Anomaly resulting from abnormal cell organization into tissue

Association

Two or more anomalies that are not pathogenetically related but occur together more frequently than expected by chance (Continued)

CHROMOSOMAL ABNORMALITIES 

TERM

DEFINITION

Field defect

Pattern of anomalies caused by disturbance in a region of the embryo that develops in a contiguous physical space

Gametopathy

Developmental defect produced by chromosomal ­aberrations within ovum, sperm, or zygote

Blastopathy

Developmental defect that occurs during blastogenesis (between day 1 and 18)

Embryopathy

Developmental defect that occurs between day 19 and week 12 (end of month 3)

Fetopathy

Developmental defect that occurs between week 13 and birth

Anomaly

Structural deviation from the average or norm

Hypoplasia

Underdevelopment of an organism, organ, or tissue caused by a decrease in cell number

Hyperplasia

Overdevelopment of an organism, organ, or tissue caused by an increase in cell number

Atrophy

Decrease in cell size and number, resulting in a decrease in organ size

Hypertrophy

Increase in cell size, resulting in an increase in organ size

Agenesis

Complete absence of an organ or body part and its ­associated primordium

Aplasia

Absence of a structure caused by failure of primordium development

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CHROMOSOMAL ABNORMALITIES n TURNER SYNDROME

2A

2D

2B

2E

2C

2F

Figure 2.2  Turner syndrome. Cytogenetic abnormalities in Turner syndrome include monosomy X (45 X), mosaicism (45 X/46 XX), or structural abnormality of one X chromosome. Most affected fetuses die in utero, with only 1 in 100 surviving to term. This 21-week-gestation fetus (A) demonstrates bilateral large cystic hygromas, whereas this 38-week-gestation stillborn fetus (B) has redundant skin of the neck, probably caused by regressed lymphedema. Other typical features include shield chest (C), congenital heart defects (in this case, hypoplastic left ventricle) (D), and streak gonads (E). Histologically, the ovaries are characterized by few or absent primordial follicles and primitive sex cord–like structures within ovarian-type stroma (F). Renal anomalies (often horseshoe kidney) are also common.

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n TRISOMY 21

3B 3A

3C

3D

Figure 2.3  Trisomy 21 (Down syndrome). The most common chromosomal abnormality in live births, occurs in 1 of 730 live births. Most cases are caused by nondisjunction of chromosome 21, and the minority by a Robertsonian translocation or mosaicism. Characteristic dysmorphic features seen here include upslanting palpebral fissures, epicanthal folds, flat nasal bridge, open mouth, protruding tongue, short neck (A), short broad hands, and transverse palmar crease (B). Almost 50% of patients with Down syndrome have congenital heart disease, most commonly atrial septal defect (C) and ventricular septal defect (D). Source: Figures 2.2A and 2.2B courtesy of Jerome B. Taxy, MD.

CHROMOSOMAL ABNORMALITIES 

33

n TRISOMY 18

4A

4C

4E

Figure 2.4  Trisomy 18 (Edwards syndrome) occurs in 1 in 5500 live births and is the second most common trisomy encountered in live births. Most cases are caused by nondisjunction of chromosome 18, and the minority by translocation. Intrauterine growth restriction and polyhydramnios are common prenatal findings. This syndrome occurs more often in females than males. Most fetuses with Edwards syndrome spontaneously abort in utero, and those that are delivered often die within 1 year. The few long-term survivors are severely mentally and physically retarded. Illustrated here are two neonates with typical features of trisomy 18, including cleft lip (A); dolichocephaly (in which the length of the head is greater than the width) (B); micrognathia, high eyebrows, low-set ears, preauricular skin appendages (C); flexion deformity of fingers, rocker-­bottom feet (D); ventricular septal defect (in this case, with overriding aorta) (E); and horseshoe kidney (F). The characteristic flexion deformity of the fingers shows second and fifth fingers overlapping the third and fourth fingers, respectively. Congenital heart disease can also include valvular deformities, patent ductus arteriosus, and single umbilical artery. Other features include: hypertelorism; dysplastic, rotated, and pointed ears (satyr’s ears); small mouth; cleft palate; absent distal joint creases; diaphragmatic hernia; hypoplasia of diaphragm.

4B

4D

4F

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Congenital Malformation Syndromes

n TRISOMY 13

5a

5c

5b

5d

Figure 2.5  Trisomy 13 (Patau syndrome) is the least-encountered trisomy in live births. Most cases are caused by nondisjunction of chromosome 13, and the minority by translocation of the long arm of chromosome 13 or mosaicism. Illustrated here is a fetus (21 weeks gestational age) with bilateral cleft lip and palate resulting in abnormally protruding philtrum. Polydactyly is also seen in this photo (A). Bicornuate uterus (B) as well as genitourinary and cardiovascular malformations (not seen here) are common anomalies of internal organs. Cerebral malformations range from arrhinencephaly (absence of olfactory bulbs and tracts) to holoprosencephaly. The latter is seen on coronal sections of the brain as hemispheric fusion with absent corpus callosum (C). Cyclopia and proboscis (D) may also be seen in severe cases.

DISRUPTIONS 

DISRUPTIONS n AMNIOTIC BAND SEQUENCE

6A

6C

6E

6B

6D

6F

Figure 2.6  Amniotic band sequence (ABS) occurs in 1 in 1,200–15,000 live births and 1 in 70 still births. The pathogenesis is thought to be related to amniotic rupture, resulting in adherence of amniotic bands to various sites, mechanically interfering with development of the otherwise normal fetus. The extent of the disruption varies from non-life threatening [e.g., amputation of a hand due to strangulation by an amniotic band, (A)] to severe. Illustrated are examples of ABS that are incompatible with life: (B) shows a macerated fetus (18 weeks gestation) with the amniotic band clearly visible between the placenta and the deformed cranium. (C) shows an infant (26 weeks gestation) with multiple, severely deforming amniotic bands from placenta to occiput, placenta to left arm, and right hand to head, resulting in facial, thoracic, abdominal, and limb defects. Also present is an encephalocele. X-ray is shown in (D). (E) and (F) demonstrate posterior and anterior views, respectively, of a 42-week-gestation infant with placenta adherent to the cranium, resulting in bifid cranium, anencephaly, and multiple facial anomalies.

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FUSION DEFECTS n CONJOINED TWINS

7A 7D

7B

7C

7E

7F

Figure 2.7  Conjoined twins. Twin gestations naturally occur in approximately 1 in 80 pregnancies in the United States, with increased risk attributed to advancing maternal age and fertility treatments. The spectrum of malformations in monozygotic twins extends from minor (skin attachments that are surgically correctible) to shared organs to fetus-in-fetu. The figures illustrate conjoined anencephalic twins (A) at 18 weeks gestation (craniopagus); thoracopagus twins (B) with shared liver (C) demonstrated at autopsy; parasitic twin attached to face (D) and ­abdomen (E); and surgically resected abdominal parasite (F). Source: Figures 2.7B and 2.7C courtesy of Jerome B. Taxy, MD.

FUSION DEFECTS 

n SIRENOMELIA

8A

8C

8B

8D

Figure 2.8  Sirenomelia is the extreme manifestation of the sporadic acrorenal field defect (1 in 60,000 newborns). Here, a defect in the limb and renal primordia, which are spatially contiguous in the blastemal phase, results in malformations of these two systems that separate spatially as development progresses. Abnormal vascular development, such as persistent vitelline artery, may result in a vascular steal phenomenon leading to ischemia and maldevelopment of the limb and renal primordia. Uncontrolled diabetes with embryonic hyperglycemia can also result in abnormal organogenesis and caudal dysplasia. Demonstrated here is external rotation and fusion of the lower extremities (A), with toes directed posteriorly and laterally (B). The lower limb skeletal defects range from a single set of bones to variably fused long bones to two sets of bones within a single skin–covered limb remnant. Renal agenesis with flattened adrenal glands (C) is typical, and the urinary bladder is hypoplastic. These genitourinary malformations result in oligohydramnios, typical Potter’s facies (A) (also see Figure 2.12: Potter sequence) and hypoplastic lungs (D). Gastrointestinal defects include atretic rectum and anus and malrotation (not pictured).

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Congenital Malformation Syndromes

n FAILURES OF CLOSURE

9A

9C

9E

9B

9D

9F

Figure 2.9  Failures of closure are divided into ventral (A–D) and dorsal (E, F) types, which are relatively common but vary substantially in severity. These defects may be sporadic or associated with a specific genetic defect; therefore, chromosomal analysis is warranted. In omphalocele (A) the protruding abdominal viscera are covered by a thin membrane on which the umbilical cord inserts. In gastroschisis (B) the viscera are not covered by a membrane, and the umbilical cord lies to one side of the protruding abdominal contents. Demonstrated in (C) is an unusual submucosal cleft palate in the midline, with bony cleft covered by mucosa. (D) shows a bilateral cleft lip. Incomplete failure of closure of the neural canal results in a bony defect covered by skin, containing meninges (meningocele), meninges and spinal cord (myelomeningocele, see Figure 15.1C), or brain [encephalocele (E)]. Complete failure of closure of the neural canal results in anencephaly (F), in which neural tissue is damaged from exposure to amniotic fluid.

GROWTH DEFECTS 

GROWTH DEFECTS n MACROSOMIA/MICROSOMIA/ORGANOMEGALY

10A

10D

10B 10E

10C

10F

10G

Figure 2.10  Macrosomia is defined as growth greater than expected for gestational age. At term, weight greater than 4,000 g is considered macrosomic. Common risk factors include postterm pregnancy, maternal obesity, multiparity, advanced maternal age, and maternal diabetes. Shown in (A) is a 38-week-gestation, 11,350 g infant of a diabetic mother. Twin–twin transfusion syndrome results in the “recipient” twin being macrosomic and plethoric (B), whereas the “donor” twin is microsomic and anemic (C). Genetic causes of macrosomia include Beckwith-Wiedemann syndrome (D), which is caused by various defects affecting imprinted genes on chromosome 11p15.5. The phenotypic expression of the syndrome is variable depending on the defect, including omphalocele (D), macroglossia (D), and organomegaly, as well as increased risk of tumorigenesis (most commonly Wilms tumor). Organomegaly (specifically, renomegaly) is also seen in Meckel-Gruber syndrome (E), but it is not associated with macrosomia. Distinguishing features include cystic renal dysplasia, occipital encephalocele (E), and polydactyly (F,G).

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DEFORMATIONS n POTTER SYNDROME

11A

11B

11C

11D

Figure 2.11  Potter syndrome. Edith Potter first recognized the association of bilateral renal agenesis and pulmonary hypoplasia in 1946. Since then, this set of defects has come to be known as the Potter syndrome. She also recognized that any cause of severe oligohydramnios can lead to the typical deformities. Currently, the term Potter syndrome is used to designate the sequence resulting from renal agenesis, whereas the term Potter sequence designates all other causes. Illustrated here is a case of Potter syndrome, which occurs in 1 in 4,000 to 1 in 8,000 fetuses. The characteristic Potter facial expression (A,B) has been described as one of “extreme age,” typified by prominent epicanthal folds, flat nose, small chin, and low-set pointed ears. The appearance of excessive, wrinkled skin gives the impression of severe dehydration. Oligohydramnios also leads to positional deformities, including bowed legs and clubbed feet (C). Death is caused by severe pulmonary hypoplasia (D), as prolonged oligohydramnios results in decreased fluid pressure in the developing airways and deficiency in growth factors thought to be present in amniotic fluid.

DEFORMATIONS 

n POTTER SEQUENCE AND PRUNE BELLY SEQUENCE

12A

12C

12B

12D

Figure 2.12  Potter sequence and prune belly sequence. As introduced in Figure 2.11, Potter sequence is the term used to define the set of physical alterations resulting from oligohydramnios caused by any cause other than renal agenesis. Illustrated here is an example of the typical external deformities (A) resulting from bilateral cystic dysplastic kidneys (B). Another common cause of Potter sequence is prolonged amniotic leak, for which amnioinfusion has been attempted with only a few successful cases.   Prune belly sequence (C,D) is a similar constellation of physical findings also caused by defects in the urinary tract, predominantly affecting males. It occurs in 1 in 29,000 to 1 in 40,000 live male births. Specifically, urethral obstruction results in bladder distention, hydroureter, and hydronephrosis (D), as well as ascites, degeneration of the abdominal muscles (C), and failure of testicular descent. Oligohydramnios results in pulmonary hypoplasia and Potter’s facies. Fetuses with Potter (A) or prune belly (C) sequence demonstrate a small bell-shaped chest corresponding to bilateral severe pulmonary hypoplasia. Source: Figures 2.12C and 2.12D courtesy of Jerome B. Taxy, MD.

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ASSOCIATION n VATER/VACTERL

13C

13A

13B

13D

Figure 2.13  The VATER/VACTERL association (Vertebral anomalies, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal and/or Radial anomalies, Limb anomalies) is a series of seemingly unrelated malformations that are seen together more frequently than expected by chance, the etiology for which is unknown. It occurs sporadically in 16 per 100,000 live births, being more common in infants of diabetic mothers. When one of the VACTERL anomalies is identified, a search for other associated defects should be performed. The specific anomalies vary in type and severity, and may or may not be surgically correctible. Illustrated here is a 31-week-gestation infant with VACTERL association. Low-set dysplastic right ear, short neck, left torticollis, and right upper limb phocomelia are seen in (A), imperforate anus in (B), blind end (atretic) upper esophagus and unilobate lungs in (C), and tracheoesophageal fistula (lower esophagus continuous with trachea) in (D). The stomach is seen in the lower left corner of (C) and lower right side of (D). Also identified but not illustrated are a double outlet right ventricle, right renal agenesis, vertebral dysgenesis, and agenesis of left 11th and 12th ribs and right 12th rib.

Suggested Readings Bohm N. Pediatric Autopsy Pathology. Philadelphia: Hanles & Belfus, Inc.; 1988. Gilbert-Barness, E. Potter’s Atlas of Fetal and Infant Pathology. St. Louis: Mosby; 1998. Gilbert-Barness, E. Potter’s Pathlogy of the Fetus, Infant and Child. 2nd ed. Philadelphia: Mosby Elsevier; 2007. Kapur RP, Siebert, JR. Chromosomal abnormalities. In: Stocker JT, Dehner LP, Husain AN, eds. Pediatric Pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; in press:chap 3. Potter EL. Bilateral renal agenesis. J Pediatr. 1946;29:68–76. Siebert JR. Congenital anomalies and malformation syndromes.In: Stocker JT, Dehner LP, Husain AN, eds. Pediatric Pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; in press:chap 4.

3

Infections David M. Parham

n

VIRAL INFECTIONS Herpes Simplex Virus Varicella-Zoster Virus Cytomegalovirus Epstein-Barr Virus Adenovirus Enterovirus Human Immunodeficiency Virus Molluscum Contagiosum Virus Measles Virus Parvovirus Respiratory Syncytial Virus

n

n

BACTERIAL INFECTIONS Corynebacterium Pseudomonas aeruginosa Mycobacterium tuberculosis Staphylococcus aureus Bartonella henselae FUNGAL INFECTIONS Blastomycosis Coccidiomycosis Cryptococcosis Histoplasmosis Pneumocystosis Candidiasis

Aspergillosis Pseudallescheriasis Fusariosis Mucormycosis n

PROTOZOAL INFECTIONS Amebiasis Leishmaniasis Toxoplasmosis

n

METAZOAL INFECTIONS Enterobiasis

n

ARTIFACTS RESEMBLING INFECTIONS Pulse Peritonitis

viral inFeCTions n herPes siMPleX virus FiGure 3.1 Herpes simplex virus (HSV) occurs primarily as oral (HSV1) and genital (HSV2) infections, but in immunocompromised and unborn children, severe systemic infections can be seen. In this section of adrenal gland from a congenitally infected infant, the virus forms brightly eosinophilic intranuclear inclusions, with peripheral margination of chromatin. Some nuclei have a homogenous, smooth appearance likened to ground glass. Note that the inclusions do not enlarge the host nuclei or form cytoplasmic bodies. HSV is a cytodestructive agent that causes foci of coagulative necrosis, as seen in the left side of the photomicrograph. The diagnosis may be confirmed by tissue culture, immunohistochemistry, electron microscopy, or polymerase chain reaction (PCR). Serologic studies may be misleading, because single positive immunoglobulin G (IgG) tests only signify past infection. Sera from immunocompromised patients may show false-negative serological results. Like all infections caused by herpesviridae, HSV exists in both active and latent forms. Emotional stress, sunlight exposure, immunologic decline, and coexistent viral infections all potentially activate latent infections. (H&E; 3200)

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n VARICELLA-ZOSTER VIRUS FIGURE 3.2  Varicella-zoster virus (VZV) is a form of herpesvirus that has clinical and histological features similar to HSV. It has historically been a common childhood illness, although vaccination is now widely available. Typically, the primary lesion presents as a disseminated, pruritic, vesicular rash and assumes a dormant stage within dorsal ganglia following the initial infection. Subsequent periods of reactivation occur during f luctuations of immunity and lead to a painful erythematous, vesicular rash with a dermatome distribution. In the immunocompromised, VZV ­i nfections can be devastating. This figure shows a photomicrograph of the lung of a leukemic patient who died of hemorrhagic pneumonia. There is alveolar hemorrhage and edema, and some nuclei contain eosinophilic inclusions similar to HSV. Note the ­multinucleated “mulberry” cell near the center of the figure. Multinucleated, inclusion-bearing giant cells comprise another common histological feature of VZV and HSV infections. (H&E; 3200)

n CYTOMEGALOVIRUS FIGURE 3.3  Cytomegalovirus (CMV) belongs to the herpesvirus group but has distinct and overlapping properties that separate it from VZV and HSV. It commonly occurs as a mononucleosislike infection that causes fever, rash, lymphadenopathy, and general malaise. Like other herpeviruses, it then assumes a latent state and can be reactivated in times of decreased immunologic surveillance. CMV infections are among the most common congenital infections and may be found in placentas with lymphoplasmacytic villitis. CMV also causes severe infections in the immunocompromised, as in this child who was undergoing cancer chemotherapy. There is diffuse alveolar damage, with cuboidal metaplasia of the pneumocytes and edema of the interstitium. Note the prominently enlarged pneumocyte, which dwarfs adjacent uninfected cells. The virocyte contains a large, eosinophilic nuclear inclusion that imparts an owl’s eye appearance. Cells infected with CMV also contain granular, eosinophilic cytoplasmic inclusions, as are here displayed in cells whose nuclei are out of the plane of section as well as within the prominent central virocyte. The diagnosis of CMV infection can be confirmed with immunohistochemistry, electron microscopy, direct immunofluorescence, fluorescence in situ hybridization (FISH), or PCR. CMV infections are prevalent, so that a single IgG titer is not diagnostic of infection. (H&E; 3200)

n EPSTEIN-BARR VIRUS FIGURE 3.4  Epstein-Barr virus (EBV), another member of the herpesvirus family, does not form inclusion-laden virocytes but instead produces a florid proliferation of B and T lymphocytes that occurs in successive waves. The initial wave of B-lymphocyte proliferation is caused by insertion of EBV into their nuclei. EBV preferentially infects B lymphocytes because of the C3d component of complement found on the B-cell cytoplasmic membranes. This initial lympho­proliferative phase normally elicits a secondary wave of suppressor T cells that react to viral proteins expressed by infected cells. The cytotoxic T cells then cause massive apoptosis of infected B lymphocytes. Macrophages ingest the resultant necrotic debris. As a result, the histological picture of primary EBV infection comprises a mixture of infected B cells, mature and reactive T cells, and macrophages with apoptotic debris, as shown in this photomicrograph of a tonsil from a patient with infectious mononucleosis. The reactive B and T cells have plasmacytoid and immunoblastic features and can exhibit substantial atypia leading to overdiagnosis of malignancy. Caution in diagnosis of patients with mononucleosis symptoms is thus advisable, and correlation with serologic findings is invaluable. Like the other members of the herpesvirus group, EBV adapts a dormant phase after the initial infection, but persistent infection may lead to chronic fatigue syndrome and immunologic disorders. (H&E; 3200)

VIRAL INFECTIONS 

45

FIGURE 3.5  Epstein-Barr virus (EBV). If cellular immunity has been suppressed by factors such as human immunodeficiency virus (HIV), organ transplantation, or primary immunodeficiency, then EBV-infected B cells may continue to proliferate, and the initial phase of infection will continue unabated. This leads to EBV-related B-cell lymphoproliferative disease, characterized by tumorous lesions in organs such as intestine, liver, and lungs. The liver of this heart transplant patient contains a polymorphous proliferation of plasmacytoid lymphocytes with purple cytoplasm and round to eccentric nuclei. Some cells are enlarged and contain bizarre nuclei with prominent nucleoli and irregular nuclear contours. Diagnosis of EBV-induced lymphoproliferative disease is best accomplished by Epstein-Barr encoded RNA (EBER) FISH, which highlights the infected cells. Monoclonality studies with flow cytometry or heavy chain gene rearrangement may demonstrate oligoclonality or monoclonality as preneoplastic clones emerge. As the lesion progresses, frank lymphomas with monomorphous features result unless the lesion can be controlled by titration of the T-cell suppressive therapy. EBV has also been associated with B-cell lymphoma (particularly the epidemic forms of Burkitt lymphoma), some forms of Hodgkin lymphoma, and some T-cell lymphomas. EBV infections may also produce epithelial lesions such as hairy leukoplakia and nasopharyngeal carcinoma. (H&E; 3200)

n ADENOVIRUS FIGURE 3.6  Adenoviruses comprise a group of viruses that show structural similarity to herpes viruses but lack the viral envelope produced by viral protrusion of herpes particles through the nuclear membrane. Adenoviruses typically cause a self-limited infection associated with cell destruction, tissue necrosis, and a brisk inflammatory response. These infections usually occur in the upper aerodigestive tract and lung, producing enterocolitis, nasopharyngitis, and/or bronchiolitis. On occasion, hepatitis may occur, particularly in immunocompromised individuals. As pictured here, the liver of a leukemia patient exhibits necrotizing hepatitis with numerous effete hepatocytes. Some residual viable hepatocytes show a dense nuclear basophilia; these have been referred to as “smudge cells.” Occasional cells, such as the one at the extreme left of the photomicrograph, contain poorly defined, eosinophilic nuclear inclusions. However, it is important not to confuse viral inclusions with the prominent nucleoli of regenerating or reactive cells. Similarly, nuclei that resemble those of smudge cells may simply represent the early stages of nuclear pyknosis associated with cell death. Confirmation of the diagnosis may be achieved by viral culture, direct immunofluorescence, or immunohistochemistry. Electron microscopy demonstrates geometrically precise icosahedral adenovirus virions within the nuclei of infected cells, and the viral structure resists the deleterious effects of fixation and embedding. (H&E; 3200)

n ENTEROVIRUS FIGURE 3.7  Enteroviruses encompass a broad group of viruses that includes poliovirus, coxsackievirus, and echovirus. These viruses comprise part of the family of picornaviruses, so named because of the small size of the particles and their RNA content. Although they have a proclivity for the gastrointestinal tract, enteroviruses have protean manifestations including myelopathy (poliovirus); herpangina; hand, foot, and mouth disease; upper respiratory tract infection; meningoencephalitis; myocarditis, pericarditis, and hepatitis. Even autoimmune diseases have been linked to enteroviruses. In neonates, enteroviral infections cause devastating disease. Neonatal infections are usually acquired during passage through the birth canal, and symptoms first occur during the nadir of immunoglobulin production. Transplacental passage of maternal IgG protects the infant prior to birth. The photomicrograph of liver pictured here shows massive hemorrhagic necrosis, with total dissolution of the hepatocytic cords and preservation of portal bile ductules and blood vessels. Numerous vessels contained fibrin thrombi in other areas (not shown). This patient died from hepatic failure and viral sepsis, and the diagnosis was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). RT-PCR furnishes an effective means of confirmation, because viral cultures may be unrevealing if all infected cells have been destroyed. Electron microscopic confirmation is difficult because of the small size and elusive nature of the viral particles. Acetaminophen toxicity can cause a similar pattern of disease, and administration of the drug may potentiate the hepatotoxic effects of the infection. (H&E; 340)

46 

Infections

n HUMAN IMMUNODEFICIENCY VIRUS FIGURE 3.8  Human immunodeficiency virus (HIV), a member of the retrovirus family, causes profound acquired immunodeficiency as a result of its preferential homing for T lymphocytes and dendritic cells. This thymus, examined at autopsy from an HIV-infected child, reveals extreme shrinkage of the lobular architecture with marked reduction in medullary lymphocytes and total absence of thymic cortex. The epithelium is also infected, resulting in a “dysinvolution” that mimics changes seen in primary immunodeficiency diseases. Cystic degeneration of thymic epithelium is another feature of HIV thymitis. Loss of T-cell function leads to EBV-induced lymphoproliferative disease and results in pediatric manifestations of AIDS such as high-grade B-cell lymphoma and lymphoid interstitial pneumonitis. T-cell deficiency also leads to infections caused by diverse bacteria, fungi, viruses, protozoa, and helminthes. (H&E; 340)

FIGURE 3.9  Human immunodeficiency virus (HIV). Another target organ of HIV is the central nervous system (CNS). Primary infection of the CNS by HIV results in changes primarily affecting the white matter, such as demyelination, gliosis, extracellular mineralization, vacuolar myelopathy, and infiltrates of mononuclear and multinuclear cells. The latter cells are infected with HIV. The white matter of this brain from an HIV-infected child shows a prominent gliosis and a subtle pallor suggestive of demyelinization. Note the sprinkling of microglia and occasional lymphocytes. When inflammatory infiltrates are encountered, one should also consider the possibility of a secondary viral infection such as CMV. Secondary CNS lymphomas may also be encountered as a result of HIV infection. (H&E; 340)

n MOLLUSCUM CONTAGIOSUM VIRUS FIGURE 3.10  Molluscum contagiosum virus is a member of the poxvirus group. These RNA viruses are among the largest seen by electron microscopy. Rather than being simply a cytolytic virus, molluscum also leads to cell proliferation and formation of elevated papules. The core of the papule comprises an expansile pilosebaceous unit lined by infected keratinocytes. These cells contain large cytoplasmic inclusions that expand and obliterate cellular boundaries, which fill with compressed nuclear ­chromatin. The inclusions have a brightly eosinophilic, ­homogeneous character likened to poker chips. The cells eventually die and become extruded into the center of the papular core, where the outlines of the viral inclusions become more distinct. Molluscum contagiosum usually occurs in the genital and inguinal regions of infected children. Smallpox virus, also a member of the poxvirus group, infects epidermal cells that form cutaneous vesicles and pustules and contain similar inclusions (referred to as Guarnieri bodies). (H&E; 340)

VIRAL INFECTIONS 

47

n MEASLES VIRUS FIGURE 3.11  Measles virus is an RNA virus that is a member of the paramyxovirus group. Once a universally common childhood infection, the incidence of measles infections has waned considerably since the advent of vaccination. Nevertheless, the disease persists in the unvaccinated and can cause serious infections, particularly in the immunocompromised. The typical lesions consist of an exanthema characterized by a morbilliform rash, an enanthem characterized by Koplik spots, and generalized lymphadenopathy. Measles may cause appendicitis and reactive mesenteric lymphadenitis. Longstanding chronic cerebral infection leads to subacute sclerosing panencephalitis, which has clinical features of slow virus disease. Patients with immune deficiency may have fatal giant cell pneumonia, as pictured here. In virus cultures, infected cells fuse and form syncytia. Similarly, in vivo, they form distinctive multinucleated giant cells known as Warthin-Finkeldey cells. These prominent cells contain eosinophilic intranuclear and intracytoplasmic inclusions. Their presence may be noted in surgically excised tonsils and appendices, and abdominal symptoms related to mesenteric lymphadenitis may precede the characteristic rash. Confirmation of the diagnosis is usually accomplished via serologic testing, which requires paired acute and convalescent sera. (H&E; 3200)

n PARVOVIRUS FIGURE 3.12  Parvovirus is a DNA virus that causes distemper in dogs and cats and a bright red malar rash known as slapped cheek disease in children. It has a propensity for infection of erythrocytes, leading to aplastic anemia, particularly in sickle cell patients. Prenatal infections lead to fetal anemia, high-output cardiac failure, hydrops fetalis, placental erythroblastosis, and intrauterine fetal demise. Parvovirus has now become the leading cause of viral myocarditis in some centers. It is usually diagnosed by PCR of infected cardiac tissues in patients with congestive cardiomegaly. Histologically, one sees features that should fulfill the Dallas criteria for myocarditis (i.e., interstitial lymphoid infiltrates and necrotic myocytes). In the photomicrograph of cardiac explant pictured here, there is a prominent lymphocytic infiltrate that permeates the interstitium and epicardium. Rare cells have enlarged nuclei with eosinophilic inclusions and marginated chromatin. Similar features are seen in infected normoblasts, and giant promyelocytes may also be noted on bone marrow examination. Confirmation may also be obtained using immunohistochemistry, electron microscopy, or viral culture. (H&E; 3200)

n RESPIRATORY SYNCYTIAL VIRUS FIGURE 3.13  Respiratory syncytial virus (RSV) is an RNA virus that is part of the paramyxovirus group. It causes an extremely common seasonal infection of infants, who develop coryza, croup, wheezing, and bronchiolitis. Although the high morbidity of this infection leads to many pediatric emergency room visits, the mortality rate is low, probably less than 1%. Nevertheless, RSV can be a devastating infection, particularly in immunodeficient premature infants or bone marrow transplant recipients. Both populations may develop a progressive subacute infection with necrotizing bronchiolitis and bronchiectasis. Pictured here is a photomicrograph of lung from a premature infant who died from an intractable RSV pneumonia with severe lower airway destruction. Bronchial epithelium has focally regenerated with squamous metaplasia related to the effects of both the virus and long-term ventilation. Note that the epithelium contains occasional binucleate cells; like measles, RSV causes cell fusion and syncytium formation. Careful close inspection discloses tiny, eosinophilic, intracytoplasmic inclusions, here seen best near the surface epithelium. These inclusions may also be noted in bronchoalveolar lavages obtained from bone marrow transplant recipients. In immunocompetent patients, RSV produces a lymphocytic bronchiolitis and vasculitis, and inclusions and syncytia are usually absent. Diagnosis can be confirmed by culture, direct immunofluorescence, or electron microscopy. (H&E; 3200)

48 

Infections

BACTERIAL INFECTIONS n CORYNEBACTERIUM FIGURE 3.14  Corynebacterium. Corynebacterium species are tiny gram-positive coccobacilli that generally exist as commensals within the oropharynx. They rarely cause disease, with the exception of Corynebacterium diphtheriae, the causative agent of diphtheria. Diphtheria infections create a necrotic pseudomembrane that fills the upper tracheobronchial tree, resulting in asphyxiation, and the organisms produce an exotoxin with toxic effects on the myocardium. Skin infections may also occur. Gram-positive diphtheroids, on the other hand, are generally not toxin producers and rarely invade the mucosa. However, this severely immunocompromised leukemia patient acquired a systemic infection during a period of profound neutropenia, resulting in sepsis, terminal hypotension, and death. The photomicrograph of glomerulus pictured here contains myriads of organisms that fill capillary lumens. On routine stains, bacterial colonies are recognized by the purplish blue, finely granular appearance produced by the hematoxyphilic bacterial nucleic acids. Gram stains can be misleading with corynebacteria, because they are easily overdecolorized, resulting in Gram negativity. (H&E; 3200)

n PSEUDOMONAS AERUGINOSA FIGURE 3.15  Pseudomonas aeruginosa is a nonfermentative, oxidative, gram-negative bacillus that can produce severe, necrotizing infections, particularly in the immunocompromised. Nosocomial infections are frequent, and in-house organisms typically show more antibiotic resistance than community ones. P. aeruginosa shows a propensity for vascular invasion and vasculitis, a property that results in downstream coagulative necrosis and spread of the infection. The lungs, eye, gastrointestinal tract, and pelvic organs are particularly susceptible to infection, and cutaneous infections result in a necrotizing lesion known as ecthyma gangrenosum. Gastrointestinal infections in neonates may clinically resemble necrotizing enterocolitis. This P. aeruginosa infection produced massive necrosis of the pelvic floor, rectovaginal septum, uterus, and rectum of a child undergoing cancer chemotherapy, resulting in fatal sepsis. In this picture, we see a congested blood vessel and surrounding soft tissue necrosis and hemorrhage. The vessel is surrounded by a pale purple cloud of organisms; a Gram stain (not shown) revealed gram-negative bacilli. (H&E; 3200)

n MYCOBACTERIUM TUBERCULOSIS FIGURE 3.16  Mycobacterium tuberculosis, the causative agent in tuberculosis, is a beaded, gram-neutral, acid-fast organism that causes infections with variable degrees of severity. Neutrophils do not effectively kill mycobacteria, which possess a waxy, mycophenolate-laden cell wall that infers acid-fastness and forms a protective shell. However, macrophages vigorously ingest mycobacteria, and the efficiency of the subsequent dampening of the infection depends on efficient macrophage activation and lysosomal degradation. The macrophages of some patients lack this efficiency and thus fail to contain the infection, as seen with the lepromatous form of leprosy, whose destructive features contrast with the comparatively innocuous tuberculous form of the disease. With ineffective activation and killing, macrophages become a cradle for mycobacterial propagation rather than a disposal site. In this photomicrograph of lung taken from the autopsy of a young child, granulomas form caseating centers lined by neutrophils; acid fast stains (not shown) showed myriads of bacilli. Miliary tuberculosis, characterized by rapid blood borne dissemination of the organism, causes an overwhelming infection that is often clinically mistaken for gram-negative sepsis. Miliary tuberculosis is a recurring unexpected finding in autopsies of patients dying from fulminant infections and septicemia. Less severe forms of the disease show efficient granuloma formation with subsequent calcification and lesser degrees of necrosis and dissemination. Because acid-fastness is lost after bacillary demise, acid-fast stains are not as sensitive for detection of these infections as silver stains such as WarthinStarry or fluorescent procedures such as auramine-rhodamine. Conversely, nocardia may have a similar histology on acid-fast stains. (H&E; 340)

FUNGAL INFECTIONS 

49

n STAPHYLOCOCCUS AUREUS FIGURE 3.17  Staphylococcus aureus is a gram-positive, catalase-positive, coagulase-positive coccus that causes a necrotizing, liquefactive necrosis by virtue of bacterial enzymes such as hyaluronidase and lipase. The organisms produce toxins responsible for clinical conditions such as staphylococcal scalded skin syndrome and toxic shock. Cutaneous infections effect an acute folliculitis that progresses to furuncles, carbuncles, and cellulitis. A maculovesicular rash in children characterizes staphylococcal impetigo. Staphylococcal infections may cause necrotizing fasciitis, a rapidly spreading soft tissue infection that necessitates prompt surgical attention. Organisms acquire adhesive properties that enable them to stick to indwelling catheters, central lines, and foreign devices, with subsequent bacteremia and endocarditis. In the lung, staphylococcal pneumonia follows aspiration or antecedent infection and produces necrotizing abscesses, pleuritis, and empyema. The photomicrograph illustrates a biopsy from the lung of a patient with neutropenia and shows a well-defined area of liquefactive necrosis. The center of this abscess contains a plethora of purple-staining bacterial colonies. Clusters of gram-positive cocci were seen on Brown and Brenn stain (not shown). (H&E; 320)

n BARTONELLA HENSELAE FIGURE 3.18  Bartonella henselae is the causative agent of cat scratch disease, which causes a suppurative lymphadenopathy, usually following a cat bite. The bite wound produces a primary erythematous papule, followed by unilateral, painful enlargement of regional lymph nodes. Lymph nodes are often biopsied on the suspicion of lymphoma and contain stellate, necrotizing abscesses, caseating granulomas, and confluent pyogranulomas. Pyogranulomas show both granulomatous and suppurative features and contain a mixture of activated macrophages, giant cells, and neutrophils. Silver impregnation stains such as the Warthin-Starry or Steiner reveal the organism, which is characteristically a pleomorphic bacillus. One should be aware that similar findings may be seen with infections by Mycobacteria, Nocardia, and other organisms, so that serological studies, bacterial cultures, or possibly PCR are necessary for definitive diagnosis. Nevertheless, excision is curative for most infections, so that additional studies are rarely indicated. Unusual complications include osteomyelitis, arthritis, granulomatous hepatitis, and splenitis. B. henselae infection also produces bacillary angiomatosis, a peculiar vasoproliferative lesion seen in immunocompromised patients. (H&E; 3100)

FUNGAL INFECTIONS n BLASTOMYCOSIS FIGURE 3.19  Blastomycosis. Blastomyces dermatitidis, the causative agent of blastomycosis, is a dimorphic fungus that exists as yeast in vivo and a mycelium in vitro. This organism comes from contaminated soil and causes pulmonary, cutaneous, and osseous infections. Infections can be quite destructive and may cause tumorous masses grossly resembling neoplasia. When it infects the nasal passages, Blastomyces elicits an exuberant pseudoepitheliomatous reaction that can easily be confused with low-grade carcinoma. The typical host response consists of both granulomatous and pyogranulomatous inflammation. Usually, Blastomyces yeasts can be identified on routine stains, as they contain a thick, refractile cell wall that highlights organisms found in macrophages and multinucleated giant cells. They are intensely positive with both Gomori methenamine-silver (GMS) and periodic acid-Schiff (PAS) stains. The photomicrograph illustrates a cluster of yeasts demonstrated on the GMS stain: they measure 10–15 mm in diameter and have smooth, even, round contours. Broadbased, nipplelike budding microscopically distinguishes them from other organisms. In vitro identification requires lollypop-shaped conidia that convert to a yeast form at 37°C. (GMS; 3200)

50 

Infections

n COCCIDIOMYCOSIS FIGURE 3.20  Coccidiomycosis. Coccidioides immitis, the causative agent of coccidiomycosis, is a dimorphic fungus that makes endospores in vivo and arthrospores in vitro. Culture plates bearing this fungus’s cottony white mycelia must be handled carefully, because the organism easily becomes airborne and infectious. It is also spread by dust storms. Infections primarily affect the lung and skeleton, although hematogenous organisms disseminate widely in immunocompromised hosts. This leukemia patient developed a disseminated infection and died of widespread disease in multiple viscera. This photograph illustrates the characteristic findings on routine stains. Endosporulation occurs in spherules that develop cleavage furrows and divide into ovoid yeasts of varying size. The spherule grows as the endospores develop, forming structures that are quite large by microbiological standards: 50–80 mm. Eventually, the spherule ruptures, releasing endospores that become new spherules and restart the maturation process. Diagnosis can be difficult if organisms are few in number, because early stage spherules overlap with B. dermatitidis, and only empty spherules may be present. Serologic studies are usually helpful in diagnosis. (H&E; 3200)

n CRYPTOCOCCOSIS FIGURE 3.21  Cryptococcosis. Cryptococcus neoformans, the causative agent for cryptococcosis, is a budding yeast. Unlike most yeastlike pathogens, it is not dimorphic in vitro. It exists in pigeon excreta and usually infects humans by an aerosol route, although skin inoculation from contaminated soil also occurs. Once inhaled, it can cause a primary respiratory illness, and it may form infiltrative masses that are grossly mistaken for neoplasia. Hematogenous dissemination of the organism leads to cerebromeningeal infections, which occur most commonly in immunocompromised patients. Skeletal and visceral forms of the disease arise less frequently. This figure illustrates the key morphological features of cryptococcosis as seen on routine stains. Thick pericellular capsules produce prominent empty halos around each organism. The capsules’ mucopolysaccharide content makes them intensely mucicarmine stain–positive; this is a key point for distinguishing cryptococcosis from other yeast infections. Note the pinched budding of Cryptococcus, which contrasts with the broad-based buds of Blastomyces. Size is also important for diagnosis, but the organism’s range of 2–20 mm overlaps with both B. dermatitidis and Histoplasma capsulatum. Mycelial elements may rarely be produced in tissue, similar to Candida species. Capsule-deficient forms of the organism can be difficult to recognize on histological examination. (H&E; 3200)

n HISTOPLASMOSIS FIGURE 3.22  Histoplasmosis. Histoplasma capsulatum is the primary causative agent for North American histoplasmosis, and Histoplasma duboisii is responsible for an African form of the infection. In North America, histoplasmosis is endemic to the Mississippi River valley, where it is propagated by birds and bats. Disease may thus appear in spelunkers and poultry farmers, but primary forms of the disease are extremely common throughout the region. Aerosolized particles produce a primary granulomatous lesion in the lungs, which often spreads to a secondary nodal focus in the mediastinum. These foci calcify and create a characteristic Ghon complex seen on radiographs; a similar phenomenon occurs with primary tuberculosis. A more severe form of disease may appear on reactivation, which can occur during period of decreased immunity. Sparse numbers of organisms may be found in the primary nodule of an immunocompetent individual, and a massive infection affecting multiple viscera may be seen in an immunodeficient person. In this photomicrograph of a lymph node of a child with leukemia, macrophages contain large numbers of yeasts and become a site for propagation rather than killing. The yeasts stain strongly in this GMS preparation, and they measure only 2–5 mm in diameter, a comparatively small size. They are round to oblong and show pinched budding. H. capsulatum is a dimorphic fungus that grows as yeasts at 37°C and conidia-bearing mycelia at room temperature. (GMS; 3200)

FUNGAL INFECTIONS 

51

n PNEUMOCYSTOSIS FIGURE 3.23  Pneumocystosis. The causative agent for pneumocystosis, Pneumocystis jirovici (formerly Pneumocystis carinii), has a history marked by controversy and confusion. Because of its ultrastructural appearance, resistance to standard antifungal agents, and susceptibility to antiprotozoal drugs, P. jirovici was classified as a protozoan for most of the 20th century. However, recent genetic discoveries reinforced the conviction that this is a fungus, and this concept has become the prevailing classification of the organism. Sporadic infections prey only on the immunocompromised, as we continually breathe this organism; infection can be induced in lab animals solely by administration of steroids and exposure to room air. Pneumocystosis was a feared complication of leukemia treatment until antibiotic prophylaxis became the norm. Its abrupt appearance in homosexuals and drug abusers during the early 1980s led to the discovery of HIV. This photomicrograph illustrates a GMS stain of the infection. Although it resembles histoplasmosis and overlaps in size, note that it forms intra-alveolar clusters independent of macrophage ingestion, and its cellular contours are more irregular, jagged, and sometimes helmet shaped. Thickening of the cell wall forms a characteristic dotlike pattern in a well-prepared GMS stain. (GMS; 3200)

n CANDIDIASIS

24a

24b

FIGURE 3.24  Candidiasis is caused by infection with organisms of the Candida genus, which exist in low levels as part of the normal gastrointestinal flora and propagate in perpetually moist areas such as the vagina, mouth, and intertriginous and inframamillary folds. Several species of Candida, such as albicans, tropicalis, glabrata, and parapsilosis, are capable of causing infections. Of these, only C. glabrata is histologically distinctive by virtue of its comparatively small size and lack of pseudohyphae. Otherwise, candidiasis can be distinguished from other infections by its characteristic mixture of yeasts and pseudohyphae. Pseudohyphae form by budding and elongation of yeasts and can be elicited in vitro as “germ tubes” by adding fetal calf serum to broth cultures. One must be careful to distinguish pseudohyphae from true mycelia; conversely, mycelia cut in a transverse plane can be confused with yeasts. (A) illustrates a GMS stain of a fungal abscess found in the liver of a neutropenic leukemia patient. The edge of a large colony displays the mixture of budding yeasts and pseudohyphae. In the center of the abscess (B), the pseudohyphae form long strands resembling hyphae but containing intercellular constrictions imparting a resemblance to a string of sausages. Invasive and systemic candidiasis complicate immunodeficiency and occur in multiple viscera, primarily the gastrointestinal tract, liver, spleen, and lungs. Systemic candidiasis and candidal endocarditis may also be acquired by contaminated intravenous catheters. (GMS; 3200)

52 

Infections

n ASPERGILLOSIS

25a

25b

FIGURE 3.25  Aspergillosis, like candidiasis, is caused by several different species of Aspergillus that show no identifying species characteristics on histopathological analysis. Aspergillus species primarily cause respiratory infections that create a cavitating fungus ball in central portions of the lung, or they may colonize preexisting cavities. Hypersensitive individuals may acquire allergic bronchopulmonary aspergillosis, in which the airways fill with mycelia bathed in a mucinous, eosinophilic exudate. Patients with profound neutropenia are at risk for invasive aspergillosis, which spreads by mycotic emboli and occludes smaller arteries, causing fungal infarcts that resemble those caused by thromboemboli. Like most fungi, Aspergillus species thrive in a warm, moist, dark environment, and they produce microconidia that freely spread by air currents. Microscopically, aspergillosis is usually recognized by its radiating hyphae that multiply in waves of dichotomous branching, as with the GMS stain in (A). The hyphae are typically septate and contain even, parallel walls. However, this pattern is not always diagnostic of aspergillosis and may be produced by a variety of other opportunistic fungi. The PAS stain in (B) illustrates the diagnostic fruiting heads, which are conidial vesicles coated by radiating phialides. The genus name of Aspergillus derives from these structures, which resemble water pouring from the aspergilla used in Catholic masses. Unfortunately, fruiting heads occur only in areas of high oxygen tension, such as fungus cavities and sputum, and are of little use in systemic and invasive infections. [(A) GMS, 3200; (B) PAS, 3200]

n PSEUDALLESCHERIASIS FIGURE 3.26  Pseudallescheriasis. Pseudallescheria (formerly Allescheria and Petriellidium) boydii is a soil saprophyte that produces an infection that can be clinically and morphologically identical to aspergillosis. This organism exists in both sexual and asexual forms, the latter producing septate hyphae with parallel walls and dichotomous branching. As this PAS stain illustrates, some infections contain diagnostic light brown, spherical conidia borne on short conidiophores and resembling lollypops. This feature does not require high oxygen tension and can be seen in systemic infection. Intercalary chlamydospores comprise another characteristic feature. Pseudallescheriasis primarily affects immunocompromised patients and can infect surgical wounds, implants, and corneas. Superficial soft tissue infections (mycetomas) arise in normal patients, and rare cases of invasive disease occur in the immunocompetent, usually after exposure to overwhelming numbers of organisms. Allergic bronchopulmonary mycosis may also occur. In spite of their histological and clinical similarities, it is important to differentiate pseudallescheriasis from aspergillosis, because their antibiotic susceptibilities differ. (PAS; 3200)

FUNGAL INFECTIONS 

53

n FUSARIOSIS FIGURE 3.27  Fusariosis. Fusarium species are soil saprophytes and plant pathogens with a worldwide distribution. Like P. boydii, they cause superficial mycetomas and keratitis, as well as onychomycosis, osteomyelitis, and in the immunocompromised, serious systemic infection. The infection pictured in the figure occurred following a superficial extremity wound acquired by a patient with neutropenic leukemia. The wound failed to heal with antibiotic therapy and was followed by crops of hemorrhagic subcutaneous nodules over the chest, abdomen, and extremities. A biopsy of one revealed deep dermal vessels impacted by branching, septate hyphae, as shown in this GMS stain. A presumptive diagnosis of systemic aspergillosis was made, but Fusarium solani was grown instead. The patient died of fatal systemic mycosis. Although one may see features suggestive of fusariosis, such as chlamydospores and vesicles, definitive diagnosis of this infection currently requires isolation and identification of the organism on standard mycological media. Fortunately, the organism grows relatively quickly and produces characteristic multiseptate, bean pod-shaped macroconidia. (GMS; 3200)

n MUCORMYCOSIS FIGURE 3.28  Mucormycosis (also known as zygomycosis and phytomycosis) is a severe, necrotizing infection common to patients with severe burns, diabetic ketoacidosis, and chemotherapy-induced neutropenia. Major clinical manifestations include rhinocerebral, gastrointestinal, and pulmonary infections, and like Aspergillus, mucormycosis can be caused by colonization of preexisting lung cavities. Rhinocerebral mucormycosis is a fulminating infection of the nasal, orbital, and periorbital soft tissues that spreads into the cerebrum via the cavernous sinus. Like other deep mycelial infections, invasive mucormycosis typically affects blood vessels, causes septic infarcts, and spreads to adjacent organs or disseminates throughout the viscera. It is caused by genera of Mucor, Absidia, and Rhizopus, which show identical histologic features in vivo and sporangiospores in vitro. These genera differ mainly by the presence and position of rhizoids, rootlike structures that anchor mycelia. The photomicrograph illustrates the typical tissue manifestations of mucormycosis: broad, aseptate hyphae resembling twisted ribbons and showing irregular branching and nonparallel, irregular walls. The fruiting heads, or sporangia, may rarely be seen in organisms exposed to ambient air, such as found inside pulmonary cavities or intestinal lumens. (H&E; 3200)

54 

Infections

PROTOZOAL INFECTIONS n AMEBIASIS FIGURE 3.29  Amebiasis may occur as a gastrointestinal disease caused by Entamoeba histolytia or as a fulminating cerebromeningeal infection caused by Naegleria species, Acanthamoeba species, or Balamuthia mandrillaris. Amebic keratitis and mucocutaneous infections also occur, with Acanthamoeba species as the usual isolate. Intestinal amebiasis occurs relatively frequently in tropical countries and causes flask-shaped ulcers that burrow laterally into the submucosa. The infection may spread to the liver, brain, and other organs. Cerebromeningeal amebiasis is a relatively infrequent infection in North America. It occurs after exposure to heavily contaminated water or soil. The organisms rapidly proliferate during the warmer months of the year, causing a potential hazard for fans of water sports and hot tubs. However, some patients relate no water exposure, so that soil and dust have also been suspected as sources of infection. The infection pictured here occurred in an infant, so that lake or pool exposure can be excluded, but bathwater was a possible source. The etiology of this overwhelming meningoencephalitis was not clinically suspected, and the infant rapidly succumbed to infection. Histologically, macrophagelike trophozoites contain irregular, thickened cell membranes, small reddish nuclei, and coarsely vacuolated cytoplasm. They occlude a cerebral blood vessel and infiltrate the surrounding Virchow-Robin space. Compare the organisms to adjacent macrophages, which are smaller, contain darkly basophilic nuclei, and possess smoother cytoplasm and evener cell membranes. B. mandrillaris was identified as the causative agent by the Centers for Disease Control and Prevention. (H&E; 3200)

n LEISHMANIASIS FIGURE 3.30  Leishmaniasis. Leishmania donovani, the causative agent of leishmaniasis, produces cutaneous, mucocutaneous, and visceral infections. Sandf lies of the Phlebotomus and Lutzoyia genera, respectively, cause the infection in the Old and New World. The disease occurs in Africa, South America, and Asia, in both desert and tropical climes, and many Americans have become infected as a result of travel to the Middle East. Cutaneous leishmaniasis can be variable in distribution and chronicity, and focal lesions are known as “oriental sore.” Visceral leishmaniasis, also known as kala-azar, occurs months to years after primary inoculation and presents as massive hepatosplenomegaly, pancytopenia, lymphadenopathy, and wasting, features reminiscent of leukemia or lymphoma. A post–kala-azar infection may involve the skin, producing leprosylike disfigurement. This photomicrograph illustrates the features of a skin nodule on a young girl whose family had temporarily lived in Saudi Arabia and returned to the United States. The skin contains a packed dermal infiltrate of macrophages stuffed with small, ovoid leishmania. Similar infiltrates of leishmania-laden macrophages fill organs and bone marrow involved with visceral disease. The identifying features of leishmaniasis (i.e., amastigotes with polar nuclei and kinetoplasts) are best demonstrated by Giemsa-stained touch preparations. (H&E; 3200)

METAZOAL INFECTIONS 

55

n TOXOPLASMOSIS

31a

31b

FIGURE 3.31  Toxoplasmosis. Toxoplasma gondii, the causative agent of toxoplasmosis, is an amastigote that assumes an intracellular cystic form and an extracellular, unicellular form. The encysted, multicellular form, which allows the organism to survive for a long time in adverse conditions, is referred to as a bradyzoite (i.e., slow organism), and the nonencysted unicellular form, in which the organism assumes a cytodestructive, free-living existence, is referred to as a tachyzoite (i.e., fast organism). T. gondii primarily parasitizes cats, which excrete the cysts into soil such as flower beds and sand boxes. The organisms can survive there for a long time and become active after ingestion by an unwitting gardener or playground denizen. Once ingested, the bradyzoites are released in the gut and burrow into the intestinal wall, where they become bloodborne and typically cause a brief, mononucleosislike illness with enlarged lymph nodes and spleen. Fortunately, an intact immune system effectively suppresses the infections and kills the tachyzoites, so that reactive lymphadenitis and splenitis with perifollicular and intrafollicular infiltrates of reactive macrophages and intrasinusoidal accumulations of monocytoid lymphocytes comprise the major histologic features of the disease. Toxoplasma cysts are rare or absent on examination of biopsies with this form of infection. However, organisms persist at low levels and can become active during pregnancy, when they cause chronic villitis and fetal infection that can lead to intrauterine fetal demise, neonatal sepsis, birth defects, and intracerebral calcifications. Cerebral toxoplasmosis is a major scourge for the immunocompromised, particularly those with HIV infection, and disseminated visceral infections occur as well. In these patients, tachyzoites multiply in large numbers and cause extensive tissue destruction. (A) shows a focus of toxoplasmosis in a placenta with chronic villitis. A single cyst is visible in the perivillous space and contains multiple tiny bradyzoites. This cyst was the only one found in this placenta after careful searching, and they are often missed. In contrast, (B) shows cerebellar toxoplasmosis in an HIV-positive patient. There was extensive necrosis, with areas of necrosis containing large numbers of tachyzoites. Bradyzoites and tachyzoites are visible in the adjacent tissues. (H&E; 3200)

METAZOAL INFECTIONS n ENTEROBIASIS FIGURE 3.32  Enterobiasis. Worms of various types infect children, particularly in developing nations. Infectious worms comprise nematodes (roundworms), trematodes (flatworms), and cestodes (tapeworms). Enterobius vermicularis, the causative agent of enterobiasis or pinworm, is a nematode that primarily exists as a commensal within the colon and rectum. It causes symptoms when female worms crawl through the anus for ovulation, which leads to intense perianal irritation and pruritus. At that point, clinical diagnosis can be confirmed by use of an adhesive tape application to the perianal region, followed by microscopic search for the characteristic worm ova. Otherwise, the infestation is incidentally discovered in appendices removed for other reasons. On rare occasions, the worms cause appendicitis, and cases of worm-induced abortion and perisalpingitis as a result of wayward enterobial migration have been reported. This image shows a cross section of a pinworm found incidentally within an appendiceal lumen. Note the circumferential chitinous cuticle and muscular exterior, highlighted by opposing lateral spines. The interior of the worm contains cross sections of the gut and uterus. The latter contains flattened ova with a smooth exterior, typical of Enterobius. All nematodes contain these general histologic features, hence the term roundworm. (H&E; 320)

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Infections

ARTIFACTS RESEMBLING INFECTIONS n PULSE PERITONITIS FIGURE 3.33  Pulse peritonitis. A wide variety of staining artifacts, plant materials, contaminants, and endogenous cellular structures can sway the microscopist into a false-positive diagnosis of infection. Wright-Giemsa and Gram stains may form bacterialike precipitants at improper reagent pH levels; these should be distinguished by their size, pleomorphism, and unevenness. Saprophytes such as Exophiala jeanselmei or Burkholderia cepacia may contaminate reagents used for GMS or Steiner stains, which is why the plane of infectious agents should always be carefully evaluated. Petroleum compounds introduced into body orifices and dermis cause a peculiar artifact known as myospherulosis, which results from the action of the oils on erythrocytes. Ceroid pigments within inflammatory cells can create a yeastlike structure known as Hamasaki-­Wesenberg bodies, are recognized by their size, inherent color, and irregular staining pattern. In the photomicrograph shown here, a portion of a child’s colon was removed following bowel perforation. The adjacent peritoneum contained mononuclear cell infiltrates with scattered giant cells and funguslike structures, which have a distinct cell wall and contain ovoid, glassy subunits with molding and differing shapes. They consist of pulse granules, components of legumes such as beans and peas that are liberated during the digestive process. Pulse granules may be aspirated, causing pulse pneumonia, or may leak into the peritoneum following bowel perforation, as with this child. It is thus best to have a healthy degree of skepticism with all unusual-appearing “infections.” (H&E; 3200)

4

The Skin Vijaya B. reddy

n

INTRODUCTION

n

SKIN BIOPSY: WHEN, WHY, AND HOW

n

GENODERMATOSES Ichthyosis Darier Disease, Hailey-Hailey Disease, and Porokeratosis Epidermolysis Bullosa Incontinentia Pigmenti

n

n

NONINFECTIOUS ACQUIRED VESICULOBULLOUS DISEASES Linear IgA Bullous Dermatosis Dermatitis Herpetiformis Erythema Multiforme Eczematous/Spongiotic Dermatitis NONINFECTIOUS PAPULOSQUAMOUS DERMATOSES Psoriasis Lichen Planus Lichen Nitidus and Lichen Striatus Pityriasis Rosea, Pityriasis Rubra Pilaris, and Pityriasis Lichenoides

n

n

n

INFECTIOUS DISEASES Bacterial Infections: Impetigo, Staphylococcal Scalded Skin Syndrome, and Echtyma Gangrenosum Viral Infections: Verruca Plana, Molluscum Contagiosum, and Herpes Zoster Fungal Infections: Superficial Fungal Infections (Tinea) and Deep Mycoses

n

NONINFECTIOUS PANNICULITIS Erythema Nodosum, Subcutaneous Fat Necrosis of the Newborn, and Sclerema Neonatorum

n

VASCULITIS Henoch-Schönlein Purpura and Polyarteritis Nodosa

n

SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS MANIFESTATIONS Lupus Erythematosus

NONINFECTIOUS NEUTROPHILIC DERMATOSES Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome) and Neutrophilic Eccrine Hidradenitis

n

CYSTS, NEOPLASMS, AND HAMARTOMAS Epidermal Nevus

n

MELANOCYTIC PROLIFERATIONS Congenital Melanocytic Nevi Malignant Melanoma

n

HEMATOPOIETIC PROLIFERATIONS Mast Cell Disease Langerhans Cell Histiocytosis

NONINFECTIOUS GRANULOMATOUS DERMATOSES Granuloma Annulare, Necrobiosis Lipoidica, and Sarcoidosis

inTroduCTion A wide array of skin disorders that affect adults can also occur in children. Because a complete description of all skin disorders is beyond the scope of this atlas, the emphasis will be on the conditions that are commonly seen in children and diseases that can be life threatening when diagnosis is delayed. Skin diseases can be classified in many different ways—based on etiology, clinical appearance, and histopathologic patterns. This chapter illustrates the histopathologic features of selected skin disorders seen in children, which are grouped according to etiology and pathogenesis. Many atlases focusing on clinical dermatology are available for the interested reader.

skin BioPsy: when, why, and how Most nonneoplastic pediatric skin diseases can be diagnosed based on clinical presentation, and a biopsy is only rarely warranted. In other situations, a histopathologic diagnosis may be the mainstay of diagnosis. A punch biopsy is the preferred method of tissue procurement for nonneoplastic/inflammatory conditions of the skin and shave biopsy/excisions are reserved for neoplastic/proliferative processes. Routine processing and hematoxylin/eosin staining is appropriate in most situations with special stains/ immunohistochemistry used as an adjunct. In selective conditions such as erythema multiforme/toxic epidermal necrolysis, which can be life threatening, frozen section diagnosis may be necessary to facilitate appropriate clinical management. Direct immunofluorescence testing is indicated in the evaluation of blistering disorders. Electron microscopy is reserved for special cases such as subclassifying type of epidermolysis bullosa. Both fetal and neonatal skin biopsies may be a useful medium for cytogenetic analysis of some congenital disorders.

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GENODERMATOSES n ICHTHYOSIS

1A

1B

1C

1D

FIGURE 4.1  Ichthyoses are a heterogenous group of disorders that are generally inherited and characterized clinically by dryness and scaling of the skin (A). The most common form of ichthyosis is ichthyosis vulgaris that is inherited in an autosomal dominant pattern and manifests clinically after 3 months of age. Fine white to larger platelike scales involving large areas of the body are visible; the scales are most prominent on the extensor surface of the extremities with relative sparing of the flexural areas. Histologically, there is a moderate hyperkeratosis with a thinned or absent granular layer (B). Follicular plugging resulting from follicular hyperkeratosis may be present. X-linked ichthyosis shows hyperkeratosis with a normal or thickened granular layer. Epidermolytic hyperkeratosis or bullous congenital ichthyosiform erythroderma is inherited in an autosomal dominant pattern and presents with generalized erythroderma at the time of birth, with development of superficial bullae shortly thereafter. Within a few days, thick verrucous scales develop with marked involvement of the flexural areas. Histologically, there is marked hyperkeratosis, a characteristic vacuolization of the cells in the spinous and granular layer, and prominent keratohyaline granules (C). Lamellar ichthyosis, inherited in an autosomal recessive pattern, presents with large scales involving face, trunk, and extremities with a predilection for flexor areas. The histologic findings are nonspecific and consist of hyperkeratosis and mild epidermal hyperplasia (D) (Table 4.1). Source: Courtesy of Sarah Stein, MD, University of Chicago Medical Center.

TABLE 4.1  Ichthyosis Ichthyosis Vulgaris

X-Linked Ichthyosis

Epidermolytic Hyperkeratosis

Lamellar Ichthyosis

Mode of inheritance Autosomal d ­ ominant

X-linked ­recessive

Autosomal d ­ ominant

Clinical

Large scales on the extensor aspects of extremities

Dark, large scales Generalized erythroderma, on face and neck; progressing to bullae and flexural areas may be verrucous scales; flexural areas involved are involved

Dense platelike scales; flexural areas involved

Histopathology

Hyperkeratosis, diminished or absent granular layer

Hyperkeratosis, normal Hyperkeratosis, vacuolization of or slightly thickened keratinocytes and prominent granular layer keratohyaline granules

Nonspecific changes; hyperkeratosis and epidermal hyperplasia

Autosomal recessive

GENODERMATOSES 

n DARIER DISEASE, HAILEY-HAILEY DISEASE, AND POROKERATOSIS

2A

2B

2C

2D

FIGURE 4.2  Darier disease, also known as keratosis follicularis, is inherited as an autosomal dominant disorder and typically manifests in children aged 5–15 years as keratotic papules in the seborrheic areas of the body and flexural areas of the extremities. Histologically, there is suprabasal acantholysis covered by dyskeratotic cells (corps ronds) and parakeratosis (corps grains). Associated epidermal hyperplasia and hyperkeratosis are characteristic (A). The lesions may be follicular centered. Hailey-Hailey disease is an autosomal dominant genodermatosis that typically manifests after puberty as recurrent vesicles and erosions on the neck, axillae, and groin areas. Histologically, there is suprabasal acantholysis resulting in a dilapidated brickwall-like appearance (B). In contrast to Darier disease, where dyskeratosis is more prominent, acantholysis is more prominent in Hailey-Hailey disease. Histologic differential diagnosis of intraepidermal acantholysis includes the pemphigus group of disorders that require immunofluorescence testing for diagnosis (C). Porokeratosis, inherited as an autosomal dominant disorder, manifests in infancy and childhood as asymptomatic keratotic papules that enlarge to form plaques with raised edges. Variants of porokeratosis seen in children include classic plaque type, linear porokeratosis, porokeratosis palmaris et plantaris, and punctuate porokeratosis that is limited to palms and soles. The histopathologic hallmark of all variants of porokeratosis is cornoid lamella, which is a column of parakeratosis that corresponds to the peripheral raised keratotic edge seen clinically. At the base of the cornoid lamella, there is epidermal invagination and an abnormal clone of epidermal keratinocytes that are dyskeratotic (D).

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n EPIDERMOLYSIS BULLOSA

3a

3B

Figure 4.3  Epidermolysis bullosa represents a heterogenous group of inherited disorders with variable modes of transmission and characterized clinically by bullae that develop spontaneously or secondary to minor trauma (A). The three major categories are: simplex that is associated with generally good prognosis; junctional type in which blistering begins at birth (A), with death occurring in the first 2 years of life; and dystrophic type with a dominant type that has good prognosis, and a recessive type that has poor prognosis. The histological hallmark of all types of epidermolysis bullosa is a subepidermal blister without significant inflammation (B). Immunomapping studies are essential for subtyping, prognostication, and genetic counseling.

n INCONTINENTIA PIGMENTI

4a

4B

FIGURE 4.4  Incontinentia pigmenti is an X-linked dominant disorder affecting mostly females and presenting with skin lesions by 6 weeks of age. The lesions evolve from crops of vesicles and bullae arranged in linear or whorled pattern on trunk and extremities to verrucous hyperkeratotic lesions that subside and leave streaks and whorls of hyperpigmentation. Histologically, the vesicular stage is characterized by intraepidermal spongiotic vesicle filled with eosinophils (A). In the verrucous stage, hyperkeratosis and epidermal hyperplasia with focal dyskeratosis are seen in addition to eosinophils (B). The hyperpigmented stage corresponds to dermal melanosis typical of postinflammatory pigmentary change.

NONINFECTIOUS ACQUIRED VESICULOBULLOUS DISEASES 

NONINFECTIOUS ACQUIRED VESICULOBULLOUS DISEASES n LINEAR IgA BULLOUS DERMATOSIS

5a

5B

FIGURE 4.5  Linear IgA bullous dermatosis, also known as chronic bullous dermatosis of childhood, occurs predominantly in preschool children and presents with widespread vesicles and bullae with predilection for the lower part of the trunk, including groin, and genitalia and perioral areas. Bullae arranged like a string of pearls may occur at the periphery of a healing lesion. Light microscopic features consist of subepidermal blister with neutrophils and eosinophils (A). In early lesion, neutrophilic microabscesses may be seen at the tips of dermal papillae. The histologic differential diagnosis includes dermatitis herpetiformis and bullous systemic lupus. Immunofluorescence studies showing linear staining with antibodies against IgA are confirmatory (B). Deposits of IgG and/or IgM at the basement membrane zone are helpful in the diagnosis of lupus.

n DERMATITIS HERPETIFORMIS

6a

6B

FIGURE 4.6  Dermatitis herpetiformis, although more common in young adults, may also affect infants and children. It typically presents with intensely pruritic papulovesicular eruption on the scalp, elbows, knees, and back. There is strong association with gluten-sensitive enteropathy. Histologic features are similar to linear IgA bullous dermatosis and characterized by subepidermal blister, with neutrophils and neutrophilic microabscesses in the dermal papillae (A). ­Immunofluorescence studies show granular deposits of IgA in the dermal papillae (B).

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n ERYTHEMA MULTIFORME

7a

7B

7C

7D

FIGURE 4.7  Erythema multiforme ranges in severity from a maculopapular skin eruption to vesiculobullous lesions with mucosal involvement (Stevens-Johnson syndrome) to widespread full thickness epidermal necrosis of toxic epidermal ­necrolysis (Lyell syndrome). Stevens-Johnson syndrome is more common in childhood. Histologic hallmark of this group of disorders is necrotic keratinocyte. In early lesions, there is interface dermatitis with vacuolar alteration of the basal cell layer, inflammatory cells that obscure the dermoepidermal junction, and necrotic keratinocytes in the epidermis (A). In more advanced lesions, there is separation at the basement zone and necrotic keratinocytes are abundant (B). In the most severe cases, there is full-thickness epidermal necrosis with subepidermal bulla formation and minimal inflammatory cell ­infiltrate (C). The stratum corneum is typically unaltered. The histologic differential diagnosis includes graft-versus-host disease, seen in children most often as a complication of treatment of acute leukemia. Histologic sections of early lesions of acute graft-versus-host disease show interface dermatitis with vacuolar alteration of the basal cell layer and necrotic ­keratinocytes surrounded by lymphocytes known as satellite necrosis (D).

NONINFECTIOUS ACQUIRED VESICULOBULLOUS DISEASES 

n ECZEMATOUS/SPONGIOTIC DERMATITIS

8a

8B

8C

8D

FIGURE 4.8  Eczematous/spongiotic dermatitis refers to a group of disorders characterized clinically by erythematous scaling vesicular lesions covered with serum crust and histologically by the presence of epidermal spongiosis. This group of disorders includes atopic dermatitis, n ­ ummular dermatitis, contact dermatitis, and dyshidrotic dermatitis. Specific diagnosis is based on clinical history, morphology, and distribution of lesions. Spongiotic dermatitis, irrespective of etiology, can be acute, subacute, or chronic. In acute spongiotic dermatitis, there is epidermal spongiosis with vesicles containing serum and inflammatory cells (A). The underlying dermis shows edema and perivascular inflammatory cell infiltrate. A prominent eosinophilic infiltrate is most suggestive of contact dermatitis (B). In the subacute stage, there is a mild to moderate spongiosis, epidermal hyperplasia, and a parakeratotic cornified layer with serum (C). In the chronic stage, the spongiosis is mild or absent, but changes of chronicity manifest as ­hyperkeratosis, hypergranulosis, epidermal hyperplasia, and a fibrotic papillary dermis with vertically oriented collagen bundles (D). These changes are referred to as lichen simplex chronicus.

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NONINFECTIOUS PAPULOSQUAMOUS DERMATOSES n PSORIASIS

9a

9B

9C

9D

FIGURE 4.9  Psoriasis is frequently encountered in children younger than the age of 16 years and often presents as asymptomatic scaly erythematous plaques (plaque type) or slightly pruritic small red droplike scaly lesion (guttate type). Classic histologic features of psoriasis include confluent parakeratosis with neutrophils (Munro microabscesses), regular epidermal hyperplasia with thinning of suprapapillary plates, dilated blood vessels in the papillary dermis and mild superficial perivascular lymphohistiocytic inflammation (A). In guttate lesions, the epidermal hyperplasia is less prominent and parakeratosis alternates with areas of orthokeratosis (B). The granular layer of the epidermis is absent in plaque stage and at least diminished in guttate lesions. Pustular psoriasis is characterized by epidermal spongiosis with large collections of neutrophils (spongiform pustule) (C). Erythrodermic and pustular variants of psoriasis are less common in children. Seborrheic dermatitis, a common disorder seen in infants and adolescents, has clinical and histologic features that overlap those of psoriasis. Histologically, epidermal hyperplasia with spongiosis, exocytosis, and patchy ­parakeratosis are often more prominent at the opening of the follicular infundibula, and are ­characteristics of seborrheic dermatitis (D).

NONINFECTIOUS PAPULOSQUAMOUS DERMATOSES 

n LICHEN PLANUS

10a

10B

FIGURE 4.10  Lichen planus is a self-limiting pruritic eruption that can be seen occasionally in children. The lesions consist of flat-topped violaceous papules typically affecting the flexor regions of the extremities and lower back. Characteristic histologic features are hyperkeratosis, hypergranulosis, irregular epidermal hyperplasia with sawtooth rete pattern, and a dense bandlike lymphohistiocytic infiltrate that obscures the dermoepidermal junction (A). Artifactual clefts between the epidermis and the dermal infiltrate, colloid bodies, and melanophages are the frequent findings (B).

n LICHEN NITIDUS AND LICHEN STRIATUS

11a

11B

FIGURE 4.11  Lichen nitidus is a common disorder of childhood that is seen more frequently in African American children. It presents as asymptomatic, closely grouped, tiny, flat-topped, ­flesh-colored papules on the abdomen, genitalia and extremities. Histologically, each papule of lichen nitidus consists of a well-circumscribed lymphohistiocytic infiltrate that is typically confined to a widened dermal papilla (A). The infiltrate is bordered on either side by a slightly hyperplastic epidermis, likened to a claw clutching a ball. The epidermis overlying the infiltrate is flattened and covered by focal parakeratosis. Lichen striatus is an uncommon disorder, occurring most frequently in young children as unilateral eruption of minute, slightly raised papules that eventually coalesce to form a linear band. The histologic features are variable but generally include a superficial perivascular and patchy lichenoid lymphohistiocytic infiltrate that obscures the dermoepidermal junction. There is also focal epidermal spongiosis and parakeratosis. A characteristic feature is the presence of inflammatory cell infiltrate around the adnexal structures in the reticular dermis (B).

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n PITYRIASIS ROSEA, PITYRIASIS RUBRA PILARIS, AND PITYRIASIS LICHENOIDES

12a

12B

12C

12D

FIGURE 4.12  Pityriasis rosea is a self-limiting dermatosis that is most common in adolescents. It typically starts with a herald patch, followed by an eruption of round to oval salmon-colored patches with a peripheral scale along the lines of cleavage on the trunk. Histologically, the patches show focal epidermal spongiosis, mounds of parakeratosis, and a superficial perivascular lymphocytic infiltrate with extravasated red blood cells that also extend into the epidermis (A). Pityriasis rubra pilaris is a chronic follicular-centered erythematous papular eruption that frequently coalesces to form orange-red plaques with islands of normal skin. The histologic features of a fully developed lesion consist of epidermal hyperplasia with broad and short rete, and alternating hyperkeratosis and parakeratosis in vertical and horizontal directions (B). Follicular plugging is seen in the biopsy of a follicular papule. Pityriasis lichenoides is a self-limiting eruption that can present in children during the first decade of life. The acute form, pityriasis lichenoides et varioliformis acuta (PLEVA, Mucha-Haberman disease) presents as recurrent erythematous, papular, papulonecrotic, or papulovesicular eruption on the trunk and proximal extremities. The chronic form, pityriasis lichenoides chronica, is characterized by scaly papules that resolve in a few weeks with postinflammatory pigmentary changes. Histologically, PLEVA shows interface dermatitis with a lichenoid pattern, as well as a superficial and deep perivascular lymphocytic dermatitis. Confluent parakeratosis with plasma and neutrophils, scattered necrotic keratinocytes, and extravasated red blood cells are characteristic (C). In the chronic form, the findings are similar but parakeratosis with neutrophils is less conspicuous and melanophages may be seen in the papillary dermis (D).

INFECTIOUS DISEASES 

INFECTIOUS DISEASES n BACTERIAL INFECTIONS: IMPETIGO, STAPHYLOCOCCAL SCALDED SKIN SYNDROME, AND ECTHYMA GANGRENOSUM

13a 13B

13C

13D

FIGURE 4.13  Bacterial infections. Impetigo is a common bacterial infection of the skin seen in children. Impetigo contagiosa, often caused by group A beta-hemolytic streptococci and Staphylococcus aureus, is characterized by vesiculopustular lesions that rupture and develop heavy yellow crusts. Histologic sections show a subcorneal pustule, which may reveal gram-positive cocci with special stains (A). Bullous impetigo, caused by exfoliative toxins of S. aureus, is like a localized form of staphylococcal scalded skin syndrome. Histologic sections show a cleavage plane at or below the level of granular layer and a superficial perivascular neutrophilic infiltrate. Staphylococcal scalded skin syndrome (SSSS) is a generalized blistering disorder seen most commonly in neonates and young children and caused by epidermolytic toxin-producing S. aureus. It presents with abrupt onset of fever and diffuse erythema that evolves into large flaccid bullae filled with clear fluid. The bullae rupture and sheets of epidermis peel off, imparting a scalded appearance. Histologic findings are similar to those of bullous impetigo but typically lack the dermal inflammatory cell infiltrate (B). Despite the clinical similarities, SSSS can be easily distinguished from toxic epidermal necrolysis based on the absence of full thickness epidermal necrosis seen in the latter. Ecthyma gangrenosum is an ulcerative lesion, seen in patients with pseudomonas aeruginosa sepsis. Predisposing factors include an underlying immunodeficiency and chemotherapy for cancer. Histologic sections show ischemic necrosis and ulceration of the epidermis associated with hemorrhage and necrotizing vasculitis (C). Bacilli infiltrating the vessels and adjacent dermis can be seen on routine stains. Neutrophils are conspicuously absent (D).

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n VIRAL INFECTIONS: VERRUCA PLANA, MOLLUSCUM CONTAGIOSUM, AND HERPES ZOSTER

14a

14B

14C

14D

Figure 4.14  Viral infections. Human papillomavirus infection manifests most commonly as verruca vulgaris. Histologically, there is papillomatous epidermal hyperplasia, hyper- and parakeratosis, and large vacuolated cells (koilocytes) toward the surface of the epidermis (A). Verruca plana shows hyperkeratosis and viral cytopathic effect but without significant papillomatosis (B). Molluscum contagiosum, caused by a DNA poxvirus is commonly seen in children and presents with discrete, umbilicated waxy papules, typically on the face. Histologically, there is surface invagination lined by hyperplastic epidermis. Intracytoplasmic inclusions (molluscum bodies) compress the nuclei of the epidermal keratinocytes. They can also be found in the keratin layer of the invagination (C). Herpes simplex virus infection manifests most commonly as primary gingivostomatitis and rarely as Kaposi varicelliform eruption. Herpes zoster is most commonly seen in children as chicken pox, a highly contagious generalized vesiculopustular eruption. Histologic changes of all herpes virus infections are similar and consist of intraepidermal acantholytic blister with balloon degeneration and multinucleated giant cells with intranuclear inclusions (D).

n FUNGAL INFECTIONS: SUPERFICIAL FUNGAL INFECTIONS (TINEA) AND DEEP MYCOSES Figure 4.15  Fungal infections. Primary cutaneous infection with Candida is often seen in the diaper area of infants. In addition, both superficial and deep fungal infections can be seen in the pediatric population. Superficial fungal infections (tinea) typically present as annular lesions with scaly borders on the body (ringworm, tinea corporis) or patches of alopecia on the scalp (tinea capitis). Histologic sections show parakeratosis with neutrophils and mild superficial perivascular inflammation. Fungal hyphae can be demonstrated with a PAS stain in the cornified layer in tinea corporis (A) and in the follicular units in tinea capitis (B). Deep mycoses are generally caused by saprophytic organisms such as blastomycosis, chromoblastomycosis, and coccidiomycosis as primary cutaneous infection or as part of systemic disease. Characteristic histological features include suppurative and granulomatous inflammation with associated pseudoepitheliom15a atous hyperplasia. The organisms can be seen as pigmented spores (copper pennies) on routine stain in chromoblastomycosis (C). Special stains are necessary to identify the typical morphology of the organisms in other infections. Broad-based budding is typical of blastomycosis (D, GMS stain). Cryptococcosis typically presents as cellulitis. Mucicarmine stain shows numerous spores and some with narrow-based budding (E). (Continued)

NONINFECTIOUS NEUTROPHILIC DERMATOSES 

15B

15C

15D

15E

Figure 4.15  Fungal infections. (Continued)

NONINFECTIOUS NEUTROPHILIC DERMATOSES n ACUTE FEBRILE NEUTROPHILIC DERMATOSIS (SWEET SYNDROME) AND NEUTROPHILIC ECCRINE HIDRADENITIS

16A

16B

Figure 4.16  Acute febrile neutrophilic dermatosis (Sweet syndrome) is infrequently seen in children but as in adults, it may be associated with underlying malignancy or inflammatory diseases. Patients present with fever, leukocytosis, and tender, violaceous plaques on the face or extremities. Vesicles and pustules may occur on the plaques but the lesions are sterile. Histologic changes include a dense upper dermal infiltrate of neutrophils, papillary dermal edema, and swelling of the vascular endothelium but no evidence of vasculitis (A). The histologic differential diagnoses include infectious causes and pyoderma gangrenosum. Neutrophilic eccrine hidradenitis has been reported in children treated with chemotherapy for acute leukemia but more commonly presents as (idiopathic) palmoplantar hidradenitis in otherwise healthy children. Lesions present as painful erythematous papules and nodules on the palms and soles. Histologic features are similar in both entities and consist of diffuse neutrophilic infiltrate centered on eccrine sweat gland coils (B). In addition, abscess formation is typical of palmoplantar hidradenitis, whereas squamous syringometaplasia is seen only in chemotherapy-related neutrophilic eccrine hidradenitis. An infectious etiology should be excluded in all cases.

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NONINFECTIOUS GRANULOMATOUS DERMATOSES n GRANULOMA ANNULARE, NECROBIOSIS LIPOIDICA, AND SARCOIDOSIS

17A

17C

17B

17D

FIGURE 4.17  Granuloma annulare presents with single or multiple asymptomatic papules arranged in an annular fashion most commonly on the dorsa of hands and feet. Histologic changes are characterized by zones of myxoid degeneration of collagen surrounded by a palisade of histiocytes in the upper dermis (A). Perivascular lymphocytic infiltrates may be present. A subcutaneous form occurs more frequently in children than in adults and shows histologic similarity to rheumatoid nodule. Necrobiosis lipoidica is more common in young adults but can be seen in children. There is an association with diabetes. It presents as well-demarcated oval plaques typically on the shins and can be bilateral. Histologically, there are palisading granulomas surrounding zones of degenerated collagen, which alternate with layers of sclerotic collagen bundles. The granulomas involve the reticular dermis and may extend into the subcutaneous fat (B). Plasma cells are present in the inflammatory cell infiltrate. Sarcoidosis is a multisystem disorder characterized by noncaseating granulomas that can be seen in children between the ages of 9 and 15. It can also be seen in preschool children manifesting with skin, joint, and eye involvement. Skin involvement seen in a fourth of all patients with sarcoidosis, manifests as red-yellow or violaceous papules. Histologic changes are characteristic and consist of noncaseating epithelioid granulomas with only a sparse lymphocytic infiltrate at the periphery of the granulomas (C). Infectious etiology and reaction to foreign body should be excluded in even the classical cases. Foreign body material is present in this noncaseating granuloma (D).

NONINFECTIOUS PANNICULITIS 

NONINFECTIOUS PANNICULITIS n ERYTHEMA NODOSUM, SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN, AND SCLEREMA NEONATORUM

18A

18B

FIGURE 4.18  Erythema nodosum manifests as symmetric, tender, erythematous subcutaneous nodules on the extensor aspects of the lower legs. Histological features are those of a predominantly septal panniculitis with acute and chronic inflammation and septal fibrosis. Older lesions show granulomatous inflammation of the septa but typically no necrosis (A). Erythema nodosum-like pattern can be seen in various infections and in association with systemic diseases such as inflammatory bowel disease and, therefore, a diagnosis of erythema nodosum should prompt investigation for one of the associated disorders. Subcutaneous fat necrosis of the newborn is a relatively uncommon, self-limiting disorder that typically affects full-term or post-term infants. It manifests in the first 2 weeks of life as asymptomatic, firm nodules on cheeks, shoulders, buttocks, and thighs. 18C Histologic changes are typical and consist of lobular panniculitis with fat necrosis and mixed inflammatory cell infiltrates with multinucleated giant cells. Radially arranged ­ needle-shaped crystals of lipid are present in the cytoplasm of histiocytes and adipocytes (B). Hypercalcemia is a known complication that requires treatment. Sclerema neonatorum is a rare condition affecting premature and otherwise ill newborns. Histologically, fat necrosis and cells containing needle-shaped crystals similar to those seen in subcutaneous fat necrosis of the newborn are present. However, the inflammatory cell infiltrate is sparse in sclerema, which can be helpful in differentiating the two in addition to clinical history (C).

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VASCULITIS n HENOCH-SCHÖNLEIN PURPURA AND POLYARTERITIS NODOSA

19A

19B

19C

19D

FIGURE 4.19  Henoch-Schönlein purpura is the most common type of vasculitis seen in children, typically presenting with palpable purpura on lower extremities, arthralgias, abdominal pain, and hematuria following streptococcal upper respiratory tract infection. Histologically, there is leukocytoclastic vasculitis characterized by superficial perivascular infiltrates of neutrophils, neutrophilic nuclear dust, extravasated red blood cells, and fibrin deposits around the blood vessel walls (A). Deposits of IgA around the blood vessels by direct immunofluorescence testing differentiate Henoch-Schönlein purpura from other causes of leukocytoclastic vasculitis (B). Polyarteritis nodosa, although more common in adults, is well described in children both as a systemic disease and limited to the skin. The cutaneous manifestations of polyarteritis nodosa include painful subcutaneous nodules that may ulcerate and cause gangrene of fingers and toes (C). Histologically, small to mediumsized arteries in the subcutis are infiltrated and surrounded by neutrophils, neutrophilic nuclear dust, and, occasionally, eosinophils. Necrosis and deposition of fibrin may be seen in the affected vessels (D).

SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS MANIFESTATIONS 

SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS MANIFESTATIONS n LUPUS ERYTHEMATOSUS

20a

20B

20C

20D

FIGURE 4.20  Lupus erythematosus affects children of all ages. Systemic lupus is the most common form that peaks in early adolescence and manifests frequently with cutaneous changes, including malar rash, oral ulcerations, photosensitivity, alopecia, and discoid lesions. Neonatal lupus presents with erythematous, sharply demarcated lesions around the eyes. The characteristic histologic changes are those of interface dermatitis with marked vacuolar alteration of the basal cell layer and a dermoepidermal junction that is obscured by lymphocytic infiltrate. In a well-established lesion, there is also hyperkeratosis, epidermal atrophy and a thickened basement membrane (A). Direct immunofluorescence testing shows granular deposits of C3 and IgG at the dermoepidermal junction (B). A superficial and deep perivascular lymphocytic infiltrate and interstitial mucin deposits may be found in early lesions. Systemic sclerosis or scleroderma shows less significant involvement of other organs and is associated with better outcome than in adults. A localized form of scleroderma (morphea) is a disease of children and young adults and presents as plaque, linear, guttate, or generalized forms. Histologic sections of early lesions show perivascular and interstitial lymphocytic infiltrate associated with thickened collagen bundles in the dermis (C). Older lesions show less inflammatory cell infiltrate and more prominent hyalinization of the dermal collagen bundles and superficial displacement of the eccrine sweat glands. The septa of the subcutaneous fat are thickened (D).

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CYSTS, NEOPLASMS, AND HAMARTOMAS n EPIDERMAL NEVUS

21a

21B

21C

21D

FIGURE 4.21  Epidermal nevus presents as rough-surfaced lesions at birth or shortly after as localized lesions or in widespread and segmental distribution. Histologic patterns can be variable and include epidermolytic hyperkeratosis, acantholytic dyskeratosis, verruciform xanthoma, and seborrheic keratosis-like patterns (A). Benign adnexal tumors can be seen in children but less commonly than in adults. Pilomatrixoma is the most common adnexal neoplasm seen in the pediatric age group. It presents as a hard dermal/subcutaneous mass, typically in the head and neck area. Histologic changes vary with the age of the lesion but essentially consist of a cystlike structure lined by basaloid cells that mature by forming masses of “shadow/ghost” cells toward the center (B). Older lesions show smaller epithelial components and consist mostly of shadow cells. Calcification and ossification may also be seen. Eccrine syringoma is seen in children in association with trisomy 21 syndrome and present as an eruption of small papules on the face and sometimes on the vulva. Histologic features include multiple, small epithelial structures that form elongated (tadpole like) shapes and tubular structures that contain eosinophilic material within the lumina (C). Nevus sebaceus of Jadassohn is a hamartoma that occurs as yellowish round-oval hairless plaque on the scalp, forehead, and lateral aspect of the face. The clinical and histologic appearance varies with age, with the sebaceous lobules in the lesion following normal maturation of sebaceous lobules elsewhere. In addition to sebaceous lobules at various stages of maturation, rudimentary hair follicles, and apocrine glands can be seen (D).

MELANOCYTIC PROLIFERATIONS 

MELANOCYTIC PROLIFERATIONS n CONGENITAL MELANOCYTIC NEVI

22A

22C

22B

22D

22f

FIGURE 4.22  Congenital melanocytic nevi are present at birth or appear shortly thereafter as generally large pigmented lesions. Giant congenital nevi occupy a large part of the body, sometimes 22e in a garmentlike distribution. The surface is verrucous, variably pigmented in shades of brown and blue and may have excessive hair. Histologically, there is hyperkeratosis, epidermal hyperplasia, and melanocytes arranged as nests at the dermoepidermal junction and extending deep into the dermis (A). Extension into the reticular dermis and subcutaneous fat is seen in giant congenital nevi. A characteristic histologic feature of congenital nevi of all sizes is the extension of dermal melanocytes around the dermal vessels and adnexal structures (B). Spitz nevus is also known as spindle and epithelioid cell nevus typically occurs in children before the age of 14 years as solitary, small, pink papules, clinically resembling a hemangioma or pyogenic granuloma. Histologically, Spitz nevus is characterized by a well circumscribed, symmetric proliferation of large, spindled or epithelioid melanocytes arranged as nests at the dermoepidermal junction and in the dermis, where they show maturation with progressive descent (C). Hyperkeratosis and hyperplasia of the overlying epidermis and presence of dull-pink globules (Kamino bodies) at the dermoepidermal junction are additional features in Spitz nevus (D). Blue nevus presents clinically as a blue-gray papule or nodule often on the scalp and lumbosacral area. Histologically, dendritic melanocytes with melanin pigment arranged as nests and fascicles predominantly in the dermis are characteristic (E). Clark’s dysplastic nevus presents as clinically atypical nevus and as multiple nevi in a subgroup of genetically predisposed individuals with familial melanoma syndrome. Histologically, dysplastic nevus is a broad junctional or compound nevus with bridging of nests of melanocytes across adjacent rete and concentric and lamellar fibroplasia (F). The junctional component is always much broader than the dermal component (shoulders).

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n MALIGNANT MELANOMA

23a

23B

23C

23D

FIGURE 4.23  Malignant melanoma occurs only rarely in the first decade of life and often in association with congenital nevus. In addition to large size, asymmetry, and pagetoid pattern of melanocytes typical of melanoma (A), atypical melanocytes arranged in confluent sheets may be seen adjacent to nests of monomorphous melanocytes of preexisting nevus (B). A distinct type of melanoma with features overlapping with Spitz nevus occurs in prepubescent children. Histologically, these lesions are characterized by a vertical growth of large epithelioid melanocytes that fail to mature with progressive descent (C). Melanocytes can be even larger at the base (reverse of maturation) and mitotic figures can be found (D).

HEMATOPOIETIC PROLIFERATIONS n MAST CELL DISEASE

24A

24B

FIGURE 4.24  Mast cell disease in children can manifest as solitary mastocytoma at birth or as urticaria pigmentosa presenting as a maculopapular eruption in infants 3 to 9 months of age, and rarely as a systemic disease. Histologically, cutaneous lesions in all forms are characterized by dense dermal infiltrate of monomorphous mononuclear cells with oval bland nuclei and abundant amphophilic cytoplasm (A). Special stains such as Giemsa, toluidine blue, and immunohistochemical for mast cell tryptase are helpful (B).

HEMATOPOIETIC PROLIFERATIONS 

n LANGERHANS CELL HISTIOCYTOSIS

25A

25C

25B

25D

FIGURE 4.25  Langerhans cell histiocytosis can involve skin in all its clinical forms but cutaneous involvement is most common in the acute disseminated form. Cutaneous involvement may be in the form of diffuse papular eruption of the scalp and anogenital area resembling seborrheic dermatitis. Histologically, the papillary dermis and the overlying epidermis are infiltrated by histiocytic cells with abundant pale cytoplasm and characteristic reniform nuclei. Multinucleated histiocytes and eosinophils may also be present in the infiltrate (A). By immunohistochemistry, the histiocytic cells are positive for S-100 protein and CD1a (B). Congenital self-healing reticulohistiocytosis is characterized by the presence of histiocytes with abundant eosinophilic cytoplasm with a ground-glass appearance (C). Juvenile xanthogranuloma is a common non-Langerhans histiocytosis seen in children. It presents as single or multiple yellowish papules or nodules of skin, typically in the first year of life. Histologically, sections show dense dermal infiltrate of histiocytes with foamy cytoplasm and multiple nuclei arranged in a wreathlike arrangement (D).

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5

Soft Tissue Lesions Zhongxin Yu David M. Parham

n

n

FIBROUS LESIONS Nodular Fasciitis Myofibroma-Myofibromatosis Lipofibromatosis Fibrous Hamartoma of Infancy Infantile Digital Fibromatosis Gardner-Associated Fibroma Desmoid Tumor Inflammatory Myofibroblastic Tumor Infantile Fibrosarcoma Sclerosing Epithelioid Fibrosarcoma Low-Grade Myofibrosarcoma Low-Grade Fibromyxoid Sarcoma MYOGENIC LESIONS Genital Rhabdomyoma Embryonal Rhabdomyosarcomas Botryoid Rhabdomyosarcoma Alveolar Rhabdomyosarcomas

n

NEURAL LESIONS Plexiform Neurofibroma Schwannoma Malignant Peripheral Nerve Sheath Tumor

n

FATTY LESIONS Lipoblastoma Myxoid Liposarcoma

n

VASCULAR LESIONS Juvenile/Infantile Hemangioma Congenital Non-Progressive Hemangiomas Vascular Malformation Glomangioma Kaposiform Hemangioendothelioma

n

FIBROHISTIOCYTIC LESIONS Juvenile Xanthogranuloma Dermatofibrosarcoma Protuberans Angiomatoid Fibrous Histiocytoma Plexiform Fibrohistiocytic Tumor

n

LESIONS OF INDETERMINATE HISTOGENESIS Ewing Sarcoma/Primitive Neuroectodermal Tumor Synovial Sarcoma Desmoplastic Small Round Cell Tumor Clear Cell Sarcoma Clear Cell Myomelanocytic Tumor Alveolar Soft Part Sarcoma Epithelioid Sarcoma Extrarenal Rhabdoid Tumor

FiBrous lesions n nodular FasCiiTis FiGure 5.1 Nodular fasciitis. In spite of its benign nature, nodular fasciitis often shows rapid initial growth, raising concerns for malignancy. To make matters worse, its initial proliferative nature often mimics the histology of sarcoma, but careful inspection and familiarity should prevent an unfortunate overdiagnosis. Nodular fasciitis most frequently occurs in the subcutis of extremity, but in children, it particularly favors the head and neck. This is a low-power view of a typical case and shows plump, spindle-shaped cells that are loosely arranged in a tissue culture–like pattern, with focal myxoid, torn, and feathery features. Extravasated red blood cells (RBCs) are easily seen. These lesions can appear quite cellular and mitotically active with a storiform pattern that is easily misdiagnosed as pleomorphic-storiform sarcoma (malignant fibrous histiocytoma) if a benign diagnosis is not considered. Nodular fasciitis is composed of a mixture of fibroblastic and myofibroblastic cells and typically contains a secondary component of inflammatory cells, usually lymphocytes and occasional multinucleated giant cells.

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n Myofibroma-Myofibromatosis

2A

2b

2c

2d

2e

2f

FIGURE 5.2  Myofibroma-myofibromatosis is one of the most common fibrous tumors of infancy and childhood. So-called infant hemangiopericytoma is now also considered a form of these tumors. They occur as solitary or multifocal lesions (myofibromatosis) in the wide variety of peripheral soft tissue locations or internal organs. When myofibroma arises in soft tissue, it often presents as a 1–5 cm lobulated, nonencapsulated nodule. Solitary peripheral soft tissue lesions are usually benign and often undergo spontaneous regression, but multifocal lesions with internal organ involvement may cause mortality. Myofibromas usually contain two components: a highly vascular and cellular hemangiopericytoma-like core, which is apparent in the lower portion of the picture, and a peripheral shell composed predominantly of smooth muscle–like myofibroblasts, shown in the upper portion of the picture (A). Sometimes, the tumor can be quite cellular and mimic a soft tissue sarcoma (B). High-power view (C) of the cellular area in (B). Areas with a mixture of plump immature cells and bundles of smooth muscle–like myofibroblasts are often seen, especially in resected tumor specimens (D). The myofibroblasts are stained red, whereas the collagenized stroma is stained blue by trichrome stains (E). An actin stain highlights the bundles of smooth muscle–like myofibroblasts (F).

Fibrous Lesions 

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n Lipofibromatosis FIGURE 5.3  Lipofibromatosis is a desmoidlike lesion characterized by a mixed content of fat and streaks of cellular fibroblastic areas. Lipofibromatosis is a biphasic tumor that somewhat resembles fibrous hamartoma of infancy, but it lacks the primitive mesenchymal component of the latter tumor. Its behavior mimics that of a desmoid tumor, but it tends to arise in infants and young children and has been referred to as infantile desmoidlike fibromatosis. However, unlike desmoid tumors, lipofibromatosis does not overexpress beta-catenin by immunohistochemistry. Some argue that the fatty component represents native tissue infiltrated by tumor, and indeed the invasive nature of this lesion confuses the picture.

n Fibrous Hamartoma of Infancy FIGURE 5.4  Fibrous hamartoma of infancy is a triphasic tumor characterized by organoid bundles of intervening mature fat, streaks of moderately cellular fibroblastic areas, and small clusters of oval more primitive cells. Fibrous hamartomas typically occur as subcutaneous plaques that arise in the extremities and trunk of infants and toddlers. These lesions can be quite large and alarming, but they have a benign behavior, analogous to hamartomas at other sites. The organoid features of this lesion usually suffice for diagnosis; the myofibroblastic component is typically actin-positive (as in most of the lesions of this genre).

n Infantile Digital Fibromatosis

5a

5B

FIGURE 5.5  Infantile digital fibromatosis. Hematoxylin and eosin (H&E)–stained section shows dense fibrous tissue with intracytoplasmic round eosinophilic inclusions (A). Trichrome-stained section demonstrates the eosinophilic globular cytoplasmic inclusion (B). By electron microscopy (not shown), these inclusions comprise bundles of actin microfilaments. This rare tumor typically occurs in infants and young children, and some may be congenital. It usually arises on the extensor surfaces of the second to fifth fingers and toes. It often recurs after incomplete surgery (60% recurrence rate) but usually regresses with time, so that a conservative approach is typically curative.

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n Gardner-Associated Fibroma FIGURE 5.6  Gardner-associated fibroma involves superficial and deep soft tissues of the paraspinal region, back, chest wall, flank, head and neck, and extremities. Histologically resembling nuchal-type fibromas, Gardner fibroma is a paucicellular neoplasm that contains thick, haphazardly arranged collagen bundles. Occasional bland fibroblasts are seen between the collagen bundles. This tumor may serve as a sentinel lesion for patient with Gardner syndrome, familial adenomatous polyposis, and/or APC mutation.

n Desmoid Tumor

7a

7B

FIGURE 5.7  Desmoid tumor (desmoid-type fibromatoses, aggressive fibromatoses) is considered a tumor of adulthood, but it does occur in pediatric patients. Based on its anatomic location, this tumor has been subclassified into three categories: intra-abdominal, abdominal, and extraabdominal fibromatoses. Regardless of the location, these tumors share clinical, morphologic, immunohistochemical, and molecular genetic features. The most common type of this tumor in children is the extra-abdominal fibromatosis, which is further subclassified as juvenile desmoid fibromatosis. In children, the common sites are the head and neck region, extremities, trunk, and hip region. Most patients present with a slowly growing, nontender mass, which is locally aggressive and recurs frequently after incomplete excision. The relationship of childhood desmoid tumor 7c with Gardner syndrome and familial polyposis coli is well known. Grossly, the tumor varies in size, from a small nodule to a bulky mass (A). It is deceptively well circumscribed, with a firm trabeculated appearance. The tumors are paucicellular to moderately cellular and contain fibroblasts and myofibroblasts that merge with surrounding collagen (B). Slitlike vessels are commonly seen with in the tumor, and some of these vessels show perivascular edema (C). There is no mitosis or nuclear atypia. The tumor often infiltrates into the surrounding skeletal muscle (D). Microscopically, the tumor often involves the margin of resection, leading to frequent recurrence (E). Most tumors show nuclear staining for beta catenin (not shown here), which may be used to separate desmoids from other ­fibroblastic lesions. (Continued)

Fibrous Lesions 

7d

7e

Figure 5.7  Desmoid tumor. (Continued)

n Inflammatory Myofibroblastic Tumor

8A

8B

FIGURE 5.8  Inflammatory myofibroblastic tumor (IMT). As part of the spectrum of so-called inflammatory pseudotumors, IMT is a true neoplastic lesion with characteristic genetic changes involving ALK1 gene. Several fusion partners are involved. IMT has a potential for local recurrence but usually does not metastasize; however, on occasion, they are aggressive, and metastasizing lesions have been coined inflammatory fibrosarcoma. IMT often occurs in the lung (previously called plasma cell granuloma), where it is the most common primary pulmonary neoplasm in children. Other primary sites include the urinary bladder, omentum, gastrointestinal tract, and other viscera. Grossly, the tumor is circumscribed, but not encapsulated (A). The cut surface is white to tan, with a whorled, fleshy, or myxoid appearance. Histologically, the tumor features proliferation of myofibro8C blastic and fibroblastic spindle cells with inflammatory infiltrates of lymphocytes and plasma cells; sometimes, the inflammation may obscure the underlying myofibroblastic proliferation (or vice versa). The background often has abundant blood vessels, sometimes with a hemangiopericytomatous appearance (B) and area with typical appearance of spindled myofibroblastic cells and inflammatory infiltrate (C). Positive ALK immunostain confirms the diagnosis, but this marker does not stain all lesions. Other “inflammatory pseudotumors” include dendritic cell tumors and lesions associated with autoimmune diseases, particularly hyper-IgG4 syndromes.

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n Infantile Fibrosarcoma

9A

9B

FIGURE 5.9  Infantile fibrosarcoma is a rare malignant mesenchymal tumor of young children who are usually less than 2 years of age; one half of them are congenital. It is more common in boys and chiefly affects the extremities and the head and neck regions. It often presents as a painless, rapid growing mass in the subcutaneous and deep soft tissue, often reaching a huge size by the time of surgery and infiltrating subcutaneous fat, muscle, fascia, and even bone. In spite of these alarming features, this tumor generally has a good clinical outcome. Grossly this tumor is poorly circumscribed and often infiltrates surrounding soft tissue (A). It has a firm, white, fibrous appearance on cut sections. Histologically, the tumor is composed of hypercellular spindle cells arranged in interlacing fascicles (B). The tumor cells are uniform and plump with prominent mitotic activity and are often accompanied by focal collagen formation. Some tumors contain prominent vessels arranged in a pericytomatous pattern, resembling hemangiopericytoma or infantile myofibromatosis. Immunohistochemically, this tumor usually shows positivity for smooth muscle actin and negativity for desmin and CD34. Infantile fibrosarcomas typically contain a characteristic TEL-NTRK3 fusion, resulting from reciprocal t(12;15). TEL-NTRK3 fusion is also found in the cellular congenital mesoblastic nephroma and some types of congenital acute lymphocytic leukemia. Gene fusion studies can differentiate infantile fibrosarcoma from mimics such as rhabdomyosarcoma, infantile myofibromatosis, and infantile hemangiopericytoma.

n Sclerosing Epithelioid Fibrosarcoma FIGURE 5.10  Sclerosing epithelioid fibrosarcoma is a rare variant of fibrosarcoma characterized by a deceptive low-grade tumor histology but aggressive clinical behavior with local recurrence and distant metastasis. It has a wide-age distribution from adolescence to the older years. It is localized mainly in deep soft tissues at the extremities, trunks, and head and neck areas. It may arise as a primary bone tumor. This tumor usually presents as a painless mass of a few months to years. This is a classic picture of this tumor, which features cords of infiltrating epithelioid cells in a hyalinized fibrous stroma. The tumor cells are small to medium in size, and round to ovoid, often with clear or eosinophilic cytoplasm and uniform bland nuclei. The tumor cells are often arranged in a single file pattern resembling carcinoma. Mitotic figures are either scant or absent, and necrosis is uncommon. The bland cytology of the tumor cells and the hyalinized stroma raise the possibility of benign lesions such as desmoid tumor, and its epithelioid appearance may mimic an infiltrating carcinoma. This tumor is consistently positive only for vimentin. Many cases show focal or weak positivity for epithelioid membrane antigen (EMA) and bcl-2. Rare cases show focal or weak positivity for S100. They are usually negative for CAM5.2, AE1/AE3, HMB45, and leukocyte common antigen (LCA). Carefully choosing a good panel of immunohistochemical stains may help in deriving a right diagnosis. It is important that pathologists realize the existence of this tumor entity in order to avoid a misdiagnosis. Cytogenetically, sclerosing epithelioid fibrosarcoma is characterized by rearrangement of 10p11 and amplification of 12q13 and 12q15, including the HMGIC gene. A more recent study demonstrated that a subset of sclerosing epithelioid fibrosarcoma has a FUS-CREB3L2 fusion gene, a characteristic genetic change of low-grade fibromyxoid sarcoma/hyalinizing spindle cell tumor with giant rosettes. It has thus been suggested that these tumors comprise varying histologies of the same pathological entity.

Fibrous Lesions 

n Low-grade Myofibrosarcoma

11A

11B

FIGURE 5.11  Low-grade myofibrosarcoma. As the name implies, this is a low-grade malignant tumor characterized by a diffusely infiltrative growth of myofibroblasts. It usually occurs in young to middle aged adults. Clinically, this tumor usually presents as a painless, enlarging mass in the soft tissues and in almost every organ. In pediatrics, it typically affects adolescents and arises in the head and neck. It histologically resembles a cellular fibrosarcoma or leiomyosarcoma and is composed of fascicles or broad sheets of cells, with or without a focal herringbone arrangement or storiform whorls. Low magnification shows a cellular area with a storiform growth pattern (A). The cells have tapered nuclei and ill-defined, pale, eosinophilic cytoplasm (B). The cells show at least focally moderate nuclear atypia with enlarged, hyperchromatic, and irregular nuclei. Occasional atypical mitoses and focal necrosis can be found. Immunohistochemically, the tumor is most often positive for smooth muscle actin and vimentin and sometimes positive for desmin. It is therefore evident that immunohistochemistry cannot be used alone to reliably separate myofibroblastic lesions from smooth muscle tumors, such as leiomyosarcoma. Some new immunohistochemical markers such as calponin and h-caldesmon may be useful in separating low-grade myofibroblastic lesions from leiomyosarcomas: low-grade myofibrosarcomas usually show diffuse positivity for calponin but are rarely and focally positive for h-caldesmon, whereas leiomyosarcomas show positivity for both antibodies. By electron microscopy, neoplastic myofibroblasts share features of both fibroblasts (rough endoplasmic reticulum, procollagen granules) and smooth muscle cells (peripheral microfilaments with focal densities). They also contain specialized anchoring elements known as fibronexus junctions or anchoring fibrils. In difficult cases, electron microscopic examination may assist in diagnosis.

n Low-grade Fibromyxoid Sarcoma

12A

12B

FIGURE 5.12  Low-grade fibromyxoid sarcoma (LGFMS)/hyalinizing spindle cell tumor with giant rosettes commonly occurs in young and middle-aged adults. It exhibits a deceptively benign fibromyxoid appearance but recurs frequently and occasionally metastasizes. Hyalinizing spindle cell tumor with giant rosettes is a variant of LGFMS and is characterized by large rosettelike structures. Both tumors share clinical, histological, and genetic similarity, so that they are now regarded as part of the histological spectrum of a single entity. This group of tumors usually presents as a slow growing, painless, deep soft tissue mass that most commonly originates in the lower extremities. They often extensively infiltrate into adjacent soft tissue. Low-power magnification shows characteristic features of the LGFMS: low-to-moderate cellular spindle cells arranged in fibrous and myxoid background, with a linear or whorled growth pattern (A). Cells in myxoid areas often show an increased perivascular cellularity. Probably the most striking feature in LGFMS is a zonated sharp demarcation between myxoid and fibrous areas (B, C). The central fibrous nodule in this picture represents an early giant rosette (D). Immunohistochemically, these tumors show focal positivity for smooth muscle actin and epithelial membrane antigen. Rare cases show focal staining for desmin, CD34, and cytokeratin. Both show fusions of the FUS and CREB3L2 or CREB3L1, so that break-apart fluorescence in situ hybridization (FISH) for the FUS gene at chromosome 16 may assist in diagnosis of LGFMS. However, FUS is also disrupted in myxoid liposarcoma, so that one must correlate the results of break-apart FISH with the morphologic features of the tumor in question. (Continued)

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12C

12D

FIGURE 5.12  Low-grade fibromyxoid sarcoma (LGFMS). (Continued)

Myogenic Lesions n Genital Rhabdomyoma

13A

13B

FIGURE 5.13  Genital rhabdomyoma. This is a benign tumor exclusively occurring in the vagina. This tumor is morphologically similar to fetal type rhabdomyoma, which is often seen in the head and neck of children and composed of less-differentiated fusiform rhabdomyoblasts. The tumor often presents as a well-circumscribed polypoid submucosal mass (A). The tumor consists of haphazard skeletal muscle cells and fibromyxoid stroma. There is no cambium layer. Higher magnification of the tumoral muscle cells reveals no cross-striations, necrosis, or nuclear pleomorphism (B). Although this lesion has features reminiscent of botryoid rhabdomyosarcoma, it typically arises in adolescents and young adults, often in conjunction with pregnancy. Thus, the diagnosis of cervicovaginal rhabdomyosarcoma should be made in older females only after careful evaluation and even outside consultation, to avoid overdiagnosis of malignancy.

Myogenic Lesions 

n Embryonal Rhabdomyosarcomas

14A

14B

14C

14D

14E

14F

FIGURE 5.14  Embryonal rhabdomyosarcomas (ERMS). ERMS is one of the most common subtypes of rhabdomyosarcoma and is usually seen in young children. It is commonly seen in the genitourinary, retroperitoneal, or head and neck areas. This subtype of tumors has a strikingly wide histologic spectrum, as the tumor cells range from very immature and primitive to differentiated and cross-striated. ERMS shows striking similarity to developing embryonal muscle. This low-power microscopic view characterizes the histological features of the tumor: alternating vascular, highly cellular areas and hypocellular, myxoid regions resembling embryonal, and early fetal skeletal muscle (A). ERMS show a wide spectrum of histology (B–H): undifferentiated primitive cells (B), dense cellular zones (C), clear cell appearance (D), rhabdoid appearance (E), atypical mitosis and enlarged hyperchromatic nuclei in an anaplastic ERMS (F), tumor with scattered strap cells (G), tumor with rhabdomyoma-like area (H), spindle cell variant of ERMS (I). The tumor cells show nuclear staining for myogenin, usually in a patchy or scattered pattern (J). (Continued)

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14G

14H

14I

14J

Figure 5.14  Embryonal rhabdomyosarcomas. (Continued)

n Botryoid Rhabdomyosarcoma

15A

15C

15B

FIGURE 5.15  Botryoid rhabdomyosarcoma is a variant of ERMS that has a relatively better prognosis. It usually occurs in young children. Common locations are near an epithelial surface in the urinary bladder, vagina, and bile ducts. Grossly, the tumor has a polypoid configuration with focal areas resembling a bunch of grapes (botryos in Greek) (A). Histologically, the tumor is characterized by a cambium layer, a dense zone of undifferentiated tumor cells beneath the epithelium (B). The tumor cells are composed of small, round blue cells with eccentric nuclei and eosinophilic cytoplasm, enmeshed in a fibrovascular stroma. Atypical fibroepithelial polyp, a benign reactive lesion, resembles a botryoid rhabdomyosarcoma in that both have a polypoid configuration and commonly occur in the genital tract (C, D). In contradistinction to botryoid rhabdomyosarcoma, atypical fibroepithelial polyp lacks a cambium layer, shows negative staining for myogenin, and typically arises in adolescents and young women (E). (Continued)

Myogenic Lesions 

15D

15E

FIGURE 5.15  Botryoid rhabdomyosarcoma. (Continued)

n Alveolar Rhabdomyosarcomas

16A

16B

16C

FIGURE 5.16  Alveolar rhabdomyosarcomas (ARMS) is more common in older children than ERMS, but it also occurs in young children. The tumors usually occur in the extremity or head and neck areas and have a more aggressive behavior with early metastasis to regional lymph nodes and bone marrow. ARMS is a high-grade round cell malignancy with an alveolar growth pattern (i.e., discohesive tumor cells are arranged in nests or cords separated by fibrous septa) (A). The solid variant of ARMS is a highly cellular neoplasm that contains uniformly round cells and resembles a lymphoma (B). ARMS usually shows diffuse and strong positivity to myogenin staining (C). Genetically, most ARMS contain a PAX3- or PAX7-FOXO1 fusion. The former fusion predominates and correlates with a highly aggressive neoplasm, often with poor outcome.

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Neural Lesions n Plexiform Neurofibroma FIGURE 5.17  Plexiform neurofibroma is a benign neurogenic tumor and a signature lesion in patients with neurofibromatosis type 1. This picture is a classic case of this lesion characterized by tortuous bundles of spindle cells separated by fibrous septa and embedded in a myxoid matrix. Plexiform neurofibromas generally contain wiry bundles of collagen reminiscent of shredded carrots, often in a targetoid configuration. Some lesions have greater cellularity and occasional mitoses, prompting a consideration of malignant peripheral nerve sheath tumor (MPNST). An intermediate form of neurofibromas may show partial features of malignancy. These have been termed cellular neurofibromas.

n Schwannoma

18A

18B

FIGURE 5.18  Schwannoma is a common benign peripheral nerve sheath tumor seen in all age groups. In children, the most common sites are the head and neck area and upper extremity. Bilateral involvement of the eighth cranial nerve is diagnostic of neurofibromatosis type 2, and multiple schwannomas often occur in children with this condition. Grossly, schwannoma appears as an encapsulated, expansile nodule (A). The cut surface is firm and lobulated with myxoid foci. Histologically, a conventional tumor is characterized by compact spindle cells with nuclear palisading adjacent to amorphous pools of cellular processes (Verocay bodies) (B). Densely cellular, palisaded foci (Antoni A pattern) usually abut loosely cellular myxoid foci (Antoni B pattern, not shown in this picture).

n Malignant Peripheral Nerve Sheath Tumor FIGURE 5.19  Malignant peripheral nerve sheath tumor often arises within anatomic component of a major nerve or contiguous with neurofibroma. The figure shows MPNST arising from a plexiform neurofibroma (A). On the left upper portion of the photomicrograph, the tumor is contiguous with a neurofibroma. The cellularity is significantly increased in MPNST, compared to the benign neurofibroma. Conventional MPNST (B) is hypercellular and composed of spindle shaped cell with variable pleomorphism and occasional bizarre giant cells. There are increased mitoses. MPNST may have nodular appearance tactoid bodies (C). Plump epithelioid cells with acidophilic cytoplasm comprise the epithelioid variant of MPNST (D). These tumors are usually strongly positive for S100, in contradistinction to the focal or absent staining of most conventional MPNST. (Continued) 19A

Fatty Lesions 

19B

19C

19D

FIGURE 5.19  Malignant peripheral nerve sheath tumor. (Continued)

Fatty Lesions n Lipoblastoma

20A

20B

FIGURE 5.20  Lipoblastoma is a rare benign fatty tumor occurring in young children. It is typically located in the subcutis and deeper soft tissues of the extremities or, less commonly, trunk, but deep mesenteric and retroperitoneal tumors have been reported. Lesions that invade adjacent skeletal muscle (so-called lipoblastomatosis) are more difficult to excise and may recur. Grossly, this tumor is lobulated and encapsulated and has a yellow or yellow-white cut surface (A). Histologically, the tumor is composed of cells with all stages of adipose differentiation, from stellate mesenchymal cells to lipoblasts to mature lipocytes (B). Lipoblasts are signet ringlike cells with round cytoplasmic lipid vacuoles and an eccentric oval nucleus. The tumor cells are arranged in lobules separated by fibrous septa. The characteristic genetic change of this tumor is the rearrangement of chromosome 8q11–13 where the PLAG1 is gene located. Overexpression of PLAG1 gene in this tumor has been reported.

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n Myxoid Liposarcoma

21A

21B

FIGURE 5.21  Myxoid liposarcoma occurs as one of the most frequent sarcomas seen in adults. It is infrequent in children but is the most common “adult” type of sarcoma in pediatrics. Adolescents are usually affected. The tumor consists of monomorphic, stellate, or fusiform cells intersected by a prominent arcuate (“chicken wire”) vasculature (A). The latter feature consists of delicate thin walled branching vessels whose recognition is key to the diagnosis. Cystic degeneration produces a pulmonary edema–like appearance, typical to this tumor. Closer examination of the tumor reveals many lipoblasts containing cytoplasmic lipid vacuoles (B). The cells are not very atypical and there are no mitotic figures. The background is rich in mucoid matrix. Genetically, myxoid and round cell liposarcomas both contain a FUS-CHOP genetic fusion resulting from a reciprocal t(12;16). However, round cell liposarcomas are high-grade and aggressive neoplasms whose behavior are notably worse than that of the low-grade myxoid liposarcoma.

Vascular Lesions n Juvenile/Infantile Hemangioma

22A

22B

FIGURE 5.22  Juvenile/infantile hemangioma is the most common benign vascular proliferation of infancy. Clinically, it ranges from superficial strawberry birthmarks to large disfiguring lesions with morbidity. It usually has three stages: a rapidly proliferating stage, a prolonged involuting stage, and an end stage when the tumor becomes a fibrofatty residuum. In the proliferating stage, the tumor contains masses of plump endothelial cells and attendant pericytes that form small lumina containing erythrocytes (A). In the late involuting phase, the tumor is characterized by dilation of vascular lumina, flattening of endothelial cells, and dropout of lesional capillaries (B). In all stages, the lesional endothelial cells show positive staining for glucose transporter 1 (GLUT-1), an erythrocyte glucose transport protein (C). Staining for 22C GLUT-1 is a very useful property of this tumor, as other histological mimics, such as congenital non-progressive hemangiomas and vascular malformations, are negative for this stain.

Vascular Lesions 

n Congenital Non-Progressive Hemangiomas

23A

23B

FIGURE 5.23  Congenital non-progressive hemangiomas have been subclassified into two groups, the rapidly involuting congenital hemangioma (RICH) and the noninvoluting congenital hemangioma (NICH). In contradistinction to the proliferating infantile hemangiomas, both tumors are fully formed at birth. While RICH completely regresses within the first 6 months to 1 year of life, NICH grows proportionally with the patient, or expands slightly over time, and does not regress. Some cases of RICH undergo rapid but incomplete involution, with a resulting clinical appearance and histology similar to NICH. It has been proposed that RICH and NICH may lie within the same spectrum of vascular tumors. Histologically, RICH and NICH have much similarity to infantile hemangioma. RICH in involuting phase 23C with many hemosiderin pigments (A). NICH contains masses of plump endothelial cells and small lumina resembling infantile hemangioma (B). RICH and NICH were thought to be congenital forms of infantile hemangioma until North and colleagues demonstrated in 2000 that GLUT-1 is expressed in infantile hemangioma but not in these congenital subtypes including both RICH and NICH (C). This is a GLUT-1 stain on a NICH, which shows negative GLUT-1 staining in tumoral endothelial cells (intraluminal RBCs stained with the GLUT-1 serve as internal positive control).

n Vascular Malformation

24A

24B

FIGURE 5.24  Vascular malformation. Once under the generic name “hemangioma,” vascular malformation is a separate vascular lesion that differs from hemangiomas both clinically and histologically. This group of lesions always presents at birth and grows in proportion to body growth, never regressing spontaneously. They can be arterial, capillary, venous, lymphatic, or any combination of these components. A diagnosis of vascular malformation often relies on a multidisciplinary approach and requires clinical information, magnetic resonance imaging, and computed tomography; sometimes an angiogram may be needed. Histological examination is useful in confirming the type of malformation. Lymphatic malformation (cystic hygroma) contains dilated lymphatic channels containing amorphous lymph and lymphocytes within the lumen and lymphoid aggregates on the wall (A). The endothelial lining is positive for lymphatic endothelial marker, D2–40, an immunohistochemical stain that typically stains lymphatic endothelium but not other types of blood vessels (B).

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n Glomangioma FIGURE 5.25  Glomangioma (glomovenous malformation) consists of dilated, branching vascular channels separated by fibrous stroma. Monotonous small glomus cells are arranged around vessels. The glomus cells show no significant cytological atypia. These cells comprise modified epithelioid smooth muscle cells and are typically found in the distal extremities. They may be multiple and inherited.

n Kaposiform Hemangioendothelioma

26A

26B

FIGURE 5.26  Kaposiform hemangioendothelioma. The tumor is composed of packed round and spindled endothelial cells with elongated and slitlike vessels containing scattered RBCs (A). ­Glomeruloid clusters of epithelial cells are characteristic of this tumor. The endothelial cells are positive for CD34 (B); the endothelial cells are focally positive for D2–40, a lymphatic marker (C). Kaposiform hemangioendotheliomas usually arise in infants and cause Kasabach-Merritt syndrome, a hemorrhagic diathesis caused by platelet consumption within the lesional vessels.

26C

Fibrohistiocytic Lesions 

Fibrohistiocytic Lesions n Juvenile Xanthogranuloma

27A

27B

FIGURE 5.27  Juvenile xanthogranuloma (JXG). Low-power examination shows dense cellular infiltration in the dermis, which may extend into subcutis (A). The infiltrates consist of histiocytes, Touton giant cells, lymphocytes, and occasional eosinophils and neutrophils (B). Touton giant cells contain a circular wreath of nuclei and, although characteristic, may be sparse in early lesions. JXGs are CD34-negative and factor XIIIa-positive. These phenotypic features may assist in diagnosis of deep-seated or visceral lesions. JXGs are a form of histiocytosis and may arise from dermal dendritic cells. They are separated from Langerhans cell histiocytosis by their CD1a, langerin, and S100-negativity and lack of Birbeck granules by electron microscopy.

n Dermatofibrosarcoma Protuberans

28A

28B

FIGURE 5.28  Dermatofibrosarcoma protuberans (DFSP) is an uncommon intermediate grade soft tissue tumor arising from the subcutis, usually in the trunk or proximal extremities. It is a locally aggressive lesion with great capacity for recurrence and limited potential for malignant transformation and metastasis. Most tumors are diagnosed in young adults around the fourth decade of life, but many may begin during childhood. Bednar tumor and giant cell fibroblastoma are two variants of this tumor. Bednar tumors contain melanin pigment with otherwise classic DFSP features. Giant cell fibroblastomas predominantly arise in children younger than 5 years old, thus representing a juvenile form of DFSP. This is a classic type of DFSP, which features fibroblastic proliferation 28C centered in deep dermal and/or subcutaneous tissue (A). The cellularity is low to moderate. Spindle-shaped tumor cells are arranged in a storiform fashion in the background of moderately abundant collagen. The same tumor in part A recurred 3 years later, with malignant transformation into a fibrosarcoma showing high cellularity and interlacing fascicular arrangement of the tumor cells (B). This is giant cell fibroblastoma, which is composed of infiltrative, loosely arranged, wavy spindle cells, with variable cellularity and variable numbers of giant cells (C). DFSP and its variants are CD34-positive and contain a COL1A1-PDGFB gene fusion, often occurring within the duplicated portion of a ring chromosome. COL1A1/PDGFB fusion testing can be used for clinical diagnosis.

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n Angiomatoid Fibrous Histiocytoma FIGURE 5.29  Angiomatoid fibrous histiocytoma is a neoplasm of uncertain histogenesis with intermediate malignant potential. It consists of a proliferation of histiocytelike cells rimmed by a dense lymphoid infiltrate. Often, there are abundant intralesional blood-filled spaces (not shown in this picture), associated with hemosiderin-laden macrophages. Some lesions lack the angiomatoid spaces but can be recognized by a dense peritumoral lymphoid infiltrate that creates a resemblance to metastatic tumor. Angiomatoid fibrosarcomas are often positive for desmin, as well as EMA, CD68, and CD99. Genetically, they may contain an EWS-ATF1 fusion, similar to that of clear cell sarcoma, or a FUS-ATF1 fusion.

n Plexiform Fibrohistiocytic Tumor FIGURE 5.30  Plexiform fibrohistiocytic tumor is characterized by a plexiform or nodular proliferation of fibrohistiocytic cells separated by thick fibrous stroma. The tumor cells usually show minimal atypia and are sometimes accompanied by osteoclastlike giant cells and chronic inflammatory infiltrates. Plexiform fibrohistiocytic tumor is an intermediate, rarely metastasizing soft tissue neoplasm according to the current World Health Organization (WHO) criteria. It frequently recurs if not completely excised. Its immunophenotype includes positivity for vimentin, CD68, and smooth muscle actin, CD68 being expressed in giant cells and histiocytoid cells and actin in spindle cells.

Lesions of Indeterminate Histogenesis n Ewing Sarcoma/Primitive Neuroectodermal Tumor FIGURE 5.31  Ewing sarcoma/primitive neuroectodermal tumor (PNET). Ewing sarcoma and PNET are morphologically and clinically diverse lesions that comprise a single neoplastic entity. Ewing sarcomas typically arise in bones and show patternless sheets of primitive cells proliferation, whereas PNETs usually arise in soft tissue and show cytologic and histologic features of primitive neuroblastoma-like differentiation. Intermediate entities sharing features of both lesions (atypical Ewing sarcoma) commonly appear, and all variants may occur in either bone or soft tissue. Ewing sarcoma imprint stained with Diff-Quick reveals small round cells with scanty cytoplasm and a high nuclear-to-cytoplasmic ratio (A). In contrast to lymphoblastic lymphoma, there is distinct cellular cohesion, and no lymphoglandular bodies are seen in the background. Typical Ewing sarcoma usually contains mixtures of two types of cells, the “light” cells with round nuclear contours, smooth, even chromatin, and clear to vacuolated glycogen-rich cytoplasm, 31A and the “dark” cells with angulated nuclear contours and hyperchromatic chromatin (B). Sometimes the dark cells present a streaming pattern among the lighter elements. Although considered as part of the same tumor category as Ewing sarcoma, PNET often has primitive neural differentiation with variable numbers of Homer Wright rosettes (C). Both Ewing sarcoma, and PNET show strong membrane reactivity with anti-CD99 antibody (D). In spite of their morphologic dissimilarity, Ewing sarcoma and PNET share identical genetic alterations (E). The most common genetic changes are t(11;22)(q24;q12) and t(21;22)(q22;q12), which result in EWS-FLI1 and EWS-ERG fusion genes. Although a partner fusion gene cannot be established by the break-apart FISH approach, the split signal of EWS gene (green) from its centromere (red) in chromosome 22 indicates that a rearrangement of the EWS gene has occurred. (Continued)

Lesions of Indeterminate Histogenesis 

31B

31C

31D

31E

FIGURE 5.31  Ewing sarcoma/primitive neuroectodermal tumor (PNET). (Continued)

n Synovial Sarcoma

32A

32B

FIGURE 5.32  Synovial sarcoma can be biphasic, monophasic, or undifferentiated. It is often deep-seated around large joints, sometimes with a tendonlike tissue attachment (A). However, true intrasynovial tumors are rare. Dense cellular plump spindles are arranged in fascicles in a monophasic spindle cell tumor (B). Epithelial cells form glands and cords in some tumors (C). The tumor often has a hemangiopericytomatous vascular pattern (D). Another feature of the synovial sarcoma is focal calcification, which tends to be a feature of lower-grade lesions (E). Synovial sarcomas usually stain for epithelial membrane antigen and/or cytokeratin. Bcl-2 staining is typical but nonspecific. Confirmatory testing in problematic cases is best done by testing for the SSX1-SYT or SSX2-SYT gene fusions, which result from a reciprocal t(X;18). Synovial sarcoma is one of the most frequently occurring soft tissue malignancies in children and adolescents. Tumor grading is necessary to guide management and depends on mitotic index and presence of geographic necrosis. (Continued)

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32C

32D

32E

FIGURE 5.32  Synovial sarcoma. (Continued)

n Desmoplastic Small Round Cell Tumor FIGURE 5.33  Desmoplastic small round cell tumor (DSRCT) usually arises as a large mass in abdomen or pelvis, although it rarely occurs in other locations. In pediatrics, it usually occurs in adolescents. It is composed of nested primitive round/oval cells surround by a dense, collagenous stroma. The small round tumor cells often show prominent karyorrhexis, and sometimes there are marked central necrosis and cystic degeneration. Cytologic features of DSRCT vary from epithelioid to rhabdoid. Polyphenotypic diversity characterizes its immunophenotype. Co-expression of epithelial (cytokeratin, epithelial membrane antigen), neural (neuron-specific enolase, S100), and mesenchymal (desmin, vimentin) markers usually occurs, although some lesions lack cytokeratin expression. A dotlike desmin pattern (not shown) is typical. Genetically, DSRCTs contain a EWS-WT1 fusion, so that EWS FISH can be useful for diagnosis. WT1 immunostaining is also useful, but usually only the C-terminus portion of the protein is expressed, so that antibodies against N-terminus portions of the fusion are typically negative for nuclear staining.

Lesions of Indeterminate Histogenesis 

n Clear Cell Sarcoma

34A

34B

FIGURE 5.34  Clear cell sarcoma is also known as melanoma of soft parts. It tends to occur near tendons, fascia, or aponeuroses. The lower extremities are particularly favored locations, and like melanoma, they may metastasize to draining lymph nodes. Characteristic histological features include a nested or fascicular growth pattern with a mixture of spindle and epithelioid cells containing eosinophilic to clear glycogen-rich cytoplasm (A). Some of the cells contain dark brown melanin pigment. This feature can be accentuated with the Fontana melanin stain (not shown).Tumor cells demonstrate a melanoma-like appearance, including a large nucleus with a prominent, deeply basophilic or eosinophilic nucleolus (B). This tumor is positive for HMB45, S100, and other melanocytic markers. Ultrastructural study shows cytoplasmic melanosomes and/or premelanosomes. Genetically, clear cell sarcomas contain an EWS-ATF1 fusion, so that break-apart FISH is a useful tool to distinguish them from melanoma.

n Clear Cell Myomelanocytic Tumor

35A

35B

FIGURE 5.35  Clear cell myomelanocytic tumor (CCMMT) is a member of the perivascular epithelioid cell tumor (PEComa) family of neoplasms, along with sugar tumor, angiomyolipoma, and lymphangioleiomyomatosis. This soft tissue lesion is a well circumscribed, nonencapsulated neoplasm that often arises from falciform ligament or ligamentum teres. The tumor is composed of spindle cells arranged in a nested or fascicular pattern (A). The tumor cells contain lightly eosinophilic to clear cytoplasm and ovalshaped nuclei with prominent nucleoli. The most significant feature of this tumor is its property of co-expression of melanocytic and muscle markers demonstrated in pictures B and C. The tumor is diffusely positive for HMB45, a melanocytic marker (B). Of note, these lesions are usually negative for 35C S100 (not shown). The tumor is strongly positive for muscle actin (C). This property is useful in distinguishing these tumors from clear cell sarcomas of soft tissue. Unlike other forms of PEComa, CCMMTs are generally not associated with tuberous sclerosis.

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n Alveolar Soft Part Sarcoma

36A

36B

FIGURE 5.36  Alveolar soft part sarcoma (ASPS). The tumor is characterized by a nested arrangement of the tumor cells separated by dedicate fibrovascular septa (A). Within the nests, discohesive tumor cells give rise to an alveoluslike appearance. The tumor cells are usually large, with clear to finely granular cytoplasm and round nuclei with prominent nucleoli. Mitoses and necrosis are rare. A diagnostic feature of this tumor is the presence of needleshaped cytoplasmic crystals (arrows) demonstrated by PAS stain (B). Ultrastructurally, the PAS-positive crystals comprise membrane-bound rhomboidal structures with internal 70 Å periodicity (C). Genetically, ASPS contains an 36C ASPL-TFE3 fusion, which causes overexpression of TFE3 protein. This can be useful for immunohistochemical confirmation in difficult cases, as the lesion may express desmin and may be confused with rhabdomyosarcoma.

n Epithelioid Sarcoma

37A

37B

FIGURE 5.37  Epithelioid sarcoma is a high-grade tumor with unknown histogenesis. It can be divided into two types based on location and histology: distal (or classical) and proximal. The tumor is characterized by epithelioid cells arranged in a nodular fashion with central necrosis and hyalinization, a pattern that mimics a granuloma (A). Because of this, this tumor can be misdiagnosed as a granulomatous lesion such as granuloma annulare. The tumor cells often show a rhabdoid appearance (B). This appearance is particularly notable in the proximal subtype, which shares the aggressive tendencies of rhabdoid tumors. Epithelioid sarcomas show the same genetic alterations as classic rhabdoid tumor (i.e., INI1 gene deletion, which raises the question as to whether these tumors form a single entity). Classical epithelioid sarcomas tend to arise in the extremities, particularly the hand, and often metastasize to regional lymph nodes. Immunohistochemical stains reveal co-expression of cytokeratin, vimentin, and epithelial membrane antigen; other markers such as desmin and CD34 may be positive.

Lesions of Indeterminate Histogenesis 

n Extrarenal Rhabdoid Tumor

38A

38B

FIGURE 5.38  Extrarenal rhabdoid tumor. The tumor is composed of sheets or nests of large epithelioid cells with large nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (A). The tumor cells typically contain a round, deeply eosinophilic cytoplasmic inclusion. Ultrastructural study shows prominent intermediate filaments in the cytoplasm (B). INI1 gene deletion is the primary genetic alteration in rhabdoid tumor. Absence of INI1 expression can be detected using anti-INI1 antibody (C). The nontumoral endothelial cells in the center of the picture show positive staining for INI1, which serves as an internal positive control. Rhabdoid tumor at all sites are extremely aggressive tumors, but it is necessary to separate “true” rhabdoid tumors from “composite” rhabdoid tumors, the latter comprising various epithelial and mesenchymal neoplasms that share similar 38C cytologic features. The presence of INI1 deletions, absence of INI1 staining, and occurrence within an infant or young child are features that typify true rhabdoid tumors. Other tumors with rhabdoid cells are poorly defined and may have no relationship to this lesion. Another feature of a rhabdoid tumor is its unfortunate propensity to occur as an inherited lesion. Rhabdoid predisposition syndrome should be suspected in any child with multiple primaries or other affected family members, and testing for a constitutional INI1 deletion should be performed. Source: (C) From M. Mietten: Modern Soft Tissue Pathology, 2010, Cambridge University Press.

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6

Bone and Joints karen S. thompson

n

INTRODUCTION

n

NONNEOPLASTIC BONE DISEASES Genetic Nonneoplastic Skeletal Disorders Thanatophoric Dysplasia Achondrogenesis Type 2 Osteogenesis Imperfecta Craniosynostosis Syndromes Nongenetic Nonneoplastic Skeletal Disorders Osteomyelitis Congenital Syphilis

n

BONE TUMORS AND TUMORLIKE CONDITIONS Bone-Forming Tumors Osteoma Osteoid Osteoma

Osteoblastoma Osteosarcoma Conventional Osteosarcoma Osteosarcoma Variants Cartilage-Forming Tumors Osteochondroma and Multiple Osteochondromas Enchondroma/Enchondromatosis Chondroblastoma Chondromyxoid Fibroma Mesenchymal Chondrosarcoma Cystic Bone Lesions Solitary Bone Cyst Aneurysmal Bone Cyst Fibrous and Osteofibrous Bone Lesions Nonossifying Fibroma/ Metaphyseal Fibrous Defect

Fibrous Dysplasia Osteofibrous Dysplasia Small Cell Tumors and Marrow Cell Tumors Ewing Sarcoma/Primitive Neuroectodermal Tumor Langerhans Cell Histiocytosis of Bone Giant Cell Tumor n

JOINT DISORDERS Transient Synovitis/Perthes Disease Juvenile Idiopathic Arthritis

inTroduCTion A multidisciplinary approach to the diagnosis of bone lesions is essential. Radiographic images characterize the gross appearance of the lesion, while intraoperative findings can provide important clues to its nature. This information is especially critical when only a small biopsy or curettage specimen is received in pathology, which is often the case. Age and location of the lesion provide significant pieces to the diagnostic puzzle and can be quite specific for some bone tumor types. Diagnosis of a bone lesion based purely on histological findings in isolation from clinical and radiographic information can be misleading and even dangerous, as reactive bone is formed in response to practically all bone lesions, and many bone-forming processes can appear deceptively aggressive or deceptively bland histologically. Cytogenetic and molecular information can be extremely valuable in the diagnosis and management of bone diseases. This chapter focuses on nonneoplastic bone and joint diseases, bone tumors, and tumorlike lesions most commonly seen in the pediatric population.

nonneoPlasTiC Bone diseases The constitutional diseases of the bone embody a vast array of abnormalities, most of which are diffuse in nature and represent intrinsic defects in the formation or metabolism of bone. Classification systems have been created and published to organize this disease category. nomenclature of Constitutional (or Intrinsic) Disorders of Bone was originally published in 1970, with revisions in 1977, 1983, 1992, 1997, 2001, and 2007. The most recent revision in the series reflects new developments in molecular genetics and is entitled, nosology and Classification of Genetic Skeletal Disorders. This publication lists 372 different conditions placed into 37 groups defined by molecular, biochemical, and/or radiographic criteria (Table 6.1). The following are examples from some of these categories as well as examples of nongenetic nonneoplastic bone diseases.

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TABLE 6.1  Nosology and Classification of Genetic Bone Diseases     1. FGFR3 group

21. Neonatal osteosclerotic dysplasias

   2. Type 2 collagen group

22. Increased bone density group (without modification of bone shape)

   3. Type 11 collagen group    4. Sulphation disorders group    5. Perlecan group   6. Filamin group      7. Short-rib dysplasia (with or without polydactyly) group   8. Multiple epiphyseal dysplasia and pseudoachondroplasia group    9. Metaphyseal dysplasias 10. SMD 11. SE(M)D

23. Increased bone density group with metaphyseal and/or diaphyseal ­involvement 24. Decreased bone density group 25. Defective mineralization group 26. Lysosomal storage diseases with ­skeletal involvement (dysostosis multiplex group) 27. Osteolysis group 28. Disorganized development of skeletal components group 29. Cleidocranial dysplasia group

12. Severe spondylodysplastic dysplasias

30. Craniosynostosis syndromes and other cranial ossification disorders

13. Moderate spondylodysplastic dysplasias (brachyolmias)

31. Dysostoses with predominant ­craniofacial involvement

14. Acromelic dysplasias

32. Dysostoses with predominant vertebral and costal involvement

15. Acromesomelic dysplasias 16. Mesomelic and rhizo-mesomelic dysplasias

33. Patellar dysostoses

17. Bent bones dysplasias

34. Brachydactylies (with or without extraskeletal manifestations)

18. Slender bone dysplasia group 19. Dysplasias with multiple joint ­dislocations 20. CDP group

35. Limb hypoplasia-reduction defects group 36. Polydactyly-syndactyly-triphalangism group 37. Defects in joint formation and ­synostoses

Abbreviations: CDP indicates chondrodysplasia punctata; FGFR3, fibroblast growth factor receptor; SE(M)D, spondyloepi(-meta)physeal dysplasias; SMD, spondylometaphyseal dysplasias. Source: Modified from Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2007;1;143(1):1–18.

n GENETIC NONNEOPLASTIC SKELETAL DISORDERS Thanatophoric Dysplasia FIGURE 6.1  Thanatophoric dysplasia (fibroblast growth factor receptor 3 [FGFR3] group). Thanatophoric dysplasia is the most common form of lethal short-limb dysplasia. It is an autosomal dominant disorder that is caused by a mutation in the 4p16.3 locus resulting in an abnormal FGFR3 protein. Although the trunk is of normal length, the thorax is 1A 1B 1C short and bell shaped. A disproportionately large skull with enlarged fontanels, prominent forehead, prominent eyes, and a flat nasal bridge are characteristic features. These patients frequently have hydrocephalus, and the pregnancy is often complicated by polyhydramnios. The limbs are extremely short with overlying redundant skin folds. Radiographically, the vertebral bodies are flat with ossification defects and wide intervertebral spaces. The thorax is very narrow with short ribs that demonstrate flared anterior ends. Radiographic analysis of the long bones reveals short, broad bones with flared metaphyses. The femora are curved and have been likened to a telephone receiver (A, B). The clavicles have been described as having a shape similar to bicycle handle bars. The iliac bones are small. Histologically, the growth plate is narrow with markedly decreased proliferation. The chondrocytes are hypertrophic with disrupted columnar alignment (C). Bone formation is irregular with broad and short spicules.

NONNEOPLASTIC BONE DISEASES 

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Achondrogenesis Type 2 FIGURE 6.2  Achondrogenesis type 2 (type 2 collagen group). Achondrogenesis type 2 (LangerSaldino) is an autosomal dominant lethal skeletal dysplasia of the short-trunk type. The defect is in the collagen type II, alpha 1 (COL2A1) gene on chromosome 12q13.1 that encodes type 2 collagen. Limbs are moderately to severely short. The head is large and the abdomen is protuberant. Radiographically, the 2A 2B 2C skull is ossified and metaphyses are flared. Deficient vertebral, pubic, and ischial ossification is typical (A,B). Histologic sections exhibit a deficient cartilaginous matrix with enlarged lacunae and large, fibrous cartilage canals (C). The physeal growth plate is disorganized.

Osteogenesis Imperfecta

3A

3B

3C

3D

FIGURE 6.3  Osteogenesis imperfecta (decreased bone density group). Osteogenesis imperfecta (OI) is an inherited disorder of collagen type I that results in bone fragility. Seven types of OI have been described of varying severity, most of which are caused by a point mutation that affects a glycine residue in either COL1A1 or COL1A2. Blue or gray sclerae are noted in types I through IV (C, inset), and dentinogenesis imperfecta is present in types III and IV. OI type II is a perinatal lethal form that presents with broad, crumpled long bones with pronounced deformities, multiple congenital fractures including rib fractures, and an undermineralized calvarium (A–C). Bony trabeculae are thin and are severely lacking in ossification while chondrocyte columns remain well aligned (D).

Craniosynostosis Syndromes FIGURE 6.4  Craniosynostosis syndromes. Craniosynostosis is the premature closure of one or more cranial sutures that results in the alteration of head shape. Craniosynostosis is an isolated abnormality in most cases and has been reported in more than 100 different genetic syndromes including Alpert’s syndrome. Mutations in three FGFR genes account for most syndromic cases. Craniosynostosis is classified according to the suture that has prematurely closed (e.g., dolichocephaly refers to premature closure of the sagittal suture, and plagiocephaly refers to premature closure of unilateral coronal or lambdoidal sutures).

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n NONGENETIC NONNEOPLASTIC SKELETAL DISORDERS Osteomyelitis FIGURE 6.5  Osteomyelitis. The vast majority of cases of osteomyelitis in children arise via the hematologic route and are usually localized to the metaphyses of long bones. In all age groups, the most common organism causing osteomyelitis in children is Staphylococcus aureus. Streptococcal infections as well as gram-negative organisms are the next most prevalent causes of osteomyelitis seen predominantly in neonates, and patients with sickle cell anemia are at particular risk for Salmonella osteomyelitis. Radiographically, osteomyelitis often has an aggressive permeative 5B appearance that can mimic malignancy, notably Ewing sarcoma (A). Periosteal reactions may be seen after 10 to 14 weeks of infection. Magnetic resonance imaging (MRI) is the most sensitive modality for identifying the bone marrow edema associated with osteomyelitis. Histological sections of osteomyelitic bone reveal inflammatory infiltrates within the marrow with accompanying osteoclastic erosions of devitalized trabecular bone (B). In acute osteomyelitis, the infiltrate is largely comprised of neutrophils with loss of normal marrow fat. In chronic osteomy5A 5C elitis, the inflammatory infiltrate is predominantly lymphocytic and plasmacytic, with the presence of plasma cells being more specific for chronic osteomyelitis. Marrow fibrosis and reactive osteoblastic bone formation in the form of appositional bone growth (C, arrow) are observed in longstanding cases. Granulomatous osteomyelitis is characteristic of Mycobacterium infection. Sequestrum refers to the devitalized portion of bone in osteomyelitis, whereas involucrum describes the associated subperiosteal new bone formation surrounding the sequestrum. Surgical sequestrectomy is contraindicated in the absence of involucrum formation.

Congenital Syphilis

6A

6B

FIGURE 6.6  Congenital syphilis. Congenital syphilis remains a significant problem in some parts of the world. The characteristic radiographic skeletal findings in congenital syphilis are symmetrical metaphyseal bony erosions known as Wimberger’s sign and features of periostitis and osteochondritis. (A) reveals radiodense lines at the epiphyses (arrows) indicating osteochondritis. The periosteal and osteochondral reactions are manifested histologically by an irregular epiphyseal plate interface with accumulation of calcified matrix (B).

BONE TUMORS AND TUMORLIKE CONDITIONS 

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BONE TUMORS AND TUMORLIKE CONDITIONS n BONE-FORMING TUMORS Osteoma

7A

7B

FIGURE 6.7  Osteoma. The osteoma is a benign slow-growing bone-forming lesion that typically arises in the frontal and nasal sinuses and the outer calvarium. It is thought by some investigators to be a hamartomatous rather than a neoplastic lesion. Cortical, juxtacortical, and medullary (bone island, enostosis) types have been described. The incidence of osteomas has been reported as 0.4%, although the actual incidence may be higher, as most remain asymptomatic. Symptoms produced by larger lesions are location dependent: they may block nasal ducts, cause headache pain, or result in exophthalmos. Plain films demonstrate an ivorylike sclerotic mass attached to the bone. Borders are well-defined and noninvasive. Grossly, osteomas are dense and compact bony masses adjacent to the underlying cortex (A), and histological sections display a thick mass of mature lamellar bone with decreased marrow, similar in morphology to compact cortical bone (B). Osteomas are associated with Gardner syndrome, an autosomal dominant disorder characterized by multiple sebaceous cysts or skin fibromas, desmoid tumors, and intestinal polyposis. Most osteomas require no treatment and do not recur if excised surgically. Differential diagnoses include parosteal osteosarcoma, osteochondroma, and periosteal osteoblastoma.

Osteoid Osteoma FIGURE 6.8  Osteoid osteoma. Osteoid osteoma is a benign osteoid-forming tumor of the bone that has a distinct male predilection (2:1). It usually appears during the first 2 decades of life, and comprises approximately 12% of all benign bone tumors. The long bones are the most common location (70% to 80% of cases), especially the femur, tibia, and humerus. The tumor forms a discrete bony nidus that is surrounded by sclerotic bone. The classical clinical presentation is that of localized pain that worsens at night and is promptly relieved by salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs). It is thought that the nocturnal pain is secondary to prostaglandins produced by the vascular capillary network and by the presence of numerous unmyelinated nerve fibers within the osteoid osteoma stromal tissue.   Plain films demonstrate an area of sclerosis with a central lucency that corresponds to the nidus (A, arrow). The lesion may arise in a cortical, 8A 8B medullary, or subperiosteal location. Computed tomography (CT) is the definitive study for osteoid osteomas, and scintigraphy is extremely sensitive in identifying the highly vascular nidus (B, arrow; arrowhead indicates the epiphyseal plate). The nidus of osteoid osteoma is a rounded soft and granular or hard and gritty mass measuring less than 1 cm in greatest dimension. It is often pink or cherry red in color, reflecting its stromal vascularity (C, arrow). Microscopically, the nidus is a well-demarcated mass composed of interlacing and irregular trabeculae of osteoid and woven bone within a fibrovascular stroma rich in capillaries, surrounded by reactive and sclerotic bone (D). Osteoblastic rimming of the trabeculae is a characteristic finding (D, inset). Surgical removal of the nidus is curative and results in immediate relief. This can be accomplished by “shelling out” of the nidus, or by en bloc resection or curettage. Pain may persist if any part of the nidus remains. The differential diagnoses include stress fracture, bone island (enostosis), and osteoblastoma. Source: (C) Courtesy of M. John Hicks, MD, Texas Children’s Hospital. (Continued)

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8D

8C

FIGURE 6.8  Osteoid osteoma. (Continued)

Osteoblastoma Osteoblastoma is similar to osteoid osteoma in many respects. It is a benign osteoid and bone-forming tumor that resembles osteoid osteoma histologically. However, the clinical and radiographic picture as well as the location can help to differentiate these two lesions. Osteoblastoma accounts for approximately 3% of benign bone tumors. Although the long bones may be affected, it has a predilection for the vertebral bones. The patients may experience localized pain, but unlike those with osteoid osteoma, the pain is not characteristically nocturnal nor does it respond consistently to aspirin. Osteoblastoma usually presents within the first 2 decades of life, although aggressive forms can be seen in older patients (average age of 33 years). A comparison of clinical and pathologic features of osteoid osteoma and osteoblastoma is highlighted in Table 6.2. Osteoblastoma may have a radiographic appearance similar to that of osteoid osteoma although the nidus, if present, is larger (usually greater than 2 cm) and more irregular in shape. Like osteoid osteoma, a periosteal reaction can be prominent, but a lesser degree of reactive sclerosis is exhibited. A radiographic picture typical of vertebral osteoblastomas is that of a blown-out lesion similar to an aneurysmal bone cyst (ABC). In addition, osteoblastoma may display an aggressive imaging pattern simulating a malignant bone tumor. Microscopically, it is strikingly similar to osteoid osteoma with only subtle differences (Table 6.2). Osteoblastomas tend to be progressive destructive lesions with aggressive forms described; therefore, surgical removal is required. Curettage with allograft implantation is sufficient for nonaggressive tumors. Differential diagnoses include osteoid osteoma, bone abscess, and osteosarcoma.

TABLE 6.2  Comparison of Osteoid Osteoma and Oteoblastoma OSTEOID OSTEOMA

OSTEOBLASTOMA

Age

5–20 years

10–30 years

Common location

Long bones

Vertebral column

Clinical presentation

Progressive pain, worse at night, NSAID relief

Pain less localized, fewer relieved by NSAIDs

Nidus

Rounded nidus (,1 cm), 3–6 cm, surrounded by reactive sclerotic bone

Less well-defined margins, 2–11 cm, less associated r­ eactive sclerotic bone

Characteristic histologic features

Peripheral m ­ aturation seen in the nidus

Peripheral maturation not c­ haractertistic Trabeculae more disorganized Stroma more vascular Enlarged osteoblasts in a ­ ggressive forms

Clinical course

Nonprogressive or regressive

Progressive, aggressive

Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

BONE TUMORS AND TUMORLIKE CONDITIONS 

Osteosarcoma FIGURE 6.9  Osteosarcoma. Osteosarcoma is the most common primary malignant bone tumor in children. It is an osteoid and/or bone-forming tumor that occurs most commonly in the rapidly growing regions of bone in adolescents, especially the distal femur and proximal tibia. Persistent bone pain is the usual presenting symptom, and serum alkaline phosphatase may be elevated. Risk factors related to the development of osteosarcoma include rapid bone growth adjacent to the epiphyseal plate, previous radiation exposure, genetic predisposition to the Li-Fraumeni or Bloom syndrome, and mutations in genes associated with osteosarcoma. The requisite diagnostic feature of osteosarcoma that distinguishes it from all other bone- and osteoidforming tumors is the presence of malignant cells forming osteoid. 9A 9B This is an essential distinction, as almost all bone tumors have some degree of associated reactive bone formation that must be discriminated from osteosarcoma histologically. Various anatomic and histological subtypes of osteosarcoma exist, to be described in the following pages.   Radiographic features of conventional osteosarcomas are variable, and reflect the location, extent, and predominant matrix of the tumor. The lesion is usually poorly defined. Periosteal reactions are commonly seen in response to cortical penetration, typically in the form of a Codman’s triangle with periosteal lifting (A) or a “sunburst” pattern. The matrix may be variably sclerotic and lytic, depending upon the amount and location of osteoid and bone formation. Sclerosis extending into soft tissues is indicative of and specific for osteosarcoma. Although plain films remain a valuable modality in the evaluation of osteosarcomas, MRI and CT better delineate the tumor extent.   The gross appearance of conventional osteoblastic osteosarcoma is also variable. Most conventional osteosarcomas are metaphyseal in location. If the tumor is predominantly osteoblastic, the tumor can resemble cortical bone grossly and may contain fleshy areas. A prominent chondroid matrix imparts a blue-gray appearance reminiscent of cartilage. Penetration of the cortex by the tumor may be apparent grossly, often with an adjacent soft tissue mass (B). The epiphyseal plate may be penetrated as well. Skip lesions are identified in up to 15% of patients. Source: (B) Courtesy of M. John Hicks, MD, Texas Children’s Hospital.

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Conventional Osteosarcoma

10A

10B

10C

10D

FIGURE 6.10  Conventional osteosarcoma. Conventional osteosarcoma, the most common type of osteosarcoma, arises within the medullary cavity of bone and progresses to cortical penetration and soft tissue invasion. These tumors are highgrade histologically and are characterized as osteoblastic, chondroblastic, or fibroblastic, depending on the predominant tumor matrix and cellular background. The malignant osteoid-producing cells in conventional osteosarcoma are atypical, pleomorphic, and hyperchromatic histologically. Osteoid deposition is usually lacelike and trabecular bone formation is unusual (A). Bizarre cells with many atypical mitoses may be observed (B). Osteosarcoma, by definition, must have at least a small focus of osteoid/bone formation by the malignant cells, regardless of the prominent background tissue element. (C) depicts a chondroblastic osteosarcoma with malignant cartilage and adjacent malignant osteoid formation. Osteosarcoma nuclei may be small or inconspicuous in osteosclerotic areas (D), but permeation of marrow spaces discloses the tumor’s malignant nature. Benign reactive bone, in contrast to osteosarcoma, demonstrates trabecular formation with osteoblastic rimming.   A large variety of karyotypic abnormalities have been described in osteosarcoma, including gain of regions of chromosome 1 and loss of regions of chromosomes 6, 9, 10, 13, and 17. Mutations of the Rb and p53 genes occur in osteosarcoma, as well as abnormal expression of the c-jun, c-fos, c-myc, and H-ras oncogenes. The c-fos oncogene is known to play a role in bone and cartilage differentiation. These genetic and molecular abnormalities are thought to be related to osteosarcoma pathogenesis.   Prognostic factors in osteosarcoma are numerous and include grade, location, type, and size of the tumor. Increased expression of the urokinase plasminogen activator and receptor (uPA/PAR) is associated with osteosarcoma progression and the presence of p-glycoprotein (encoded by the multidrug resistance [MDR] gene, MDR1) is considered an adverse prognostic factor.   Osteosarcoma commonly metastasizes via the hematogenous route to the lungs. It is thought that pulmonary micrometastases already exist at the time of presentation in most cases, and approximately 20% of children with osteosarcoma present with detectable metastases. Current treatment of high-grade osteosarcoma consists of diagnostic biopsy followed by neoadjuvant chemotherapy with subsequent surgical resection. Pathologic evaluation of the postchemotherapy resection specimen includes the assessment of tumor necrosis versus residual viable tumor. Differential diagnoses include aggressive osteoblastoma (osteoblastic osteosarcoma) and chondrosarcoma (chondroblastic osteosarcoma).

BONE TUMORS AND TUMORLIKE CONDITIONS 

111

Osteosarcoma Variants

11b

FIGURE 6.11  Osteosarcoma variants. A rare but important type of osteosarcoma that must be differentiated from aneurysmal bone cyst (ABC) grossly and radiographically is the telangiectatic osteosarcoma, 11A which represents 3% of osteosarcomas. This type of osteosarcoma, like ABC, presents as a destructive, purely lytic lesion at the distal end of the bone. Fluid–fluid levels may be detected on MRI. Grossly, hemorrhagic areas and cystic spaces filled with blood are evident (A). Although they may resemble the septa of ABC on low-power microscopy (B), high-power evaluation of telangiectatic osteosarcoma septa reveals cells that are histologically malignant and high-grade (B, inset).   Other histological variants of osteosarcoma include giant cell-rich osteosarcoma and small cell osteosarcoma. Small cell osteosarcoma is a rare variant (less than 1% of osteosarcomas) that resembles Ewing sarcoma histologically, and is comprised of small round blue cells within a lacelike osteoid matrix. CD99 can be positive in these tumors, so the absence of a t(11:22) distinguishes it from Ewing sarcoma/primitive neuroectodermal tumor (PNET). Periosteal osteosarcoma, parosteal osteosarcoma, and high-grade surface osteosarcoma are rare types of osteosarcoma that arise on the periosteal surface of the affected bone and together comprise 5% to 10% of osteosarcomas. Other osteosarcoma variants exist, but these do not typically present in the pediatric population.

n CARTILAGE-FORMING TUMORS Osteochondroma and Multiple Osteochondromas

12A

12B

12C

FIGURE 6.12  Osteochondroma and multiple osteochondromas (MO). Osteochondroma, also known as osteocartilaginous exostosis, is the most common bone tumor in children, comprising 58% of childhood bone tumors with a slight male predominance. Osteochondromas are exophytic bony lesions that may be pedunculated or sessile. They occur most often in the long bones, but can arise in any bone that undergoes endochondral ossification, such as the scapula and iliac crest. Osteochondromas were thought to be the result of a benign epiphyseal developmental abnormality, but are now believed to represent a neoplastic process. Like the epiphyseal plate, osteochondromas are composed of a cartilaginous components in the form of a cartilaginous cap that exhibits endochondral-type ossification. It is thought that osteochondromas form adjacent to the epiphysis of the attached bone, and as the long bones grow, their location becomes progressively more diaphyseal. Their growth halts with the onset of skeletal maturity. A lthough exostoses are usually solitary, they can be multiple and hereditary, as seen in the syndrome of MO, also known as multiple hereditary exostoses. This syndrome is inherited in an autosomal dominant fashion with variable penetrance and can result in skeletal deformity and short stature. Plain films reveal a bony exostosis that exhibits cortical continuity with the attached bone and a medullary cavity contiguous with that of the underlying bone (A, arrow). Osteochondromas vary in size from 1–2 cm in greatest dimension to large sessile masses of 15–20 cm. The cartilaginous cap covers the distal end of the exostosis. It is gray-blue and glistening, and measures up to a few millimeters in thickness (B). (Continued)

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FIGURE 6.12  Osteochondroma and multiple osteochondromas (MO). (Continued) Osteochondromas resemble the epiphyseal plate microscopically: the cartilaginous cap contains chondrocytes arrayed in columns, and ossifies to form mature trabecular bone within the underlying stalk (C). Occasional binucleated cartilaginous lacunae can be identified, which are not a worrisome feature in young patients. The cortex of the stalk is covered by periosteum. Exostoses from MO are similar pathologically to solitary osteochondromas, except that they are often larger and can show increased numbers of binucleated chondrocytes. Mutations in the EXT1 and EXT2 tumor suppressor genes, located on chromosomes 8q24 and 11p11–p12, respectively, have been implicated in MO. These mutations are localized to the cartilaginous cap, indicating that the cartilage is neoplastic while the bony stalk is reactive. The protein products of these genes are involved in growth-signaling pathways within the epiphyseal growth plate. Surgical excision is not necessary unless the osteochondroma produces discomfort or deformity. Recurrence after surgical excision is unusual if the cartilaginous cap is completely removed. The incidence of malignant transformation in solitary osteochondromas is exceedingly rare. MO, on the other hand, have a significant incidence of malignant transformation (1% to 5%) that usually occurs after skeletal maturity. Therefore, MO should be closely monitored in older patients for increasing size and thickness of the cartilaginous cap (greater than 1–2 cm), both of which are worrisome for sarcomatous transformation.

Enchondroma/Enchondromatosis

13A

13B

FIGURE 6.13  Enchondroma/enchondromatosis. Enchondromas are benign tumors of mature hyaline cartilage that arise predominantly in the small tubular bones of the hand, but can be located in the large tubular bones as well. Enchondromas are the second most common bone tumor in children, representing 24% of all bone tumors in this age group. Clinical presentation is that of local pain and/or swelling or pathologic fracture in some cases. Enchondromas are usually solitary, but syndromes of multiple enchondromas (also known as dyschondroplasia) exist. Ollier disease is a disorder of abnormal ossification of growth plate cartilage, resulting in persistent cartilaginous rests that continue to grow in size to occupy the spongiosa. When multiple enchondromas are associated with skin or soft tissue hemangiomas, the condition is termed Maffucci syndrome. Patients with multiple enchondromas present at an earlier age than those with solitary enchondromas, and because of their initial proximity to the growth plates, multiple enchondromas can cause significant shortening and skeletal deformity. Radiographically, enchondromas are well-defined and radiolucent lesions situated within the medullary cavity of the metaphyseal or diaphyseal bone, as illustrated here in the radius of a young patient (A). Cortical penetration is not seen. Enchondromas may result in cortical expansion and thinning with endosteal scalloping, reflective of lobulation. Stippled calcification within the enchondroma may be evident, a feature characteristic of cartilage-forming tumors. Grossly, enchondromas are lobulated, glistening, and gray-blue, indicative of their cartilaginous nature. Microscopically, they resemble lobulated masses of mature and benign cartilage with variable cellularity. Chondrocytes are arrayed within a bluish cartilaginous matrix. Although no significant nuclear atypia is appreciated, occasional binucleated chondrocytes, as well as increased cellularity may be observed, especially in the bones of the extremities in children. These are not considered to be worrisome features in this context (B). Active enchondromas in children may also display occasional mitotic figures. It is difficult if not impossible to distinguish an active enchondroma from a low-grade chondrosarcoma histologically. Features that suggest benignancy in enchondroma have been described as nodules of cartilage separated by areas of marrow fat (“benign islands of cartilage pattern”) and nodules of cartilage with partial to complete encasement by plates of lamellar bone (“endochondral encasement pattern”). Enchondromas of Ollier disease or Maffucci syndrome tend to be more cellular with more binucleated cells than their solitary counterparts. Several karyotypic abnormalities have been reported in Ollier disease: a deletion of 9p has been noted, which may indicate involvement of the CDKN2A tumor suppressor gene. A mutation has also been reported in the PTH/PTHrP type I receptor. Malignant transformation in solitary enchondromas is very rare. In contrast, multiple enchondromas have a considerable malignant transformation rate, reported to be as high as 15% to 30% in Ollier disease and 20% to 30% in Maffucci syndrome. Those with multiple enchondromas should be monitored closely for rapid growth of the tumors that would signal concern for transformation to chondrosarcoma. MRI is the best modality for this evaluation, as it can identify cortical penetration and soft tissue extension. Biopsy is not recommended for this purpose.

BONE TUMORS AND TUMORLIKE CONDITIONS 

113

Chondroblastoma

14C

FIGURE 6.14  Chondroblastoma. Chondroblastoma is a benign cartilage-forming tumor that typically involves the long bone epiphyses of skeletally immature patients. It has a male predominance (2:1) and 14A 14B comprises 1% of all bone tumors. It is well-circumscribed radiographically, often with a sclerotic margin, as seen in this MRI of a femoral epiphysis in a young patient (A, arrow). Chondroblastomas are lytic lesions that may show central radiodensities typical of chondroid tumors. Histologically, they are comprised of characteristic mononuclear immature cartilage cells (chondroblasts), lobules of benign cartilage, and scattered giant cells (B). The chondroblasts are round to oval with bland-appearing nuclei, many of which demonstrate nuclear grooves (C, inset). Linear pericellular calcifications are often present and are referred to as “chicken wire” calcifications. Chondroblastomas can be keratin positive. Although karyotypic abnormalities have been identified, no recurrent chromosomal aberrations have been described. Thorough curettage with bone grafting is the treatment of choice. It is speculated that the higher risk of recurrence observed in the pediatric population (32%) may be related to surgical concerns of performing extensive curettage in close proximity to an open physis. Although chondroblastoma is considered to be a benign lesion, rare aggressive forms have been reported. Differential considerations are giant cell tumor, clear cell chondrosarcoma, and chondromyxoid fibroma (CMF).

Chondromyxoid Fibroma

15B

15A

15C

FIGURE 6.15  Chondromyxoid fibroma (CMF). CMF is a rare benign neoplasm that, as the name implies, is comprised of chondroid, myxoid, and fibrous components. It can arise in any bone but is most often located in the long bones. It can occur in patients of any age, but is most common in children and adolescents. The radiographic appearance of CMF is that of a radiolucent lesion with well-­defined, scalloped, and sclerotic margins (A). Grossly, the tumor is well-circumscribed with a blue-white glistening and lobulated cut surface (B). Microscopic sections reveal characteristic cartilaginous lobules with a myxoid matrix. Benign fibrous tissue admixed with scattered giant cells is located at the periphery of the lobules (C). The chondroid cells are spindle to stellate in shape and may be mildly atypical. Mitoses and necrosis are not present. Aberrations of several regions of chromosome 6, including the 6q13 region (which maps to the COL12A1 locus) have been described in CMF. They are benign lesions that are treated with extensive curettage and bone grafting. Recurrences have been reported. Myxoid chondrosarcoma is the main differential diagnosis. Source: (B) Courtesy of M. John Hicks, MD, Texas Children’s Hospital.

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Mesenchymal Chondrosarcoma

16A

16B

FIGURE 6.16  Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma is a rare malignant cartilage-forming tumor with a small round blue cell component that arises predominantly in the craniofacial bones, jaw, and long bones of teenagers and young adults. The vertebrae, ribs, and pelvis are also common sites of involvement. Although rare, this entity is important to consider in the differential diagnosis of small round blue cell tumors of bone such as skeletal Ewing/PNET and small cell osteosarcoma, as all three of these tumors stain positively for CD99. Radiographically, this tumor presents as a destructive, radiolucent lesion with stippled calcifications, indicative of its chondroid matrix. Grossly, mesenchymal chondrosarcomas are variably mineralized and may have a glistening cut surface in areas of cartilage formation as seen in this mesenchymal chondrosarcoma of the rib (A). The characteristic histologic feature that distinguishes this tumor from other small round blue cell tumors of bone is the presence of a low-grade cartilaginous component, which may be quite prominent (B), and stains with S100. Cartilaginous differentiation may be present in small cell osteosarcoma, but these foci are usually high-grade. A hemangiopericytomatous vascular pattern is often evident in the small round blue cell component but may be inconspicuous or absent in some cases. Like conventional chondrosarcomas, metastases often appear late in the course, and surgical excision is the primary treatment.

n CYSTIC BONE LESIONS Solitary Bone Cyst FIGURE 6.17  Solitary bone cyst (SBC). SBCs, otherwise known as unicameral bone cysts (UBCs), occur most often in children between the ages of 9 and 15 with a distinct male predominance (3:1). The usual clinical presentation is that of mild pain and swelling. Pathologic fractures are common. These cysts have a predilection for the proximal humerus and proximal femur and consist of a unilocular fluid-filled cavity within the medulla of long bones with thinning of the associated bony cortex. The cyst fluid is typically clear and straw-colored unless pathologic fracture with hemorrhage has rendered the fluid bloody or brown. The etiology of this entity is unknown; because it arises immediately beneath the epiphyseal plate, venous obstruction caused by a developmental abnormality has been proposed as a causative factor. SBCs that are located in direct continuity with the growth plate are considered “active,” whereas those separated from the epiphyseal plate by cancellous bone are considered to be “inactive.”   Plain films demonstrate a purely lytic lesion with thinning and inflating of the adjacent cortex (A). There is usually no periosteal reaction except when pathologic fracture has occurred. Curettings are the most common surgical specimens received. Fragments of the thinned cortex surrounding the cyst may be identified grossly as well as portions of the membranous cyst wall that may display a smooth or trabeculated lining (B). Sections of active SBCs reveal a thin membrane comprised of mesenchymal cells, capillaries, scattered osteoclast-type giant cells, a few osteocytes, and little or no hemosiderin. Osteoid or bone formation may be evident. Inactive SBCs have thicker membranes, more frequent giant cells, hemosiderin deposition, and cholesterol clefts. A histologic feature characteristic of SBCs is the ribbonlike fibrinous material within the cyst wall (C).   Treatment modalities are aimed at obliterating the cyst and strengthening the bone. Curetting, allogeneic bone grafting, and steroid injections have been used with good results. Complete healing has been reported in 46% and 41% of grafted versus steroid-injected patients, respectively. The main differential diagnosis is ABC. Source: (B) Courtesy of M. John Hicks, MD, Texas Children’s Hospital. (Continued) 17A

BONE TUMORS AND TUMORLIKE CONDITIONS 

17B

115

17C

FIGURE 6.17  Solitary bone cyst (SBC). (Continued)

Aneurysmal Bone Cyst FIGURE 6.18  Aneurysmal bone cyst (ABC). ABC is a locally destructive cystic bone lesion composed of multiple septated blood-filled cavities lined by connective tissue. The most common locations are the metaphyses of long bones and the vertebrae. ABC can occur at any age, but presents most commonly in the first and second decades of 18B life with a female predilection. In one third of cases designated as “secondary ABC,” the ABC arises in association with other bone tumors such as giant cell tumor or fibrous dysplasia (FD). Primary ABCs appear to be more common in children, whereas secondary ABCs may account for more than 50% of adult cases. Presenting symptoms of both include pain, swelling, tender mass, and pathologic fracture. Like SBC, the precise etiology of ABC is unknown, but there has been much speculation. One hypothesis is that ABC is caused by a local alteration in hemodynamics resulting in markedly increased venous pressure with vascular 18A 18C dilatation and proliferation of reactive osteoblastic tissue.   A recurrent chromosomal translocation t(16;17)(q22;p13) has been reported in primary ABCs that fuses the promotor region of the osteoblast cadherin 11 gene (CDH11) to the coding sequence of the ubiquitin protease gene (USP6). These findings indicate that primary and secondary ABCs are distinct lesions, the former being a neoplastic process and the latter representing a reactive phenomenon. ABCs are expansile osteolytic lesions that inflate the periosteum with associated cortical destruction. Pathologic fracture is frequently seen, as demonstrated in this radiograph (A). The characteristic gross appearance is that of multiple septated blood-filled cavities (B). Microscopically, the thin septa contain mesenchymal tissue, osteoclast-type giant cells, and osteoblasts. Blood-filled spaces that are not endothelial-lined are characteristic (C). Like SBC, osteoid and bone formation may be evident within the cyst wall. In some cases of ABC, the tumor may be predominantly solid (“solid variant of ABC,” or “giant cell reparative granuloma”).   The preferred treatment option is curettage with bone grafting. Surgical resection or excision is indicated for cysts in locations that do not interfere with function. These lesions have a propensity to recur after curettage, with more frequent recurrences seen in younger patients and in active or aggressive lesions. ABC must be differentiated from SBC, giant cell tumor, brown tumor, and telangiectatic osteosarcoma.

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n FIBROUS AND OSTEOFIBROUS BONE LESIONS Nonossifying Fibroma/Metaphyseal Fibrous Defect FIGURE 6.19  Nonossifying fibroma(NOF)/ metaphyseal fibrous defect (MFD). Nonossifying fibroma (NOF) is a benign fibrous lesion of bone usually seen in young patients less than 20 years of age. It is most commonly located in the metaphysis of long bones. Some investigators consider this tumor to represent a developmental abnormality rather than a neoplasm, although clonal karyotypic abnormalities have been reported. Metaphyseal fibrous defect (MFD) and NOF represent the same entity, differentiated by location and size. MFD, as the name implies, is located within the cortical metaphysis of the long bones. MFDs are very common in skeletally immature children with an estimated incidence of 30% to 40%. Most are less than 2 cm in size. Larger lesions involving the medullary cavity are referred to as NOF. NOF has a significant incidence of pathologic fracture that is often the presenting symptom. MFD and NOF are 19A 19B identical histologically and share a common natural history.   Plain films of MFD and NOF show a well-demarcated, cortically based lucent lesion with a sclerotic, often scalloped rim. Pathologic fracture, as seen in (A), is common in larger tumors. Sections of both MFD and NOF reveal a spindle cell lesion arranged in a storiform pattern with scattered multinucleated giant cells (MNGC) (B). Nuclei are bland appearing and mitotic figures are absent or minimal. In some cases, clusters of foamy histiocytes are observed, which impart a bright yellow color to the tissue grossly. Although spicules of reactive bone formation are frequently noted within the tumor sections, the lesion is predominantly fibrous unlike FD and osteofibrous dysplasia (OFD) that are fibro-osseous.   MFDs are asymptomatic and usually regress. Most NOFs regress as well; however, if symptomatic, curettage and autograft/allograft packing can be undertaken. There is an association between multiple NOFs and neurofibromatosis, cherubism, and Jaffe-Campanacci syndrome. Differential diagnosis includes OFD, FD, and benign fibrous histiocytoma of bone.

Fibrous Dysplasia FIGURE 6.20  Fibrous dysplasia (FD). FD is a benign fibro-­osseous lesion (BFOL) that can occur in any bone, but has a predilection for the craniofacial and long bones. It usually appears in patients younger than 30 years and affects both genders equally. Monostotic and polyostotic forms are seen. FD is a component of the McCune-Albright syndrome triad (FD, abnormal skin pigmentation, precocious puberty). Mutations of the signal-transducing G-proteins, which have been implicated in the etiology of McCune-Albright syndrome, are thought to play a possible role in the pathogenesis of FD itself.   Plain films of FD characteristically show a ground-glass appearance with expansion of bone (A, arrow). Margins tend to be indistinct with widespread involvement in some cases. Shepherd’s crook deformity of the proximal femur is seen in advanced disease. (B) shows marked maxillary deformity secondary to FD. FD is composed histologically of curved bony trabeculae within a benign cellular fibrous stroma. The trabecular shapes have been described as “slender and curled” and “letters of the alphabet,” especially “C-shaped” (C). Osteoblastic rimming is absent or inconspicuous (C, inset), and for this reason, the bone formation in FD has been termed fibro-osseous metaplasia. The stromal tissue may be variably cellular as well as variably collagenous.   Although sporadic chromosomal aberrations have been observed, no characteristic cytogenetic abnormalities have been described.   Treatment may not be required in solitary lesions of FD, and the prognosis is excellent. Sarcomatous transformation is a very rare complication. Differential diagnosis encompasses other fibrous and fibro-osseous tumors, and osteosarcoma. (Continued)

20A

BONE TUMORS AND TUMORLIKE CONDITIONS 

20B

117

20C

FIGURE 6.20  Fibrous dysplasia (FD). (Continued)

Osteofibrous Dysplasia

21A

FIGURE 6.21  Osteofibrous dysplasia (OFD). OFD is one of the BFOLs of bone. It is a rare tumor composed of bony trabeculae situated within a benign fibrous stroma. OFD is located almost exclusively in the tibia and fibula of children within the first decade of life. It is similar in morphology to the ossifying fibroma of the orofacial bones but is distinct histologically and cytogenetically, as illustrated in Table 6.3. It is thought that OFD shares a common histogenesis with adamantinoma of the long bones. Positive staining for cytokeratin is seen in 80% of OFD cases and by definition, the 21B epithelial cells are not readily identifiable on hematoxylin and eosin (H&E)-stained sections. If, however, epithelial differentiation is clearly visible on H&E-stained sections, the tumor should be designated as “OFD-like adamantinoma” (OFD/LA).   Well-demarcated lytic lesions with surrounding sclerosis characterize OFD radiographically. Anterior tibial bowing may be seen (A). Grossly, OFD is a well-circumscribed tan mass ranging in size from 4 to 8.5 cm in greatest dimension. Microscopically, curved woven bony trabeculae are situated within a bland fibrous stroma. The histologic hallmark of OFD that distinguishes it from FD is the presence of conspicuous osteoblastic rimming (B). Unlike ossifying fibroma, cementicles are not observed in OFD. OFD, OFD/LA, and adamantinoma are thought to represent a spectrum of the same disease process, distinguished by the quantity of epithelial differentiation; most OFDs are cytokeratin positive, emphasizing this relationship.   Extraperiosteal excision is recommended, as curettage may result in a high rate of recurrence. There is an established risk for OFDs to progress to OFD/LA or adamantinoma, a far more aggressive lesion than OFD. Ossifying fibroma, FD, and OFD/LA are the primary differential considerations.

TABLE 6.3  Comparison of Fibrous and Fibro-osseous Bone Lesions

Location

NONOSSIFYING FIBROMA

FIBROUS DYSPLASIA

OSTEOFIBROUS DYSPLASIA

OSSIFYING FIBROMA

Metaphysis of long bones

Craniofacial bones, femur, tibia

Tibia and fibula almost ­exclusively

Orofacial bones

Radiographic Radiolucent appearance Well-demarcated Scalloping border Sclerotic margin

“Ground glass” appearance Radiolucent Indistinct margins Well-demarcated Widespread involvement Sclerotic margin

Radiolucent Well-­demarcated Thin, sclerotic margin Some with ­central radiopacity

Distinctive ­histologic ­findings

Predominantly fibrous Storiform pattern Foamy histiocytes may be present

Osteofibrous Slender curved bony trabeculae Absent or ­inconspicuous osteoblastic r­ imming

Osteofibrous Curved bony trabeculae ­Osteoblastic rimming ­present Cementicles

Cytogenetic ­findings

Karyotypic abnormalities Karyotypic ­abnormalities observed observed

Osteofibrous Curved bony trabeculae Osteoblastic rimming present Zonal ­architecture Keratin positive in many cases

Extra copies of chromosomes t(X;2)(q26;q33) 7, 8, 12, and/or 21 reported

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n SMALL CELL TUMORS AND MARROW CELL TUMORS Ewing Sarcoma/Primitive Neuroectodermal Tumor

22A

22B

22E

22C

22D

22F

FIGURE 6.22  Ewing sarcoma/primitive neuroectodermal tumor (PNET). Ewing sarcoma and PNET are small round blue cell tumors of childhood that belong to the Ewing family of tumors. They constitute the second most common malignant bone tumor of adolescents and children after osteosarcoma and demonstrate a slight male predominance (1.3:1). Ewing sarcoma and PNET share the same translocation, a similar histology, and uniform immunohistochemical staining characteristics. The two tumors represent different ends of a spectrum of neuroectodermal differentiation and may be either skeletal or extraskeletal. The most frequent skeletal locations include the pelvis (26%), femur (20%), tibia/fibula (18%), and chest wall (16%), although any bone may be involved. Thoracopulmonary tumors (Askin tumors) are also members of the Ewing family of tumors (A). Unlike osteosarcomas that tend to occur in the metaphysis, Ewing sarcoma most often arises in the diaphysis of the long bones. A distinct racial distribution of Ewing sarcoma/PNET is noted: the tumor occurs most commonly in Caucasians, is less frequent in Asians and Hispanics, and is practically absent in those of African descent. The presenting symptom is often localized pain that may be intermittent. Low-grade fevers, fatigue, leukocytosis, and elevated erythrocyte sedimentation rates (ESR) may be detected in advanced or metastatic disease, findings which may be mistaken for osteomyelitis. The pathogenesis of these tumors is related to their consistent chromosomal translocation that connects the EWS gene to the ETS family of transcription factors resulting in cell proliferation, as discussed further in the following.   Plain films demonstrate a large osteolytic tumor in a diaphyseal location with extensive permeative bone destruction. A classic radiographic presentation of Ewing sarcoma is that of an “onion skin” or lamellar periosteal reaction (B). Cortical destruction and soft tissue penetration are usual, best illustrated on CT and MRI. Grossly, the tumor is a soft and gray-white mass infiltrating the medullary cavity with yellow-tan areas of cystic necrosis, simulating suppurative osteomyelitis grossly. Compact sheets, strands, or lobules of small uniform tumor cells are seen microscopically. Tumor necrosis is characteristically seen at a distance from blood vessels (C). The cytoplasm is often clear with indistinct cytoplasmic outlines and no matrix production. Nuclei are round with dispersed chromatin and inconspicuous nucleoli. Scattered mitoses are identified (D). Pseudorosette formation may be observed, the degree of which differentiates Ewing sarcoma and PNET histologically. Periodic acid-Schiff (PAS) stain is usually positive because of the high content of intracytoplasmic glycogen (E). CD99 (MIC2) immunohistochemical stain is strongly positive in almost all Ewing sarcoma/PNETs (F). This stain is highly sensitive but not entirely specific, because it can also be positive in lymphoblastic lymphoma, small cell osteosarcoma, rhabdomyosarcoma, and mesenchymal chondrosarcoma. An immunohistochemical battery to rule out other small round blue cell tumors of childhood should include MyoD1 and/or myogenin, leukocyte common antigen (LCA), and neuron-specific enolase (NSE) and/or synaptophysin. (Continued)

BONE TUMORS AND TUMORLIKE CONDITIONS 

FIGURE 6.22  Ewing sarcoma/primitive neuroectodermal tumor (PNET). (Continued) Nearly all Ewing sarcoma/ PNETs harbor one of five chromosomal translocations that underlie their pathogenesis (Table 6.4). In all of these instances, the translocation involves the EWS gene on chromosome 22q12 and genes from different members of the ETS family of transcription factors. Increased transcription activation by EWS may inactivate INK4, a locus that encodes the cell cycle inhibitor CDKM2A, or it may downregulate the tumor suppressor transforming growth factor-b type II. Reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in-situ hybridization (FISH) can be used to identify these translocations.   Treatment begins with neoadjuvant multiagent chemotherapy. Further treatment depends on the stage of the disease: surgical resection for localized disease responsive to chemotherapy and salvage chemotherapy with possible radiation therapy or surgery in metastatic or recurrent disease. Up to one-third of patients present with metastases, and their prognosis is poor despite aggressive chemotherapy. Other prognostic factors include the percentage of postchemotherapy tumor necrosis (the grading system is similar to that of osteosarcoma), and various biologic factors, such as mutations in INK4a gene, p53 mutations, and aneuploidy. Survival rates in nonmetastatic disease are as high as 60% to 80%.   Other small round blue cell tumors of childhood that may involve the bone must be ruled out: leukemia/lymphoma, embryonal and alveolar rhabdomyosarcoma, synovial sarcoma, small cell osteosarcoma, metastatic neuroblastoma, and mesenchymal chondrosarcoma. Source: (A) Courtesy of M. John Hicks, MD, Texas Children’s Hospital. TABLE 6.4  Translocations Seen in Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET) TRANSLOCATION

BREAKPOINTS

PERCENTAGE OF CASES

EWS-FLI-1

t(11;22)(q24;q12)

85%

EWS-ERG

t(21;22)(q24;q12)

5–8%

EWS-ETV1

t(7;22)(p22;q12)

,1%

EWS-E1AF

t(17;22)(q12;q12)

,1%

EWS-FEV

t(2;22)(q33;q12)

,1%

Langerhans Cell Histiocytosis of Bone

23A

23B

FIGURE 6.23  Langerhans cell histiocytosis of bone (LCH). LCH is a disorder of unknown etiology that is characterized by a clonal proliferation of dendritic cells. Debate exists as to whether LCH represents a reactive disorder of immune dysfunction or a neoplasm, although X chromosome studies suggest a clonal nature. The disease can be solitary (eosinophilic granuloma), multifocal, disseminated (Letterer-Siwe disease), or associated with cranial lesions, diabetes insipidus, and exophthalmos (Hand-SchullerChristian disease). LCH has a peak incidence of 1–4 years of age and is most commonly located in the bone. The skull is the bone most frequently affected, followed by the femur, tibia, scapula, rib, mandible, and vertebrae.   Plain films in LCH have various appearances, including well-defined oval punched-out lesions to large and poorly defined permeative lesions. This x-ray film shows the skull of an infant with an oval lytic lesion in the occipital region (A, arrow). Grossly, LCH is red-tan, friable, and hemorrhagic appearing, resembling granulation tissue. A polymorphous population of cells is appreciated histologically, including Langerhans cells, eosinophils (often abundant), lymphocytes, plasma cells, macrophages, and giant cells. The Langerhans cells are large and ovoid with abundant cytoplasm and irregular lobulated or indented nuclei with nuclear grooves (B). Langerhans cells stain with CD68, but unlike regular macrophages, they also stain with S100 and CD1a (B, inset upper right). The presence of Birbeck granules ultrastructurally is pathognomonic (B, inset lower right).   In general, conservative treatment is undertaken in LCH. Solitary bone lesions may spontaneously regress and curettage can be curative. Chemotherapy is reserved for systemic disease with organ dysfunction. The most important adverse prognostic factors are young age at presentation (,2 years) and extensive organ involvement. Although the overall prognosis is excellent for LCH without systemic involvement, recurrence is a concern, because it has been reported to recur in one-third of patients.

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n GIANT CELL TUMOR

24B

24C

FIGURE 6.24  Giant cell tumor (GCT). GCTs represent 3% to 5% of all primary bone tumors. Although GCT typically arises in skeletally mature individuals, it can occur in children and has a differential diagnosis that overlaps with several entities seen more commonly in the pediatric population, such as ABC and telangiectatic osteosarcoma. It is a locally aggressive lesion that often causes bone destruction resulting in pathologic fracture in up to one-third of patients with GCT. The most 24A common clinical presentation is that of pain and deformity in the distal or proximal femur, tibia, or wrist, as these lesions tend to arise in the meta-epiphyseal region of the long bones. The tumor is composed not only of MNGC but also of mononuclear cells that are precursors to the giant cells. Both the mononuclear histiocytic cells (MNHCs) and the MNGCs express CD68. It is now accepted that the giant cell tumor stroma cells (GCTSCs) represent the actual neoplastic cell population rather than the MNCH or the MNGC. GCTSCs do not belong to the monocytic–histiocytic lineage.   Plain films demonstrate an expansile lytic lesion located in the epiphyseal region. Cortical thinning and/or destruction may be observed, as seen in this fibular GCT (A), and MRI is useful in the assessment of soft tissue invasion. Grossly, the affected end of the bone is expanded, usually with a softened or eroded cortex, and contains a hemorrhagic soft and lobulated mass (B). Microscopic sections reveal innumerable MNGC, some of which are enormous and may contain 5–10 to upward of 100 nuclei per cell (C). The background stromal cells are mononuclear and may be round-to-oval or spindle-shaped without significant atypia. Stromal cell nuclei are round-to-oval with inconspicuous nucleoli, and they appear strikingly similar to the giant cell nuclei. Mitotic figures may be identified but are not atypical. Reactive bone formation as well as cortical destruction or soft tissue extension may be evident on histologic sections.   Much progress has been made in elucidating the pathogenetic mechanisms resulting in GCT. In contrast to osteoclasts in normal bone tissue, receptor activator for nuclear factor k B ligand (RANKL) is expressed by the neoplastic GCTSC promoting the fusion of MNHC to MNGC via macrophage colony-stimulating factor (M-CSF). In addition, autocrin/paracrin factors and cell cycle regulatory proteins are associated with the formation of GCTs such as activation of c-jun, overexpression of tumor suppressor gene NME2, and overexpression of cyclin D1.   Although giant cell tumors are considered benign, they are locally aggressive, and rare malignant forms with pulmonary metastases have been described. The treatment of choice is surgical resection which results in a less than 20% recurrence rate compared to a 50% recurrence rate in curetted GCTs. Bisphosphonates have been used to inhibit tumor-induced osteolysis.

JOINT DISORDERS 

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JOINT DISORDERS n TRANSIENT SYNOVITIS/PERTHES DISEASE FIGURE 6.25  Transient synovitis/Perthes disease. Transient synovitis of the hip is the most common cause of painful limp in childhood, accounting for about 30% of nontraumatic cases. Although the etiology is not known for certain, it has been reported to occur subsequent to infection, trauma, and autoimmune processes. It is an important clinical diagnosis from the standpoint that more serious causes of hip pain such as septic arthritis, osteomyelitis, Perthes disease, juvenile idiopathic arthritis (JIA), and tumors must be ruled out. Transient synovitis is normally self-limited and resolves with rest, but it is associated with the development of Perthes disease.   Perthes disease, otherwise known as Legg-Calve-Perthes disease or idiopathic avascular necrosis of the femoral head, occurs in children during the first 2 decades of life. Radiographs of Perthes disease show varying degrees of joint space widening, and femoral head flattening and destruction. Grossly, the femoral head is misshapen and articular cartilaginous erosion may be apparent. Anterior (left) and superior (right) views of a resected proximal femur with Perthes disease show a large concave defect on the surface of the femoral head, secondary to avascular necrosis. Histologic sections demonstrate loss of articular cartilage in the depressed areas and necrotic bone with noninflamed marrow. During the healing phase, appositional bone growth may be seen. Treatment options are controversial, all of which aim to contain the femoral head within the acetabulum, thus preserving the spherical shape of the femoral head. Treatment may entail prolonged rest, casting, bracing, osteotomy, or a combination thereof.

n JUVENILE IDIOPATHIC ARTHRITIS FIGURE 6.26  Juvenile idiopathic arthritis (JIA). JIA is the most common childhood rheumatic disease, with an incidence ranging from 7 to 21/100,000 in the United States and northern European countries. Three classification systems exist for this entity, based on the number of involved joints and the presence or absence of systemic systems. JIA is thought to have an autoimmune etiology with various autoantibodies reported in these patients. Rheumatoid factor (RF) and antinuclear antibodies (ANA) are routinely used to make the diagnosis. Histologic findings are similar to those of adult rheumatoid arthritis, and include hypertrophy of the synovium with marked lymphoplasmacytic and histiocytic synovitis and reactive synovial cell hyperplasia. Lymphoid aggregates with or without germinal centers may be present, and fibrin deposition may be noted on the synovial surface. Studies suggest that antigen-specific T cells play a role in JIA pathogenesis, and that the JIA cytokine pattern is polarized toward a type 1 profile.   NSAIDs are the mainstay of therapy, although more aggressive treatment such as low-dose methotrexate has been implemented as a second-line treatment choice. Tumor necrosis factor (TNF)-a blockers such as etanercept, infliximab, and adalimumab have been investigated, and autologous stem cell transplantation appears to be effective in patients refractory to other treatments. Rates of remission vary depending on the type of JIA, but range overall from 25% to 69%. Although 45% to 65% of JIA patients report no disability, joint damage is severe enough to require prosthetic replacement in many cases.

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BIBLIOGAPHY leck K. Craniosynostosis syndromes in the genomic era. Semin Pediatr Neurol. 2004;11(4):256–261. A Bjorkstén B, Boquist L. Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg Br. 1980;62(3):376–380. Borchers AT, Selmi C, Cheema G, Keen CL, Shoenfeld Y, Gershwin ME. Juvenile idiopathic arthritis. Autoimmun Rev. 2006;5(4):279–298. Brien EW, Mirra JM, Kerr R. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. 1. The intramedullary cartilage tumors. Skeletal Radiol. 1997;26(6):325–353. Campanacci M, Capanna R, Picci P. Unicameral and aneurysmal bone cysts. Clin Orthop Relat Res. 1986;(204):25–36. Gilbert EF, Yang SS, Langer L, Opitz JM, Roskamp JO, Heidelberger KP. Pathologic changes of osteochondrodysplasia in infancy. Pathol Annu. 1987;22(pt 2):283–345. Greenspan A. Benign bone-forming lesions: osteoma, osteoid osteoma, and osteoblastoma. Clinical, imaging, pathologic, and differential considerations. Skeletal Radiol. 1993; 22(7):485–500. Hameed M. Small round cell tumors of bone. Arch Pathol Lab Med. 2007;131(2):192–204. Khanna M, Delaney D, Tirabosco R, Saifuddin A. Osteofibrous dysplasia, osteofibrous dysplasia-like adamantinoma and adamantinoma: correlation of radiological imaging features with surgical histology and assessment of the use of radiology in contributing to needle biopsy diagnosis. Skeletal Radiol. 2008;37(12):1077–1084. Landin LA, Danielsson LG, Wattsgård C. Transient synovitis of the hip. Its incidence, epidemiology and relation to Perthes’ disease. J Bone Joint Surg Br. 1987;69(2):238–242. Oliveira AM, Perez-Atayde AR, Inwards CY, et al. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol. 2004;165(5):1773–1780. Parham DM, Bridge JA, Lukacs JL, Ding Y, Tryka AF, Sawyer JR. Cytogenetic distinction among benign fibro-osseous lesions of bone in children and adolescents: value of karyotypic findings in differential diagnosis. Pediatr Dev Pathol. 2004;7(2):148–158. Rasool MN, Govender S. The skeletal manifestations of congenital syphilis. A review of 197 cases. J Bone Joint Surg Br. 1989;71(5):752–755. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004;363(9418):1377–1385. Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilaginous tumors of bone: from morphology to somatic and germ-line genetics. Adv Anat Pathol. 2009;16(5):307–315. Schajowicz F. Bone-forming tumors. In: Schajowicz F, ed. Tumors and Tumorlike Lesions of Bone: Pathology, Radiology, and Treatment. 2nd ed. New York: Springer-Verlag; 1994:71–130. Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2007;143(1):1–18. Tan ML, Choong PF, Dass CR. Osteosarcoma: conventional treatment vs. gene therapy. Cancer Biol Ther. 2009;8(2):106–117. Unni KK. Osteosarcoma of bone. J Orthop Sci. 1998;3(5):287–294. Vlychou M, Athanasou NA. Radiological and pathological diagnosis of paediatric bone tumours and tumour-like lesions. Pathology. 2008;40(2):196–216. Werner M. Giant cell tumour of bone: morphological, biological and histogenetical aspects. Int Orthop. 2006;30(6):484–489.

7

The Heart Bahig M. Shehata Charlotte k. Steelman

n

STRUCTURAL CARDIOVASCULAR DISEASES Septal Defects Ventricular Septal Defect Atrial Septal Defect Atrioventricular Septal Defect Malformations of Conus and Truncus Transposition of the Great Arteries Persistent Truncus Arteriosus Malformations of Ventricular Outflow Tracts Hypoplastic Left Heart Syndrome Tetralogy of Fallot Malformations of Aortic Arch Interrupted Aortic Arch Patent Ductus Arteriosus Coarctation of the Aorta Malformations of Position and Situs Ectopia Cordis Dextrocardia Juxtaposition of Atrial Appendages Valvular Defects Ebstein Anomaly Mitral Valve Prolapse

n

INFECTIOUS AND INFLAMMATORY CARDIOVASCULAR DISEASES Endocarditis Infective Endocarditis Nonbacterial Thrombotic Endocarditis Myocarditis Pericarditis Rheumatic Fever and Rheumatic Heart Disease Kawasaki Disease Cardiac Manifestations of Autoimmune Disease Cardiomyopathies Dilated Cardiomyopathy Hypertrophic Cardiomyopathy Restrictive (Infiltrative) Cardiomyopathy Arrhythmogenic Right Ventricular Dysplasia Cardiomyopathy in Infants With Diabetic Mothers Endocardial Fibroelastosis Noncompaction of Ventricular Myocardium

n

METABOLIC DISORDERS Glycogen Storage Disease Pompe Disease

n

CONDUCTION SYSTEM ABNORMALITIES Congenital Heart Block

n

CARDIAC TUMORS Benign Cardiac Tumors Rhabdomyoma Fibroma Myxoma Teratoma Hemangioma Histiocytoid Cardiomyopathy Cystic Tumor of Atrioventricular Node Malignant Cardiac Tumors

n

HEART TRANSPLANT PATHOLOGY Hyperacute Rejection Acute Cellular Rejection Chronic Rejection Opportunistic Infections Posttransplant Lymphoproliferative Disorders

sTruCTural CardiovasCular diseases n sePTal deFeCTs ventricular septal Defect Ventricular septal defect (VSD) is a common congenital heart defect and occurs in 50% of children with congenital heart disease. VSD is characterized by an opening in the ventricular septum and may be perimembranous, supracristal, or muscular. Perimembranous VSDs represent the most common VSDs and are found in the left ventricular outflow tract beneath the aortic valve. Supracristal VSDs are situated below the pulmonary valve and communicate with the right ventricular outflow tract above the supraventricular crest (Figure 7.1). Muscular VSDs are less frequent and located in the muscular wall at any site on the septum; they are often small and multiple. In children, spontaneous closure of small VSDs is common, and the prognosis is good.

Atrial septal Defect Atrial septal defect (ASD) is a congenital defect of the interatrial septum that is more frequent in females than males. Anatomically, ASD may be classified as secundum ASD (75%), primum ASD (15%), or sinus venosus defect (10%). Secundum ASD occurs in the central portion of the atrial septum and appears as multiple perforations or as a deficiency of the septum primum. Primum ASD is found in the

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FIGURE 7.1  Supracristal ventricular septal defect.

FIGURE 7.2  Atrioventricular septal defect.

lower portion of the atrial septum, just above the atrioventricular (AV) valves; it most commonly occurs as AV septal defect. Sinus venosus defect involves the upper portion of the septum near the junction of the superior vena cava. Complete absence of the atrial septum is rare and often associated with multiple cardiac anomalies.

Atrioventricular Septal Defect Atrioventricular septal defect (AVSD) is a congenital anomaly that affects the AV valves and septa (Figure 7.2). Atrioventricular septal defect results from incomplete valvuloseptal morphogenesis caused by a failure of endocardial cushion formation; thus, AVSD is sometimes called endocardial cushion defect. In complete AVSD, the most severe form, there is a persistent AV canal allowing unrestricted communication between the atria and ventricles; this most commonly occurs in association with trisomy 21. Partial AVSD, also known as primum ASD, is the most common form of nonsyndromic AVSD and usually presents with a cleft mitral valve.

n MALFORMATIONS OF CONUS AND TRUNCUS Transposition of the Great Arteries Transposition of the great arteries (TGA) occurs when the aorta arises from the morphological right ventricle and the pulmonary artery arises from the morphological left ventricle. The hallmark of TGA is ventriculoarterial discordance. In the majority of cases, the aorta lies to the right of the pulmonary artery (d-TGA; complete TGA); however, it can lie to the left of the pulmonary artery (l-TGA; congenitally corrected TGA). In both cases, systemic and pulmonary ­circulations proceed in parallel, rather than in series. Thus, survival is only possible if communication is established between the two circulations (e.g., by ASD, VSD, patent ductus arteriosus). VSD is present in approximately half of all childhood cases.

STRUCTURAL CARDIOVASCULAR DISEASES 

Persistent Truncus Arteriosus Persistent truncus arteriosus (PTA) occurs when there is a failure of fusion and descent of the spiral ridges of the truncus and conus that would normally divide into the aortic and pulmonary trunk, respectively. This defect results in a single large arterial trunk overlying a perimembranous VSD. The single arterial trunk gives rise to the aorta, one or both pulmonary arteries, and the coronary arteries. Four subtypes have been described. In type I, a single pulmonary trunk arises from the PTA, and the left and right pulmonary arteries branch from the pulmonary trunk. In types II and III, the left and right pulmonary arteries originate directly from the PTA. Type IV is now recognized as a form of pulmonary atresia with VSD. Commonly associated cardiac anomalies include interrupted aortic arch, right-sided aortic arch, and absent ductus arteriosus.

n MALFORMATIONS OF VENTRICULAR OUTFLOW TRACTS Hypoplastic Left Heart Syndrome Hypoplastic left heart syndrome is characterized by abnormal development of the left-sided cardiac structures and marked hypoplasia of the left ventricle and ascending aorta (Figure 7.3). Additionally, mitral atresia or stenosis may be present. This malformation results in obstruction of blood flow into systemic circulation. Approximately 10% of cases are associated with ­premature closure of the foramen ovale. Without intervention, the condition is usually fatal within the first few days of life. Hypoplastic left heart syndrome has been associated with monosomy X, trisomies 8 and 13, and mutations in 11q23.3.

Tetralogy of Fallot Tetralogy of Fallot (TOF) is a cyanotic heart defect characterized by four major cardiac abnormalities—VSD, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy (­Figure 7.4). In most cases, the VSD is large and nonrestrictive. Commonly associated anomalies include coronary artery defects, ASD, right aortic arch, and overriding tricuspid valve. The etiology of TOF is unknown; however, familial recurrence has been reported in 3% of cases, and chromosomal abnormalities like trisomies 13, 18, and 21 as well as chromosome 22q11 microdeletions (DiGeorge syndrome critical region) have been associated with the tetralogy.

FIGURE 7.3  Hypoplastic left heart syndrome. Gross image of the heart showing marked hypoplasia of the left ventricle.

FIGURE 7.4  Tetralogy of Fallot (TOF). TOF is characterized by ventricular septal defect, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy.

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n MALFORMATIONS OF AORTIC ARCH Interrupted Aortic Arch Interrupted aortic arch (IAA) is an uncommon malformation in which there is a lack of luminal continuity between the ascending and descending thoracic aorta. IAA has been classified into 3  subtypes according to the site of aortic interruption. In type A (13%), the interruption occurs distal to the left subclavian artery origin. In types B (84%) and C (3%), the interruption occurs distal and proximal to origin of the left common carotid, respectively. IAA is often associated with patent ductus arteriosus and VSD. The genetic basis of IAA is uncertain, but approximately half of all cases are associated with a deletion in chromosome 22q11 (DiGeorge critical region).

Patent Ductus Arteriosus Patent ductus arteriosus is defined as abnormal persistence of patency of the ductus arteriosus between the aorta and pulmonary artery after birth. The condition primarily affects premature infants, and there is a predilection for females. On the other hand, premature closure of the ductus arteriosus in utero is lethal and has been associated with maternal use of indomethacin.

Coarctation of the Aorta Coarctation of the aorta is defined as a constriction of a segment of the aorta. The majority of cases occur in the aortic arch either preductal (infantile) or opposite of the closed ductus (adult form). It shows a male predominance of 2:1 not including cases seen with Turner syndrome. It can be associated with several cardiac anomalies including bicuspid aortic valve (50%), ASD, VSD, and aneurysms of the circle of Willis. A rare form of coarctation can be seen in the abdominal aorta.

n MALFORMATIONS OF POSITION AND SITUS Ectopia Cordis Ectopia cordis is a rare congenital anomaly in which the heart is located outside of the thoracic cavity. The condition may be thoracic (60%), abdominal (30%), thoracoabdominal (7%), or cervical (3%). In thoracic cases, the heart is typically positioned on the anterior surface of the chest without skin or pericardial covering. In abdominal cases, the heart is often found in a common omphalocele sac (Figure 7.5). VSD, ASD, TOF, and left ventricular diverticulum are commonly associated with ectopia cordis. Furthermore, the condition is often linked to pentalogy of Cantrell or one of its variants with large diaphragmatic hernia and sternal defect. Although the molecular–genetic basis is not understood, trisomies 13, 18, and 21 and familial X-linked inheritance have been implicated in ectopia cordis.

Dextrocardia Dextrocardia is a congenital malposition in which the heart is located in the right side of the chest and has a right-sided apex (Figure 7.6). It may occur in conjunction with situs inversus or as an isolated finding. It is important to note the distinction between dextrocardia and cardiac dextroposition, in which the heart is displaced to the right because of extracardiac abnormalities.

Juxtaposition of Atrial Appendages Juxtaposition of atrial appendages is a rare condition in which both atrial appendages lie side by side either to the left or to the right of the great arteries. Left juxtaposition is more common than the right. This rare anomaly is usually accompanied by other cardiac defects such as TGA.

STRUCTURAL CARDIOVASCULAR DISEASES 

FIGURE 7.5  Abdominal ectopia cordis. Heart from a patient with pentalogy of Cantrell. The heart is positioned outside of the thoracic cavity at the top of the omphalocele sac.

FIGURE 7.6  Dextrocardia. The heart is situated in right of the chest. Note that the liver is on the left side, and the stomach and spleen are on the right.

n VALVULAR DEFECTS Ebstein Anomaly Ebstein anomaly is a malformation of the tricuspid valve characterized by downward displacement of the septal and posterior leaflets (Figure 7.7). In severe cases, the septal leaflet is adhered to the septum, and the posterior leaflet is attached to the posterior ventricular wall. The leaflets are often hypoplastic

FIGURE 7.7  Ebstein anomaly. Heart with enlarged dilated right atrium and very small right ventricle secondary to downward displacement of the tricuspid valve.

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and thickened. Additionally, such displacement results in atrialization of the right ventricle with a reduction in size of the functional right ventricle. The endocardium of the right ventricle is often fibrotic with underdeveloped trabeculations. This anomaly has been associated with other cardiac abnormalities such as ASD, VSD, patent foramen ovale, and pulmonary stenosis or atresia. Maternal use of lithium carbonate during pregnancy has also been linked to Ebstein’s anomaly.

Mitral Valve Prolapse Mitral valve prolapse (MVP) is, in general, a clinically benign condition characterized by the displacement of abnormally thickened mitral valve leaflet(s) into the left atrium during systole. MVP is more common in females than males, and its general prevalence is 2.5%. The majority of affected children and adolescents are asymptomatic. Additionally, MVP is associated with various conditions such as infective endocarditis, severe mitral regurgitation, sudden cardiac death, and heritable connective tissue disorders (e.g., Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum). Pathologically, MVP is characterized by interchordal hooding of the valve leaflets, and upon microscopic examination, myxoid degeneration of the loose spongiosa and fragmentation of the collagen fibrils are the most common observations.

INFECTIOUS AND INFLAMMATORY CARDIOVASCULAR DISEASES n ENDOCARDITIS Endocarditis is classified as infective or noninfective. Heart valves are the most common sites of inflammation, but endocarditis also occurs on atrial walls, along trabeculae, and on papillary muscles or chordae tendineae.

Infective Endocarditis Infective endocarditis (IE) occurs when bacteria or fungi are incorporated into thrombotic vegetations attached to the endocardial surface. Such vegetations are most frequently found on the atrial surface of AV valves and on the ventricular surface of semilunar valves (Figure 7.8). They may also occur in structural defects or damaged tissue. The most common microorganisms are gram-positive bacteria such as Streptococci and Staphylococci. Congenital heart disease, cardiac surgery, central vascular devices, rheumatic heart disease, and immunodeficiency are common predisposing conditions. Grossly, IE vegetations demonstrate an irregular granular surface and can be gray, grayish pink, or grayish yellow in color. They are composed of colonies of microorganisms surrounded by fibrin, leukocytes, and necrotic debris with associated acute and chronic inflammation. Valve leaflet erosion, adhesions, or perforation may also occur. FIGURE 7.8  Infective endocarditis. Mitral valve with vegetation and perforation.

INFECTIOUS AND INFLAMMATORY CARDIOVASCULAR DISEASES 

129

FIGURE 7.9  Viral myocarditis. Lymphocyte-rich infiltrate with interstitial edema and myocyte degeneration and necrosis (H&E; 3400).

Nonbacterial Thrombotic Endocarditis Nonbacterial thrombotic endocarditis (NBTE) has sterile thrombotic vegetations devoid of microorganisms that develop on usually normal heart valves. The nodular vegetations vary in size and may be whitetan to pink in color. Microscopically, the lesions are composed of fibrin, platelets, erythrocytes, and sporadic leukocytes with minimal inflammation. The etiology of NBTE is unclear; however, it can be associated with hypercoagulable conditions and autoimmune disease such as systemic lupus erythematosus (SLE), where valvular vegetation can be seen on both sides of the mitral valve leaflets (Libman-Sacks vegetation).

Myocarditis Myocarditis is defined as nonischemic myocardial inflammation resulting from infectious, toxic, or autoimmune etiologies. In children, the most common cause is viral infection. It is often associated with dilated cardiomyopathy. Macroscopically, the heart chambers may be dilated, and the myocardium may be soft and flimsy. Fibrosis and endocardial thickening are also common observations. Histologically, endomyocardial biopsies are characterized by abundant inflammatory infiltrates, interstitial edema, and myocyte degeneration and necrosis. Inflammatory infiltrates are primarily lymphocytic, but macrophages, plasma cells, and neutrophils may be present in pediatric cases (Figure 7.9). In addition to lymphocytic myocarditis, several subtypes of myocarditis exist. In giant cell myocarditis, myocardial necrosis and degeneration are accompanied by extensive inflammatory infiltrates, including multinucleated giant cells (Figure 7.10). Eosinophilic myocarditis is characterized by intense eosinophilic infiltrates and peripheral eosinophilia (Figure 7.11). Eosinophilic myocarditis may be further subclassified into hypersensitivity myocarditis, hypereosinophilic myocarditis, and in association with parasitic infection such as Chagas disease (Figure 7.12) and toxoplasmosis (Figure 7.13).

FIGURE 7.10  Giant cell myocarditis. Large multinucleated cells (H&E; 3400) confirmed by CD-68 positivity (inset).

FIGURE 7.11  Eosinophilic myocarditis. Endomyocardial fibrosis with intense eosinophilic infiltrate (H&E; 3400).

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FIGURE 7.12  Chagas disease. Acute chagasic myocarditis showing Trypanosoma cruzi–filled cyst, interstitial lymphocytic infiltrates, and myocyte degeneration (H&E; 31000).

FIGURE 7.13  Toxoplasmosis. Toxoplasma gondii cyst of the myocardium (H&E; 31000).

Pericarditis Pericarditis is an acute or chronic inflammation of the pericardium. In children and adolescents, the most common causes of pericarditis are bacterial or viral infection, connective tissue disease, metabolic disease, postpericardiotomy syndrome, and neoplasms. It can be associated with myocarditis as well as pericardial tamponade. The characteristic histological features include inflammatory infiltrates, increased pericardial vascularity, and pericardial fibrosis and thickening. In acute pericarditis, exudates that are serous, fibrinous, purulent, or hemorrhagic may be seen.

Rheumatic Fever and Rheumatic Heart Disease Rheumatic fever and rheumatic heart disease is the leading cause of acquired heart disease in children and young adults, particularly in developing countries, and it primarily affects children between the ages of 5 and 15 years following a group A streptococcal infection. In up to 40% of cases, rheumatic fever results in acute rheumatic carditis. Sterile inflammatory lesions may be found in the endocardium, myocardium, and pericardium, commonly as a pancarditis. Vegetations are most commonly adhered to the closing margins of the mitral (65%) and aortic (25%) valves (Figure 7.14A). Histologically, the ­hallmark of rheumatic carditis is the Aschoff nodule, which

14A

14B

FIGURE 7.14  Rheumatic heart disease. Thickened mitral valve leaflets with adhesions (A). Aschoff nodule. Subendocardial granulo­ matous lesion containing lymphocytes, plasma cells, and abnormal macrophages (Anitschkow cells; yellow arrow) (B, H&E; 3400).

INFECTIOUS AND INFLAMMATORY CARDIOVASCULAR DISEASES 

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15B

FIGURE 7.15  Kawasaki disease. Note the marked aneurismal dilatation of the coronary vessel (A). Section of the vessel wall with the lumen containing an organizing thrombus and adjacent myocardium showing extensive lymphoplasmocytic infiltrates (H&E; 3400) (B). 15A

may be found within the interstitium of the myocardium, subendocardium, and valve leaflets (Figure 7.14B). These ­scattered granulomatous lesions contain lymphocytes, plasma cells, and abnormal macrophages (Anitschkow cells) accompanied by focal necrosis. Additionally, thickened subendocardial ridges in the left atrium, known as MacCallum patches, are seen in approximately 50% of cases.

Kawasaki Disease Kawasaki disease is an acute systemic vasculitis of unknown etiology that affects infants and young children. Following acute illness, many patients will develop intense inflammation of the coronary arteries, commonly resulting in stenosis, occlusion, dilatation, and aneurysm (­Figure 7.15A,B). Furthermore, myocarditis and cardiomegaly may be present. Ultimately, chronic fibrosis and thickening of arterial endothelium may lead to complete heart block and myocardial infarction.

Cardiac Manifestations of Autoimmune Disease Cardiac involvement in autoimmune diseases is well documented and includes a range of manifestations. Myocardial fibrosis, myocarditis, pericarditis, conduction system abnormalities, and heart failure are among the most commonly reported (Table 7.1). Table 7.1  Cardiac Manifestations of Autoimmune Disease Autoimmune Disease

Cardiac Manifestations

SLE

Pericarditis; myocarditis; Libman-Sacks ­endocarditis; coronary artery disease; ­hematoxylin bodies; ­calcification; necrosis

Infants of SLE mothers

Congenital heart block; atrioventricular node ­lymphocytic infiltrate, fibrosis, and calcification

Polymyositis and dermatomyositis

Myocarditis; lymphocytic infiltration and fibrosis in the conduction system; ­arrhythmias; heart failure

Progressive systemic sclerosis (scleroderma)

Patchy myocardial fibrosis of both ­ventricles; ­cardiac hypertrophy; myocarditis; ­pericardial disease; fibrosis of SA node and bundle branches; heart failure

Mixed connective tissue disease

Pulmonary hypertension; pericarditis; mitral valve prolapse; cardiomyopathy; valvular changes

Polyarteritis nodosa

Congestive heart failure; hypertension; ­pericarditis; arrhythmias; coronary artery ­aneurysm, thrombosis, dissection, and stenosis

Abbreviations: SLE, systemic lupus erythematosus.

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Figure 7.16.  Dilated cardiomyopathy. Cross sections from a heart with prominent dilated cardiomyopathy.

n CARDIOMYOPATHIES Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common cardiomyopathy. It is characterized by dilatation and impaired contraction of the left or both ventricles as well as increased myocardial mass (Figure 7.16). DCM is inherited in 25% to 35% of cases, but many other acquired conditions (e.g., viral myocarditis, autoimmune disease, toxins, hypertensive heart disease) may lead to this disorder. It has been proposed that viral myocarditis is responsible for the majority of acquired DCM cases in children and young adults. DCM has nonspecific histological features. However, interstitial fibrosis, variability in myocyte size and shape, degenerative changes, and diminished intracellular myofibrils may be seen.

Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, characterized by unexplained left ventricular hypertrophy (Figure 7.17 A). HCM is one of the most frequent causes of

17A

17B

FIGURE 7.17  Hypertrophic cardiomyopathy. Heart with markedly thickened ventricular walls and intraventricular septum (A). Histologic section showing myocyte hypertrophy, abundant fibrosis, and myofibrillar disarray (B, H&E; 3200).

INFECTIOUS AND INFLAMMATORY CARDIOVASCULAR DISEASES 

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premature sudden cardiac death in young adults. HCM is a genetically and phenotypically heterogeneous disease, with the majority of cases being autosomal dominant. More than 450 mutations in sarcomere (60%) and myofilament-related genes have been associated with HCM. Mutations in MYH7 (b-myosin heavy chain), MYBPC3 (myosin-binding protein C), TNNI3 (cardiac troponin I), and TNNT2 (troponin T) have the highest frequencies. Typical morphological changes include myocyte disarray and hypertrophy with interstitial fibrosis (Figure 7.17B).

Restrictive (Infiltrative) Cardiomyopathy Restrictive (infiltrative) cardiomyopathy (RCM) is a rare condition in which ventricular filling is impaired and diastolic volume is reduced (Figure 7.18). Systolic function and myocardial thickness are usually unaffected. RCM may be inherited or sporadic. Several recent molecular-genetic studies have associated RCM with mutations in sarcomeric disease genes also implicated in HCM and DCM. Sporadic RCM is frequently associated with local inflammatory or systemic diseases (e.g., hypereosinophilic syndromes, amyloidosis in adults, endomyocardial disease with or without hypereosinophilia). Marked interstitial fibrosis and myofibrillar disarray are characteristic of the histological findings in RCM. When diagnosed in childhood, the prognosis is generally unfavorable.

Arrhythmogenic Right Ventricular Dysplasia Arrhythmogenic right ventricular dysplasia (ARVD) is a rare form of cardiomyopathy characterized by progressive fibrofatty infiltration of the right ventricular myocardium (Figure 7.19A). It can be associated with syncope, ventricular tachycardia, heart failure, and sudden death in children and young adults. It shows a male predominance. ARVD shows a heterogeneous inheritance pattern with 12 genetic loci identified to date. The majority of cases are autosomal dominant; however, a few autosomal recessive loci have been identified. Familial tendency (30% to 50%) and clusters in certain communities have also been reported. Histologically, ARVD shows thinning of the myocardium of the right ventricular wall accompanied by fibrofatty replacement of the atrophic myocardium, especially in the arrhythmogenic triangle (Figure 7.19B,C). Rarely, the fibrofatty infiltrates can be seen in both ventricles.

FIGURE 7.18  Restrictive cardiomyopathy. Longitudinal section of heart showing dilated ventricles with increased trabeculations. Note the normal thickness of the ventricular walls and ventricular septum.

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19A

19B

FIGURE 7.19  Arrhythmogenic right ventricular dysplasia. Right ventricular wall demonstrating extensive infiltration of fibrofatty tissue (A). Right ventricular wall showing diffuse fibrofatty replacement of the myocardium (B, Trichrome; 320). Extensive fat infiltrate between myocardial fibers and reaching beneath the endocardium (C, H&E; 3200).

19C

Cardiomyopathy in Infants With Diabetic Mothers Cardiomyopathy in infants with diabetic mothers. Infants of diabetic mothers (IDM) are at an increased risk of being born with HCM or DCM. In such cases, cardiomegaly as well as hyperplasia and hypertrophy of myocardial cells are observed. In HCM of IDM, the interventricular septum is hypertrophic. Histologic features include myocyte disarray, focal fiber necrosis, hypertrophy of fibers, and focal edematous changes of the myocytes. DCM of IDM is less common and associated with severe hypoglycemia and acidosis. Histologically, myocardial cells filled with glycogen may be seen.

Endocardial Fibroelastosis Endocardial fibroelastosis (EFE) is defined as focal or diffuse proliferation of fibroelastic tissue under the ventricular endocardium. The condition may lead to DCM or RCM. EFE may be primary in which no other cardiac abnormalities are present or secondary, which is associated with congenital heart disease. Viral myocarditis, metabolic diseases, abnormal endocardial tension, myocardial infarction, and hypoxia have all been linked to EFE. Additionally, autosomal and X-linked recessive genetic forms of EFE have been identified. On gross examination, the left ventricular wall is usually hypertrophied. The endocardium displays an opaque, pearly white appearance, and its marked thickening often obscures trabeculae and thebesian vessels (Figure 7.20). Microscopically, the endocardium is composed of thick hypocellular layers of dense collagen and coarse elastic fibers. Focal calcification and necrosis can also be seen. The fibroelastic process can involve the Purkinje fibers and papillary muscles as well.

Metabolic Disorders 

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FIGURE 7.20  Endocardial fibroelastosis. Markedly thickened endocardium displaying an opaque, pearly white appearance.

Noncompaction of Ventricular Myocardium Noncompaction of ventricular myocardium, also known as persistence of spongy myocardium, is a rare congenital cardiomyopathy caused by arrest in endomyocardial morphogenesis. Approximately 50% of all cases occur in children. The etiology of noncompaction of the ventricular myocardium remains unclear; however, it has been associated with HCM, mitochondrial disorders, and Barth syndrome. It is characterized by a prominent meshwork of ventricular trabeculations and deep intertrabecular recesses. Interwoven myocardial strings lined with endocardium create a spongy myocardial layer distinct from the underlying compacted ­myocardium.

Metabolic Disorders n GLYCOGEN STORAGE DISEASE Glycogen storage disease is an autosomal recessive deficiency in enzymes involved in glycogen metabolism. Cardiac involvement most commonly occurs in types II (Pompe’s disease), III (Cori disease), and IV (Anderson disease).

Pompe Disease Pompe disease (glycogen storage disease type II) is perhaps the most famous infantile glycogen storage disease. It causes progressive destruction of muscle tissue. Mutations in the GAA gene on chromosome 17q21–23 lead to a decrease in alpha glucosidase activity and result in glycogen accumulation. Cardiac involvement is characteristic of the rapidly lethal infantile form. Fibroelastic thickening of the endocardium and progressive cardiomegaly due to glycogen accumulation in myocardial cells are common cardiac findings (Figure 7.21A–C).

21A

21B

21C

FIGURE 7.21  Pompe disease. Cardiomegaly (weight, 590 g; expected weight, 90 g) of a 5-year-old child (A). Fibroelastic thickening of endocardium (B, H&E; 3200). Vacuolated myocytes due to glyocogen accumulation (C, H&E; 3400).

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A list of other metabolic disorders may be found in Table 7.2.

Table 7.2  Metabolic Disorders With Associated Cardiac Manifestations Disease

Associated Heart Findings

Storage Disease   Fabry disease

Endocardial fibrosis; myofilament structure disarray; sarcoplasmic vacuolization

  Fatty acid oxidation disorders

Congestive heart failure; lethal arrhythmia

  Gangliosidosis

Cardiomegaly; nodular thickening of mitral and ­tricuspid valves

  Gaucher disease

Rare cardiovascular involvement; ­congestive cardiomyopathy; cardiomegaly; ­calcification and thickening of valves; ­constrictive ­pericarditis; diffuse infiltration of ­myocardium by Gaucher cells

 Glycogen storage type II     ( Pompe ­disease)

Fibroelastic thickening of endocardium; ­cardiomegaly

  Mucolipidosis II (I-cell disease)

Cardiomegaly; left ventricular hypertrophy; thickened and ­nodular mitral, tricuspid, aortic valvular leaflets

  Mucopolysaccharidoses

Intimal thickening of heart valves; raised ­intimal plaques in aorta; endocardial fibroelastosis

 Neuronal ceroid ­lipofuscinosis     ( ­Batten-Spielmeyer-Vogt s­ yndrome)

Cardiomegaly; thickened valvular tissue

Mitochondrial Disorders  Barth syndrome (X-linked cardiomyopathy)

Dilated cardiomyopathy

 Cytochrome c oxidase coenzyme deficiency

Hypertrophic cardiomyopathy

  Cytochrome c oxidase deficiency

Hypertrophic cardiomyopathy

  Kearns-Sayre syndrome

Progressive heart block

  MELAS and MERRF syndromes

Dilated cardiomyopathy

Amino Acid Metabolism   Alkaptonuria

Myocardial infarction; deposition of onchronotic pigment on heart valves, endocardium, aorta, and coronary arteries

  Carnitine deficiency

Lipid accumulation in myocardium; progressive ­cardiomyopathy; enlarged, globular heart with endocardial fibroelastosis

  Homocystinuria

Fibrous intimal thickening, fragmentation of internal elastic lamella, and cystic medial necrosis of aorta

  Oxalosis

Accumulation of oxalate crystals in cardiac myocytes, conduction system, interstitium; necrosis, fibrosis, and mononuclear and foreign body giant cell reaction may accompany crystal deposits

Metal and Pigment Metabolic Disorders   Hemosiderosis and hemochromatosis

Congestive heart failure; supraventricular arrhythmias

  Hyperlipoproteinemias, types I–IV

Accelerated atherosclerosis; accumulation of yellow patches in left atrial endocardium

  Wilson disease

Hypertrophic cardiomyopathy

Connective Tissue Disorders   Marfan syndrome

Dilation and dissection of aorta; mitral valve prolapsed; mitral annular dilation and ­calcification; ventricular arrhythmia

  Osteogenesis imperfecta

Dilation of aortic root; mitral valve prolapsed; cystic medial ­necrosis and thinning of aorta; myxomatous degeneration of mitral valve leaflets; chordae tendinae prone to rupture

Abbreviations: MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy and ragged red fibers.

Cardiac Tumors 

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FIGURE 7.22  Calcification of atrioventricular node. Note the artery to the AV node in the center (H&E; 3100).

Conduction System Abnormalities n CONGENITAL HEART BLOCK Congenital heart block (CHB), also known as third-degree AV block, is a complete failure of atrial depolarization to reach the ventricles. CHB may occur in a structurally normal heart or, more commonly, with congenital heart disease. Most cases are spontaneous, but CHB may be a manifestation of maternal lupus erythematosus. The condition usually presents with persistent bradycardia and congestive heart failure. Histologically, chronic inflammatory infiltrate, fibrosis, and calcification of the conduction system, especially the AV node, are consistently seen (Figure 7.22).

Cardiac Tumors Pediatric cardiac tumors are extremely rare, and most (90%) are histologically benign. In the pediatric population, nearly 20% of primary cardiac tumors present within the first year of life. Rhabdomyomas comprise most of the pediatric cardiac tumors, followed by fibromas, myxomas, and teratomas. These frequencies are slightly different for infants compared to children and adolescents. Malignant and metastatic cardiac tumors in children have been reported but are exceedingly rare. Rhabdomyosarcoma and angiosarcoma are the most common primary malignant cardiac tumors. Secondary metastatic tumors are very rare; neuroblastoma, leukemia, lymphoma, and melanoma are among those reported. Despite the benign nature of most pediatric cardiac tumors, tumors of the heart can restrict blood flow, compromise myocardial function, induce arrhythmias, and ultimately cause death.

n BENIGN CARDIAC TUMORS Rhabdomyoma Rhabdomyoma is the most common cardiac tumor of infancy and childhood. This benign hamartomatous lesion may arise at any age, but the majority of cases (75%) are seen in children younger than the age of 1 year, and one third of cases are congenital. Cardiac rhabdomyomas may be sporadic or they may occur in association with structural congenital heart disease (e.g., hypoplastic left heart syndrome, Ebstein’s anomaly, TGA, EFE). However, the highest ­percentage of rhabdomyomas occurs in association with tuberous sclerosis. Approximately 80% of individuals with cardiac rhabdomyoma have a

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The Heart

23A

23B

FIGURE 7.23  Rhabdomyoma. Multiple endocardial nodules (arrows) obstructing the aortic outflow in a patient with tuberous sclerosis (A). Section showing multiple rhabdoymoma nodules in the myocardium (B, H&E; 3200). Characteristic spider cells. Note the normal myocardial fibers on the right side (C, H&E; 3400).

23C

clinical or family history of tuberous sclerosis, and half of all patients with tuberous sclerosis have cardiac rhabdomyomas. An unusual association of tuberous sclerosis and Down’s syndrome with congenital rhabdomyoma has also been reported. Cardiac rhabdomyoma is associated with a good prognosis. Spontaneous regression of cardiac rhabdomyomas is well documented, and surgery is only performed in cases associated with uncontrolled arrhythmia or severe hemodynamic compromise. Rhabdomyomas may arise anywhere in the heart, but they are most commonly found within the myocardium of the ventricles and the ventricular septum. In approximately 50% of cases, cardiac rhabdomyomas are intracavitary. Such tumors may impede intracardiac blood flow and interfere with valve function. Multiplicity of tumors is typical of cases associated with tuberous sclerosis (Figure 7.23A). Rhabdomyomas are light-brown or yellow in color and are composed of firm, well-demarcated nodules. Microscopically, they consist of swollen cardiac myocytes with clear cytoplasm. Most cells contain large glycogen-filled vacuoles with sparse cytoplasm and myofilaments (Figure 7.23B). Some cells display a unique architectural arrangement of delicate strands of eosinophilic cytoplasm connecting a centrally located nucleus to the cell membrane (spider cells; Figure 7.23C). Immunohistochemical studies reveal the characteristic striated muscle features of rhabdomyoma cells as well as immunoreactivity with actin, desmin, myoglobin, and vimentin.

Fibroma Fibroma is the second most common pediatric heart tumor. Like cardiac rhabdomyoma, this benign tumor generally presents within the first year of life. Cardiac fibromas have been associated with

Cardiac Tumors 

several extracardiac malformations and syndromes, including cleft lip and palate, Beckwith-Wiedemann syndrome, and Gorlin’s syndrome. Mutations of the tumor suppressor gene PTCH1 (9q22.3) were recently implicated in sporadic cardiac fibroma, regardless of an association with Gorlin’s syndrome. Cardiac fibromas rarely spontaneously regress, and, as a result, surgical resection is required for cure. Unfortunately, because of their infiltrative nature, complete excision is not always possible. Cardiac fibromas typically arise as solitary lesions in the myocardium of the ventricular septum or the free wall of either ventricle. Grossly, they are firm, white, trabeculated, encapsulated lesions, which resemble fibromatoses (Figure 7.24A). Cardiac fibromas are composed of spindle-shaped fibroblastic cells with large oval nuclei embedded in a collagenous matrix containing abundant elastic fibers (Figure 7.24B,C). Marked cellularity is seen in cases of young infants, but this generally decreases with age. Conversely, collagen content tends to increase with age. In one fourth of cases, foci of calcification are present and may serve as a differential feature when differentiating fibromas from rhabdomyomas. Additionally, central regions of the tumor may show extramedullary hematopoiesis and microcystic changes. Myocardial fibers are often entrapped in the lesion, particularly around the tumor’s periphery. Tumor cells demonstrate diffuse vimentin and focal smooth muscle actin immunoreactivity.

24B

24A

24C

FIGURE 7.24  Fibroma of right ventricle. Gross appearance, trabeculated pale cut surface (A). Histologic section, demonstrating interlacing bundles of spindled cells (B, H&E; 3200). Trichrome stain demonstrating the myocardium (left) and ill-defined border of the fibroma (right) (C, trichrome; 3100) (C).

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The Heart

Myxoma Myxoma represents the most common primary tumor of the heart in adults; however, it is rarely encountered in young children. Approximately 5% of cardiac myxomas are associated with Carney syndrome, which also includes abnormal skin pigmentation and endocrinopathy. Complete surgical excision is the recommended treatment and is associated with an excellent prognosis. Nevertheless, most reported myxomas in young children have been fatal. Recurrent myxomas have been reported in 12% to 22% of familial/syndromic cases and 1% to 3% of sporadic cases. Most cardiac myxomas are sporadic and located in the left atrium (75%) or right atrium (20%). They present as solitary grayish white gelatinous lesions with a smooth or gently lobulated surface (Figure 7.25A). On cut section, they are highly vascular and often blotchy with foci of hemorrhage, calcification, or necrosis.

25B

FIGURE 7.25  Myxoma of right atrium. Fungating gelatinous mass occupying the right atrium (A). Stellate mesenchymal cells embedded in a myxoid stroma (B, H&E; 3200). Pseudo-glandular structures lined by goblet-like cells (C, H&E; 3400). 25A

25C

Cardiac Tumors 

Cardiac myxomas have a spectrum of histological characteristics. Typically, they are composed of stellate mesenchymal cells embedded in a myxoid stroma containing variable amounts of proteoglycans, collagen, and elastin. Myxoma cells are characterized by pale ovoid nuclei, eosinophilic cytoplasm, and indistinct cell borders (Figure 7.25B). Furthermore, tumor cells can form an array of complex structures such as rings around blood vessels and branching cords at the tumor’s periphery. In approximately 1% of cases, cardiac myxomas also contain glandular structures lined by goblet-like cells (Figure 7.25C). Degenerative changes such as fibrosis, extramedullary hematopoiesis, calcification, thrombosis, and ossification are common. Interestingly, gamna-gandy bodies can be seen in cases with ossification. When associated with Carney’s syndrome, they can be multifocal. Rare mitoses can be seen; however, it is not a predictive factor for recurrence. Immunohistochemically, the tumor cells show reactivity with calretinin, vimentin, CD34, and alpha-1-antichymotrypsin.

Teratoma Teratoma is rare in any age group, but more than 75% occur before age 15 years. It usually arises in the pericardial cavity and is often adherent to the great vessels; however, intracardiac origin can rarely occur. Sometimes cardiac teratoma has extracardiac extension. Additionally, there is an increased tendency of cardiac teratoma in twins. Macroscopically, cardiac teratoma displays a cystic and multilobulated appearance and ranges in size from 2 to 9 cm in diameter. Like extracardiac teratoma, derivatives of the endodermal, mesodermal, and neuroectodermal germ layers may be seen on microscopic examination. Both mature and immature elements may be present; however, most pediatric cardiac teratomas are composed of benign mature tissues. Although teratomas are considered to be benign, malignant degeneration and tumor recurrence have been reported. S­urgical removal is the recommended treatment for cardiac teratomas. Most cases of intrapericardial teratomas can be easily dissected; however, excision of intracardiac teratomas can prove quite difficult.

Hemangioma Hemangioma is very rare in the pediatric population; less than 25% of these vascular lesions occur in children. They may arise anywhere in the heart but have a slight predilection to the ventricular septum and right atrium. Pathologically, hemangiomas present as subendocardial nodules and may contain capillary, cavernous, or hemangioendotheliomatous features. Although rare, some children with cardiac hemangioma also present extracardiac hemangiomas. In many cases, cardiac hemangiomas spontaneously resolve, and the prognosis is good. The outcome may be less favorable in infants due to high-output cardiac failure, hemorrhage, or central nervous system involvement.

Histiocytoid Cardiomyopathy Histiocytoid cardiomyopathy (HC) is a rare, but distinctive arrhythmogenic disorder characterized by incessant ventricular tachycardia, cardiomegaly, and often sudden death within the first 2 years of life. A total of 60% of cases are diagnosed within the first year of life, and less than 3% are diagnosed after age 2 years. Furthermore, there is a predilection for females, and 5% of cases are familial. Until recently, HC was diagnosed only at autopsy. However, due to the increasing awareness of HC, children with uncontrolled arrhythmia undergo electrophysiologic mapping followed by ablation of the arrhythmogenic foci which improves the dismal outcome of this disease to greater than 90% survival. In some cases, infants with extensive involvement of the myocardium undergo heart transplantation. Pathologically, HC is defined by abnormal development of the Purkinje fibers within the cardiac conduction system, which results in disrupted cardiac conduction, myocardial thickening, and

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The Heart

26A

26B

26C

26D

FIGURE 7.26  Histiocytoid cardiomyopathy. Myocardial thickening and yellowish tan subendocardial nodules (arrow) and nodules over the aortic valve leaflets (arrows) (A). SA node showing extensive infiltrate of HC cells (B, H&E; 3100). Note the HC cells intermingled with wavy conduction fibers (insert; H&E; 3400). Electron microscopy demonstrating HC cells packed with mitochondria. Diminished myofibrils are displaced to the periphery of the cell (arrow) (C). Subendocardial histiocytoid nodule (D, H&E; 3400).

subendocardial nodules. Multiple yellowish tan nodules on both ventricles and valves are usually present. Microscopically, these nodules are composed of pale, granular, foamy histiocyte-like cells containing abundant swollen mitochondria. HC cells are usually found in aggregates beneath the endocardium along the bundle branches of the conduction system (Figure 7.26). The underlying genetic mechanism of HC has eluded researchers for decades. However, recently, the authors of this chapter and colleagues identified two gene sets aligned sequentially along the genome that are significantly down regulated in HC. These genes include S100A8, S100A9, and S100A12 at 1q21.3 as well as IL1RL1 (ST2), IL18R1, and IL18RAP at 2q12.1a. Furthermore, strong decreases in IL-33 expression were observed. Data suggest a model in which the IL33-IL1RL1/p38-MAPK/S100A8S100A9 axis is down regulated in HC.

Cystic Tumor of Atrioventricular Node Cystic tumor of atrioventricular node, previously known as AV node mesothelioma, is a rare congenital lesion capable of causing complete heart block and sudden death. This small tumor primarily affects females, and a familial tendency has been suggested. Microscopically, the tumor is composed

Heart Transplant Pathology 

27A

27B

FIGURE 7.27  Cystic tumor of the atrioventricular node. Tumor cells infiltrate and destroy the AV node (A, H&E; 3100). The tumor is composed of mucin-filled cystic spaces lined by cuboidal, squamous, and transitional cells (B, H&E; 3400).

of mucin-filled cystic spaces that are lined by cuboidal, squamous, and transitional cells. Tumor cells infiltrate and destroy the AV node (Figure 7.27A,B). Ante-mortem diagnosis and successful surgical excision are rare.

n MALIGNANT CARDIAC TUMORS Malignant cardiac neoplasms are rare in the pediatric age group. The majority of those are metastatic to the heart and pericardium. Among primary malignant cardiac tumors, 95% are sarcomas such as rhabdomyosarcoma and angiosarcoma. Lymphomas represent the remaining 5% of primary malignant cardiac tumors in children. Metastatic cardiac tumors in children include non-Hodgkin lymphoma, neuroblastoma, Wilms tumor, soft tissue sarcoma, and osteosarcoma.

Heart Transplant Pathology Heart transplantation is becoming the accepted treatment with good results and prognoses for pediatric patients with end-stage heart disease or complex congenital heart disease. Among infants and children, cardiomyopathy and congenital heart disease are the most common indications for heart transplantation. Routine endomyocardial biopsy continues to be the gold standard for rejection surveillance in the cardiac allograft.

n HYPERACUTE REJECTION Hyperacute rejection is rarely seen in children. Pathogenesis is believed to be antibody mediated, resulting in severe damage to the capillary network and endothelial cells. Histologically, inflammatory infiltrates, interstitial edema and hemorrhage, and global myocardial ischemic injury are seen. Initially, such changes appear as discrete foci but quickly spread throughout the entire allograft. Immunofluorescent techniques can be used to confirm the diagnosis; however, recently the immunohistochemical

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The Heart

FIGURE 7.28  Antibody-mediated rejection. C4d immunostain showing strong immunoreactivity in endothelial cells (C4d; 3400).

stain C4d, which stains the endothelium of blood vessels, has become the most frequently used to identify antibody-mediated rejection in endomyocardial biopsies (Figure 7.28).

n ACUTE CELLULAR REJECTION Acute cellular rejection is characterized by a mononuclear inflammatory infiltrate of the cardiac allograft that is predominantly T-cell mediated. Acute rejection is subclassified into grades 0, 1, 2, and 3. Grade 0 denotes no rejection. Grade 1 (mild rejection) is defined as interstitial and perivascular infiltrates with up to one focus of myocyte damage (Figure 7.29). In grade 2 (m­oderate rejection), two or more foci of myocyte damage are identified. Finally, grade 3 (severe rejection) is defined as diffuse infiltrate with numerous foci of myocyte damage; additionally, vasculitis, hemorrhage, and edema may be present (Figure 7.30). It is important to distinguish rejection lesions from a phenomenon known as the Quilty lesion. Quilty lesions, or endocardial lymphocytic infiltrates, are found in the endocardium of cardiac allografts but do not represent acute rejection. They are composed of T-lymphocytes with scattered B cells, macrophages, and plasma cells. Small capillaries, dense collagen bundles, and prominent endothelial cells may also be present (Figure 7.31). When Quilty lesions invade the underlying myocardium (invasive Quilty), differentiating from true rejection can be challenging.

FIGURE 7.29  Grade 1 rejection. Interstitial and perivascular infiltrates with one focus of myocyte damage (H&E; 3400).

FIGURE 7.30  Grade 2 rejection. Diffuse infiltrate with multiple foci of myocyte damage and edema (H&E; 3400).

Heart Transplant Pathology 

FIGURE 7.31  Quilty lesion. Endocardial lymphocytic infiltrate (H&E; 3400).

n CHRONIC REJECTION Chronic rejection is a common cause of cardiac allograft failure and death and is characterized by coronary artery disease. Both epicardial and intramyocardial coronary arteries may be affected. The classic histological feature is diffuse concentric narrowing of the arteries with luminal stenosis. Lymphocytic infiltrate may be seen as well (Figure 7.32). Additionally, the authors of this chapter and colleagues have observed Fibrofatty changes in failed cardiac allografts. Endocardial biopsy demonstrating fibrofatty replacement of the right ventricular wall may predict a shortened life of the pediatric cardiac allograft and can be seen more frequently in children with repeated cardiac transplantation (Figure 7.33).

n OPPORTUNISTIC INFECTIONS Because of immunosuppressive therapy, opportunistic infections are common in postcardiac transplantation children; however, they rarely involve the transplanted heart, rather they are usually seen in the lungs. Infections may be bacterial (47%), viral (41%), fungal, or protozoal. Toxoplasma and cytomegalovirus are the most commonly identified infectious agents that involve the heart.

FIGURE 7.32  Chronic rejection. Concentric narrowing of the coronary vessel with lymphocytic infiltrate (H&E; 3100).

FIGURE 7.33  Arrhythmogenic right ventricular dysplasia like changes in failed cardiac allograft. Fibrofatty replacement of the right ventricular wall muscle fibers (H&E; 3100).

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FIGURE 7.34  Posttransplant lymphoproliferative disorders. Intense lymphoplasmacytic infiltrate of the myocardium with scattered immunoblasts (H&E; 3400).

n POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS Posttransplant lymphoproliferative disorders (PTLD) are rare but commonly fatal complications after cardiac transplantation. PTLD refers to a wide range of abnormal lymphocytic growths that range from benign to aggressive and disseminated disease, which, like infections, only rarely involve the transplanted heart (Figure 7.34). Most cases are of B-cell origin, and Epstein-Barr virus is thought to play a causative role. In some cases, reducing immunosuppressive therapy can reverse the proliferation.

Acknowledgment. The author acknowledges the contribution of Dr. Carlos Abramowsky and Dr. Richard Ricketts for some of the gross photos.

BIBLIOGRAPHY Adelfinger G. Genetic factors in congenital heart malformation. Clin Genet. 2008;73(6):516–527. Barron DJ, Kilby MD, Davies B, et al. Hypoplastic left heart syndrome. Lancet. 2009;374(9689):551–564. Burke AP, Veinot JP, Loire R, et al. Tumours of the heart: introduction. In: Travis WD, Brambilla E, MullerHermelink HK, Harris CC, eds. Pathology & Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: Springer-Verlag; 2004:251–253. Burke AP, Virmani R. Pediatric heart tumors. Cardiovasc Pathol. 2008;17(4):193–198. Cooper LT. Myocarditis. N Engl J Med. 2009;360:1526–1538. Gilbert-Barness E. Review: metabolic cardiomyopathy and conduction system defects in children. Ann Clin Lab Sci. 2004;34(1):15–34. Gilbert-Barness E, Barness LA. Pathogenesis of cardiac conduction disorders in children genetic and histopathologic aspects. Am J Med Genet. 2006;140(19):1993–2006. Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies. Int J Exp Pathol. 2000;81(6):349–372. Isaacs H Jr. Fetal and neonatal cardiac tumors. Pediatr Cardiol. 2004;25(3):252–273. Kornosky JL, Salihu HM. Getting to the heart of the matter: epidemiology of cyanotic heart defects. Pediatr Cardiol. 2008;29(3):484–497. McDaniel NL. Ventricular and atrial septal defects. Pediatrics in Review. 2001;22:265–270. Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia. Prog Cardiovasc Dis. 2008; 51(1):31–43. Sharieff GQ, Wylie TW. Pediatric cardiac disorders. J Emerg Med. 2004;26(1):65–79. Tan CD, Baldwin WM III, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med, 2007;131(8):1169–1191. Wilcken DE. Overview of inherited metabolic disorders causing cardiovascular disease. J Inherit Metab Dis. 2003;26(2–3):245–257.

8

The Lung and Mediastinum J. thomas Stocker Aliya n. Husain

n

CONGENITAL PULMONARY AIRWAY MALFORMATION (CONGENITAL CYSTIC ADENOMATOID MALFORMATION)

EXTRALOBAR PULMONARY SEQUESTRATION

n

ALVEOLAR CAPILLARY DYSPLASIA

n

INTRALOBAR PULMONARY SEQUESTRATION

n

n

TRACHEOESOPHAGEAL FISTULA AND ESOPHAGEAL ATRESIA

n

BRONCHOGENIC CYST

n n n

PULMONARY HYPOPLASIA

n

INFANTILE LOBAR EMPHYSEMA (CONGENITAL LOBAR EMPHYSEMA)

n

CONGENITAL PULMONARY LYMPHANGIECTASIS

n

IDIOPATHIC PULMONARY HEMOSIDEROSIS

n

MYOFIBROBLASTIC TUMOR (INFLAMMATORY PSEUDOTUMOR)

PERIPHERAL CYSTS

n

JUVENILE SQUAMOUS PAPILLOMAS

HYALINE MEMBRANE DISEASE, BRONCHOPULMONARY DYSPLASIA, AND CHRONIC LUNG DISEASE OF THE PREMATURE

n

PLEUROPULMONARY BLASTOMA

n

CYSTIC FIBROSIS

n

ASTHMA

n

CONGENITAL SURFACTANT DEFICIENCY

n

n

INTERSTITIAL PULMONARY EMPHYSEMA

DIAPHRAGMATIC HERNIA AND DIAPHRAGMATIC EVENTRATION

TraCheoesoPhaGeal FisTula and esoPhaGeal aTresia Tracheoesophageal fistula (TEF) with or without esophageal atresia (EA) occurs in approximately 1 in 3,500 live births and is associated with maternal polyhydramnios in 30% of cases and prematurity in 35%. Those infants with both TEF and EA (95% of cases) usually present with excessive oral and pharyngeal secretions. With their first attempts at feeding, they exhibit coughing, choking, and cyanosis. TEF is associated with other anomalies in more than 50% of cases, including its nonrandom association with the malformations of the VATER association–Vertebral or Vascular Anal atresia, TracheoEsophageal fistula, Renal or Radial (limb). Other anomalies include diaphragmatic hernia, biliary atresia, duodenal atresia, trisomy 18, sirenomelia, and congenital pulmonary airway malformation (CPAM). An acquired TEF may be seen following mediastinal surgery or chemotherapy. 1a

1B

FiGure 8.1 Types of tracheoesophageal fistula (TEF) and esophageal atresia (EA). EA with TEF to the distal esophageal segment (more that 85% of cases) (A). ES without TEF (8%) (B). TEF without EA (4%) (C). EA with TEF to the proximal esophageal segment (1%) (D). EA with TEF to both proximal and distal esophageal segments (1%) (E). (Continued)

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1D

1E

FIGURE 8.1  Types of TEF and EF. (Continued)

2B

2A

FIGURE 8.2  Tracheoesophageal fistula (TEF) and esophageal atresia (EA). Unopened TEF with EA viewed from behind (A). Note the blind-ending esophagus (arrow). The distal esophagus (opened) is attached to the trachea at the level of the carina (B).

BRONCHOGENIC CYST 

BRONCHOGENIC CYST The bronchogenic cyst is a discrete, extrapulmonary mass filled with fluid and composed of a wall lined by respiratory epithelium overlying fibromuscular connective tissue that contains seromucinous glands and cartilage plates. It is noted most frequently in the hilar or middle-mediastinal area, but it may be present in a midline location from the subcutaneous region of the suprasternal area to beneath the diaphragm. Bronchogenic cysts are rarely connected to the tracheobronchial tree or involve the pulmonary parenchyma. Bronchogenic cysts are seen most frequently in children and young adults as incidental findings on chest radiographs, at surgery, or at autopsy, but they may present with symptoms related to secondary infection of the cyst, including fever, hemorrhage, or perforation. In infants, bronchogenic cysts located near the trachea, especially the carina, may produce obstruction and respiratory distress.

FIGURE 8.3  Bronchogenic cyst. A large cystic mass is present in the mediastinum immediately adjacent to the heart.

FIGURE 8.4  Bronchogenic cyst. The cyst is surrounded by connective tissue but is separate from the pulmonary parenchyma.

FIGURE 8.5  Bronchogenic cyst. In this newborn infant, the bronchogenic cyst developed immediately adjacent to the right main stem bronchus in the region of the carina.

FIGURE 8.6  Bronchogenic cyst. The wall of the cyst is composed of respiratory epithelium (ciliated pseudostratified columnar epithelium) overlying a loose connective tissue wall with seromucinous glands. Note the cartilage plate at lower right.

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EXTRALOBAR PULMONARY SEQUESTRATION Extralobar sequestrations (ELS) of the lung are discrete masses of pulmonary parenchyma outside the normal pleural investment of the lung and are not connected to the tracheobronchial tree. They apparently originate from an out pouching of the foregut, separate from the normally developing lung. ELSs are diagnosed prenatally in about 25% of cases and about 60% of patients present by 3 months of age. Presenting symptoms, often noted on the first day of life, include cyanosis, dyspnea, and difficulty in feeding. Approximately 10% of patients are asymptomatic. Fetal nonimmune hydrops, anasarca, pleural effusion, or localized edema may be present along with maternal polyhydramnios. Associated anomalies are present in more than 65% of cases of ELS, with 50% of lesions containing CPAM, type 2 within the sequestration, or, less frequently, in a lobe of the “normal” lung.

FIGURE 8.7  Extralobar pulmonary sequestration (ELS). A large mass was noted in the right hemithorax in this newborn infant. At autopsy, the ELS partially filled the hemithorax causing severe hypoplasia of the right lung. Note the relatively normal-sized left lung.

FIGURE 8.8  Extralobar pulmonary sequestration (ELS). Cut section of the mass displays normally appearing, though expanded, pulmonary ­parenchyma.

FIGURE 8.9  Extralobar pulmonary sequestration FIGURE 8.10  Extralobar pulmonary sequestration (ELS). Microscopically, the mass in Figure 8.8 is composed (ELS). A cross section of a different ELS displays an of pulmonary parenchyma with well-formed acinar irregular cut surface with numerous small cysts. structures. Note the expanded parenchyma all the way from the respiratory bronchiole to the farthest alveolus.

INTRALOBAR PULMONARY SEQUESTRATION 

151

FIGURE 8.11  Extralobar pulmonary sequestration. The microscopic section from Figure 8.10 shows multiple small cysts lined by cuboidal epithelium, a pattern typical of CPAM, type 2. This feature is seen in 50% of ELS.

INTRALOBAR PULMONARY SEQUESTRATION Intralobar sequestration (ILS), by definition, consists of a portion of lung within the normal pleural investment that is isolated (sequestered) from the tracheobronchial tree, and is supplied by a systemic artery. ILSs involve the lower lobe in 98% of cases. Radiographic findings include cystic areas, some with fluid levels, along with homogenous and inhomogeneous shadows. Lack of communication with the tracheobronchial tree is demonstrable by bronchography in about 85% of cases; the other 15% of cases show some communication between the bronchial tree and the sequestration. Arteriography demonstrates single (84%) or multiple (10%) systemic arteries. Venous drainage occurs through the pulmonary veins in 95% of cases, and the remaining 5% of cases drain into the systemic circulation.

FIGURE 8.12  Intralobar pulmonary sequestration. A density in the left lobar lobe is present in this child with a history of recurrent pulmonary infections. A systemic artery supply to the lesion was demonstrated by arteriography.

FIGURE 8.13  Intralobar pulmonary sequestration. The resected lower lobe displayed a firm fibrotic mass with cysts of varying sizes. A systemic artery from the thoracic aorta passed through the pulmonary ligament to the lesion.

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FIGURE 8.14  Intralobar pulmonary sequestration. The microscopic sections display marked chronic inflammation and fibrosis surrounding cysts lined by cuboidal epithelium. Small islands of residual acinar parenchyma are also present.

PULMONARY HYPOPLASIA Pulmonary hypoplasia is the incomplete or defective development of the lung resulting in overall reduced size caused by reduced numbers or size of acini. Pulmonary hypoplasia is noted in more than 10% of neonatal autopsies and occurs in association with another malformation (or malformations) in more than 85% of cases. The most frequently occurring anomalies are diaphragmatic defects (discussed later in this chapter) and renal malformations. The common feature of most of these anomalies is that they directly or indirectly compromise the thoracic space available for lung growth. The cause of the decreased thoracic space may be intrathoracic (e.g., abdominal contents herniated through a defect in the diaphragm), extrathoracic (e.g., oligohydramnios with uterine fetal compression), or an intrinsic malformation of the thorax itself (e.g., Jeune asphyxiating thoracic dystrophy).

FIGURE 8.15  Pulmonary hypoplasia. An infant with autosomal recessive polycystic kidney and liver disease (ARPKLD) displays markedly enlarged kidneys that have pushed up the liver and diaphragm, severely compromising the thoracic space.

FIGURE 8.16  Pulmonary hypoplasia. This infant with Jeune asphyxiating thoracic dystrophy has a markedly narrowed thorax that barely allows room for the heart. The infant lungs were only 28% of expected weight.

INFANTILE LOBAR EMPHYSEMA (CONGENITAL LOBAR EMPHYSEMA) 

153

FIGURE 8.17  Pulmonary hypoplasia. The hypoplastic lungs are characterized by acini that are reduced in size as indicated by a reduced radial alveolar count (RAC). Note in the region beneath the pleura (left), the short distance between the terminal-respiratory bronchioles and the pleura (orange line). The RAC in this case was 2 with an expected normal range of 4–6.

INFANTILE LOBAR EMPHYSEMA (CONGENITAL LOBAR EMPHYSEMA) Infantile lobar emphysema (ILE) is the overdistension or hyperplasia of a pulmonary lobe as the result of a partial or complete obstruction of the bronchus to the lobe by an intrinsic or extrinsic factor. Boys are more frequently affected than girls (1.5:1). ILE presents in the first week of life in about 50% of cases (with about 40% presenting in the first day of life) and in the first 6 months of life in more than 80%, but ILE can occasionally be seen in children and young adults from 7 months to 20 years of age. Symptoms are those of mild respiratory distress increasing over a period of hours to days to weeks; cyanosis, respiratory infections, vomiting, choking, and feeding difficulties may also be seen. Associated anomalies are present in from 5% to 40% of patients, and 70% of these anomalies are cardiovascular. The upper lobes are involved in more than 95% of cases—the left slightly more often than the right. Multiple lobe involvement occurs in about 15% of cases, usually with at least one lobe being an upper lobe. FIGURE 8.18  Infantile lobar emphysema. In this classic hyperinflation of an upper lobe of the lung, the markedly expanded left upper lobe has shifted the mediastinum to the right.

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FIGURE 8.19  Infantile lobar emphysema. At surgery, the hyperexpanded lobe pushes out through the incision into the thorax.

FIGURE 8.20  Infantile lobar emphysema. A section of the hyperinflated lobe displays a large bronchovascular bundle (top center) and distended individual alveoli that are rarely visible in a normally expanded lung.

FIGURE 8.21  Infantile lobar emphysema. Classic form (70% of cases). At a low magnification, the uniformly distended acini are readily seen. A RAC in this lung was normal for the age of the infant (approximately 4–6).

FIGURE 8.22  Infantile lobar emphysema. Hyperplastic or complex form (30% of cases). In the complex form of ILE, the lung is not so much hyperexpanded as it is hyperplastic. The RAC of this distal acinus is more than 12 (orange line) with an expected normal of 4–6.

CONGENITAL PULMONARY LYMPHANGIECTASIS Congenital pulmonary lymphangiectasis (CPL) is a rare, usually fatal disorder that presents in the first hours to days of life. It is characterized by the presence of dilated thin-to thick–walled lymphatics within the interlobular septa and beneath the pleura of the lung. CPL may be seen as a primary disorder or as secondary to obstructive cardiovascular lesions, particularly total anomalous pulmonary venous return, but it may occur as part of a generalized lymphangiectasis or as an isolated pulmonary lesion. There is a distinct male predominance in occurrence of CPL of more than 2.5:1, and 5% to 10% of affected infants are stillborn. Symptoms include cyanosis and acute respiratory distress. Fluid abnormalities including chylothorax, pleural effusion, fetal hydrops, and maternal polyhydramnios have been described in utero and postpartum. In addition to the 60% of cases with cardiovascular anomalies, CPL is associated with renal malformations, generalized lymphangiectasis, and other anomalies in another 20% of cases.

CONGENITAL PULMONARY AIRWAY MALFORMATION (CONGENITAL CYSTIC ADENOMATOID MALFORMATION)  

FIGURE 8.23  Congenital pulmonary lymphangiectasia. The white linear pattern beneath the pleura represents dilated subpleural and interlobular lymphatics.

155

FIGURE 8.24  Congenital pulmonary lymphangiectasia. The dilated lymphatics are present throughout the interlobular septa and beneath the pleura.

FIGURE 8.25  Congenital pulmonary lymphangiectasia. The dilated lymphatics extend up the interlobular septum (center) then laterally beneath the pleura.

CONGENITAL PULMONARY AIRWAY MALFORMATION (CONGENITAL CYSTIC ADENOMATOID MALFORMATION) Congenital pulmonary airway malformation (CPAM) is a hamartomatous lesion of the lung, with an incidence of about 1 in 5,000 live births, which can be separated into five major types based on clinical and pathologic features. FIGURE 8.26  Congenital pulmonary airway malformation, type 0. CPAM, type 0, also known as acinar dysplasia or agenesis, is a rarely occurring and infrequently described malformation that is largely incompatible with life. It is seen in term and premature infants who are cyanotic at birth and survive only a few hours, and is associated with cardiovascular abnormalities and dermal hypoplasia. Grossly, the lesion displays a finely nodular surface.

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FIGURE 8.27  Congenital pulmonary airway malformation (CPAM), type 0. Microscopically, the “parenchyma” consists only of large bronchi and bronchioles surrounded by loose fibrovascular tissue. There is a virtual absence of acinar structures beyond the bronchial level.

FIGURE 8.28  Congenital pulmonary airway malformation (CPAM), type 1. CPAM, type 1, the large or predominant cyst type, presents primarily within the first week to month of life but can be seen in older children and even young adults. It accounts for nearly 65% of cases and is usually readily amenable to surgery with a good prognosis. Radiographically, the air-filled multicystic lesion compresses the adjacent lung and produces mediastinal shift.

29B

FIGURE 8.29  Congenital pulmonary airway malformation (CPAM), type 1. Grossly, the lesion is composed of cysts often exceeding 2 cm in diameter that can be seen as lucent areas beneath the pleura (A). On cut section, the cysts are noted to be interconnected and with cyst walls composed of thin to opaque tissue (B).

29A

CONGENITAL PULMONARY AIRWAY MALFORMATION (CONGENITAL CYSTIC ADENOMATOID MALFORMATION)  

157

FIGURE 8.30  Congenital pulmonary airway malformation (CPAM), type 1. Microscopically, the cysts are lined by cuboidal to pseudostratified columnar epithelium. The underlying tissue may contain smooth muscle and occasional cartilage plates.

31A

31B

FIGURE 8.31  Congenital pulmonary airway malformation (CPAM), type 1. There are 35% to 50% of type 1 lesions that contain clusters of mucogenic “goblet” cells either along the surface of the cysts or within the bronchiolar or alveolarlike structures adjacent to the cysts. These clusters of cells are thought to predispose the patient to the development of bronchioloalveolar carcinoma in later life (A). Bronchioloalveolar carcinoma in a young adult whose CPAM, type 1 was partially resected 14 years previously (B).

FIGURE 8.32  Congenital pulmonary airway malformation (CPAM), type 2. CPAM, type 2, the medium cyst type, accounts for 10% to 15% of cases, is seen exclusively within the first year of life, and has a poorer outcome owing to its more frequent association with other anomalies, some of which are incompatible with life (e.g., renal agenesis). Grossly, the lesion is composed of cysts rarely more than 1.5 cm in diameter that tend to blend with the normal adjacent parenchyma.

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33A

33B

FIGURE 8.33  Congenital pulmonary airway malformation (CPAM), type 2. Microscopically, the type 2 lesion is composed of back-to-back bronchiole-like structures with very little intervening tissue (A). Many of the type 2 lesions may contain striated muscle fibers (rhabdomyomatous dysplasia) around and between cysts and vessels (B).

FIGURE 8.34  Congenital pulmonary airway malformation (CPAM), type 3. CPAM, type 3, the small cystic or solid type, occurs infrequently (5% of cases), is seen exclusively in the first days to month of life, has a notable male predominance, and owing to its large size and association with maternal polyhydramnios and fetal anasarca, has a high mortality rate. Grossly, the lesion is “noncystic” and appears more like dense pulmonary parenchyma.

FIGURE 8.35  Congenital pulmonary airway malformation (CPAM), type 3. Microscopically, the lesion consists of bronchiole-like and more distal acinar structures, all of which are lined by simple cuboidal epithelium. Note the paucity of vessels.

FIGURE 8.36  Congenital pulmonary airway malformation (CPAM), type 4. CPAM, type 4, the peripheral acinar cyst type, appears to be a hamartomatous malformation of the distal acinus. This variant is seen equally in boys and girls, with an age range of newborn to 4 years and accounts for 10% to 15% of cases. Clinically, the type 4 lesions may present with mild respiratory distress, sudden respiratory distress from tension pneumothorax, pneumonia, or on occasion, as an incidental finding with no symptoms. Care must be taken to differentiate this lesion from the purely cystic pleuropulmonary blastoma (PPB) (discussed later in this chapter). Grossly, the lesion may vary from one with large cysts (top) to one with smaller cysts and more compact parenchyma.

ALVEOLAR CAPILLARY DYSPLASIA 

37A

159

37B

FIGURE 8.37  Congenital pulmonary airway malformation, type 4. Microscopically, the cysts, especially in the younger patients, are thin-walled with a notable absence of cuboidal or columnar epithelium (A). At high power (B) (and with appropriate immunohistochemical stains), the lining cells can be seen to be type 2 alveolar lining cells.

ALVEOLAR CAPILLARY DYSPLASIA Congenital alveolar capillary dysplasia with or without misalignment of pulmonary veins is a rare entity that presents as progressive hypoxemia in the newborn and is uniformly fatal. Familial occurrence has been noted. Associated anomalies are seen in more than 50% of cases and include duodenal atresia, congenital heart disease, asplenia, phocomelia, and ureteric and urethral obstruction, among others. It is characterized by the failure of formation and ingrowth of alveolar capillaries. FIGURE 8.38  Alveolar capillary dysplasia. Grossly, on cut section, a noncystic parenchyma contains what appears to be dilated blood filled vessels.

39A

39b

FIGURE 8.39  Alveolar capillary dysplasia. The key microscopic features include (A) pulmonary arteries with pulmonary veins within their adventitia, a prominent capillary bed in the central portion of the alveolar septa (B), and muscularized arterioles at the periphery of the acini (C).

39c

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PERIPHERAL CYSTS Peripheral air-containing cysts of the lung can be seen in neonates, infants, and young children; it occurs in association with Down’s syndrome, as a result of pulmonary infarction, or in association with idiopathic spontaneous pneumothorax. Occlusion of the pulmonary artery in infants can result in peripheral infarction of the lung, which, with necrosis and organization, can produce subpleural cysts of varying size. Gonzalez et al. (1991) reported peripheral cysts in 18 of 98 patients with Down syndrome and suggested that the cysts are an intrinsic feature of the disease that may result from reduced postnatal production of peripheral small air passages and alveoli.

FIGURE 8.40  Peripheral lung cysts. Peripheral cysts develop after the acinar tissue between interlobular septa is infarcted, becomes necrotic, and is removed. The occluded pulmonary artery supply leads to peripheral necrosis, whereas the more central tissue continues to be supplied by bronchial artery anastomoses.

FIGURE 8.41  Peripheral lung cysts. The septa between the peripheral cysts represent uninfarcted interlobular septa that are supplied by branches of the bronchial arteries, not the pulmonary artery.

HYALINE MEMBRANE DISEASE, BRONCHOPULMONARY DYSPLASIA, AND CHRONIC LUNG DISEASE OF THE PREMATURE Hyaline membrane disease (HMD) is the pathologic counterpart of neonatal or idiopathic respiratory distress syndrome (RDS). It is characterized by firm, atelectatic lungs with an uneven air-expansion pattern, focal hemorrhage, edema fluid in alveoli, and hyaline membranes along terminal and respiratory bronchioles and alveolar ducts. Bronchopulmonary dysplasia (BPD) was first described in 1967 by Northway et al. The pathologic features occur in stages starting with the typical findings of HMD (e.g., atelectasis, uneven air expansion pattern, hemorrhage, and hyaline membranes). During the next stage, there is necrosis of bronchiolar (necrotizing bronchiolitis) and alveolar epithelium with persistence of hyaline membranes and alveolar cell hyperplasia/dysplasia. In the transition to chronic

HYALINE MEMBRANE DISEASE, BRONCHOPULMONARY DYSPLASIA, AND CHRONIC LUNG DISEASE OF THE PREMATURE  

disease, injury to alveolar epithelium continues, along with widespread bronchial and bronchiolar mucosal metaplasia and marked mucus secretion. Clusters of hyperexpanded alveoli alternated with areas of atelectasis. In the chronic stage, alveolar septa display fibrosis and bronchioles display marked peribronchiolar smooth muscle hypertrophy associated with clusters of “emphysematous alveoli.” A long-standing “healed” stage occurs when the oxygen and mechanical ventilation are removed and the injured lung “heals” with areas of simplified acini and other areas with diffuse alveolar septal fibrosis. In recent years, with the advent of surfactant replacement therapy and increased sophistication in the use of mechanical ventilation (including high-frequency jet ventilation) and oxygen supplementation, another stage in the evolution of the pathology of BPD has been seen. The few infants who now die from “bronchopulmonary dysplasia” display what might best be described as “acinar simplification.” These simplified acini are characterized by uniformly dilated alveoli whose walls consist of thin alveolar septa with little or no interstitial fibrosis. This disease might now best be called chronic lung disease of the premature infant rather than BPD.

FIGURE 8.42  Hyaline membrane disease. The lungs are often atelectatic and airless at the time of autopsy. Hemorrhage may be a component seen as well.

FIGURE 8.43  Hyaline membrane disease. Microscopically, the distal acini are usually collapsed, pushing the air into the terminal and respiratory bronchioles. Hyaline membranes (bright pink) are closely applied to the walls or bronchioles and alveolar ducts.

44B

44A

44C

FIGURE 8.44  Acute bronchopulmonary dysplasia. In the acute stages of BPD, acini may be protected from oxygen and barotrauma (A) by occlusion of the bronchiole by necrotizing bronchiolitis. Other acini (B and C) with bronchioles that remain partially or completely open may show varying degrees of injury.

FIGURE 8.45  Acute bronchopulmonary dysplasia. Necrotic debris (necrotizing bronchiolitis) fills a bronchiole, preventing oxygen or mechanical pressure from reaching and injuring the acinus beyond the obstruction.

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47A

47B

47C

FIGURE 8.46  Acute bronchopulmonary dysplasia. A bronchiole (top center) that has remained patent allows the high oxygen concentration and barotrauma to injure the acinus it supplies.

FIGURE 8.48  Healed bronchopulmonary dysplasia. An acinus (left) previously “protected” by an obstructed ­bronchiole displays little damage compared to the “unprotected” acinus (right) that now has expensive alveolar septal fibrosis.

FIGURE 8.47  Healed bronchopulmonary dysplasia. Following removal of the oxygen and barotrauma, the obstructive necrotizing bronchiolitis resolves leaving an “uninjured” acinus (A). The acini injured by the oxygen and barotrauma may either heal with alveolar septal fibrosis (B) or be largely destroyed (C).

49A

49B

49C

49D

FIGURE 8.49  Chronic lung disease of prematurity. With low oxygen concentration and little barotrauma, the immature lung (A) is rarely injured (note the mild alveolar septal fibrosis in D) and may develop normally (note the alveolar development in B) or may remain “simplified” (C) with little new alveolar development.

CONGENITAL SURFACTANT DEFICIENCY 

163

FIGURE 8.50  Chronic lung disease of prematurity. A markedly “simplified” acinus has expanded without the development of additional alveoli much beyond the number present at the time of the premature birth.

CONGENITAL SURFACTANT DEFICIENCY Inherited deficiency of one or more surfactant proteins (most frequently surfactant protein B) is often a fatal autosomal recessive disorder of lung cell metabolism and is characterized by rapidly progressive respiratory failure immediately after birth. The disease is caused by a deficiency of adenosine triphosphate–binding cassette (ABC) protein, most frequently ABCA3. Chorionic villous sampling can be used to identify the homozygous state in utero. Less frequently, abnormalities of surfactant protein A and C may occur. Lung transplantation has been successful although patients may develop antisurfactant protein B antibody. FIGURE 8.51  Congenital surfactant deficiency. Alveoli are lined by hyperplasic alveolar lung cells, some of which have desquamated in the alveolar lumen.

52A

52B

FIGURE 8.52  Congenital surfactant deficiency. In this infant with surfactant B deficiency, surfactant A is readily apparent (A) but surfactant B is absent (B). Immunoperoxidase stains for surfactant A (A) and surfactant B (B).

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INTERSTITIAL PULMONARY EMPHYSEMA Interstitial pulmonary emphysema (IPE) is the dissection by air around bronchovascular ­bundles and along intralobular septa as the result of rupture of alveoli, usually in association with mechanical ventilation. Dissection of air peripherally through the pleura produces pneumothorax, whereas medial dissection can lead to pneumomediastinum, pneumopericardium, and rarely, pneumomyocardium. Although these air leaks can occasionally be observed in ­normal infants and may spontaneously occur in about 5% of infants with RDS, the highest incidence is seen in infants with RDS who are receiving mechanical ventilation. IPE can be acute (less than 7 days’ duration) or persistent and may be localized to a single lobe or distributed diffusely through all lobes.

FIGURE 8.53  Acute interstitial pulmonary emphysema. Air enters the interstitial spaces of the lung through rupture of an alveolus where it abuts the interlobular septa. The air then dissects peripherally to the pleura (note the air-filled cysts beneath the pleura) or centrally to the mediastinum.

FIGURE 8.54  Acute interstitial pulmonary emphysema. In a cross section of lung, the airspaces can be seen along the interlobular septa and beneath the pleura (top).

FIGURE 8.55  Acute interstitial pulmonary emphysema. Microscopically, the air is present around bronchovascular bundles and may compress some of the vessels.

IDIOPATHIC PULMONARY HEMOSIDEROSIS 

FIGURE 8.56  Pneumomediastinum. Interstitial air may dissect toward the mediastinum and become trapped in that tissue.

FIGURE 8.57  Pneumopericardium. Interstitial air that dissects along the pulmonary arteries or veins may extend into the pericardial sac. Source: Courtesy of Ralph Franciosi, MD.

FIGURE 8.58  Persistent interstitial pulmonary emphysema. Interstitial air that persists for 7 or more days, produces a foreign body giant cell reaction along with fibrosis. Note the white tissue in the cysts beneath the pleura.

FIGURE 8.59  Persistent interstitial pulmonary emphysema. The foreign body giant cell reaction may be prominent along the walls of the cysts.

IDIOPATHIC PULMONARY HEMOSIDEROSIS Idiopathic pulmonary hemosiderosis (IPH) presents with symptoms including anemia, hypoxemia (85%), dyspnea, and hemoptysis (65%). It occurs primarily in children 3–6 years of age but can be seen in children as young as 4–6 months. Consanguinity and environmental factors may be involved in the development of IPH. Sex incidence is equal, and 15% to 20% of cases occur in adolescents and young adults. Less specific nonpulmonary symptoms include fever (in as many as 79% of cases), lymphadenopathy, hepatomegaly, and splenomegaly. Radiographically, early stages are characterized by patchy or diffuse pulmonary infiltrates or massive confluent shadows that may rapidly clear. In later stages of the disease, there is a perihilar reticulation or a pattern of diffuse interstitial disease. The clinical triad of hemoptysis, iron deficiency ­anemia, and diffuse parenchymal infiltrates is strongly suggestive of IPH.

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FIGURE 8.60  Idiopathic pulmonary hemosiderosis. Fluffy densities are present throughout the lung.

FIGURE 8.61  Idiopathic pulmonary hemosiderosis. The densities in Figure 8.60 correlate with areas of hemorrhage in the parenchyma, here beneath the pleura.

FIGURE 8.62  Idiopathic pulmonary hemosiderosis. A Prussian blue stain for iron displays the marked hemosiderosis within the lung.

FIGURE 8.63  Idiopathic pulmonary hemosiderosis. The Prussian blue stain for iron also displays hemosiderin within the adventitia of the pulmonary vessels.

MYOFIBROBLASTIC TUMOR (INFLAMMATORY PSEUDOTUMOR) Myofibroblastic tumor of the lung is by far the most common benign tumor of the lung in ­children, accounting for up to 84% of cases; these tumors are more common in older children, and only anecdotally in infancy. Children with myofibroblastic tumor present with fever (22%), cough (20%), chest pain (11%), hemoptysis (9%), or pneumonia (8%). Although this tumor is thought by many to begin as a reactive process, a history of preceding pulmonary disease is noted in only 20% to 33% of cases, and about 30% of cases (70% in some series) are asymptomatic when discovered. The lesion is usually seen as a firm, circumscribed, 3- to 10-cm, grayish white mass, peripherally or centrally, although they may also involve the major bronchi and trachea. Even peripheral lesions have been suggested to be closely related to airways, as peribronchial, submucosal, or endobronchial nodules.

JUVENILE SQUAMOUS PAPILLOMAS 

FIGURE 8.64  Myofibroblastic tumor. A discrete round opacity is present in the right lower lobe.

FIGURE 8.65  Myofibroblastic tumor. The resected circumscribed lesion is moderately firm to hard and appears intimately associated with the adjacent pulmonary parenchyma.

FIGURE 8.66  Myofibroblastic tumor. The dense lesion abuts the normal lung with no discrete capsule separating the two.

FIGURE 8.67  Myofibroblastic tumor. The lesion is composed of varying concentrations of plasma cells, lymphocytes, myofibroblasts, and collagen. Entrapped bronchioles may be present as well.

JUVENILE SQUAMOUS PAPILLOMAS Juvenile squamous papillomas are benign neoplasms that occur most commonly in the larynx, but extend into the trachea in 5% of patients and, rarely, into the pulmonary parenchyma. The papillomas occur in 1,500–2,000 infants and children in the United States each year and are caused by a human papillomavirus (HPV) 6 and 11, which may be transmitted to the child from the mother during parturition. The papillary growths in the larynx produce hoarseness and inspiratory stridor, which may progress to acute respiratory distress. Treatment includes standard surgical resection, cryosurgery, and laser therapy. Recurrences are noted in many patients requiring multiple resections and even tracheostomy. However, spontaneous regression may occur in older children. With repeated manipulation (e.g., surgery, intubation), fragments of the papillomas may spread down the trachea into the bronchi and pulmonary parenchyma and produce solid and cavitary lesions composed of sheets of squamous epithelial cells. The incidence of lung involvement in recurrent papillomatosis has been estimated at 3.3%.

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69A

FIGURE 8.68  Juvenile squamous papillomas. The larynx and upper trachea are partially obstructed by papillary growths originating in the squamous mucosa.

69b

FIGURE 8.69  Juvenile squamous papillomas. The papillary growths (A) may break off and “seed” the lower airway and parenchyma, where they may grow as independent lesions (B).

FIGURE 8.70  Juvenile squamous papillomas. The papillary lesion along the trachea and larynx as well as those that seed the lung consist of clusters of stratified squamous epithelium with a central fibrovascular core.

PLEUROPULMONARY BLASTOMA PPB is a rare distinct embryonic primary pulmonary tumor in children, with more than 220 confirmed cases in the International Pleuropulmonary Blastoma Registry (www.ppbregistry.org). There is an equal gender incidence, and the vast majority (94%) present in the first 6 years of life, although cases have been reported in older children and even in adulthood. Presenting symptoms include respiratory distress, nonproductive cough, fever, chest pain, or a combination of symptoms of days’ to weeks’ duration. The lesion is considered part of a hereditary tumor predisposition syndrome, and there is often a positive family history of childhood neoplasms, including PPBs in siblings, cousins, and other close relatives. Other associations in PPB patients include familial cystic nephroma and

PLEUROPULMONARY BLASTOMA 

169

other renal tumors, medulloblastoma, ovarian tumors (germ cell tumor and sex cord stromal tumor), seminoma, Hodgkin disease, leukemia, thyroid neoplasia, and intestinal polyps. Imaging studies may show a solid and/or cystic lesion that may be intrapulmonary, pleural-based or mediastinal; a cystic component is more prominent in younger children consistent with the supposed progression of lesions with increasing age. Tumors are classified as type I (cystic, 14% of cases, median age is 9 months), type II (cystic and solid, 48% of cases, median age is 36 months), and type III (solid, 38% of cases, median age is 42 months).

FIGURE 8.71  Pleuropulmonary blastoma (PPB). The type I purely cystic PPB often consists of a single large cyst.

FIGURE 8.72  Pleuropulmonary blastoma (PPB). The type II cystic and solid PPB may contain nodules or masses of tissue attached to an integral part of the cyst wall.

FIGURE 8.73  Pleuropulmonary blastoma (PPB). The type III solid PPB may attach to the pleura or even the thoracic wall.

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FIGURE 8.74  Pleuropulmonary blastoma (PPB). The cyst walls contain strips of cuboidal or respiratory epithelium overlying a densely cellular “cambium” layer of rhabdomyosarcoma.

FIGURE 8.75  Pleuropulmonary blastoma (PPB). The solid areas of PPB display areas of malignant tumor varying from rhabdomyosarcoma to chondrosarcoma to undifferentiated sarcoma.

CYSTIC FIBROSIS Cystic fibrosis (CF) is a multisystem disorder of children and adults, the most common lethal genetic disease of the white population, and the major cause of severe chronic lung disease of children. CF is inherited as an autosomal recessive disorder, with 70% of cases caused by mutations in the CF transmembrane conductance regulator gene located on chromosome 7 at DF508. The other 30% of the mutations number more than 1,000. CF is characterized by high viscosity of the mucoid secretion products in the lungs, ­pancreas, liver, and gastrointestinal tract, which causes plugging and secondary damage to these organs. Nasal and sinus polyposis are commonly seen in patients with CF, and pulmonary infection has long been recognized to be the most common cause of morbidity and mortality in these patients. The respiratory flora of patients with CF includes Staphylococcus aureus and Haemophilus ­influenzae in the early stages of the disease, but repeated and chronic infections with ­Pseudomonas aeruginosa frequently occur. Eradication of P. aeruginosa is extremely difficult in CF patients, and the organism may be the dominant respiratory pathogen for years.

FIGURE 8.76  Cystic fibrosis. In this resected lung from an 18-year-old woman at the time of pulmonary transplantation, the bronchi are extremely dilated (bronchiectasis) and filled with viscid mucoid material.

ASTHMA 

FIGURE 8.77  Cystic fibrosis. At low magnification, the bronchiectasis is readily apparent and the bronchi are filled with inflammatory debris.

FIGURE 8.78  Cystic fibrosis. This large bronchus, filled with mucus and inflammatory debris, shows a wall whose submucosal glands are suffused with lymphocytes and neutrophils. The alveoli adjacent to the bronchus are free of inflammation.

ASTHMA Asthma is an acute, usually reversible airway disease that results in spasmodic, diffuse airway narrowing, with persistent airway hyperreactivity. It affects 3% to 8% of the population and accounts for 2,000–3,000 deaths each year in the United States. In autopsy specimens of patients dying during an acute attack, the lungs show alternating areas of atelectasis and hyperexpansion. Mucus plugs composed of soft, gelatinous, or rubbery grey material fill medium to small bronchi. The smooth muscle of bronchi is markedly thickened, often 2.5-fold or more than normal.

FIGURE 8.79  Asthma. This large bronchus, filled with mucus, shows a wall with marked smooth muscle ­hypertrophy.

FIGURE 8.80  Asthma. A prominent feature of asthma is the marked thickening of the basement membrane beneath the mucosa.

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DIAPHRAGMATIC HERNIA AND DIAPHRAGMATIC EVENTRATION Diaphragmatic hernia is one of the most frequently occurring anomalies of the lungs and thorax, seen once in every 2,000–5,000 births. Herniation of abdominal contents into the thoracic cavity through a defect in the diaphragm occurs early in gestation and results in varying degrees of pulmonary hypoplasia. The defect is usually in the posterolateral (i.e., foramen of Bochdalek) aspect of the diaphragm. The size of the defect and location on the right (20% to 35% of cases) or left (65% to 80% of cases) side influences the degree of pulmonary hypoplasia and the clinical presentation. Infants with the more typical large and left-sided hernia may present in the first minutes to hours of life with severe respiratory distress. Herniation of abdominal contents including liver, spleen, and loops of intestine may result in severe pulmonary hypoplasia. Survival rates for infants with congenital diaphragmatic hernia (CDH) have increased dramatically with the increased availability of surgical repair of the hernia (both in utero and after birth) and the development of extracorporeal membrane oxygenation (ECMO) to support infants with mild-to-moderate pulmonary hypoplasia. Current survival rates are up to 75% to 95% of live-born infants with CDH.

FIGURE 8.81  Diaphragmatic hernia. Shortly after birth, this infant experienced increasing respiratory distress. Note the air-filled loops of bowel extending into the left hemithorax.

FIGURE 8.82  Diaphragmatic hernia. At autopsy of the infant from Figure 8.81, loops of bowel along with portions of the liver can be seen in the left hemithorax.

Aplasia or hypoplasia of musculature within the leaflets of the diaphragm, either partial or complete, produces eventration of the diaphragm. Congenital eventration, usually seen in boys (62%), is unilateral in 85% of cases, with the right side involved in 67% and the left in 33%. Associated anomalies, present in more than 30% of cases, are similar to those seen with diaphragmatic hernia but also include cases of arthrogryposis. The involved segments of the ­diaphragm display normal parietal thoracic and abdominal mesothelium separated by delicate fibrovascular connective tissue either devoid of muscle or with only a few skeletal muscle fibers present.

Suggested readings 

FIGURE 8.83  Diaphragmatic hernia. When the abdominal organs are returned to the abdomen, the marked hypoplasia of the left lung can be seen.

FIGURE 8.84  Diaphragmatic eventration. While intact, this diaphragm contains virtually no musculature between its membranes, effectively allowing the abdominal contents to push up the diaphragm and impinge on the space in the thorax.

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Mani H, Suarez E, Stocker JT. The morphologic spectrum of infantile lobar emphysema: a study of 33 cases. Paediatr Respir Rev. 2004;5(suppl A):S313–S320. Matsumura Y, Ban N, Ueda K, Inagaki N. Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J Biol Chem. 2006;281(45):34503–34514. Moideen I, Nair SG, Cherian A, Rao SG. Congenital lobar emphysema associated with -congenital heart disease. J Cardiothorac Vasc Anesth. 2006;20(2):239–241. Montaudon M, Lederlin M, Reich S, et al. Bronchial measurements in patients with asthma: comparison of quantitative thin-section CT findings with those in healthy subjects and correlation with pathologic findings. Radiology. 2009;253(3):844–853. Morton J, Glanville AR. Lung transplantation in patients with cystic fibrosis. Semin Respir Crit Care Med. 2009;30(5):559–568. Nobre LF, Müller NL, de Souza Júnior AS, Marchiori E, Souza IV. Congenital pulmonary lymphangiectasia: CT and pathologic findings. J Thorac Imaging. 2004;19(1):56–59. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357–368. Page DV, Stocker JT. Anomalies associated with pulmonary hypoplasia. Am Rev Respir Dis. 1982;125(2): 216–221. Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP. Pleuropulmonary blastoma: a clinicopathologic study of 50 cases. Cancer. 1997;80(1):147–161. Pursnani SK, Amodio JB, Guo H, Greco MA, Nadler EP. Localized persistent interstitial pulmonary emphysema presenting as a spontaneous tension pneumothorax in a full term infant. Pediatr Surg Int. 2006;22(7):613–616. Qiu X, Kulasekara BR, Lory S. Role of horizontal gene transfer in the evolution of pseudomonas aeruginosa virulence. Genome Dyn. 2009;6:126–139. Ramos SG, Barbosa GH, Tavora FR, et al. Bronchioloalveolar carcinoma arising in a -congenital pulmonary airway malformation in a child: case report with an update of this association. J Pediatr Surg. 2007;42(5):E1–E4. Regamey N, Ochs M, Hilliard TN, et al. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2008;177(8):837–843. Rosado-de-Christenson ML, Stocker JT. Congenital cystic adenomatoid malformation. Radiographics. 1991;11(5):865–886. Ruano R, Martinovic J, Aubry MC, Dumez Y, Benachi A. Predicting pulmonary hypoplasia using the sonographic fetal lung volume to body weight ratio—how precise and accurate is  it? Ultrasound Obstet Gynecol. 2006;28(7):958–962. Saeed MM, Woo MS, MacLaughlin EF, Margetis MF, Keens TG. Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest. 1999;116(3):721–725. Schnitzer JJ. Control and regulation of pulmonary hypoplasia associated with congenital diaphragmatic hernia. Semin Pediatr Surg. 2004;13(1):37–43. Sen P, Thakur N, Stockton DW, Langston C, Bejjani BA. Expanding the phenotype of -alveolar capillary dysplasia (ACD). J Pediatr. 2004;145(5):646–651. Shaw-Smith C. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J Med Genet. 2006;43(7):545–554. Somers GR, Tabrizi SN, Borg AJ, Garland SM, Chow CW. Juvenile laryngeal papillomatosis in a pediatric population: a clinicopathologic study. Pediatr Pathol Lab Med. 1997;17(1):53–64. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol. 1977;8(2):155–171. Stocker JT, Madewell JE. Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome. Pediatrics. 1977;59(6):847–857. Stocker JT, Malczak HT. A study of pulmonary ligament arteries. Relationship to intralobar pulmonary sequestration. Chest. 1984;86(4):611–615. Stocker JT, McGill LC, Orsini EN. Post-infarction peripheral cysts of the lung in pediatric patients: a possible cause of idiopathic spontaneous pneumothorax. Pediatr Pulmonol. 1985;1(1):7–18. Stocker JT. Congenital and developmental diseases. In: Tomashefski JF Jr, ed. Dail and Hammer’s Pulmonary Pathology. New York: Springer; 2008:132–175. Stocker JT. Congenital pulmonary airway malformation—a new name for and an expanded classification of congenital cystic adenomatoid malformation of the lung. Histopathology. 2002;41(suppl 2): 424–430.

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Stocker JT. Cystic lung disease in infants and children. Fetal Pediatr Pathol. 2009;28(4):155–184. Stocker JT. Pathologic features of long-standing “healed” bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol. 1986;17(9):943–961. Stocker JT. Sequestrations of the lung. Semin Diagn Pathol. 1986;3(2):106–121. Stocker JT. The respiratory tract. In: Stocker JT, Dehner LP, eds. Pediatric Pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2010. Stocker, JT. Cystic lung disease in infants and children. Fetal Pediatr Pathol. 2009;28(4):155–184. Susarla SC, Fan LL. Diffuse alveolar hemorrhage syndromes in children. Curr Opin Pediatr. 2007;19(3): 314–320. Thibeault DW, Garola RE, Kilbride HW. Alveolar capillary dysplasia: an emerging syndrome. J Pediatr. 1999;134(5):661–662. Tireli GA, Ozbey H, Temiz A, Salman T, Celik A. Bronchogenic cysts: a rare congenital cystic malformation of the lung. Surg Today. 2004;34(7):573–576. Yang JI. Left diaphragmatic eventration diagnosed as congenital diaphragmatic hernia by prenatal sonography. J Clin Ultrasound. 2003;31(4):214–217.

9

The Kidney Anthony Chang neeraja kambham elizabeth J. Perlman

n

INTRODUCTION

n

DEVELOPMENTAL DEFECTS Renal Agenesis Renal Hypoplasia Renal Fusion Renal Dysplasia

n

n

CYSTIC DISEASES Polycystic Kidney Disease Autosomal Recessive Polycystic Kidney Disease Autosomal Dominant Polycystic Kidney Disease Medullary Cystic Kidney Disease Glomerulocystic Disease Renal Cysts in Hereditary Syndromes GLOMERULAR DISEASES Congenital Nephrotic Syndrome Minimal Change Disease Focal Segmental Glomerulosclerosis Variants of Minimal Change Disease/Focal Segmental Glomerulosclerosis Membranous Nephropathy Immunoglobulin A Nephropathy/ Henoch-Schönlein Purpura Postinfectious Glomerulonephritis

Membranoproliferative Glomerulonephritis Crescentic Glomerulonephritis Lupus Nephritis Hereditary Nephritis n

TUBULOINTERSTITIAL AND VASCULAR DISEASES

n

KIDNEY TRANSPLANT PATHOLOGY Acute Rejection Chronic Rejection Viral Infections Calcineurin Inhibitor Toxicity Posttransplant Lymphoproliferative Disorder

n

RENAL NEOPLASMS Nephroblastoma (Wilms Tumor) Triphasic Nephroblastoma (Wilms Tumor) Blastemal Predominant Wilms Tumor Epithelial Predominant Wilms Tumor WT1 Immunohistochemistry in the Diagnosis of Wilms Tumor Anaplastic Wilms Tumor

Perilobar Nephrogenic Rest Hyperplastic Perilobar Nephrogenic Rest Adenomatous Change Within a Perilobar Nephrogenic Rest Intralobar Nephrogenic Rest Hyperplastic Intralobar Nephrogenic Rest Cystic Nephroma Cystic Partially Differentiated Nephroblastoma Metanephric Adenoma Metanephric Stromal Tumor Congenital Mesoblastic Nephroma Karyotype of Cellular Congenital Mesoblastic Nephroma Classic Congenital Mesoblastic Nephroma Ossifying Renal Tumor of Infancy Clear Cell Sarcoma of the Kidney Rhabdoid Tumor Renal Cell Carcinoma With Xp11.2 Translocation Papillary Renal Cell Carcinoma Postneuroblastoma Oncocytoid Renal Cell Carcinoma Renal Medullary Carcinoma

inTroduCTion Developmental defects of the urinary system are structural anomalies primarily acquired during gestation and may be present in up to 10% of all births. Developmental defects are the leading cause of endstage renal disease in pediatric patients. Cystic kidney diseases represent another important diagnostic group and are a significant but less common cause of end-stage renal disease. In addition to imaging studies, surgical resections and autopsy examinations of these specimens would be the methods to diagnose either a developmental defect or cystic kidney disease. The kidney biopsy is the gold standard for the diagnosis of nonneoplastic parenchymal diseases involving the anatomic compartments of the native kidney (glomeruli, tubules, interstitium, and vessels) and requires the utilization of light, immunofluorescence (IF), and electron microscopy (EM). In addition, renal transplant pathology has additional considerations of donor disease, surgical complications, drug toxicity, immunologic responses (allograft rejection), and potential recurrence of original disease or development of de novo diseases. Approximately 7% of all childhood cancers arise within the kidney. Wilms tumor (nephroblastoma) is the most common primary malignant renal tumor of childhood, with approximately 500 new cases annually in the United States. Pediatric renal tumors are largely treated with protocols developed and monitored by cooperative groups, and this has resulted in the implementation of consistent diagnostic

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criteria as well as treatment stratification based on stage and histology. This has allowed dramatic improvements in the prognosis for most, but not all, patients with pediatric renal tumors. Staging of most pediatric renal tumors has been consistent for several years. Stage I tumors are confined to the kidney, stage II tumors penetrate the renal capsule or involve the renal sinus but are completely excised, stage III tumors show evidence of residual abdominal disease (positive margin, positive lymph nodes, piecemeal excision, rupture, or spillage), and stage IV tumors demonstrate distant metastasis.

DEVELOPMENTAL DEFECTS n Renal Agenesis FIGURE 9.1  Renal agenesis. Complete absence of kidney development can be either unilateral or bilateral. Isolated unilateral agenesis results in compensatory contralateral nephromegaly and may also be associated with ipsilateral anomalies of the urogenital system and other organ malformations. This 2-day-old neonate (33 weeks of gestation) with right renal agenesis (arrow) also had an absence of the right renal artery, ureter, ovary, and atretic right fallopian tube. Bilateral renal agenesis is associated with oligohydramnios, pulmonary hypoplasia, and Potter sequence, and results in stillbirth or death in the immediate postnatal period.

n Renal Hypoplasia

2B

2a

2C

FIGURE 9.2  Renal hypoplasia refers to developmentally small kidneys, often unilateral, measuring more than two standard deviations below the expected size. This right kidney (arrowhead) from a stillborn with multiple congenital anomalies and trisomy 18 is half the size of the left kidney (A). True hypoplasia is usually associated with a reduced number of renal lobes (6). Most small kidneys have features of dysplasia (hypodysplasia) with acquired scarring caused by infections, vascular problems, obstructive urinary anomalies, or in utero vesicoureteral reflux (B, H&E; kidney at term measured 1.8 cm). Oligomeganephronic hypoplasia is a distinct entity with bilateral small kidneys and reduced numbers of nephrons. These children often present in the first 2 years of life with polyuria, polydipsia, and urinary concentration defects. Microscopically, the glomeruli (C, H&E) and tubules are markedly hypertrophic. Patients develop progressive worsening of renal function in the first decade of life with proteinuria, accompanied by segmental and global glomerulosclerosis.

DEVELOPMENTAL DEFECTS 

179

n Renal Fusion FIGURE 9.3  Renal fusion. The kidneys may be fused across the midline anterior to the blood vessels, but retain their separate pelvicalyceal systems with normal insertions into the urinary bladder. The fusion is often at the lower poles resulting in a horseshoe kidney, located lower than normal (ectopia). The detached structures are bilateral ­adrenal glands. Often asymptomatic, horseshoe kidneys may be predisposed to infection and nephrolithiasis.

n Renal Dysplasia

4a 4B

4C

4D

FIGURE 9.4  Renal dysplasia is often sporadic, unilateral, and caused by abnormal metanephric differentiation. Varying degrees of cyst formation can be observed, ranging from a small solid hypoplastic kidney (hypodysplasia) to multicystic irregularly enlarged kidney (A). The characteristic histological features include abnormal lobar organization with rudimentary lobules and paucity of nephrons; medullary structures are poorly formed with only few vasa recta and loops of Henle. Immature collecting ducts are seen with cuffs of primitive mesenchyme (B, H&E) and sometimes persistence of cartilage (C, H&E). Most cases of renal dysplasia are associated with congenital urinary obstruction or reflux nephropathy, which interferes with renal morphogenesis. Cases of obstructive dysplasia often have associated hydronephrosis. A child with vesicoureteral reflux has a dilated pelvicalyceal system (bottom) and lobar disorganization (D, H&E). Renal obstructive dysplasia may be bilateral in cases of posterior urethral valves or urethral strictures.

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CYSTIC DISEASES TABLE 9.1  Differential Diagnosis of Pediatric Nonobstructive Bilateral Multicystic Kidney Diseasea NPH

DIFFUSE CYSTIC DYSPLASIA

Heterogenous (50% represent early onset ADPKD)

Autosomal ­recessive

Often autosomal recessive

Incidental or prior family history

Renal insufficiency, hypertension, hematuria

Polyuria, ­polydipsia, renal ­insufficiency

Variable based on associated congenital anomalies

Enlarged, reniform, maintains fetal lobulation

Enlarged, reniform, distorted cortical surface

Enlarged or ­normal size

Normal or slightly small

Enlarged, reniform, distorted cortical surface

Location of cysts

Cortex and medulla

Cortex and medulla

Cortex (and medulla if associated with other renal diseases)

Corticomedullary junction 6 deep medulla

Cortical with ­rudimentary medulla

Cyst size

Radial cysts, 1–2 mm in diameter

Round cysts, few millimeters to 3 cm

Round cysts, a few millimeters in diameter

1 mm to 1.5 cm in diameter

Round cysts, few ­millimeters to ­several centimeters

Nephron segment affected

Collecting duct

All nephron ­segments

Expanded ­Bowman’s space

Mostly distal tubules

Abnormal cystic ­collecting ducts

Glomerular cysts

No

Present

Predominant

No

6

Extrarenal manifestations

1

1

6

6

Often 1

Liver

Biliary ­dysgenesis and hepatic fibrosis

Liver cysts

Liver cysts if ADPKD

Hepatic fibrosis

6

Other

Pulmonary ­hypoplasia and Potter sequence in classic form

Pancreatic cysts, aortic and ­cerebral ­aneurysms, cardiac valve anomalies

6

Retinitis pigmentosa, skeletal defects, ­cerebellar abnormalities

Components of malformation syndrome often present

Gene m ­ utations

PKHD1

PKD1, PKD2

­Heterogenous group of ­diseases

NPHP 1–4

Heterogenous, no specific mutations

Affected ­protein

Fibrocystin

Polycystin-1, 2

Nephrocystin

Localization in kidney

Primary cilia of tubular epithelium

Primary cilia of tubular epithelium

Primary cilia of tubular epithelium

ARPKD

ADPKD

Inheritance

Autosomal ­recessive

Autosomal ­dominant

Clinical ­presentation

Perinatal ­mortality in ­classic form

Kidney

GLOMERULOCYSTIC DISEASE

a Multicystic renal dysplasia can also be occasionally bilateral. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; NPH, nephronophthisis.

CYSTIC DISEASES 

181

n Polycystic Kidney Disease Autosomal Recessive Polycystic Kidney Disease

5a

5B

5C

5D

FIGURE 9.5  Autosomal recessive polycystic kidney disease (ARPKD). In its classic form, ARPKD often results in stillbirth or death in the immediate neonatal period with associated oligohydramnios and Potter sequence. The spongy kidneys are bilaterally enlarged, but maintain their fetal lobulation (A). On cross section, the cortex and medulla are composed of radially arranged cysts measuring 1–2 mm in diameter (B, H&E), which represent dilated collecting ducts and not glomerular cysts (C, H&E). Liver abnormalities include biliary dysgenesis characterized by persistence of embryological interconnecting bile duct structures within the portal tracts as highlighted by cytokeratin 7 immunohistochemistry (D), and are referred to as “congenital hepatic fibrosis.” ARPKD can also present in older children and adults and with increasing age, the renal cystic change is less prominent, but hepatic fibrosis with portal hypertension predominates. Mutations have been identified in the PKHD1 gene (chromosome 6) that encodes fibrocystin, a protein localized to primary cilium of the tubular epithelium. Although its function is unknown, fibrocystin may be a receptor involved in collecting duct and biliary differentiation.

Autosomal Dominant Polycystic Kidney Disease FIGURE 9.6  Autosomal dominant polycystic kidney disease (ADPKD) usually manifests in adulthood, but may be diagnosed in children with a family history of ADPKD or rarely because of early presentation of symptoms. The cysts are variably sized (up to 3 cm) throughout cortex and medulla (A) and are derived from various segments of nephrons including glomeruli (B, H&E). The cysts may be identified radiologically and the diagnosis is confirmed by detecting mutations in genes encoding polycystin-1 (PKD1 on chromosome 16) and/or polycystin-2 (PKD2 on chromosome 4). Polycystin-1 is a transmembrane glycoprotein involved in cell–cell and cell–matrix interactions. Polycystin-2 is activated by polycystin-1 and acts as a calcium channel protein. The mutations in these genes affect cell cycle regulation and probably the mechanosensory function 6a of tubular cilia that results in tubular epithelial proliferation and cyst formation. Patients with ADPKD can have numerous hepatic cysts (C), pancreatic cysts, aortic and cerebral aneurysms, and cardiac valvular anomalies. (Continued)

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6B

6C

FIGURE 9.6  Autosomal dominant polycystic kidney disease (ADPKD). (Continued)

n Medullary Cystic Kidney Disease

7a

7B

7C

FIGURE 9.7  Medullary cystic kidney disease (MCKD) is characterized by cysts predominantly within renal medulla and falls into two distinct categories of medullary cystic kidney disease–familial nephronophthisis complex (MCKD– NPH) and medullary sponge kidney. MCKD and NPH have 7D similar clinical and pathological features, but MCKD is an autosomal dominant disease with adult onset, whereas the nephronophthisis (NPH) inheritance pattern is autosomal recessive and usually presents in the pediatric population. Defects in tubular concentration abilities results in polyuria, polydipsia, and tubular acidosis, and patients with NPH rapidly progress to end-stage kidney disease. NPH kidneys are small with cysts in the corticomedullary junction and medulla (A). Diffuse tubulointerstitial inflammation and tubular atrophy are seen (B, H&E) with widespread thickening of the proximal and distal tubular basement membranes, but the glomeruli (not shown) are generally spared (C, H&E). By EM, the tubular basement membranes show thickening and lamination that are more prominent than expected in nonspecific chronic kidney disease (D). Mutations have been identified in genes NPHP1-4 in patients with juvenile (NPHP1,4), infantile (NPHP2), and adolescent (NPHP3) forms of disease. These genes encode nephrocystins that are localized to tubular cilia, but the exact mechanism of cyst formation is unknown. Medullary sponge kidney is a benign entity with ectatic collecting ducts within the medullary pyramids. These patients are often asymptomatic and come to medical attention because of urolithiasis and urinary infections in adulthood. Source: (A) Courtesy of Helen Liapis, MD, Washington University.

CYSTIC DISEASES 

n Glomerulocystic Disease

8a

8B

FIGURE 9.8  Glomerulocystic disease. This bisected fetal kidney with numerous small cortical cysts is twice the expected size (A). Glomerulocystic disease is characterized by prominent glomerular cysts (i.e., dilated urinary spaces) (B, H&E). This pathologic finding can be observed in early onset ADPKD, Zellweger syndrome, trisomy 13, tuberous sclerosis, orofaciodigital syndrome, and some cases of renal dysplasia. Genetic counseling for syndromic associations and gene linkage studies are helpful for accurate diagnosis. Isolated glomerulocystic disease without extrarenal manifestations is seen sporadically and may be related to glomerulotubular junction stenosis.

n Renal Cysts in Hereditary Syndromes

9a

9B

FIGURE 9.9  Renal cysts in hereditary syndromes. Bilateral renal cysts can be observed in various hereditary syndromes, including trisomy syndromes, Ehlers-Danlos syndrome, Zellweger syndrome, and Meckel-Gruber syndrome, and some of these also have glomerular cysts and biliary dysgenesis similar to ARPKD. The cysts range from minor focal cysts to diffuse cystic change distorting the kidney. Tuberous sclerosis with autosomal dominant inheritance is characterized by renal microhamartomas (A, H&E) and cysts (B, H&E). The gene involved TSC2 is contiguous to PKD1 gene (of ADPKD) and approximately 50% of patients with tuberous sclerosis have renal cysts lined by distinctive large cells with abundant eosinophilic cytoplasm. Von Hippel-Lindau syndrome is an autosomal dominant disease characterized by renal angiomas, cerebellar angiomas, and renal and pancreatic cysts. The renal 9C cysts are variable in size and number with bilateral involvement. They are lined by flat epithelium (C, H&E) with occasional papillary projections into the lumens; small renal cell carcinomas may arise from these cyst walls.

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Glomerular DISEASES n Congenital Nephrotic Syndrome

10A

10B

FIGURE 9.10  Congenital nephrotic syndrome. Nephrotic syndrome in a newborn (,3 months of age) is primarily caused by two diseases—congenital nephrotic syndrome (CNS) of Finnish type and diffuse mesangial sclerosis (DMS). CNS is an autosomal recessive disease caused by gene mutations in NPHS1, which encodes nephrin, a slit diaphragm protein in the podocyte. The glomerular alterations are not specific for CNS, but there may be variable degrees of glomerulosclerosis, mesangial sclerosis, or hypercellularity with dilated or cystic tubules (A, H&E). A representative glomerulus from a patient with CNS shows marked mesangial hypercellularity (B, PAS). Diffuse effacement of the podocyte foot processes can be observed by EM (not shown). DMS is 10C characterized by increased mesangial matrix with prominence of the visceral epithelial cells (podocytes) and loss of capillary lumina (C, Jones methenamine silver). Some glomeruli resemble the collapsing variant of focal segmental glomerulosclerosis (FSGS). Given that patients with Denys-Drash syndrome (male pseudohermaphroditism and increased risk of Wilms tumor) caused by mutations in WT1 will exhibit DMS, this pathologic finding should result in careful monitoring to exclude the presence of Wilms tumor. Both CNS and DMS are unresponsive to steroid therapy and progress rapidly to end-stage renal disease.

n Minimal Change Disease

11a

11B

FIGURE 9.11  Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children. The glomeruli are normal with delicate glomerular basement membranes as shown in a representative glomerulus using hematoxylin and eosin (H&E) (A), periodic acid-Schiff (PAS) (B), and Jones methenamine silver stains (C). In pediatric patients, the presence of any interstitial fibrosis or tubular atrophy in the setting of nephrotic-range proteinuria should raise the consideration of FSGS that may not have been sampled in the biopsy. EM reveals diffuse effacement of the podocyte foot processes (D), which can be observed in either MCD or FSGS. (Continued)

Glomerular DISEASES 

11C

185

11D

FIGURE 9.11  Minimal change disease. (Continued)

n Focal Segmental Glomerulosclerosis

12a

12B

12C

12D

12e

12f

FIGURE 9.12  Focal segmental glomerulosclerosis. Accumulation of foam cells (arrows) within the glomerular capillaries at the “tip” (opposite the vascular pole) can herniate into the urinary pole in the tip variant of FSGS (A, Jones methenamine silver), which clinically behaves like MCD. Nonspecific trapping of immunoglobulin M (IgM) and C3 may be seen by IF in the areas of glomerular sclerosis, but immune deposits are not present in intact glomeruli by IF or EM. The perihilar variant of FSGS can be found in association with secondary causes of FSGS, but it recently has been observed in patients with ACTN4 mutations, an autosomal dominant inherited form of FSGS (B, PAS). Accumulation of hyaline in the glomerular capillaries on the right half of this glomerulus is characteristic of FSGS (C, PAS), which satisfies the not otherwise specified category. The cellular variant (D) is characterized by endocapillary hypercellularity (arrow) and has an intermediate clinical course between the tip and collapsing variants. Segmental or global collapse of glomerular tufts with podocyte hypertrophy and hyperplasia exemplify the collapsing variant of FSGS (E). This variant is the least common yet most aggressive form of FSGS in pediatric patients. EM for all variants shows variable but typically extensive effacement of the podocyte foot processes (F). Source: (B) Courtesy of Joel Henderson, MD, Boston University.

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Variants of Minimal Change Disease/Focal Segmental Glomerulosclerosis

13a

13B

13C

13D

FIGURE 9.13  Variants of MCD/FSGS. Diffuse mesangial hypercellularity (A, PAS), defined as three or more mesangial cells per mesangial area (evaluated on a 2 mm thick section), in more than 75% of the glomeruli may be found in either MCD or FSGS. Significant IgM mesangial IF staining (greater than 21 on a scale from 0 to 4) (B) may be seen in a subset of MCD, which has been termed IgM nephropathy. This finding correlates with the presence of mesangial electron dense deposits similar to those seen in (D). Some IgM nephropathy cases progress to FSGS. C1q nephropathy can also be considered a variant of MCD/FSGS and is characterized by significant C1q IF staining in mesangial areas (C), which corresponds with discrete mesangial electron dense deposits (arrows) seen by EM (D). The finding of diffuse mesangial hypercellularity or IgM or C1q nephropathy predicts an increased likelihood for resistance to steroid therapy in nephrotic patients.

n Membranous Nephropathy

14A

FIGURE 9.14  Membranous nephropathy (MN) is uncommon in the pediatric population, as opposed to being one of the most common causes of idiopathic nephrotic syndrome in adults. Thickened glomerular basement membranes with a focal vacuolated appearance are noted (arrow) when compared with adjacent tubular basement membranes in this young male (A, Jones methenamine silver). Glomerular basement membranes with a vacuolated appearance or subepithelial “spike” formation is characteristic of MN. In females, MN may be the earliest manifestation of lupus nephritis (LN), as some patients with renal dysfunction may not have developed other clinical signs of systemic lupus erythematosus. Granular IF staining of the capillary walls for immunoglobulin G (IgG) characterizes MN (B). EM reveals many subepithelial electron dense deposits with basement membrane material (“spikes”–arrows) between the deposits and diffuse effacement of the podocyte foot processes (C). A rare neonatal form of MN caused by transmission of maternal antibodies targeting neutral endopeptidase may demonstrate microspherular substructure of the subepithelial deposits (not shown). (Continued)

Glomerular DISEASES 

14B

14C

FIGURE 9.14  Membranous nephropathy. (Continued)

n Immunoglobulin A Nephropathy/Henoch-Schönlein Purpura

15A

15B

FIGURE 9.15  Immunoglobulin A (IgA) nephropathy/ Henoch-Schönlein purpura. IgA nephropathy is the most common glomerulonephritis in the world. There is a wide spectrum of glomerular alterations that may be present in IgA nephropathy. A few are highlighted in the recent Oxford classification for IgA nephropathy as the presence of any of four pathologic features (mesangial hypercellularity [A, PAS], segmental sclerosis, endocapillary hypercellularity, and interstitial fibrosis and tubular atrophy) predicts worse disease progression. Advanced stages show prominent glomerular and tubulointerstitial scarring. The presence of systemic symptoms such as purpuric rash is consistent with Henoch-Schönlein purpura, but no pathologic features in a biopsy can reliably distinguish this entity from IgA nephropathy. Granular mesangial IgA IF staining (B) as the 15C dominant or codominant immunoglobulin is diagnostic for IgA nephropathy. A similar staining pattern and intensity for IgG may be observed. Lambda light chain often reveals more intense IF staining than kappa light chain (not shown). Discrete electron dense deposits (arrowhead) in primarily mesangial regions (C) corresponding with the IF results are typical but not always observed by EM. Subendothelial and/or subepithelial deposits may be seen but are generally not prominent.

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n Postinfectious Glomerulonephritis

16a

16B

16C

16D

16e

16f

FIGURE 9.16  Postinfectious glomerulonephritis (PIGN). Prominent infiltration of neutrophils in glomerular capillaries is consistent with an immune complex-mediated glomerulonephritis (GN), and PIGN is the main diagnostic consideration (A, H&E). Cellular crescent formation in this glomerulus (B, Jones methenamine silver) can often be observed in PIGN, but crescents usually, if present, involve less than 50% of the glomeruli. Aggregates of neutrophils in tubular lumina (C, H&E) and the interstitium can mimic acute bacterial pyelonephritis. Granular IgG (D) and C3 (E) IF staining of glomerular capillaries and mesangial regions is characteristic of PIGN. The capillary wall staining is often coarse and irregular, which corresponds with the larger subepithelial “humps” (arrows) and other glomerular immune complexes that are seen by EM (F). Prominent C3 IF staining may be the only finding in latent or resolving PIGN. This finding in intact glomeruli should prompt careful scrutiny by EM for subepithelial “humps,” which do not illicit a basement membrane reaction around the deposit. Distinguishing PIGN from an early stage of MN can be difficult.

n Membranoproliferative Glomerulonephritis FIGURE 9.17  Membranoproliferative glomerulonephritis (MPGN). Accentuation of the lobular architecture of the glomerular tufts with duplication of the glomerular basement membranes [(A) PAS and (B) Jones methenamine silver] characterizes MPGN. Granular IgG (C) and C3 (D) IF staining of the capillary 17a 17B walls and focal mesangial areas is present. EM reveals many immune-type electron dense deposits in subendothelial (arrowhead) and mesangial locations, and the presence of significant subepithelial deposits (arrow) satisfies a designation of type 3 MPGN (E). Type 2 MPGN is also known as dense deposit disease and demonstrates primarily C3 IF staining with a characteristic dense appearance of the glomerular basement membrane (GBM) by EM (F). Some of these patients have mutations in complement factor H or other related proteins in the complement cascade. Given that a subset of these type 2 lesions shows an MPGN pattern of glomerular injury, dense deposit disease is a more appropriate term for this entity. (Continued)

Glomerular DISEASES 

17C

17D

17e

17f

FIGURE 9.17  Membranoproliferative glomerulonephritis (MPGN). (Continued)

n Crescentic Glomerulonephritis

18a

18B

FIGURE 9.18  Crescentic glomerulonephritis. Cellular crescent formation represents the most severe injury of the glomerulus (A, PAS). The cellular crescent evolves to a fibrocellular (B, Jones methenamine silver) and eventually a fibrous crescent (C, PAS). In children, the most common cause of crescentic GN is the immune complex-mediated category, which includes LN, membranoproliferative GN, PIGN, and IgA nephropathy. The second most common cause is pauci-immune crescentic GN, which is often associated with the presence of antineutrophil cytoplasmic antibodies (ANCAs). Prominent fibrinoid necrosis and granulomatous inflammation around the injured artery can be seen in approximately 20% of cases (not shown). Strong linear IgG IF staining of the GBMs is diagnostic of anti-GBM disease (D), which may correlate with the clinical presentation of Goodpasture syndrome (pulmonary hemorrhage). This is the most severe yet least common form of crescentic GN in both children and adults. Mesangial or endocapillary hypercellularity typically distinguishes the immune complex-mediated GNs from pauci-immune or anti-GBM antibody-mediated crescentic injury. Of note, the presence of greater than 50% crescent formation is a critical value in surgical pathology, but the presence of any crescents should always be reported. (Continued)

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18C

18D

FIGURE 9.18  Crescentic glomerulonephritis. (Continued)

n Lupus Nephritis

19A

19B

FIGURE 9.19  Lupus nephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus. The glomerular injury is separated into six categories according to the 2003 International Society of Nephrology/Renal Pathology Society LN classification. Class I (minimal mesangial LN) shows normal glomeruli (Figure 9.11A–C) by light microscopy with detection of mesangial immune complexes by IF. Class II (mesangial proliferative LN) demonstrates varying degrees of mesangial hypercellularity (A) or mesangial matrix expansion caused by mesangial immune complexes (B). Class III (focal LN) and class IV (diffuse LN) are distinguished based on whether active (proliferative) and/or chronic (sclerosing) glomerular lesions involve fewer than 50% (class III) or greater than 50% (class IV) of the glomeruli. Active lesions include fibrinoid necrosis, cellular or fibrocellular crescents (C), prominent subendothelial (“wire-loop,” arrowhead in D, PAS and E, IgG IF) or intraluminal (hyaline “thrombi,” arrow in D and E) deposits, and endocapillary proliferation. Chronic lesions include segmental or global glomerular sclerosis, fibrous adhesions, and fibrous crescents. Class V (membranous LN) is diagnosed when more than 50% of the glomerular tufts in greater than 50% of all glomeruli contain subepithelial immune complexes, and this will have a similar appearance to idiopathic MN (Figure 9.14A) with variable degrees of mesangial hypercellularity. Class V LN can occur concurrently with class III or IV LN. Mesangial hypercellularity is permitted in the diagnosis of class V LN, so the additional diagnosis of class II mesangial proliferative LN is not necessary, if present. Class VI advanced sclerotic LN is diagnosed when greater than 90% of the glomeruli are globally sclerotic without any active lesions. Extraglomerular immune complex deposition is common in LN, as demonstrated by granular IgG staining in the tubular basement membranes, and the strong nuclear staining in tubular epithelial cells is the equivalent of a “tissue antinuclear antibodies (ANA)” (F). EM often reveals mesangial (arrow) and subendothelial (arrowhead) deposits (G). The presence of many subepithelial deposits with basement membrane material (“spikes”) allows for the designation of membranous (class V) LN (Figure 9.14C). A tubuloreticular inclusion (arrow) in an endothelial cell is often observed in LN, but can also be present in other settings, including viral infections (hepatitis or HIV) or interferon therapy (H). (Continued)

Glomerular DISEASES 

19c

19d

19e

19f

19g

19h

Figure 9.19  Lupus nephritis. (Continued)

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n Hereditary Nephritis

20A

20B

20C

20D

20e

20f

FIGURE 9.20  Hereditary nephritis caused by abnormalities of the GBM (Alport syndrome) demonstrates an X-linked inheritance pattern in 85% of cases involving the a-3 or a-4 chains of collagen IV with occasional autosomal recessive and autosomal dominant cases. The glomerular findings are nonspecific and include irregular segmental scarring with subsequent interstitial fibrosis and tubular atrophy (A). EM reveals a characteristic “basket-weave” or lamellated appearance of the GBM (B). Indirect IF microscopy for the a-3 and a-5 chains of collagen IV shows absence of GBM staining in males with X-linked Alport syndrome (C, with IF positive control [inset]). Young female patients with the X-linked form of Alport syndrome may manifest only thin GBMs, and IF staining for the a-3 and a-5 chains of collagen IV may show segmental staining (not shown). The finding of appropriate linear staining of the GBMs does not exclude the diagnosis of Alport syndrome. Fabry disease is also an X-linked hereditary disease caused by a mutation of alpha-galactosidase A. Male patients often have signs and symptoms (angiokeratoma, corneal opacities, fever, and proteinuria) before puberty, whereas female patients present much later in life and generally have a milder form of the disease. The affected glomeruli reveal podocytes with a characteristic foamy or bubbly cytoplasm (D, PAS). The cytoplasmic inclusions (also called zebra or myelin-like bodies) are easily visualized on the semi-thin sections (E, toluidine blue) and by EM (F) in the podocytes and less commonly in mesangial, endothelial, tubular epithelial cells, or myocytes (not shown). The diagnosis is confirmed by measuring the alpha-­galactosidase A plasma activity level. Certain drugs, including amiodarone and chloroquine, may iatrogenically decrease the plasma activity of this enzyme and mimic Fabry disease. Establishing the correct diagnosis is essential because of the option of recombinant enzyme replacement.

TUBULOINTERSTITIAL AND VASCULAR DISEASES 

TUBULOINTERSTITIAL AND VASCULAR DISEASES

21a

21B

21C

21D

FIGURE 9.21  Tubulointerstitial and vascular diseases. Numerous calcium oxalate crystals in renal tubules (A) are easily identified under polarized light (B). This finding was caused by primary hyperoxaluria type 1 as a result of a deficiency of alanine-glyoxylate aminotransferase, which rapidly led to end-stage renal disease in this 3-year-old boy. Combined liver and kidney transplantation is a promising therapeutic option in advanced cases. Prominent interstitial inflammation with lymphocytes and tubulitis is present in a young male with acute renal failure and clinical features of the autoimmune disorder known as tubulointerstitial nephritis with uveitis (C, H&E). The differential diagnosis includes drug-induced acute interstitial nephritis. The presence of eosinophils may increase the suspicion for this diagnosis, but clinical correlation is required. Acute thrombotic microangiopathy (TMA) is characterized by the presence of thrombi in arteries, arterioles, or glomerular capillaries, which is identical to Figure 9.22E. Typical clinical signs include hemolytic anemia, thrombocytopenia, and renal failure. TMA can be observed in a limited number of clinicopathologic entities that include, but are not limited to, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, scleroderma, malignant hypertension, antiphospholipid antibody syndrome, preeclampsia, drug toxicity, or sickle cell nephropathy. In the chronic phase, only double contours or duplication of the GBMs may be present. Vasculitis with characteristic fibrinoid necrosis (arrow) and focal infiltration with inflammatory cells may be observed in association with pauci-immune crescentic glomerulonephritis or sometimes LN (D). The absence of a crescentic glomerular injury would raise the diagnostic consideration of polyarteritis nodosa.

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KIDNEY TRANSPLANT PATHOLOGY n Acute Rejection

22a

22B

22C

22D

FIGURE 9.22  Acute rejection. Prominent interstitial inflammation that involves greater than 25% of the cortex and consists of predominantly lymphocytes with frequent tubulitis (lymphocytes between tubular epithelial cells and/or the tubular basement membrane) is consistent with acute tubulointerstitial (type I) rejection according to the Banff classification (A, PAS). Tubulitis with greater than 4 lymphocytes per tubular cross section (roughly 10 epithelial cells) satisfies a designation of type IA rejection, and greater than 10 lymphocytes per tubular cross section satisfies a designation of type IB rejection. The inflammatory infiltrate is often accompanied by interstitial edema and typically involves the renal cortex. Intimal infiltration by leukocytes (arrow) in an artery is diagnostic of acute (type II) rejection (B). The presence of interstitial hemorrhage or lymphocytes adherent to arterial endothelial cells should increase the suspicion for type II rejection and may warrant additional level sections. Fibrinoid necrosis is present in this large artery, which is consistent with type III acute rejection (C, H&E). Increased number of leukocytes within glomerular and/or peritubular capillaries is termed capillaritis and is a finding suggestive of acute humoral rejection (D). TMA (arrows) may also be observed in the setting of acute humoral rejection (E). Immunolocalization of C4d in the peritubular capillaries suggests the diagnosis of acute humoral rejection (F, IF), but establishing the presence of donor-specific antibodies is necessary to confirm this diagnosis. (Continued)

KIDNEY TRANSPLANT PATHOLOGY 

22E

22F

FIGURE 9.22  Acute rejection. (Continued)

n Chronic Rejection

23a

23B

FIGURE 9.23  Chronic rejection. Chronic transplant glomerulopathy is characterized by double contours or duplication of the GBMs (arrows) in the absence of glomerular immune complex deposition (A, Jones methenamine silver). Segmental or global glomerulosclerosis can be present in advanced cases. This finding is caused by a chronic endothelial cell injury that results in separation of the endothelial cell from the GBM. Multilayering of the peritubular capillary basement membrane (arrows) is also considered an injury caused by chronic humoral rejection, which is usually observed by EM (B) and sometimes by light microscopy. Chronic transplant arteriopathy is characterized by a fibrous intima in this artery from a transplant nephrectomy, but the presence of numerous foamy macrophages and lymphocytes suggests an additional active 23C immunologic process (C, H&E). The presence of interstitial fibrosis and tubular atrophy may be is not necessarily caused by chronic rejection. Chronic allograft nephropathy was used to remove the presumption that all tubulointerstitial scarring is necessarily caused by rejection, but the use of this term is not recommended by the current Banff classification.

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n Viral Infections

24a

24B

24C

24D

24E

24F

FIGURE 9.24  Viral infections. Prominent interstitial inflammation with frequent tubulitis (­ lymphocytes between tubular epithelial cells and basement membrane) involving both the renal medulla and cortex is characteristic of polyomavirus nephropathy (PVN). Intranuclear viral inclusions with a “ground glass” appearance (arrow) may be prominent (A, H&E). In early phases of polyomavirus infection or when JC virus is the infectious agent, viral cytopathic effect may not be present and may mimic acute tubulointerstitial (type I) rejection. Strong nuclear immunohistochemical staining for the simian virus 40 (SV40) large T antigen in the tubular epithelial cell nuclei confirms active proliferation of polyomavirus (B). Polymerase chain reaction (PCR) testing is necessary to determine whether there is BK or JC virus. The large majority of cases are caused by BK virus. Prominent interstitial inflammation involving the renal medulla is unusual for acute rejection, and this finding should raise the consideration of PVN or acute interstitial nephritis. The presence of interstitial hemorrhage and necrosis in addition to prominent interstitial inflammation is suggestive of adenovirus infection (C, H&E). Prominent granulomatous inflammation may also be observed (not shown). Immunohistochemistry for adenovirus confirms the diagnosis (D). Prominent “owl-eye” nuclear inclusions in endothelial cells are characteristic of cytomegalovirus (CMV) infection in this glomerulus (E, H&E) and peritubular capillaries (F, H&E). Immunohistochemistry for CMV (not shown) confirms strong nuclear and focal cytoplasmic staining in many endothelial cells in this kidney allograft. In contrast, neonatal CMV infection typically involves tubular epithelial cells. Source: (D) Courtesy of Louis Novoa-Takara, MD, Medical College of Wisconsin.

KIDNEY TRANSPLANT PATHOLOGY 

n Calcineurin Inhibitor Toxicity

25A

25B

FIGURE 9.25  Calcineurin inhibitor toxicity (CIT) can lead to multiple injuries of the different renal compartments. This injury can also occur in the native kidneys of patients with heart, liver, or hematopoietic cell transplantation. Tubular epithelial cells can manifest isometric vacuolization (A, H&E), but the differential diagnosis for this finding includes administration of sucrose-rich preparations of intravenous immunoglobulin, mannitol, or dextran. Discrete adventitial hyaline nodules (arrow) caused by smooth muscle cell necrosis are a pathologic feature that is most suggestive of CIT (B, H&E). In contrast, arteriolar subendothelial hyalinosis is a common finding that could be caused by diabetes, hypertension, CIT, or a combination of these injuries. TMA is also well described in CIT and would appear identical to other causes of TMA (Figure 9.22E). Given that humoral rejection and other etiologies can cause TMA, careful clinical correlation is necessary.

n Posttransplant Lymphoproliferative Disorder

26a

26B

FIGURE 9.26  Posttransplant lymphoproliferative disorder (PTLD). Prominent inflammatory infiltrates with a vague nodular arrangement in the kidney allograft should raise the consideration of PTLD (A, H&E). Overall, PTLD is rare in kidney transplant patients and most cases are caused by Epstein-Barr virus, as demonstrated by Epstein-Barr encoded ribonucleic acid (EBER) mRNA in-situ hybridization (B). Prominent aggregates of plasma cells may represent the early lesion of PTLD. More apparent cytologic atypia as demonstrated by CD20 immunohistochemistry in this young female patient is noted in the polymorphic variant (C), which is the most common variant seen in kidney allografts.

26C

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RENAL NEOPLASMS n Nephroblastoma (Wilms Tumor) Triphasic Nephroblastoma (Wilms Tumor) FIGURE 9.27  Triphasic nephroblastoma (Wilms tumor). Nephroblastoma is a malignant embryonal neoplasm commonly showing several types of differentiation and often replicating the histology of the developing kidney. Most nephroblastomas show triphasic differentiation, with undifferentiated blastema and differentiated stromal and tubular elements in varying amounts. Approximately 10% of nephroblastomas develop in association with an underlying syndrome, the most common of which are WAGR (Wilms tumor, aniridia, genitourinary malformation, mental retardation), Denys-Drash (mesangial sclerosis, pseudohermaphroditism), and BeckwithWiedemann (hemihypertrophy, macroglossia, omphalocele, and visceromegaly).

Blastemal Predominant Wilms Tumor FIGURE 9.28  Blastemal predominant Wilms tumor. Blastemal cells are closely packed, mitotically active, and show minimal evidence of differentiation. Their nuclei contain slightly coarse chromatin, small nucleoli, and prominent overlapping of adjacent nuclei. Blastemal cells occur in several distinctive patterns including diffuse, serpentine, nodular, and basaloid. More than one pattern is often found in the same tumor. The diffuse blastemal pattern is characterized by a general lack of cellular cohesiveness and an aggressive pattern of invasion into adjacent connective tissues and vessels, resulting in an infiltrative rather than the sharply circumscribed border characteristic of most Wilms tumors. In contrast, other blastemal patterns tend to be cohesive and lack the aggressive invasiveness characterized by the diffuse blastemal type. The nodular and serpentine blastemal patterns are the most frequently encountered and are characterized by sharply defined cords or nests of blastemal cells set in a loose, myxoid, or fibromyxoid stroma. These growth patterns are rarely seen in other primitive neoplasms of childhood and are virtually diagnostic of a nephroblastoma. A basaloid blastemal pattern results when the serpentine or nodular patterns are outlined in a distinctive epithelial layer (illustrated).

Epithelial Predominant Wilms Tumor FIGURE 9.29  Epithelial predominant Wilms tumor varies widely from relatively mature glomeruloid differentiation to poorly differentiated epithelial structures. Most common are those showing tubular features (illustrated). Foci of mature cell types with low mitotic rates and increasing cytoplasmic content may represent differentiation toward a more mature state, particularly following therapy. Heterologous epithelial differentiation may occur, the most common elements being mucinous and squamous epithelium. Occasionally, ciliated epithelium is present.

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WT1 Immunohistochemistry in the Diagnosis of Wilms Tumor FIGURE 9.30  WT1 immunohistochemistry in the diagnosis of Wilms tumor. Staining for the WT1 antigen may be seen in approximately 75% of Wilms tumors, and is more commonly seen in areas of the tumor that are blastemal or that show certain types of epithelial differentiation. The positive staining should be identified in the nucleus and not within the cytoplasm. Normal glomerular podocytes serve as an excellent positive control.

Anaplastic Wilms Tumor FIGURE 9.31  Anaplastic Wilms tumor. The single most important histologic predictor of response and survival in patients with Wilms tumor is the presence or absence of anaplasia. There are two histologic criteria for anaplasia, namely multipolar polyploid mitotic figures and marked nuclear enlargement with hyperchromasia. If these features are circumscribed, surrounded by nonanaplastic tissue, confined to the kidney, and if the remainder of the tumor lack features bordering on anaplasia, the tumor may meet the criteria for focal anaplasia. Otherwise, they should be considered to represent diffuse anaplasia.

n Perilobar Nephrogenic Rest Hyperplastic Perilobar Nephrogenic Rest FIGURE 9.32  Hyperplastic perilobar nephrogenic rest. Nephrogenic rest is the term applied to abnormally persistent foci of embryonal cells following 32 weeks of gestation. Nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests are classified as perilobar or intralobar. Perilobar nephrogenic rests are located at the periphery of the renal lobule, and hence are commonly located on the surface of the kidney. They are sharply circumscribed and are composed of blastemal and epithelial elements with a spectrum of differentiation. Perilobar rests that are of microscopic size, quiescent, and composed of blastemal cells are termed “incipient” in a neonate and “dormant” in an older infant or child. When a perilobar rest begins to proliferate, it becomes more oval in shape and is referred to as hyperplastic (illustrated). Mitotic figures are evident. When composed of blastemal and other embryonal cells, a hyperplastic rest is distinguished from a small nephroblastoma by its shape, which preserves the original rest shape, and by the lack of a fibrous capsule separating it from the adjacent kidney. Rarely, perilobar nephroblastomatosis forms a more or less continuous band around the surface of the kidney in a condition classified as diffuse perilobar nephroblastomatosis.

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Adenomatous Change Within a Perilobar Nephrogenic Rest

FIGURE 9.33  Adenomatous change within a perilobar nephrogenic rest. Discrete nodules are often identified later in the evolution of perilobar nephroblastomatosis. These nodules show increased pale eosinophilic cytoplasm, often with a tubular or papillary architecture. Collagenous bands are commonly seen within these nodules. These changes have been referred to as adenomatous, although they are not considered to represent a further step toward malignancy. Numerous adenomatous rests are usually identified when they occur, as is seen in this figure.

n Intralobar Nephrogenic Rest

FIGURE 9.34  Intralobar nephrogenic rest is most commonly identified deep within the renal lobule rather than on its surface. The illustrated small lesion demonstrates the key features intralobar nephrogenic rest: it is composed of lobules of nephroblastic tubular and stromal elements with an interstitial location and intermingling with the normal nephronic elements.

n Cystic Nephroma

Hyperplastic Intralobar Nephrogenic Rest

FIGURE 9.35  Hyperplastic intralobar nephrogenic rest. When intralobar nephrogenic rests become hyperplastic, the interface of the tumor continues to be irregular in contour and lacks a fibrous pseudocapsule, however the lobulated appearance is retained, with continued intermingling among the normal renal parenchyma. The larger the lesion becomes, the more difficult is the distinction between intralobar nephrogenic rest and nephroblastoma.

FIGURE 9.36  Cystic nephroma and cystic, partially differentiated nephroblastoma are considered to represent part of the spectrum of nephroblastoma. Cystic nephroma represents an encapsulated mass composed entirely of cystic spaces separated by septa containing only mature elements and without solid nodules.

RENAL NEOPLASMS 

n Cystic Partially Differentiated Nephroblastoma

FIGURE 9.37  Cystic partially differentiated nephroblastoma. The identification of immature nephro­ blastic elements within the septa distinguishes cystic partially differentiated nephroblastoma from cystic nephroma. The presence of any solid nodules indicates the diagnosis of cystic Wilms tumor and excludes the diagnosis of cystic, partially differentiated nephroblastoma or cystic nephroma.

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n Metanephric Adenoma

FIGURE 9.38  Metanephric adenoma. Metanephric tumors refer to a spectrum of benign lesions that are derived from the metanephric blastema. At one end of the pathologic spectrum are tumors that are composed exclusively of epithelial cells, referred to as metanephric adenoma. At the other end are tumors that are composed exclusively of stromal elements, the metanephric stromal tumor. Tumors that include a composite of both are called metanephric adenofibromas.   Metanephric adenomas are sharply circumscribed but are unencapsulated masses. The presence of a fibrous capsule surrounding an epithelial lesion precludes the diagnosis of metanephric adenoma. Small tubules, papillary structures, or glomeruloid structures may be seen within a metanephric adenoma. Bland, overlapping, oval nuclei without nucleoli or mitotic figures are defining features. Immunoreactivity for cytokeratin 7 is only focally present, if at all, in metanephric adenomas, in contrast with the diffuse positivity characteristic of papillary renal cell carcinoma.

n Metanephric Stromal Tumor FIGURE 9.39  Metanephric stromal tumor is a mesenchymal lesion characterized by alternating regions of increased and decreased cellularity, a feature best appreciated on low power. The cellularity varies highly from tumor to tumor. The lesion illustrated is quite cellular. A characteristic feature of metanephric stromal tumor is the presence of “collars” of stromal cells surrounding entrapped tubules and vessels. Angiodysplasia is the most diagnostic feature of this tumor, although it is not seen in all cases. Nodules of heterologous tissue such as glia, cartilage, or fat are present in a minority of cases. The interface between the stromal component and the kidney is quite irregular and unencapsulated.

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n Congenital Mesoblastic Nephroma

FIGURE 9.40  Congenital mesoblastic nephroma is a mesenchymal neoplasm confined to infancy. There are two major types, classic and cellular; those that show foci of both are referred to as mixed. The most common variant is cellular mesoblastic nephroma, which is composed of monomorphous, plump cells with a high cellular density growing in a diffuse pattern. The tumor is frequently circumscribed yet unencapsulated. The cells have vesicular nuclei and a moderate amount of cytoplasm. Although the nuclear cytology is often rather bland, occasional tumors show atypical features with prominent nuclei.

Classic Congenital Mesoblastic Nephroma

FIGURE 9.42  Classic congenital mesoblastic nephroma is composed of spindle cells with a prominent fascicular, interlacing pattern. Mitotic activity is variable but generally less conspicuous than in the cellular pattern. The tumor commonly interdigitates deeply with the adjacent renal parenchyma, without compression or distortion of renal structures. Classic congenital mesoblastic nephromas lack characteristic cytogenetic features.

Karyotype of Cellular Congenital Mesoblastic Nephroma

FIGURE 9.41  Karyotype of cellular congenital mesoblastic nephroma. Cellular mesoblastic nephromas contain the same cytogenetic translocation found in infantile fibrosarcoma, t(12;15)(p13;q25). The ETV6 gene on 12p13 is fused to the neurotrophin-3 receptor (NTRK3) gene on 15q25. Note the similarities between the derivative chromosomes and the normal chromosomes. This may prevent the recognition of this translocation in samples that lack sufficient karyotypic detail, which often occurs with the culture of solid tumors.

n Ossifying Renal Tumor of Infancy

FIGURE 9.43  Ossifying renal tumor of infancy. These rare lesions are composed of bland but occasionally quite cellular spindled cells with varying amounts of osteoid matrix. The tumors are small and characteristically protrude into the collecting system, resulting in hematuria. The cellular component may closely resemble cellular congenital mesoblastic nephroma or Wilms tumor, as is seen in the top of this figure.

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n Clear Cell Sarcoma of the Kidney FIGURE 9.44  Clear cell sarcoma of the kidney (CCSK) is composed of undifferentiated cells of unknown histogenesis with abundant extracellular matrix separated into cords and nests by a fine vascular network. CCSKs comprise 5% of pediatric renal tumors. Although the histologic appearance of CCSK is unique, it has a wide spectrum and often mimics other pediatric renal tumors, resulting in considerable diagnostic difficulty. CCSKs are composed of two cell types, cord cells and septal cells. The cord cells often predominate and are plump, rather bland, and demarcated by delicate, regularly spaced fibrovascular arcades. Occasionally, these fibrovascular areas may contain expansion of elongated, spindled septal cells (illustrated).

FIGURE 9.45  Clear cell sarcoma of the kidney. Cytologically, the cells of CCSK contain nuclei with finely dispersed chromatin and lack conspicuous nucleoli. Often the nuclei have a characteristic “empty” appearance, with the chromatin located at the edge of the nucleus. This figure demonstrates a cellular pattern showing closely spaced, embryonal appearing cells, with persistence of the vascular pattern. CCSKs are generally sharply demarcated grossly; however, they slowly infiltrate and “nibble” at the normal renal parenchyma, resulting in entrapment and separation of individual renal tubules, a feature virtually never seen in nephroblastomas.

n Rhabdoid Tumor FIGURE 9.46  Rhabdoid tumor. Malignant rhabdoid tumor has been reported throughout the body, however the most common sites are the kidney and brain. Rhabdoid tumors of all sites have been shown to contain deletions and mutations of the hSNF5/INI1. Characteristic features of rhabdoid tumor include the vesicular nuclei, prominent nucleoli, and occasional pale cytoplasmic inclusions (inset). Aggressive infiltration of soft tissue and vessels in the renal parenchyma and sinus is characteristic of this neoplasm. Dense sclerosis may be seen, resembling osteoid production. Spindling of the tumor cells may occasionally be seen.

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FIGURE 9.47  Rhabdoid tumor. Many rhabdoid tumors lack characteristic features, and instead have the appearance of a small blue cell tumor. In these instances, the diagnosis relies on immunohistochemistry and/or genetic analysis. Rhabdoid tumors show polyphenotypic differentiation with positivity for several antibodies in a pattern characterized by very focal but very intense staining. Most recently, the BAF47 antibody, which is directed against the INI-1protein, has become available and is negative in rhabdoid tumors.

n Renal Cell Carcinoma With Xp11.2 Translocation FIGURE 9.48  Renal cell carcinoma with Xp11.2 translocation. Malignant epithelial tumors arising in the kidney of children account for more than 5% of new pediatric renal tumors. Pediatric renal cell carcinomas differ in their histologic appearance from those of adulthood and comprise a heterogeneous group of malignancies. The most common type of renal cell carcinoma in children is characterized by translocations involving TFE3 gene located on Xp11.2. The tumor cells often form papillary structures and commonly show voluminous cytoplasm. Some tumors have a tubular appearance and may mimic clear cell renal cell carcinoma. Psammomatous calcifications are commonly seen. Clues to the diagnosis of translocation-associated renal cell carcinomas include the paucity of staining for epithelial membrane antigen and vimentin.

n Papillary Renal Cell Carcinoma FIGURE 9.49  Papillary renal cell carcinoma. Classic papillary renal cell carcinomas in children show the same pathologic and genetic features as those found in adults (gains of chromosomes 7 and 17). These may have a basophilic appearance (type 1) or may have eosinophilic cytoplasm (type 2). Cytokeratin 7 staining is typical of type 1 papillary renal cell carcinoma, which aids in its distinction from epithelial differentiated Wilms tumor or metanephric adenoma. Papillary renal cell carcinoma may also arise in the setting of Wilms tumor, metanephric adenoma, and metanephric adeno­ fibroma.

Suggested Readings 

n Postneuroblastoma Oncocytoid Renal Cell Carcinoma

FIGURE 9.50  Postneuroblastoma oncocytoid renal cell carcinoma. A rare form of renal cell carcinoma is seen in a small number of children previously treated for neuroblastoma 5–13 years prior to diagnosis. These tumors show an oncocytoid appearance usually with a solid appearance, although papillae may be evident.

n Renal Medullary Carcinoma

FIGURE 9.51  Renal medullary carcinoma is a rare and highly aggressive tumor that develops in patients with at least one copy of the sickle cell gene. These tumors show variable degrees of gland formation surrounded by desmoplasia and often accompanied by an acute inflammatory reaction. Eosinophilic cytoplasmic inclusions and prominent nucleoli, often indistinguishable from rhabdoid tumor, are present in the many cases. Drepanocytes (sickled cells) can be found in most cases as a result of formalin fixation.

Suggested Readings Argani P, Perlman EJ, Breslow NE, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol. 2000;24:4–18. Arroyo MR, Green DM, Perlman EJ, Beckwith JB, Argani P. The spectrum of metanephric adenofibroma and related lesions: clinicopathologic study of 25 cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol. 2001;25:433–444. Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr Pathol. 1990;10(1–2):1–36. Bruder E, Passera O, Harms D, et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol. 2004;28:1117–1132. D’Agati VD, Jennette JC, Silva FG. Atlas of Nontumor Pathology: Non-Neoplastic Kidney Diseases. Silver Spring, Md: ARP Press; 2005. Faria P, Beckwith JB, Mishra K, et al. Focal versus diffuse anaplasia in Wilms’ tumor—new definitions with prognostic significance: a report from the National Wilms’ Tumor Study Group. Am J Surg Pathol. 1996;20:909–920. Fogo AB, Kashgarian M. Diagnostic Atlas of Renal Pathology. Philadelphia, PA: W.B. Saunders; 2005. Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol. 2004;28:1485–1491. Jennette JC, Olsen JL, Schwartz MM, Silva FG. Heptinstall’s Pathology of the Kidney. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2007. Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;58:5046–5048. Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol. 1999;23:772–780.

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Murphy WM, Grignon DG, Perlman EJ. Tumors of the Kidney, Bladder, and Related Urinary Structures. 4th ed. Washington, DC: Armed Forces Institute of Pathology; 2004. Perlman EJ, Faria PA, Ritchey ML, Shamberger ML, Green DM, Beckwith JB. Diffuse hyperplastic perilobar nephroblastomatosis: the National Wilms’ Tumor Pathology Center experience. Submitted 2002. Renshaw AA. Basophilic tumors of the kidney. J Urol Pathol. 1998;8:85–102. Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology. 2002;60:1083–1089. White FV, Dehner LP, Belchis DA, et al. Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11. Am J Surg Pathol. 1999;23:249–256. Zhou XJ, Laszik Z, Nadasdy T, D’Agati VD, Silva FG. Silva’s Diagnostic Renal Pathology. New York, NY: Cambridge University Press; 2009. Zuppan CW, Beckwith JB, Luckey DW. Anaplasia in unilateral Wilms’ tumor: a report from the National Wilms’ Tumor Study Pathology Center. Hum Pathol. 1988;19:1199–1209.

Female and Male Reproductive Systems

10

Michael k. Fritsch elizabeth J. Perlman

n

n

NORMAL DEVELOPMENT OF REPRODUCTIVE STRUCTURES Primordial Germ Cells and the Indifferent Gonad Gonadal Specification Ductal and External Genitalia Development SPECIFIC REPRODUCTIVE TRACT ANOMALIES Gonadal Anomalies

Mesonephric (Wolffian) Duct and Paramesonephric (Müllerian) Duct Anomalies External Genitalia Anomalies n

DISORDERS OF SEX DEVELOPMENT (PREVIOUSLY KNOWN AS INTERSEX DISORDERS) Nomenclature for Disorders of Sex Development

Proposed Classification for the Causes of Disorders of Sex Development n

INFLAMMATORY DISORDERS

n

GONADAL TUMORS

norMal develoPMenT oF reProduCTive sTruCTures The reproductive tract consists of the external genitalia, the ductal system, and the gonads (testes, ovaries). Primordial germ cells are first identified about 4–5 weeks following fertilization and migrate to the urogenital ridge, which is destined to become the male or female gonad. The differentiating gonad orchestrates the molecular signals and hormones necessary for sex-appropriate development of the ductal system and external genitalia. Anomalies of the reproductive tract most often occur in association with other anomalies or as part of a syndrome. Abnormal gonad development can result in ambiguous genitalia or abnormal secondary sex characteristics referred to as disorders of sex development (DSD), previously known as intersex disorders.

n PriMordial GerM Cells and The indiFFerenT Gonad Primordial germ cells (PGCs) arise from cells of the proximal epiblast (embryonic ectoderm) during the 4th week after conception through signaling via members of the TGF-beta family and other molecular pathways. PGCs are first recognized in the yolk sac endoderm at the base of the allantois. PGCs migrate into the ventral visceral endoderm and migrate along the dorsal mesentery to populate the genital ridges (Figure 10.1A). PGCs that do not occupy the genital ridges are thought to undergo apoptosis, and it is proposed that failure to undergo apoptosis following aberrant PGC migration may represent the source of nongonadal germ cell tumors. The PGCs are indifferent during migration and until the 7th week postconception. These PGCs express specific marker proteins once they reach the gonadal ridges, but the gonads cannot be distinguished as male or female until about weeks 7–8. The gonadal ridge first appears medial to the mesonephric epithelium during week 5. The indifferent gonad consists of the PGCs, mesenchyme, and the coelomic epithelium. The coelomic epithelium will grow into the genital ridge to form the primary sex cords. In XX (female) embryos, the cortex of the indifferent

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AORTA MESONEPHRIC DUCT

PRIMORDIAL GERM CELLS PARAMESONEPHRIC DUCT COELOMIC EPITHELIUM

GENITAL RIDGE

1A

HINDGUT

Figure 10.1  Early gonadal development. The undifferentiated gonad lies adjacent to the mesonephros and the Wolffian and Müllerian ducts. The mesonephros has a profound effect on normal gonadal differentiation. The ovary can be identified at 7–8 weeks gestation by the absence of testicular cords. Schematic diagram of early genital ridge formation and primordial germ cell migration (A). Histology of an indifferent gonad with adjacent mesonephric and paramesonephric ducts (B). 1B

gonad will become the ovary and the medulla will regress, whereas in XY (male) embryos, the medulla becomes the testis and the cortex will remain as the rete testis (Figure 10.1B) (1).

n Gonadal Specification A limited number of cell types contribute to the developing gonad. The major cell types include the PGCs and support cells derived from the coelomic epithelium. In males, the support cells will differentiate into Sertoli (sustentacular) cells and, in females, the support cells will contribute to the formation of granulosa cells. The steroidogenic cells of the differentiating gonad include interstitial cells of Leydig in the male (androgen producing) and the theca cells in females (estrogen, progesterone, and androgen producing). Other somatic cells found in the gonads include peritubular myoid cells, fibroblasts, and vascular cells that likely arise from undifferentiated mesenchyme. Abnormalities in the expression of a limited number of critical genes can result in abnormal gonad development with resulting disorders in sex development (discussed later). The morphology of the developing testis is demonstrated in Figure 10.2. The morphology of the developing ovary is depicted in Figure 10.3.

n Ductal and External Genitalia Development The development of the urinary and reproductive tracts is intimately interrelated. The urogenital ridges arise from intermediate mesoderm adjacent to the aorta by 4–5 weeks postconception. These areas contain the primitive embryonic kidneys known as mesonephron and associated excretory ducts (the mesonephric ducts). These structures will briefly act as embryonic excretory organs until about week 6, when the ureteric bud and metanephric blastema develop and will eventually form the components of the mature urinary tract system. The presence of the mesonephric (Wolffian) ducts is essential for the formation of the paramesonephric (Müllerian) ducts. Both ductal systems develop in males and females.

Normal Development of Reproductive Structures 

2A

2B

2C

2D

Figure 10.2  Testicular maturation. Testis differentiation from the indifferent gonad is initiated by expression of the transcription factor SRY in support cells. This results in expression of SOX9 and eventually in Sertoli cell differentiation, which is critical for testis development. The primary sex cords arising from the coelomic epithelium condense and extend into the medulla, which acts as the primary site of testis development. The cords, lined by Sertoli cells, elongate and branch while enclosing the PGCs that have migrated in. The cords become the seminiferous tubules, tubuli recti, and rete testis. A fibrous capsule, the tunica albuginea, develops and distinctive testis morphology can usually be discerned by week 8–9. The interstitial cells of Leydig arise from the mesenchyme and begin producing androgens by about week 8. Sertoli cells produce MIS, which results in paramesonephric (Müllerian) duct regression in males. The rete testis becomes continuous with the mesonephric tubules, which will become the efferent ductules, and these are in continuity with the remnant mesonephric duct as the ductus epididymis. Spermatogonia do not enter meiosis until puberty. At 15 weeks gestation, seminiferous tubules containing Sertoli cells and male germ cells (larger cells at the base with clear cytoplasm) are easily identified. Numerous interstitial cells of Leydig are seen between the tubules (A). At 20 weeks gestation, the morphology is similar to 15 weeks but the tubules are better defined (B). At term, the number of Leydig cells is markedly reduced from earlier gestation (C). Leydig cells are very difficult to identify in infants at 8 months of age (D). The interstitial space between tubules is reduced, but Sertoli cells and germ cells are easily identified.

The paramesonephric ducts will contribute to the female internal reproductive structures and the mesonephric ducts will regress in females. The mesonephric ducts will contribute to the male internal structures, including the ductus deferens and the ejaculatory duct. The paramesonephric ducts regress in males because of the secretion of Müllerian inhibiting substance (MIS) by each ipsilateral testis. The ventral cloaca becomes the urogenital sinus following division by the urorectal septum. The caudal portion of the urogenital sinus will become the prostatic urethra in males and the entire urethra in females. Mesonephric (Wolffian) duct and male external genitalia development is demonstrated in Figure 10.4 and Figure 10.5, while the paramesonephric (Müllerian) duct and female external genitalia development are summarized in Figure 10.6 and Figure 10.7.

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3A

3B

3C

3D

Figure 10.3  Ovarian maturation. Ovarian differentiation proceeds more slowly than for the testis, and ovarian morphology cannot be definitively determined until about week 10. Ovarian development proceeds in the absence of the male molecular events described previously. WNT4 has been identified as a testis-suppressing gene in the ovary, such that aberrant loss of expression of WNT4 in an XX-indifferent gonad can result in some degree of testis differentiation. The primary sex cords extend into the medulla and form the rete ovarii, but these degenerate in the ovary with the cortex acting as the primary site of ovarian development. The secondary sex cords (cortical cords) increase in size and incorporate the PGCs. By 16 weeks postconception, the cords break up into isolated cell oocyte clusters with intercellular connections between oocytes. 3E The germ cells migrate into the early ovary at approximately 8 weeks. After their arrival, they undergo active mitotic cell division, a process that continues until birth. The germ cells are intermixed with and difficult to distinguish with the gonadal stromal cells. At approximately 12 weeks gestation, the first germ cells begin to enter into meiosis, a process first seen deep in the medullary region. Upon entering meiosis, the primary oocyte will arrest at the diplotene stage of the first meiotic prophase and become enclosed by follicular cells to form primordial follicles. This gradual process of oogenesis is generally complete by the third trimester, and there is no further increase in the number of primary oocytes thereafter. During late fetal life and throughout the prepubertal period, many oocytes are lost, presumptively via apoptosis, and the ovarian stroma increases. The ovary at term shows numerous primordial follicles and the development of a subepithelial c­ollagenous connective tissue layer that will become more prominent with age. The ovarian stroma becomes less cellular. Prior to birth, some primordial follicles can continue to mature and at term, some ovaries contain primary, secondary, and mature (antral) follicles. In addition, large follicular cysts are common in newborns. The steroidogenic theca cells begin to function by about week 8–10, but cannot be histologically identified until the first portion of the second trimester. The ovary at 16 weeks gestation predominantly consists of oocytes and poorly delineated stroma (A). By 26 weeks, most of the oocytes are surrounded by a single layer of follicular cells to form primordial follicles (B). At term, well-formed primordial follicles predominate with a clearly defined stroma (C). Primary, secondary, and mature follicles are not uncommon at term (D). By 5 years of age, primordial follicles still predominate in the ovary, but the numbers are reduced and a well-formed ovarian stroma is present (E).

Normal Development of Reproductive Structures 

4A

4B

4C

4D

211

Figure 10.4  Histology of the internal male reproductive tract at term. Male ductal and external genitalia development relies on the presence of the testes primarily because of the production of androgens and MIS. MIS production by Sertoli cells is regulated by SF1, and begins at about 8 weeks. MIS secretion results in regression of the paramesonephric duct between weeks 8 and 11. The mesonephric duct will form the epididymis, ductus deferens, and ejaculatory ducts. Testosterone is produced by Leydig cells starting at about 8 weeks. An intact androgen-signaling pathway is critical for normal male development, including testosterone production from the Leydig cells, 5-alpha-reductase production in peripheral tissues for ­conversion of testosterone to dihydrotestosterone (DHT), and a functional androgen receptor in end-organs. Androgen signaling is essential for: (a) the prostate gland to form from the urogenital sinus as evaginations from the urethral wall, (b) to prevent vagina formation, (c) to facilitate growth of the genital tubercle to form the glans penis, (d) for differentiation of the urethral folds into the penile shaft with closure of the penile urethra, and (e) for the genital swellings (­labioscrotal folds) to fuse to form the scrotal sac. In addition, the seminal vesicles arise as outpouchings from the ductus deferens near the insertion into the urethra. The descent of the testes through the abdomen to the inguinal ring (week 15) is guided by the gubernaculum, and final descent into the scrotal sac usually occurs by week 35. This process is predominantly regulated by the INSL3 signaling pathway. The photomicrograph is a low-power view at term of rete testis (with vascular congestion) (A), epididymis (B), vas deferens (C), and prostate (D). Figure 10.5  Histology of the external male genitalia. The penis (at 17 weeks) is covered by skin, and the prepuce or foreskin (P) remains attached to the glans penis by a thin cell layer. The penile urethra (U) is seen within the shaft of the penis and is surrounded by the corpora spongiosum (CS). The corpora cavernosa (CC) is seen superior to the urethra. S, scrotum.

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6B

Figure 10.6  External and internal female reproductive tract at term. Male and female external genitalia cannot be easily distinguished until about week 9–12. The genital tubercle gives rise to the phallus, which will form the glans penis or the clitoris. The labioscrotal swellings and urogenital folds form on each side of the cloacal membrane. In females, the urogenital folds fuse posteriorly to form the frenulum of the labia minora. The labioscrotal 6A folds remain unfused in females as the labia majora. The external genitalia in females consist of labial folds and the clitoris (A). The internal reproductive tract includes the ovaries (O), fallopian tubes (F), uterus (U), cervix (C), and vaginal cuff (V). Source: (B) Courtesy of Don Singer, MD.

Figure 10.7  Histology of the internal female reproductive tract at term. Female ductal and external genital development is not strictly dependent on the presence of ovaries. In females, the absence of testosterone results in degeneration of the mesonephric ducts beginning at about week 10. Mesonephric duct remnants are commonly found as tubular or ductal structures lateral to the internal female reproductive tract (often in the mesovarium). In females, the cranial portion of the paramesonephric ducts will form the uterine (fallopian) tubes, which remain open into the peritoneum. In the pelvis, the paramesonephric ducts merge to form a Y-shaped uterovaginal primordium at about 10 weeks. The cavities of the ducts become a single genital canal, and this will form the uterus and superior portion of the vagina. At term, the cervix is about twice the length of the body of the uterus. The cervix is lined by endocervical glands composed of columnar epithelium that produce mucus. At term, these glands can extend out onto the portion of the cervix and appear as erosions, but following birth, they regress back into the cervical canal. Following birth, the 7A size of the uterus actually reduces for the first several months. The ratio of uterine: cervical length slowly increases until puberty such that the cervix composes a smaller percentage of the structure as the individual ages. Vaginal development is more complex. The uterovaginal primordium contacts the urogenital sinus to form the sinus tubercle. This induces paired endodermal outgrowths referred to as sinovaginal bulbs, which grow and fuse to form the vaginal plate. The cells in the center degenerate and the lumen of the vagina is separated from the vestibule by a membrane (hymen). The hymen is derived from the posterior wall of the urogenital sinus. The vagina is lined by squamous epithelium. Following birth, the vagina contains thick yellow mucous and desquamated cells caused by the withdrawal of maternal hormones. Some of the molecular pathways regulating female duct development include PAX2, members of the WNT and HOX families, and the estrogen receptors (alpha and beta). Several female genital glands occur as outpouchings of the urethra or urogenital sinus. The urethral glands and paraurethral glands (of Skene) form from urethral evaginations similar to the prostatic glands. The greater vestibular glands (of Bartholin) represent outgrowths of the urogenital sinus and are homologous to the bulbourethral glands in males. Remnants of the mesonephric duct can frequently be seen adjacent to the uterine tubes, uterus, cervix, or lateral walls of the vagina. These include the appendix vesiculosa near the cranial end of the mesonephric duct, the epoophoron and paroophoron, and the ducts of Gartner found adjacent to the uterus, cervix, or lateral walls of the vagina. Cysts formed from paramesonephric duct remnants near the ovary are referred to as hydatid of Morgagni. At term, the fallopian tube consists of numerous papillary folds lined by a nonstratified epithelium that can have cilia (A). The epoophoron, a remnant of the mesonephros, is a series of ducts commonly found in the mesovarium; that portion of the broad ligament that lies between the fallopian tube and the ovary (B). The uterus consists of endometrial glands that are often proliferative because of exposure to maternal estrogens, although the cells can appear to be secretory as well (C). These changes regress within a couple of weeks of birth and the endometrium becomes thin and inactive until puberty. The myometrium consists of a highly cellular smooth muscle stroma. The exocervix consists of a mature squamous epithelium demonstrating the expected maturation pattern from basal to superficial cells. The clear cytoplasm represents glycogen. The endocervix consists of a single layer of glandular epithelium with basilar nuclei and cytoplasm full of mucin. During fetal development and during childhood, the length of the cervix is larger than the length of the uterine corpus (D). The vagina is lined by mature nonkeratinizing stratified squamous epithelium, often with glycogenated cytoplasm caused by the influence of maternal estrogens. The normal vagina lacks mucosal glands (E). (Continued)

Specific Reproductive Tract Anomalies 

7B

7C

7D

7E

Figure 10.7  Histology of the internal female reproductive tract at term. (Continued)

Specific Reproductive Tract Anomalies Anomalies of the reproductive tract can occur as isolated defects, associated with presumed teratogenic exposure in utero (especially exogenous or endogenous hormones), associated with urinary tract abnormalities, as part of chromosomal defects, or as part of malformation syndromes. The spectrum of malformations is wide and correct diagnosis requires careful assessment of all reproductive structures.

n Gonadal Anomalies Abnormalities in the number of testes have been reported, but are relatively rare events. Abnormalities in the size of the testis can also occur (Table 10.1). Abnormalities in the number, size, and location of female gonads are also relatively rare (Table 10.2).

213

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Female and Male Reproductive Systems

Table 10.1  Testicular Anomalies Testicular Anomaly

Characteristics and Etiology

Anorchia (absence of both testes)

Complete absence of both testes (anorchia) in an individual with a Y chromosome is rare. This can occur as an isolated defect or as part of a syndrome or major developmental field defect such as in sirenomelia.

Monorchidia (a single testis)

A single testis can occur in the setting of vascular injury, cryptorchidism, or as part of testicular regression syndrome.

Testicular regression syndrome (2)

Testicular regression syndrome is also known as vanishing testis and occurs in XY individuals missing a testis or who have a microscopic testicular remnant. There are five overlapping subtypes categorized by the time during intrauterine life when testicular function fails. These include gonadal aplasia, early fetal testicular dysgenesis, early fetal testicular regression, midfetal testicular regression, and late fetal testicular regression (3). The cause remains unknown but may be related to prenatal testicular torsion with resulting infarction. Because there is no significant r­emaining testicular tissue, there is no increased risk of neoplasia. In cases with small amounts of residual tissue, there is usually fibrosis, calcifications, hemosiderin, and an increased number of blood vessels. A vas deferens and epididymis can remain, usually with the vas ending blindly.

Polyorchidism (more than two testes)

Polyorchidism can represent duplication of both testes or can occur as triorchidia. The extra testis can show a range of appearances from completely normal with intact spermatogenesis to disorganized s­eminiferous tubules and decreased spermatogenesis.

Macroorchidia (enlarged testes)

Abnormally large testes are usually idiopathic but can occur as part of many other conditions, a classic example being in Fragile X syndrome (OMIM #300624) (4).

Microorchidia (small testes)

Small testes occur in the setting of several disorders including Klinefelter syndrome (XXY) and Prader-Willi syndrome (OMIM #176270) (4). Usually there is a reduction in the volume and function of the affected testis.

Testicular atrophy

Testicular atrophy can result from several processes including orchitis, leprosy, tuberculosis, mumps, and other infections. Testis infarction in the newborn is usually caused by torsion or results from a strangulated hernia. Torsion is more common at a young age because the testis and gubernaculum can freely rotate. Following torsion, the testis may be enlarged and painful, and there is hemorrhagic and coagulative necrosis. The long-term outcome is testicular atrophy.

Hypogonadism (decreased testicular function often associated with decreased size)

Hypogonadism refers to decreased testicular function and is often associated with a reduction in the size of both testes. This can occur associated with numerous syndromes (1, 5).

Cystic dysplasia

Cystic dysplasia of the testis is a rare congenital malformation that results from failure of afferent seminiferous tubules at the levels of the rete testis to connect to the mesonephric derived efferent tubules. The affected testis is characterized by small cystic spaces lined by flattened epithelium occurring in the mediastinum of the testis. The ­ectasia of the rete testis can cause atrophy of the seminiferous tubules. This can be ­unilateral or bilateral and often there may be anomalies of the ipsilateral kidney.

Cryptorchidism (undescended testis)

Normal testicular descent is complex and regulated by a n­umber of processes, including normal production of androgens, MIS production with resolution of Müllerian structures, insulin-like growth factor 3 (ILGF3) activity facilitating gubernaculum growth and regression, an intact hypothalamic-pituitary axis and intra-abdominal pressure. Testes originate within the abdomen; migrate to the inguinal canal by 10–15 weeks, through the canal by 28 weeks and into the scrotum by 35–40 weeks. Failure of testicular descent is relatively common in term infants (2% to 3%) and can be uni or bilateral. Cryptorchidism can result from any of multiple causes, including abnormal androgen production, failure of g­ubernaculum development (mutations in ILGF3 or the gene coding its receptor RXFP2), anatomic obstructions of the inguinal canals (prune belly syndrome [Figure 10.8], posterior urethral valves, congenital abdominal wall malformations), or neuromuscular defects that prevent the transmission of intra-abdominal p­ressure to the testis (6–8). Long-standing cryptorchidism can result in abnormal testis morphology, including small tubules often devoid of germ cells and thereby lacking spermatogenesis. Leydig cells can degenerate. There is an 8–10-fold increased risk of n­eoplasia in an undescended testis. Undescended testes that fail to descend with hormonal therapies are usually surgically placed in the scrotum, and if performed before 5 years of age, the testis has a high likelihood of functioning. (Continued)

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215

Table 10.1  Testicular Anomalies (Continued) Testicular Anomaly

Characteristics and Etiology

8A

8B

Figure 10.8  Cryptorchidism. Gross photo of a male fetus at 32 weeks with prune belly syndrome and bilateral abdominal testes (A). Only one testis is seen here (T). The label U in this photo is the ureter, whereas the label B is the bladder. The histology of an adult testis that was cryptorchid shows decreased spermatogenesis and decreased numbers of s­permatogonia (B). Hydrocele

A hydrocele represents an accumulation of fluid in the tunica ­vaginalis adjacent to the testis. This is relatively common in newborns and is ­usually of little consequence, as it will spontaneously resolve over several weeks (Figure 10.9).

Figure 10.9  Hydrocele in an adult testis. Hydroceles are very common in newborn males and usually resolve. In adults, hydroceles can develop for various reasons and can be mistaken for a testicular mass.

Dysgenetic testis

10A

Dysgenetic testes occur in some DSD. The affected testes show a ­spectrum of changes, but are characterized by immature tubules with atypical branching and decreased germ cells. The tubules are separated by a loose fibrous stroma. In addition, normal testicular function is impaired. A ­number of disorders are associated with gonadal dysgenesis, including Swyer syndrome (pure gonadal dysgenesis, 46,XY) (OMIM #400044), mixed gonadal dysgenesis (OMIM #233420 & #607080), c­ ampomelic d­ysplasia (OMIM #114290), Frasier syndrome (OMIM #136680), ­Denys-Drash syndrome (OMIM #194080), and others (Figure 10.10) (4).

10B

Abbreviation: OMIM, Online Mendelian Inheritance in Man.

Figure 10.10  Dysgenetic male reproductive tract. Gross photo of Müllerian duct derivatives from a 7-day-old boy with 46,XY. The specimen consists of a hypoplastic cervix, uterus, and bilateral fallopian tubes (A). The histology of a dysgenetic left gonad from a 3-year-old boy with 46,XY reveals focal atrophic tubules, and other tubules demonstrate elongation and increased convolution with focally increased numbers of germ cells (B).

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Female and Male Reproductive Systems

Table 10.2  Ovarian Anomalies Ovarian Anomaly

Characteristics and Etiology

Gonadal agenesis (no gonads at birth)

Gonadal agenesis (no gonads) usually results in female internal and external genitalia. These individuals can be either XX or XY. This can occur as part of a major malformation ­syndrome such as in sirenomelia (Figure 10.11A).

Single ovary

A single ovary can occur, especially associated with other anomalies or as part of a ­malformation syndrome (Figure 10.11B).

Figure 10.11  Malformations of the female reproductive tract are commonly associated with malformation syndromes. Complete absence of the external and internal reproductive tract, including no gonads, occurred in this 46,XX term female with sirenomelia and there was also bilateral renal agenesis with Potter sequence (A). The internal reproductive tract from a 7-monthold female infant who had documented deletion of ­chromosome 11B 16p13.3 by polymerase chain reaction (PCR) (Rubinstein-Taybi syndrome—OMIM #180849). Although abnormalities of the female r­ eproductive tract are not listed as part of this syndrome, this infant had congenital absence of the right fallopian tube, ovary, and kidney. This is a posterior view of the internal reproductive tract. Grossly, this was a unicornuate uterus, but histology revealed a hypoplastic right-sided Müllerian duct. The left ovary was small and 11A 11C dysplastic with few remaining follicles and a disorganized ovarian stroma. The left mesovarium was prominent with mesonephric duct remnants (epoophoron) (courtesy of Dr. Michael Stier) (B). This female reproductive tract demonstrates marked bilateral ovarian e­nlargement caused by numerous cysts in a patient with Donohue syndrome (OMIM #246200), also known as leprechaunism. Source: (C) Courtesy of Don Singer, MD. Anomalies in ovarian number or location

Accessory, ectopic, and supernumerary ovaries can arise at many sites but are rare.

Gonadal dysgenesis (streak gonad)

Structural anomalies in the ovary include gonadal dysgenesis that occurs in patients with ­monosomy X and other chromosomal defects. In monosomy X, the ovary is ­morphologically normal during most of fetal development and, during the first 2 years of life, the oocytes ­disappear. In the end, the ovaries are referred to as streak gonads and consist of a ­cellular stroma with no germ cells or follicles. Streak gonads occur with other DSD as well (­Figure 10.12).

Ovotestis

In patients with true hermaphroditism, one or both gonads can be ovotestes, consisting of both ovarian and testicular tissue. The ovarian tissue usually has a normal a ­ ppearance, including follicles with oocytes. The accompanying ductal structures can either be ­Wolffian or Müllerian. There is an increased risk of developing a gonadal neoplasm, although the risk is much less than that seen in dysgenetic gonads (1Y) (Figure 10.13). (Continued)

Specific Reproductive Tract Anomalies 

217

Table 10.2  Ovarian Anomalies (Continued) Ovarian Anomaly

Characteristics and Etiology

12A

Figure 10.12  Dysplastic and streak gonads. Most sex chromosomal abnormalities may result in a spectrum of gonadal abnormalities ranging from a streak gonad to a ­relatively normal ovary or testis (A). Within a single ­genotypic abnormality and genetic background, the ­phenotype may vary widely. Illustrated is a streak gonad of a 46,XY phenotypic female that is composed of wavy ­ovarian-type stroma and no primordial follicles. This is an example of pure or complete gonadal dysgenesis, most 12B often caused by an X-linked recessive mutation or deletion of the SRY gene on the short arm of the Y chromosome. Such patients usually have a female phenotype complete with a uterus and fallopian tubes, despite a 46,XY karyotype. Patients with dysgenetic gonads are at risk for the development of gonadoblastomas, which are benign tumors found only in patients with both Y chromosomal material and dysgenetic gonads (B). Histologically, gonadoblastomas are ­characterized by sharply defined nests containing both germ cells and stromal cells of granulosa-Sertoli cell type; a common feature is the presence of calcifications. ­Gonadoblastomas may become extensively hyalinized. The significance of gonadoblastoma is the associated high frequency of concurrent or future development of a ­malignant germ cell tumor, most ­commonly dysgerminoma. Figure 10.13  Ovotestis. True hermaphrodites are quite rare and contain both fully developed ovarian and testicular tissues either separately or combined as an ovotestis (illustrated). The external phenotype may be either male or female, but usually the genitalia are ambiguous. Ovotestes may lie anywhere along the descent pathway but are most commonly abdominal. The ovarian and testicular tissues within an ovotestis are commonly immediately adjacent to each other and sharply ­demarcated. This gonad demonstrates an area immediately below the capsule with ovarian stroma and numerous primordial follicles, and deeper gonadal tissue contains seminiferous tubules with reduced numbers of germ cells.

Ovarian cysts

Ovarian cysts at birth usually represent the effects of maternal hormones on ­maturing f­ ollicles. These usually regress within weeks of birth as hormone levels decrease in the infant. Disorders can also present with ovarian cysts early in life, including Donohue ­syndrome (OMIM #246200) (Figure 10.11C), Rudiger syndrome (OMIM 268650), congenital generalized lipodystrophy, Type 1 (OMIM #608594) or Type 2 (OMIM #269700), and others (4).

Abbreviation: OMIM, Online Mendelian Inheritance in Man.

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Female and Male Reproductive Systems

n Mesonephric (Wolffian) Duct and Paramesonephric (Müllerian) Duct Anomalies Common male ductal anomalies are summarized in Table 10.3. Common female ductal anomalies are discussed in Tables 10.4 and 10.5. The paramesonephric duct is destined to give rise to the fallopian tubes, uterus, and upper third of the vagina. Müllerian duct anomalies are estimated to have an incidence of 0.1% to 3.5% in women. Müllerian duct defects can occur sporadically, in association with limited other anomalies, especially renal and axial skeletal anomalies, or as part of a multiple malformation syndrome. Ovarian function and external genitalia morphology are usually unaffected. In the absence of other malformations, affected individuals usually present in adulthood for assessment of recurrent pregnancy loss, premature delivery, dyspareunia, or dysmenorrhea. Although infertility can represent the problem, it is more common that these women cannot carry pregnancy to term because of the structural defects and often suffer recurrent spontaneous abortions. Classification of these defects have varied and include categorization based on morphology and developmental time of onset of the defect with at least three categories often described, including: (a) complete failure of the formation of the Müllerian duct (uni or bilateral),

Table 10.3  Mesonephric (Wolffian) Duct and Associated Male Anomalies Anomaly

Characteristics and Etiology

Congenital absence of vas deferens

Absence of a portion of the Wolffian duct is usually detected later in life because of male infertility. The most common anomaly is congenital absence of the vas deferens. Bilateral congenital absence of the vas deferens occurs in many males with cystic fibrosis. Renal anomalies occur with increased frequency in patients with congenital anomalies of the vas deferens.

Prostatic cysts

There are several types of prostatic cysts (9). Congenital utricle cysts in the prostate usually arise in association with the verumontanum and are highly associated with other GU anomalies, including hypospadias, cryptorchidism, and renal anomalies. Utricle cysts are difficult to distinguish from Müllerian duct cysts in the prostate.

Hypoplastic p­rostate

A hypoplastic prostate with a marked reduction in the number and size of the prostatic glands is usually present in patients with prune belly syndrome (10 and references therein) (Figure 10.8A).

Müllerian duct remnants

Müllerian duct remnants in males are a prominent feature of a defect in normal MIS signaling (failure to synthesize MIS or a defect in the MIS receptor) and are seen in some patients with DSD (Figure 10.10A). Isolated Müllerian duct remnants can also occur in males, frequently as cysts and commonly associated with the prostatic utricle. Müllerian duct cysts arise from remnants of the Müllerian duct and are not associated with a higher frequency of GU anomalies (Figure 10.14).

14A

14B

Figure 10.14  Müllerian duct remnants. Müllerian duct remnants in males often appear as tubular structures consisting of smooth muscle lined by ciliated or glandular cuboidal to columnar epithelium (uterus-like). This specimen was removed from a 3-year-old boy (A). Müllerian structures (fallopian tube—upper right) and Wolffian structures (epididymis—lower left) are found adjacent to each other in a resection from a 5-month-old girl with an ovotestis on the ipsilateral side (B). Abbreviations: DSD, disorders of sex development; GU, genitourinary; MIS, Müllerian inhibiting substance.

Specific Reproductive Tract Anomalies 

219

Table 10.4  Paramesonephric (Müllerian) Duct Anomalies (Figure 10.15) American Fertility Society Classification

Characteristics and Etiology

15A

15B

15C

15D

15E

15F

Figure 10.15  Müllerian duct anomalies. Schematic diagram comparing normal uterus (A); unicornuate uterus (Class II) (B); uterus didelphys (Class III) (C); bicornuate uterus (Class IV) (D); septate uterus (Class V) (E); and arcuate uterus (Class VI) (F).

Class I—Müllerian aplasia

Müllerian aplasia (also known as vaginal agenesis) is characterized by the absence or hypoplasia of the uterus, proximal vagina, and sometimes the fallopian tubes. This is relatively uncommon with an estimate of 1 in 5,000 newborn females. Müllerian aplasia can be partial or complete. In the partial form, the uterus is usually ­normal and the vaginal pouch distal to the cervix is small. Complete Müllerian aplasia is also known as MRKH sequence and is characterized by ­congenital absence of the vagina and uterus in more than 90% of cases. The ovaries function normally and the fallopian tubes are frequently normal as well. Coexisting urologic anomalies occur in 15% to 40% of patients and coexisting skeletal anomalies occur in 12% to 50% of cases. The MURCS association is proposed to represent an extreme variant of this process. Patients with Müllerian aplasia usually have age‑appropriate external genitalia and their karyotype is usually 46,XX. Patients often present in adolescence for primary amenorrhea.

Class II—Unicornuate uterus

Unicornuate uterus occurs when one Müllerian duct partially or completely fails to elongate and the other develops normally. Although the ipsilateral ovary is usually normal, there are case reports of unicornuate uterus with ipsilateral ovarian agenesis, as seen in Figure 10.11B. Unicornuate uterus represents a broad spectrum of defects, which can occur in the presence or absence of a ­rudimentary horn. Associated urologic anomalies are common. Although pregnancy in an affected mother can usually occur, there is an increased risk of miscarriage and premature delivery (14).

Class III—Uterus didelphys

Uterus didelphys arises when there is failure of midline fusion of the Müllerian ducts, which can be either complete or incomplete. The complete form ­consists of two uteri and two endocervical canals with fusion of the cervices at the lower uterine ­segment. The vagina may be single or double. The double vagina usually has a longitudinal septum that can be of any length extending from the cervices to the introitus. The ­fallopian tubes and ovaries are usually normal. Renal anomalies, including renal ­agenesis, are common (about 20%) with this defect. Patients are usually ­asymptomatic unless there is obstruction with ­resulting hematometrocolpos, hematometra, or hematosalpinx. Affected patients also suffer from poor reproductive outcomes with increased rates of miscarriage and premature delivery (Figure 10.16A). (Continued)

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Female and Male Reproductive Systems

Table 10.4  Paramesonephric (Müllerian) Duct Anomalies (Continued) American Fertility Society Classification

Characteristics and Etiology

16A 16B

16C

Figure 10.16  Müllerian fusion defects. The photo shows an adult uterus didelphys with a septate cervix (C) (A). A bicornuate uterus (U) exposed at autopsy in an otherwise unremarkable 16D third trimester stillbirth. The bladder (B) and attached umbilical stump are pulled forward in this photo. The ovaries (O) and fallopian tubes are normally formed (B). Low-power photomicrograph of the bicornuate uterus in B. Note the longitudinal septum extends almost to the internal cervical os, and there is a single cervix (C). The photomicrograph shows a longitudinal septate upper vagina in a different patient with a bicornuate uterus (D). Class IV—Bicornuate uterus

Bicornuate uterus is characterized by Müllerian ducts that incompletely fuse at the level of the uterine fundus. The lower uterus and cervix are normally fused. There are two separate but communicating uterine cavities with a single cervix and vagina. There is a muscular intrauterine septum and on the external s­ urface of the uterus there is an indentation or groove on the fundus. The length of the ­intrauterine septum allows for subclassification into complete or partial ­categories. These patients usually do not have an increased risk of infertility, but there is an increased risk of miscarriage (Figure 10.16B and Figure 10.16C).

Class V—Septate uterus

A septate uterus results from incomplete resorption of the separating septum following complete Müllerian duct fusion. The septum consists of vascularized fibromuscular tissue. Many variations exist, ranging from a complete septum that extends from the fundus to the internal os and produces two distinct cavities. This complete form may also be accompanied by a longitudinal vaginal septum (Figure 10.16D). A partial septum does not extend to the internal os. A septate uterus represents the most common Müllerian duct anomaly. Although fertility is seldom a problem for these patients, they have a very high rate of miscarriage, even greater than for the other classes.

Class VI—Arcuate uterus

An arcuate uterus is the mildest anomaly and may represent a normal variant or the mildest form of septate uterus. This represents a defect with only a small remnant (usually less than 1 cm) of a uterine septum present in the fundus. This anomaly is clinically benign.

Class VII —T-shaped uterus ­secondary to DES exposure

This is a T-shaped uterus resulting from DES exposure in utero.

Abbreviations: DES, diethylstilbestrol; MRKH, Mayer-Rokitansky-Kuster-Hauser; MURCS, Müllerian duct aplasia, unilateral renal aplasia, cervicothoracic somite dysplasia. Source: Adapted from Refs. 11–13.

Specific Reproductive Tract Anomalies 

221

Table 10.5  Other Female Genital Tract Anomalies Anomaly

Characteristics and Etiology

Transverse vaginal septum

A transverse vaginal septum divides the vagina into two portions and effectively reduces its length. The septum arises because of failure of complete resorption of the tissue where the vaginal plate meets the caudal portion of the fused ­Müllerian ducts. The septum can be imperforate or perforate and this is a relatively rare anomaly.

Vaginal atresia

Vaginal atresia represents failure of the urogenital sinus to contribute to the distal portion of the vagina. Müllerian duct-derived structures are usually normal. This anomaly can mimic vaginal agenesis or imperforate hymen. Vaginal atresia is ­usually sporadic.

Imperforate hymen

Imperforate hymen usually forms at the site of confluence between the urogenital sinus and the fused sinovaginal bulbs. An entirely imperforate hymen results in obstruction because of the absence of a communication between the introitus and the vaginal canal. An associated hymenal cyst can accompany an imperforate hymen.

Paraovarian cysts

These usually represent dilated remnants of the mesonephric (Wolffian) duct, but can also arise directly from the fallopian tubes or the peritoneum. They are uncommon in infants and children and more common in adults. They usually have little clinical significance, unless large (Figure 10.17A–B).

17B

Figure 10.17.  Paraovarian cysts. Incidental tubal cyst in a young adult is shown in the photo (A). An incidental ­epidermoid cyst is found in the mesovarium of a stillborn near-term fetus (B).

17A

Source: Adapted from Ref. 15.

(b) arrested Müllerian duct development (Müllerian aplasia), and (c) abnormal fusion of the Müllerian ducts. However, the most widely accepted classification scheme proposed by the American Fertility Society (AFS) includes seven categories of Müllerian malformations (Table 10.4) (16). The AFS classification scheme is based on the degree of developmental failure and clinical manifestations. However, the spectrum of Müllerian duct anomalies is broad and some do not neatly fit into every classification scheme. The molecular aspects of normal and abnormal Müllerian duct and vagina development are being studied with identified potential target gene families, including WNT and HOX members, as well as others (17, 18). Exposure to teratogens, especially well studied in female infants born to mothers treated with diethylstilbestrol (DES), can alter normal Müllerian development. Other internal genitalia anomalies, not necessarily derived from the Müllerian ducts, that are not classified by the AFS scheme, include the transverse vaginal septum, vaginal atresia, and imperforate hymen (Table 10.5) (15).

222 

Female and Male Reproductive Systems

n External Genitalia Anomalies Common male anomalies are listed in Table 10.6. Common female anomalies are listed in Table 10.7. Abnormalities and normal variations of the perineum, labia, and clitoris are occasionally encountered (15). Representative human syndromes associated with abnormal external genitalia formation have been recently reviewed (1, 19).

Table 10.6  Male External Genitalia Anomalies Anomaly

Characteristics and Etiology

Hypospadias

Hypospadias is a common anomaly (2–4/1,000) characterized by abnormal location of the urethral meatus on the ventral surface of the penis. This results from incomplete fusion of the urethral folds on the inferior aspect of the genital tubercle. Hypospadias can range from very mild to severe. In severe forms, the penis is often small and if there is associated cryptorchidism, the external genitalia can resemble that of a female, resulting in incorrect sex assignment at birth. Hypospadias can occur as an isolated defect but is more commonly observed associated with chromosomal abnormalities or as part of a syndrome such as Smith-Lemli-Opitz (OMIM #270400) or Fraser (OMIM #219000) syndromes (4).

Epispadias

When the urethral meatus occurs on the dorsum, or even more rarely, on the side of the penis, it is referred to as epispadias. In the most severe forms, epispadias can be accompanied by ­bladder exstrophy. Epispadias can also occur in females, usually with the urethral meatus displaced anteriorly and the meatus can even occur in the clitoris.

Secondary penile meatus

There can be a secondary penile meatus, usually on the dorsum of the penis.

Absent penile meatus

Failure of the penile meatus to open, often representing a ­keratin-like plug at the tip of the penis, can result in prune belly syndrome (10).

Posterior urethral valves

Posterior urethral valves usually occur in the region of the ­verumontanum. These can result in partial to complete ­obstruction to urine outflow and in the worst cases, the patients can present with prune belly syndrome (1, 10, 20, 21).

Absence of ­corpora cavernosa and/or corpora ­spongiosum (megalourethra)

Absence of the corpora cavernosa and/or corpus ­spongiosum results in megalourethra. The penis is enlarged and this ­anomaly frequently occurs in the setting of prune belly ­syndrome. Other anomalies can also occur in association with megalourethra (1, 20, 21).

Micropenis

A small penis is usually morphologically normal and is defined as a penis less than 2.5 cm at term (stretched length). ­Micropenis most commonly occurs because of insufficient androgen activity caused by either decreased androgen production ­(hypogonadism) or decreased androgen ­signaling. Several ­conditions are ­associated with micropenis, many of which overlap with ­hypogonadism, including Prader-Willi (OMIM #176270), Robinow (OMIM #180700), Kallmann (OMIM #308700 & #147950), Bardet-Biedl (OMIM #209900), and partial ­androgen insensitivity (OMIM #312300) syndromes (4).

Chordee

Chordee is a midline fibrous band that can occur on the ­ventral or dorsal aspect of the penis, resulting in penile curvature. This can occur as an isolated anomaly or in conjunction with ­hypospadias.

Other penile ­anomalies

Other anomalies of the penis, all of which are very rare, include diphallus, aphallia (penile agenesis), and penoscrotal ­transposition (1).

Abbreviation: OMIM, Online Mendelian Inheritance in Man.

Specific Reproductive Tract Anomalies 

223

Table 10.7  Female External Genitalia Anomalies Anomaly

Characteristics and Etiology

Complete absence of external genitalia

The most extreme form encompasses complete absence of the external genitalia, which usually occurs as part of major m ­ alformation syndromes including ­sirenomelia (Figure 10.11A), limb-body wall defects, Robinow syndrome (OMIM #180700), multiple ­pterygia syndromes, Fryns syndrome (OMIM %229850), and CHARGE association (OMIM #214800) (4).

Duplication of the vulva

Duplication of the vulva is rare and frequently ­associated with multiple congenital anomalies.

Perineal groove

A perineal groove or cleft is a minor anomaly that ­connects the anus with the vaginal orifice or ­scrotum in males (Figure 10.18A).

Absent clitoris

Clitoral and labial abnormalities may make it difficult to assign sex at birth. Complete absence of the clitoris is rare.

Clitoral hypertrophy

Clitoral hypertrophy can occur in the setting of endocrine ­dysfunction (classically with androgen excess as seen in ­congenital adrenal hyperplasia) or associated with other anomalies as part of a syndrome. Excess androgen ­exposure in utero related to increased fetal adrenal gland ­function, a maternal virilizing tumor, or exposure to ­exogenous ­compounds with androgen activity can result in clitoral hypertrophy and partial fusion of the posterior portions of the labia (Figure 10.18B and C). The ­molecular aspects of early genital tubercle (the anlage for the penis and clitoris) ­development are complex (19).

Labial adhesions

Labial adhesions represent fibrous adhesions between the labia majora. Patients ­usually present in early childhood (peak between 13–23 months) with the adhesions that are found incidentally. Labial adhesions are rare in the newborn and are presumed to be predominantly an acquired disorder. Other disorders such as an imperforate hymen must be excluded. The etiology is unknown but has been proposed to be related to low estrogen levels or chronic inflammation (22).

18A

18B

18C

Figure 10.18  Perineal groove and clitoromegaly. Perineal groove/cleft is in a near-term ­live-born male infant with trisomy 18 (A). Female siblings, born several years apart, each with Frasier syndrome and prominent clitoromegaly (23) (B, C). Abbreviation: OMIM, Online Mendelian Inheritance in Man.

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Disorders of Sex Development (Previously known as Intersex Disorders) The assignment of sex, male or female, usually occurs at birth. However, some individuals present with anomalies of the external genitalia (ambiguous genitalia), making it difficult to make the correct sex assignment. Ambiguous genitalia can be seen associated with chromosomal anomalies, single-gene mutations, syndromes, environmental exposures, or as sporadic defects (Figure 10.19). The term “intersex” was used to refer to infants born with ambiguous external genitalia such that sex assignment was precluded. Both clinician and patient dissatisfaction with the nomenclature (terms such as intersex, hermaphrodite, and pseudohermaphrodite) associated with abnormalities of sex development prompted a new definition and reclassification system (24–30). The newly adopted term for these disorders is “Disorders of Sex Development (DSD)” and this is defined as “a congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.” These disorders are characterized by a wide spectrum of phenotypic variation. This new definition includes a broader range of genital variations, including ambiguous genitalia, micropenis, cryptorchidism, and congenital malformation syndromes with abnormalities of the external genitalia. Use of the term “congenital” excludes entities that present later in life such as precocious or delayed puberty.

19A

19B

19D

Figure 10.19  Ambiguous genitalia. The photo shows a female infant with congenital adrenal hyperplasia and masculinization of the external genitalia (A); triploid fetus (69,XX) with partial labial scrotal fusion, poorly formed enlarged clitoris, and a prominent perineal groove (B); female neonate with a 19C chromosomal anomaly and masculinized external genitalia (C); and a male fetus (47,XY,+18) with appropriately formed phallus but hypoplastic scrotum, cryptorchid testes, and a midline perineal groove/cleft (D).

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225

Table 10.8  Nomenclature for Disorders of Sex Development DSD

Intersex Disorders

46,XY DSD

Male pseudohermaphrodite Undervirilization of XY male Undermasculinization of XY male

46,XX DSD

Female pseudohermaphrodite Overvirilization of XX female Masculinization of XX female

Ovotesticular DSD

True hermaphrodite

46,XX testicular DSD

XX male or XX sex reversal

46,XY complete gonadal dysgenesis

XY sex reversal

Abbreviation: DSD, disorders of sex development. Source: Adapted from Refs. 24–27.

The new classification system uses the karyotype as a prefix to define the category of DSD. In Table 10.8, the old intersex classification nomenclature is compared to that of the newly proposed DSD system. Perhaps the most important diagnostic categories for these disorders are based on the underlying cause. Shown in Tables 10.9A–C are a summary of a proposed classification for the causes of DSD. The first category (Table 10.9A) is based on abnormal sex chromosomes and the other two categories (Tables 10.9B & C) include various etiologies, such as single gene mutations, syndromic disorders, exposure to exogenous substances (hormones and medications), and others of unknown etiology. The details of each of these specific disorders are reviewed in (1). Many of the DSD are associated with an increased risk of germ cell malignancy (31). A summary of a recently reported review of multiple studies assessing these risks is shown in Table 10.10 (adapted from reference 24). Table 10.9  Proposed Classification for the Causes of Disorders of Sex ­Development A:  Sex Chromosome Disorders of Sex Development A. 47,XXY Patients with Klinefelter syndrome are phenotypic males that present at various times with hypogonadism, small (Klinefelter testes, oligospermia, androgen deficiency, increased gonadotropin levels, and gynecomastia. The associated ­syndrome karyotype is 47,XXY. Although these patients do not have an increased risk of gonadal germ cell neoplasia, they and ­variants) do have an increased risk of developing extragonadal germ cell neoplasia (CNS, mediastinum, retroperitoneum) as well as an increased risk for breast carcinoma. B. 45,X (Turner Patients with Turner syndrome usually present later in life with bilateral streak gonads similar to those with pure ­syndrome gonadal dysgenesis, but these patients also have the other characteristics of Turner syndrome. The karyotype is and ­variants) 45,X or mosaic 45,X/46,XX. These patients have a very low risk for developing gonadal germ cell neoplasms. C. 45,X/46,XY (mixed gonadal dysgenesis)

Mixed gonadal dysgenesis is the second most common cause for ambiguous genitalia after congenital adrenal hyperplasia. These patients have at least one streak gonad with the other being either another streak or a testis. These patients usually have a male phenotype with small testes. Some patients have a uterus and at least one fallopian tube. The external genitalia are ambiguous. Prior to puberty, the histology of the testis shows decreased numbers of germ cells, 1/2 ovarian stroma, and tubules with distorted branching. After puberty, the histology of the testis reveals tubular atrophy and sclerosis with marked loss of germ cells and Leydig cell hyperplasia. There is an increased risk of germ cell neoplasia in these gonads. The diagnosis between true hermaphroditism (DSD terminology includes 46,XX/46,XY chimerism and ovotesticular DSD [46,XX or 46,XY]), and mixed gonad dysgenesis can be difficult at times, as the histologic appearances of the gonads can overlap substantially. The most common karyotype is 45,X/46,XY and the next most common is 46,XY.

D. 46,XX/46,XY This category, along with the ovotesticular DSD 46,XX and 46,XY, refer to the old terminology for true hermaph(­chimerism) rodite. True hermaphroditism occurs when both testicular and ovarian tissue are present in the same individual. This can occur in separate gonads but more commonly, there is one or two ovotestis. The testes are usually in the labium or scrotum, ovaries are abdominal, and ovotestes are most commonly abdominal but can occur in the inguinal area or labium/scrotum. A uterus is usually present and can be bicornuate or unicornuate. Absence of a uterine horn indicates ipsilateral testicular tissue (testis or ovotestis). The histology of the ovotestis frequently reveals relatively normal ovarian tissue but abnormal (dysplastic) testicular tissue, often with degenerative changes. The external genitalia can be male or female but often with some degree of ambiguity. There is a slightly increased risk of germ cell neoplasia. The karyotype can vary including 46,XX, 46,XY, and mosaicism. Abbreviation: DSD, disorders of sex development.

(Continued)

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Table 10.9  Proposed Classification for the Causes of Disorders of Sex ­Development (Continued ) B:  46,XY Disorders of Sex Development This new category encompasses the older term male pseudohermaphroditism, which is caused by deficient androgen signaling in males. Males present with underdeveloped male genitalia, ambiguous genitalia, or female genitalia. The testes can be located in the abdomen, inguinal area, or scrotum. A. Disorders of gonadal (testicular) development

1. Complete or partial gonadal dysgenesis (e.g., mutations in SRY, SOX9, SF1, WT1, DHH): Patients with pure gonadal dysgenesis are phenotypic females with streak gonads located at the usual site of the ovaries. They often present later in life because of primary amenorrhea, infertility, or premature ovarian failure. The karyotype can be 46,XX or 46,XY. 2. Ovotesticular DSD 3. Testis regression (Table 10.1).

B. Disorders of ­androgen synthesis or action

1. Disorders of androgen synthesis: Steroid enzyme deficiencies lead to decreased androgen production. SmithLemli-Opitz syndrome represents a defect in cholesterol biosynthesis and results in deficient androgen production, frequently with associated gonadal dysgenesis and/or anomalies of the external male genitalia. Other target genes can include defects in testosterone production or deficient 5-alpha-reductase, which converts testosterone to DHT. DHT is essential for normal development of male external genitalia, the prostate gland, and elimination of the lower third of the vagina. In the absence of DHT, these patients usually have a female phenotype at birth but may have problems with partial sex reversal at puberty, which is when testosterone is normally produced. Gonadotropin and Leydig cell abnormalities can result in a feminized male phenotype. Essentially, the Leydig cells do not respond normally to hCG or LH because of either decreased hormone levels or inactive receptor pathways. The phenotype can be female with ambiguous genitalia or male with cryptorchidism and micropenis. Histology reveals few Leydig cells and hyalinized tubules. 2. Disorders of androgen action: Androgen insensitivity syndrome can be complete or partial and is related to defects in androgen receptor signaling, most often caused by mutations in the androgen receptor gene itself. Patients with complete androgen insensitivity syndrome have normal female external genitalia, a short blind vagina, absence of both Wolffian and Müllerian ducts, and abnormal testicular descent. The histology of the testis is usually normal early but there is gradual loss of germ cells with time. Patients with partial androgen insensitivity syndrome usually have ambiguous external genitalia. These patients are at increased risk for developing testicular hamartomas and germ cell neoplasms. Drugs and environmental modulators can also disrupt normal androgen action.

C. Other

1. Syndromic associations 2. Persistent Müllerian duct syndrome: Persistent Müllerian duct syndrome occurs in males with mutations that inactivate MIS or its receptor. Both Müllerian and Wolffian duct derivatives are present. The external genitalia are usually normal in males because of the effects of androgens produced by the testes. There is often a unilateral or bilateral cryptorchidism, normal Wolffian duct derivatives, a uterus, and bilateral fallopian tubes. An upper vagina may drain into the prostatic utricle. 3. Vanishing testis syndrome (Table 10.1) 4. Isolated hypospadias 5. Congenital hypogonadotropic hypogonadism is characterized by inappropriately low serum concentrations of LH and FSH in the setting of hypogonadism. Features at birth include micropenis and cryptorchidism. This usually reflects a defect in the hypothalamic-pituitary-gonadal axis. Congenital hypogonadotropic hypogonadism can be either an isolated defect or associated with other anomalies as part of a syndrome (5). 6. Cryptorchidism (mutations in INSL3, GREAT) 7. Environmental factors

Abbreviations: DHT, dihydrotestosterone; DSD, disorders of sex development; FSH, follicle stimulating hormone; hCG, human chorionic gonadotrophin; LH, luteinizing hormone; MIS, Müllerian inhibiting substance. (Continued)

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Table 10.9  Proposed Classification for the Causes of Disorders of Sex ­Development (Continued ) C:  46,XX Disorders of Sex Development This new category encompasses the older term female pseudohermaphroditism, which results in masculinization of a female. A. Disorders of gonadal (ovarian) development

1. Gonadal dysgenesis

B. Androgen excess

1. Fetal: Includes the enzyme defects associated with congenital adrenal hyperplasia (adrenogenital syndrome). Congenital adrenal hyperplasia is the most common cause for ambiguous genitalia. Varying degrees of masculinization of the female external genitalia are observed. In females, the urethra and vagina usually open at the base of an enlarged clitoris. The external genitalia resemble a male but with undescended testes. Various genes involved in steroid hormone synthesis from cholesterol are the targets of mutation with a deficiency of 21-hydroxylase being the most common cause. Males are usually normal (1, 32).

2. Ovotesticular DSD 3. Testicular DSD (e.g., targets of genetic defects including SRY1, dup SOX9, RSPO1)

2. Fetoplacental: Includes enzyme defects in aromatase (CYP19) and oxidoreductase (POR), which result in increased androgen levels. 3. Maternal: Other sources of excess androgen-like activity that can affect the developing female fetus include high maternal progesterone levels, exposure to androgenic medications such as danazol, or maternal tumors that produce androgens. C. Other

1. A ssociations or developmental field defects (cloacal anomalies or sirenomelia). 2. Müllerian duct abnormalities, which include a broad range of anomalies in both females and males. Failure of Müllerian duct development in 46,XX females is discussed as the MRKH syndrome and some cases have been linked to an inactivating mutation in WNT4 (OMIM %277000 and *603490). This includes MURCS (OMIM %601076) (4). 3. Uterine abnormalities associated with other syndromes arising from single gene defects (e.g., renal cysts and diabetes syndrome—OMIM #137920 [mutation in MODY5]) (4). 4. Vaginal atresia associated with other syndromes arising from single gene defects (e.g., McKusickKaufman syndrome—OMIM #236700) (4).

Abbreviations: DSD, disorders of sex development; MRKH, Mayer-Rokitansky-Kuster-Hauser; MURCS, Müllerian duct aplasia, unilateral renal aplasia, cervicothoracic somite dysplasia; OMIM, Online Mendelian Inheritance in Man. Source: Adapted from Refs. 24–27.

Table 10.10  Risk of Germ Cell Neoplasia for Some Disorders of Sex Development Risk

Disorder

Malignancy Risk (%)

High

1. Gonadal dysgenesis (1Y) not otherwise specified (46,XY, 46,X/46,XY, mixed, ­partial, complete) with intra-abdominal gonad

15–35

2. Partial androgen ­insensitivity syndrome (nonscrotal gonad)

50

3. Frasier

60

4. Denys-Drash (1Y)

40

1. Turner (1Y)

12

2. 17 beta-hydroxysteroid dehydrogenase d ­ eficiency

28

3. Gonadal dysgenesis (1Y) scrotal gonad

Unknown

1. Complete androgen insensitivity syndrome

2

2. Ovotestis DSD

3

3. Turner (2Y)

1

1. 5-alpha-reductase

0

2. Leydig cell hypoplasia

0

Intermediate

Low

No (?)

Abbreviation: DSD, disorders of sex development. Source: Adapted from Ref. 24.

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Inflammatory Disorders Inflammatory disorders most commonly present at birth or during infancy are listed in Table 10.11 for males and Table 10.12 for females. Table 10.11  Male Inflammatory Disorders Inflammatory Disorder

Characteristics and Etiology

Acquired inflammatory processes

Various inflammatory conditions can occur related to the male genital tract, including injury from forceful retraction of the prepuce, dermatitis of the glans penis, and infection following circumcision or related to a sexually transmitted disease acquired in the peripartum period. Other dermatologic conditions can affect the skin of the penis and scrotum.

Meconium periorchitis

Meconium periorchitis often presents as a calcified paratesticular mass. Meconium periorchitis usually occurs when there is perforation of the bowel in utero with meconium leakage around the tunica vaginalis. With time, dystrophic calcification occurs. There are often associated intra-abdominal calcifications as well.

Table 10.12  Female Inflammatory Disorders Inflammatory Disorder

Characteristics and Etiology

Vulvovaginitis (lower genital tract)

The cause for vulvovaginitis in young females varies depending on their age. In infants, lack of estrogen or poor perineal hygiene with associated bacterial, Candida, or pinworm infection, are common causes for vulvovaginitis (Figure 10.20).

Figure 10.20  Cervicitis. There is focal acute inflammation in both the endocervix and exocervix in this near-term stillbirth. There was no other inflammation and no chorioamnionitis (courtesy of Dr. Don Singer).

Infectious and sexually transmitted diseases

Inflammatory lesions of the lower genital tract in females are usually related to infectious diseases. Most newborn females have some mucoid exudate from the vagina caused by maternal hormones. However, if the amount is large, then an acquired infection should be suspected. Both gonorrhea and Trichomonas vaginalis have been reported to be acquired during delivery. Candida vaginitis in the newborn is relatively rare, but can be acquired postpartum, especially in infants exposed to antibiotics. The presence of any sexually transmitted disease in a preadolescent female should immediately raise concern for sexual abuse. Adolescent females who are sexually active can acquire all the same STD organisms as adult females (Figure 10.21A–B). (Continued)

Gonadal Tumors 

Table 10.12  Female Inflammatory Disorders (Continued) Inflammatory Disorder

Characteristics and Etiology

Noninfectious inflammatory processes

Various noninfectious inflammatory processes can also affect the vulva or vagina, including dermatitides, Crohn disease, Behçet syndrome, lichen sclerosis, and bullous skin disorders.

21A

21B

Figure 10.21  Condyloma acuminata. Infection of the vulvar, vaginal, cervical, urethral, and perianal mucosa with the human papillomavirus (HPV) results in multiple lesions that are commonly papillary and occasionally flat (particularly on the cervix). Histologically, parakeratosis, acanthosis, hyperkeratosis, and dyskeratosis are evident. The typical koilocytic cells with perinuclear cytoplasmic halos surrounding irregularly contoured (“raisinoid”) nuclei may be seen in the more superficial or intermediate layers (A). Molluscum contagiosum is usually an asymptomatic viral infection often passed through sexual contact (B). The lesions are generally multiple, small papules with a central umbilication. The intracytoplasmic inclusion bodies, the molluscum bodies, are typically found in the lower cells of the stratum malpighii. They compress the nucleus, which appears as a thin crescent at the periphery of the cell. Diagnosis rarely requires biopsy. Cytologic identification of the typical intracytoplasmic inclusion bodies within scrapings or in biopsy material is adequate to confirm the diagnosis.

Gonadal Tumors The majority of gonadal tumors in both genders are germ cell tumors. However, although germ cell tumors in the female gonad present following puberty, those in the male gonad are bimodal, with a small peak during infancy and a larger peak following puberty. Ovarian tumors are more likely to be composed of teratomatous elements. In addition to germ cells, gonadal stromal cells, including granulosa cells, Sertoli cells, and Leydig cells, populate the gonads. Neoplasms arising in these cells are grouped together as sex-cord-stromal tumors and account for 10% of all pediatric gonadal neoplasms. Precocious puberty and virilization are the major clinical manifestations. Epithelial gonadal neoplasms, which comprise about 15% of ovarian neoplasms of children, are virtually confined to the ovary and occur after menarche. The majority are unilateral and benign; approximately 15% are malignant. The pathologic categorization of these epithelial lesions is based on an evaluation of type and character of the epithelial proliferative changes. They are virtually all either serous or mucinous and are classified as benign, atypically proliferating (“borderline” tumors), or malignant (Figures 10.22–10.34).

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Figure 10.22  Immature teratoma. Most germ cell tumors in the testis showing only teratomatous elements occur in infancy, whereas, in the ovary, these tumors occur following puberty. Mature teratomas represent approximately half of all childhood ovarian neoplasms and can be subdivided into those that are predominately cystic and those that are predominately solid. The latter have a higher frequency of immature and malignant elements. The presence of immature elements within a teratoma is associated with a higher risk of recurrence and with the development of malignant elements. Immature teratomas can be graded histologically according to the quantity of immature neuroectoderm (illustrated). Grade 1 lesions have immature tissue limited to rare low magnification fields, with not more than one field in any one slide. Grade 2 lesions contain immature neuroectoderm not exceeding three low-power fields. Grade 3 tumors show extensive immature neural epithelium.

Figure 10.23  Gliomatosis peritonei is a rare condition that occurs in association with solid ovarian mature or immature teratoma. It is characterized by small gray-white nodules of mature glial tissues on peritoneal surfaces. These mature nodules may require additional surgery but do not have an adverse prognostic significance and do not affect the staging of the ovarian lesion.

Figure 10.24  Germinoma (dysgerminoma of the ovary and seminoma of the testis) is commonly pure and composed of aggregates or nests of uniform neoplastic cells with distinct, nonoverlapping cellular borders and prominent nucleoli. Lymphocytes and occasional multinucleate cells may be seen in the stroma. Most germinomas are positive for placental-like alkaline phosphatase (PLAP), a cell surface glycoprotein. Although PLAP is a valuable marker for germinomas, it may also be present focally in embryonal carcinomas and endodermal sinus tumors, as well as most somatic tumors. A more specific antibody has been reported recently that strongly and specifically recognizes germinomas, embryonal carcinomas, and intratubular germ cell neoplasia, namely Oct4. This protein is highly expressed in pluripotent stem cells, and has been demonstrated to be useful in the distinction of metastatic germ cell tumor (GCT) from other tumor types. It is negative in endodermal sinus tumors.

Gonadal Tumors 

Figure 10.25  Endodermal sinus tumor. The most common histologic subtype of malignant germ cell tumor in children is endodermal sinus tumor, also called yolk sac tumor. This is virtually the sole histologic subtype of malignant germ cell tumor in infants. The histology and cytology of endodermal sinus tumors vary widely, often causing difficulty in diagnosis. The prototypic Schiller-Duvall body is present in 50% to 75% of endodermal sinus tumors. These are composed of a central vascular core lined by tumor cells, a space, and then an outer rim of tumor cells (illustrated). Solid regions may be seen within endodermal sinus tumors; however, they are usually a minority component. Hyaline bodies are occasionally seen.

Figure 10.27  Embryonal carcinoma is seen predominately as a minor component of a mixed germ cell tumor within the adolescent and adult ovary and testis. Like endodermal sinus tumors, embryonal carcinomas may show papillary, glandular, and solid areas. The cells are large, epithelioid, and often anaplastic with large nucleoli, abundant mitotic activity, amphophilic cytoplasm, with lack of defined cell borders. Embryonal carcinomas show immunoreactivity for cytokeratin, but not for epithelial membrane antigen, a feature that may help to distinguish embryonal carcinoma from other epithelial neoplasms. Embryonal carcinomas, but not other germ cell tumor histologic types, show immunopositivity for CD30. Embryonal carcinomas are also reliably positive for Oct4.

Figure 10.26  Endodermal sinus tumor. A pattern of endodermal sinus tumor that presents difficulties, particularly if found within an immature teratoma, is the reticular pattern. This is characterized by a network of communicating spaces often lined by cuboidal or flat attenuated tumor cells. The cytology of the tumor cells remains characteristic.

Figure 10.28  Choriocarcinoma is likewise rarely seen as the sole histologic type, but typically comprises a minor component within a mixed germ cell tumor. Choriocarcinomas are composed of both medium-sized cytotrophoblastic and multinucleate syncytiotrophoblastic cells with frequent evidence of hemorrhage. Immunohistochemical stains for human chorionic gonadotrophin (hCG) identify syncytiotrophoblastic cells, with unreliable staining of cytotrophoblasts.

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Figure 10.29  Juvenile granulosa cell tumor. Granulosa cell tumor is the most common type of functioning gonadal stromal neoplasm in children and may present in the ovary or infantile testis. Most granulosa cell tumors in children are histologically distinct from the adult-type granulosa cell tumors. Grossly, juvenile granulosa cell tumors are solid with fibrous bands separating yellow nodules and are usually confined to the ovary. Microscopically, juvenile granulosa cell tumors have a rather complex growth pattern with nodules of incompletely luteinized cells. Follicles may be present that are irregular and resemble large graafian follicles, but are often absent. The stromal cells resemble fibroblasts or have polygonal outlines and pale cytoplasm containing abundant lipid. Luteinization is commonly greater and the nuclei are more hyperchromatic and immature than those in the adulttype granulosa cell tumors. Call-Exner bodies are not a feature of juvenile granulosa cell tumors, and the nuclear grooves typical of adult granulosa cell tumors are infrequent. These tumors are often quite cellular with mitotic activity and nuclear atypia, resulting in their frequent misdiagnosis as malignant germ cell tumors. Inhibin, calretinin, and CD99 are useful immunohistochemical markers that positively mark most sex-cordstromal tumors, and most of these are negative for epithelial membrane antigen. Figure 10.30  Sex-cord tumors with annular tubules (SCTATs) represent multifocal cortical stromal tumors composed of epithelial nests with single or multiple hyaline bodies representing annular tubules. These bodies may resemble the hyaline bodies seen in gonadoblastomas; however, the cells of the annular tubules have more abundant, pale, and vacuolated cytoplasm and lack germ cells. Hyperestrinism is common. Approximately one third of patients with SCTAT have Peutz-Jeghers syndrome.

Figure 10.31  Sertoli cell tumor may be seen in either the testis or the ovary as the sole element of sex-cord-stromal tumor or in combination with other components. These tumors vary from well differentiated (illustrated) to poorly differentiated. The tubules may or may not have central lumina and are often surrounded by a basement membrane. Sertoli cell tumors commonly stain with vimentin and cytokeratin, in addition to variable staining with inhibin.

Figure 10.32  Leydig cell tumor. Leydig cell tumors are composed of large and polygonal cells with abundant eosinophilic cytoplasm with variable lipid content. Mitotic activity is generally low, although nuclear atypia may be present. Approximately 10% of Leydig cell tumors are malignant and show cytologic atypia, increased mitotic activity, and necrosis. This is exceptionally rare in childhood.

REFERENCES 

Figure 10.33  Serous cystadenoma is composed of multiple cysts containing watery contents and lined by an epithelium resembling that of either the fallopian tube or the surface epithelium of the ovary, and may be ciliated or nonciliated. Nodular papillary excrescences may be scattered over the lining of the cysts. These papillary processes are covered by a single layer of columnar to cuboidal cells. Intermediate neoplasms show more extensive and complex papillary patterns with stratification of the epithelial lining, loss of polarity, nuclear pleomorphism, and increased mitotic activity. The presence of stromal invasion is required for the diagnosis of malignancy.

Figure 10.34  Mucinous cystadenoma. Mucinous neoplasms contain multiple cysts filled with thick mucinous material and lined by columnar nonciliated cells with faintly basophilic cytoplasm and small and basally oriented nuclei, similar to that seen in the endocervix. Some tumors show scattered goblet cells. The supportive stroma is cellular and commonly has a thecal and even luteal appearance. Intermediate neoplasms are characterized by stratification of epithelial cells, loss of nuclear polarity, nuclear pleomorphism, and frequent mitoses. The presence of stromal invasion defines the category of ovarian mucinous c­ arcinoma.

REFERENCES 1. Fritsch MK, Isaacs H, Gilbert-Barness E, Gunasekaran S. Reproductive systems. In: Gilbert-Barness E, ed. Potter’s Pathology of the Fetus, Infant, and Child. 2nd ed. China: Mosby-Elsevier; 2007: 1375–1452. 2. Spires SE, Woolums S, Pulito AR, Spires SM. Testicular regression syndrome—a clinical and pathologic study of 11 cases. Arch Pathol Lab Med. 2000;124:694–698. 3. Rutgers JL, Scully RE. Pathology of the testis in intersex syndromes. Semin Diagn Pathol. 1987;4: 275–291. 4. Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/omim. Accessed multiple times in 2009 to 2010. 5. Pallais JC, Caudill M, Pitteloud N, Seminara S, Crowley WF. Hypogonadotropic hypogonadism overview. NCBI-Bookshelf-GeneReviews. 2007. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br. fcgi?book=gene&part=ihh-ov. Accessed March 23, 2010. 6. Nation TR, Balic A, Southwell BR, Hutson JM. The hormonal control of testicular descent. Pediatr Endocrinol Rev. 2009;7:22–31. 7. Barthold JS. Undescended testis: current theories of etiology. Curr Opin Urol. 2008;18:395–400. 8. Husmann DA. Testicular descent: a hypothesis and review of current controversies. Pediatr Endocrinol Rev. 2009;6:491–495. 9. McDermott VG, Meakem TJ, Stolpen AH, Schnall MD. Prostatic and periprostatic cysts: findings on MR imaging. AJR. 1995;164:123–127. 10. Volmar KE, Fritsch MK, Perlman EJ, Hutchins GM. Patterns of congenital lower urinary tract obstructive uropathy: relation to abnormal prostate and bladder development and the prune belly syndrome. Pediatr Dev Pathol. 2001;4(5):467–472. 11. Amesse LS, Pfaff-Amesse T. Müllerian duct anomalies. Emedicine.medscape.com. February 16, 2009. Accessed February 10, 2010. 12. Shulman LP. Müllerian anomalies. Clin Obstet Gynecol. 2008;51:214–222.

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13. Breech LL, Laufer MR. Müllerian anomalies. Obstet Gynecol Clin North Am. 2009;36:47–68. 14. Ribeiro SC, Tormena RA, Peterson TV, et al. Müllerian duct anomalies: review of current management. San Paulo Med J. 2009;127:92–96. 15. Spence JEH. Vaginal and uterine anomalies in the pediatric and adolescent patient. J Pediatr Adolesc Gynecol. 1998;11:3–11. 16. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Müllerian anomalies, and intrauterine adhesions. Fertil Steril. 1988;49:944–955. 17. Christopoulos P, Gazouli M, Fotopoulou G, Creatsas G. The role of genes in the development of Müllerian anomalies: where we are today? Obstet Gynecol Surv. 2009;64:760–768. 18. Cai Y. Revisiting old vaginal topics: conversion of the Müllerian vagina and origin of the “sinus” vagina. Int J Dev Biol. 2009;53:925–934. 19. Yamada G, Suzuki K, Haraguchi R, et al. Molecular genetic cascades for external genitalia formation: an emerging organogenesis program. Dev Dyn. 2006;235:1738–1752. 20. Becker A, Baum M. Obstructive uropathy. Early Hum Dev. 2006;82(1):15–22. 21. Kajbafzadeh A. Congenital urethral anomalies in boys. Part II. Urol J. 2005;2(3):125–131. 22. Nepple KG, Cooper CS, Alagiri M. Labial adhesions. Emedicine. March 23, 2009. Available at: http:// emedicine.medscape.com/article/953412-overview. Accessed March 26, 2010. 23. De Jong A, Warren M, Rehrauer W, et al. Fraser syndrome: affected siblings born to nonconsanguineous parents and diagnosed at autopsy. Pediatr Dev Pathol. 2008;11(3):220–225. 24. Hughes IA, Houk C, Ahmed SF, LWPES1/ESPE2 Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91:554–562. 25. Lee PA, Houk CP, Ahmed SF, Hughes IA, International Consensus Conference on Intersex. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118:e488–e500. 26. Hughes IA, Houk C, Ahmed SF, Lee PA, LWPES/ESPE Consensus Group. Consensus statement on management of intersex disorders. J Ped Urol. 2006;2:148–162. 27. Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. Pediatrics. 2006;118:753–757. 28. Hughes IA. Disorders of sex development: a new definition and classification. Best Prac Res Clin Endocrinol Metab. 2008;22:119–134. 29. Hughes IA, Nihoul-Fekete C, Thomas B, Cohen-Kettenis PT. Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development. Best Prac Res Clin Endocrinol Metab. 2007;21:351–365. 30. Yang JH, Baskin LS, DiSandro M. Gender identity in disorders of sex development: review article. Urology. 2010;75:153–159. 31. Robboy SJ, Jaubert F. Neoplasms and pathology of sexual developmental disorders (intersex). Pathology. 2007;39:147–163. 32. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365:2125–2136.

11

Gastrointestinal Tract J. thomas Stocker Haresh Mani John Hart

n

ESOPHAGEAL DUPLICATION/ENTERIC CYST/OTHER GASTROINSTESTINAL DUPLICATIONS

n

INTESTINAL ATRESIA AND STENOSIS

n

CROHN DISEASE

n

MECKEL DIVERTICULUM AND OTHER VITELLINE DUCT ANOMALIES

n

BACTERIAL DIARRHEA

n

GASTROINTESTINAL TUMORS Juvenile Polyps and Juvenile Polyposis Syndrome Peutz-Jeghers Polyposis Syndrome Familial Adenomatous Polyposis Adenocarcinoma of the Colon and Rectum Lymphoma Appendiceal Carcinoid Tumors Inflammatory Myofibroblastic Tumors Gastrointestinal Stromal Tumors

n

TRACHEOESOPHAGEAL FISTULA WITH OR WITHOUT ESOPHAGEAL ATRESIA

n

MECONIUM AND MECONIUM ABNORMALITIES

n

REFLUX ESOPHAGITIS/BARRETT ESOPHAGUS

n

HIRSCHSPRUNG DISEASE

n

INTUSSUSCEPTION

n

CELIAC DISEASE

n

INTESTINAL LYMPHANGIECTASIA

n

NEONATAL NECROTIZING ENTEROCOLITIS

n

ULCERATIVE COLITIS

n

EOSINOPHILIC ESOPHAGITIS

n

HYPERTROPHIC PYLORIC STENOSIS

n

OMPHALOCELE

n

GASTROSCHISIS

n

MALROTATION

esoPhaGeal duPliCaTion/enTeriC CysT/ oTher GasTroinsTesTinal duPliCaTions Duplication of the esophagus is rare. The duplicated segment may be a separate cylindrical tube alongside part of the normal esophagus with a complete mucosa, submucosa, and two-layered muscularis externa (double esophagus). Alternatively, a spherical, intramural esophageal cyst may form and share a portion of muscularis propria with the adjacent esophageal wall. Esophageal duplication cysts may be asymptomatic and discovered incidentally, or they may cause tracheal or esophageal compression. Mediastinal enteric (gastroenteric) cyst is distinct from the esophagus; however, because of its location, it may be confused with esophageal duplication cyst. Vertebral anomalies, especially cervical hemivertebra, are associated in a high percentage of cases. Gastric duplication presents as a cystic mass on the greater curvature or at the pylorus and may present with bleeding, rupture, or obstruction. Gastrointestinal (enteric) (GI) duplications are tubular or cystic structures that lie alongside the intestinal tube. The duplication and the intestinal tube often share a muscular wall (intramural); less often, the duplication is separated from the intestine proper but near to it (extramural). Duplications may occur anywhere near the GI tract from the neck to rectum; the single most common site is the ileum.

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1A

1B

Figure 11.1  This esophageal duplication cyst, filled with cloudy yellow fluid, was present in the middle mediastinum adjacent to but separate from the esophagus (A). The cyst is lined by stratified squamous epithelium overlying a submucosa and a thick muscular wall composed of two separate layers of both smooth and skeletal muscle (B).

Tracheoesophageal Fistula With or Without Esophageal Atresia Esophageal atresia occurs sporadically, with or without tracheoesophageal fistula. These entities are discussed together in the pulmonary chapter (Chapter 8).

Reflux Esophagitis/Barrett Esophagus Most children with reflux esophagitis are otherwise normal, but certain groups of children are predisposed, including those with mental retardation, cystic fibrosis, and bronchopulmonary dysplasia, and those who have undergone repair of esophageal atresia and tracheoesophageal fistula in infancy. Histologic features in children with reflux esophagitis are similar to those widely described in adults with the same condition. Barrett esophagus, in which columnar epithelium replaces the normal squamous lining of the distal esophagus, is an acquired metaplastic condition caused by chronic gastroesophageal reflux. Barrett esophagus is usually found in association with severe reflux esophagitis. Figure 11.3  Barrett esophagus. In this esophagus opened at the esophageal-gastric junction, distinct areas of metaplastic mucosa extend from the esophagogastric (EG) junction well into the lower third of the esophagus.

Figure 11.2  Reflux esophagitis. The lower esophagus displays irregular patches of pale to hyperemic mucosa, some of which appears thickened.

Hypertrophic Pyloric Stenosis 

Eosinophilic Esophagitis Esophageal biopsies containing large numbers of intraepithelial eosinophils and exhibiting basal cell hyperplasia can represent an allergic reaction to dietary or inhaled allergens. This disorder, termed eosinophilic esophagitis, often presents in childhood and may present with difficulty feeding, prolonged irritability and crying, failure to thrive, and growth delay.

4A

4B

Figure 11.4  Eosinophilic esophagitis. Circumferential rings of thickened esophageal squamous epithelium are seen on endoscopy (A). A heavy but patchy infiltrate of eosinophils, including clusters of eosinophils (microabscesses), are present near the luminal surface (left). Basal cell hyperplasia is also quite prominent (B).

Hypertrophic Pyloric Stenosis Pyloric stenosis is a common condition, seen in 1 out of 200 infant boys. The male-to-female ratio is 5:1 or greater, and white, firstborn boys are at greatest risk. A definite familial incidence has been noted, but there is no definite inheritance pattern. The circular muscle layer undergoes hypertrophy and elongation, and gastric outlet obstruction ensues. Progressive nonbilious vomiting, the primary manifestation, commences at 2 to 6 weeks of age in an otherwise healthy infant. The diagnosis is suggested when the hypertrophic pyloric muscle mass, approximately the size of an olive, is palpated in the right upper quadrant after feeding. Abdominal x-ray films show marked gaseous distension of the stomach, and barium studies demonstrate a narrow and elongated pyloric channel (“string sign”).

5A

Figure 11.5  Hypertrophic pyloric stenosis. The “olive-sized” mass palpated externally consists at surgery 5B of a firm muscular mass at the pyloric region (A). A longitudinal surgical incision of the hypertrophic muscle down to the submucosa (pyloromyotomy) immediately and efficaciously relieves the obstruction (B). Histologically the muscle appears normal but hypertrophic.

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Omphalocele Omphalocele (exomphalos) is a developmental defect of the anterior abdominal wall in which the abdominal musculature, fascia, and skin are absent in the midline at the point of insertion of the umbilical cord. Abdominal organs extrude anteriorly through the defect and are covered by a saclike membrane consisting of amnion externally and parietal peritoneum internally. Omphalocele results from failure of the intestine to return to the body cavity after its normal herniation into the umbilical stalk during embryonic life. Omphaloceles vary in size; the defect may be a few centimeters in diameter, or most of the anterior abdominal wall may be lacking. Depending on the size of the defect, small intestine, liver, spleen, and pancreas may be in the sac. Figure 11.6  Omphalocele. Loops of bowel, including the cecum and appendix, are visible through the translucent omphalocele sac. Note the umbilical cord inserting at the dome of the sac.

Gastroschisis Gastroschisis occurs much less frequently than omphalocele. In gastroschisis, a relatively small paraumbilical abdominal wall defect (right side-to-left side ratio of 9:1) is distinctly separate from the normally placed umbilicus. Loops of bowel, not covered by a membrane, extrude through the opening. Because the extruded intestine has been bathed in amniotic fluid in utero, it appears abnormally thickened and edematous and may be coated with fibrin. The intestine is usually not rotated and is much shorter than normal. Figure 11.7  Gastroschisis. Multiple dilated loops of bowel protrude from a defect in the abdominal wall just adjacent to the insertion of the umbilical cord. Note that the extruded abdominal contents are not covered by any membrane.

Malrotation 

239

Malrotation The term malrotation includes a group of congenital positional and associated abnormalities of the intestine and mesentery, resulting from nonrotation or abnormal rotation and fixation of the developing embryonic gut. During the most rapid period of growth, the embryonic intestine extends outside the abdominal cavity. During weeks 10 and 11 of gestation, the intestine returns to the abdomen in sequential stages in such a manner as to position the small bowel behind the large bowel, with the large bowel rotating counterclockwise to move the cecum and ascending bowel into the right side of the abdomen, the transverse colon to the upper abdomen, and the descending and sigmoid colon to the left side. At week 11, fixation of the gut to the abdominal wall occurs. A broad-based mesentery extending from the ligament of Treitz to the ileocecal area attaches the intestine to the posterior abdominal wall and stabilizes it. The right and left portions of the colon become fixed retroperitoneally. Failure of this fixation leaves the bowel susceptible to moving and twisting that may lead to a volvulus. Figure 11.8  (A) Gastrointestinal development within the umbilical sac. Early in gestation, loops of bowel protrude into the umbilical sac but return to the abdomen by the 10–11th week. (B) Volvulus. Malrotation of the bowel has led to the loops twisting along the axis of the mesentery, effectively obstructing the bowel lumen.

8A

8B

Figure 11.8C  Volvulus with intestinal infarction. The twisting of the bowel along the axis of the mesentery has resulted in occlusion of the blood supply to the bowel and its infarction (top and center). Note the viable bowel at the bottom of the image.

8C

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Figure 11.8D  Resected segments of bowel. The section of bowel at left is essentially unremarkable. The section at the right, however, is diffusely hemorrhagic and infarcted.

8D

Intestinal Atresia and Stenosis Intestinal atresia is the complete absence of a segment of the intestine or complete occlusion of the intestinal lumen. Either situation is a common cause of neonatal intestinal obstruction, with a prevalence of 2 in 10,000 live births. The rates of atresia in the duodenum and in the more distal jejunum and ileum are approximately equal; colonic atresia is much less frequent. Multiple jejunoileal atresias are found in approximately 10% of cases.

9A

9C

Figure 11.9  Intestinal atresia is thought to occur during development when one or more small mesenteric arteries become occluded and lead to infarction of the portion of the developing intestine the arteries supply. The result is atrophy and loss of all or part of that tissue leading to a simple mucosal fibrosis/obstruction (I), segmental loss of mucosa and bowel wall (II), complete loss of a wedge-shaped portion of mesentery and bowel (III), or a combination of I, II, or III in multiple segments of bowel (IV) (A). Source: Adapted from Stocker and Dehner, Pediatric Pathology, 2nd ed., p. 644. Air in the stomach and proximal small bowel is readily seen in this ultrasound of an infant with intestinal atresia in the jejunal area (B). At surgery, a gap is present between the proximal dilated small intestine (right) and the nondilated distal segment of bowel (left) (C). Atresia may occur at the very end of the GI tract as with the infant with anal atresia (D).

9B

9D

Meckel Diverticulum and Other Vitelline Duct Anomalies 

Meckel Diverticulum and Other Vitelline Duct Anomalies The vitelline (omphalomesenteric) duct usually becomes obliterated by week 10 of embryonic life and subsequently disappears completely. In approximately 2% of the population, however, it remains in various forms. These include Meckel diverticulum or, less commonly, a fibrous cord extending from ileum to umbilicus, a cyst, or an umbilical sinus. Many of these remnants are asymptomatic, but others cause symptoms that develop most frequently in the first few years of life.

Figure 11.10A  Vitelline duct remnants. Persistence of the entire vitelline duct from ileum to umbilicus (A), vitelline duct cyst (B), vitelline sinus (C), Meckel diverticulum (D), and vitelline band (E). Source: Adapted from Stocker and Dehner, Pediatric Pathology, 2nd ed., p. 646.

10B

10C

Figure 11.10B–D  Meckel diverticulum. A dilated Meckel diverticulum is perforated with inflammatory debris covering its serosal surface (B). Gastric mucosa lines the diverticulum that extends from the small intestine (C). Higher power shows diverticulitis (D).

10D

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Gastrointestinal Tract

Meconium and Meconium Abnormalities Meconium is the dark green to black mucoid material that fills the neonatal colon and distal small intestine. It consists predominantly of water (75%) admixed with mucous glycoproteins, swallowed vernix caseosa, GI secretions, bile, pancreatic enzymes, plasma proteins, minerals, and lipids. More than 90% of healthy-term newborns pass a meconium stool averaging 200 mL within the first 24 hours of life, and nearly all have done so by 48 hours. Abnormalities of meconium (e.g., in cystic fibrosis) or of intestinal motility (e.g., in Hirschsprung disease) result in a delayed meconium passage.

11A

11B

Figure 11.11  Meconium ileus. (A–C) A section of bowel is mildly distended by dark viscid material visible through the intestinal wall (A). Dark viscid meconium is firmly attached to the mucosa of the ileum (B). The base of the glands of the small intestine are distended by hyper-eosinophilic focally calcified material that extends up the gland to cover the mucosal surface in this patient with cystic fibrosis (C). (D) Cystic fibrosis—pancreas. Viscid hyper-eosinophilic material similar to that seen in the bowel is present in pancreatic ducts.

11C

11D

Hirschsprung Disease 

243

Hirschsprung Disease Hirschsprung disease is a congenital disorder with an incidence of 1 per 5,000 live births, and is much more common in male (85%) than female infants. Most cases are sporadic, although a familial component has been noted in approximately 10% of cases. Hirschsprung disease is characterized by an absence of intramural parasympathetic ganglion cells in the distal GI tract, in association with a loss of tonic neural inhibition, persistent contraction of the affected segment, and subsequent colonic obstruction.

12A

12B

12C

12D

12E

12F

Figure 11.12  The distal large bowel, including the sigmoid colon, is massively distended in this 2-month-old infant with aganglionosis of the distal sigmoid colon (A). A segment of bowel from the colon proximal to the area of aganglionosis displays a normal ganglion in the intermyenteric plexus. Note the large ganglion cells with the large eccentric nuclei, one of which contains a prominent nucleolus (B). In a section of muscular wall from the “contracted” aganglionic section of bowel, a nodule in the intermyenteric plexus displays hypertrophic nerve fibers but no ganglion cells (i.e., aganglionosis) (C). In some segments of the aganglionic bowel, hypertrophic nerve bundles may be prominent (D). A stain for acetylcholinesterase (ACE) may be helpful in establishing the diagnosis by demonstrating numerous dark staining ACE-positive nerve fibers in the lamina propria (E) when compared with the normal bowel (F).

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Gastrointestinal Tract

Intussusception Intussusception, or the invagination of a portion of the intestine into itself, is a relatively common pediatric surgical problem. Infants, particularly those between 5 and 9 months of age, are most commonly affected. More than 90% of cases of childhood intussusception begin at the ileocecal valve, and the intussusceptum may reach as far as the descending colon or rectum. Progressive compression of the mesentery and blood supply of the invaginated bowel causes edema, hemorrhage, and ischemic necrosis. In the classic case, severe, intermittent, colicky pain begins suddenly in an infant, followed after a few hours by vomiting and the passage of blood and mucus from the rectum. Barium enema is both diagnostic and therapeutic.

13A

13B

Figure 11.13  The telescoping of one portion of the bowel inside the other is noted on this computed tomography (CT) scan just beneath the anterior abdominal wall (A). At surgery, the invaginated segment of bowel (right) is gently pulled from the distal bowel (left). Note the normal appearing muscular wall of both sections (B). When hemorrhagic or frankly infarcted, the section of bowel would usually be resected. In this cross section of a resected specimen, both the invaginated and the covering sections of bowel are infarcted (C).

13C

Celiac Disease Celiac disease, or gluten-sensitivity enteropathy, is the most common small intestinal mucosal disease causing malabsorption in Caucasian children. It can be diagnosed at any age after institution of gluten into the diet. Classic symptoms of malabsorption (diarrhea, steatorrhea, abdominal bloating and pain, weight loss, poor weight gain, failure to thrive, fatigue, metabolic bone disease) may be present, but a wide range of “atypical” symptoms may occur, including low serum folate, calcium, magnesium, or phosphorus levels, intracranial calcifications causing seizures, and growth retardation. Unexplained iron deficiency anemia is now one of the leading presenting signs of celiac disease, particularly among adolescent patients.

Celiac Disease 

245

Figure 11.14  When compared with the mucosa of the normal duodenum (left), celiac disease (right) produces villous blunting (and nearly villous loss) and crypt hyperplasia.

15A

15B

Figure 11.15  Microscopically, the normal duodenal mucosa (A) contains long villi (over 90% of the thickness of the mucosa) and short crypts. In contract, the mucosa in celiac disease [(B) right, at the same magnification as (A)] may consist almost entirely of hyperplastic crypts, with villous atrophy. Figure 11.16  Higher magnification shows an increased number of mitotic figures in the crypts, dense mixed inflammatory cell infiltration of the lamina propria (mostly plasma cells and lymphocytes, with scattered admixed eosinophils), and an increased number of intraepithelial lymphocytes.

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Intestinal Lymphangiectasia Intestinal lymphangiectasia is a disease category rather than a single entity. It is characterized by greatly dilated lymphatic vessels in the lamina propria of the small intestine with leakage of lymph into the intestine and consequent protein-losing enteropathy. Primary (congenital) forms often are associated with extraintestinal lymphatic abnormalities. Secondary forms are caused by lymphatic obstruction resulting from cardiac failure, pericarditis, abdominal tumors, inflammatory bowel disease, and other conditions. Patients with both primary and secondary forms present with diarrhea and protein-losing enteropathy (i.e., intestinal protein loss, hypoalbuminemia, edema). Lymphocyte and immunoglobulin losses into the intestine through the lymphatics also produce lymphopenia and hypogammaglobulinemia. Figure 11.17  The dilated lymphatics can be seen through the endoscope and in the biopsy specimen as multiple, white, pinhead-sized spots on the small-intestinal mucosa.

Figure 11.18  Abnormally dilated lymphatic vessels are often grouped at the tips of villi but may appear elsewhere in the lamina propria. A distinct endothelial lining helps differentiate lymphatic vessels from artificial tears caused by biopsy trauma.

Figure 11.19  A stain for lipids (oil red-O) displays multiple lipid droplets within the distended lymphatics of the lamina propria.

Neonatal Necrotizing Enterocolitis Neonatal necrotizing enterocolitis is a distinctive common disease of premature infants in the neonatal intensive care unit characterized by coagulative and hemorrhagic necrosis and inflammation of portions of the small and large intestine. Important contributing factors include altered bowel motility and digestion, immature intestinal circulatory regulation, abnormal bacterial colonization, immature intestinal mucosal barrier, and enteral formula feedings. Intestinal ischemia results from reduced splanchnic perfusion, systemic hypoperfusion, systemic hypoxia, or local factors such as intestinal gaseous distension. Bacterial

Neonatal Necrotizing Enterocolitis 

colonization is nearly always present, although neonatal necrotizing enterocolitis is not primarily an infectious process in the usual sense and no specific organisms or group of organisms has been implicated. Immature innate intestinal immune function likely contributes to the process of bacterial colonization. Neonatal necrotizing enterocolitis occurs primarily in premature infants with birth weights ranging from 1,000 to 1,500 g, who are more than 2 weeks of age, and who are severely ill with respiratory distress syndrome. However, up to 10% of infants with neonatal necrotizing enterocolitis are born at term, and the disease may develop as early as the first day of life. Manifestations include abdominal distension, bloody stools, diarrhea, gastric retention of feedings, shock, and apnea. As many as onethird of the affected infants have a fulminant course with intestinal perforation and a similar number have bacterial sepsis. The overall mortality is approximately 15% to 30%. The diagnosis of neonatal necrotizing enterocolitis requires a suggestive clinical picture and radiographic demonstration of pneumatosis intestinalis (i.e., gas within the bowel wall) or gas in the portal or hepatic veins. However, positive radiologic signs may be lacking in one-third of the patients, in whom the diagnosis is confirmed at surgery or autopsy. In most cases, the most severely affected portions of the GI tract are the terminal ileum and cecum (80%) and the ascending colon, although either the small intestine or colon alone may be affected, or the entire small intestine and colon.

20A

20B

Figure 11.20  An abdominal x-ray reveals a markedly distended small and large bowel with evidence of air leakage beneath the mucosa, known as pneumatosis intestinalis (arrows) (A). Air escaping through a rupture in the bowel wall produces a striking pneumoperitoneum (B).

21B

Figure 11.21  At surgery, numerous scattered and discontinuous areas of necrotic bowel (yellow-tan areas) are readily apparent (A). In a resected specimen, the irregular areas of necrotic bowel are demarcated from areas of viable bowel (B). 21A

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Figure 11.22  In another surgical case, the distended bowel is “paper thin” and virtually transparent. Numerous air bubbles are present in the serosa and mesentery. This air may enter the portal veins and extend into the liver.

23a

23B

Figure 11.23  In this section, the mucosa is diffusely necrotic, while the muscularis propria is relatively spared (A). In another section (B), submucosal air-filled cysts (pneumatosis intestinalis) are visible. While the mucosa is entirely necrotic on the left side, the basal epithelium appears preserved on the right. The inner layer of the muscular wall is undergoing necrosis and dissolution.

Ulcerative Colitis Ulcerative colitis is an idiopathic chronic inflammatory disease that begins in the rectum and extends proximally and contiguously for a variable distance. In a given patient, disease may be limited to the rectum, involve only the left colon, or involve the right colon as well. A fluctuating clinical course with exacerbations and remissions is typical. A fulminant presentation with toxic megacolon is also seen. Ulcerative colitis is limited to the colon, although in patients with active pancolitis, mild inflammation may also involve the mucosa of the distal few centimeters of the terminal ileum (so-called backwash ileitis). Diarrhea and rectal bleeding are the presenting symptoms in nearly all cases, although abdominal pain, cramping, anorexia, and weight loss are also frequently seen. A small percentage of patients have a fulminant presentation, with acute abdominal signs and toxic megacolon. As many as 20% of children have extraintestinal manifestations, with arthritis of the large joints the most common; uveitis, growth failure, skin involvement, and liver disease are more unusual.

Ulcerative Colitis 

Figure 11.24  This specimen of opened transverse, descending, and sigmoid colon shows a mucosa that varies from hyperemic and irregular (upper two-thirds) to necrotic and denuded (lower one-third).

Figure 11.25  An opened segment of distal colon (with the rectum to the left) displays a relatively sharp junction between normal mucosa (far right) and a “meaty” irregular tan-brown mucosa (center and left).

Figure 11.26  In this cross section of bowel, the mucosa has been partially undermined by necrosis allowing a still-attached segment to rise up in a polyp-like configuration (pseudopolyp). Note the intact and seemingly uninvolved muscular wall.

Figure 11.27  Multiple crypt abscesses are present throughout the mucosa, although the left end of the mucosa is totally necrotic and produces an ulcer that undermines the adjacent mucosa.

Figure 11.28  The crypt abscesses of ulcerative colitis are relatively nonspecific and before a diagnosis can be made, infections (e.g., with Shigella, Salmonella, Campylobacter, Clostridium difficile, Yersinia, Entamoeba histolytica) must be ruled out.

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Crohn Disease In contrast to ulcerative colitis, Crohn disease may arise anywhere in the GI tract, from mouth to anus. In approximately 50% of children with Crohn disease, the classic distal ileal and proximal colonic involvement is seen. Approximately 15% of children have only diffuse small-bowel disease, another 15% have only distal ileal involvement, and 10% have isolated colonic disease. The remaining 10% have disease in another site, as in gastroduodenal Crohn disease, or combination of sites. Symptoms depend on the site of involvement, but in general, the presentation of Crohn disease is more insidious than that of ulcerative colitis, so that the diagnosis is often delayed. Vague abdominal pain, diarrhea, growth failure, and anorexia are common. Small-bowel involvement may present as diarrhea and malabsorption. Colonic involvement may present as bloody diarrhea and mimic ulcerFigure 11.29  This segment of bowel and adjacent mesentery is thick, hyperemic, and edematous. Note also the prominent lymph nodes within the mesentery.

30A

Figure 11.30  An open segment of colon (cecum is at upper right) displays a mucosa that is diffusely nodular. Note, however, a few discontinuous areas of normal mucosa near the cecum (A). Compared to the normal mucosa (top), the involved mucosa is swollen and hyperemic. Note the linear “tracks” along the length of the mucosa formed by necrosis of the mucosa (B).

30B

Crohn Disease 

251

Figure 11.31  A probe follows a fistula tract between two segments of bowel, which are adherent to each other by granulation tissue and scarring resulting from the transmural inflammation characteristic of this disease.

ative colitis. Unlike ulcerative colitis, Crohn disease is characterized by a segmental or skip pattern, in which involved areas of intestine are often separated by normal intestine. Another important distinguishing feature is that the inflammation in Crohn’s disease is transmural rather than mucosal, so that fissures, fistulas, intramural abscesses, strictures, and fibrous adhesions develop. Thickening of the bowel wall as a result of edema and fibrosis occurs at the expense of the lumen and causes intestinal obstruction. Inflammation, edema, and fibrosis of the bowel and regional lymph nodes may cause adjacent structures to mat together and form an ileocecal mass. Perianal fissures, skin tags, and rectalperineal fistulas and abscesses are common in children with Crohn’s disease.

32A

Figure 11.32  This full thickness section of bowel (A) displays inflammation and diffuse necrosis of the mucosa with extension of the inflammation into the submucosa and both of the muscular layers. Within the wall (B), the inflammatory infiltrate can be seen to consist of lymphocytes and plasma cells, along with a granuloma containing multinucleated giant cells.

32B

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Gastrointestinal Tract

Bacterial Diarrhea Bacteria cause diarrhea through multiple pathophysiologic mechanisms that are categorized as inflammatory or noninflammatory. Salmonella species, Shigella species, and Campylobacter jejuni are the most common causes of inflammatory infectious diarrhea in children, with Clostridium difficile, Yersinia enterocolitica, enteroinvasive Escherichia coli and the protozoan Entamoeba histolytica causing a similar picture. Most of these organisms invade the mucosa, usually in the colon and distal small intestine, and cause epithelial necrosis and a neutrophilic response. The same inflammatory response may be elicited by the cytotoxins of some noninvasive pathogens, such as C. difficile and some toxin-producing E. coli, including enterohemorrhagic E. coli 0157:H7. Dysentery is said to be present if inflammatory diarrhea is accompanied by systemic manifestations such as fever, abdominal pain, and prostration. The stool contains neutrophils, mucus, and blood. A mucosal biopsy is not usually obtained if the organism is identified by stool culture, but a biopsy may be performed in a patient with infectious colitis before the organism is cultured or if rectal bleeding persists. The pathologist may be asked to distinguish infection from ulcerative colitis or Crohn disease.

33A

33B

Figure 11.33  Yersinia enterocolitica. Mucosal ulceration and necrosis in this case of Y. enterocolitica (A) might be confused with that of ulcerative colitis or Crohn’s disease. Microscopically, the mucosa (B) is heavily infiltrated by lymphocytes that markedly widen the lamina propria. With Yersinia infection, lymphoid tissue in the submucosa may be necrotic (C).

33C

Figure 11.34  Shigella. Enteric infections with Shigella organisms may directly invade the epithelium, leading to cell death crypt abscesses, goblet cell depletion, ulceration, and a flattened surface layer.

Gastrointestinal Tumors 

253

Figure 11.35  Escherichia coli. Enteropathogenic types of E. coli adhere to the borders of enterocytes and may be identified with appropriate antibodies, here using anti-0157.

Gastrointestinal Tumors n Juvenile Polyps and Juvenile Polyposis Syndrome Juvenile polyposis is an autosomal dominant syndrome characterized by the development of multiple hamartomatous GI polyps. The prevalence is approximately 1 in 100,000. Germ line mutations in either of two genes of the TGF-beta signaling pathway, the SMAD4 gene located on chromosome 18q21, or the BMPR1a gene on chromosome 10q23, are identified in about 45% of affected patients. In between 25% and 50% of cases, there is no family history of the disorder. Polyps usually develop during childhood, and number between 5 and 100. Because isolated colonic juvenile type polyps occur in up to 2% of children who do not have juvenile polyposis syndrome, criteria for the diagnosis of the syndrome have been developed. The diagnosis requires either (a) documentation of five juvenile polyps, (b) the presence of juvenile polyps in the stomach or small bowel, or (c) the presence of any juvenile polyp and a positive family history of juvenile polyposis syndrome. Figure 11.37  Juvenile polyp. Hyperplastic and cystically dilated crypts are set in an abundant edematous and markedly inflamed stroma (A and B). Note the extensively eroded surface, resulting in the development of abundant superficial granulation tissue (A).

37A

Figure 11.36  Juvenile polyp. This isolated juvenile polyp was excised from the rectum of a 6-month-old boy. Note the irregularity of the mucosal surface of this polyp.

37B

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Gastrointestinal Tract

Figure 11.38  Familial juvenile polyposis. Dozens of polyps are present along this section of colon in an 8-year-old girl with familial juvenile polyposis coli.

Figure 11.39  Familial juvenile polyposis. The individual polyps have the characteristic strawberry-like appearance.

Figure 11.40  Familial juvenile polyposis. Microscopically, all of the tumors resemble the single juvenile polyps (Figure 11.37) with numerous dilated crypts. Note also the lymphoid aggregates within the polyp.

n Peutz-Jeghers Polyposis Syndrome Peutz-Jeghers syndrome is an autosomal dominant disorder with an incidence between 1:8,300 and 1:280,000 in the general population. It is characterized by the development of mucocutaneous hyperpigmentation, hamartomatous polyps throughout the GI tract, and an increased risk of malignancy at

Figure 11.41  PeutzJeghers polyposis ­syndrome. Mucocutaneous hyperpigmentation of lips (A) and hands (B) is often the first sign of this syndrome.

41A

41B

Gastrointestinal Tumors 

many sites. The median age of symptom onset caused by the GI polyps is 13 years. Presenting symptoms include bowel obstruction, intussusception, and GI bleeding or anemia. Recognition of the characteristic hyperpigmented macules can also lead to proper diagnosis. They occur most often on the lips, buccal mucosa, or periorbital skin, but can also develop on the skin of the fingers, palms and soles, genitalia, and perianal area.

Figure 11.43  Peutz-Jeghers polyposis ­syndrome. The hamartomatous polyp contains hyperplastic and disorganized epithelial elements. Figure 11.42  Peutz-Jeghers polyposis s­ yndrome. The polyp displays a stalk with prominent tan-white tissue. Figure 11.44  Peutz-Jeghers polyposis ­syndrome. Haphazardly arranged smooth muscle bundles are a distinctive feature of this hamartomatous lesion.

n Familial Adenomatous Polyposis Familial adenomatous polyposis (adenomatous polyposis coli), the most common of the polyposis syndromes, is an autosomal dominant disorder with an incidence of 1:8,000 persons. Approximately one-third of the cases are sporadic. In patients with familial adenomatous polyposis, hundreds of adenomatous polyps usually carpet the colonic mucosa. The disease may become symptomatic in adolescents, usually causing diarrhea and abdominal pain. The incidence of colonic adenocarcinoma is very high in patients with familial polyposis, approaching 100% by age 50. Malignancy may occur as early as the second decade.

255

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Gastrointestinal Tract

Figure 11.46  Familial adenomatous polyposis. A cross section of colon displays adenomatous polyps virtually side by side along the mucosa.

Figure 11.45  Familial adenomatous polyposis. Hundreds of small nodules stud the mucosa of the bowel.

Figure 11.47.  Familial adenomatous polyposis. The individual polyps show dysplastic spithelium with hyperchromatic, elongate and stratified nuclei with increased mitotic activity. Abundant apoptosis may also be present, as seen here.

Figure 11.48  Familial adenomatous polyposis. Nonpolypoid epithelium can show surface adenomatous change.

Gastrointestinal Tumors 

257

n adenocarcinoma of the Colon and Rectum Adenocarcinoma of the colon and rectum remains a rare diagnosis in children, with an incidence of only 1 in several million. Recognized antecedent conditions such as familial adenomatous polyposis, familial juvenile polyposis, and ulcerative colitis account for a minority of the cases.

Figure 11.49  Adenocarcinoma of the colon. A “napkin-ring” type adenocarcinoma markedly narrows the ascending colon in this 9-year-old boy with familial adenomatous polyposis.

50A

50b

Figure 11.50  Adenocarcinoma of the colon. The submucosa and muscular layers of the colon (A) have been infiltrated by moderately differentiated adenocarcinoma (B).

n lymphoma The intestine is the most common site of primary extranodal lymphoma, and non-Hodgkin lymphoma is the most common malignant intestinal tumor in children. Boys from 5 to 10 years of age account for most of the affected children, and the usual clinical presentation is abdominal pain and a palpable right lower quadrant mass. Burkitt lymphoma is by far the most common GI lymphoma of childhood. It usually arises in the submucosal lymphoid tissue of the ileocecal region and extends transmurally to involve local mesenteric lymph nodes and form a bulky tumor mass. Less-advanced cases may present with intussusception or intestinal obstruction.

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Gastrointestinal Tract

Figure 11.51  Burkitt lymphoma-cecum. The submucosa and muscular wall of the cecum is markedly thickened and the lumen narrowed.

52a

52b

Figure 11.52  Burkitt lymphoma-cecum. The lymphoma cells heavily infiltrate the mucosa and submucosa (A) and display a typical “starry sky” pattern (B).

n Appendiceal Carcinoid Tumors About 70% of GI carcinoids are located at the tip of the appendix, with most of the remaining present in the terminal ileum. Females are more frequently affected (3:1). The tumor usually occurs in the 7- to 14-year age group and is rarely associated with the carcinoid syndrome. Figure 11.53  Carcinoid of the appendix. The midportion of the appendix (left) is occluded by yellow-tan tumor. Note the dilated distal appendix (right).

Gastrointestinal Tumors 

259

Figure 11.54  Carcinoid of the appendix. The tumor consists of nests of cells usually reactive with neuroendocrine markers such as synaptophysin, chromogranin A, neuron-specific enolase, and CD56.

n Inflammatory Myofibroblastic Tumors Approximately 50% of inflammatory myofibroblastic tumors occur in the mesentery, omentum, or other intra-abdominal sites, often presenting with pain, weight loss, and malaise.

Figure 11.56  Inflammatory myofibroblastic tumors. The cut section of the tumor displays a moderately firm tan-white surface. Figure 11.55  Inflammatory myofibroblastic tumors. This tumor was resected from the gastric antrum of a 7-year-old girl.

57a

57b

Figure 11.57  Inflammatory myofibroblastic tumors. Histologically, the tumor is composed of loosely arrayed stellate-to-plump spindle cells in an edematous, myxoid background with brisk but normal appearing mitotic activity and an inflammatory infiltrate of lymphocytes, neutrophils, and eosinophils (A). Some areas display dense areas of sparsely cellular plate-like collagen (B).

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Gastrointestinal Tract

n Gastrointestinal Stromal Tumors GI stromal tumors present occasionally in children, either as sporadic tumors or in the setting of a syndrome. Most, but not all, GI stromal tumors in children occur in the stomach. Iron deficiency anemia is the most common presenting symptom in sporadic cases, whereas abdominal pain, a palpable mass, or vomiting occurs rarely. Carney triad is used to describe patients with paragangliomas, pulmonary chondromas, and gastric GI stromal tumors. About 85% of patients with Carney triad are female, and the GI stromal tumors are often multifocal, which is unusual for sporadic tumors. The recently described Carney-Stratakis syndrome comprises a dyad of paraganglioma and gastric stromal sarcomas, lacks pulmonary chondromas, and affects both genders with an autosomal dominant inheritance.

58a

Figure 11.58  GI stromal tumors. This 14-year-old girl presented with mild abdominal pain and with imaging studies was noted to have a gastric mass (A) and a lesion in the right upper lobe (B).

58b

Figure 11.59  GI stromal tumors. At surgery, a large mass was found in the wall of the stomach and resected.

Additional Readings 

60a

60b

Figure 11.60  GI stromal tumors. The tumor consists of fascicles of spindle cells and epithelioid areas. Note the paranuclear vacuoles (A). The tumor cells are diffusely positive for CD117 (B).

Additional Readings Abramowsky C, Hupertz V, Kilbridge P, Czinn S. Intestinal lymphangiectasia in children: a study of upper gastrointestinal endoscopic biopsies. Pediatr Pathol. 1989;9(3):289–297. Agaram NP, Laquaglia MP, Ustun B, et al. Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res. 2008;14(10):3204–3215. Allende DS, Yerian LM. Diagnosing gastroesophageal reflux disease: the pathologist’s perspective. Adv Anat Pathol. 2009;16(3):161–165. Alsaad KO, Serra S, Schmitt A, Perren A, Chetty R. Cytokeratins 7 and 20 immunoexpression profile in goblet cell and classical carcinoids of appendix. Endocr Pathol. 2007;18 (1):16–22. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45(1):1–14. Epub 2007 Oct 26. Antonioli D. Colitis in infants and children. Perspect Pediatr Pathol. 1997;20:77–110. Antonioli DA. Pediatric inflammatory bowel disease. Pediatr Dev Pathol. 2005;8(1):2–19. Epub 2005 Feb 21. Barnard J. Screening and surveillance recommendations for pediatric gastrointestinal polyposis syndromes. J Pediatr Gastroenterol Nutr. 2009;(48 suppl 2):S75–S78. Beardmore HE, Wiglesworth FW. Vertebral anomalies and alimentary duplication. Pediatr Clin North Am. 1958;5:457–474. Bentley JF, Smith JR. Developmental posterior enteric remnants and spinal malformations: the split notochord syndrome. Arch Dis Child. 1960;35:76–86. Berry CL, Keeling JW. Gastrointestinal lymphoma in childhood. J Clin Pathol. 1970;23 (6):459–463. Bianchi LK, Burke CA, Bennett AE, et al. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6(2):180–185. Blisard KS, Kleinman R. Hirschsprung’s disease: a clinical and pathologic overview. Hum Pathol. 1986;17(12):1189–1191. Boyle JT. Gastroesophageal reflux in the pediatric patient. Gastroenterol Clin North Am. 1989;18(2):315– 337. Brosens LA, van Hattem A, Hylind LM, et al. Risk of colorectal cancer in juvenile polyposis. Gut. 2007;56(7):965–967. Buchino JJ, Suchy FJ, Snyder JW. Bacterial diarrhea in infants and children. Perspect Pediatr Pathol. 1984;8(2):163–180. Cai YC, Banner B, Glickman J, Odze RD. Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors. Hum Pathol. 2001;32(10):1087–1093. Carney JA. The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extraadrenal paraganglioma: a five-year review. Medicine. 1983;62(3):159–169. Chen HM, Fang JY. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009;24(8):865–874.

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Cheung KM, Oliver MR, Cameron DJ, et al. Esophageal eosinophilia in children with dysphagia. J Pediatr Gastroenterol Nutr. 2003;37(4):498–503. Coffin CM. Polyps and neoplasms of the gastrointestinal tract in childhood and adolescence. Perspect Pediatr Path. 1997:20:127–171. Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991;11(4):569–588. Coffin CM, Watterson J, Priest JR, et al. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19(8):859–872. Cover TL, Aber, RC. Yersinia enterocolitica. N Eng J Med. 1989;321(1):16–24. de Leng WW, Jansen M, Keller JJ, et al. Peutz-Jeghers syndrome polyps are polyclonal with expanded progenitor cell compartment. Gut. 2007;56(10):1475–1476. DeSa DJ. Congenital stenosis and atresia of the jejunum and ileum. J Clin Pathol. 1972; 25(12):1063–1070. Dickerman JD, Colletti RB, Tampas JP. Gastric outlet obstruction in chronic granulomatous disease of childhood. Am J Dis Child. 1986;140(6):567–570. Ein SH, Stephens CA. Intussusception: 354 cases in 10 years. J Pediatr Surg. 1971;6(1):16–27. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33(5):459–465. Ford EG, Senac MO Jr, Srikanth MS, Weitzman JJ. Malrotation of the intestine in children. Ann Surg. 1992;215(2):172–178. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342– 1363. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362(9381):383–391. Groen EJ, Roos A, Muntinghe FL, et al. Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg Oncol. 2008;15(9):2439–2450. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209–3215. Hemming V, Rankin J. Small intestinal atresia in a defined population: occurrence, prenatal diagnosis, and survival. Prenat Diagn. 2007;27(13):1205–1211. Henry MC, Moss RL. Neonatal necrotizing enterocolitis. Semin Pediatr Surg. 2008;17(2):98–109. Herbst JJ. Gastroesophageal reflux. J Pediatr. 1981;98(6):859–870. Holsclaw DS, Eckstein HB, Nixon HH. Meconium ileus. A 20-year review of 109 cases. Am J Dis Child. 1965;109(2):101–113. Hou YY, Lu SH, Zhou Y, et al. Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors. Mod Pathol. 2009;22(4):556–569. Hsueh W, Caplan MS, Tan X, MacKendrick W, Gonzalez-Crussi, F. Necrotizing enterocolitis of the newborn: pathogenetic concepts in perspective. Pediatr Dev Pathol. 1998;1(1): 2–16. Huppertz HI, Soriano-Gabarró M, Grimprel E, et al. Intussusception among young children in Europe. Pediatr Infect Dis J. 2006;25(1 suppl):S22–S29. Jass JR. Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract. 2008;204:431–447. Jenkins D, Balsitis M, Gallivan S, et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol. 1997;50(2):93–105. Kapel RC, Miller JK, Torres C, et al. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology. 2008;134(5):1316–1321. Kapur RP, Reed RC, Finn LS, Patterson K, Johanson J, Rutledge JC. Calretinin immunohistochemistry versus acetylcholinesterase histochemistry in the evaluation of suction rectal biopsies for Hirschsprung Disease. Pediatr Dev Pathol. 2009;12(1):6–15. Kim B, Barnett JL, Kleer CG, Appelman HD. Endoscopic and histological patchiness in treated ulcerative colitis. Am J Gastroenterol. 1999;94(11):3258–3262. Lenaerts C, Roy CC, Vaillancourt M, Weber AM, Morin CL, Seidman E. High incidence of upper gastrointestinal tract involvement in children with Crohn disease. Pediatrics. 1989;83(5):777–781. Liegl B, Hornick JL, Lazar AJ. Contemporary pathology of gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2009;23(1):49–68, vii–viii. Lin PW, Nasr TR, Stoll BJ. Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention. Semin Perinatol. 2008;32(2):70–82. Lowichik A, Book L. Pediatric celiac disease: clinicopathologic and genetic aspects. Pediatr Dev Pathol. 2003;6(6):470–483.

Additional Readings 

Martin LW, Torres AM. Omphalocele and gastroschisis. Surg Clin North Am. 1985; 65(5):1235–1244. Mastracci L, Spaggiari P, Grillo F, et al. Microscopic esophagitis in gastro-esophageal reflux disease: individual lesions, biopsy sampling, and clinical correlations. Virchows Arch. 2009;454(1):31–39. Epub 2008 Dec 2. Misdraji J. Neuroendocrine tumors of the appendix. Curr Diagn Pathol. 2005;11:180–193. Moertel CG, Weiland LH, Nagorney DM, et al. Carcinoid tumor of the appendix: treatment and prognosis. N Engl J Med. 1987;317(27):1699–1701. Murray KF, Patterson K. Escherichia coli O157:H7-induced hemolytic-uremic syndrome: histopathologic changes in the colon over time. Pediatr Dev Pathol. 2000;3(3):232–239. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Colitis Foundation of America, Bousvaros A, et al. Differentiating ulcerative colitis from Crohn’s disease in children and young adults. J Pediatr Gastroenterol Nutr. 2007;44 (5):653–674. Peter G, Myers MG, National Vaccine Advisory Committee, National Vaccine Program Office. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics. 2002;110(6):e67. Rao BN, Pratt CB, Fleming ID, et al. Colon carcinoma in children and adolescents. a review of 30 cases. Cancer. 1985;55(6):1322–1326. Schnabl KL, Van Aerde JE, Thomson AB, Clandinin MT. Necrotizing enterocolitis: a multifactorial disease with no cure. World J Gastroenterol. 2008;14(14):2142–2161. Seashore JH, Collins FS, Markowitz RI, Seashore MR. Familial apple peel jejunal atresia: surgical, genetic, and radiographic aspects. Pediatrics. 1987;80(4):540–544. Shen-Schwartz S, Fitko R. Multiple gastrointestinal atresias with imperforate anus: pathology and pathogenesis. Am J Med Genet. 1990;36(4):451–455. Shorter NA, Georges A, Perenyi A, Garrow E. A proposed classification system for familial intestinal atresia and its relevance to the understanding of the etiology of jejunoileal atresia. J Pediatr Surg. 2006;41(11):1822–1825. Spicer RD. Infantile hypertrophic pyloric stenosis: a review. Br J Surg. 1982;69(3):128–135. Straumann A, Hruz P. What’s new in the diagnosis and therapy of eosinophilic esophagitis? Curr Opin Gastroenterol. 2009;25(4):366–371. Trier JS. Diagnosis of celiac sprue. Gastroenterology. 1998;115:211–216. Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies. Experience with 217 childhood cases. Arch Surg. 1987;122(5):542–547. Walsh SV, Antonioli DA, Goldman H, et al. Allergic esophagitis in children: a clinicopathological entity. Am J Surg Pathol. 1999;23(4):390–396. Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103(3):788–797. Washington K, Greenson JK, Montgomery E, et al. Histopathology of ulcerative colitis in initial rectal biopsy in children. Am J Surg Pathol. 2002;26(11):1441–1449. Westerman AM, van Velthuysen ML, Bac DJ, et al. Malignancy in Peutz-Jeghers syndrome? The pitfall of pseudo-invasion. J Clin Gastroenterol. 1997;25(1):387–390. Yazbeck S, Ndoye M, Khan AH. Omphalocele: a 25-year experience. J Pediatr Surg. 1986; 21(9):761–763.

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Liver, Biliary Tract, and Pancreas Haresh Mani J. thomas Stocker

n

LIVER AND BILIARY TRACT Embryology Histology Neonatal Jaundice Extrahepatic Biliary Atresia Neonatal Hepatitis Paucity of Bile Ducts Metabolic Disorders Galactosemia Glycogen Storage Diseases Mucopolysaccharidoses Niemann-Pick Disease Gaucher Disease Tyrosinemia Bile Acid Metabolism Disorders Alpha-1-Antitrypsin Deficiency Iron Storage Disease Neonatal Iron Storage Disease Wilson Disease

Infections Total Parenteral Nutrition–Related Injury Hepatic Steatosis and Steatohepatitis Cystic Diseases Fibropolycystic Disease of the Liver Associated With Cystic Renal Disease (Ductal Plate Malformations) Caroli Disease Choledochal Cyst Tumors Focal Nodular Hyperplasia Nodular Regenerative Hyperplasia Hepatocellular Adenoma Mesenchymal Hamartoma Infantile Hemangioendothelioma

Hepatoblastoma Hepatocellular Carcinoma Undifferentiated Embryonal Sarcoma Nested Stromal Epithelial Tumor of the Liver Embryonal Rhabdomyosarcoma of the Biliary Tract n PANCREAS Embryology Histology Benign Lesions Pancreatic Cysts Cystic Fibrosis Nesidioblastosis Tumors Pancreatic Endocrine Tumor Pancreatoblastoma Solid Pseudopapillary Neoplasm

liver and Biliary TraCT n eMBryoloGy The liver develops in the area of the transverse septum at the embryonic junctional site (externally where the ectoderm of the amnion meets the endoderm of the yolk sac, and internally where the foregut meets the midgut). The hepatic diverticulum originates at this site and differentiates cranially into the proliferating hepatic cords and caudally into the extrahepatic bile ducts and the gallbladder. The proliferating hepatic cords grow into the mesenchyme of the transverse septum, the latter forming the connective tissue elements of the hepatic stroma and capsule (Figure 12.1). The fetal liver is also the major site for

1a

1B

FiGure 12.1 Hepatic cords. The fetal liver shows proliferating hepatic cords in mesenchyme (A), with extensive hematopoiesis (B).

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FIGURE 12.2  Ductal plate remnants. Ductal plate remnants can be seen in neonates and is highlighted by CK7 immunostain.

FIGURE 12.3  Heterotopic liver tissue. Heterotopic liver tissue may be found above and within the diaphragm and in the upper abdomen.

hematopoiesis, and extramedullary hematopoiesis (EMH) may also be seen in the liver of infants with systemic illnesses or severe stress. The epithelium of the intrahepatic bile ducts is probably generated by interaction of the primitive hepatic epithelium and the mesenchyme surrounding the developing and branching portal vein. The ductal plate develops at around 8 weeks gestation, appearing as a cylindrical cleft around the mesenchyme of the progressively developing and branching portal vein. The ductal plate (Figure 12.2) undergoes gradual remodeling (by a balance of proliferation and apoptosis) to form the interlobular bile ducts in the portal tract and disappears by birth or soon thereafter. Lack of remodeling results in the persistence of embryonic bile duct structures in their primitive ductal plate configuration. Ectopic liver tissue may be seen in or above the diaphragm (Figure 12.3).

n Histology The conventional histologic unit of the liver is the hepatic lobule, which consists of a central efferent vein with cords of hepatocytes radiating to several peripheral portal tracts (Figure 12.4).

4a

4B

FIGURE 12.4  Hepatic lobule. The functional unit, the hepatic acinus (A and B), traces blood flow—from the portal tract (zone 1) (C) to the central vein (zone 3) (D)—and bile via the canaliculi toward the portal tracts, emptying through the canals of Hering into the interlobular bile ducts. The portal tracts contain branches of bile duct, portal vein, and hepatic artery; the ratio of bile ducts to hepatic artery being an average of 1:1 (range 0.9–1.8) (C). However, neonates may have a lower ratio, with bile ducts being often inconspicuous on an H&E stain, but better highlighted on a CK7 or CK19 stain. Care must be taken not to mistake ductules/ductal plate remnants for bile ducts (E). Although children older than 5 or 6 years of age have hepatocytes organized into single-cell–thick plates (F), two-cells–thick plates are common in younger children. In the preterm infant, the lobular structure of the liver is poorly defined. In childhood, hepatocytes often have nuclear glycogen, and cytoplasmic lipofuscin is scanty. (Continued)

LIVER AND BILIARY TRACT 

4C

4E

4D

4F

Figure 12.4  Hepatic lobule. (Continued)

n Neonatal Jaundice Neonatal hyperbilirubinemia may be physiologic or pathologic. Physiologic jaundice occurs between 2 and 5 days of age with a serum bilirubin of 5 to 6 mg/dL (up to 12 mg/dL in Asian and Native American neonates). Hereditary hyperbilirubinemias that present in early infancy are rare and include type 1 Crigler-Najjar syndrome and Dubin-Johnson syndrome (ABCC2 gene mutation). However, in a clinical setting, neonatal cholestasis far surpasses the above in importance (1). Biochemically, there is conjugated or mixed hyperbilirubinemia, with elevated alkaline phosphatase (even for age) and gamma-glutamyl transpeptidase (GGT). However, some cases of progressive familial intrahepatic cholestasis (PFIC) and bile acid synthesis defects may have normal GGT. Other metabolic diseases and alpha-1-antitrypsin (A1AT) deficiency also need biochemical evaluation for diagnosis. The salient features of the more common congenital and acquired cholestatic diseases of neonates and infants are shown in Table 12.1.

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TABLE 12.1  Neonatal Cholestatic Disorders DUCT PLUGGING

DUCTULAR REACTION

LOBULAR DISARRAY

Neonatal ­hepatitis

No

No

May be marked No

11

Typically absent

EHBA

Yes

Yes, 11

Mild

No

1/2

Portal, early

Metabolic d­iseases

No

Focal, mild, duct paucity

Variable

Yes, marked in galactosemia, tyrosinemia, fructosemia

1/2

Periportal, ­pericellular

A1AT ­deficiency

Yes

Yes, 1

Variable

No

1/2

Portal, maybe early

STEATOSIS

EXTRAMEDULLARY HEMATOPOIESIS

PFIC

No

Mild

In type 2 PFIC

No

1/2

Bile acid ­synthesis defect

No

No or mild

Yes

No

11 1/2

TPN

Yes

Yes, 11

Yes

1/2

Infections

No

1/2

Yes

No

1

FIBROSIS

Portal, late Portal, late Typically absent

Abbreviations: A1AT indicates alpha-1-antitrypsin; EHBA, extrahepatic biliary atresia; EMH, extramedullary hematopoiesis; PFIC, progressive familial intrahepatic cholestasis; TPN, total parenteral nutrition.

Extrahepatic Biliary Atresia The first step in the evaluation of neonatal cholestasis is to identify or exclude extrahepatic biliary atresia (EHBA) (2–3). Although in the present day this is ably achieved by imaging studies, biopsies are still commonly performed in the work-up, reliably establishing the diagnosis in 85% to 97% of cases. EHBA usually presents in a perinatal form, but may present as an embryonic or fetal type (10% to 35%). The embryonic or fetal form is characterized by early onset of neonatal cholestasis without a jaundice-free period and is associated with other congenital anomalies (e.g., polysplenia, asplenia, cardiovascular defects, abdominal situs inversus, intestinal malrotation, portal vein and hepatic artery anomalies). The perinatal form presents as late onset ­neonatal cholestasis (4–8 weeks of age) without associated anomalies. A classification of biliary atresia is depicted in Figure 12.5. The most frequently observed changes within the liver in EHBA are cholestasis, portal edema, ductular proliferation, and portal fibrosis (Figure 12.6A). Ductular proliferation is a significant and salient diagnostic feature of EHBA (Figure 12.6B), and may be highlighted with a CK7 immunostain. However, a CK7 immunostain can highlight ductal plates that may ­completely involute only in later infancy, and these should not be mistaken for ductular proliferation. Persistent ductal plates are reguFIGURE 12.5  Classification of biliary atresia.

LIVER AND BILIARY TRACT 

larly arranged along the perimeter of the portal tract, whereas ductular proliferation is more haphazard with elongated and branching ductular profiles. Ductules should also be differentiated from bile ducts; the latter tend to be more rounded and are usually adjacent to the hepatic artery (Figure 12.4E). Bile duct branches, ductules, and ductal plate are all highlighted by a CK7 or CK19, and immunostains cannot be used to differentiate these. Ductal lining epithelium shows degenerative changes. Periductal edema is prominent early and reactive fibrosis supervenes with time, progressing to biliary cirrhosis. Portal inflammation present is comprised of a mix of lymphocytes and neutrophils, with the presence of cholangitis and cholangiolitis (Figure 12.7). There is severe cholestasis (canalicular, hepatocellular), most prominent in zone 3, but also in the bile ducts and ductules (bile plugs) (Figure 12.8). With progressive ductal injury, large interlobar portal tracts may also show absence of bile ducts. At a later stage, cholestasis results in feathery (pseudoxanthomatous) degeneration (Figure 12.9) and this may be highlighted by a copper stain. Pseudoacini may form around canalicular bile plugs, so-called cholestatic rosettes (Figure 12.10). However, bile “lakes,” as seen in adults with biliary obstruction, is rare in infants

6a

6B

FIGURE 12.6  Portal edema (A) and ductular proliferation (B).

FIGURE 12.7  Severe cholangitis.

FIGURE 12.8  Bile plugs and portal fibrosis.

FIGURE 12.9  Pseudoxanthomatous change.

FIGURE 12.10  Cholestatic rosette.

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with EHBA. In the absence of surgical correction, portal edema and fibrosis progresses to secondary biliary cirrhosis (Figure 12.11). Other causes of obstruction (bile duct stenosis, choledochal cyst, mucous, or bile plug) produce similar changes, as will disorders such as A1AT deficiency and total parenteral nutrition (TPN)–associated cholestasis. Extrahepatic ducts (Figures 12.12–12.14) may display changes ranging from mild inflammation and duct epithelial dysmorphism to complete obliteration. The lining of preserved larger ducts is often inflamed and ulcerated, with intraluminal and extraluminal fibrosis distorting the lumen. With progressive epithelial inflammation and degeneration, fibrosis eventually obliterates the duct. Rarely, islands of hyaline cartilage may be found in the porta hepatis, suggesting a congenital malformation as the cause of the atresia in these selected cases. The gallbladder may be diminutive and exhibit varying degrees of fibrosis, epithelial degeneration and destruction, and luminal compromise. Occasionally, the entire extrahepatic biliary tree may be missing, and the liver abuts the duodenum ­(Figure 12.15).

FIGURE 12.11  Biliary cirrhosis.

FIGURE 12.12  Large bile duct inflammation and ulceration. FIGURE 12.13  Scarring of large interlobar bile duct.

14A

14B

FIGURE 12.14  Interlobar septa (A) and porta hepatis (B) with missing bile duct.

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271

FIGURE 12.15  Missing extrahepatic biliary tree. Complete absence of the extrahepatic biliary apparatus may result in the liver abutting the duodenum.

Neonatal Hepatitis Neonatal hepatitis is not a single entity but a pattern of injury with varied etiology including metabolic diseases, infections, progressive familial intrahepatic cholestasis (PFIC), and A1AT deficiency (4). When no underlying cause is found, it is referred to as idiopathic neonatal hepatitis (INH). Unlike in EHBA, cholestasis is usually seen in zone 3 hepatocytes and canaliculi, and rarely in the interlobular bile ducts. Portal tracts are neither expanded nor edematous, and are not prominent on low-power examination ­(Figure 12.16). Giant cell transformation is usually prominent, but is a nonspecific finding, because it may be seen in many neonatal liver disorders. Hepatocyte ballooning, apoptosis, and pseudoglandular or acinar formation may be seen (Figure 12.17A and B). EMH is usually prominent (Figure 12.18). Lobular or portal inflammation is usually sparse, and if prominent, should suggest an infectious (e.g., viral) etiology. FIGURE 12.16  Neonatal hepatitis. Portal tracts are relatively normal in INH, without significant inflammation, ductular proliferation, or bile plugs.

17A

17B

FIGURE 12.17  Ideopathic neonatal hepatitis (INH). Lobular cholestasis, hepatocyte ballooning (A), and giant cell transformation (B) in INH.

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Liver, Biliary Tract, and Pancreas

FIGURE 12.18  Prominent EMH in INH.

Paucity of Bile Ducts The next important histopathologic parameter to be assessed in neonatal cholestasis is paucity of bile ducts (Figures 12.19–12.22). Paucity of bile ducts may be syndromic (Alagille syndrome, Byler syndrome) or nonsyndromic (A1AT deficiency, congenital syphilis, cytomegalovirus [CMV] infection,

FIGURE 12.19  Normal bile duct. A normal bile duct is usually rounded in configuration, lies adjacent to the hepatic artery, and is of similar caliber as the hepatic artery.

FIGURE 12.20  Bile duct paucity. In this example of bile duct paucity, the portal tract shows two hepatic arterial cross sections, but no bile duct profile. The adjacent liver shows canalicular cholestasis.

FIGURE 12.21  Ductules. Ductules, on the other hand, are more peripheral, have elongate configuration, and may show branching and epithelial dysmorphism in a setting of ductular proliferation.

FIGURE 12.22  Ductal plate. The ductal plate is also peripheral and of elongated configuration, but usually occupies most of the perimeter of the portal tract and does not show branching, epithelial degeneration, or mitoses. Also, the ductal plate cannot be identified on routine stains except in a setting of ductal plate malformation.

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273

TABLE 12.2  Metabolic Diseases That Present With Neonatal Hepatitis ELECTRON MICROSCOPic FINDINGS

CONDITION

HISTOLOGIC FEATURES

DIAGNOSTIC TEST

A1AT deficiency

PAS-D 1 globules

Fructosemia

Steatosis 11, fibrosis

Galactosemia

Steatosis 11, fibrosis, iron overload

Glycogenosis (IV)

Abnormal glycogen (PAS-D 1 material), early cirrhosis

Fibrillar ­nonmembrane bound dense ­material

Branching enzyme activity in cultured fibroblasts

Niemann-Pick disease

Vacuolated/foamy Kupffer cells, stored sphingolipids on ­histochemistry

Pleomorphic ­lamellar inclusions in ­lysosomes

WBC sphingomyelinase

Tyrosinemia

Steatosis 11, ­fibrosis, iron overload, regenerative ­nodules, hepatocellular ­dysplasia

A1AT phenotype and serum levels Fructose holes

Fructose challenge test; liver aldolase B Enzyme deficiency in RBCs

Urine succinylacetone

Abbreviations: A1AT indicates alpha-1-antitrypsin; EM, electron microscope; PAS-D, ­periodic acid-Schiff diastase.

Turner syndrome, Down syndrome, medications, toxins, and immune-mediated disease, including graft-versus-host disease) (5). Ideally, to determine bile duct paucity, one requires assessment of 20 portal tracts. Unlike in adults, where a bile duct to portal tract (or hepatic artery) ratio of less than 0.9 is considered abnormal, bile duct development may not be complete in the neonatal period and one cannot be entirely dogmatic with these figures, without adequate follow-up and clinical correlation. Some authors have suggested a cutoff ratio of 0.4 to diagnose bile duct paucity.

n Metabolic Disorders Metabolic disorders may present in the neonatal period with cholestasis or later in life with more specific signs and symptoms (6–10). In the neonatal period, these may show significant clinical and histopathologic overlap with neonatal hepatitis, although there may be certain clues to etiology (Table 12.2). However, definitive diagnosis may need electron microscopic evaluation and biochemical studies.

Galactosemia Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-­phosphate uridyl transferase (11). Neonates present with jaundice, diarrhea, vomiting, and hepatomegaly (Figure 12.23). Investigations reveal hypoglycemia, generalized aminoaciduria, and presence of reducing substances in the urine. If a galactosemic infant is fed milk, unmetabolized sugars build up, leading to cataracts and liver, brain, and renal damage. Biopsy pathology includes canalicular and intracelFIGURE 12.23  Galactosemia. Severe hepatomegaly with abdominal protuberance in this affected neonate.

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lular cholestasis, pseudoacinar transformation, bile ductular proliferation, focal giant cell transformation of hepatocytes, and presence of intracellular lipid (Figures 12.24 and 12.25). Fibrosis occurs early and, if left untreated, progresses to cirrhosis within the first 3 to 6 months of life (Figure 12.26). Similar histology is seen in tyrosinemia and fructosemia. Diagnosis is established by demonstrating enzyme deficiency in erythrocytes.

24A

24B

FIGURE 12.24  Galactosemia. Biopsy pathology includes canalicular and intracellular cholestasis, pseudoacinar transformation, bile ductular proliferation, focal giant cell transformation of hepatocytes (A), and steatosis (B).

25A

25B

FIGURE 12.25  Galactosemia. Perl stain (A) highlights mild iron overload in this case, whereas an oil red O stain (B) for fat is strongly positive.

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26A

275

26B

FIGURE 12.26  Galactosemia. Untreated infants invariably progress to cirrhosis.

Glycogen Storage Diseases Glycogen storage diseases (GSDs) are a result of enzyme defects in the glycogen metabolic pathways, with resultant accumulation of glycogen in various tissues. Hepatic manifestations occur in GSD types I, II, III, IV, VI, and IX (Table 12.3), type I being the most common form (Figures 12.27–12.30). Types V and VII GSD affect skeletal muscles and spare the liver. Type II GSD is a lysosomal storage disorder, whereas the other forms show cytoplasmic glycogen accumulation (7). Some forms of the disease present in infancy and others in early childhood, with failure to thrive, developmental delays, seizures, hepatomegaly, lactic acidosis, and/or hypoglycemia. Disease course may be further complicated by hyperlipidemia, xanthomata, hyperuricemia, cyclic neutropenia with recurrent infections, nephropathy, and chronic bowel inflammation. TABLE 12.3  Salient Features of Glycogen Storage Diseases GLYCOGEN STORAGE DISEASES TYPE

HISTOPATHOLOGY

ELECTRON MICROSCOPE FINDINGS

I (von Gierke)

Excess cytoplasmic and nuclear glycogen with uniform mosaic pattern, rare Mallory bodies, fibrosis absent

Pools of monoparticulate ­glycogen in cytoplasm and nuclei with displacement of other organelles; lipid ­vacuoles; megamitochondria

II (Pompe)

Nonuniform, mild distension and vacuolation of cytoplasm, acid phosphatase 1

Lysosomal monoparticulate glycogen

III (Cori)

Similar to type I, uniform mosaic pattern; portal fibrosis Similar to type I, lesser lipid and nuclear glycogen

IV (Anderson)

Amylopectin (PAS-D1) Lafora body-like inclusions with Central fibrillar ­glycogen ­surrounded by ­polyparticulate glycogen rosettes ­nonmembrane haloes in zone 1; inclusions colloidal iron 1; cirrhosis bound fi ­ brillary inclusions and ­glycogen

VI (Hers)

Nonuniform enlargement of hepatocytes, portal fibrosis

Glycogen and finely granular material in cytoplasm

VIII

Excess cytoplasmic glycogen

Cytoplasmic glycogenosis

IX

Excess cytoplasmic glycogen

Glycogen in a starry sky pattern

X

Excess cytoplasmic glycogen

Cytoplasmic glycogenosis

Abbreviations: EM, electron microscope; GSD, glycogen storage diseases; PAS-D, periodic acid-Schiff diastase.

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FIGURE 12.27  Glycogen storage disease (GSD). In this example of type I GSD, the hepatocytes are markedly distended with glycogen (“­vegetable-like”), compressing the sinusoids.

28A

28B

FIGURE 12.28  Glycogen storage disease (GSD). The cytoplasm is strongly PAS-positive (A), and the intense stain is lost following diastase digestion (B).

FIGURE 12.29  Glycogen storage disease (GSD). In type II GSD, the cytoplasmic distension and vacuolation is milder and nonuniform.

FIGURE 12.30  Glycogen storage disease (GSD). Type IV GSD is characterized by amylopectin storage, which is diastase resistant. The PAS-D stain highlights the Lafora bodylike inclusions with haloes.

LIVER AND BILIARY TRACT 

FIGURE 12.32  Hepatocytes and Kupffer cells show foamy vacuolation.

FIGURE 12.31  Hurler syndrome. This young boy with Hurler syndrome has distinct facial features, including coarse facies, depressed nasal bridge, and bulging forehead. He has an umbilical hernia necessitating wearing of a truss.

FIGURE 12.33  Mucopolysaccharidoses. The vacuoles represent acid mucopolysaccharides that stain positive with colloidal iron stain.

Mucopolysaccharidoses The mucopolysaccharidoses are a diverse group of genetic disorders (12). Enzyme deficiencies result in accumulation of acid mucopolysaccharides (glycosaminoglycans), dermatan sulfate, heparan sulfate, chondroitin sulfate, and keratin sulfate in the tissues, with excretion of these substances in the urine. The major clinical manifestations are caused by involvement of the brain, skeletal system, liver, cornea, and other organ systems. Morphologically and ultrastructurally, all syndromes appear similar (Figures 12.31–12.33). The liver is involved in all types with marked cytoplasmic vacuolization of the hepatocytes, Kupffer cells, and Ito cells. Stored acid mucopolysaccharide can be demonstrated with colloidal iron staining, but requires frozen sections or nonaqueous fixatives. Ultrastructurally, there are numerous electron-lucent membrane-bound vacuoles, corresponding to acid mucopolysaccharides. Finely granular to flocculent material may be seen in some of the vacuoles arranged in concentric whorls.

Niemann-Pick Disease Niemann-Pick disease (sphingomyelinase deficiency), an autosomal recessive lysosomal storage disorder, may present in the neonatal period with jaundice, hepatosplenomegaly and failure to thrive, and rapidly progress to death in months (13). The liver is enlarged and pale, with maintained lobular architecture (7). In its classic form, Kupffer cells and hepatocytes have swollen, foamy vacuolated

277

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Liver, Biliary Tract, and Pancreas

34A

34B

FIGURE 12.34  Niemann-Pick disease. The liver in Niemann-Pick disease may show features of neonatal cholestasis (A). Additionally, hepatocytes show foamy cytoplasmic vacuolation that are strongly PAS-positive (B).

cytoplasm (Figure 12.34). Fibrosis is unusual. Lipofuscin, cholesterol, and phospholipids accumulate in the cells. The stored material is best demonstrated by the Baker hematin reaction for phospholipids. Histochemical staining for acid phosphatase activity reveals a reticular pattern. Ultrastructurally, there are large, pleomorphic, membrane-bound inclusions composed of concentric or parallel osmiophilic lamellae, especially in the Kupffer cells, and, to a lesser extent, in hepatocytes. Sea- blue histiocytes are seen in the bone marrow.

Gaucher Disease Gaucher disease (glucocerebrosidase deficiency) is an autosomal recessive condition with variable clinical severity (14). Type II Gaucher (acute neuropathic or infantile form) is the most severe, as compared to type I (adult or chronic nonneuropathic) and type III (juvenile or subacute neuropathic) forms. There is massive hepatosplenomegaly and portal hypertension, and the liver has similar morphology in all three clinical types (Figures 12.35–12.37). The hallmark Gaucher cells are distended and have a characteristic striated, “wrinkled tissue paper” cytoplasm. These striations are accentuated with the PAS stain, and acid phosphatase activity can be demonstrated histochemically. Hemosiderin and lipofuscin are frequently present. Some cases may progress to cirrhosis. Ultrastructurally, there are closely apposed, irregular lysosomal inclusions composed of innumerable tubules with circular profiles on cross section.

FIGURE 12.35  Gaucher disease. The hallmark Gaucher cells have a characteristic wrinkled tissue paper cytoplasm (PAS stain).

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279

FIGURE 12.36  Gaucher disease. The cells are predominantly CD68positive macrophages (A) and acid phosphatase can be demonstrated histochemically (B).

36A

36B

FIGURE 12.37  Gaucher disease. With progression, there is increasing fibrosis (trichrome stain).

Tyrosinemia Tyrosinemia is a result of fumaryl acetoacetate hydrolase deficiency. It may present as an acute fulminant disease in infancy or as a more chronic disease later in childhood. In the acute form, there may be lobular disarray, progressive acinar transformation, extensive fibrosis, giant cell transformation and bile duct proliferation, iron overload and regenerative nodules (Figure 12.38A and B). Necrosis and inflammation are usually not prominent. The chronic form is characterized by cirrhosis with little inflammation or bile duct proliferation. The hepatocytes in the nodules show macrovesicular steatosis or may be pale and ballooned. Multifocal dysplasia and hepatocellular carcinoma may occur.

FIGURE 12.38A  Tyrosinemia. In tyrosinemia, the liver shows features of neonatal hepatitis. There is lobular disarray, hepatocyte apoptosis, steatosis, and EMH. Similar findings are seen in fructosemia.

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Liver, Biliary Tract, and Pancreas

FIGURE 12.38B  Tyrosinemia. Iron overload may also be present in tyrosinemia.

Bile Acid Metabolism Disorders Bile acid synthesis defects are inherited in an autosomal recessive manner and present with neonatal cholestasis. Unlike with other causes of neonatal cholestasis, patients have high alkaline phosphatase but low to normal GGT. Urinary bile acids are elevated and diagnosis can be established by mass spectroscopy on urine samples. Histological features are similar to other cases of neonatal hepatitis, although older children with milder forms of disease may show a more chronic hepatitis-like picture. Bile acid substitution may halt and reverse the disease. Untreated children progress to cirrhosis.

Alpha-1-Antitrypsin Deficiency A1AT deficiency is the most common genetic cause of neonatal liver disease, accounting for more than 10% of cases of neonatal cholestasis (8, 15). It is inherited in an autosomal recessive manner and is caused by mutations in the protease inhibitor (Pi) gene on chromosome 14. The resultant anti-elastase deficiency leads to liver and lung disease. Clinical presentations vary from neonatal hepatitis with cholestatic jaundice to recurrent/chronic hepatitis and cirrhosis in young adults. Neonates may also present with bleeding diathesis, probably related to an associated vitamin K deficiency. Liver morphology varies with age at presentation. Neonates show features of neonatal hepatitis with cholestasis, pseudoacinar and giant cell transformation, and extramedullary hematopoiesis, similar to other metabolic hepatopathies. A variant morphologic pattern simulates extrahepatic biliary atresia, with greater frequency of progression to cirrhosis. Some patients may show paucity of bile ducts, whereas others may suffer from extensive hepatocellular necrosis and fulminant liver failure. The morphologic hallmark of the disease is the presence of A1AT in the hepatocytes, predominantly in zone 1 and occasionally in bile duct epithelium. The stored material appears as diastase resistant PAS-positive eosinophilic hyaline globules (Figure 12.39). However, these globules may not be morphologically visible until late infancy and their absence does not exclude the diagnosis in the neonatal period. However, the stored material may be identified with immunohistochemistry in these cases. Ultrastructurally, the stored material appears as flocculent, moderately electron-dense material within dilated cisternae of rough endoplasmic reticulum. Currently, the diagnosis is more reliably made by serum A1AT levels and phenotype testing. With progression, cirrhosis ensues (Figure 12.40).

LIVER AND BILIARY TRACT 

281

39B

FIGURE 12.39  A1AT deficiency. The A1AT inclusions may be evident on H&E stains (A), and are diastase-resistant PAS-positive (B).

39A

FIGURE 12.40  A1AT deficiency. The disease is pernicious and progresses to cirrhosis.

Iron Storage Disease Iron overload may be primary (hemochromatosis) or secondary (transfusion related or following excessive intake). The clinical features of hemochromatosis include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. Liver disease progresses to cirrhosis, complicated by hepatocellular carcinoma, although this is rare in the pediatric age group (7, 16). Classic hemochromatosis is an autosomal recessive disorder most often caused by mutation in the HFE gene (chromosome 6p21.3). Other forms of hemochromatosis involve mutations in hemojuvelin gene (HJV, 1q21), hepcidin antimicrobial peptide gene (HAMP, 19q13), transferrin receptor-2 gene (TFR2, 7q22), and ferroprotein gene (SLC40A1, 2q32). Hepatic iron accumulation begins periportally and extends to zone 3. Unlike in hemosiderosis, in both the inherited (hemochromatosis) and secondary (transfusion) forms of iron storage, iron accumulates in both Kupffer cells and hepatocytes. Iron deposition in biliary epithelial cells usually indicates inherited hemochromatosis.

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Liver, Biliary Tract, and Pancreas

41A

41B

FIGURE 12.41  Iron storage disease—hepatocyte pigment (iron positive) is evident. The background liver shows features of giant cell hepatitis (A, B). There is pericellular fibrosis (C).

41C

Neonatal Iron Storage Disease Although most children with hemochromatosis are asymptomatic, neonatal iron storage disease (NISD) is a fatal neonatal disorder characterized by massive iron overload (17). In addition to the liver, iron is also deposited in multiple other organs. The condition is distinct from hemochromatosis and is postulated to be the result of intrauterine fetal liver injury by maternal antibodies. NISD should also be differentiated from other disorders associated with iron overload, such as tyrosinemia, galactosemia, and Zellweger syndrome. Diagnosis can be made in oral mucosal biopsies, because iron is deposited also in minor salivary glands. In NISD, the hepatic architecture is markedly disorganized with lobular collapse and early fibrosis (Figure 12.41). Heavy iron deposits may be seen in hepatocytes, Kupffer cells, and biliary epithelium.

Wilson Disease Wilson disease is an autosomal recessive inborn error of copper metabolism caused by a defect in a transmembrane copper-transporting ATPase on the hepatocyte canalicular membrane (18). This results in reduced biliary excretion of copper and decreased copper incorporation into ceruloplasmin. Clinical features are described by the synonym “hepatolenticular degeneration.” Severity varies with patient age and disease stage. Liver involvement is manifested as a chronic hepatitis, progressing to cirrhosis (Figures 12.42 and 12.43). Quantitative biochemical tests on fresh tissues or paraffin blocks show markedly increased hepatic copper (.250 mg/g dry weight). Ultrastructurally, there are enlarged pleomorphic mitochondria with cristal abnormalities. Electron-dense copper deposits can be seen in lysosomes. Rarely, patients may present with acute or fulminant hepatitis. Central nervous system (CNS) involvement is characterized by copper deposition in the basal ganglia and neuropsy-

LIVER AND BILIARY TRACT 

42A

42B

FIGURE 12.42  Wilson disease. Liver biopsy variably shows a chronic hepatitis pattern with interface hepatitis (A). Mallory bodies may be seen (B).

FIGURE 12.43  Wilson disease. Copper can be demonstrated by a rhodanine stain and is most pronounced in periportal hepatocytes.

FIGURE 12.44  Wilson disease. Kayser-Fleischer ring.

chiatric symptoms. Hemolytic anemia is frequent. Kayser-Fleischer rings (green-brown copper deposits in the corneal Descemet membrane at the limbus) may develop in the course of the disease (Figure 12.44).

n Infections In children, the common viral hepatitides are the self-limiting hepatitis A and hepatitis E, which are not usually biopsied. Congenital hepatitis B is more common than hepatitis C and tends to be asymptomatic with silent progression to chronic hepatitis. In these children, cirrhosis occurs in young adulthood. As such, viruses that are more commonly seen in biopsy material are ­herpes viruses (CMV, herpes simplex virus [HSV]) and adenovirus, usually in a setting of systemic infection ­(Figures 12.45–12.49). Histologically, these show a neonatal hepatitis pattern. Inflammation is usually greater than in idiopathic and metabolic forms. Viral inclusions, when seen, are diagnostic and immunostains are helpful ancillary techniques. Fungal infections may be seen in immunocompromised hosts (Figure 12.50).

283

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Liver, Biliary Tract, and Pancreas

FIGURE 12.46  Neonatal herpes. The liver shows geographic areas of coagulative necrosis.

FIGURE 12.45  Neonatal herpes with widespread skin rash.

FIGURE 12.47  HSV hepatitis may show nuclear smudging and inclusions with different morphology (A). The characteristic triad is of multinucleation, molding, and chromatin margination (B, arrow).

47A

47B

FIGURE 12.48  Congenital CMV infection with massive hepatomegaly.

LIVER AND BILIARY TRACT 

49A

49B

FIGURE 12.49  Neonatal hepatitis. Histologically, there is a neonatal hepatitis pattern (A) with characteristic “owl-eye” viral inclusions (B).

50A

50B

FIGURE 12.50  Candida hepatitis. The liver may also be involved in systemic fungal infections, especially in immunocompromised hosts. This liver shows Candida hepatitis (A, H&E, and B, GMS).

n Total Parenteral Nutrition–Related Injury Total parenteral nutrition is associated with a cholestatic hepatitis (19). The associated cholestasis is seen most frequently in the premature infant; the incidence and severity of the disease are greater in infants with gastrointestinal disease or intestinal resection. Pathogenetic factors include loss of intestinal length (“short bowel”), infection, hypoxia, and toxicity of the infusate, especially amino acid composition and lipid content. Clinically, insidious jaundice (3 to 4 weeks after TPN initiation) may be the only evidence of liver disease, whereas the earliest biochemical abnormality is the elevation of serum bile acids. Grossly, the liver looks bile-stained and fibrotic (Figure 12.51). Histologically, there is mixed FIGURE 12.51  TNP-induced liver injury. Gross appearance of TPNinduced liver injury.

285

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Liver, Biliary Tract, and Pancreas

52A

52B

FIGURE 12.52  TNP-induced liver injury. Lobular disarray, cholestasis and ductular proliferation are evident in this example (A). There is giant cell transformation (B).

53A

53B

FIGURE 12.53  TNP-induced liver injury. Iron overload (A, Perl stain) and fibrosis (B, trichrome stain) may be present.

cholestatic and hepatocellular injury with zone 3 dominant canalicular and hepatocellular cholestasis, lobular disarray, hepatocyte ballooning, prominent Kupffer cells with lipofuscin pigment, and at least focal lymphocyte predominant inflammation (Figure 12.52). Variable findings include intracellular iron, giant cell transformation, pseudoacinar formation, scattered foci of hepatocyte necrosis, extramedullary hematopoiesis, pericholangitis, ductular proliferation, and focal fibrosis (Figure 12.53). Findings are reversible after cessation of TPN and commencement of enteral feedings.

n Hepatic Steatosis and Steatohepatitis Fatty liver or steatosis is a nonspecific finding with many causes including metabolic diseases (urea cycle deficiency, fatty acid oxidation defects, organic acidemia, carnitine deficiency, cystic fibrosis, Wilson disease), drugs, malnutrition, mitochondrial disease, and infections (29, 104). Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children and adolescents in the United States (20). Morphologically, steatosis may be macrovesicular (large fat droplets displacing the nucleus) or microvesicular (multiple small droplets without nuclear displacement) (Figure 12.54). Microvesicular steatosis is related to severe impairment of the mitochondrial beta-oxidation of fatty acids, and megamitochondria may be identified in the affected hepatocytes. Pure microvesicular steatosis is uncommon (Figure 12.55) and may be seen in Reye syndrome (a relatively rare entity), druginduced diseases, or in the presence of mitochondrial disorders. Extensive microvesicular steatosis has also been reportedly associated with liver failure (even when the bilirubin and transaminases are only modestly elevated), hypoglycemia, azotemia, and pancreatitis (21).

LIVER AND BILIARY TRACT 

FIGURE 12.54  Macrovesicular steatosis and glycogenated nuclei in an obese child. There is no steatohepatitis.

287

FIGURE 12.55  Pure or predominant microvesicular steatosis, as seen here, is uncommon.

Although steatosis is reversible, steatohepatitis is associated with fibrosis and progressive disease. One must remember that steatosis and inflammation does not equal steatohepatitis. Rather, steatohepatitis is characterized by hepatocyte injury (usually ballooning degeneration), Mallory bodies and/ or pericellular fibrosis, with or without significant steatosis (Figure 12.56). Steatohepatitis is associated with obesity, diabetes, insulin resistance, and hypertriglyceridemia. Children with steatohepatitis generally present in the prepubertal age group. Clinical markers of insulin resistance such as obesity, diabetes, acanthosis nigricans, and polycystic ovary syndrome may be present (22). There are distinct histologic differences between adult and childhood steatohepatitis. Although some children have disease resembling adult-type steatohepatitis (so-called type 1) with predominantly zone 3 (centrilobular) involvement, most have so-called type 2 steatohepatitis, characterized by predominant zone 1 (periportal) inflammation and fibrosis, panacinar steatosis and relative lack of ballooning degeneration and Mallory bodies (Figure 12.57) (23). Type 2 steatohepatitis is associated with a greater degree of fibrosis than type 1 steatohepatitis. Type 2 steatohepatitis is more common in younger children, obese boys, and non-White (Asian, Native American, and Hispanic) ethnicity. Older children (adolescents) tend to have adult type (type 1) histology, probably reflecting puberty-related hormonal changes (24). Some children show overlapping features. Grading systems have been proposed for NAFLD, based on the proportion of hepatocytes demonstrating macrovesicular steatosis, hepatocyte injury (ballooning degeneration), lobular inflammation, and stage of fibrosis (25).

FIGURE 12.56  Steatohepatitis is characterized by ballooning degeneration and Mallory bodies.

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Liver, Biliary Tract, and Pancreas

57A

57B

FIGURE 12.57  Type 2 (pediatric type) NAFLD has a periportal distribution.

n CYSTIC DISEASES Fibropolycystic Disease of the Liver Associated With Cystic Renal Disease (Ductal Plate Malformations) Abnormalities of the ductal plate are commonly associated with renal abnormalities, manifesting as cystic disease of the liver and kidney in several inherited syndromes, including ­polycystic kidney disease, nephronophthisis, Meckel-Gruber syndrome, Jeune syndrome, Joubert syndrome, Ivemark syndrome, Down’s syndrome, Laurence-Moon-Biedl syndrome, and COACH syndrome (26, 27). Morphologically, there is a varying proportion of ductal plate persistence, cystic dilatation of bile duct radicles, and portal fibrosis (Figure 12.58). Ductal plate remnants are identified by their dilated, cleftlike, irregular contours and their distribution along the periphery of the portal areas. In contrast to ductular proliferation associated with biliary tract obstruction, the ductal epithelium is bland, lacks epithelial degenerative changes or mitoses, and is not inflamed. However, cholestasis may be seen occasionally. Hepatocytes appear normal. FIGURE 12.58  Ductal plate malformations in fibropolycystic liver disease. Dilated and “garlanding” peripherally placed ductal structures (A), with irregular complex contours, cholestasis (B), and fibrosis (C). (Continued)

58A

LIVER AND BILIARY TRACT 

58B

58C

FIGURE 12.58  Ductal plate malformations in fibropolycystic liver disease. (Continued)

59A

59B

FIGURE 12.59  Congenital hepatic fibrosis showing dilated ductal plate structures in the portal tracts (A). These are lined by cuboidal epithelium and contain bile (B).

Congenital hepatic fibrosis (CHF) could conceptually be considered the progression and end result of ductal plate malformations (Figure 12.59). Caroli disease and choledochal cyst may be associated with CHF, suggesting a shared pathogenesis (28). Children with CHF present with portal hypertension. Microscopically, portal areas contain increased numbers of concentrically arranged “garlanding” bile duct structures, that branch and anastomose. Ductal structures are lined by cuboidal to columnar epithelium and the lumina may contain pink or orange secretions. Progressive fibrosis affects portal tracts and interlobular septa. The end result is a fibrotic accentuation of the lobular architecture, yielding an appearance of so-called “biliary type cirrhosis.” Unlike cirrhosis, the fibrosis does not have portal to central bridging, and there are no regenerative nodules, although the distinction may be difficult in needle biopsy material.

Caroli Disease Caroli disease or congenital polycystic segmental dilatation of the larger intrahepatic bile ducts (Figure 12.60) is seen more often in adults than children. It may be incidentally diagnosed on abdominal imaging or may present with complications including cholangitis, liver abscess, and portal hypertension (29). Histologically, in addition to cystically dilated bile ducts with peripheral sacculation, there may be overlap with duct plate malformation and congenital hepatic fibrosis. The combination of intrahepatic bile duct cystic changes and congenital hepatic fibrosis has been termed Caroli syndrome. About half the patients with Caroli disease have medullary sponge kidney.

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60A

60B

FIGURE 12.60  Caroli disease. This CT scan shows dilated intrahepatic ducts (A). Bile duct profiles show cystic dilatation, and a CHF pattern of fibrosis may develop (B).

Choledochal Cyst Choledochal cyst is a presumed congenital anomaly of the intrahepatic and extrahepatic ducts characterized by segmental ductal dilatation, bile stasis, and hyperbilirubinemia (30–32). There may be associated malunion of the pancreatic and distal common bile ducts. The prevalence of choledochal cysts is 1:15,000 live births and is higher in Asian populations and girls. Patients may be asymptomatic or have nonspecific symptoms. The classic triad of pain, jaundice, and right upper quadrant mass is seen in 40% of affected children. The cysts are classified as follows (Figure 12.61): n

Type I – Dilatation of the choledochus Type Ia—large cystic or saccular dilatation of the choledochus Type Ib—segmental dilatation with no pancreaticobiliary malunion Type Ic—diffuse cylindrical or fusiform dilatation

n

Type II—diverticulum of the common bile duct or gallbladder Type III—choledochocele of the distal common bile duct that usually extends into the wall of the duodenum

n

FIGURE 12.61  Types of choledochal cysts.

LIVER AND BILIARY TRACT 

62A

62B

FIGURE 12.62  Type III choledochal cyst involved the duodenal wall (A, MRI) and shows small intestinal-type lining (B, H&E).

n

n n

Type IVa—multiple choledochal cysts with intrahepatic and extrahepatic involvement (Caroli ­disease) Type IVb—multiple extrahepatic cysts Type V—single or multiple intrahepatic dilatations

The excised cyst wall is usually 1- to 2-mm thick and bile stained. The epithelium is usually denuded to flattened, although a biliary type columnar lining may be seen overlying a dense fibrous wall that may show mild inflammation. Occasionally, the epithelium may be complex. In type III (intraduodenal) choledochal cysts, the lining may resemble that of the small intestine (Figure 12.62). Often, there is associated biliary atresia and these children show hepatic morphology of EHBA. Even in children without biliary atresia, the cyst may cause obstruction to the bile duct; in these children, liver pathology may regress after cyst excision. Other complications include ascending cholangitis, choledocholithiasis, pancreatitis, and carcinoma.

n Tumors Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is a benign tumor-like lesion of the liver that is probably a hyperplastic response to local hemodynamic disturbances (33, 34). Although it is more commonly detected in adults, about 8% of cases occur in children, especially girls. Grossly, FNH usually presents as a single mass, although multiple and bilateral lesions may occur in 10% of cases. The lesion has a variable size (up to 17 cm), appears irregular in outline, and often bulges from the liver surface. On cut section, it is unencapsulated but sharply demarcated, is tan-brown in color, and characteristically has a central area of fibrosis with radiating septa (Figure 12.63). The fibrous septae may give an impression of cirrhosis (Figure 12.64). Hemorrhage and necrosis are rare. Histologically, the central scar and the septae contain dystrophic vessels and numerous ductular structures (Figure 12.65). The dystrophic vessels are ectatic and have eccentric intimal thickening and medial hyperplasia. In a biopsy, the fibrous septae with the proliferating ductules may be reminiscent of biliary cirrhosis, congenital hepatic fibrosis, or other ductal plate malformations (35). However, the dystrophic vessels help in making the correct diagnosis. The septae also have a frequent lymphocytic

291

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Liver, Biliary Tract, and Pancreas

FIGURE 12.63  Focal nodular hyperplasia. CT scan with contrast showing an approximately 8.7-cm mass within the right hepatic lobe, that is hypervascular on the arterial phase, with a low attenuation central scar.

FIGURE 12.64  Focal nodular hyperplasia. This resection specimen shows a large central scar but also multinodularity, as a result of the fibrous septae. Although this has the appearance of cirrhosis, the focality of the lesion with surrounding normal liver parenchyma (on top) should suggest the diagnosis.

65A

65B

FIGURE 12.65  Focal nodular hyperplasia. Histologically there are radiating fibrous septae from the central scar (A), containing ductular structures and dystrophic vessels (B).

LIVER AND BILIARY TRACT 

and variable neutrophilic infiltrate. The hepatocytes in the nodules between fibrous septae may be organized in two- to three-cell–thick cords, but are otherwise unremarkable, although steatosis may be seen. A partial capsule may be sometimes seen, and may show a large “feeder artery.” The lesion compresses the adjacent parenchyma. FNH with atypical clinical and/or histopathologic features may be difficult to distinguish from hepatocellular adenomas. Indeed, some lesions have histological features of both adenoma and FNH and have been classified as the telangiectatic type of FNH (33).

Nodular Regenerative Hyperplasia Nodular regenerative hyperplasia (NRH) is also more common in adults than children, with an increasing incidence with age (33, 36–37). Grossly, the liver with NRH shows a diffuse nodularity without fibrosis, the individual nodules usually being regular and up to 3 mm in size (­Figure 12.66). The characteristic histopathologic feature is of light and dark areas on low power microscopy, the former representing zones/nodules of widened hepatocyte plates, and the dark zones comprised of compressed liver cell plates in between nodules (Figure 12.67). The compressed zone usually has a centrilobular (zone 3) distribution, and is highlighted by a reticulin stain that also brings out the sinusoidal dilatation that may be frequently seen adjacent to the compressed atrophic liver cell plates. The regenerating (zone 1 or periportal) compartment shows increased granular staining for A1AT, and this may be helpful to identify cases with otherwise subtle findings. Central veins may show veno-occlusive features and portal veins in smaller portal tracts may also be absent, suggesting a vascular pathogenesis. Hepatic arteries and bile ducts are normal. There is no associated inflammation or cholestasis. Any significant fibrosis rules out a diagnosis of NRH. NRH may be the only histopathologic abnormality in some cases of non-cirrhotic portal hypertension.

FIGURE 12.66  Nodular regenerative hyperplasia. CT scan shows a diffuse nodularity involving the bulk of the hepatic parenchyma.

67A

67B

FIGURE 12.67  Nodular regenerative hyperplasia. Histologically, there is the characteristic dark and light zonal appearance (A), the dark zone representing compressed/atrophic zone 3 hepatocyte cords (B).

293

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Liver, Biliary Tract, and Pancreas

Hepatocellular Adenoma Hepatocellular adenoma (HA) is also more common in adults than in children. Most pediatric patients are teenage girls with a history of oral contraceptive or anabolic steroid use (38). However, it has also been described in children with galactosemia and GSD. On imaging and gross examination, HA is usually a solitary well-circumscribed lesion with large vessels coursing over its surface (Figure 12.68A–C). It may be single or multiple; when more than 10 lesions are present, the condition is referred to as “adenomatosis.” On cut section, the lesion is soft with a variegated appearance, with or without focal hemorrhage and necrosis (Figure 12.68D and E).

68A

68B

68C

68D

FIGURE 12.68  Hepatocellular adenoma. Imaging studies (A, CT, and B, MRI) show a 6.1-cm mass centered within the right hepatic lobe. The mass is heterogeneously hypervascular, with peripheral enhancement. Additional smaller (up to 1.1 cm) foci are seen in segment 6 and left lobe. Angiogram 68E of another lesion highlights hypervascularity (C). Grossly, this tumor shows a relatively homogeneous cut surface that is mildly nodular (D). This incidental lesion in an autopsy specimen shows a fleshy vascular mass (E).

LIVER AND BILIARY TRACT 

69A

69B

FIGURE 12.69  Hepatocellular adenoma. Histologically, the tumor shows uniform hepatocytes in one- to two-cell–thick trabeculae and with pseudoacinar formations (A). Mild steatosis is present in this case (B). Although vascular channels are seen, there is no accompanying bile duct (B).

Histopathologically, the tumors are comprised of sheets of hepatocytes in variably thick trabeculae (Figure 12.69). Although scattered thin-walled blood vessels are identified, the absence of portal tracts and bile ducts provide important clues to diagnosis even in needle biopsy material. In resection specimens, large vessels may be identified at the periphery. Hepatocyte trabeculae are separated by compressed sinusoidal spaces lined by endothelial cells and some Kupffer cells. The tumor cells are the same size as or slightly larger than the normal hepatocytes and may be either normal, clear (glycogen-rich), or fatty. Some lesions show prominent steatosis and, in this setting, an angiomyolipoma needs exclusion. Intralesional hemorrhage is not uncommon and when these heal with scarring, the lesion may simulate FNH; associated hemosiderin-laden macrophages may provide a clue to the real nature of these lesions. Lesions that show dysplastic hepatocytes, nuclear atypia, mitoses, and acinar (“pseudo-glandular”) growth pattern are termed “atypical adenoma” and are difficult to distinguish from hepatocellular carcinoma on biopsy specimens. HA and FNH show overlap both clinically and morphologically. Recently, a molecular/histologic classification of HA has been proposed based on presence or absence of inflammation, beta-catenin mutation, and hepatocyte nuclear factor 1a mutations (39).

Mesenchymal Hamartoma Hepatic mesenchymal hamartoma (HMH) accounts for about 8% of all pediatric tumors (40). They are variable in size, from incidental tiny lesions to large tumors, involving the right lobe more frequently than the left lobe (Figure 12.70). The tumor may be intrahepatic or pedunculated. Cut surface reveals multiple cysts containing serous to gelatinous material and a gray-tan to yellow lining (Figure 12.71A–D). Cysts increase in number with age. Histopathologically, as the name suggests, there is an admixture of mesenFIGURE 12.70  Hepatic mesenchymal hamartoma. CT scan shows a heterogeneous multicystic mass.

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Liver, Biliary Tract, and Pancreas

chyme, bile ducts, and cords of hepatocytes (Figure 12.72). The cysts may have a flattened (“lymphatic”), cuboidal, or biliary type lining, or may be represented by “unlined” fluid-filled loose to dense mesenchyme (Figure 12.73). The mesenchyme itself is comprised of either stellate cells in a myxomatous matrix or a collagenous stroma, the latter being more frequent in older children. Collagen is more prominent around vessels and bile ducts. Nodules of mesenchyme may be separated by dense, highly vascular connective tissue. Bile ducts may show proliferation and branching, especially at the periphery of the lesion and usually do not contain bile. Hepatocytes, when present, probably represent entrapment of adjacent/ normal parenchyma rather than an active component of the tumor. EMH may be present (Figure 12.74). Some lesions may be purely solid and these are associated with higher serum alpha-fetoprotein (AFP) levels (which may reflect the younger age of patients with solid lesions), more evenly distributed hepatocytes, smaller ducts with focal hepatocyte-bile duct transition and more frequent vascular proliferation (41). On needle biopsy material, myxomatous infantile hemangioendotheliomas can resemble HMH, but the former occurs usually in infancy, shows significant vascularity with plump endothelial cells positive for factor VIII-related antigen, CD31, and CD34. Immunostains may not be helpful in differentiating HMH from biphasic hepatoblastomas. HMH has been reported to “progress” to undifferentiated embryonal sarcoma (UES) (42) and should be extensively sampled to exclude a focus of UES.

71A

71B

71D

FIGURE 12.71  Hepatic mesenchymal hamartoma. Gross appearance is variable depending on number of cysts and proportion of mesenchyme and fibrous tissue (A–D). 71C

LIVER AND BILIARY TRACT 

72A

72B

FIGURE 12.72  Hepatic mesenchymal hamartoma. Histopathologically, this case shows nodules comprised of epithelial lined clefts with surrounding variably myxoid and collagenous mesenchyme (A and B). The nodules may grow around and entrap a normal liver (B).

73A

73B

FIGURE 12.73  Hepatic mesenchymal hamartoma. Cysts may have a cuboidal to biliary type lining (A), especially in older children, or may be unlined, when formed by stromal degeneration (B).

FIGURE 12.74  Hepatic mesenchymal hamartoma. Intralesional EMH is present along with scattered collections of neutrophils.

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Infantile Hemangioendothelioma Infantile hemangioendothelioma (IHE) is a vascular tumor that is usually seen in the first year of life (43). Tumors may be single or multiple with equal frequency and may occur in either lobe (Figure 12.75). Patients with multiple lesions may frequently have extrahepatic (cutaneous or visceral) involvement (44). Superficially located tumors often show central umbilication. Tumors are well demarcated, red-brown to tan, and soft and spongy. Larger lesions show central infarction, hemorrhage, fibrosis, and dystrophic calcification. Intraoperative ligation of feeder vessel(s) may result in infarction of the entire tumor.

75A

75B

FIGURE 12.75  Infantile hemangioendothelioma. Grossly, the tumors vary from single well-circumscribed lesions (A) to this extreme example showing widespread hepatic involvement (B).

76A

76C

FIGURE 12.76  Infantile hemangioendothelioma. Histologically, there are anastomosing vascular channels of varying caliber lined by a single layer of plump endothelial cells (A and B). GLUT-1 positive lesions (C) have a favorable outcome.

76B

LIVER AND BILIARY TRACT 

299

TABLE 12.4  Salient Features Differentiating Infantile Hemangioendothelioma From Other Tumors FEATURES

INFANTILE HEMANGIOENDOTHELIOMA

MESENCHYMAL HAMARTOMA

HEPATOBLASTOMA

EPITHELIOID HEMANGIOENDOTHELIOMA

Age

Infancy

Less than 5 y

Less than 5 y

Adults

Cysts

Rare

111

1

Rare

Hemorrhagic necrosis

11

Uncommon

11

1/2

Vascular spaces

111

1

1

Uncommon

Myxoid stroma

1

111

1

11

Abbreviations: EHE, epithelioid hemangioendothelioma; HB, hepatoblastoma; IHE, infantile hemangioendothelioma; MH, mesenchymal hamartoma.

Histologically, IHEs have traditionally been classified as type 1 or type 2. The type 1 lesion is composed of anastomosing vascular channels lined by a single continuous layer of plump endothelial cells in a supporting fibrous stroma (Figure 12.76). The lining cells stain with endothelial markers (CD31, CD34, factor VIII–related antigen, von Willebrand factor, and Ulex europaeus). Larger vascular channels resembling a cavernous hemangioma may be seen. Foci of EMH are common. The type 2 lesion shows pleomorphic and atypical lining cells with tufting and branching of vascular spaces, and is now grouped together with well-differentiated angiosarcomas. The differential diagnosis includes mesenchymal hamartoma, hepatoblastoma, and epithelioid hemangioendothelioma (Table 4). Recently, GLUT-1 immunohistochemistry has shown two clinicopathologic groups in IHE (45). Patients with GLUT-1 positive lesions tend to be asymptomatic. The lesions, detected incidentally in early infancy, are composed of multiple small nodules of closely packed capillary vessels. These tumors undergo spontaneous involution over months or years and are usually unresponsive to corticosteroids or interferon treatment. GLUT-1 negative lesions may represent a hepatic vascular malformation with capillary proliferation, and are usually symptomatic at birth or in the first few weeks of life with severe edema and congestive heart failure. The lesion is usually a single mass with malformed irregular vessels commonly associated with infarction, hemorrhage, calcification, and peripheral reactive capillary proliferation, requiring surgical resection.

Hepatoblastoma Hepatoblastoma is the most common malignant pediatric liver tumor, mostly occurring in the first two years of life. They are usually single masses, although 20% of patients have multiple masses (Figure 12.77). The right lobe is more frequently involved than the left lobe. On gross evaluation, they are bulging and lobulated. Cut surface has variable color and consistency depending on the proportion of epithelial and mesenchymal components, hemorrhage, and necrosis (Figure 12.78).

FIGURE 12.77  Hepatoblastoma. CT scan shows a 9.6-cm ill-defined, heterogeneous mass in the right lobe, with multiple areas of hypodensity, consistent with necrosis.

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Liver, Biliary Tract, and Pancreas

78A 78B

FIGURE 12.78  Hepatoblastoma. Grossly, the tumors are lobulated with variegated cut surface, cystic degeneration, and necrosis (A–C).

78C

Histologically, hepatoblastomas are classified as epithelial or mixed epithelial-mesenchymal (46). Epithelial hepatoblastomas are further subclassified as pure fetal, embryonal, macrotrabecular, and small cell variants. Classically, on low-power examination, there are alternating light and dark zones (Figure 12.79) The pure fetal pattern is characterized by thin trabeculae (2- to 3-cell thick) of small, round, uniform cells with abundant cytoplasm and distinct cytoplasmic membranes (Figure 12.80). The pure fetal subtype carries the best prognosis among hepatoblastomas. Tumors with the embryonal pattern consist of areas with fetal pattern and other areas with sheets of irregular, angulated cells with a high nuclear–cytoplasmic ratio and indistinct cytoplasmic membranes (Figure 12.81). Pseudorosettes and acinar formation are common features, as are foci of extramedullary hematopoiesis in patients not treated with preoperative chemotherapy. The macrotrabecular type refers to a growth pattern and has trabeculae more than 10 cells in thickness, as a repetitive pattern within the tumor (Figure 12.82). These large trabeculae may be comprised of fetal or embryonal type

FIGURE 12.79  Hepatoblastoma. Hepatoblastomas characteristically show an alternating light and dark zonation on low-power examination.

LIVER AND BILIARY TRACT 

80A

80B

FIGURE 12.80  Hepatoblastomas with pure fetal pattern are characterized by thin trabeculae (2- to 3-cell thick) of small, round, uniform cells with abundant cytoplasm and distinct cytoplasmic membranes (A, B). Pseudorosettes and EMH are evident. Tumor cells stain positive for AFP (C).

80C

cells, and/or a third larger (hepatocyte-like) cell type with cytoplasm that is more abundant than in normal hepatocytes. Tumors where the third (hepatocyte-like) cell type predominates may be very difficult to distinguish from hepatocellular carcinoma (HCC). The small cell undifferentiated or anaplastic pattern (Figure 12.83) resembles other small round cell tumors such as neuroblastoma, with scanty cytoplasm and hyperchromatic nuclei, and has a worse prognosis than other types. The cells do not produce glycogen, fat droplets, or bile pigment, although abortive or incompletely formed bile ductules may be present. Immunostains are required to differentiate the small cell ­u ndifferentiated hepatoblastoma from other round cell tumors such as lymphoma, large cell medulloblastoma, large cell neuroblastoma, and Ewing’s sarcoma family tumors, although some hepatoblastomas may be positive for CD99 (47). Hepatoblastomas show cytoplasmic positivity for pancytokeratin. Vascular invasion may be present (Figure 12.84).

FIGURE 12.81  Hepatoblastoma. Tumors with the embryonal pattern show sheets of irregular, angulated cells with a high nuclear–cytoplasmic ratio and indistinct cytoplasmic membranes.

FIGURE 12.82  Hepatoblastoma. The macrotrabecular variant has broad trabeculae that are composed of fetal, embryonal and/or hepatocyte-like cells.

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FIGURE 12.83  Hepatoblastoma. The anaplastic pattern resembles other pediatric malignant, small round cell tumors.

FIGURE 12.84  Hepatoblastoma. Vascular invasion may be seen with all histologic types.

The mixed epithelial and mesenchymal hepatoblastoma contains epithelial cells admixed with primitive mesenchyme/mesenchymally derived tissues (Figure 12.85). The highly cellular primitive mesenchyme consists of elongated, spindle-shaped cells with scanty cytoplasm, and elongated plump nuclei with rounded ends, resembling fibroblastoid/myofibroblastoid tissue. More mature elements such as fibroblastic tissue, collagen fibers, osteoid, and chondroid may be seen. Osteoid stromal component is reportedly more prominent following chemotherapy (Figure 12.87) (48). The prognostic significance of

85A

85B

FIGURE 12.85  Mixed-type hepatoblastomas show epithelial and mesenchymal elements (A and B).

FIGURE 12.86  Teratoid hepatoblastomas show multilineage differentiation—shown here is a tumor with a keratinizing squamous component.

FIGURE 12.87  Hepatoblastoma. Mesenchymal components such as osteoid may persist after chemotherapy.

LIVER AND BILIARY TRACT 

these stromal elements is unclear. Approximately 20% of the mixed types are “teratoid hepatoblastomas” (­Figure 12.86) that contain stratified squamous epithelium, melanin pigment, mucinous epithelium, bone, cartilage, and striated muscle. In view of the histologic heterogeneity of hepatoblastomas, anecdotal tumors with unique morphologies have been reported as “new” variants (such as mucoid anaplastic hepatoblastoma, hepatoblastomas with endocrine/neuroendocrine differentiation, cholangiocytic/ cholangioblastic hepatoblastoma, hamartoma-like hepatoblastoma/hepatoblastoma with organoid configuration) (47). The biologic significance, if any, of these morphologic variants is not known.

Hepatocellular Carcinoma Although more common in adults, hepatocellular carcinoma (HCC) accounts for up to 20% of all pediatric liver neoplasms (49, 50), with most cases occurring in children more than 10 years of age. There is an increased incidence in hepatitis B virus (HBV) endemic populations and 60% of cases occur in cirrhotic livers. Grossly, HCC may be single or multicentric masses, with involvement of both the right and left lobes in more than 70% of cases. Like hepatoblastomas, the cut surface is tan to red and soft to firm, with areas of hemorrhage and necrosis. The fibrolamellar variant is more often a single mass that is firm and gray; the adjacent liver is usually not cirrhotic, but may harbor an FNH. Serum AFP levels are high in the usual HCC, but are normal in fibrolamellar HCC (FL-HCC). Histologically, the usual HCC has a trabecular architecture, varying up to 10 cells in thickness (Figures 12.88 and 12.89). The tumor lacks bile ducts, although intracellular bile is seen at least focally. Central necrosis in larger trabeculae may impart an acinar or pseudoglandular architecture. The cells

FIGURE 12.88  Hepatocellular carcinoma with trabecular and acinar architecture, and bile production.

89A

89B

FIGURE 12.89  Hepatocellular carcinoma. This example shows numerous Mallory body-like eosinophilic globules (A). The adjacent liver is cirrhotic (B).

303

304 

90A

Liver, Biliary Tract, and Pancreas

90B

FIGURE 12.90  Hepatocellular carcinoma. The fibrolamellar variant shows large eosinophilic cells with intervening lamellar collagen (A and B).

show high nuclear–cytoplasmic ratios, multinucleation (“epithelial syncytial giant cells”), nuclear hyperchromasia, multiple nucleoli, and frequent mitoses. Vascular invasion may be prominent, and metastases to lung and lymph nodes may occur. Immunostains are helpful in needle biopsy material and the tumors are classically positive for HepPar-1, AFP, and glypican-3. There is “arterialization” of sinusoids in that the lining endothelial cells stain positive for CD34, unlike in the nonneoplastic liver. Hepatocellular carcinomas of higher histologic grade have been reported to have loss of E-cadherin, nonnuclear overexpression of beta-catenin, and overexpression of osteopontin, with overexpression of osteopontin independently correlating with vascular invasion (51). Pediatric HCCs have been reported to be CK7-positive (52). Epidermal growth factor receptor (EGFR) overexpression is also reported in most HCCs; however, the increased expression does not correlate with an increase in the EGFR gene copy number (53). The fibrolamellar variant accounts for 13%–22% of HCC in younger patients. This variant is characterized by large, deeply eosinophilic (oncocytic) hepatocytes embedded within lamellar fibrosis (Figure 12.90). Individual cells often contain discrete, pale eosinophilic bodies. Occasional FL-HCCs show glandular-type differentiation and mucin production (54). Immunohistochemically, FL-HCC may stain positive for fibrinogen, C-reactive protein, ferritin, and A1AT. AFP staining is present in 21% of FL-HCC, and hepatitis B surface antigen (HBsAg) staining is absent. In younger children, the major differential diagnosis of HCC is the macrotrabecular variant of hepatoblastoma. Unlike in HCC, hepatoblastoma is rarely multiple and vascular invasion is uncommon even in advanced stage tumors (55). Immunostains are not helpful in differentiation. Prokurat et al. (56) have described a novel group of hepatocellular neoplasias in older children and adolescents, with an intermediate histology between HCC and HB, and a distinctive beta-catenin pattern, that they term “transitional liver cell tumors” (56).

LIVER AND BILIARY TRACT 

Undifferentiated Embryonal Sarcoma Undifferentiated embryonal sarcoma (UES) are large tumors (10–35 cm), involving the right lobe more frequently than the left lobe (57–59). The tumor is well demarcated from the adjacent liver by a compressed incomplete fibrous pseudocapsule. The cut section is predominantly solid with myxoid gelatinous areas, hemorrhage, and necrosis (Figure 12.91). Areas of cystic degeneration may be present. Calcification is rare to absent in the absence of prior therapy, and the uninvolved liver is normal in appearance. Histologically, the viable areas of the tumors are predominantly composed of myxomatous stroma with loose to dense masses of stellate, spindle-shaped, or polygonal cells (Figure 12.92). Larger epithelioid and multinucleated cells with hyperchromatic nuclei and eosinophilic cytoplasmic globules are seen in variable numbers (Figure 12.93). The globules are PAS-positive diastase resistant and may also be seen extracellularly. Numerous mitotic figures, including atypical and bizarre forms, are present. Some densely cellular areas have small round cells with hyperchromatic nuclei without nucleoli. Extramedullary hematopoiesis may be present. In a few tumors, there are foci of direct invasion into hepatic sinusoids. There may be sarcomatous appearing foci, mimicking osteosarcoma, leiomyosarcoma, liposarcoma, and malignant fibrous histiocytoma. Immunostains also show evidence of widely divergent mesenchymal and epithelial phenotypes and are not routinely helpful. However, the tumors are usually negative for myoglobin, myogenin, muscle specific actin, h-caldesmon, S-100, anaplastic lymphoma kinase 1 (ALK-1), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), Factor-VIII, and AFP (57, 58). Ultrastructurally, the

FIGURE 12.91  Undifferentiated embryonal sarcoma. This specimen of UES shows a relatively circumscribed complex solid and cystic mass.

FIGURE 12.92  Undifferentiated embryonal sarcoma. The tumor is comprised of anaplastic and bizarre cells within a myxoid, edematous and necrotic stroma.

93A

93B

FIGURE 12.93  Undifferentiated embryonal sarcoma. Classically, tumor cells show cytoplasmic eosinophilic globules (A) that are PAS-positive and diastase resistant (B).

305

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Liver, Biliary Tract, and Pancreas

FIGURE 12.94  Undifferentiated embryonal sarcoma. Entrapped bile ducts may also show significant epithelial atypia.

hallmark features are dilated rough endoplasmic reticulum (RER) and secondary lysosomes with dense precipitates, which correlate with the eosinophilic globules seen on light microscopy. Dilated mitochondria and mitochondrial-RER complexes are often seen (4). The periphery of the tumor may contain entrapped hepatocytes and bile ducts. The bile ducts may extend some way (up 1 cm) into the lesion and show hyperplastic, reactive or degenerative epithelial changes that may even appear anaplastic (Figure 12.94). Following chemotherapy, resected pathologic specimens show central necrosis, fibrosis, and dystrophic calcification. Histologic dedifferentiation has been described following multiple recurrences, with greater cellularity, anaplasia, and pluripotential differentiation (60).

Nested Stromal Epithelial Tumor of the Liver Nested stromal epithelial tumor is a recently described primary pediatric hepatic neoplasm, with less than 30 cases described in the literature. Synonyms include “ossifying stromal-epithelial tumor,” “calcifying nested stromal-epithelial tumor,” and “desmoplastic nested spindle-cell tumor” (61, 62). The tumors are well-circumscribed but not encapsulated and range in size from 4–30 cm. On cut surface, they are multinodular, with a homogeneous, tan, granular-appearing cut surface. Variably sized foci of softening, cyst formation, calcification, or gritty ossification may be observed. Histologically, they are nonhepatocytic, nonbiliary tumors with an organoid arrangement of cellular nests comprised of spindled and/or epithelioid cells surrounded by a variably prominent collar of delicate myofibroblasts (Figure 12.95). There is variable calcification and ossification. The cellular nests have rounded edges and are relatively uniform in size in a given case. The stroma between the nests is usually desmoplastic. The periphery of the tumor shows a bile duct component, probably entrapped in nature. Some cases are associated with Cushing syndrome and these tumors may show a focal neuroendocrine-appearing architecture and adrenocorticotrophic hormone (ACTH) staining. The nests are composed predominantly of plump to fusiform spindled cells with centrally placed or scattered epithelioid cells (Figure 12.95C). Both spindle and epithelioid cells have bland oval nuclei with welldefined nuclear membrane, stippled chromatin, and variably conspicuous nucleoli. The cytoplasm is predominantly eosinophilic, with focal cells containing clear cytoplasm; epithelioid cells have distinct cellular borders. Mitoses are rare to scattered. Immunohistochemically, the tumor cells coexpress vimentin and cytokeratins, at least focally (Figure 12.96A). They also exhibit moderate to strong diffuse nuclear staining for WT-1 (Figure 12.96B). There is variable staining for EMA, CD56, CD57, S-100, and other mesenchymal markers. Synaptophysin and chromogranin stains are reportedly negative in all cases. ACTH immunohistochemistry may be positive in tumors associated with Cushing syndrome (63). The desmoplastic stroma has been reported to prominently display collagen type IV and smooth muscle actin.

LIVER AND BILIARY TRACT 

95A

95B

FIGURE 12.95  Nested stromal epithelial tumor. This liver biopsy shows rounded tumor cell nests (A) interspersed within a desmoplastic stroma (B). There are entrapped bile ducts (A). The cells in the nests are ovoid to rounded (C).

95C

96A

96B

FIGURE 12.96  Nested stromal epithelial tumor. Cytokeratin immunostain highlights bile ducts and epithelial tumor cell nests (A). The cells in the nests show nuclear WT-1 staining (B).

307

308 

Liver, Biliary Tract, and Pancreas

Embryonal Rhabdomyosarcoma of the Biliary Tract Rhabdomyosarcoma is the most common malignant tumor of the biliary tree in childhood and usually occurs in patients less than 5 years of age (64). Patients present with obstructive jaundice, fever, abdominal distension, nausea, and vomiting. Imaging studies and cholangiography may clearly demonstrate the site of obstruction, usually in extrahepatic ducts. Because of its rarity, it may be misdiagnosed as a choledochal cyst (65). Grossly, as in other mucosal sites, the tumor appears as an occlusive botryoid, gelatinous mass (Figure 12.97A). The ducts proximal to the lesion are frequently dilated, and the walls of the duct containing the lesion are thickened. The tumor may extend into the liver as a soft lobulated mass. Microscopically, the overlying biliary epithelium may be intact or ulcerated, with a cambium layer of tumor cells beneath (­Figure 12.97B). The tumor cells in the cambium layer are small and hyperchromatic, with scant cytoplasm (Figure 12.98). The deeper stroma has more typical features of

FIGURE 12.97  Rhabdomyosarcoma. This resection specimen shows a fleshy mass (A) filling and extending along bile ducts (B).

97A

97B

FIGURE 12.98  Rhabdomyosarcoma. Higher power examination shows a subepithelial infiltrating tumor, with a cambium layer (A), and comprised of rhabdomyoblasts (B).

98A

98B

PANCREAS 

embryonal rhabdomyosarcoma with round, spindle, or straplike shapes; elongate nuclei; scant acidophile cytoplasm; and frequent mitoses lying in a loose myxoid stroma. The cells are positive for muscle markers on immunostain. Occasionally, in biopsy material, UES may mimic a biliary ­rhabdomyosarcoma, and immunostains may be required for differentiation. Although polyclonal desmin and muscle-specific actin are variably immunoreactive in both tumors, myogenin, and myogenic regulatory protein D1 (MyoD1) are mostly negative in UES, but positive in rhabdomyosarcoma. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UES, whereas initial chemotherapy is often recommended for the treatment of biliary tract rhabdomyosarcoma.

PANCREAS n Embryology The pancreas develops from dorsal and ventral anlagen that arise from the endodermal lining of the duodenum (66). The dorsal anlage arises directly from the dorsal side of the duodenum, whereas the ventral anlage is located close to the bile duct. In the 6th week of gestation, the ventral pancreas rotates counterclockwise around the duodenum and fuses with the dorsal ­pancreas. Failure of complete fusion results in “pancreas divisum” and a failure to rotate completely results in annular pancreas. The latter abnormality can lead to duodenal obstruction. The ventral anlage gives rise to the uncinate process and part of the pancreatic head, whereas the larger dorsal anlage predominantly forms the pancreatic tail. The fusion of the two ductal systems is a complicated process. The main pancreatic duct (of Wirsung) is derived from the duct of the ventral anlage and the distal portion of the duct of the dorsal anlage. The proximal portion of the dorsal duct may disappear or persist as the accessory pancreatic duct or the duct of Santorini. The pancreatic head is relatively more prominent than the body and tail in children. Heterotopic pancreatic tissue is found in and around the stomach, duodenum, and jejunum, most commonly located submucosally. These ectopic rests may clinically manifest with pancreatitis, intussusception, bowel obstruction or rarely, as a malignancy. The complex process of pancreas morphogenesis might explain the occurrence of several anatomic variants and developmental abnormalities of the pancreas and its ducts. Congenital and pediatric disorders of the pancreas include the following (67): n

n

n

n n

developmental anomalies—for example, agenesis, hypoplasia (absent dorsal part), annular pancreas, pancreas divisum, heterotopia, congenital pancreatic cysts exocrine insufficiency—cystic fibrosis, Shwachman-Diamond syndrome, isolated enzyme deficiency endocrine dysfunction—congenital hyperinsulinism and islet cell adenomatosis, neonatal diabetes mellitus, polyendocrinopathy hereditary pancreatitis miscellaneous—Jeune syndrome, autosomal recessive polycystic kidney disease, Beckwith-Wiedemann syndrome, renal-hepatic-pancreatic dysplasia, lipoprotein lipase deficiency, apolipoprotein C-II deficiency, familial hypertriglyceridemia, glycogen storage disease

n Histology The pancreas is composed of acini arranged in lobules that drain into ducts (Figure 12.99). Interspersed within the substance of the pancreas are the islets of Langerhans (Figure 12.100). Islets contain at least five different endocrine cell types, each of which is characterized by its own typical secretory granule morphology, different peptide hormone content, and specific endocrine, paracrine, and neuronal interactions. The a and b cells were first described by Lane based on their histochemical staining characteristics and respectively secrete glucagon and insulin. The D cells, first recognized by Bloom, secrete somatostatin, the PP cells secrete pancreatic polypeptide and the epsilon cells secrete ghrelin.

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FIGURE 12.99  Developing pancreas. Developing pancreas at 18 weeks gestation.

FIGURE 12.100  Normal pancreas. Section of pancreas showing normal histology.

n BENIGN LESIONS Pancreatic Cysts Congenital pancreatic cysts are usually serous cysts and may be seen in von Hippel-Lindau disease and autosomal dominant polycystic kidney disease (66). Cysts may also be seen in cystic fibrosis.

Cystic Fibrosis Cystic fibrosis (CF), the most common life-threatening recessive genetic trait in Caucasians, causes exocrine pancreatic insufficiency (68). CF is caused by mutations in the CFTR gene encoding an epithelial chloride channel that is important in regulating electrolyte transport in absorptive and secretory epithelia. The pancreatic ductal system is obstructed by inspissated secretions, with resultant progressive chronic inflammation, fibrosis, glandular atrophy, acinar ectasia, diffuse calcifications, and cystic duct ectasia (Figure 12.101). Secretory material obstructing pancreatic ducts is an early pathologic finding that can be found even in preterm infants. Exocrine pancreatic atrophy without fibrosis may be seen in Shwachman-Diamond syndrome and Johanson-Blizzard syndrome.

101B

FIGURE 12.101  Cystic fibrosis. Cross section of pancreas from a patient with CF shows a scarred parenchyma (A). Histologically, there is loss of acinar mass, fatty involution, fibrosis, and cystic dilatation of the pancreatic duct with inspissated secretions (B). 101a

PANCREAS 

FIGURE 12.102  Cystic fibrosis. The liver may have multiple capsular depressed scars, with a resemblance to hepar lobatum.

FIGURE 12.103  Cystic fibrosis. Secondary biliary cirrhosis in CF.

Patients with CF have secondary hepatic involvement with progressive changes resembling those of extrahepatic biliary obstruction progressing to secondary biliary cirrhosis (­Figure 12.102). Although pulmonary complications are the predominant clinical manifestation, up to 5% of patients with CF may have substantial hepatic dysfunction, and an even larger proportion have the typical histologic lesions of CF in the liver without abnormal liver function tests (69, 70). In fact, the incidence of symptomatic liver disease has increased over the past several decades with the increasing life expectancy of patients with CF. The pathognomonic lesion in early stages is termed focal biliary cirrhosis. This is characterized by focal irregular areas of fibrosis with bile duct proliferation and intraluminal inspissated eosinophilic or pale orange secretions. The basis for progression from neonatal cholestasis to focal biliary cirrhosis is not clear. Steatosis may be present, especially in infants with newly diagnosed CF who have not yet been treated with pancreatic enzyme replacement. In due course, secondary biliary cirrhosis supervenes without treatment (Figure 12.103). Although the ­prevalence of cirrhosis increases through childhood, there is a diminished prevalence of cirrhosis in those surviving to young adulthood, suggesting that liver disease may influence premature respiratory death in ­teenagers. The gallbladder is often small, with epithelial mucinous metaplasia. Diagnostic imaging may show a diminutive or nonfunctioning gallbladder. Cholesterol gallstones are seen with increasing frequency as patients survive into adulthood. The duodenal mucosa also shows inspissated secretions and Brunner gland hyperplasia (Figure 12.104).

104a

104B

FIGURE 12.104  Cystic fibrosis. Duodenal mucosa showing inspissated secretions (A) and Brunner gland hyperplasia (B).

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105A

105B

FIGURE 12.105  Nesidioblastosis. In these examples of nesidioblastosis, there is irregular hyperplasia of islets (A), and islets are abnormally located in septae adjacent to pancreatic ducts (B).

Nesidioblastosis Nesidioblastosis refers to hyperplasia or hypertrophy of the islets (71). These changes can be diffuse or focal. Nesidioblastosis usually affects beta cells characteristically resulting in transient neonatal hyperinsulinism (lasting days to weeks). However, alpha cell hyperplasia has also been described (72). Islet cell hyperplasia may be a consequence of chronic fetal exposure to maternal hyperglycemia, and is associated with Beckwith-Wiedemann syndrome. Congenital nesidioblastosis or familial hyperinsulinemia is described in association with mutations in genes encoding pancreatic cell potassium channels. Congenital hyperplasia of other endocrine cells or deregulation of their hormone output is rare. Histopathologic findings in nesidioblastosis include nuclear pleomorphism, hypertrophic islets, ductuloinsular complexes, and neoformation of islets from ducts (Figure 12.105).

n Tumors Pancreatic Endocrine Tumor Endocrine tumors of the pancreas are rare in children (73) and should alert the pathologist to the possibility of syndromic associations such as multiple endocrine neoplasia, von Hippel-Lindau syndrome, and neurofibromatosis. Morphologically, they resemble endocrine tumors at other sites. The tumors may be unifocal or multifocal (Figure 12.106); in the latter setting there is associated islet cell hyperplasia or “adenomatosis” (similar to nesidioblastosis).

Pancreatoblastoma Pancreatoblastoma is the most common pancreatic malignancy of childhood and represents 0.5% of epithelial tumors of the pancreas. The average age of affected children is 2.4 years, with a greater incidence in Asians (74). There is no gender predilection. The typical presentation is a large, palpable abdominal mass, which, along with the high AFP levels commonly seen, may raise a clinical possibility of hepatoblastoma. There is a known association with Beckwith-Wiedemann ­syndrome. Grossly, the tumor is usually solitary and multilobate and may involve any region of the pancreas. The tumor is often locally invasive and tends to recur locally, prior to developing metastases. Sites of metastases are regional lymph nodes, liver, and lung. Histologically, there are multiple lines of differentiation including acinar, endocrine, and ductal, highlighted both architecturally and on immunostains (Figure 12.107). A characteristic and pathognomonic feature is the presence of squamous morules. It is therefore thought to be an “embryonal tumor” arising from a pluripotent pancreatic stem cell during foregut development.

PANCREAS 

106B

106a

FIGURE 12.106  Pancreatic endocrine tumor. This pancreas from a 9-year-old child shows an endocrine tumor arising in an islet (compare the size of the tumor to the islets in the background) (A). The tumor shows trabecular and acinar architecture (B). There was multifocal disease, with infiltrating tumor at other foci (C).

107a

106C

107B

FIGURE 12.107  Pancreatic endocrine tumor. This tumor shows a lobular architecture, with intervening fibrous septae (A). The tumor cells are relatively uniform with distinct cell borders, pale cytoplasm, central nuclei, and prominent nucleoli (B). Squamous morules are evident (C). There is perineural invasion (D). (Continued)

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107C

107D

FIGURE 12.107  Pancreatic endocrine tumor. (Continued)

Solid Pseudopapillary Neoplasm Solid pseudopapillary neoplasm (also called solid-cystic-papillary tumor, papillary epithelial neoplasm, solid and papillary epithelial neoplasm, solid and cystic acinar cell tumor, papillary cystic epithelial neoplasm, papillary cystic carcinoma, low-grade papillary neoplasm, and Frantz tumor) was first described by Frantz in 1959 (75). There is a strong predilection for young adult women of Asian and African descent. Approximately 20% of reported cases occur in children (adolescence). The tumor presents as a palpable abdominal mass with abdominal pain; jaundice is unusual. Typical imaging findings are of a large, well-defined lesion with variable solid and cystic components. Calcification is noted in 30% of cases (76). Grossly, they are usually large (mean size about 10 cm), solitary, well circumscribed, and at least partially encapsulated, with central cavitation. The proportion of the cystic component can vary from none to predominant. Histologically (Figure 12.108) the solid areas show sheets of monomorphic polygonal cells with intervening delicate capillaries (77, 78). Nuclei may appear polarized away from the capillaries. Nuclei are oval to uniform and frequently show longitudinal grooves. The cytoplasm may contain diastase resistant, PAS-positive hyaline globules. The cystic foci are formed by tumor degeneration and not true necrosis. This degeneration starts off with discohesion of tumor cells, initially giving these areas a pseudopapillary appearance. The tumor may show microscopic infiltration into surrounding pancreatic acini without eliciting a desmoplastic response. Immunohistochemically, tumors are positive for vimentin, CD10, CD56, progesterone receptor, and A1AT.

FIGURE 12.108  Solid pseudopapillary neoplasm with sheets of uniform epithelial cells and interspersed delicate vascularity. Nuclei may be polarized away from the capillaries (A). Degenerative changes render a pseudopapillary appearance (B). CD56 is strongly positive (C). (Continued)

108a

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108B

108C

FIGURE 12.108  Solid pseudopapillary neoplasm. (Continued)

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John Hicks

n

THYROID GLAND Thyroid Cancer in Children

n

PARATHYROID GLANDS

n

ADRENAL GLAND Neuroblastic Family of Tumors Pheochromocytoma and Extra-Adrenal Paraganglioma Adrenal Cortical Neoplasms

Carney Complex Adrenal Cytomegaly Congenital Vascular Neoplasms Mimicking Primary Adrenal Tumors

Thyroid Gland The thyroid gland arises from the median thyroid anlage diverticulum located between the anterior and posterior tongue muscle regions during early gestation (1–3). This anlage is caudally displaced in the neck and fuses with the lateral thyroid anlage (fourth and fifth branchial pouches) to create the thyroid gland. The median thyroid anlage elongates ahead of the thyroid gland to allow for descent into the neck, and forms the thyroglossal duct. Through the thyroglossal duct, the thyroid gland descends anterior to the eventual location of the hyoid bone and into the midline of the lower neck. The thyroglossal duct becomes obliterated by the 5th week of gestation, but leaves behind the foramen cecum at the base of the tongue as a proximal remnant. Persistence of the thyroglossal duct occurs if it fails to become obliterated before the mesodermal anlage of the hyoid bone is formed. This may result in a thyroglossal duct cyst in the affected child (Figure 13.1). The thyroglossal duct cyst is one of the most common congenital neck masses and is the most common midline cervical lesion occurring in children (Figure 13.1) (1–3). The thyroglossal duct remnants can occur anywhere from the base of the tongue to the lower neck midline region. It is usually closely associated with the hyoid bone. This structure can contain functional thyroid gland tissue. Most often, the child has a painless cystic midline cervical mass, which presents during the first 5 years of life. Because of possible communication with the oral cavity through the foramen cecum, thyroglossal duct cysts may become infected and there may be periodic oral drainage with halitosis. Cutaneous draining sinuses may also occur in the midline of the neck through a fistulous or sinus tract. Excision of the thyroglossal duct cyst includes the hyoid bone. The cyst-like structure may be lined by epithelium or granulation tissue, and thyroid gland or epithelial remnants in the surrounding fibroconnective tissues (Figure 13.1). In 1.5% of children with thyroglossal duct cysts, a solid midline ectopic thyroid gland is present within the substance of the thyroglossal duct cyst. Some may have ectopic lingual thyroid tissue located in close proximity to the foramen cecum in the posterior dorsum of the tongue. Careful evaluation for a functional thyroid gland in its expected location is important prior to surgical excision of the thyroglossal duct cyst. There are reports of thyroid cancer arising within the thyroglossal duct cyst (4). The most common type is papillary thyroid carcinoma, but other thyroid carcinomas may occur, including medullary carcinoma. Cancer development occurs in about 1% of cases with most affected individuals being adults; however, thyroid cancer has been reported in children as young as 6 years of age. The differential diagnosis for a midline mass in a child includes thyroglossal duct cyst, dermoid cyst, plunging ranula, midline cervical cleft cyst, and abscess.

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1A

1B

1C

1D

FIGURE 13.1  Thyroglossal duct cyst. Gross appearance of bisected thyroglossal duct cyst with attached hyoid bone (top) and cystic structure (bottom) (A). Thyroid follicle rests in soft tissue in close proximity to cortex of hyoid bone (B). Thyroid follicle rests in soft tissue of thyroglossal duct cyst (C). Mucocele-like area closely associated with residual epithelial rests (D).

Congenital hypothyroidism is the most common congenital endocrine disorder and affects 1 in 3,000 to 4,000 newborns (5–8). If undetected and not treated, this can lead to severe neuro­developmental impairment. This condition can be classified as permanent (1:3,000) or transient (1:2,250–1:25,000). Transient hypothyroidism may be attributed to maternal iodine deficiency, exposure to excess iodine around delivery due to iodinated compounds, maternally derived blocking antibodies or antithyroid drugs in women with autoimmune thyroid disease, protein-losing nephropathy, prematurity, or idiopathic. Permanent hypothyroidism occurs in up to 20% of congenital cases and is due to defects in thyroid hormonogenesis (dyshormonogenesis, Figure 13.2) because of mutations in several different genes (5–8). This condition usually occurs sporadically, but may be inherited in up to 2% of thyroid dysgenesis cases either in an autosomal dominant or recessive pattern. The major genes associated with thyroid development and initial differentiation from precursor cells are the thyroid transcription factors 1 and 2 (TTF1, 14q13; TTF2 [HuF2], 1p13.1) and PAX8 (paired box gene 8, 2q12–14). Mutations in these genes may lead to failure of thyroid gland formation (athyreosis) or failure of the thyroid gland to migrate (ectopy). Mutations in thyroid-­stimulating hormone receptor (TSHR; 14q31) lead to a defect in proliferation of thyroid gland precursor cells and results in orthotopic hypoplasia. Terminal differentiation is controlled by thyroglobin (8q24), thyroperoxidase (2p25), sodium-iodide symporter (19p13), GNAS 1 (20q13), Pendrin (7q31), DUOX2 (15q15), DUOXA2 (15q15), and DHAL1 (6q24). Mutations in these genes cause defects in iodine transportation and recycling, leading to dyshormonogenesis and goiter formation (Figure 13.2). The severity of disease may be quite variable from mild to severe, depending on the specific gene mutation and the inheritance pattern.

THYROID GLAND 

2A

2B

2C

2D

FIGURE 13.2  Dyshormonogenetic goiterous thyroid. Gross appearance of markedly enlarged, nodular thyroid from child (A). Adenomatous nodules with relatively well-defined membranous capsules (B). Follicular adenomatous appearance of gross nodules without cytologic atypia (C). Atypical, hyperchromatic follicular cells in area of a disorganized adenomatous nodule (D).

Chronic lymphocytic thyroiditis (Hashimoto disease, Figure 13.3) occurs as an autoimmune disease, most commonly in females, and causes diffuse thyroid enlargement (3, 9). Antithyroid microsomal or antithyroid peroxidase antibodies are detected in the vast majority of affected patients. Activated CD4 T-cells recruit cytotoxic CD8 T-cells, leading to cellular injury, and may slowly progress to hypothyroidism. In a small percentage of patients (10%), ­hyperthyroidism may occur. The thyroid gland is tender on palpation and has a granular to pebbly texture. About one third of children have spontaneous resolution with return to normal thyroid function and loss of antibodies. Thyroid hormone replacement is initiated for children that become hypothyroid. Graves disease or diffuse toxic goiter is responsible for hyperthyroidism in about 95% of children (Figure 13.4) (3, 9). This autoimmune disease occurs when antibodies to the plasma membranes of follicular cells develop (TSHR antibodies in 95%). This results in stimulation of the follicular cells to increase hormone production. The clinical symptoms are weight loss, heat intolerance, sweating, palpitations, emotional lability, nervousness, and intellectual decline. There is a female preponderance (5F:1M) with a peak in adolescence. Congenital-diffuse toxic goiter occurs in a small percentage of infants (1%) born to mothers with active Graves’ disease. The thyroid on physical examination is goiterous and is smooth, firm, and nontender. Treatment is directed toward decreasing hormone production. Those resistant to treatment may undergo ablation with radioiodine therapy (iodine 131 [131I]), or surgical resection. Subtotal thyroidectomy results in less frequent hypothyroidism than radioiodine therapy.

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3A

3B

3C

3D

FIGURE 13.3  Lymphocytic thyroiditis (Hashimoto thyroiditis). Lymphoid follicles with germinal centers and mantle layers with no cytologic atypia (A, B). Collections of lymphocytes and plasma cells with infiltration between and disruption of thyroid follicles (C, D).

n Thyroid Cancer in Children The prevalence of thyroid nodules in childhood is not well documented. It is estimated that the incidence is approximately 1.5% (3, 9–27). Postmortem and ultrasound studies have shown that 13% of young adults have thyroid nodules, and by the age of 50 years, up to 50% will have thyroid nodules. The risk for developing thyroid cancer in nodules is much higher in childhood than in adulthood. Malignancy is identified in only 5% to 10% of thyroid nodules in adults; whereas, cancer is present in 30% to 50% of thyroid nodules in children. Children are also more likely to present with disseminated disease at diagnosis than adults. Almost 80% of children with papillary thyroid carcinoma have cervical lymph node involvement, 20% will have extrathyroidal extension (ETE) and 5% will have pulmonary metastases. Although children present at a more advanced stage of disease than adults, children rarely die of disease, with a mortality of only 1% to 2% being most commonly reported. In children with distant metastases, it was found over a 10-year period that overall survival was 100%, with persistent stable disease in 30% to 45%. This is remarkably different from that reported in adults (70% mortality with pulmonary disease). Before puberty, thyroid nodules and cancer are less common; whereas there is an increased prevalence in postpubertal adolescents. The gender ratio is approximately equal below 15 years of age (1.5F:1.0M); but females predominant between 15 and 20 years of age (3F:1M). Overall, thyroid carcinoma represents 3% of all pediatric malignancies (3, 9, 19, 26, 27). About 10% of thyroid carcinomas occur in children. The peak incidence occurs in children from 10 to 18 years of age. Risk factors for thyroid cancer development include radiation therapy and treatment of a prior malignancy. The latency period for cancer development is 4 to 6 years. Thyroid cancer represents

THYROID GLAND 

4A

4B

4C

4D

FIGURE 13.4  Graves disease of thyroid. Gross appearance of thyroid with generalized expansion of right and left lobes and isthmus (A). Enlarged thyroid follicles lined by tall columnar epithelial cells and prominent scalloping of colloid and papillary hyperplasia (B, C, D).

almost 10% of second malignancies, with Hodgkin lymphoma being the most common primary malignancy in affected children. The differential for thyroid nodules in children is similar to that for adults (solitary nodule goiter, multinodular goiter, autoimmune thyroid disease [Hashimoto’s thyroiditis, Graves’ disease], adenoma) (3, 9, 19, 26, 27). With children, ultrasound is often used to assess thyroid lesions. Ultrasound features associated with malignancy include: (a) solitary solid lesion; (b) hypoechogenic; (c) subcapsular localization; (d) irregular margins; (e) invasive growth pattern with no compression of adjacent tissues; (f) heterogeneity; (g) microcalcifications (,2 mm); (h) multifocal lesions within clinically solitary nodule; (i) high intranodular blood flow; and (j) suspicious regional lymph nodes associated with a thyroid nodule (3, 9, 26). Thyroid tumors have been classified into thyroid carcinomas, thyroid adenomas, and other thyroid tumors (Table 13.1) (3, 9–27). The vast majority of tumors are sporadic nonmedullary carcinomas (97%) and not of a familial type (Table 13.2). The majority are papillary carcinomas (85%) with infrequent follicular carcinomas (10%) and medullary carcinomas (3.2%). Inherited or familial forms of thyroid cancer are relatively infrequent (5%), with the majority of thyroid cancers (95%) being sporadic occurrences (Table 13.2). There are also specific syndromes that are associated with both nonmedullary and medullary thyroid cancers. Within the papillary thyroid carcinoma category, there are many histopathologic types. The remaining discussion will be limited to papillary, follicular and medullary carcinomas, and follicular ­adenoma. With children, thyroid cancers tend to be well differentiated, with most being classic or follicular variants of papillary carcinoma (Figure 13.5) (3, 9–27). Papillary thyroid carcinoma has distinctive his-

323

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Table 13.1  Thyroid Tumors: World Health Organization Classification Thyroid carcinomas

Thyroid adenomas and related tumors

  Papillary

  Follicular adenomas

  Follicular

  Hyalinizing trabecular tumor

  Poorly differentiated

Other thyroid tumors

  Undifferentiated

  Teratoma

  Squamous cell

  Primary lymphoma

  Mucoepidermoid

  Plasmacytoma

  Sclerosing mucoepidermoid with ­eosinophils

  Ectopic thymoma

  Mucinous

  Angiosarcoma

  Medullary

  Smooth muscle tumors

  Spindle cell tumor with thymus-like ­differentiation

  Peripheral nerve sheath tumors

  Carcinoma with thymus-like ­differentiation

  Solitary fibrous tumor

  Paragangliomas   Follicular dendritic cell tumor   Langerhans cell histiocytosis   Secondary tumors

topathologic features with nuclear clearing, nuclear grooves, and cytoplasmic nuclear inclusions, as well as complex branching papillary architecture, and calcified psammoma bodies. This tumor may be multifocal, involving both lobes and the isthmus. When necessary, immunocytochemical staining for TTF1, high–molecular-weight cytokeratins (including CK19), thyroglobulin, galectin-3, HBME1, and RET are positive with the epithelial cells. ­Determination of ETE, lymph node involvement, and distant metastatic disease are primary determinants of prognosis and overall survival. Papillary thyroid carcinomas are shown to express RET oncogene by immunocytochemistry in about 80% of cases, and this correTable 13.2  Thyroid Carcinoma Types and Distribution Sporadic

Nonmedullary thyroid carcinomas Papillary

Familial

Total

93%

4%

97%

81%

4%

85%

  Classic (40%)   Follicular variant (30%)   Solid variant (10–35%)   Mixed variant (20–30%)   Cribriform-morular variant (rare) Follicular cell Hürthle cell

10% 0.4%

Very rare

10%

0.1%

0.5%



1.6%

Anaplastic



Gardner’s syndrome



0.1%



Werner’s syndrome



Very rare



Carney’s complex



Very rare



Cowden’s disease



Very rare



Peutz-Jeghers s­ yndrome



Very rare



Medullary thyroid ­carcinoma

2.7%

0.5%

3.2%

MEN2A



0.15%



MEN2B



0.1%



Isolated medullary ­carcinoma Combined ­papillary and medullary ­carcinoma

– 0.1%

0.25% –

– –

THYROID GLAND 

5A

5B

5C

5D

5E

5F

5G

FIGURE 13.5  Papillary carcinoma of thyroid. Gross appearance of thyroid gland with marked capsular surface irregularity and nodularity (A). Gritty firm replacement of typical red-brown thyroid gland by tumor on cross sectioning (B). Classic papillary architecture with malignant epithelial cells with optically clear and occasionally grooved nuclei and cellular crowding (C, D). Follicular variant of papillary carcinoma with malignant epithelial cells with optically clear and occasionally grooved nuclei and cellular crowding (E). Psammomatous calcifications associated with papillary thyroid carcinoma (F). Vascular invasion by tumor cells (G). Near total involvement of lymph node by papillary thyroid carcinoma (H). Metastatic tumor involving lymph node (I). (Continued)

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Thyroid, Parathyroid, and Adrenal Glands

5H

5I

Figure 13.5  Papillary carcinoma of thyroid. (Continued)

lates well with translocations with RET as a dominant partner in many of the translocations associated with this thyroid cancer (Table 13.3). Tyrosine kinase is also another partner in some translocations associated with about 10% of papillary thyroid cancers. For children with a history of radiation-associated papillary thyroid cancer, RET/PTC3 is the most common translocation. BRAF (b-type RAF kinase) mutations are also relatively common in this tumor, and are becoming a ­commonly requested genetic test by clinicians for children with thyroid cancer. BRAF mutations are associated with more aggressive tumor behavior. Metastatic disease is more common when papillary thyroid cancer has a solid pattern and is also seen with microcarcinomas (,1 cm) in children in contrast to adults. There are many different hereditary syndromes associated with thyroid carcinomas and these have specific gene mutations (Table 13.4) (3, 9, 13–18, 22, 26, 27). Most of these are associated with “­traditional” nonmedullary thyroid carcinomas. A pattern which is quite specific for adenomatous polypsis coli (APC) gene mutation associated with familial adenomatous polyposis (FAP) syndrome

Table 13.3  Molecular Pathology and Cytogenetics of Thyroid Adenomas and Carcinomas Follicular Adenomas

RAS (RAS-RAF-MEK-MAPK pathway) H-RAS K-RAS N-RAS Clonal cytogenetic aberrations (45%)   Trisomy 7 and other trisomies   t(2;19)(p21;q13)   Deletions of 3p, 10, 13, 19 Atypical Follicular Adenoma (tumor of uncertain malignant potential)

N-RAS codon 61 mutation PAX8/PPAR-gamma rearrangements Microfollicular Adenoma

RET/PTC rearrangements (continued)

THYROID GLAND 

Table 13.3  Molecular Pathology and Cytogenetics of Thyroid Adenomas and Carcinomas (Continued) Papillary Thyroid Carcinomas: Translocations

RET/PTC1-H4

inv(10)(q11.2;q21)

RET/PTC2-PRKAR1A

t(10;17)(q11.2;q23)

RET/PTC3-NCOA4

inv(10)(q11.2;q10)

RET/PTC4-NCOA4

inv(10)(q11.2:q10)

RET/PTC5-GOLGA5

t(10:14;)(q11.2;q32)

RET/PTC6-HTlF1

t(7;10)(q32–34;q11.2)

RET/PTC7-TIF1G

t(1;10)(p13;q11.2)

RET/PTC8-KTN1

t(10;14)(q11.2;q22.1)

RET/PTC9-RFG9

t(10;18)(q11.2;q21–22)

ELKS/RET

t(10;12)(q11.2;q13.3)

PCM1/RET

t(8;10)(p21–22;q11.2)

RFP/RET

t(6;10)(p21;q11.2)

HOOK3/RET

t(8;10)(p11.21;q11.2)

TRK/T1

TPR (1q25)

TRK/T2

TPR (1q25)

TRK/TPM3

TPM3 (1q22–23)

TRK/T3

TFG (3q11–12)

Follicular Carcinoma

PAX8/PPAR-gamma

t(2;3)

FTCF/PPAR-gamma

t(3;7)

X/PPAR-gamma

t(1;3)

Chromosomal imbalances

2, 3p, 6, 7q, 8, 9, 10q, 11, 13q, 17p, 22

Table 13.4  Hereditary Syndromes Associated With Thyroid Carcinoma (­Nonmedullary) Familial adenomatous polyposis syndrome

APC (5q21)

Gardner’s syndrome

APC (5q21)

Peutz-Jeghers syndrome

STK11 (19q13.3)

Cowden’s syndrome

PTEN (10q22–23)

Werner’s syndrome

WRN (8q11–21)

Carney’s complex

PRKAR1-a (17q23–24; 2p16)

McCune-Albright syndrome

GNAS1 (20q13.1–13.2)

Succinate dehydrogenase complex   Subunit B/subunit D

PGL4 (1p36) PGL1 (11q23)

Papillary renal neoplasia syndrome

PTCPRN (1q21)

Familial papillary thyroid carcinoma with clear cell renal carcinoma

t(3;8)(p14.2;q24.1)

Familial papillary thyroid carcinoma with or ­without oxyphilia

TCO (19q13.2)

Familial papillary thyroid carcinoma

NMTC1 (2q21)

Familial multinodular goiter with papillary ­thyroid carcinoma

MNG1 (14q21) MNG3 (Xp22)

Familial papillary thyroid carcinoma

PTC1 (10q11–12)

Familial follicular thyroid carcinoma

NMTC1 (2q21)

327

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Thyroid, Parathyroid, and Adrenal Glands

and ­Gardner syndrome is the cribriform-morular variant of papillary ­carcinoma (­Figure 13.6). Although this rare pattern of thyroid cancer can occur sporadically, the identification of this type of papillary cancer warrants genetic testing for associated syndromes. The tumor is characterized by squamoid morules and/or a cribriform architecture. The lumina of the cribriform regions lack colloid material. The tumors may have a mixed pattern with papillary, follicular, and trabecular areas. Psammoma bodies and geographic necrosis are usually not present. Translocations associated with typical papillary carcinoma have also been shown to be present (RET/PTC1, RET/PETC3). In addition, there is APC tumor suppressor gene inactivation, and CTNNB1 (beta-catenin) mutation. These are important components in the Wnt signaling pathway. Interestingly, BRAF mutations have not been identified. Follicular thyroid carcinoma is less common in children (3% to 20%) than in adults (5% to 10%) (3, 9, 11, 18, 26, 27). In the past, follicular carcinoma (25% to 40%) accounted for a higher proportion of thyroid cancers in endemic regions with iodine deficiency. Follicular thyroid cancer is comprised of microfollicles and macrofollicles of epithelial cells with crowding, irregular nuclear placement, and increased mitotic rates (Figure 13.7). The diagnosis of follicular carcinoma is linked to vascular invasion and capsular penetration. Capsular penetration is defined by tumor extending through the tumor capsule at a site not associated with a prior fine needle biopsy site. Vascular invasion is defined as involving a vessel within the tumor capsule or outside the tumor capsule. Documentation of vascular invasion

6B

6A

6D

6C

FIGURE 13.6  Cribriform-morular variant of papillary carcinoma of thyroid associated with APC gene mutations (familial adenomatous polyposis and gardner syndromes). Gross appearance of diffusely and markedly enlarged thyroid gland (A). Papillary architecture with occasional squamous morulae (B); Squamoid morulae lacking keratinization, luminal spaces and colloid (C, D).

THYROID GLAND 

7A

7B

7C

7D

FIGURE 13.7  Follicular carcinoma of thyroid. Gross appearance of thyroid with several nodules with ill-defined capsules and central hemorrhage (A). Lack of capsule between follicular carcinoma (left) and normal thyroid follicles (right) (B). Follicular carcinoma invasion displacing normal thyroid follicles (C). Extension of follicular carcinoma into adjacent perithyroidal soft tissues (D). Vascular invasion by follicular carcinoma (E). Varying appearance of follicular structures in follicular carcinoma with variable nucler pleomorphism, nuclear crowding, microfollicular formation, and variable colloid (F–H). Microscopic involvement of lymph node by follicular carcinoma (I). Total replacement of lymph node by follicular carcinoma (J). (Continued) 7E

may require immunocytochemistry for endothelial markers (CD34). Usually the tumor is a single solid nodule that tends to be encapsulated and more than 1 cm in diameter. Follicular carcinomas have been divided into minimally invasive and widely invasive tumors (14, 21). Minimally invasive follicular cancers have a gross appearance that is similar to follicular adenomas, except for possessing irregular, thickened capsules. These tumors demonstrate focal capsular and/or vascular invasion. This term has also been used for tumor with only focal vascular invasion. Another term that may be used for this tumor is grossly encapsulated angioinvasive follicular carcinoma, when only vascular invasion outside the capsule is present. Widely invasive follicular carcinoma is not difficult to identify with widespread infiltration of the adjacent thyroid tissue and vascular invasion. The difference is important because minimally invasive follicular carcinoma may warrant surgical excision

329

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Thyroid, Parathyroid, and Adrenal Glands

7F

7G

7H

7I

Figure 13.7  Follicular carcinoma of thyroid. (Continued)

7J

only. There are many different histopathologic subtypes of follicular carcinoma, such as oncocytic, tall cell, columnar, and clear cell. When necessary for diagnosis, immunocytochemistry shows thyroglobulin, TTF1, and low–molecular-weight cytokeratin reactivity. There may be only focal high–molecularweight cytokeratin staining, in contrast to papillary carcinoma. Nonrandom and recurrent molecular and cytogenetic abnormalities have been identified with follicular carcinomas (Table 13.3) (10–20, 22–25). The genetics of follicular thyroid cancer is not as well defined as papillary thyroid cancers. Follicular adenomas are benign encapsulated follicular neoplasms, as evidenced by the demonstration of clonality (Table 13.3, Figure 13.8) and the fact that adenomas can undergo malignant transformation to follicular carcinoma with capsular invasion or penetration and capsular or extracapsular

THYROID GLAND 

8a

8B

8c

8d

8e

8f

FIGURE 13.8  Follicular adenoma. Gross appearance of thyroid lobectomy demonstrating uniform enlargement (A). Well-demarcated nodule from adjacent normal red-brown thyroid parenchyma (B). Fibrous capsule separates the follicular adenoma (left) from the adjacent thyroid parenchyma (right), with no evidence of capsular invasion or penetration by the follicular adenoma (C). Microfollicular adenoma with intact fibrous capsule surrounding entire circumference of the adenoma (D). Microfollicles, normofollicles, and macrofollicles within adenoma with no cellular crowding or cytologic atypia (E, F).

331

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Thyroid, Parathyroid, and Adrenal Glands

vascular invasion (3, 9–27). Follicular adenomas are one of the most common benign thyroid lesions in children, accounting for up to 30% of all benign nodules. These lesions more commonly affect girls (4.5F:1.0M). Association with prior radiation exposure with a long latency period and iodine deficiency is well documented with follicular adenomas. These thyroid nodules may be seen in Cowden’s syndrome and with thyroid dyshormonogenesis. The lesions usually present as asymptomatic palpable nodules that may enlarge and become painful if spontaneous hemorrhage occurs. Adenomas tend to be much smaller than follicular carcinomas, hypofunctioning, and well demarcated. The typical size ranges from 1 to 3 cm. Histopathologic features include a fibrous capsule and follicular to trabecular architecture (Figure 13.8). There may be microfollicles, macrofollicles, or normofollicles. The epithelial cells range from cuboidal to columnar to polygonal, and have uniform nuclei. Mitotic figures are rare. There is scant stroma with delicate capillary-sized vessels. ­Myxoid change may be seen in subcapsular areas. Secondary features maybe present, such as fibrosis, hyalinization, calcification, metaplastic cartilage, cystic changes, and ischemic ­necrosis. Immunocytochemical staining will demonstrate TTF1, thyroglobulin, and cytokeratin expression. The tumor cells will be negative for CK19. The most important aspect of histopathologic examination is ensuring that there is no capsular invasion, or vascular invasion as seen with minimally invasive follicular carcinoma. Cytogenetic abnormalities are seen with follicular adenomas (Table 13.3) (10–20, 22–27). Disruption of the RAS-RAF-MEK-MAPK pathway occurs commonly, as well as other clonal cytogenetic abnormalities. As noted previously, most nonmedullary thyroid cancers in children are well differentiated. Anaplastic or undifferentiated thyroid cancers occur rarely in children, but are associated with poor outcomes. Poorly differentiated and anaplastic carcinomas have certain recurring genetic mutations (Table 13.5). These tumors will not be discussed (10–20, 22–27). There are certain differences between sporadic and familial nonmedullary thyroid carcinomas (Table 13.6) (10–20, 22–27). Familial tumors tend to occur at a younger age, and are more often bilateral with local tissue invasion. Lymph node metastases and tumor recurrence are more frequent. BRAF gene mutations are seen more frequently in sporadic thyroid cancers. With respect to papillary thyroid microcarcinomas, the factors, which are more prevalent in familial tumors, include multifocality, bilaterality, lymph node metastases, and vascular invasion. Recurrence of the tumors is also more common in familial papillary thyroid microcarcinomas. Although medullary thyroid carcinomas comprise only about 3% of all thyroid carcinomas, the genetics are much better understood (Table 13.7) (3, 9, 12–14, 16–18, 22, 25, 26). Medullary carcinomas are derived from the C cells or parafollicular cells, which secrete calcitonin. The C cells originate from the lateral thyroid anlage of the fourth branchial pouch, whereas the follicular cells of the thyroid are derived from the median anlage. C-cell hyperplasia occurs as a precursor lesion in hereditary syndromes that are predisposed to medullary carcinoma and other endocrine and nonendocrine tumors (Table 13.7). Sporadic medullary thyroid carcinoma represents about 75% of cases, whereas hereditary tumors make up the remaining 25% of the cases. With multiple endocrine neoplasia type 2 A (MEN2A), MEN2B, and familial medullary carcinoma syndromes, infants and children may present with C-cell hyperplasia and even medullary thyroid carcinoma. In fact, the timing of thyroidectomy is based on specific RET oncogene codon mutations (Table 13.8). Thyroidectomy may be done as early as 6 months of age with certain RET oncogene codon mutations. The syndromes associated with medullary thyroid carcinoma (Table 13.7) include MEN2A, MEN2B, and familial medullary thyroid carcinoma syndromes. MEN2A and MEN2B syndromes may present initially with other signs and symptoms of tumors involving other organ systems (Table 13.7) (3, 9, 12–14, 16–18, 22, 25, 26), such as adrenal pheochromocytomas, extraadrenal paragangliomas, parathyroid hyperplasia or carcinoma, mucosal neuromas, and enteric ganglioneuromatosis. The initial symptoms may be cutaneous flushing and diarrhea due to high serum calcitonin levels. Some patients present with Cushing syndrome due to elevated adrenocorticotrophic hormone (ACTH) serum levels. Sporadic and hereditary medullary thyroid carcinomas have similar pathologic features (3, 9, 12–14, 16–18, 22, 25, 26). The tumors tend be located in the middle third of affected thyroid lobe, and are firm, gray-white nodules that vary in size from ,1 cm to several centimeters in diameter. Although well circumscribed, the tumors are not encapsulated. Sporadic tumors tend

THYROID GLAND 

Table 13.5  Prevalence of Genetic Mutations in Thyroid Cancer Papillary Carcinoma

  BRAF

45%

  RET/PTC

20%

  RAS

10%

  TRK

,5%

Follicular Carcinoma

  RAS (N-RAS, H-RAS)

45%

  PAX8-PPARgamma

25–50%

  PIK3CA

,10%

  PTEN

,10%

Poorly Differentiated Carcinomas

  RAS

35%

  Beta-catenin (CTNNB1)

20%

  TP53

20%

  BRAF

20%

  AKT1

15%

Anaplastic Carcinoma

  TP53

70%

  Beta-catenin (CTNNB1)

60%

  RAS

50%

  BRAF

20%

  PIK3CA

20%

  PTEN

.10%

Medullary Carcinoma

  Familial Forms: RET

.95%

  Sporadic Forms: RET

50%

Table 13.6  Comparison of Sporadic and Familial Nonmedullary Thyroid Carcinoma Sporadic

Familial

Age

Older

Younger ,10 yr

Bilateral

19%

43%

20–30%

42–93%

4–16%

32%

Multifocal Local invasion Lymph node metastases

38–43%

57%

5–15%

29–50%

Multinodular hyperplasia

29%

41%

BRAF gene

40%

0%



0.59 cm

Recurrence

Papillary thyroid microcarcinoma Size Multifocal

19%

71%

Bilateral

  8%

43%

Lymph node metastases

28%

57%

Vascular invasion

  5%

43%

Recurrence rate

  5%

43%

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Thyroid, Parathyroid, and Adrenal Glands

Table 13.7  Syndromes Associated With Medullary Thyroid Carcinoma and/or Parathyroid Disease MEN1 (AD) (Wermer syndrome)

MEN1 (Menin; 11q13)

Parathyroid (100%), pancreas, intestinal islets, anterior pituitary, thyroid adenomas, lipomas

MEN2A (AD) (Sipple syndrome)

RET exons 10 and 11 Codons 609, 611, 618, 620, 634 (10q21)

Multiglandular, thyroid (100%), adrenal (50–70%), parathyroid (25%), enteric ganglia (rarely)

MEN2B (AD) (Wagenmann­Froboese syndrome)

RET exon 16, Codon 918 (10q21)

Thyroid (100%), mucosal ­neuromas (100%), skeletal system (75%), enteric ganglioneuromatosis (.40%), adrenal (50%)

Familial medullary thyroid ­carcinoma syndrome (AD)

RET exons 10 and 11 Codons 618, 620, 209, 611 (10q21)

Thyroid (100%)

Hyperparathyroidism jaw tumor syndrome (AD)

HRPT2 (1q21–32)

Hyperparathyroidism, parathyroid carcinoma, fibro-osseous jaw lesions, kidney lesions

Familial isolated hyperparathyroidism (AD)

MEN1 (11q13)

Parathyroid disease

CaSR (19p13.3)

Breast, colon, endometrium, and others

Familial hypocalciuric ­hypocalcemia (AD)

CaSR (3p21.1, 19p13.1, 19q13)

Normal or increased calcium hyperphosphatemia, low urine calcium, normal, or increased parathyroid hormone

Neonatal severe hypoparathyroidism (AR)

CaSR (3q21.1)

Hyperparathyroidism

Autosomal dominant mild ­hyperparathyroidism (AD)

CaSR (3q21.1)

Hyperparathyroidism

Abbreviations: AD, autosomal dominant; AR, autosomal recessive

to be unilateral, whereas hereditary tumors are multiple and involve both thyroid lobes. The tumors tend to metastasize early to the liver, lungs, bone, brain, soft tissues, and bone marrow. There are many different histopathologic patterns with medullary thyroid carcinoma (Figure 13.9). The tumor cells typically are arranged in sheets, nests, or trabeculae comprised of polygonal, round to spindle cells. Occasional plasmacytoid tumor cells may be seen. Some tumors resemble carcinoids. The nuclei are round to oval with coarse chromatin. Mitotic figures are scant. The cytoplasm tends to be granular and eosinophilic to amphophilic. The tumor typically infiltrates the adjacent thyroid tissue with entrapment of normal thyroid follicles. There can be hyalinized stroma and amyloid-like substance. Immunocytochemistry is positive for calcitonin (95%) and carcinoembryonic antigen (CEA, .95%). Chromogranin A and synaptophysin may also be positive. TTF1 and low–molecular-weight keratins are positive. Electron microscopy shows type I (280 nm) and type II (130 nm) neurosecretory granules. Genetic studies of sporadic medullary thyroid carcinomas have shown somatic RET mutations in codon 918 with 20% to 80% of tumors (12–14, 16–18, 22, 25–27). In addition, loss of hetero­zygosity with 11p (40%), 3p (30%), 3q (40%), 11p (11%), 13q (10%), 17p (8%), and 22q (30%) have been shown by cytogenetics and comparative genomic hybridization with sporadic tumors.

Table 13.8  Recommended Age at Thyroidectomy With RET Oncogene Mutations RET codon mutation

Recommended age at thyroidectomy

883, 918, 922

6 months

611, 618, 620, 634

By age 5 years

609, 630, 768, 790, 791, 804, 891

Between ages 5 and 10 years

THYROID GLAND 

9a

9b

9c

9d

9e

9f

FIGURE 13.9  Medullary carcinoma of thyroid. Moderately enlarged thyroid with irregular, vaguely nodular surface (A). Nesting pattern of medullary carcinoma with ovoid to round tumor cells with amphophilic cytoplasm and nuclei with fine chromatin (B–D). Tumor cells embedded in hyalinized, amyloid-like stroma (E). Small nests of tumor displacing normal thyroid follicles (F). Metastatic tumor in lymph node (G). Perithyroidal soft tissue involvement by tumor (H). C-cell hyperplasia in uninvolved thyroid parenchyma (I). (Continued)

9g

335

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Thyroid, Parathyroid, and Adrenal Glands

9h

9i

FIGURE 13.9  Medullary carcinoma of thyroid. (Continued)

The mainstay of treatment is surgical (3, 9, 12–14, 16–18, 22, 25, 26). Radiation therapy and chemotherapy have not proven to be beneficial. Molecular targeted therapy may prove to be of benefit for those with residual or recurrent disease in the future. Overall survival at 10 years is about 75%. Poor prognostic risk factors are older age, male gender, and degree of local invasion. Individuals with sporadic microcarcinomas (,1 cm) have improved survival compared to individuals with tumors .1 cm in diameter. With medullary thyroid carcinoma, the serum markers calcitonin and CEA may be followed to evaluate for residual or recurrent disease.

PARATHYROID GLANDS The parathyroid glands are derived from the third and fourth branchial pouches and are first identified in the 8- to 9-mm stage embryo as bilateral cellular clusters (3, 14). Formation of the parathyroid glands is associated with the genes EOLVO and GCM2 on chromosome 6 (6p24.2). Other genes associated with parathyroid development and migration include HOX3a (12q13), PAX1 (7q36), EYA1 (8q13.3, branchiootorenal syndrome 1), SIX1 (14q23, branchiootorenal ­syndrome), and TBX1 (22q11.2, DiGeorge syndrome). Dysregulation or mutation in these genes results in absence, hypoplasia, or ectopic parathyroid glands. Hypercalcemia in children may occur with many different disease processes (Table 13.9) (3,12–14). Elevated parathyroid hormone may be due to hyperparathyroidism resulting from hyperplasia, adenomas, carcinomas, or ectopic production of parathyroid hormone, such as in subcutaneous fat necrosis of the newborn, or paraneoplastic syndromes. Other causes of hypercalcemia include hypervitaminosis A or D, sarcoidosis, and thiazide diuretics. Familial syndromes (Tables 13.7 and 13.9) may be associated with hyperparathyroidism, including those associated with mutations in CaSR (calcium sensing receptor) and HRPT2 genes and ­parathyroid hyperplasia, adenomas, and carcinomas (MEN1, MEN2A, and familial isolated hyperparathyroidism syndromes) (3, 12–14, 16–18, 22, 25, 26). Primary hyperparathyroidism in children is rare, with a prevalence of 2–5 per 100,000 (3–14). Girls are more commonly affected than boys (1.5F:1.0M). The cause is usually a single parathyroid adenoma, and less commonly diffuse hyperplasia of all glands. Neonatal hyperparathyroidism is usually associated with MEN1 and MEN2A syndromes, with diffuse gland hyperplasia. The presenting signs of primary hyperparathyroidism in infancy usually occur by 3 months of age with failure to thrive, hypotonicity, respiratory distress, lethargy, and polyuria. Typically, diffuse parathyroid hyperplasia is present with elevated serum parathyroid hormone. With secondary hyper­calcemia, symptoms include fatigue, anorexia, weakness, renal colic, pancreatitis, and osteitis ­fibrosa cystica. Secondary hyperparathyroidism is most commonly associated with chronic renal disease or malabsorption of calcium, resulting in parathyroid gland hyperplasia with increased parathyroid hormone

PARATHYROID GLANDS 

Table 13.9  Differential Diagnosis of Hypercalcemia in Children Elevated parathyroid hormone Hyperparathyroidism, primary, secondary, or tertiary   Parathyroid hyperplasia   Parathyroid adenoma   Parathyroid carcinoma Ectopic parathyroid hormone production Hypervitaminosis D Sarcoidosis Subcutaneous fat necrosis of newborn Familial hypocalciuric hypercalcemia Idiopathic hypercalcemia (Williams syndrome) Thyrotoxicosis Hypervitaminosis A Hypophosphatasia Prolonged immobilization Thiazide diuretics

levels (3, 14). Severe cases may have renal osteodystrophy with fractures and metastatic calcifications in various tissues. Treatment may involve decreasing phosphorus absorption, use of cinacalet medication that increases parathyroid gland sensitivity to calcium levels, and parathyroid resection with autotransplantation of parathyroid tissue. Parathyroid hyperplasia has nonspecific histopathologic features with enlargement and hypercellularity of all parathyroid glands (Figure 13.10) (3, 14). The gland weight may range from ,50 mg (normal weight) to over 10 g. In addition to increased cellularity, the glands may have fibrosis, hemosiderin deposition, and cystic, degenerative changes. Rarely, carcinoma arises on a background of parathyroid hyperplasia. Hereditary syndromes contribute to about 25% of cases with parathyroid hyperplasia (Table 13.7). Parathyroid adenomas may be present at the typical gland location, or located anywhere from the mandible to cervical thymus to mediastinal thymus or within the substance of the thyroid gland (intrathyroidal) (3, 14). Ultrasound and nuclear medicine scans are important in localizing abnormal glands prior to surgery. Parathyroid adenomas are typically oval with a smooth capsule and have a homogenous red-tan cut surface. Usually, the adenomatous gland has a weight of about 1 g. The histopathologic features include hypercellularity, stromal loss, and lack of cytoplasmic lipid (Figure 13.10). Residual normal glandular tissue may be seen focally at the periphery of the gland. The adenoma is well circumscribed, confined to the gland and lacks pleomorphism with minimal mitotic activity. These benign tumors are monoclonal, with loss of 1p being a common finding. The genetic mutations associated with inherited syndromes are found with parathyroid adenomas (Table 13.7). More than one adenoma may occur in 7% to 15% of affected patients. Parathyroid carcinomas are very rare and typically present with moderate to very high serum calcium levels associated with clinical symptoms (3, 14). Malignancy may be suspected when the patient presents with a palpable mass, symptomatic hypercalcemia, and ­hoarseness. Histopathologic diagnosis is difficult. The features of malignancy are relatively nonspecific and include broadbands of fibrosis, increased mitoses, high-proliferative index, and nuclear pleomorphism and atypia. The features, which clinch the diagnosis of parathyroid ­carcinoma are invasion of adjacent tissues, peritumoral lymphovascular and/or ­perineural invasion, and metastatic disease. Molecular features include tumor-suppressor gene mutations in ­particular Rb and MEN1 genes, and frequent loss of heterozygosity of HRPT2 gene ­(parafibromin ­protein loss by immunocytochemistry). In addition, association of this ­cancer with hereditary syndromes is well recognized, as well as sporadic occurrences (Table 13.7) (3, 9, 12–14, 16–18, 22, 25).

337

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10a

10b

10c

10d

10e

10F

FIGURE 13.10  Parathyroid gland: Normal, hyperplastic, and adenomatous. Normal appearance of parathyroid gland cells (A). With parathyroid hyperplasia, cells become uniformly enlarged (B). With parathyroid adenomas, cells are enlarged but not uniform and have a certain degree of atypia (C, D). Parathyroid gland adenoma increased size (245 mg; expected ,50 mg) with prominent “glandular” changes (E, F). Note: Small rim of residual normal parathyroid gland tissue (right) (E).

Cystic parathyroid lesions are relatively rare lesions, but of clinical importance, because they can be the cause of hyperparathyroidism (28–31). Parathyroid cysts are classified as functional (15% to 80%) or nonfunctional, based on whether elevated parathyroid hormone levels or symptoms of hyperparathyroidism are identified. These lesions account for as many as 10% of hyperparathyroidism cases, and accounts for about 1% of all thyroid and parathyroid masses. These cysts are often ­mistaken for thyroid cysts, because there is no radiologic or ultrasound method that differentiates ­parathyroid

ADRENAL GLAND 

11b

FIGURE 13.11  Parathyroid cyst. Cyst wall composed of dense connective tissue and underlying normal thyroid (A). Wall of cyst with residual parathyroid cells and prominent thin-walled vessels (B).

11a

cysts from thyroid cysts. These cysts may be located anywhere from the mandible to the mediastinum. The cysts typically contain clear colorless fluid when aspirated compared with the cloudy, gelatinous-to-bloody aspirate fluid from ­t hyroid cysts. The aspirate material tends to be acellular or paucicellular with rare histiocytes or parathyroid cells. Resection of the cysts shows a smooth, glistening semitransparent to fibrous wall, which may be loosely attached to adjacent thyroid tissue and surrounding soft ­tissue. Microscopic examination shows a fibrous-to-fibromembranous cyst wall with parathyroid ­tissue embedded within the cyst wall (Figure 13.11). Only rarely has a parathyroid cyst been associated with MEN syndromes.

ADRENAL GLAND The cortex of the adrenal gland is derived from the adrenogonadal primordium that develops from the urogenital ridge (32, 33). WT1 and WNT4 genes play an early role in development, along with steroidogenic factor-1 (transcription factor) and a nuclear hormone receptor gene (DAX1, Xp21). The fetal cortex zone develops and is followed by the more peripheral definitive adult cortex zone. During the first 3 months of life, the fetal zone undergoes apoptosis and is replaced entirely by the adult zone. The adult zone forms the zona glomerulosa (mineralocorticoids, aldosterone), zona fasciculata (glucocorticoids, cortisol), and zona reticularis (androgens). Zonation is complete by the 2nd decade of life. The medulla is derived from neural crest cells that migrate into the developing medial portion of the ­adrenocortical primordium during the 8th week. The neural crest cells are sympathetic postganglionic cells of the autonomic nervous system. The medulla is comprised of pheochromocytes. These are polygonal cells with eosinophilic, granular cytoplasm and possess neurosecretory granules containing epinephrine and norepinephrine. The endocrine nature of the adrenal medulla is demonstrated by the rich capillary network that is closely associated with the clusters of pheochromocytes. These cells are concentrated in the head of the adrenal gland and not uniformly distributed throughout the medulla.

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Table 13.10  Diagnoses With Pediatric Adrenalectomies Neuroblastoma

45%

Adrenal cortical neoplasms

27%

Benign adrenal cyst

12%

Wilms tumor   Direct extension

  3%

  Intra-adrenal

  1%

Pheochromocytoma

  3%

Soft tissue tumor

  3%

Teratoma

  1%

Pigmented micronodular hyperplasia

  1%

Hemangioma

  1%

Adrenal glands may have many different types of lesions originating from either the cortical component or the medullary component. In a 20-year review of adrenal resections at a pediatric center, the most common diagnosis was neuroblastoma (45%) followed by adrenal cortical neoplasms (27%), benign adrenal cysts (12%), Wilms tumor by direct extension or intra-­adrenal location (4%), and pheochromocytoma (3%). Other uncommon primary adrenal tumors included soft tissue tumors (3%), teratoma (1%), pigmented micronodular hyperplasia (1%), and hemangioma (1%) (Table 13.10) (33).

n Neuroblastic Family of Tumors Neuroblastoma is an embryonal tumor derived from the neural crest and specifically from the sympathetic component of the autonomic nervous system (34–39). The neuroblast is an incompletely committed neural crest precursor cell. Neuroblastoma occurs in young children with a median age of 17 months, with some neonates possessing the congenital form of this tumor. Neuroblastoma is the most common solid tumor in children younger than 1 year of age. The prevalence is 1 per 100,000 children younger than 15 years of age. Neuroblastoma accounts for 15% of all neoplasms occurring during the first 4 years of life. The vast majority of neuroblastomas (90%) are diagnosed during the first 5 years of life. Tumors arise in the location of the sympathetic chain, most commonly from the adrenal medulla, sympathetic paravertebral ganglia, and sympathetic paraganglia, such as the organ of Zuckerkandl. ­Neuroblastic tumors may be found in the neck, posterior chest, abdomen, and pelvis. ­Clinical presentation is quite variable, ranging from an asymptomatic mass to locally invasive disease to widespread metastatic disease. The variable clinical presentation is related to the fact that a certain proportion of tumors have the ability to involute or spontaneously regress and have a relatively benign course. This is supported by identification of neuroblastoma in situ in about 0.5% of autopsies performed on infants younger than 3 months of age who died of nontumor-related causes. Others have the ability to mature into ganglion cells with ­Schwannian stroma. Oncologic management of neuroblastomas may induce maturation from ­neuroblastic cells to ganglion cells and Schwannian stromal cells. In contrast, a certain proportion are highly malignant, have very aggressive clinical courses, and are poor responders to oncologic ­management. The neuroblastic family of tumors is comprised of three major classes of neuroblastic tumors, based on the degree of differentiation of the neuroblastic cells and Schwannian stromal cells (Table 13.11, Figures 13.12 and 13.13) (34–47). The Schwannian stroma–poor neuroblastoma class is further subclassified as undifferentiated, poorly differentiated, and differentiating neuroblastoma. Undifferentiated neuroblastoma is a small round cell tumor of childhood, which lacks histopathologic evidence of neuroblastic differentiation. The tumor cells have a high nuclear to cytoplasm ratio and lack neuropil cell processes. There is no Schwannian ­differentiation. The nuclear morphology may have fine granular chromatin (salt and pepper) and distinct nucleoli. The differential diagnosis includes rhabdomyosarcoma, Ewing’s ­sarcoma, blastemal Wilms’ tumor, lymphoma, leukemic involvement of

ADRENAL GLAND 

341

Table 13.11  Neuroblastic Family of Tumors Classification of Neuroblastic Family of Tumors

Neuroblastoma (Schwannian stroma-poor)   Undifferentiated: Tumor cells lacking cytologic differentiation, no neuropil and none to minimal Schwannian stroma   Poorly differentiated: ,5% of tumor cells with differentiation toward ganglion cells, neuropil present, and none to minimal Schwannian stroma   Differentiating: 5% of tumor cells with differentiation toward ganglion cells, neuropil present, and none to minimal to ,50% Schwannian stroma Ganglioneuroblastoma (Schwannian stroma-rich)   Intermixed (Schwannian stroma-rich): Ganglioneuromatosis component .50% with well-delineated microscopic foci of neuroblastomatous component   Nodular (Composite, Schwannian stroma-rich/stroma-dominant, and stroma-poor): Grossly visible single nodule, multiple ­nodules or large nodule of neuroblastomatous component (usually hemorrhagic or congested) with ganglioneuromatous component peripheral to nodule; multinodules, or large nodule with abrupt transition between neuroblastic nodule or multinodules and adjacent ganglioneuromatous component. Neuroblastic component comprised of undifferentiated, poorly differentiated, or differentiating tumor cells   No nodule, but with metastatic disease: Primary tumor with features of intermixed ganglioneuroblastoma or ganglioneuroma with neuroblastomatous metastasis to lymph node, bone, or other sites Ganglioneuroma (Schwannian stroma-dominant)   Maturing: Few scattered poorly delineated foci of differentiating neuroblasts, neuropil unassociated with neuroblasts (naked neuropil), and mature ganglion cells in predominant ganglioneuromatous background   Mature: Tumor comprised of exclusively ganglioneuromatous component with ganglion cells and no evidence of immaturity or atypia of cellular elements Favorable Histology Group

Ganglioneuroma, maturing and mature: Any age Ganglioneuroblastoma, intermixed (Schwannian stroma-rich): Any age Ganglioneuroblastoma, nodular (single nodule [classical], multiple nodules, or large nodule)    Age ,1.5 years: Nodule with poorly differentiated or differentiating neuroblastoma and low or intermediate MKI    Age 1.5–5.0 years: Nodule with differentiating neuroblastomas and low MKI   Neuroblastoma (Schwannian stroma-poor), poorly differentiated and low or intermediate MKI: Age ,1.5 years   Neuroblastoma (Schwannian stroma-poor), differentiating, and low MKI: Age 1.5 to ,5 years Unfavorable Histology Group

Ganglioneuroblastoma, nodular (single nodule [classical], multiple nodules, or large nodule)    Age ,1.5 years: Nodule with undifferentiated neuroblastoma and high MKI    Age 1.5 to 5 years: Nodule with undifferentiated or poorly differentiated neuroblastoma with intermediate to high MKI    Age .5 years: All nodular ganglioneuroblastomas   Neuroblastoma (Schwannian stroma-poor), undifferentiated and any MKI: Any age   Neuroblastoma (Schwannian stroma-poor), poorly differentiated or differentiating and high MKI: Age ,1.5 years   Neuroblastoma (Schwannian stroma-poor), poorly differentiated and any MKI: Age 1.5 to ,5 years   Neuroblastoma (Schwannian stroma-poor), differentiating and intermediate or high MKI: Age 1.5 to ,5 years   Neuroblastoma (Schwannian stroma-poor), any subtype and any MKI: Age 5 years Mitotic-Karyorrhexis Index (MKI)

Low MKI: ,100 mitotic and karyorrhectic cells per 5,000 tumor cells or ,2% of tumor consisting of cells with ­mitoses or karyorrhexis Intermediate MKI: 100 to 200 mitotic and karyorrhectic cells per 5,000 tumor cells or 2% to 4% of tumor consisting of cells with mitoses or karyorrhexis High MKI: .200 mitotic and karyorrhectic cells per 5,000 tumor cells or .4% of tumor consisting of cells with ­mitoses or karyorrhexis International Neuroblastoma Staging System

Stage 1: Localized tumor with complete gross excision with or without microscopic residual disease and negative nonadherent ipsilateral lymph nodes (lymph nodes attached to or adjacent lymph nodes removed with tumor may be positive) Stage 2A: Localized tumor with incomplete gross excision and representative negative ipsilateral nonadherent lymph nodes (continued)

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Table 13.11  Neuroblastic Family of Tumors (Continued) International Neuroblastoma Staging System (Continued)

Stage 2B: Localized tumor with or without complete gross excision and positive ipsilateral nonadherent lymph nodes, but negative contralateral lymph nodes Stage 3: Unresectable unilateral tumor infiltrating across midline with or without positive regional lymph node; or localized unilateral tumor with positive contralateral regional lymph nodes; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement with midline defined as vertebral column. Tumor originates on one side and infiltrates or extends beyond the opposite side of the vertebral column Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs except as defined for stage 4S Stage 4S: Localized tumor (stage 1, 2A, 2B) with dissemination limited to skin, liver, and/or bone marrow (limited to infants ,1 year of age). Minimal marrow involvement (,10% of nucleated cells in marrow). More extensive marrow disease considered to be stage 4. MIBG scans should be negative for disease in bone marrow

soft tissues, and other blastemal embryonal tumors of childhood. Location of the tumor and elevated urinary catecholamine metabolites (vanillylmandelic acid, homovanillic acid) may provide evidence for a neuroblastic tumor. Immunocytochemistry, electron microscopy, and cytogenetics are usually necessary to establish a diagnosis. Neuroblastomas immunoreact with antibodies to NB84, PGP9.5, ­neuron-specific enolase, chromogranin A, synaptophysin, tyrosine hydroxylase, and GD2. Neuroblastoma cells are typically negative for vimentin, desmin, low–molecular-weight cytokeratins, and leukocyte common antigens. Membranous staining with CD99, which is characteristic for Ewing’s sarcoma, is usually negative with neuroblastoma. Electron microscopy will demonstrate fine neurite cell processes and dense core neurosecretory granules typical of n ­ euroblastic cells. Poorly differentiated neuroblastomas may be recognized by its neuropil background. Neuropil is variable and may require searching many microscopic fields and all tissue blocks. Poorly differentiated neuroblastoma demonstrates less than 5% of tumor cells with differentiation toward ganglion cells. In addition, Schwannian stroma may be variably present, but is usually absent to minimal. Differentiating neuro-

Absent Absent > 50%

Microscopic Neuroblastic Foci

Macroscopically Visible Nodule(s)

Present Present

Schwannian Development 0 or < 50%

FH

Ganglioneuroblastoma intermixed

FH

Ganglioneuroblastoma nodular classic

UH/FH

Ganglioneuroblastoma variant (with or without macroscopically visible nodule(s)

UH/FH

MKC Any MKI

Age Any age

UH

Poorly differentiated

>4% Any MKI 1.5 years 5 years