color atlas of pediatric pathology - a. husain, j. stocker (demos, 2011)

Disruptive Intervillous Thrombi Fetomaternal Hemorrhages Fetal Vessel Rupture n DEVELOPMENTAL ABNORMALITIES Villous Architecture Distal Villous Hypoplasia Distal Villous Immaturity

Color Atlas

of Pediatric Pathology

Aliya N Husain

J Thomas Stocker

Color Atlas

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:

n Comprehensive coverage of both common and uncommon diseases in pediatric

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

5 Soft Tissue Lesions

6 Bone and Joints

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

A Look Inside the Book

Pathology

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

Color Atlas of

Pediatric Pathology

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

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ISBN 978-1-933864-57-0

eISBN 978-1-935281-40-5

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Medicine is an ever-changing science Research and clinical experience are continually expanding our edge, 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 omis-sions 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

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Color atlas of pediatric pathology / editors, Aliya N Husain, J Thomas Stocker

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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]

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5 soFT Tissue lesions 79

Zhongxin Yu and David M Parham

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7 The hearT 123

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Haresh Mani and J thomas Stocker

Contents

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

com-mon 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

subspe-cialty in the United States and Canada since 1991 The majority of pediatric pathologists work in

chil-dren’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

pic-tures.” 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

accompa-nying 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 specifi c 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 fi nd 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

Preface

Anthony Chang, MD

Associate Professor of Pathology

University of Chicago Medical Center

Associate Professor of Pathology

Northwestern University Feinberg School

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

ProfessorDepartment of PathologyUniversity of Oklahoma Health Science CenterOklahoma City, Oklahoma

Elizabeth J Perlman, MD

Head, Pathology and Laboratory MedicineArthur C King Professor of Pathology and Laboratory Medicine

Professor of PathologyNorthwestern University Feinberg School

of MedicineChildren’s Memorial HospitalChicago, Illinois

Peter Pytel, MD

Department of PathologyUniversity of Chicago Medical CenterChicago, Illinois

Vijaya B Reddy, MD

Professor of PathologyRush University Medical CenterChicago, Illinois

Raymond W Redline, MD

Department of PathologyCase Western Reserve UniversityCleveland, Ohio

Andrea M Sheehan, MD

Assistant Professor of Pathology and ImmunologyAssistant Professor of Pediatrics, Section of Hematology-Oncology

Texas Children’s Hospital and Baylor College

of MedicineHouston, Texas

Bahig M Shehata, MD

Professor of Pathology and PediatricsEmory University School of MedicineDepartment of Pathology

Children’s Healthcare of AtlantaAtlanta, Georgia

Contributors

xii COntrIButOrS

Charlotte K Steelman, BS

Emory University School of Medicine

Children’s Healthcare of Atlanta

Zhongxin Yu, MD

Assistant ProfessorDepartment of PathologyUniversity of Oklahoma Health Science CenterOklahoma City, Oklahoma

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

(neutrophilic Infl ammation 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 fi rst and second

trimes-ter 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

bacte-ria, 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

mem-branes, maternal fever, maternal/fetal tachycardia, uteri and tenderness, or a foul-smelling discharge

However, the majority of cases are clinically silent

2 PlACentA

Pathology

Gross: Cloudiness or opacity may be seen on the fetal surface, particularly surrounding the major

cho-rionic vessels In severe cases, a yellow-green discoloration may be noted Marginal abruption

(dis-cussed later) often accompanies ACA in premature deliveries

Microscopic: The neutrophilic inflammatory response to microorganisms in the membranes and

amniotic fluid 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

mem-branes (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 inflammatory 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

interme-diate (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

surround-ing vessels in the umbilical cord (subnecrotizsurround-ing funisitis, Figure 1.4) A histologically severe fetal

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

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 3

acute inflammatory 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 inflammation to the amniotic surface, while the

corre-sponding 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

pic-ture 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

patho-logic 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

falci-parum 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

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

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

No other pregnancy or placental abnormalities

Chorangioma Spherical, smooth, firm,

usually marginal or chorionic (capillary vascular lesion)

sub-Preeclampsia, multiple pregnancy

Intervillous thrombus Spherical, smooth, soft,

tan-red, laminated hematoma, surrounded by villi

Fetomaternal hemorrhage (small to large)

Placental atrophy Area of decreased

placen-tal thickness, fibrin coats stem villi and surfaces of

BP and CP

Uterine abnormality, low implantation, abnormal placental shape

Septal cyst Extravillous

trophoblast-lined cyst within a decidual septum, clear-bloody fluid content

No other pregnancy or placental abnormalities

Villous agglutin ation VUE Villi with lymphocytes in

stroma, agglutinated

by fibrin

FGR, abnormal fetal monitoring, prior pregnancy loss, decidual plasma cellsFindings consistent with MMP Villi with increased syncytial

knots agglutinated by direct contact

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

Massive PVF deposition Villi  trophoblast necrosis

agglutinated by fibrinoid matrix and extravillous tro-phoblast

FGR, fetal monitoring abnormalities, recurrent pregnancy loss

Avascular villi Fetal thrombotic vasculopathy Intermediate to large

seg-ments of villous tree with hyalinized AV (average

 15 AV per slide)

Pathologic UC abnormalities, neonatal coagulopathy/thrombosis

Findings consistent with UCO Widely scattered small foci of

AV (2–10 AV per focus) Pathologic UC abnormalities, intimal fibrin cushions, large vessel ectasiaVUE with obliterative fetal

vasculopathy VUE with small to large areas of hyalinized AV, and stem

villous arteritis/periarteritis

FGR, fetal monitoring abnormalities, natal encephalopathy

neo-Changes 2° to fetal death Diffuse AV, varying stages,

affecting entire placenta Villous hemosiderin, fibromuscular sclero-sis of large fetal vesselsPerivillous fibrin 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

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

placen-tal thickness, fibrin coats stem villi and surfaces of

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 eclampsia/FGR

pre-Laminar necrosis Focal neutrophilic debris with

a background of ischemic necrosis in choriodecidua

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

Inflammation,

fetal vessels 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

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

Iron-stain positive in 2/3 of cases, old ginal blood clot, circumvallation, green-brown discoloration

mar-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

accompa-nies this pattern Chronic intervillositis shows a predominance of intervillous monocyte/macrophages

with abundant PVF In malaria infections, areas of trophoblast necrosis and hemozoin pigment

deposi-tion 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,

trypano-soma 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

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

“zoster-like” 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

fol-lows) 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)

Promi-nent involvement of fetal blood vessels with hemosiderin deposition and the presence of viral

inclu-sions 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

granu-lomatous features Diagnostic toxoplasma cysts may be seen in the umbilical cord stroma

Special studies: Microbial proteins and DNA may be detected by immunohistochemistry or

poly-merase 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

asso-ciated with noncandidal fungi and circulating parasites are usually confined to the intervillous space,

where an inconspicuous inflammatory infiltrate and fibrin surround diagnostic organisms (14)

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

InFlAMMAtOrY leSIOnS 7

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

n idioPaThiC

vIllItIs of Unknown etIology

(Patchy Chronic lymphocytic Infiltrate in villous stroma)

Prevalence/gestational age: Chronic villous inflammation not associated with recognizable

microor-ganisms (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

pregnan-cies, 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

contain-ing clusters of less than 10 contiguous inflamed villi (focal: confined to one slide; multifocal: affectcontain-ing

mul-tiple 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

vas-culopathy (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

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

8 PlACentA

Differential diagnosis: Villous agglutination and PVF, sometimes seen in VUE, should be

distin-guished 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

associ-ated with chronic endometritis in nonpregnant women, retained placental tissue from previous

preg-nancies, 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

mac-rophages without clinical pathologic evidence of malaria infection is a rare but important cause of

recur-rent reproductive failure (23) The presence of coexisting villitis excludes this diagnosis

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

MAternAl VASCulAr leSIOnS 9

Chronic periarteritis: Nonspecific lymphocytic infiltrates in the perivascular connective tissue

sur-rounding 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

FiGure 1.13 Chronic deciduitis, lymphoplasmacytic (H&E; 340)

Small lymphocytes and plasma cells infiltrate decidualized endometrium

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

second-ary 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

mus-cularized 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

10 PlACentA

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

essen-tial 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

tri-mesters of pregnancy

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

MAternAl VASCulAr leSIOnS 11

FiGure 1.15 Decidual arteriopathy, mural hypertrophy

(H&E; 320) Decidual arterioles show medial hypertrophy

exceeding two-thirds of the total diameter

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

pla-centas, and is a nonspecific finding in some chromosomal abnormalities

Pathology

Gross: Placentas with villous changes consistent with MMP are often small with an increased

fetopla-cental 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

necro-sis in the decidua (laminar necronecro-sis) 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

periv-illous 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

auto-immune disease, especially when associated with antiphospholipid antibodies (37)

FiGure 1.16 Findings consistent with maternal sion (H&E; 34) Distal villi show excessive numbers of

malperfu-syncytial knots and focal agglutination in the presence of ill-defined aggregates of intervillous fibrin

12 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

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)

Mas-sive 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

fol-lowed 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

deliv-ery, fetal brain injury, and recurrent reproductive failure One case report documented rapid

develop-ment over a 3-week period in association with accelerating maternal hypertension (40) Localized PVF

plaques have no known clinical significance (41)

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

MAternAl VASCulAr leSIOnS 13

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

abrup-tio placentae occurs most commonly after 30 weeks of gestaabrup-tion in women with hypertensive disorders

Etiology: Abruptio placentae represents rupture of one or more spiral arteries There are three

recog-nized 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

rup-ture 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,

ret-romembranous extension, and dissection into the villous parenchyma (basal intervillous thrombus)

(Figure 1.19) Premature placentas often show acute villous stromal hemorrhage Retroplacental

hem-orrhages present for 6 or more hours prior to delivery have changes indicative of overlying recent

vil-lous 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

occur-ring 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

14 PlACentA

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

periph-ery 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

mem-brane 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

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

FetAl VASCulAr leSIOnS 15

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

near-term 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

antiphospho-lipid 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

mon-itoring, and oligohydramnios Affected infants are at risk for neonatal encephalopathy, cerebral palsy,

thrombocytopenia, disseminated intravascular coagulation, major vessel thrombi, and severe liver

dis-ease (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

hem-orrhagic endovasculitis) (Figure 1.23) Organized thrombi in major fetal vessels are identified in

one-third to two-one-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)

16 PlACentA

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

umbili-cal 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

sono-graphic 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)

Cir-culatory 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

previ-ously

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

avas-cular villi or villi with villous stromal–vasavas-cular karyorrhexis are usually concentrated near the basal

plate (Figure 1.24)

FiGure 1.22 Fetal thrombotic vasculopathy:

intermediate 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 endovasculi- tis”) (H&E; 320) Distal villi with karyorrhectic debris and

fragmented red blood cells in the stroma

FetAl VASCulAr leSIOnS 17

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

prev-alence of fetomaternal hemorrhage as determined by the presence of fetal red blood cells in the

mater-nal 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

correspond-ing 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

move-ment, 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

Kleihauer-Betke 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

ges-tational age

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

18 PlACentA

Etiology: Intramembranous fetal vessels, usually associated with membranous insertion of the

umbil-ical 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 pla-centa 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 cally reduced perfusion of the placenta and other organs not directly required for fetal viability (i.e., heart and brain) (66, 67)

chroni-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 19

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

pregnan-cies 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

mater-nal 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.

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

20 PlACentA

Microscopic: More than 10 capillary cross sections should be observed in at least 10 villi in several

dif-ferent 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

preva-lence 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

gesta-tions 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

prom-inent 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,

infarc-tion can lead to obliterainfarc-tion 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

cel-lular 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)

Hyper-capillarization 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 21

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

associ-ated 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

perfu-sion 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

vascu-lar 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

eXTrinsiC ProCess

FiGure 1.30 Membrane meconium (recent exposure)

(H&E; 340) Vacuolated macrophages containing ill-defined

granular red-brown pigment Amniotic epithelium shows

22 PlACentA

Microscopic: Abundant pigment-laden macrophages are seen in the dense fibrous stroma of the

chori-onic plate (Figure 1.31) Macrophages may also be observed in the wall of large chorichori-onic 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

vas-cular smooth muscle in the umbilical cord and chorionic plate (Figure 1.32) (92, 93) Adjacent

myo-cytes 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

submit-ted to pathology and is most common at term (94)

Etiology: Prolonged severe fetal hypoxia and selected cytokines such as erythropoietin and IL-6

stimu-late 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 blastemia) (H&E; 340) Normoblasts with circular hyper-

(normo-chromatic nuclei and scant glassy eosinophilic cytoplasm are noted in some villous capillaries

MultIPle PreGnAnCY 23

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

incom-patibility, 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

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

n diChorioniC Twin PlaCenTas

Prevalence/gestational age: Dichorionic twin placentas may result from either implantation of

mul-tiple 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

under-going 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

MulTiPle PreGnanCy

24 PlACentA

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

mem-brane 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

sep-arately weighed and assessed for abnormalities, such as abnormal umbilical cord insertion site

Plaque-like 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

dichori-onic 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

arte-riovenous 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 25

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

occu-pied 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

inter-vening 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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