bladder pathology · 2013-07-23 · embryology early in fetal life, when cloacal dilation ﬁrst...

BLADDER PATHOLOGY

BLADDER PATHOLOGY

LIANG CHENG, MDProfessor of Pathology and UrologyChief of Genitourinary Pathology DivisionDirector of Fellowship in Urologic PathologyDirector of Molecular Pathology LaboratoryIndiana University School of MedicineIndianapolis, Indiana, USA

ANTONIO LOPEZ-BELTRAN, MD, PHDProfessor of Anatomic PathologyDepartment of SurgeryCordoba University School of MedicineCordoba, Spain

DAVID G. BOSTWICK, MD, MBAMedical DirectorBostwick LaboratoriesGlen Allen, Virginia, USA

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright © 2012 by Wiley-Blackwell. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

Cheng, Liang.Bladder pathology / Liang Cheng, Antonio Lopez-Beltran, David G. Bostwick.

p. ; cm.Includes bibliographical references.ISBN 978-0-470-57108-8 (cloth)I. Lopez-Beltran, Antonio. II. Bostwick, David G. III. Title.[DNLM: 1. Urinary Bladder—pathology. 2. Neoplasm Staging. 3. Urinary Bladder Diseases—

pathology. 4. Urinary Bladder Neoplasms—pathology. WJ 500]616.6′2071—dc23

2011044251

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Contents

Preface vii

1 Normal Anatomy and Histology 1

2 Inflammatory and InfectiousConditions 17

3 Urothelial Metaplasia andHyperplasia 45

4 Polyps and Other NonneoplasticBenign Conditions 71

5 Benign Epithelial Tumors 85

6 Flat Urothelial Lesions withAtypia and Urothelial Dysplasia 99

7 Urothelial Carcinoma in Situ 113

8 Bladder Cancer: General Features 137

9 Grading of Bladder Cancer 161

10 Stage pT1 Urothelial Carcinoma 193

11 Staging of Bladder Cancer 217

12 Histologic Variants of UrothelialCarcinoma 239

13 Adenocarcinoma and Its PutativePrecursors and Variants 283

14 Squamous Cell Carcinoma andOther Squamous Lesions 305

15 Neuroendocrine Tumors 323

16 Sarcomatoid Carcinoma(Carcinosarcoma) 355

17 Bladder Tumors with InvertedGrowth 383

18 Congenital Disorders andPediatric Neoplasms 399

19 Soft Tissue Tumors 423

20 Lymphoid and HematopoieticTumors 461

21 Urothelial Carcinoma FollowingAugmentation Cystoplasty 471

22 Other Rare Tumors 485

23 Secondary Tumors 497

24 Treatment Effects 507

25 Handling and Reporting ofBladder Specimens 525

26 DiagnosticImmunohistochemistry 545

27 Pathology of the Urachus 567

28 Pathology of Renal Pelvis, Ureter,and Urethra 581

29 Molecular Determinants ofTumor Recurrence 609

30 Urinary Cytology 623

31 Evaluation of Hematuria andUrinalysis 645

32 Urine-based Biomarkers 655

33 Tissue-based Biomarkers 679

34 Molecular Pathology of BladderCancer 707

Index 735

v

Preface

The urinary bladder is subject to a unique andextraordinarily diverse array of congenital, inflamma-tory, metaplastic, and neoplastic abnormalities. Theobjective of Bladder Pathology is to provide contem-porary, comprehensive, and evidence-based practiceinformation for pathologists, urologists, and medicaloncologists. A full spectrum of pathologic conditionsthat afflict the bladder and urothelium are describedand illustrated. The book is aimed especially atthe practicing pathologist, with an emphasis ondiagnostic criteria and differential diagnoses. It is ourhope that this very comprehensive book, consistingof 34 chapters, 754 pages, 112 tables, and 1741full color photographs, will aid in the pathologist’srecognition, understanding, and accurate interpre-tation of the light microscopic findings in bladderspecimens.

This is an age of enlightenment in surgical pathol-ogy. The emergence of personalized medicine withnew understandings of cancer genetics has created aparadigm shift in our practice. Greater weight con-tinues to be placed on an evidence-based approachto diagnosis and patient management. This includesan emphasis on the scientific validation of our diag-nostic methods and their meaningful application inpractice. This is especially true in the managementof patients with medical conditions involving the uri-nary bladder. Cancer of the bladder represents thefifth most common cancer in the human body, withmore than 60,000 new carcinoma diagnoses annuallyin the United States. Many patients with bladder can-cer have a prolonged survival, necessitating long-termfollowup, including the procurement of numerous sub-sequent cystoscopic biopsies and urine samples forhistologic and cytopathologic evaluation. This, in turn,has generated a considerable diagnostic burden for thepathologist and cost to the health care system. It is ourhope that continuing advances in the urinary bladder

field can lessen the impact of these burdens on bothpractitioners and patients.

In the text we strive to provide a comprehensiveresource for practicing surgical pathologists and theirclinical colleagues so that they may better meet thedaily demands and challenges of this ever-evolvingfield. We hope that this volume has captured our senseof excitement as we strive to stay on the cutting edgeof these advances in medical practice. We have incor-porated recent advances in molecular genetics of theurinary bladder with discussion of their current orpotential impact on patient care. It is our intent toprovide a framework by which diagnostic criteria canbe compared, evaluated, and integrated with molecularand other ancillary test data.

We are indebted to many people who have beeninvolved in the preparation of this book. We are grate-ful to our mentors, colleagues, and trainees who havechallenged and inspired us. They include Drs. GeorgeM. Farrow, John N. Eble, David G. Grignon, ThomasM. Ulbright, Michael O. Koch, Gregory T. MacLen-nan, John F. Gaeta, Rodolfo Montironi, and manyothers. Our special thanks go to Ryan P. Christy fromthe Multimedia Education Division of the Departmentof Pathology at Indiana University, who edited theillustrations, and to Tracey Bender for her assidu-ous assistance in the editorial process. We also thankthe staff at Wiley-Blackwell, including Thomas H.Moore, Ian Collins, Angioline Loredo, and SheebaKarthikeyan for their invaluable support throughoutthe project. Finally, we earnestly solicit feedback andconstructive criticism from readers so that the bookmay be improved in future editions.

Liang ChengAntonio Lopez-Beltran

David G. BostwickMarch 2012

vii

Chapter 1

Normal Anatomy and Histology

Embryology 2

Anatomy 2

Gross Anatomy 2

Blood Supply and Lymphatic Drainage 2

Nerve Supply 2

Normal Histology 3

Urothelium 3

Bladder Wall 6

Paraganglionic Tissue 10

The Urachus 10

The Renal Pelvis and Ureters 10

The Urethra 11

Immunohistochemical Findings 14

References 14

Bladder Pathology, First Edition. Liang Cheng, Antonio Lopez-Beltran, David G. Bostwick.© 2012 Wiley-Blackwell. Published 2012 by John Wiley & Sons, Inc.

1


Embryology

Early in fetal life, when cloacal dilation first appears andthe hindgut ends in a blind sac, an ectodermal depressiondevelops under the root of the tail.1 This depression, knownas the proctoderm, deepens until only a thin layer of tis-sue, the cloacal membrane, remains between the gut andthe outside of the body. The division of the cloaca resultsfrom development of the urorectal fold that closes caudallytoward the cloacal membrane. As the urorectal fold cutsprogressively deeper into the cloaca, a wedge-shaped massof mesenchyme accompanies it and forms a dense septumbetween the urogenital sinus anteriorly and the rectum pos-teriorly. This separation of the cloaca is completed beforethe cloacal membrane ruptures, so that its two parts openindependently. When it first opens to the outside, the uro-genital sinus, which is the ventral division of the cloaca, istubular and continuous with the allantois. At this stage, itcan be divided into a ventral or pelvic portion, which willbecome the bladder proper, and a urethral portion, whichreceives the mesonephric and fused mullerian ducts andlater becomes the prostatic and membranous urethra in themale and the entire urethra in the female.2

After 8 weeks, the ventral part of the urogenital sinusexpands to form an epithelial sac, the apex of which tapersinto an elongated narrowed urachus. The splanchnic meso-derm surrounding both segments differentiates as interlac-ing bands of smooth muscle fibers and an outer fibrocon-nective tissue coat. By 12 weeks, the layers of the adulturethra and bladder can be recognized. This sequence ofevents indicates that the detrusor muscle and the urethralmusculature have the same origin, constituting one unin-terrupted structure.2 This arrangement is easily observed inthe female, in that the bladder and urethra form one tubu-lar unit with expansion of the upper part. However, in themale, the structure is complicated by simultaneous devel-opment of the prostate gland. The developmental sequenceis the same in both genders, and the structural arrangementin the male is only slightly more complex than that in thefemale.2

Anatomy

Gross Anatomy

The bladder is a hollow muscular organ whose main func-tion is that of a reservoir. When empty, the adult bladder liesbehind the symphysis pubis and is largely a pelvic organ.In infants and children, it is more cephalad than in adults.When full, the bladder rises above the symphysis and canreadily be palpated or percussed. When overdistended, as

in acute and chronic urinary retention, it may cause thelower abdomen to bulge visibly and is easily palpable in thesuprapubic region. The empty bladder has an apex (supe-rior surface), two infralateral or anterolateral surfaces, abase (posterior surface), and a neck. The apex extends ashort distance above the pubic bone and ends as a fibrouscord derivative of the urachus. This fibrous cord extendsfrom the apex of the bladder to the umbilicus between theperitoneum and the transversalis fascia. It raises a ridge ofperitoneum called the median umbilical ligament. There isa peritoneal covering at the apex in both sexes that alsocovers a small part of the base in men.2,3

The apex of the bladder is apposed to the uterus andileum in the female and to the ileum and pelvic portion ofthe colon in the male. The base of the bladder faces pos-teriorly and is separated from the rectum by the uterus andvagina in the female, and by the vasa deferentia, seminalvesicles, and ureters in the male. The anterolateral sur-face on each side of the bladder is apposed to the pubicbone, levator ani, and obturator internus muscles, but thecentral anterior bladder is separated from the pubic boneby the retropubic space, which contains abundant fat andvenous plexuses. The neck of the bladder, its most inferiorpart, connects with the urethra. When the bladder is dis-tended with urine, the neck remains fixed and stationary,whereas the dome rises above the pelvic cavity into thelower abdomen, touching the posterior aspect of the loweranterior abdominal wall and the small and large bowels.3

Beneath the urothelial lining of the inner bladder, there isloose connective tissue that permits considerable stretchingof the mucosa. As a result, the urothelial mucosal liningis wrinkled when the bladder is empty but smooth andflat when distended. This arrangement exists throughout thebladder except at the trigone, where the mucous membraneadheres firmly to the underlying muscle; consequently, thetrigone is always smooth, regardless of the level of disten-sion (Figs. 1-1 and 1-2).

Blood Supply and Lymphatic Drainage

The bladder is supplied by the superior, middle, and inferiorvesical arteries, all of which are branches of the anteriordivision of the hypogastric artery. Between the bladder wallproper and the outer adventitial layer, there is a rich plexusof veins that ultimately terminate in the hypogastric veinsafter converging in several main trunks.

The bladder lymphatics drain into the external iliac,hypogastric, and common iliac lymph nodes. There arerich lymphatic anastomoses between the pelvic and genitalorgans.4–6

Nerve Supply

The bladder is richly innervated by divisions of theautonomic nervous system.2,7 Sympathetic nerves originate

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Figure 1-1 Normal trigone (A and B).

from the lower thoracic and upper lumbar segments, mainlyT11–T12 and L1–L2. These sympathetic fibers descendinto the sympathetic trunk and the lumbar splanchnicnerves, connecting with the superior hypogastric plexus, aninferior extension of the aortic plexus. The latter separatesinto the right and left hypogastric nerves, and theseextend inferiorly to join the pelvic plexus of the pelvicparasympathetic nerves. Parasympathetic nerves arise fromsacral segments S2–S4, and these form the rich pelvicparasympathetic plexus. This plexus joins the sympathetichypogastric plexus, and vesical branches emerge from thisplexus toward the bladder base, innervating the bladderand urethra.7,8

Normal Histology

Urothelium

The urothelium is a unique stratified epithelium of vari-able thickness (Figs. 1-3 to 1-6). The number of cell layers

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Figure 1-2 Normal trigone in a woman during thereproductive years. Note the squamous mucosa and closelypacked underlying muscle (A and B).

Figure 1-3 Normal urothelium. The thickness of urotheliumis variable, up to seven cell layers in normal urothelium. Notethe prominent superficial umbrella cells.

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Figure 1-4 Normal urothelium (A and B). Cytoplasmicvacuolization is observed. In this preparation, the urotheliumis up to seven cells in thickness (B).

depends on the degree of distension of the bladder, usuallyvarying from three to seven layers. When distended, thebladder is three to six cell layers thick, although the typicalbiopsy contains about five layers; in the contracted state,it consists of six to eight layers.9 For practical purposes,urothelium composed of more than seven cell layers is con-sidered abnormal unless this finding can be attributed totangential cutting of tissue.10,11 In addition, the urotheliumis thought to be monoclonal in origin, with some featuresof mosaicism.12

The normal urothelium contains a layer of large superfi-cial cells that are frequently multinucleated, often referredto as umbrella cell thickness (Figs. 1-7 to 1-9). These cellshave abundant eosinophilic cytoplasm, with large nucleiwhose long axes are perpendicular to those of the smallercells of the underlying basal and intermediate cell lay-ers. The superficial cells vary in size and configurationaccording to the degree of bladder distension and angle

Figure 1-5 Normal urothelium. Note the orderlyarrangement of the urothelial cells. The long axis of urothelialcells is often perpendicular to the mucosal surface. Thesuperficial cells are less distinct. Prominent nuclear groovesare noted in some cells.

Figure 1-6 Normal urothelium. Note the variable thicknessof urothelium in this preparation. The superficial cells haveprominent cytoplasmic vacuolization.

Figure 1-7 Normal urothelium. Note the prominentsuperficial cells. Nuclear vacuolization is occasionally seen inintermediate cells. Some variation of cell size and shape canbe observed in normal urothelium and should not beinterpreted as dysplasia.

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Figure 1-8 Normal urothelium. Note the prominentsuperficial cells.

Figure 1-9 Normal urothelium. Basal and intermediate cellsare located between the basal lamina and the superficial cells.Occasional prominent nuclear grooves may be seen. Note thebinucleated superficial umbrella cells.

of tissue section; they may appear cuboidal in the dis-tended bladder, but are often flattened. In addition, superfi-cial cells are loosely attached to the underlying cells despitebeing interconnected with each other by extensive junc-tional complexes13 and may be absent from otherwise nor-mal urothelium in routine biopsies. Superficial umbrellacells express uroplakins and cytokeratin 20 with immuno-histochemistry. The apical plasmalemma is thickened, withstiff plaques, unlike the short microvilli seen in the under-lying intermediate cells.13 However, the trigonal superficialcells of women during the reproductive years have a cob-blestone pattern with long clubbed microvilli.14 Superficialcells may persist on the surface of papillary urothelial car-cinoma, particularly low grade carcinomas—a finding of

potential importance in pathologic grading of bladder can-cer (see also Chapter 9).

Basal and intermediate cells are located between thebasal lamina and the superficial cells (Figs. 1-8 to 1-10).These cells are morphologically identical to each other, andare distinguished only by their position in the mucosa.13

They are regularly arranged, with distinct cell boundariesand oval, round, or fusiform nuclei with occasional promi-nent nuclear grooves. The nuclei are located centrally inthe cells and contain finely granular chromatin that oftenaccentuates the nuclear borders. Nucleoli are usually smalland difficult to detect. Mitotic figures are rare in the nor-mal urothelium. The basal layer of epithelial cells expressesBcl-2, while the intermediate cells express RB1 and PTENat varying intensities. HER2 and p53 are not expressedby normal urothelial cells. Ki67, indicating proliferation,may not be expressed in a single field. The long axis ofthe basal and intermediate cells is perpendicular to thebasement membrane. The basement membrane is usuallynot visible in routine hematoxylin and eosin or periodicacid–Schiff stained sections, but appears as a razor-thinlayer beneath the mucosa when present. Basement mem-brane markers such as laminin and type IV collagen maybe useful diagnostically in select cases to define the base-ment membrane, but are not employed routinely.15 Delicatecapillaries of the muscularis mucosae are in intimate asso-ciation with the basement membrane, and invaginations ortangential cutting may create the factitious appearance ofintraepithelial extension.

The urothelium is able to respond to thermal, mechan-ical, and chemical stimuli (“sensor functions”) and hasthe ability to release chemicals (“transducer functions”).16

Urothelial basal cells express certain receptors and ionchannels (e.g., vanilloid receptor-1), similar to afferent

Figure 1-10 Normal urothelium. Basal and intermediatecells are more densely packed with a higher nuclearcytoplasmic ratio than that of superficial cells.

5


nerves.16 The presence of afferent nerves adjacent to theurothelium suggests that these cells may be targets fortransmitter release from bladder nerves or that chemicalsreleased by urothelial cells may alter afferent excitability.

Bladder Wall

The lamina propria, located beneath the basement mem-brane, consists of a compact layer of fibrovascular connec-tive tissue (Figs. 1-11 to 1-13). It may contain an incom-plete muscularis mucosae composed of thin delicate smoothmuscle fibers that may be mistaken for muscularis pro-pria in biopsy specimens (Figs. 1-14 to 1-16).17–23 Themuscularis mucosae is an important diagnostic pitfall inevaluating bladder carcinoma because the management ofcancer invading the muscularis propria is different from thatof tumors limited to the lamina propria and surrounding the

Figure 1-11 Normal lamina propria.



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Figure 1-14 Muscularis mucosae in the lamina propria (Aand B). The muscularis mucosae consists of scant delicatemuscle bands interspersed with blood vessels and connectivetissue stroma.

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Figure 1-15 Muscularis mucosae.

Figure 1-16 Muscularis mucosae.

muscularis mucosae. Therefore, it is important for patholo-gists to be aware of the existence of delicate muscle bundleswithin the lamina propria.21,22,24 In biopsy specimens, thesesmooth muscle fibers may appear as a continuous layer, adiscontinuous or interrupted layer, or as scattered thin bun-dles of smooth muscle fibers that do not form an obviouslayer (Fig. 1-17).22,25 These thin muscle fibers lie paral-lel to the mucosal surface, midway between the urotheliumand the underlying muscularis propria.

Moderate-sized or large thick-walled blood vessels are aconstant feature of the lamina propria, running parallel tothe surface urothelium, in close association with the smoothmuscle fibers of the muscularis mucosae (Fig. 1-18). How-ever, these vessels are variable in distribution and may beclose to the superficial lamina propria (Figs. 1-19 and 1-20).Therefore, large vessels cannot be used as a substitute formuscularis mucosae, as in some studies. It may be dif-ficult to distinguish muscularis mucosae from muscularis

Figure 1-17 Muscularis mucosae in a biopsy specimen.

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Figure 1-18 Musularis mucosae in close proximity to largevessels (A and B).

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Figure 1-19 Large vessels may be seen in the superficiallamina propria and may or may not be associated with themuscularis mucosae. Therefore, large vessels cannot be usedas a substitute for the muscularis mucosae.

Figure 1-20 Variable distribution of large vessels andvariably sized muscularis mucosae bundles.

propria (detrusor muscle). Trichome staining may be use-ful to resolve difficult cases.26 Recent studies suggest thatsmoothelin can be a marker of interest in differentiatingmuscularis mucosae (negative or weak) from muscularispropria (positive and intense) (Fig. 1-21).27–29

To avoid overstaging bladder cancer, it is also importantfor the pathologist to be aware of the existence of fat withinthe lamina propria and the muscularis propria (Figs. 1-22and 1-23).30 Occasional bizarre stroma cells may be seen inthe lamina propria and can be mistaken for invasive cancercells. In difficult cases, immunostaining for cytokeratins ishelpful. These bizarre stroma cells are negative for cyto-keratin staining (Figs. 1-24 and 1-25).

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Figure 1-21 The muscularis mucosae is negative or showsweaker staining than the muscularis propria (A to C).Smoothelin usually stains strongly in the muscularis propria(detrusor muscle) (C).

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Figure 1-22 Adipose tissue can be seen in the laminapropria.

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Figure 1-23 Adipose tissue is present in both the laminapropria and the muscularis propria (A and B). The presence offat invasion in transurethral resection specimens does notindicate extravesical extension.

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Figure 1-24 Bizarre stromal cells in the lamina propria(A and B).

Figure 1-25 Bizarre stromal cells in the lamina propria.

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Figure 1-26 Muscularis propria (detrusor muscle). Note thecontrast between the detrusor muscle and the muscularismucosae in the lamina propria.

The muscle proper (detrusor muscle) of the bladder, themuscularis propria, is moderately thick and consists of aninner longitudinal layer, middle circular layer, and outerlongitudinal layer (Fig. 1-26). It spirals around each ureteralorifice and increases in thickness around the internal ure-thral orifice, forming the internal sphincter of the bladder.The muscularis is surrounded by a coat of fibroelastic con-nective tissue, the adventitia, and perivesical fat.

Paraganglionic Tissue

Paraganglia are rarely found in routine sections of the uri-nary bladder.31 Their presence in a bladder biopsy maybe confused with neoplasm. Distinguishing features thatare useful include the distinctive arrangement of cell nests,sinusoidal vascular pattern, monotonous benign cytology ofthe cells, and the absence of a stromal reaction.32 Paragan-glionic tissue typically demonstrates immunoreactivity withneuroendocrine markers such as chromogranin, synapto-physin, and neuron-specific enolase. The sustentacular cellsexhibit immunostaining for S100 protein.

The Urachus

The urachus is an intraabdominal embryonic remnant. Itcontains the allantois, connecting the apex of the urinarybladder to the body wall at the umbilicus. The allantoisoriginates in the portion of the yolk sac that gives rise tothe cloacal portion of the hindgut. As the embryo grows,the urachus elongates to maintain its connection with thebladder dome and the body wall. At birth, the dome ofthe bladder and the umbilicus are closely opposed, andthe urachus is only 2.5 to 3 mm long, with a diameterof 1 mm throughout most of its course and 3 mm whereit joins the bladder.33 The urachus lies in a space anteriorto the peritoneum, bounded anteriorly and posteriorly bythe umbilicovesical fascia.34 Laterally, it is bounded by thetwo umbilical arteries, which, in turn, are surrounded byumbilicovesical fascia. Inferiorly, the umbilicovesical fas-cial layers cover the surface of the dome of the bladder.This space, the space of Retzius, is roughly pyramidal, andfascial planes separate it from the peritoneum and otherstructures. At the junction with the urinary bladder, the adulturachus is 4 to 8 mm wide, narrowing to about 2 mm at itssuperior end.

The urachus has three segments: supravesical, intra-mural, and intramucosal.33 Tubular urachal remnants arefound within the wall of the urinary bladder in approx-imately one-third of adults and are evenly distributedbetween men and women. There are three architecturalpatterns of intramural urachal canals, varying from simpletubular canals to complex branching canals (Fig. 1-27).35

The mucosal portion of the urachus may have a widediverticular opening, papilla, or a small opening flush withthe mucosal surface. The majority (70%) of intramuralurachal remnants are lined by urothelium; the remainderare lined by columnar epithelium, occasionally withsmall papillae or, rarely, mucous goblet cells or mucus-secreting columnar epithelium in women (Figs. 1-28and 1-29).35–37

The Renal Pelvis and Ureters

The ureter and renal pelvis develop from the ampullary bud,which arises from the distal mesonephric duct during thefourth week of development. As the ureter elongates, thereis a period of luminal obliteration followed by recanaliza-tion in the fifth week. Recanalization begins in the middleof the ureter and extends proximally and distally with theureteropelvic and ureterovesical junctions; these are the lastsegments to recanalize. The mesonephric duct distal to theampullary bud (the common nephric duct) is incorporated

10


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Figure 1-27 Patterns of intramural urachal canals: (A) type I, tubular canal without complexity; (B) type II; tubular canal withmarked segmental dilatation and variable curvature; (C) type III, tubular canal with marked tortuosity and distortion, includingsegmental dilatation.

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Figure 1-28 Normal urachus lined by stratified urothelium.

into the developing urogenital sinus, while the ureteral ori-fice migrates to the trigone and contributes to the prostaticurethra in the male.

Concomitant development of the male and femalereproductive tract forms the mesonephric (wolffian) and

mullerian ducts, respectively; division of the cloaca intobladder and hindgut occurs as the ureter and kidneydevelop. As a consequence, multiple malformations inthese areas often occur together.

The lumen of the renal pelvis and ureter is linedby urothelium, which rests on a basement membrane(Fig. 1-30). The urothelium is composed of three to fivelayers of cells in the pelvis and four to seven layers ofcells in the ureter. The pelvis and ureter have a continuousmuscular wall that originates in the fornices of the minorcalyces as small interlacing fascicles of the smooth musclecells. The muscularis propria is not divided into distinctlayers. Near the bladder, the ureter acquires an externalsheath from the detrusor muscle, and the muscle fasciclesbecome oriented longitudinally. The longitudinal fiberscontinue through the wall of the bladder and into thesubmucosa, where they surround the ureteral orifice andcontribute to the trigone muscle.

The Urethra

The epithelium of the urethra is derived from the urogen-ital sinus, which is formed when the endodermal cloacadivides into the rectum dorsally and the urogenital sinusventrally, separated by the urorectal septum. In women,the epithelium of the urethra is derived from endoderm ofthe urogenital sinus, while the surrounding connective tis-sue and smooth muscle arise from splanchnic mesenchyme.In men, the epithelium is also derived from the urogenitalsinus except in the fossa navicularis, where it is derivedfrom ectodermal cells migrating from the glans penis. Asin women, the connective tissue and smooth muscle sur-rounding the male urethra is derived from splanchnic mes-enchyme.

The male urethra is 15 to 20 cm long and is dividedin three anatomical segments (Figs. 1-31 and 1-32). The

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Figure 1-29 Urachal remnants (A to D).

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Figure 1-30 Normal ureter (A and B).

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Figure 1-31 Normal urethra in a male patient (A and B).

prostatic urethra begins at the internal urethral orifice atthe bladder neck and extends through the prostate to theprostatic apex. In the central part of the urethral crest isan eminence called the verumontanum. The verumontanumcontains a slit-like opening that leads to an epithelium-linedsac called the prostatic utricle, a mullerian vestige. The ejac-ulatory ducts empty into the urethra on either side of theprostatic utricle. The membranous urethra extends from theprostatic apex to the bulb of the penis. Cowper glands arelocated on the left and right sides of the membranous ure-thra and their ducts empty into it. The penile urethra extendsfrom the lower surface of the urogenital diaphragm to theurethral meatus in the glans penis. Bulbourethral glandsare located in the proximal (bulbous) portion of the penileurethra. In addition, scattered mucus-secreting periurethralglands (Littre glands) are present at the periphery of thepenile urethra except anteriorly (Fig. 1-33). The majorityof unmyelinated nerve fibers penetrate the smooth musclelayers at 5 o’clock and 7 o’clock, whereas the majority ofmyelinated nerve fibers penetrate the striated muscles of the

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Figure 1-32 Normal urethra and periurethral glands(A and B).

Figure 1-33 Littre glands are lined by mucus-secretingcolumnar cells.

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Figure 1-34 Transition from urothelium to squamousepithelium in the urethra.

prostatic capsule and of the urethral sphincter at 9 o’clockand 3 o’clock.

The type of epithelium lining the urethra varies alongits length (Fig. 1-34). In general, urothelium lines the pro-static urethra, pseudostratified columnar epithelium linesthe membranous segment and most of the penile urethra,and nonkeratinized stratified squamous epithelium lines thefossa navicularis and external urethral orifice. In females,the proximal one-third of the urethra is lined by urothe-lium and the distal two-thirds by nonkeratinized stratifiedsquamous epithelium. The proximal one-third consists of acircular smooth muscle sphincter, the middle one-third oftwo circular layers of smooth and striated muscle fibers,and the distal one-third of a circular layer of smooth mus-cle fibers surrounded by an omega-shaped layer of striatedmuscle fibers. In the proximal one-third of the urethralsphincter, myelinated fibers run with unmyelinated fibersfrom the pelvic plexus. These fibers are closely related tothe lateral and anterior aspects of the vagina. Unmyelinated

fibers enter the smooth muscle part of the sphincter at 4o’clock and 8 o’clock, whereas most myelinated fibers enterthe sphincter at 3 o’clock and 9 o’clock. The female urethrais approximately 4 cm long, and, at its periphery, containsparaurethral Skene glands.

Immunohistochemical Findings

The urothelium has a characteristic immunophenotype. Itexpresses cytokeratins of both low and high molecularweights, including cytokeratins 7, 8, 13, and 19; cytoker-atins 18 and 20 are present in the superficial cells.38–41

This pattern of expression differs from that of normal strat-ified squamous epithelium, which shows predominantlyhigh molecular weight cytokeratin immunoreactivity andfrom endometrium, endocervix, colorectum, and prostate,which demonstrate a preponderance of low molecularweight cytokeratin. High molecular weight cytokeratinimmunoreactivity is restricted to the basal cell layer ofthe urothelium and squamous mucosa of the trigone. Thiscan also be readily stained with antikeratin MAC387,which is not present in basal cells but in squamous cells ofthe trigone.42 Other epithelial markers, such as epithelialmembrane antigen, carcinoembryonic antigen, and LeuM1,are found on the surface of the urothelium. The normalurothelium synthesizes blood group isoantigens A, B,and H(O) as well as Lewis blood group antigens.43

As mentioned above, the basal layer of urothelial cellsexpresses Bcl-2 while the intermediate cells express RB1and PTEN at varying intensities. HER2 and p53 are notexpressed by normal urothelial cells. Ki67, indicatingproliferation, is uncommon in the normal urothelium.Prostate-specific antigen (or human glandular kallikrein3), prostatic acid phosphatase, prostate-specific membraneantigen, and human glandular kallikrein 2 are not producedby the urothelium.

REFERENCES

1. Young RH. Non-neoplastic disordersof the urinary bladder. In: BostwickDG, Cheng L, eds. Urologic SurgicalPathology, 2nd ed. Philadelphia:Elsevier/Mosby, 2008;215–58.

2. Tanagho EA. Anatomy of the urinarytract. In: Walsh PC, Retik AB, StameyTA, Vaughan ED, eds. Campbell’sUrology, 6th ed. Philadelphia: W.B.Saunders, 1992;40–54.

3. Chevallier JM. The bladder. Surgical

anatomy. Cystectomy. Soins Chir1994;41–3.

4. Poggi P, Marchetti C, Tazzi A, ScelsiR. The lymphatic vessels and theirrelationship to lymph formation in thehuman urinary bladder. Lymphology1995;28:35–40.

5. Ravery V, Chopin DK, Abbou CC.Surgical anatomy of the lymphaticdrainage of the bladder. Ann Urol(Paris) 1993;27:9–11.

6. Scelsi R, Scelsi L, Gritti A, Gozo M,Reguzzoni M, Marchetti C. Structureof the lymphatic microcirculation inthe human urinary bladder withdifferent intraluminal pressure anddistension. Lymphology 1996;29:60–6.

7. de Groat WC. Anatomy andphysiology of the lower urinary tract.Urol Clin North Am 1993;20:383–401.

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8. Takenaka A, Kawada M, Murakami G,Hisasue S, Tsukamoto T, Fujisawa M.Interindividual variation in distributionof extramural ganglion cells in themale pelvis: a semi-quantitative andimmunohistochemical studyconcerning nerve-sparing pelvicsurgery. Eur Urol 2005;48:46–52.

9. Konishi T. Architectural ultrastructureof the urinary bladder epithelium. II.Changes in the urine-blood barrier inthe contracted and distended state inthe normal and inflammatory bladder.Hinyokika Kiyo 1988;34:23–31.

10. Montironi R, Mazzucchelli R,Scarpelli M, Lopez-Beltran A, ChengL. Morphological diagnosis ofurothelial neoplasms. J Clin Pathol2008;61:3–10.

11. Montironi R, Lopez-Beltran A,Scarpelli M, Mazzucchelli R, ChengL. Morphological classification anddefinition of benign, preneoplastic andnon-invasive neoplastic lesions of theurinary bladder. Histopathology2008;53:621–33.

12. Tsai YC, Simoneau AR, Spruck CH,3rd, Nichols PW, Steven K, BuckleyJD, Jones PA. Mosaicism in humanepithelium: macroscopic monoclonalpatches cover the urothelium. J Urol1995;153:1697–1700.

13. Congiu T, Radice R, Raspanti M,Reguzzoni M. The 3D structure of thehuman urinary bladder mucosa: ascanning electron microscopy study. JSubmicrosc Cytol Pathol2004;36:45–53.

14. Davies R, Hunt AC. Surfacetopography of the female bladdertrigone. J Clin Pathol1981;34:308–13.

15. Wilson CB, Leopard J, Nakamura RM,Cheresh DA, Stein PC, Parsons CL.Selective type IV collagen defects inthe urothelial basement membrane ininterstitial cystitis. J Urol1995;154:1222–6.

16. Birder LA, Kanai AJ, de Groat WC,Kiss S, Nealen ML, Burke NE,Dineley KE, Watkins S, Reynolds IJ,Caterina MJ. Vanilloid receptorexpression suggests a sensory role forurinary bladder epithelial cells. ProcNatl Acad Sci U S A2001;98:13396–401.

17. Anderstrom C, Johansson S, NilssonS. The significance of lamina propriainvasion on the prognosis of patients

with bladder tumors. J Urol1980;124:23–6.

18. Dixon JS, Gosling JA. Histology andfine structure of the muscularismucosae of the human urinary bladder.J Anat 1983;136:265–71.

19. Keep JC, Piehl M, Miller A, Oyasu R.Invasive carcinomas of the urinarybladder. Evaluation of tunicamuscularis mucosae involvement. AmJ Clin Pathol 1989;91:575–9.

20. Cheng L, Weaver AL, Neumann RM,Scherer BG, Bostwick DG. Substagingof T1 bladder carcinoma based on thedepth of invasion as measured bymicrometer. A new proposal. Cancer1999;86:1035–43.

21. Cheng L, Montironi R, Davidson DD,Lopez-Beltran A. Staging andreporting of urothelial carcinoma ofthe urinary bladder. Mod Pathol2009;22 (Suppl 2):S70–95.

22. Ro JY, Ayala AG, el-Naggar A.Muscularis mucosa of urinary bladder.Importance for staging and treatment.Am J Surg Pathol 1987;11:668–73.

23. Younes M, Sussman J, True LD. Theusefulness of the level of themuscularis mucosae in the staging ofinvasive transitional cell carcinoma ofthe urinary bladder. Cancer1990;66:543–8.

24. Cheng L, Bostwick DG. Progressionof T1 bladder tumors: better staging orbetter biology. Cancer1999;86:910–2.

25. Paner GP, Ro JY, Wojcik EM,Venkataraman G, Datta MW, AminMB. Further characterization of themuscle layers and lamina propria ofthe urinary bladder by systematichistologic mapping: implications forpathologic staging of invasiveurothelial carcinoma. Am J Surg Pathol2007;31:1420–9.

26. Aydin A, Ucak R, Karakok M, GuldurME, Kocer NE. Vascular plexus is adifferentation criterion for muscularismucosa from muscularis propria insmall biopsies and transurethralresection materials of urinary bladder?Int Urol Nephrol 2002;34:315–9.

27. Paner GP, Shen SS, Lapetino S,Venkataraman G, Barkan GA, QuekML, Ro JY, Amin MB. Diagnosticutility of antibody to smoothelin in thedistinction of muscularis propria frommuscularis mucosae of the urinarybladder: a potential ancillary tool in

the pathologic staging of invasiveurothelial carcinoma. Am J Surg Pathol2009;33:91–8.

28. Council L, Hameed O. Differentialexpression of immunohistochemicalmarkers in bladder smooth muscle andmyofibroblasts, and the potential utilityof desmin, smoothelin, and vimentin instaging of bladder carcinoma. ModPathol 2009;22:639–50.

29. Miyamoto H, Sharma RB, Illei PB,Epstein JI. Pitfalls in the use ofsmoothelin to identify muscularispropria invasion by urothelialcarcinoma. Am J Surg Pathol2010;34:418–22.

30. Bochner BH, Nichols PW, SkinnerDG. Overstaging of transitional cellcarcinoma: clinical significance oflamina propria fat within the urinarybladder. Urology 1995;45:528–31.

31. Honma K. Paraganglia of the urinarybladder. An autopsy study. ZentralblPathol 1994;139:465–9.

32. Young RH. Non-neoplastic epithelialabnormalities and tumor-like lesions.Pathology of the Urinary Bladder.New York: Churchill Livingstone,1989:1–63.

33. Begg RC. The urachus: its anatomy,histology and development. J Anat1930;64:170–83.

34. Gearhart JP, Jeffs RD. Urachalabnormalities. In: Walsh PC, RetikAB, Stamey TA, Vaughan ED, eds.Campbell’s Urology, 6th ed.Philadelphia: W.B. Saunders,1992;1815–21.

35. Schubert GE, Pavkovic MB,Bethke-Bedurftig BA. Tubular urachalremnants in adult bladders. J Urol1982;127:40–2.

36. Eble JN. Abnormalities of the urachus.In: Young RH, ed. Pathology of theUrinary Bladder. New York: ChurchillLivingstone, 1989.

37. Tyler DE. Epithelium of intestinal typein the normal urachus: a new theory ofvesical embryology. J Urol1964;92:505–7.

38. Alonso A, Ikinger U, Kartenbeck J.Staining patterns of keratins in thehuman urinary tract. Histol Histopathol2009;24:1425–37.

39. Hodges KB, Lopez-Beltran A,Emerson RE, Montironi R, Cheng L.Clinical utility ofimmunohistochemistry in thediagnoses of urinary bladder neoplasia.

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Appl Immunohistochem Mol Morphol2010;18:401–10.

40. Lopez-Beltran A.Immunohistochemical markers inevaluation of urinary and bladdertumors. Anal Quant Cytol Histol2007;29:121–2.

41. Yildiz IZ, Recavarren R, Armah HB,Bastacky S, Dhir R, Parwani AV.

Utility of a dual immunostain cocktailcomprising of p53 and CK20 to aid inthe diagnosis of non-neoplastic andneoplastic bladder biopsies. DiagnPathol 2009;4:35.

42. Lopez-Beltran A, Requena MJ,Alvarez-Kindelan J, Quintero A,Blanca A, Montironi R. Squamousdifferentiation in primary urothelial

carcinoma of the urinary tract as seenby MAC387 immunohistochemistry. JClin Pathol 2007;60:332–5.

43. Witjes JA, Umbas R, Debruyne FM,Schalken JA. Expression of markersfor transitional cell carcinoma innormal bladder mucosa of patientswith bladder cancer. J Urol1995;154:2185–9.

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Chapter 2

Inflammatory and Infectious Conditions

Acute and Chronic Cystitis and Their Variants 18

Acute and Chronic Cystitis 18

Papillary–Polypoid Cystitis (Papillary Cystitis;Bullous Cystitis) 19

Follicular Cystitis (Cystitis Follicularis) 22

Interstitial Cystitis 22

Eosinophilic Cystitis 25

Encrusted Cystitis 26

Emphysematous Cystitis 26

Gangrenous Cystitis 26

Hemorrhagic Cystitis 27

Viral Cystitis 27

Cystitis with Atypical Giant Stromal Cells 29

Denuding Cystitis 29

Radiation Cystitis 29

Chemical Cystitis 31

Diverticulitis 31

Granulomatous Cystitis 32

Postsurgical Necrobiotic Granuloma (Granulomaafter Transurethral Resection) 32

Suture Granuloma 32

BCG-induced Granulomatous Cystitis 33

Schistosomiasis (Bilharziasis)-associated Cystitis 33

Malakoplakia 35

Tuberculosis 36

Xanthoma and Xanthogranulomatous Cystitis 36

Other Forms of Granulomatous Cystitis 37

Other Infectious Cystitides 37

Fungal Cystitis 37

Actinomycosis 38

Miscellaneous Infectious Cystitides 40

References 40

Bladder Pathology, First Edition. Liang Cheng, Antonio Lopez-Beltran, David G. Bostwick.© 2012 Wiley-Blackwell. Published 2012 by John Wiley & Sons, Inc.

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Table 2-1 Inflammatory Conditions

Acute and chronic cystitisFollicular cystitisInterstitial cystitisEosinophilic cystitisEncrusted cystitisEmphysematous cystitisGangrenous cystitisHemorrhagic cystitisViral cystitisCystitis with atypical giant stromal cellsDenuding cystitis

Granulomatous cystitisPostsurgicalSuture granulomaBCG-inducedSchistosomiasisMalakoplakiaTuberculosisXanthomaOther

Other infection cystitidesFungalActinomycosisMiscellaneous cystitides

A wide variety of nonneoplastic inflammatory condi-tions may involve the bladder primarily or secondarily(Table 2-1).1

Acute and Chronic Cystitis and TheirVariants

Acute and Chronic Cystitis

Most cases of acute and chronic cystitis result frominfection with gram-negative coliform bacteria such asEscherichia coli (E. Coli).2,3 The most common portal ofentry is the urethra. Predisposing factors include structuralabnormalities of the urinary bladder, diverticula, calculi,any process or lesion that causes outflow obstruction,and systemic illnesses such as diabetes. Infectious causesof cystitis include bacterial, viral, fungal, and protozoalagents. Irritative agents that cause cystitis include traumafrom instrumentation and catheterization, radiation therapy,chemotherapy, bladder calculi, and chemical irritants suchas formalin, turpentine, and ether (chemical cystitis).4,5

Some cases of cystitis are of unknown etiology. Otherforms of cystitis include interstitial, eosinophilic, andfollicular cystitis.6

In early acute bacterial cystitis, there is vasculardilatation and congestion, erythematous and hemorrhagic

mucosa, and moderate to severe edema. With time,polypoid or bullous cystitis may develop, sometimeswith ulceration. The urothelium may be hyperplastic ormetaplastic, and, when ulcerated, is often covered by afibrinous membrane with neutrophils and bacterial colonies(Figs. 2-1 and 2-2). Stromal edema and chronic inflam-mation gradually become more pronounced, particularlyin the lamina propria (Fig. 2-3). If the acute inflammationpersists, chronic cystitis usually develops, sometimes withprominent mural fibrosis.

In chronic cystitis, the mucosa may be thin, hyperplastic,or ulcerated, often with changes of reactive atypia (Figs. 2-4to 2-6). Granulation tissue is typically conspicuous in theearly stages, and may be replaced by dense scarring, partic-ularly in the late healing stages. Edema may also be present(Fig. 2-7). This process may be transmural and involve

Figure 2-1 Acute cystitis. Numerous neutrophils are seen inthe urothelium.

Figure 2-2 Acute cystitis. Reactive changes are commonlyseen in the setting of acute cystitis and should not be mistakenfor dysplasia or carcinoma in situ.

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Figure 2-3 Acute cystitis. Note the stromal edema.

Figure 2-4 Chronic nonspecific cystitis. The mucosa is intactbut thinned, and the lamina propria contains a mixed chronicinflammatory infiltrate.

perivesicular tissue. Squamous metaplasia may develop ata later stage (Fig. 2-8).

Papillary–Polypoid Cystitis (Papillary Cystitis; BullousCystitis)

Polypoid cystitis may be clinically and microscopicallymistaken for papillary urothelial carcinoma.7–9 Polypoidcystitis refers to lesions with edematous and broad-basedpapillae (Figs. 2-9 to 2-12); the designation papillarycystitis is used when thin finger-like papillae are present(Figs. 2-13 and 2-14). In both, there is typically abundantchronic inflammation in the stroma, accompanied byprominent and often ectatic blood vessels. Sometimes theinflammation is not prominent, and the appearance variesfrom papillary or polypoid cystitis to bullous cystitis,depending on the amount of stromal edema. In bullouscystitis, the lesion is wider than lesions of polypoid orpapillary cystitis.10 On cystoscopy, the lesion frequentlysuggests papillary urothelial carcinoma.

Figure 2-5 Chronic cystitis with mucosal erosion.

Figure 2-6 Chronic cystitis with reactive epithelial changes.

Figure 2-7 Chronic cystitis with mucosal edema. Theoverlying urothelium is metaplastic.

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Figure 2-8 Chronic cystitis. Note the transition of normalurothelium to squamous epithelium (squamous metaplasia).

Figure 2-9 Polypoid cystitis with a broad frond of mucosawith prominent blood vessels and benign urothelial lining.

Figure 2-10 Polypoid cystitis with focal bullous formation.

Figure 2-11 Polypoid cystitis.

Figure 2-12 Polypoid cystitis. Broad polypoid growth thatimparts a cobblestone appearance cystoscopically.

Exophytic growth of polypoid and papillary cysti-tis can be confused with carcinoma.7,10 Occasionally,papillary–polypoid cystitis may be associated with reac-tive and metaplastic changes in the overlying or adjacenturothelium, with squamous metaplasia being the mostcommon. The urothelium may be hyperplastic, but it lackscytologic atypia. Less commonly, florid polypoid cystitismay suggest inverted papilloma.10 Two clinical settingssuggest that an exophytic bladder lesion is reactive orinflammatory—patients with an indwelling catheter11,12

and those with vesical fistula.10 Polypoid and bullouslesions are usually less than 0.5 cm in diameter, but larger,macroscopically visible lesions may involve the dome orposterior wall. The entire bladder is sometimes involvedwhen a catheter has been present for more than sixmonths.10,13–15 Long-standing cases of polypoid cystitismay have a fibrous rather than an edematous stroma. Themucosal changes associated with vesical fistula may havethe characteristics of reactive urothelium similar to what isseen in nonspecific chronic or acute cystitis.

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bladder pathology · 2013-07-23 · embryology early in fetal life, when cloacal dilation ﬁrst...

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