BLADDER PATHOLOGY BLADDER PATHOLOGY LIANG CHENG, MD Professor of Pathology and Urology Chief of Genitourinary Pathology Division Director of Fellowship in Urologic Pathology Director of Molecular Pathology Laboratory Indiana University School of Medicine Indianapolis, Indiana, USA ANTONIO LOPEZ-BELTRAN, MD, PHD Professor of Anatomic Pathology Department of Surgery Cordoba University School of Medicine Cordoba, Spain DAVID G. BOSTWICK, MD, MBA Medical Director Bostwick Laboratories Glen Allen, Virginia, USA A JOHN WILEY & SONS, INC., PUBLICATION Copyright©2012byWiley-Blackwell.Allrightsreserved. WileyBlackwellisanimprintofJohnWiley&Sons,formedbythemergerofWiley’sglobalScientific TechnicalandMedicalbusinesswithBlackwellPublishing. PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey. PublishedsimultaneouslyinCanada. 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Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprintmaynot beavailableinelectronicformats.FormoreinformationaboutWileyproducts,visitourwebsiteat www.wiley.com. LibraryofCongressCataloging-in-PublicationData: Cheng,Liang. Bladderpathology/LiangCheng,AntonioLopez-Beltran,DavidG.Bostwick. p.;cm. Includesbibliographicalreferences. ISBN978-0-470-57108-8(cloth) I.Lopez-Beltran,Antonio.II.Bostwick,DavidG.III.Title. [DNLM:1. UrinaryBladder—pathology. 2. NeoplasmStaging. 3. UrinaryBladderDiseases— pathology. 4. UrinaryBladderNeoplasms—pathology. WJ500] 616.6(cid:2)2071—dc23 2011044251 PrintedinSingapore 10 9 8 7 6 5 4 3 2 1 Contents Preface vii 1 Normal Anatomy and Histology 1 18 Congenital Disorders and Pediatric Neoplasms 399 2 Inflammatory and Infectious Conditions 17 19 Soft Tissue Tumors 423 3 Urothelial Metaplasia and 20 Lymphoid and Hematopoietic Hyperplasia 45 Tumors 461 4 Polyps and Other Nonneoplastic 21 Urothelial Carcinoma Following Benign Conditions 71 Augmentation Cystoplasty 471 5 Benign Epithelial Tumors 85 22 Other Rare Tumors 485 6 Flat Urothelial Lesions with 23 Secondary Tumors 497 Atypia and Urothelial Dysplasia 99 24 Treatment Effects 507 7 Urothelial Carcinoma in Situ 113 25 Handling and Reporting of 8 Bladder Cancer: General Features 137 Bladder Specimens 525 9 Grading of Bladder Cancer 161 26 Diagnostic Immunohistochemistry 545 10 Stage pT1 Urothelial Carcinoma 193 27 Pathology of the Urachus 567 11 Staging of Bladder Cancer 217 28 Pathology of Renal Pelvis, Ureter, 12 Histologic Variants of Urothelial and Urethra 581 Carcinoma 239 29 Molecular Determinants of 13 Adenocarcinoma and Its Putative Tumor Recurrence 609 Precursors and Variants 283 30 Urinary Cytology 623 14 Squamous Cell Carcinoma and Other Squamous Lesions 305 31 Evaluation of Hematuria and Urinalysis 645 15 Neuroendocrine Tumors 323 32 Urine-based Biomarkers 655 16 Sarcomatoid Carcinoma (Carcinosarcoma) 355 33 Tissue-based Biomarkers 679 17 Bladder Tumors with Inverted 34 Molecular Pathology of Bladder Growth 383 Cancer 707 Index 735 v Preface The urinary bladder is subject to a unique and field can lessen the impact of these burdens on both extraordinarily diverse array of congenital, inflamma- practitioners and patients. tory, metaplastic, and neoplastic abnormalities. The In the text we strive to provide a comprehensive objective of BladderPathology is to provide contem- resource for practicing surgical pathologists and their porary, comprehensive, and evidence-based practice clinical colleagues so that they may better meet the information for pathologists, urologists, and medical daily demands and challenges of this ever-evolving oncologists. A full spectrum of pathologic conditions field.Wehopethatthisvolumehascapturedoursense that afflict the bladder and urothelium are described of excitement as we strive to stay on the cutting edge and illustrated. The book is aimed especially at of these advances in medical practice. We have incor- the practicing pathologist, with an emphasis on porated recent advances in molecular genetics of the diagnostic criteria and differential diagnoses. It is our urinary bladder with discussion of their current or hope that this very comprehensive book, consisting potential impact on patient care. It is our intent to of 34 chapters, 754 pages, 112 tables, and 1741 provide a framework by which diagnostic criteria can full color photographs, will aid in the pathologist’s becompared,evaluated,andintegratedwithmolecular recognition, understanding, and accurate interpre- and other ancillary test data. tation of the light microscopic findings in bladder We are indebted to many people who have been specimens. involvedinthepreparationofthisbook.Wearegrate- This is an age of enlightenment in surgical pathol- ful to our mentors, colleagues, and trainees who have ogy. The emergence of personalized medicine with challenged and inspired us. They include Drs. George new understandings of cancer genetics has created a M. Farrow, John N. Eble, David G. Grignon, Thomas paradigm shift in our practice. Greater weight con- M. Ulbright, Michael O. Koch, Gregory T. MacLen- tinues to be placed on an evidence-based approach nan, John F. Gaeta, Rodolfo Montironi, and many to diagnosis and patient management. This includes others. Our special thanks go to Ryan P. Christy from an emphasis on the scientific validation of our diag- the Multimedia EducationDivisionof the Department nostic methods and their meaningful application in of Pathology at Indiana University, who edited the practice. This is especially true in the management illustrations, and to Tracey Bender for her assidu- of patients with medical conditions involving the uri- ous assistance in the editorial process. We also thank nary bladder. Cancer of the bladder represents the the staff at Wiley-Blackwell, including Thomas H. fifth most common cancer in the human body, with Moore, Ian Collins, Angioline Loredo, and Sheeba more than 60,000 new carcinoma diagnoses annually Karthikeyan for their invaluable support throughout in the United States. Many patients with bladder can- the project. Finally, we earnestly solicit feedback and cerhaveaprolongedsurvival,necessitatinglong-term constructive criticism from readers so that the book followup,includingtheprocurementofnumeroussub- may be improved in future editions. sequent cystoscopic biopsies and urine samples for histologicandcytopathologicevaluation.This,inturn, Liang Cheng hasgeneratedaconsiderablediagnosticburdenforthe Antonio Lopez-Beltran pathologistandcosttothehealthcaresystem.Itisour David G. Bostwick hope that continuing advances in the urinary bladder March 2012 vii Chapter 1 Normal Anatomy and Histology Embryology 2 BladderWall 6 Anatomy 2 ParaganglionicTissue 10 GrossAnatomy 2 TheUrachus 10 BloodSupplyandLymphaticDrainage 2 TheRenalPelvisandUreters 10 NerveSupply 2 TheUrethra 11 NormalHistology 3 ImmunohistochemicalFindings 14 Urothelium 3 References 14 BladderPathology,FirstEdition.LiangCheng,AntonioLopez-Beltran,DavidG.Bostwick. ©2012Wiley-Blackwell.Published2012byJohnWiley&Sons,Inc. 1 Normal Anatomy and Histology Embryology in acute and chronic urinary retention, it may cause the lowerabdomentobulgevisiblyandiseasilypalpableinthe suprapubic region. The empty bladder has an apex (supe- Early in fetal life, when cloacal dilation first appears and rior surface), two infralateral or anterolateral surfaces, a the hindgut ends in a blind sac, an ectodermal depression base (posterior surface), and a neck. The apex extends a developsundertherootofthetail.1 Thisdepression,known short distance above the pubic bone and ends as a fibrous as the proctoderm, deepens until only a thin layer of tis- cord derivative of the urachus. This fibrous cord extends sue, the cloacal membrane, remains between the gut and from the apex of the bladder to the umbilicus between the the outside of the body. The division of the cloaca results peritoneum and the transversalis fascia. It raises a ridge of fromdevelopmentoftheurorectalfoldthatclosescaudally peritoneum called the median umbilical ligament. There is toward the cloacal membrane. As the urorectal fold cuts a peritoneal covering at the apex in both sexes that also progressively deeper into the cloaca, a wedge-shaped mass covers a small part of the base in men.2,3 of mesenchyme accompanies it and forms a dense septum The apex of the bladder is apposed to the uterus and betweentheurogenitalsinusanteriorlyandtherectumpos- ileum in the female and to the ileum and pelvic portion of teriorly. This separation of the cloaca is completed before the colon in the male. The base of the bladder faces pos- the cloacal membrane ruptures, so that its two parts open teriorly and is separated from the rectum by the uterus and independently. When it first opens to the outside, the uro- vagina in the female, and by the vasa deferentia, seminal genital sinus, which is the ventral division of the cloaca, is vesicles, and ureters in the male. The anterolateral sur- tubular and continuous with the allantois. At this stage, it face on each side of the bladder is apposed to the pubic can be divided into a ventral or pelvic portion, which will bone, levator ani, and obturator internus muscles, but the become the bladder proper, and a urethral portion, which central anterior bladder is separated from the pubic bone receives the mesonephric and fused mu¨llerian ducts and by the retropubic space, which contains abundant fat and later becomes the prostatic and membranous urethra in the venous plexuses. The neck of the bladder, its most inferior male and the entire urethra in the female.2 part, connects with the urethra. When the bladder is dis- After 8 weeks, the ventral part of the urogenital sinus tended with urine, the neck remains fixed and stationary, expands to form an epithelial sac, the apex of which tapers whereas the dome rises above the pelvic cavity into the into an elongated narrowed urachus. The splanchnic meso- lower abdomen, touching the posterior aspect of the lower derm surrounding both segments differentiates as interlac- anterior abdominal wall and the small and large bowels.3 Beneaththeurothelialliningoftheinnerbladder,thereis ing bands of smooth muscle fibers and an outer fibrocon- looseconnectivetissuethatpermitsconsiderablestretching nective tissue coat. By 12 weeks, the layers of the adult of the mucosa. As a result, the urothelial mucosal lining urethra and bladder can be recognized. This sequence of is wrinkled when the bladder is empty but smooth and events indicates that the detrusor muscle and the urethral flatwhendistended.Thisarrangementexiststhroughoutthe musculature have the same origin, constituting one unin- terruptedstructure.2 Thisarrangementiseasilyobservedin bladderexceptatthetrigone,wherethemucousmembrane adheres firmly to the underlying muscle; consequently, the the female, in that the bladder and urethra form one tubu- trigone is always smooth, regardless of the level of disten- lar unit with expansion of the upper part. However, in the sion (Figs. 1-1 and 1-2). male, the structure is complicated by simultaneous devel- opment of the prostate gland. The developmental sequence isthesameinbothgenders, andthestructuralarrangement BloodSupplyandLymphaticDrainage in the male is only slightly more complex than that in the Thebladderissuppliedbythesuperior,middle,andinferior female.2 vesical arteries, all of which are branches of the anterior divisionofthehypogastricartery.Betweenthebladderwall properandtheouteradventitiallayer,thereisarichplexus Anatomy of veins that ultimately terminate in the hypogastric veins after converging in several main trunks. The bladder lymphatics drain into the external iliac, GrossAnatomy hypogastric, and common iliac lymph nodes. There are rich lymphatic anastomoses between the pelvic and genital The bladder is a hollow muscular organ whose main func- organs.4–6 tionisthatofareservoir.Whenempty,theadultbladderlies behind the symphysis pubis and is largely a pelvic organ. NerveSupply In infants and children, it is more cephalad than in adults. When full, the bladder rises above the symphysis and can The bladder is richly innervated by divisions of the readily be palpated or percussed. When overdistended, as autonomicnervoussystem.2,7 Sympatheticnervesoriginate 2 Normal Anatomy and Histology AA AA BB BB Figure1-1 Normaltrigone(AandB). Figure1-2 Normaltrigoneinawomanduringthe reproductiveyears.Notethesquamousmucosaandclosely packedunderlyingmuscle(AandB). fromthelowerthoracicandupperlumbarsegments,mainly T11–T12 and L1–L2. These sympathetic fibers descend into the sympathetic trunk and the lumbar splanchnic nerves,connectingwiththesuperiorhypogastricplexus,an inferior extension of the aortic plexus. The latter separates into the right and left hypogastric nerves, and these extend inferiorly to join the pelvic plexus of the pelvic parasympathetic nerves. Parasympathetic nerves arise from sacral segments S2–S4, and these form the rich pelvic parasympathetic plexus. This plexus joins the sympathetic hypogastric plexus, and vesical branches emerge from this plexus toward the bladder base, innervating the bladder and urethra.7,8 Normal Histology Urothelium Figure1-3 Normalurothelium.Thethicknessofurothelium The urothelium is a unique stratified epithelium of vari- isvariable,uptosevencelllayersinnormalurothelium.Note ablethickness(Figs.1-3to1-6).Thenumberofcelllayers theprominentsuperficialumbrellacells. 3 Normal Anatomy and Histology AA Figure1-5 Normalurothelium.Notetheorderly arrangementoftheurothelialcells.Thelongaxisofurothelial cellsisoftenperpendiculartothemucosalsurface.The superficialcellsarelessdistinct.Prominentnucleargrooves arenotedinsomecells. BB Figure1-4 Normalurothelium(AandB).Cytoplasmic vacuolizationisobserved.Inthispreparation,theurothelium isuptosevencellsinthickness(B). Figure1-6 Normalurothelium.Notethevariablethickness ofurotheliuminthispreparation.Thesuperficialcellshave prominentcytoplasmicvacuolization. depends on the degree of distension of the bladder, usually varying from three to seven layers. When distended, the bladderisthreetosixcelllayersthick,althoughthetypical biopsy contains about five layers; in the contracted state, it consists of six to eight layers.9 For practical purposes, urotheliumcomposedofmorethansevencelllayersiscon- sidered abnormal unless this finding can be attributed to tangential cutting of tissue.10,11 In addition, the urothelium is thought to be monoclonal in origin, with some features of mosaicism.12 Thenormalurotheliumcontainsalayeroflargesuperfi- cial cells that are frequently multinucleated, often referred to as umbrella cell thickness (Figs. 1-7 to 1-9). These cells have abundant eosinophilic cytoplasm, with large nuclei Figure1-7 Normalurothelium.Notetheprominent whose long axes are perpendicular to those of the smaller superficialcells.Nuclearvacuolizationisoccasionallyseenin cells of the underlying basal and intermediate cell lay- intermediatecells.Somevariationofcellsizeandshapecan ers. The superficial cells vary in size and configuration beobservedinnormalurotheliumandshouldnotbe according to the degree of bladder distension and angle interpretedasdysplasia. 4 Normal Anatomy and Histology potential importance in pathologic grading of bladder can- cer (see also Chapter 9). Basal and intermediate cells are located between the basal lamina and the superficial cells (Figs. 1-8 to 1-10). Thesecellsaremorphologicallyidenticaltoeachother,and are distinguished only by their position in the mucosa.13 They are regularly arranged, with distinct cell boundaries and oval, round, or fusiform nuclei with occasional promi- nent nuclear grooves. The nuclei are located centrally in the cells and contain finely granular chromatin that often accentuates the nuclear borders. Nucleoli are usually small and difficult to detect. Mitotic figures are rare in the nor- malurothelium.Thebasallayerofepithelialcellsexpresses Bcl-2, while the intermediate cells express RB1 and PTEN at varying intensities. HER2 and p53 are not expressed Figure1-8 Normalurothelium.Notetheprominent by normal urothelial cells. Ki67, indicating proliferation, superficialcells. may not be expressed in a single field. The long axis of the basal and intermediate cells is perpendicular to the basement membrane. The basement membrane is usually not visible in routine hematoxylin and eosin or periodic acid–Schiff stained sections, but appears as a razor-thin layer beneath the mucosa when present. Basement mem- brane markers such as laminin and type IV collagen may be useful diagnostically in select cases to define the base- mentmembrane,butarenotemployedroutinely.15 Delicate capillaries of the muscularis mucosae are in intimate asso- ciation with the basement membrane, and invaginations or tangential cutting may create the factitious appearance of intraepithelial extension. The urothelium is able to respond to thermal, mechan- ical, and chemical stimuli (“sensor functions”) and has the ability to release chemicals (“transducer functions”).16 Urothelial basal cells express certain receptors and ion channels (e.g., vanilloid receptor-1), similar to afferent Figure1-9 Normalurothelium.Basalandintermediatecells arelocatedbetweenthebasallaminaandthesuperficialcells. Occasionalprominentnucleargroovesmaybeseen.Notethe binucleatedsuperficialumbrellacells. of tissue section; they may appear cuboidal in the dis- tended bladder, but are often flattened. In addition, superfi- cialcellsarelooselyattachedtotheunderlyingcellsdespite being interconnected with each other by extensive junc- tional complexes13 and may be absent from otherwise nor- mal urothelium in routine biopsies. Superficial umbrella cells express uroplakins and cytokeratin 20 with immuno- histochemistry.Theapicalplasmalemmaisthickened,with stiff plaques, unlike the short microvilli seen in the under- lyingintermediatecells.13 However,thetrigonalsuperficial cells of women during the reproductive years have a cob- blestone pattern with long clubbed microvilli.14 Superficial Figure1-10 Normalurothelium.Basalandintermediate cells may persist on the surface of papillary urothelial car- cellsaremoredenselypackedwithahighernuclear cinoma, particularly low grade carcinomas—a finding of cytoplasmicratiothanthatofsuperficialcells. 5