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Bladder
Author: Nat Pernick, M.D. (see Authors page)
Revised: 12 January 2010, UPDATE IN PROGRESS
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.
Table of contents
Primary references, embryology, normal anatomy, normal histology
Congenital anomalies: AV malformation, duplication, ectopic prostate, exstrophy, hypoplasia, persistent cloaca, urachus
Acquired non-neoplastic anomalies: amyloidosis, collagen polyp, cystocele, diverticula, endocervicosis, endometriosis, endosalpingiosis, lithiasis, obstruction, Tamm-Horsfall protein, treatment effect, urinary diversion
Cystitis: acute, BK virus, bullous, chronic, cystitis cystica / glandularis, emphysematous, eosinophilic, follicular, granulomatous, hemorrhagic, interstitial, malakoplakia, polypoid / papillary, radiation, schistosomiasis, xanthogranulomatous
Metaplasia: intestinal metaplasia, nephrogenic metaplasia, squamous metaplasia
Bladder tumors-benign: condyloma, fibroepithelial polyp, hemangioma, inflammatory myofibroblastic tumor, leiomyoma, neurofibroma, postoperative granulomas, post-operative spindle cell nodule, post-radiation/chemotherapy proliferations, prostatic-type polyps, solitary fibrous tumor, urachal lesions, villous adenoma
WHO/ISUP classification: general, flat hyperplasia, papillary hyperplasia, flat lesions with atypia, dysplasia, carcinoma in situ, papilloma, inverted papilloma, papillary neoplasm of low malignant potential
Urothelial carcinoma: general, low grade papillary, high grade papillary, invasive-WHO classification, invasive, cytology
Other carcinomas: adenocarcinoma: in situ, general, urachal; clear cell, giant and spindle cell, hepatoid, large cell neuroendocrine, lymphoepithelioma-like, metastases, micropapillary, plasmacytoid/lymphomatoid, prostatic adenocarcinoma, sarcomatoid, signet ring, small cell, squamous cell
Other tumors: angiosarcoma, carcinoid, clear cell myomelanocytic tumor, gastrointestinal stromal tumors/GIST, germ cell tumor, leiomyosarcoma, lymphoma, melanoma, osteosarcoma, paraganglioma, plasmacytoma, rhabdoid tumor, rhabdomyosarcoma, urachal sarcoma
Miscellaneous: staging, report, grossing
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology (Hum Path)
Modern Pathology (Mod Path)
Eble: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, 2004
Murphy: Tumors of the Kidney and Bladder (AFIP Atlas of Tumor Pathology, Series 3, Vol 11); 1994
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Websites: Johns Hopkins WHO/ISUP Tutorial website, PathConsult, PathoPic, PEIR Digital Library, Webpathology.com
Please refer to these primary references for more detailed discussions and photographs
Bladder develops during first 12 weeks of gestation
Urorectal septum divides cloaca into dorsal rectum and ventral urogenital sinus
Trigone develops from dilation, fusion and incorporation of caudal mesonephric ducts into urogenital sinus, forming a triangular area that is site of future ureters; mesonephric ducts are gradually absorbed and replaced by endodermal epithelium of urogenital sinus; thus, there are no mixed mesodermal tumors of the bladder
Posterior walls, dome and part of lateral walls arise from mesenchyme surrounding urogenital sinus
Anterior wall and part of lateral walls develop with closure of infraumbilical portion of abdominal wall
Note: neither urachus or allantois are involved in formation of bladder
Allantois: rudimentary structure lined by endoderm that is connected to urachus
Urachus: formed during descent of abdominal wall, connects umbilicus to apex (dome) of bladder, torn apart as embryo elongates but remnants persist in anterior abdominal wall and may persist in bladder wall
Drawings: development of bladder #1; #2
Epithelial lined muscular viscus that can distend and hold up to 400-500 ml of urine without a change in intraluminal pressure
Can also initiate and sustain a contraction until empty
Has superior surface (apex, dome), posterior surface (base) and inferolateral surfaces
Trigone is area between ureteral and urethral orifices, continuous with bladder neck
Bladder located in part within the abdomen in children, enters pelvis major at age 6, found entirely within pelvis minor after puberty
Adult bladder rests on rectum and seminal vesicles (males) or cervix and vagina (females); thus cystectomy for tumor may be combined with removal of prostate and seminal vesicles (males) or hysterectomy and partial vaginectomy (females)
Bladder neck occasionally contains prostate ducts (males)
Lymphatic drainage: internal and external iliac nodes; bladder neck drains to sacral or common iliac nodes
Blood supply: superior and inferior vesical arteries, derived from internal iliac artery; drained by vesical venous plexus, which empties into internal iliac veins
Nerve supply: sympathetic from T11-L2 nerves, play no role in micturition; parasympathetic from S2-4, travel to bladder via pelvic nerve and inferior hypogastric plexus, cause contraction of muscularis propria fibers, which puts traction on bladder neck, which opens internal sphincter
Gross: hollow viscus resembling inverted pyramid when empty, sphere when distended
Gross drawings: position of bladder in male pelvis #1; #2; bladder and seminal vesicles; position of bladder in female pelvis; interior of bladder
Bladder layers are mucosa (urothelium, lamina propria, discontinuous muscularis mucosa), muscularis propria, adventitia, serosa/peritoneum at dome
No submucosa is present
Urothelium: formerly called transitional epithelium since intermediate between nonkeratinizing squamous and pseudostratified columnar epithelium; 5-7 cell layers thick in contracted bladder, 2-3 cells thick in distended bladder; lines renal pelvis, ureters, bladder, most of urethra but not terminal urethra
Superficial urothelium is single layer of umbrella cells, which are large and elliptical with abundant eosinophilic cytoplasm and often binucleation or prominent nucleoli; one umbrella cell covers several underlying cells; inconspicuous in distended bladder; contains trilaminar (asymmetric) unit membrane composed of two dense layers of unequal thickness and a central lucent layer, and apical plaques containing uroplakins
Intermediate urothelial cells are cuboidal to low columnar cells with well defined borders, amphophilic cytoplasm rich in glycogen; nuclei are regularly arranged, ovoid with long axis at right angles to surface; chromatin is finely granular; small nucleoli; usually no mitotic figures
Basal urothelial cells are more cylindrical, can be flat when bladder wall is stretched; some have longitudinal nuclear grooves; lie on continuous basal lamina
Lamina propria: contains loose to dense connective tissue, thin-walled blood vessels that may be close to epithelium, lymphatics, variable adipose tissue; also discontinuous muscular mucosa (wisps of smooth muscle, AJSP 1987;11:668), which should not be confused with muscularis propria when assessing depth of invasion
Only 5% of bladders have well developed muscularis mucosa
Muscularis propria: consists of inner longitudinal, circular and outer longitudinal layers of thick muscle bundles (layers are distinct only near bladder neck), may also contain adipose tissue between muscle fascicles, paraganglia; muscularis propria may be greatly thickened if obstruction to urine flow develops
von Brunn’s nests (Brunn’s nests): nests of urothelium in lamina propria; present in 85%+ of bladders at autopsy; nests have regular spacing, extend to same horizontal level at base of proliferation; florid cases may mimic nested variant of urothelial carcinoma, but there is no muscle invasion (AJSP 2003;27:1243)
Micro drawings: layers of bladder (note: no submucosa is present, despite the drawing)
Micro images: bladder layers #1; #2; normal urothelium with umbrella cells #1; #2; #3; various images; Brunn’s nests #1; #2; florid hyperplasia of Brunn’s nests #1; #2
Cytology images: umbrella cells, umbrella cells, intermediate cells and basal cells #1; #2
Virtual slides: normal bladder
Positive stains: blood group antigens A, B, H; cytokeratin 7, 8/18, 19
Bladder - congenital anomalies
5 cm vestigial structure connecting dome of bladder and umbilicus; in fetus, connects bladder dome with allantois (embryonic diverticulum of hindgut, vessels are precursors to those in umbilical cord)
After birth, becomes median umbilical ligament
Arises from superior urogenital sinus
In midline or posterior bladder wall; fragmentation occurs post-partum when bladder descends into pelvis
Remnants seen at autopsy in 50% of fetuses, 33% of adults
Associated with urachal cysts, sinus, fistula, diverticulum, infections, adenocarcinoma of bladder; also urothelial carcinoma, villous adenoma, squamous cell carcinoma
Gross: remnants located in bladder dome
Micro: usually persists as fragmented tubules separated by fibrous cords, but without a desmoplastic tissue response; composed of stratified epithelium, columnar epithelium or urothelium; no goblet cells, no atypia
Micro images: dilated urachal remnant
Patent urachus
Also called persistent urachus
Rare; leads to urination through umbilicus
May be associated with infections
Gross drawings: patent urachus #1; #2
Acquired non-neoplastic anomalies
Pouchlike evaginations of bladder wall
If congenital, due to obstruction or failure of muscle development
Acquired are more common and usually due to prostatic enlargement causing muscular hypertrophy and focal mucosal herniation without muscularis propria in areas of weakness, often near ureteral orifices, bladder dome or urethral orifice
Often multiple in posterior wall or trigone
Associated with infections and stones (due to urine stasis), perforation; also urothelial or other carcinomas; tumors often large because location is hidden
Gross: narrow necks, round/ovoid pouch from 1-10 cm
Gross images: drawing, image with case history
Micro: wall consists of fibrous tissue with no/scant muscularis propria; squamous or glandular metaplasia present if inflamed
Women, mean age 39 years, range 34-65 years
Rare; benign
Associated with endometriosis, cesarean section
Gross: mass between bladder and uterus in posterior bladder wall, dome or trigone
Micro: prominent endocervical type glands in muscularis propria; glands may be cystically dilated and contain mucinous secretions with neutrophils; glands usually lined by tall mucinous columnar cells, less commonly flat or cuboidal, rare ciliated cells; cells rarely have nuclear atypia; no desmoplasia, no mitotic figures
Micro images: prominent endocervical glands in muscularis propria #1; #2; #3; #4 with mucin extravasation
DD: adenocarcinoma, adenoma malignum from uterine cervix
References: Hum Path 1996;27:816, AJSP 1992;16:533
Usually associated with history of local surgery or female GU symptoms
Bladder is most common site in urinary tract, but only occurs in <2% of all patients with endometriosis
Also occurs in men after estrogen therapy for prostate carcinoma
May develop into endocervicosis (mucinous metaplasia), endometrioid adenocarcinoma, clear cell carcinoma, adenosarcoma
Treatment: hormones, resection
Gross: usually serosal; palpable mass in 50%; may be blue mucosa at cystoscopy
Micro: endometrial glands, endometrial stroma, hemosiderin
DD: neoplasm
Called mullerianosis if two of three (endocervicosis, endometriosis or endosalpingiosis) are present
Associated with endocervicosis (glands lined by columnar mucinous cells) and endometriosis
Gross: mass of posterior wall
Micro: involvement of lamina propria and muscularis propria by tubules and cysts of mullerian-type epithelium; may replace urothelium and form polypoid projections into bladder lumen; tubules and cysts are round/oval, may have prominent branching; glands lined by tubal type epithelium (ciliated cells, intercalated cells, peg cells)
DD: adenocarcinoma
References: Mod Path 1996;9:731
More common in males, usually elderly, associated with prostatic nodular hyperplasia
Common in quadriplegia/paraplegia
Usually solitary phosphate stones; may be urate or oxalate
Treatment: mechanical removal, cystolithotripsy, extracorporeal shock wave therapy
Recur in 10% of patients after removal
References: more information
Commonly due to prostatic hypertrophy (men) or cystocele (women); also urethral narrowing/strictures, mechanical obstructions, neurogenic bladder
Gross: trabeculation of bladder wall, diverticula
Gross image: prostatic hypertrophy
High molecular weight glycoprotein normally synthesized by ascending loop of Henle and distal tubule
May accumulate in renal parenchyma, perirenal soft tissue, renal hilar lymph nodes or bladder with pathologic conditions
Found in 60% of cystectomy specimens, 4% of bladder biopsies
In bladder, 85% found in men, mean 61 years, range 45-78 years
Associated with urothelial carcinoma, nephrogenic adenoma, cystitis; deposited in areas of necrosis, inflammation, fibrinous exudates, ulcer, crystalline material
No clinical significance
Micro: large, waxy, pale or weakly eosinophilic mass; may also appear as strands of eosinophilic material obscured by fibrinous exudates or necrotic tissue
Positive stains: PAS, trichrome (pale blue), anti Tamm-Horsfall protein antibody
EM: nonbranching 4 nm wide parallel fibrils
References: AJSP 1994;18:615
See also radiation cystitis
Chemotherapy drugs may cause exfoliation of normal and abnormal urothelial cells, degeneration, multinucleation, and bizarre reactive nuclear changes; may destroy tips of papillae in papillary tumors
Topical therapy may mask early invasion and cause a local granulomatous reaction
Radiation therapy causes endothelial swelling and necrosis, mural thickening and hyalinization with late luminal narrowing; also radiation fibroblasts, destruction of bladder tumor papillae
Portions of colon or ileum used in adults and children to treat congenital anomalies, dysfunctional bladder or tumors
May enlarge capacity of bladder, channel urine into temporary artificial reservoir or to create a neobladder (new bladder after cystectomy)
Complications: intestinal adenocarcinoma in colonic conduits, reflux but only rare renal failure in ileal conduits, highest risk of adenocarcinoma or adenoma in augmentation cystoplasty
Monitor for carcinoma with cytology (direct smears after centrifugation)
Gross images: simple drawing
Micro: inflamed, atrophic and partially denuded epithelium; Candida in ileal conduits
Micro images: cytology from ileal conduit urine
References: more information
Metaplasias
See also cystitis cystica and glandularis
Low risk for carcinoma if extensive disease
Micro: replacement of urothelium by colonic mucosa; also goblet cells (single or aggregates) within Brunn’s nests, variable Paneth cells; no atypia, no involvement of muscularis propria
DD: normal epithelium in neobladder (villous atrophy, reactive atypia, lymphoid aggregates)
Also called mesonephric adenoma, nephrogenic adenoma, mesonephroid metaplasia
Metaplastic change due to inflammation, exstrophy, calculi or prolonged catheterization, all of which also cause cystitis glandularis and cystitis cystica
Often recurs, but may regress if underlying cause is removed
May be derived from shed tubular cells in kidney transplant recipients
Usually adults; 2/3 male, affects bladder, urethra, ureter and renal pelvis
Benign
Gross: polypoid, sessile or papillary, 20% are multiple
Micro: small hollow tubules similar to mesonephric tubules, usually lined by single layer of bland cuboidal or hobnail cells, surrounding eosinophilic or basophilic secretions; cells have clear or eosinophilic cytoplasm, small nuclei, no prominent nucleoli; may have thickened basement membrane; usually inflammatory infiltrate and stromal edema; involves lamina propria but spares muscularis propria; most cases also have cystic pattern; occasionally pseudoinfiltrative, may contain <10% clear cells, may have small slender papillary structures on mucosal surface; minimal atypia, minimal mitotic figures; no necrosis, no desmoplasia
Cases in prostatic urethra closely resemble prostatic adenocarcinoma
Micro images: papillary and cystic structures lined by cuboidal epithelium #1; #2; #3
Positive stains: AE1, AE3, CAM5.2, CK7, PSA or PAP (weak, 33%), variable P504S, CK20 and CA-125
Negative stains: CK903
Molecular: monosomy 9, trisomy 7
DD: clear cell adenocarcinoma (usually women, lack clinical features of nephrogenic adenoma, very large tumors, mostly clear cells, marked atypia, high mitotic rate, necrosis, high Ki-67 percentage, strong p53 staining, Hum Path 1998;29:1451); papillary urothelial carcinoma (if papillary), prostatic adenocarcinoma (more atypia, strongly PSA+), nested variant of urothelial carcinoma (more than 1 layer)
References: Mod Path 1995;8:722, Hum Path 1981;12:907, AJSP 2004;28:701 (P504S), AJSP 1986;10:268 (comparison to GU clear cell carcinoma)
Replacement of urothelium by stratified squamous epithelium, both vaginal (non-keratinized) and keratinized subtypes
Vaginal subtype in trigone is very common (also called pseudomembranous trigonitis), not associated with chronic irritation, no risk for carcinoma; non-keratinized epithelium with abundant intracytoplasmic glycogen, similar to vaginal or cervical squamous epithelium; responds to estrogen
Keratinizing subtype is also called leukoplakia, more common in males, associated with chronic irritation (catheters, stones, parasite eggs), may have atypia; risk factor for squamous cell carcinoma
Frequently associated with polypoid cystitis or cystitis glandularis
Micro images: nonkeratinizing squamous metaplasia #1; #2; #3; #4; keratinizing squamous metaplasia #1; #2
Bladder tumors - benign
Rare; usually reported in children
In adults, male predominance, median age 44 years, range 17-70 years
May be incidental / asymptomatic
Nonneoplastic
Usually near verumontanum or bladder neck
Treatment: transurethral resection, don’t recur
Micro: urothelial or rarely columnar epithelial lining; either polypoid mass with cloverleaf-like projections and florid cystitis cystica et glandularis of nonintestinal type in stalk; papillary tumor composed of numerous small, rounded fibrovascular cores containing dense fibrous tissue; or polypoid lesion with secondary tall, finger-like projections; broader stalks than papilloma; no prominent edema or inflammation; may have degenerative stromal atypia
DD: florid cystitis cystica et. glandularis (no cloverleaf pattern), polypoid or papillary cystitis (edematous, protrude into lumen, inflammatory infiltrate, often large areas of bladder involved), urothelial papilloma (more papillary and less polypoid, narrower fibrous stalks, delicate loose fibroconnective tissue), inverted papilloma (anastomosing nests, not discrete round nests)
References: AJSP 2005;29:460 (multiple images), Archives 1986;110:241 (atypical stromal cells)
In children on lateral or posterior walls; 50% are detected in adults
Associated with cutaneous hemangiomas, Klippel-Trenaunay syndrome (port-wine hemangiomas, varicose veins, soft tissue and bone hemihypertrophy)
Painless hematuria
Gross: sessile
Micro: cavernous type
Micro images: cavernous hemangioma
DD: telangiectasia, arteriovenous malformations, angiosarcoma
Inflammatory myofibroblastic tumor (IMT)
Rare in bladder, more common at other sites (lung, soft tissue, bone)
IMT is terminology for neoplastic lesions; infective or inflammatory lesions are called “pseudotumors”
Similar to postoperative spindle cell nodule, but without a history of surgery
Usually middle aged women
Pain, fever, weight loss, anemia, thrombocytosis, increased erythrocyte sedimentation rate, elevated gamma globulins
Benign, but frequently misinterpreted as leiomyosarcoma or rhabdomyosarcoma
May recur locally, don’t metastasize
Treatment: conservative surgical excision
Case reports: 2 year old child with sclerosing inflammatory pseudotumor that massively infiltrated bladder wall (AJSP 1992;16:1233)
Gross: polypoid mass with pale, firm cut surface; may be very large; often gelatinous
Micro: patterns include (1) loose stellate cells with myxoid background containing scattered inflammatory cells (nodular fasciitis-like); (2) spindle cells with a compact fascicular pattern (fibrohistiocytoma-like); (3) sparse cellular, collagenous area (desmoid-like); (4) mixed
Cells are stellate myofibroblasts with abundant eosinophilic cytoplasm, elongated nuclei, no necrosis, no significant atypia, no infiltration in any of the patterns, no/rare mitotic figures
Micro images: (1) spindle cells and inflammatory cells in myxoid stroma; (2) myofibroblastic cells and inflammatory cells in edematous stroma #1; #2; (4) figure 1A: inflammatory myofibroblastic tumor - spindle cells loosely arranged in fascicles with myxoid stroma and inflammatory cells; cells have moderate atypia (pattern 1 above); 1B: desmin+; 2: leiomyosarcoma (for comparison) that is caldesmon+; 3: embryonal rhabdomyosarcoma of prostate that is myogenin+
Micro images: (1) a/b: compact fascicles of spindle cells with inflammatory cells; c: looser spindled cells in myxoid background; d: diffuse ALK1+ in cytoplasm; (2) inflammatory myofibroblastic tumor composed of spindle cells and inflammatory cells with no atypia and no necrosis; tumor extends into muscularis propria
Positive stains: smooth muscle actin, desmin, ALK1 (also by FISH), vimentin; variable calponin and caldesmon
Negative stains: cytokeratin (usually), myogenin, p53 (Mod Path 2001;14:1043), EMA
EM: myofibroblasts (bipolar cells with eosinophilic, elongated, tapering cytoplasmic processes without striation, central oval nuclei with smooth contours, open chromatin, occasional nucleoli), no evidence of smooth muscle or skeletal muscle differentiation
Molecular images: ALK translocation is indicated by separation of green and orange probes of ALK gene in inflammatory myofibroblastic tumor (a), but not leiomyosarcoma (b)
DD: leiomyosarcoma (strong desmin staining), rhabdomyosarcoma in children (has necrosis or myxoid degeneration, moderate/severe nuclear atypia, more mitotic figures, myoD1+, myogenin+, Archives 2001;125:1070), sarcomatoid (spindle cell) carcinoma, neurofibroma
References: Mod Path 2004;17:765 (ALK1 staining), Hum Path 1994;25:181, Hum Path 1993;24:1203, AJSP 2004;28:1609, AJSP 1995;19:1224, AJSP 1993;17:264, AJSP 1985;9:366, AJCP 1986;86:583
Mean age 61 years, range 22-78 years, no gender preference
Benign; usually diploid
Often symptoms
Gross: 0.5 to 4.5 cm, well circumscribed
Micro: low cellularity, may have bizarre or symplastic nuclei; minimal/no mitotic figures, no necrosis, no atypia
Positive stains: actin and desmin (strong)
DD: well differentiated leiomyosarcoma (not well circumscribed, necrosis, mitotic figures, abnormal mitotic figures)
References: AJSP 2002;26:292
Gross: polypoid or diffuse
Micro images: lamina propria shows meissner-type corpuscles; bland spindled cells in fibrous stroma
Positive stains: S100
Negative stains: keratin, smooth muscle actin, desmin, calponin, caldesmon
Occur after catheterization or diathermy
May be due to metals deposited during diathermy or a local reaction to tissue necrosis
Not neoplastic
Micro: palisading histiocytes or giant cells surrounding central necrosis (resembles rheumatoid nodules) or foreign body type granuloma; lesions heal by fibrous scarring
Post-operative spindle cell nodule
Occurs several weeks to months after transurethral resection of bladder tumor in area of surgery
Similar to inflammatory / pseudosarcomatous myofibroblastic tumor, but with a history of surgery
Benign
Gross: friable nodule, mean size 1 cm
Micro: cellular, fascicular growth pattern of plump or elongated spindle cells which infiltrate the bladder wall and may focally destroy muscle; has delicate network of small blood vessels in edematous or myxoid stroma; ulcerated surface with acute and chronic inflammatory infiltrate; high mitotic activity but no atypical mitotic figures, resembles sarcoma but no atypia; no necrosis, no significant pleomorphism; may have red blood cell extravasation (DD: Kaposi’s sarcoma)
Micro images: myofibroblastic cells and inflammatory cells in myxoid stroma
Positive stains: low molecular weight keratin, vimentin, actin, desmin
Negative stains: EMA
Post-radiation or chemotherapy proliferations
See also radiation cystitis
85% male, mean age 69 years, range 40-85 years
Present with hematuria
Benign; no evidence of bladder cancer
Micro: epithelial proliferation may mimic invasive carcinoma within lamina propria, with pseudoinvasive urothelial or squamoid nests wrapping around vessels associated with fibrin deposition; also mild/moderate nuclear pleomorphism; also hemorrhage, fibrin deposition, fibrin thrombi, fibrosis, acute and chronic inflammation, edema, vascular congestion, thickened vessels, vascular ectasia, atypical fibroblasts; variable hemosiderin deposition and ulceration; no/rare mitotic figures
DD: invasive urothelial carcinoma (lacks epithelial cells circling blood vessels with fibrin deposition, more severe cytologic atypia, large nucleoli, no background radiation cystitis), nested variant of urothelial carcinoma (nests and cords of bland cells, muscular invasion, usually associated with conventional urothelial, squamous or adenocarcinoma, no background radiation cystitis)
References: Hum Path 2000;31:678, AJSP 2004;28:909
Similar to those in prostatic urethra
Mean age 50 years
Frequent cause of hematuria in young adults
Usually around bladder neck or ureteral orifices
Most likely a type of metaplasia
Gross: papillary or polypoid
Micro: lined by predominantly prostatic-type epithelium with foamy, faintly eosinophilic cytoplasm, with interspersed urothelium; often cystitis glandularis
Positive stains: prostatic-type epithelium - PSA, PAP
References: AJSP 1984;8:833
Rare, <50 cases reported, all benign (no recurrence after excision)
Men ages 50-67 years
Treatment: excision, usually do not recur
Gross: often very large
Gross images: well circumscribed tumor
Micro: resemble tumors of pleura with haphazard (patternless) spindle cells with hypo- and hypercellular areas, and deposition of dense collagen
Micro images: plump spindled cells with prominent vasculature; short spindle cells with delicate cytoplasm, no atypia; CD34+
Positive stains: CD34, bcl2
Negative stains: cytokeratin, EMA, smooth muscle markers
DD: sarcoma, sarcomatoid carcinoma
References: Hum Path 2000;31:63, Hum Path 1997;28:1204, web based article
Glandular lesions have similar terminology as those in ovary, appendix and pancreas
Urachal cysts: urachal remnants with cystic dilation; variable lining
Case reports: 45 year old woman with hamartoma of the urachal remnant (Archives 1989;113:1393)
Also called villous tumors
Rare; typically elderly patients, no gender preference
Arise throughout urinary tract, but most common in bladder
Wide age range, but usually 40-70 years, 2/3 male
Hematuria, mucusuria and irritative symptoms
No recurrence or invasive disease if isolated and no coexisting carcinoma
May be associated with in situ or invasive adenocarcinoma at diagnosis, less often with in situ or invasive urothelial carcinoma
Metastases or multiple recurrences if coexisting invasive adenocarcinoma (AJSP 1999;23:764, Hum Path 2002;33:236)
Case reports: arising in background of chronic cystitis, aneuploid (Mod Path 1999;12:735)
Gross: arise in urachus, dome or trigone
Micro: resembles colonic villous adenoma with pointed processes lined by pseudostratified columnar epithelium with nuclear stratification, nuclear crowding, nuclear hyperchromasia, occasional prominent nucleoli, occasional mitoses; associated with cystitis glandularis and cystitis cystica
MUST sample entire lesion to rule out adenocarcinoma
Micro images: villous adenoma arising in urachal cyst; villous adenoma with finger-like projections #1; #2 resembling colonic villous adenoma
Positive stains: acidic mucins (Alcian blue), CK20, CEA (luminal, 89%), CK7 (56%), EMA (22%)
DD: well-differentiated colonic adenocarcinoma extending into bladder
WHO/ISUP (1998) classification of urothelial neoplasms
Prior classification systems
Ash (1940): classified as transitional cell carcinoma grades 1-4; grade 1 comparable to papilloma, grade 2 comparable to low grade; grades 3 (most) and 4 comparable to high grade
Mostofi (1960): grade 1 called papilloma and not carcinoma
WHO/ISUP: World Health Organization / International Society of Urologic Pathologists consensus classification that is controversial for some lesions (low malignant potential)
Major changes from prior systems are that papillary urothelial carcinomas must exhibit atypia and carcinoma in situ need not be full thickness
WHO/ISUP grade correlates with tumor stage and recurrence
Has been validated by differences in recurrences and CK20, p53 and Ki-67 staining (AJCP 2004;121:679)
Classification:
Normal: flat mucosa with no overt thickness; includes slight disorganization of cells and nuclear pleomorphism, formerly termed mild dysplasia; size of normal urothelial cells is 3x lymphocytes;series of images
Hyperplasia: flat hyperplasia, papillary hyperplasia
Flat lesions with atypia: reactive (inflammatory) atypia, atypia of unknown significance, dysplasia (LG IUN), CIS (HG IUN)
Papillary urothelial neoplasms: papilloma, inverted papilloma, papillary neoplasm of low malignant potential, noninvasive papillary carcinoma-low grade, noninvasive papillary carcinoma-high grade
Invasive urothelial neoplasms: lamina propria invasion, muscularis propria (detrusor muscle) invasion
Low grade neoplasms
Includes papilloma, inverted papilloma, low malignant potential, low grade papillary urothelial neoplasms,
urothelial carcinoma grade 1 of 3, some urothelial carcinomas grade 2 of 3
Markedly thickened mucosa without cytologic atypia
May be adjacent to low grade papillary urothelial neoplasm
By itself has no malignant potential and requires no treatment
Micro images: series of images
Asymptomatic, found on routine follow-up cystoscopy of papillary urothelial neoplasms
Treatment: follow up if new, unknown if increased risk of papillary neoplasm in patient with prior history of papillary urothelial tumor
Micro: slight tenting, undulating or papillary growth lined by urothelium of varying thickness, without atypia; may have tent-shaped broader folds also; often has small dilated capillaries at base, but no well defined fibrovascular core; lacks discrete papillary fronds associated with papillary neoplasm
Micro images: series of images
DD: low grade papillary urothelial neoplasm
Papillary hyperplasia with atypia
Architectural pattern of papillary hyperplasia with atypia of overlying urothelium
80% male, age range 55 to 92 years
At diagnosis, 50% associated with flat carcinoma in situ, 30% with dysplasia
Prognostic implications: usually associated with high grade papillary urothelial carcinoma; also CIS and invasive urothelial carcinoma (Hum Path 2002;33:512)
Reactive atypia
Inflammatory atypia; uniformly enlarged and vesicular nuclei, central prominent nucleoli, may have frequent mitotic figures; may have history of instrumentation, stones or therapy; not neoplastic
Micro images: series of images
Flat lesions with atypia of unknown significance
Between reactive atypia and dysplasia
More pleomorphism and hyperchromasia than expected for the amount of inflammation present
Recommend close follow up and reevaluation after inflammation subsides
Micro images: series of images
DD: dysplasia
Also known as low grade intraurothelial neoplasia (LG IUN)
Mean age 60 years, 75% male, more common on posterior wall
2/3 have irritative symptoms or hematuria; 1/3 have no symptoms
Cystoscopy is abnormal in most (inflamed, suspicious for neoplasm)
Most have normal cytology
19% or less progress to invasive carcinoma, carcinoma in situ (CIS) or papillary urothelial carcinoma (AJSP 1999;23:443); only 3-10% die of bladder cancer over a 10-25 year period
Low interobserver agreement on diagnosis, even among experts
Treatment: varies from follow up to intravesical chemotherapy if history of CIS
Micro: lesions of flat, noninvasive urothelium with appreciable cytologic and architectural changes indicative of neoplasia, but less than carcinoma in situ; usually disorientation and clustering of nuclei, large nuclei, homogenous cytoplasm
Micro images: series of images
DD: carcinoma in situ, reactive processes
Controversial entity; uncommon if use restrictive diagnostic criteria (less than 1% of bladder tumors)
Benign
Either de novo (most common) or secondary to known urothelial carcinoma
Usually solitary
In de novo cases, mean age 46-58 years, 2/3 male, occasional recurrence, occasional progression to papillary urothelial carcinoma
In secondary cases, mean age 66 years, may recur
Recommended to avoid labeling these patients as having cancer (AJSP 2004;28:1615)
Treatment: excision and follow-up
Gross: soft, pink, delicate papillary structures, usually pedunculated, mean 3 mm
Micro: usually simple arrangement of well-formed papillary fronds, rarely more complex anastomosing papillae with budding; papillae appear to float above urothelial surface due to sectioning of branching papillae; papillae usually small with scant stroma and slender fibrovascular cores; also large papillae with marked stromal edema or cystitis cystica-like invaginations; lined by normal appearing urothelium with prominent umbrella cells, normal polarity, variable dilated lymphatics within fibrovascular fronds, vacuolization; no hyperplasia, no dysplasia, no fusion of adjacent fronds, no necrosis, no/minimal mitotic figures
Micro images: series of images with discrete papillary fronds lined by normal urothelium; low power #1; #2; papilloma with delicate fibrovascular core, normal urothelium and cytoplasmic vacuoles #1; #2; #3; #4; #5
Micro images: (1) papilloma with simple, nonbudding papillary architecture, slender papillae with thin fibrovascular cores; (2) A: complex, budding papillary pattern; B: anastomosis of individual papillae; (3) large fibrovascular cores with prominent edema; (4) with invaginations in fibrovascular cores, resembling an inverted papilloma; (5) prominent umbrella cell layer; (6) focal mild atypia; (7) A: H&E; B: CD44+ basal cells; C: CK20+ superficial cells
DD: papillary urothelial neoplasm of low malignant potential (longer and thicker papillae with hyperplasia, less prominent umbrella cells), papillary urothelial hyperplasia (>7 cells thick, undulating pattern of thin mucosal papillary folds of varying heights, no discrete fibrovascular cores, vascularity present at base of urothelial proliferation)
References: Mod Path 2003;16:623, AJSP 2004;28:1615
Also called brunnian adenoma
Adult and elderly men
Rare; 1-2% of bladder tumors
Present with nonspecific hematuria and symptomatic obstruction
Low risk of recurrence if completely excised
May be associated with urothelial carcinoma, rarely in the inverted urothelial papilloma itself
Cases with atypia have not been associated with urothelial carcinoma, recommended to classify as “inverted papilloma with atypia” and not low grade urothelial carcinoma (Hum Path 2004;35:1499)
Treatment: simple excision
Gross: usually solitary, smooth, polypoid, pedunculated; at trigone, bladder neck or prostatic urethra; 3 cm or less
Micro: thin anastomosing cords and nests of urothelium growing downward (invagination) from normal appearing or compressed surface epithelium into the stroma with no exophytic papillary component; urothelial cells stream within the center of the nests; peripheral palisading of nuclei; stroma is exterior to the epithelial nests; variable squamous metaplasia, focal glandular differentiation or eosinophilic secretions; usually no fibrovascular cores, no desmoplasia, minimal inflammation, no infiltration of muscular wall, no/minimal mitotic figures
May have focal atypia due to prominent nucleoli, atypical squamous features, degenerative appearing multinucleated giant cells or atypical large squamous cells with a pagetoid appearance
Micro images: inverted papilloma #1; #2; #3; basaloid appearance; with squamous metaplasia
DD: urothelial carcinoma invading into Brunn’s nests (more atypia and mitotic activity, often papillary component), exophytic papilloma, papillary urothelial neoplasm of low malignant potential
Papillary urothelial neoplasm of low malignant potential
May arise in young patients
1/3 recur, 5% as higher grade; 10 year survival 95% or more
Are rarely associated with invasion or metastases
Some question distinguishing these lesions from low grade papillary urothelial carcinomas
Add to report "Patients with these tumors are at risk of developing new bladder tumors ("recurrence"), usually of a similar histology. However, since these subsequent lesions occasionally manifest as urothelial carcinoma, follow up is warranted."
Have lower MIB-1, p53 and mitotic counts than low grade papillary carcinomas, and higher disease free survival (76 vs. 15 months, AJSP 2001;25:1528)
Note: tumors with focal high grade carcinoma act like high grade carcinomas
Treatment: resection, follow-up
Micro: orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear atypia, regardless of cell thickness; thicker epithelium than papilloma, increase in nuclear size and hyperchromasia compared to papilloma; mitotic figures if present are usually confined to basal layer; reduced cytoplasmic clearing compared to normal urothelium; neoplastic cells may extend down the stalk onto adjacent flat urothelium
Cytology: slightly larger cells with irregular nuclear borders, may appear normal
Micro images: series of images
Micro images: A/B compared to low grade papillary urothelial carcinoma (C/D); A: H&E; B: diffuse CD44+; C: superficial CK20+ in a few cells
DD: papilloma (no atypia), low grade papillary urothelial carcinoma (small cells more densely arranged on fibrovascular stalks, nuclear are rounder, more nuclear pleomorphism)
Urothelial carcinoma
Also called transitional cell carcinoma (older term)
See also Invasive (below)
90% of bladder tumors are urothelial carcinoma
#5 most common type of cancer in US with 63,000 cases and 13,000 deaths/year estimated in 2005 (#4 in males and #10 in females)
Can arise anywhere in bladder, even diverticula; often multifocal; some multiple tumors are independent and some have common origin
Epidemiology: resembles bronchogenic carcinoma (M > F, cigarettes, urban, age 50+)
Causes are cigarette smoking (50-80% of cancers); arylamines (2-naphthylamine); Schistosoma haematobium (ova are deposited in bladder wall and cause chronic inflammatory response, squamous metaplasia, dysplasia; 70% are squamous cell carcinomas), phenacetin use (usually long term use in younger women, tumors involve upper collecting system), rarely cyclophosphamide with long term use
Cytogenetics: monosomy 9, 9p- (p16 INK4 / MTS1), 9q- (gene unknown), 13q- (retinoblastoma gene), 14q-, 17p- (p53)
Low grade tumors may begin with 9p-/9q-, some acquire p53 and become invasive; high grade tumors may begin with p53 alterations
Polysomies 1 and 17 are more frequent in pT1 than pTa tumors
In pTa tumors, polysomy 1 and 17 are linked to higher risk of recurrences; polysomy 17 is associated with increased risk of progression (Hum Path 1999;30:81)
Clinical course: initial symptoms are painless hematuria, infection, obstruction if near ureteral orifices
60% are single tumors (40% are multiple), 70% of tumors are localized to bladder
Tumors tend to recur (50% of low grade tumors recur vs. 80% of high grade), often at higher grade and different site
Tumors in young adults and children tend to be low grade and indolent
Endoscopy: accurate for determining benign/reactive vs. dysplastic/malignant; not accurate for determining high grade vs. low grade papillary lesions, or determining microscopic invasion (Hum Path 2001;32:630)
Diagnosis: cystoscopy, biopsy (should include muscularis propria and benign appearing areas), cytology (see below), flow cytometry of sediment (to detect aneuploidy)
Low grade papillary urothelial carcinoma
<5% risk of progression
50-65% recur, low risk of recurrence as high grade lesions, which may lead to invasion and death
Grade 2 of 4 in Ash system
Usually diploid, multicentric and noninvasive
Theories of multicentricity are (1) field effect: carcinogenic agents cause malignant transformation of multiple urothelial cells or (2) intramucosal spreading of tumor
In one study, low-grade, noninvasive urothelial carcinomas were monoclonal, and multifocal lesions had identical clonal origin, supporting the intramucosal spreading hypothesis (Hum Path 1999;30:1197)
Represent a continuous spectrum with high grade tumors (Hum Path 2003;34:893)
Treatment: transurethral resection of bladder tumor (TURBT)
Gross: more solid cores with firmer consistency than papillomas, usually solitary
Micro: papillary with central fibrovascular cores; orderly with recognizable variation of cytologic and architectural features, even at scanning magnification; rare to numerous mitotic figures, only assess papillary fronds cut perpendicular to long axis of papillary frond; compared to papillomas have more crowding and layering of cells, more hyperchromasia and mitoses; definite cytologic atypia
Note: report highest grade area of lesion
Note: fused papillary cores may be overgraded; some cells are overtly neoplastic when compared to tumors classified as low malignant potential
Cytology: may be cellular, exist in loose clusters with high N/C ratios, irregular nuclear borders; cytoplasm may surround only a portion of the nucleus
Micro images: series of low grade (grade 1) tumors; grade 1 papillary tumor with thickened urothelium but minimal atypia #1; #2
Micro images: (1) C/D vs. papillary tumor of low malignant potential (A/B); (2) A: H&E; B: patchy loss of CD 44 in a background of accentuated staining; C: patchy CK20
Cytology images: low grade papillary urothelial carcinoma #1; #2; #3
Positive stains: blood group antigens
DD: papillary urothelial neoplasm of low malignant potential
High grade papillary urothelial carcinoma
Grade 3 of 4 in Ash system
Usually aneuploid
May invade adjacent structures or regional lymph nodes; late dissemination to liver, lung, marrow
15-40% rate of progression
Treatment: radical cystectomy, variable chemotherapy or radiation therapy; similar treatment for T2 lesions
In men, radical therapy includes cystoprostatectomy and excision of seminar vesicles; in women, includes excision of uterus, tubes, ovaries, anterior vagina, urethra
Ileal conduit is fashioned into a new bladder with reimplantation of ureters
Gross: sessile or cauliflower-like with necrosis and ulceration
Gross images: multifocal papillary tumors with delicate fronds; multifocal papillary tumor
Micro: predominantly disorderly appearance at low power with prominent architectural and cytologic abnormalities; solid, nodular, papillary or flat; more nuclear pleomorphism / anaplasia than low grade, clumped chromatin, prominent nucleoli, irregularly clustered cells, disorganized epithelium, mitotic figures at all levels, which may be atypical; highest grade tumors may not appear urothelial, may have indistinct cell borders
Associated with carcinoma in situ, dysplasia in adjacent urothelium
Grade according to highest grade within a tumor, ignoring miniscule areas of higher grade tumor
Micro images: series of high grade papillary tumors; grade 2 tumor with more atypia than grade 1 tumors - #1; #2; #3; grade 3 tumor with marked atypia and architectural disorganization - #1; #2; grade 3 tumor with voluminous cytoplasm #1; #2; grade 3 tumor with apoptotic cells; grade 3 tumor that lacks urothelial characteristics; transition from grade 2 to 3 within same tumor
Micro images: A: H&E; B: loss of CD44; C: diffusely CK20+
Cytology images: intermediate grade papillary urothelial carcinoma #1; #2; high grade #1; #2; #3
Positive stains: beta hCG in 1/3 of urothelial carcinomas, particularly high grade or high stage tumors (Hum Path 1998;29:377), estrogen receptor in 14% (Archives 2005;129:194)
Negative stains: blood group antigens, no/weak expression of E-cadherin (Hum Path 1995;26:940)
Invasive urothelial carcinoma - WHO classification
Urothelial carcinoma, not otherwise specified (NOS)
Urothelial carcinoma with squamous differentiation
Urothelial carcinoma with glandular differentiation
Urothelial carcinoma with trophoblastic differentiation
Nested
Microcystic
Micropapillay
Lymphoepithelioma-like
Lymphoma-like
Plasmacytoid
Sarcomatoid
Giant cell
Undifferentiated
See also staging (below)
pT2, pT3, pT4 lesions are often diagnosed as de novo lesions, possibly originating from flat urothelial alterations
Some, not all, have same clonal origin as prior T1 lesions (Hum Path 2001;32:468)
May spread via mucosa to seminal vesicles (AJSP 1987;11:951)
pTa may actually be invasive when studied by electron microscopy, significance unclear (AJCP 2003;120:188)
Lamina propria (pT1): invasion of lamina propria (pT1 vs. pTa) is subjective and usually not as important as invasion of muscularis propria (pT2); has nests, clusters or single tumor cells, sometimes with prominent retraction artifact (does not represent lymphovascular invasion); often has desmoplastic or inflammatory stromal response and absent or irregular basement membrane, not seen with low grade papillary carcinomas with inverted pattern; tumor cells often have abundant eosinophilic cytoplasm at advancing edge (“paradoxical differentiation”); if tumor cells hug the mucosa, they should be more anaplastic than mucosa cells
80% of urothelial carcinomas are pTis, pTa or pT1; 50% recur
Muscularis propria (pT2): assessment of muscularis propria invasion is very important (pTa/pT1 vs. pT2); mention whether muscularis propria is present in biopsies and if invasion is present; don’t confuse occasionally prominent fascicles of muscularis mucosa, part of lamina propria (more common in women) with muscularis propria invasion
Muscularis propria invasion implies tumor infiltrating thick smooth muscle bundles; can use trichrome or HHF to highlight all smooth muscle tissue to determine if muscularis mucosa or muscularis propria is invaded; tumor cells should “carve out” the muscle bundles, often desmoplastic response should be present
Can assess presence but not depth of muscularis propria invasion in TURBT specimen
Note: must clearly distinguish muscularis mucosa from muscularis propria in tumor cases
Perivesical fat (pT3): adipose tissue is often present within deep lamina propria, usually as small localized aggregates; also always found within muscularis propria (superficial and deep); beware of inappropriate staging as pT3 due to tumor infiltration of adipose tissue, particularly in TURBT specimens (AJSP 2000;24:1286)
For node positive radical cystectomy patients with meticulous lymph node dissection and thorough histologic examination, extracapsular extension has prognostic value, but N1 vs. N2 does not (AJSP 2005;29:89)
Metastases to lymph nodes in 25% of invasive tumors; also to lung, liver, bone, CNS
Often dysplasia or carcinoma in situ elsewhere in bladder; also in ureters, bladder neck, urethra, prostatic ducts, seminal vesicle
10 year survival only 40% for high grade tumors
Invasive urothelial carcinoma (continued)
Prognostic factors:
Stage most important, particularly pTa/pT1 vs. pT2 (i.e. whether or not there is muscularis propria invasion); 5 year survival is 75% if T1, 50% for T2 and 20% for T3
Predictors of prolonged survival in pTa and pT1 are small tumor size, lack of cyclin D3 expression, low proliferation index (AJCP 2004;122:444)
For muscle invasive urothelial carcinoma, pathologic T stage and lymph node status are the most powerful predictors of progression; histologic grade (Malmstrom system) of invasive component was not helpful; an infiltrative invasive pattern (vs. nodular or trabecular) is associated with poorer prognosis (AJSP 2000;24:980)
Nodal involvement
Grading (high grade vs. low grade)
Age (young patients tend to have noninvasive, low grade tumors)
Site (ureteric and lateral wall tumors tend to be low grade, dome tumors tend to be high grade, bladder neck tumors have poor prognosis)
Changes in normal-appearing mucosa (dysplasia, carcinoma in situ or independent tumors are associated with recurrence)
Vascular invasion, ploidy
Blood group antigen expression correlates with better tumor behavior
Loss of E-cadherin expression is associated with poor survival/high stage tumors (Hum Path 2001;32:18)
Low p27/Kip1 is associated with poorer overall survival in muscle invasive urothelial carcinomas (Hum Path 2000;31:751)
Loss of CD44 immunoreactivity (restricted to basal cell layer in normal urothelium) and increase of CK20 positivity (restricted to a few umbrella cells in normal urothelium) associated with increasing tumor grade and stage in pTa and pT1 patients with papillary urothelial neoplasms (Mod Path 2000;13:1315)
Case reports: urothelial and prostatic carcinoma metastasizing to same lymph node (Archives 2001;125:1354), 83 year old man with high grade carcinoma with acinar/tubular pattern resembling Gleason grade 3 prostatic adenocarcinoma (Hum Path 2004;35:769), post-menopausal woman whose tumor had choriocarcinomatous component (Hum Path 1984;15:793), 14 year old without risk factors with a high grade invasive tumor (AJSP 1989;13:1057)
Invasive urothelial carcinoma (continued)
Gross images: high grade invasive urothelial carcinoma #1; #2; tumor of trigone and dome
Micro: wide range of morphologic differentiation; glandular metaplasia with intracytoplasmic mucin vacuoles present in 25%, particularly high grade tumors (Hum Path 1992;23:860); squamous differentiation common with high grade lesions; focal clear cells or choriocarcinoma areas may be present; may have spindle cells, osteoclasts, squamous, glandular or benign stromal elements, plasmacytoid cells, lipid cells; bizarre nuclear pleomorphism associated with hCG production; may have focal pseudosarcomatous stroma; microcystic pattern is rare
Report as “with __ differentiation” if focal squamous or glandular differentiation
Cytology: spindle, pyramidal, racquet-shapes; hyperchromatic nuclei, increased N/C ratio, coarse granular chromatin, intracytoplasmic vacuoles
Micro images: high grade muscle invasive urothelial carcinoma #1; #2 with perineural invasion; high grade urothelial carcinoma with glandular, micropapillary and plasmacytoid differentiation; grade 2 tumor with focal lamina propria invasion #1; #2; vascular invasion #1; #2; sclerosing pattern #1; #2; glycogen-rich #1; #2 with PAS stain; urothelial and prostatic carcinoma metastases to same lymph node; CK20 in primary and nodal metastasis; H&E; p53+; atypical urothelial cells identified with (a) fluorescent monoclonal antibodies; (b) H&E
Virtual slides: high grade muscle invasive, urothelial carcinoma (appears high grade)
Invasive urothelial carcinoma (continued)
Positive stains: CK7, high molecular weight cytokeratin/34betaE12 (80%), thrombomodulin (60-70%), CK20 (50%), uroplakin III (40-60%, but highly specific), MUC1, CEA, p53; CA125 (27%, Int J Biol Markers 1994;9:224)
Note: CK20 staining pattern in primary tumor is replicated in metastases (Archives 2001;125:921)
Negative stains: WT1, MUC2, MUC5AC, HPV, Leu7/CD57
EM: pleomorphic microvilli; decrease in specialized junctions
DD: vasculitis (particularly with HIV or hepatitis B infection, may present as recurring mass lesion, Archives 1998;122:903); low grade lesions resemble Brunn’s nests or cystitis glandular/cystica
DD: high grade (poorly differentiated) prostatic adenocarcinoma (has foamy and pale cytoplasm, oval nuclei with smooth borders, fine, powdery, evenly distributed nuclear chromatin, large prominent nucleolus when present, lack of significant pleomorphism, no/rare mitotic figures, no/rare necrosis, no intraductal growth)
Positive in high grade prostatic adenocarcinoma and negative in high grade urothelial carcinoma: PSA or PAP, CD57/Leu7
Negative in high grade prostatic adenocarcinoma and positive in high grade urothelial carcinoma: CK7 and CK20, uroplakin III and thrombomodulin, 34betaE12, p53
Urothelial carcinoma cases diagnosed on prostatic needle biopsy often have only in-situ involvement of prostatic ducts and acini by urothelial carcinoma; compared to prostatic adenocarcinoma, have greater nuclear pleomorphism, increased mitoses and necrosis; PSA/PAP negative, CK7+, CK20+, 34betaE12+; most die of disease (mean survival 23 months), even if only in-situ involvement present; cure possible with aggressive chemotherapy and adjuvant chemoradiotherapy (AJSP 2001;25:794)
References: Mod Path 2000;13:1186, AJCP 2000;113:383; Hum Path 2002;33:1136, Archives 2003;127:e333, AJSP 2003;27:1 (stains), AJCP 2004;122:61 (mucin stains)
Endophytic growth pattern
Anastomosing cords and columns of urothelium resembling inverted papilloma or broad pushing bulbous invaginations into lamina propria (broad front pattern)
Mean age 68 years; 75% male
50% had unequivocal invasion of lamina propria or muscularis propria
All cases also had papillary urothelial carcinoma of the usual type
References: AJSP 1997;21:1057
Microcystic growth pattern
Uncommon
No prognostic significance
Micro: prominent intercellular or intracellular lumens surrounded by neoplastic urothelial or squamous cells; “cysts” are round/oval, up to 1.2 mm, lined by urothelium or low columnar cells with mucinous differentiation; occasionally flattened cells; also elongated, irregular branching spaces; pattern resembles cystitis glandularis et cystica
DD: adenocarcinoma (lined by goblet cells, not flattened, urothelial like cells), cystitis glandularis
References: AJCP 1991;96:635
Nested variant:
Either rare or underreported; estimated incidence is less than 0.3% of invasive bladder tumors
Aggressive behavior despite bland cytologic features; often advanced stage at presentation
Usually men > 60 years (similar to classic urothelial carcinoma)
Often at periureteral orifice
Treatment: radical surgical resection (currently)
Gross: often no clearly defined tumor
Micro: irregular and confluent small nests and abortive tubules composed of urothelial cells infiltrating the lamina propria or muscularis propria, usually without surface involvement; tumor cells have only mild atypia (mild pleomorphism, slightly increased N/C ratios, occasional prominent nucleoli, rare mitotic figures) and resemble cystitis glandularis et cystica, often more anaplasia with increasing depth of invasion; often a more typical urothelial carcinoma is also present
Micro images: (1) nests of bland urothelial cells in lamina propria #1; #2; #3; (4) figure 1: edematous bladder mucosa and diffusely thickened wall; 2: diffuse infiltration by ill-defined nests of cells, some with clear cytoplasm; surface mucosa is uninvolved; 3: relatively bland nuclei with minimal pleomorphism, indistinct nucleoli, rare mitotic figures; 4: strong p63+; 5: ill-defined nests of cells; 6: strongly p63+
Micro images: (1) confluent small nests and abortive tubules infiltrate the lamina propria or muscularis propria; (2) nested variant (long arrow) with overlying flat carcinoma in situ (A: short arrow) and low grade papillary carcinoma (B: short arrow)
Positive stains: p63, Ki-67, variable p53
Negative stains: bcl2, EGFR
DD: nested papilloma, Brunn’s nests, nephrogenic metaplasia (usually papillary component, prominent tubular or cystic structures lined by single layer of cuboidal cells), cystitis cystica [all lack invasion and nested growth pattern]
References: Mod Path 2003;16:1289, Mod Path 1996;9:989, Archives 2003;127:e333; AJSP 1996;20:1448, AJSP 1989;13:374
Cystoscopic biopsy of visible lesions is more sensitive than cytology in most cases
Cytology is useful to detect carcinoma in situ or marked chronic inflammation (no specific lesion to biopsy), carcinomas hidden in diverticula, detecting residual tumor from urine specimens
Bladder irrigation is superior to collecting voided urine
Most sensitive for high grade tumors; difficult to diagnose papilloma and low malignant potential lesions by cytology because they have normal histology (Mod Path 1995;8:394)
Follow up examination of urine with FISH may improve sensitivity and specificity of cytology (AJCP 2001;116:79)
DD: radiation or chemotherapy induced atypia
Other carcinomas
Also called mesonephric or mesonephroid carcinoma / adenocarcinoma
Resembles clear cell carcinoma of female genital tract
Usually women, in bladder or urethra
Arises via metaplasia or from endometriosis (AJSP 2002; 26:190)
Often high stage at diagnosis
Case reports: 35 year old woman with endometriosis (Mod Path 1993;6:225)
Gross: usually papillary, also sessile
Micro: often papillary or tubulocystic; cells have abundant clear or eosinophilic cytoplasm with glycogen and frequent hobnailing; more pleomorphic cells and more mitotic figures than adenomatoid tumor; variable necrosis; resembles urothelial carcinoma more than adenocarcinoma
Micro images: papillary tumor with prominent hobnailing #1; #2; tubules and nests of cells with clear cytoplasm; prominent papillary component with focal eosinophilic cytoplasm
Positive stains: CA125 (strong), CK7 (usually strong), Ki-67, p53
Negative stains: CK20
DD: nephrogenic metaplasia (young age, history of GU trauma, minimal atypia or pleomorphism, no/rare mitotic figures, no necrosis, no infiltrative growth), extension or metastasis from gynecologic or other clear cell carcinoma
References: Hum Path 1996;27:248, AJSP 1985;9:816
Giant and spindle cell carcinoma
Rare
Micro: resembles giant cell tumors at other sites; associated with high grade urothelial carcinoma
Positive stains: epithelial markers
DD: urothelial carcinoma with osteoclast-type giant cells, urothelial carcinoma mixed with mesenchymal-type giant cell tumor
Large cell neuroendocrine carcinoma
Rare; may coexist with urothelial carcinoma or adenocarcinoma
Case reports: 82 year old man with tumor arising in bladder diverticulum (Archives 2002;126:1229); 73 year old man post radiation therapy for prostate cancer (Mod Path 1998;11:1016)
Micro (same as similar lung tumors): large polygonal cells with low nuclear to cytoplasmic ratio, coarse chromatin, frequent nucleoli, 10+ mitotic figures/10 HPF, multiple areas of necrosis
Positive stains: chromogranin, synaptophysin, neuron specific enolase
Most common primaries are breast and melanoma; also lung, pancreas, ovary; associated with widely disseminated disease
Urothelium is usually spared
Tumors may also arise from local extension from prostate, uterine cervix or rectum; it is difficult to distinguish bladder adenocarcinoma histologically from extension of colonic adenocarcinoma
Micro images: metastatic seminoma #1; #2
Renal cell carcinoma metastatic to bladder
Rare, usually men age 35-69 years who present with hematuria after removal of known primary tumor; metastases also present in other organs; poor prognosis (Mod Path 1999;12:351)
Micro: delicate fibrovascular stroma with abundant sinusoidal vessels
Positive stains: CAM 5.2, vimentin, Leu-M1 (CD15)
Negative stains: CK20, CK7, 34betaE12, CEA, S100, HMB45, chromogranin
Note: urothelial carcinomas are positive for CEA and all cytokeratins and negative for vimentin
Adults, 80% men, mean age 67-69 years
Incidence of 0.7%
Usually high grade and high stage at presentation with marked nodal metastases and extensive lymphovascular invasion
Presence of micropapillary pattern in otherwise conventional urothelial carcinoma is associated with advanced tumor stage and poor prognosis; if surface micropapillary carcinoma present in biopsy without muscularis propria, deeper biopsy to determine muscular invasion is recommended (AJSP 1994;18:1224)
May be due to reversal in cell polarity due to MUC1, normally on apical surface, being localized on stroma-facing surface of cells (Mod Path 2004;17:1045)
Case reports: 45 year old man with mixed micropapillary and trophoblastic bladder carcinoma (Hum Path 2004;35:382), 70 year old man with gross hematuria and indurated mass in bladder (Archives 2005;129:e53)
Micro: delicate papillae with thin stromal cores and numerous secondary micropapillae; clefts form around neoplastic cell clusters and simulate lymphovascular invasion; usually marked atypia; often lower grade at surface and higher grade in deeper portion; 1-4 cell layers thick; numerous mitoses and frequent true lymphovascular invasion; edematous stroma with chronic inflammatory infiltrate; resembles serous borderline tumors of ovary, but no psammoma bodies; often mixed with urothelial carcinoma in primary, but metastases usually have only micropapillary pattern
Micro images: (1) micropapillary pattern invading muscularis propria; (2) tumor cells are arranged in papillary clusters surrounded by clefts (may resemble lymphovascular invasion); (3) micropapillary pattern with spaces filled with hemorrhage #1; #2; (5) micropapillary pattern with overlying papillary urothelial carcinoma; (6) papillae lined by cuboidal to low columnar cells; (7) focal cytologic atypia; (8) figure 1: tight nests surrounded by empty spaces; 2: tumor cells focally had high grade features; 3: nodal metastases had similar pattern
Micro images: MUC1 staining of tumor in (a) breast, (b) bladder
Positive stains: MUC1 limited to basal surface of cells (apical, intracytoplasmic or intracellular in conventional carcinomas)
DD: papillary nephrogenic adenoma, clear cell carcinoma
Plasmacytoid / lymphomatoid carcinoma
Rare
Micro: malignant epithelial cells that resemble plasma cells or lymphocytes; may be mixed with true lymphocytes
Positive stains: cytokeratin (strong)
Negative stains: plasma cell and lymphocyte markers, gamma globulin, light chains
Primary or secondary within the bladder
Primary lesions may have a history of prostatic adenocarcinoma (PAC) in the prostate, and have a favorable prognosis
Secondary prostatic adenocarcinoma is usually associated with high grade/high stage carcinoma in the prostate, but may mimic urothelial carcinoma histologically (Hum Path 2001;32:434)
Case reports: prostatic adenocarcinoma and bladder urothelial carcinoma metastasizing to same lymph node (Archives 2001; 125:1354)
Micro images: tumors in above case report
Also called carcinosarcoma (some differentiate these terms, but criteria are difficult to apply), spindle cell carcinoma, metaplastic carcinoma
Rare, <100 cases described
Often elderly men (mean age 72, range 49 to 88 years) with very aggressive and advanced disease
May involve ureter and renal pelvis
Associated with cyclophosphamide and radiation therapy
Prognosis depends on depth of invasion
Treatment: surgery (treat as a high grade carcinoma)
Case reports: 65 year old man with tumor of bladder diverticulum and coexisting prostatic adenocarcinoma (Archives 2002;126:853); ; tumors with liposarcomatous, MPNST and micropapillary components (Archives 2000;124:1172), post cyclophosphamide therapy for Wegener’s granulomatosis (Archives 2004;128:e8, AJSP 1980;4:191); post-cyclophosphamide therapy for lymphoma (Archives 1991;115:1049); causing clitoromegaly (Archives 2003;127:505),
Gross: large, polypoid or sessile mass, usually with well circumscribed base
Gross images: bladder and diverticulum containing large tumor
Micro: resembles similar tumors in upper aerodigestive tract; high grade tumor with sarcomatoid and carcinomatoid components; sarcomatoid component has spindled, round and pleomorphic giant cells, with myxoid or sclerosing areas; carcinomatoid component has papillary or nonpapillary high grade urothelial carcinoma, adenocarcinoma, squamous cell carcinoma or small cell carcinoma; may be present only as carcinoma in situ
Micro images: (1) epithelioid (upper right) and sarcomatoid (lower left) areas; (2) with osteoclast-like giant cells; (3) with squamous cell carcinoma component #1; #2; (5) undifferentiated spindle cells; (6) figure 1: gross shows large diverticulum containing polypoid tumor; 2: invasive high grade urothelial carcinoma component; 3: neoplastic glands within spindle cell stroma; 4: spindle cells; (7) figure 5: pleomorphic area; 6: prostatic adenocarcinoma; 7: CK+ glandular elements, spindle cells are CK-; 8: sarcomatous area is vimentin+; (8) figure 1a: large polypoid mass fills bladder; 1b: tumor has large polygonal epithelioid cells with irregular nuclei and prominent nucleoli; 1c: sarcomatoid component has spindle cells with elongated and blunt nuclei; 1d: CK+ epithelioid areas; 1e: smooth muscle actin+ spindle cells; 2: pleomorphic lipoblasts with signet-ring lipoblasts, (9) figure 2b: desmin+ rhabdomyosarcomatous focus; 2c: spindle cells resemble MPNST with wavy and bullet shaped nuclei; 2d: S100+ MPNST cells; 2e: lymphovascular invasion by micropapillary urothelial carcinoma; 3a: urothelial carcinoma and adjacent sarcomatous component; 3b: sarcoma shows large atypical cells with pleomorphic nuclei (10) figure 4a: small cell carcinoma; 4b: chondrosarcomatous area; (11) figure 1A: H&E, 1B: keratin+ (epithelial areas); 1C: vimentin+ (sarcomatoid areas); 2A: well differentiated liposarcoma; 2B: pleomorphic liposarcoma, 2C: dedifferentiated liposarcoma; 3A/B: rhabdomyosarcoma; 3C: desmin+; (12) figure 1: infiltration of entire clitoris, 2/3: spindle shaped tumor cells (carcinoma cells elsewhere)
Positive stains: keratin and EMA (both components), variable CEA, hCG
Negative stains: smooth muscle actin (usually), desmin (usually), calponin, caldesmon
DD: post operative spindle cell nodule, inflammatory myofibroblastic tumor, sarcoma, urothelial carcinoma with reactive stroma (negative for epithelial markers, AJCP 1988;90:216), true sarcoma (very rare)
References: Hum Path 2000;31:332, AJSP 1994;18:241, AJCP 1988;90:653
Myxoid/sclerotic sarcomatoid carcinoma
Mean age 72 years, no gender preference
Gross: 3-10 cm, rubbery/gelatinous, brown-pink-gray, polypoid or intramural mass, often with necrosis or ulceration
Micro: tapering atypical spindle cells with hyperchromatic and pleomorphic nuclei, prominent nucleoli, coarse chromatin, mixed with non-spindled cells; often coexisting carcinoma component and CIS; myxoid change variable and often resembles inflammatory pseudotumor; sclerosis and abnormal mitoses common
Positive stains: cytokeratin, vimentin
Negative stains: CEA (usually), actin, EMA, desmin, S100, CD68, CD34, CD15 (Leu-M1)
Reference: Mod Path 1997;10:908
Uncommon; limit to cases with 25% or more signet ring tumor cells
Median age 58 years
Diffuse infiltration, similar to linitis plastica of stomach, makes resection for cure virtually impossible
May lack mucosal involvement
Usually nonurachal
Very aggressive with 5 year survival of only 13% (but presence of a few signet ring cells doesn’t affect the prognosis of a bladder adenocarcinoma)
Micro: signet ring type cells with intracytoplasmic mucin, resembling lobular carcinoma of breast but larger, may be monocytoid with central nuclei; urothelial abnormalities may be difficult to find; no abundant extracellular mucin
Micro images: signet ring adenocarcinoma #1; #2
Positive stains: usually mucin, but may not be prominent
DD: direct extension from prostatic or rectal adenocarcinoma, metastasis from stomach, breast or other organs; nodular histiocytic hyperplasia (rare, one case in lamina propria of bladder, may have mild atypia and mitoses; strong CD68+, keratin-, AJSP 1998;22:285)
References: AJCP 1991;95:13
5% of bladder tumors in US, 75% in Egypt/Sudan (in Egypt, bladder cancers are 1/3 of all cancers); mixed urothelial and squamous carcinomas are more common than pure squamous cell carcinomas
Arises in background of chronic cystitis with squamous metaplasia, also bladder exstrophy, neurogenic bladder, chronic infection, bladder stones, chronic indwelling catheters, prolonged cyclophosphamide treatment, Schistosoma haematobium infection in Egypt/Sudan; associated with smoking
Difficult to detect since arises insidiously; often gross hematuria, dysuria, nocturia, frequency, pain, bacteriuria
Limit diagnosis to tumors with diffuse (80% or more), not focal squamous histology
Poor prognosis; most patients have advanced muscle invasive disease at presentation
5 year survival is 37% if pT1/pT2 vs. 13% for pT3
Regional nodal metastasis in 10-25%, distant metastases to bone and lung
Gross: large, ulcerated, necrotic; often involves areas other than bladder base; 80% involve muscular wall at diagnosis
Gross images: fungated, tan-white, indurated mass
Micro: arise in epithelium, infiltrate in sheets, nests and islands; resemble epidermal tumors with some combination of individual cell keratinization, keratin pearls and intercellular bridges; TURBT biopsies may contain only keratinous debris; keratinization of cells at stromal interface is sign of invasion (per Murphy); cells are polygonal with well defined cell borders, amphophilic to eosinophilic cytoplasm; nuclei are pleomorphic, occasionally bizarre, with irregular chromatin and prominent nucleoli; mitotic figures common; also degenerated cells
Grading is not reproducible
Cytology: high index of suspicion is needed for detection since many cells resemble squamous metaplasia; polygonal, fiber-like or tadpole like cells with well defined cell borders, amphophilic or eosinophilic cytoplasm with occasional vacuoles, enlarged and slightly pleomorphic nuclei with irregular chromatin, prominent nucleoli (if present); poorly differentiated cells resemble any high grade neoplasm
Micro images: moderately differentiated tumor #1; #2; #3
Cytology images: keratinizing squamous cell carcinoma #1; #2
Cytogenetics: 9p-
DD: high grade urothelial carcinomas with squamous components, squamous metaplasia (no anaplasia), condyloma acuminatum with nuclear atypia, verrucous carcinoma, metastatic carcinoma, direct extension of cancers from adjacent organs
References: Mod Path 2004;17:1268 (Schistosomiasis)
Basaloid squamous cell carcinoma
Case reports: 60 year woman with multiple surgeries for incontinence, intractable urinary tract infections and flat cystoscopic lesions (Archives 2000;124:455)
Micro: nests of basaloid cells with numerous mitoses; areas of squamous differentiation and squamous cell carcinoma in situ
Micro images: (1) A: nests of basaloid cells with peripheral palisading; B: pseudoglandular pattern; (2) C: invasion of muscularis propria; D: basaloid cells have high N/C ratio and numerous mitotic figures; (3) adjacent squamous carcinoma in situ
Verrucous squamous cell carcinoma
Almost all cases are associated with Schistosoma hematobium infection
Indolent growth, spreads by direct extension
Does not metastasize, although may develop foci of invasive squamous cell carcinoma
Gross: exophytic, papillary tumor projects into bladder lumen
Micro: bulbous fronds of well differentiated, acanthotic epithelium with pushing margin, minimal atypia; no/rare mitotic figures; may resemble condyloma focally
Micro images: exophytic tumor with pushing border in lamina propria; minimal atypia #1; #2
Miscellaneous
Mandatory / optional are for accreditation purposes by the American College of Surgeons Committee on Cancer
Bladder biopsy / TURBT
Mandatory
none
Optional
Site of tumor
Tumor size
Tumor histologic type
Tumor histologic grade
Pattern of growth (papillary, flat, invasive)
Type of invasion: broad spread or tentacular (like tentacles)
Depth of invasion
Layers of wall represented (muscularis propria identified or not)
Denuded/ulcerated
Lymphovascular invasion (only if unequivocal, often is overdiagnosed (Mod Path 1990;3:83)
Involvement of prostate
Additional findings: carcinoma in situ, dysplasia, hyperplasia, inflammation, normal, other
Cystectomy (total/partial), cystoprostatectomy, pelvic exenteration
Mandatory
Specimen type
Tumor size
Tumor histologic type
Tumor histologic grade
Pathologic stage (includes depth of invasion)
Regional lymph nodes (number examined, number positive, size of metastasis, extranodal extension)
Surgical margins: specify margins involved by invasive carcinoma or in situ carcinoma
If uninvolved by invasive carcinoma, specify distance from invasive carcinoma to margin
Presence of tumor at margins of urethra, ureter, paravesicular soft tissue or pelvic soft tissue
Involvement of adjacent structures: perivesical fat, ureter (specify laterality), urethra, vagina, uterus and adnexae, pelvic sidewall (specify laterality), prostate, seminal vesicle (specify laterality), rectum, other
Additional epithelial lesions: papilloma, inverted papilloma, papillary neoplasm of low malignant potential
Optional
Site of tumor
Pattern of growth (papillary, flat, invasive)
Lymphovascular invasion (only if unequivocal
Additional findings: carcinoma in situ, dysplasia, hyperplasia, inflammation, therapy related changes, squamous metaplasia, intestinal metaplasia
References: Archives 2003;127:1263
Ink entire external surface of cystectomy specimen
Either open with Y shape through anterior wall, pin and fix overnight or fill with formalin, fix overnight, and divide into anterior and posterior halves
Sections to submit:
Tumor, representative, 1 per cm of tumor diameter (up to 10 cassettes)
Note: If initial sampling shows only noninvasive or non-muscle invasive tumor, submit additional sections as necessary to rule out invasion or muscle invasion
Tumor, deepest penetration into wall (multiple sections)
Tumor and adjacent normal bladder wall
Mucosa remote from tumor (multiple sections)
Bladder neck
Bladder trigone (two sections)
Anterior and posterior wall (two sections each)
Dome (two sections)
Utereral orifices, including intramural portion
Ureteral margin, possibly additional sections if long segment is present
Urethral margin
Prostatic urethral margin (if present)
Margins of resection
Other grossly abnormal areas
Prostate (peripheral zone, central zone, seminal vesicles, grossly suspicious areas)
Lymph nodes
Pelvic wall
End of Bladder chapter