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Bladder
Author: Nat Pernick, M.D.; see reviewers for individual topics
Last revised: 20 July 2010, last major update July 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.
Table of contents
Primary references, embryology, normal anatomy, normal histology
Cytology: general, normal findings, non-neoplastic lesions, primary noninvasive urothelial neoplasms,
primary invasive neoplasms, secondary neoplasms, biomarker testing, format of diagnostic report
Congenital anomalies: AV malformation, duplication, ectopic prostate, exstrophy, hypoplasia, persistent cloaca, patent urachus
Acquired non-neoplastic anomalies: amyloidosis, collagen polyp, cystocele, diverticula, endocervicosis, endometriosis, endosalpingiosis, lithiasis, obstruction, Tamm-Horsfall protein, treatment effect, urinary diversion / neobladder
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
Nonurothelial benign tumors: condyloma, fibroepithelial polyp, hemangioma, inflammatory myofibroblastic tumor, leiomyoma, neurofibroma, postoperative granulomas, post-operative spindle cell nodule, prostatic-type polyp, solitary fibrous tumor, urachal lesions, villous adenoma
Urothelial benign lesions: WHO/ISUP classification, flat hyperplasia, papillary hyperplasia, flat lesions with atypia, dysplasia
Urothelial neoplasms-noninvasive: noninvasive urothelial carcinoma-general, carcinoma in situ, low grade papillary, high grade papillary, papillary neoplasm of low malignant potential, urothelial papilloma, inverted urothelial papilloma
Urothelial carcinoma-invasive: WHO/ISUP classification, general, chordoid, clear cell, endophytic, giant cell, large cell neuroendocrine, lymphoepithelioma-like, lymphoma-like, microcystic, micropapillary, nested, osteoclast-rich, plasmacytoid, rhabdoid, sarcomatoid, sclerosing, small tubules, villoglandular, with glandular differentiation, with squamous differentiation, with trophoblastic differentiation, undifferentiated
Adenocarcinoma: in situ, general, clear cell, hepatoid, prostatic, signet ring, urachal
Other carcinomas: metastases, 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, rhabdomyosarcoma, urachal sarcoma
Miscellaneous: staging, grossing, features to report: TURBT, cystectomy
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
Benign urothelial lesions
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
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
Urothelial carcinoma-noninvasive
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)
Sources for FISH testing (advertisements): Clarient (Cancer assay by FISH)
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
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
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
End of Bladder chapter