Bladder
Last revised 19 January 2009
Last major update April 2005
Copyright (c) 2003-2009, PathologyOutlines.com, Inc.
Excludes prostatic urethra (see prostate)
Home page
Printer
friendly version
Bold and underlined topics are hypertext links, and may open a new window
Table of contents for Bladder
Primary references, embryology, normal anatomy, normal histology
Congenital anomalies: AV malformation, cloacogenic bladder, duplication, ectopic prostate, exstrophy, hypoplasia, hyperplasia, 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, 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, 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, yolk sac tumor of urachus
Other tumors: angiosarcoma, carcinoid, clear cell myelomelanotic tumor, GIST, germ cell tumors, leiomyosarcoma, lymphoma, MFH, melanoma, osteosarcoma, paraganglioma, plasmacytoma, rhabdoid tumor, rhabdomyosarcoma
Miscellaneous: staging, report, grossing
AJCC Cancer Staging Manual (6th Ed)
American Journal of Clinical Pathology (AJCP), January 1975 to April 2005
American Journal of Surgical Pathology (AJSP), March 1977 to April 2005
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to April 2005
Human Pathology (Hum Path), March 1970 to March 2005
Modern Pathology (Mod Path), January 1988 to April 2005
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Sternberg: Histology for Pathologists (2nd edition), 1997
Johns Hopkins WHO/ISUP Tutorial website - beautiful images that illustrate the various lesions
www.Webpathology.com - beautiful images of urologic pathology
Journal search terms: urinary bladder, bladder, urothelium, urothelial
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
Usually are not isolated, but one of many manifestations of developmental failure of GU mesenchyme
By definition, direct communication is present between arterioles and venules
Very rare in bladder; more common in CNS, intestine, lung, extremities
May cause massive hematuria
Micro: abrupt changes in the thickness of the medial and elastic layers of the vessels; also abnormal vascular dilation, often advanced small vessel disease, hemorrhage, ulceration
Also called persistent cloaca
Defined as confluence of rectum, vagina and urethra into a single common chamber
A surgical challenge to achieve bowel and bladder control and normal sexual function
Occurs in 1/20,000 births, only in girls
Gross images: cloaca serves as convergence of rectum and both ureters #1; #2
Bladder is separated into compartments
Either double bladder, septal bladder or hourglass bladder
Incomplete emptying causes urinary tract infections
Gross: polypoid mass at bladder base
DD: post-surgical ingrowth of prostatic tissue
Developmental failure in lower abdominal wall or anterior wall of bladder due to failure of cloacal membrane to property differentiate; bladder communicates with body surface or lies as an opened sac
Associated with glandular metaplasia and adenocarcinoma (<10% of exstrophied bladders) or squamous metaplasia and squamous cell carcinoma (~7% of patients)
Also associated with infections and ulceration
Drawings: diagrams of exstrophy
Gross images: exstrophy in male
Normal but small bladder, seen in Potter syndrome
Boys only
Structurally and functionally abnormal bladder, shaped like cone, heart or cloverleaf
Does not empty completely
Associated with obstruction at urethral outlet but normal histology
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
Either a generalized process or amyloid tumor; often with marked giant cell or histiocytic reaction
Usually AL type (immunoglobulin light chain)
Patients present with gross hematuria
Treatment: excision of amyloid tumor usually curative (and controls bleeding), since not associated with myeloma
Gross: nodular mucosal lesions resembling carcinoma; rarely is diffuse involvement of bladder wall
Micro: large masses of eosinophilic proteinaceous material with hemorrhage in lamina propria; variable foreign body giant cell reaction to amyloid; rarely perivascular amyloid deposits; rare/no inflammatory cells
Micro images: eosinophilic proteinaceous material in lamina propria #1; #2
Positive stains: Congo red (apple green birefringence when exposed to polarized light)
EM: non-branching fibrils and associated ground substance
Injected collagen is used to control urinary stress incontinence or improve function of urinary pouches
Polypoid lesions show submucosal accumulation of eosinophilic, homogeneous, poorly cellular material
Positive stains: trichrome (strong), PAS (weak)
References: Mod Path 1999;12:1090
Pouch created due to pelvic relaxation, which causes uterine prolapse and protrusion of bladder into vagina; associated with urinary tract infections since does not empty completely
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
Cystitis
Triad of frequency, lower abdominal pain and dysuria (pain or burning during urination)
Common in young women of reproductive age and older men and women
May be caused by obstruction, cystocele or diverticula
May lead to pyelonephritis
Causes: E. coli, Proteus, Klebsiella or Enterobacter bacteria; Candida or Cryptococcus in immunocompromised, Schistosoma haematobium in Egypt, also adenovirus, chlamydia, mycoplasma
Noninfectious causes are chemotherapy, radiation therapy, trauma
Gross: hyperemic mucosa with variable exudate
Due to infection with human polyoma BK virus
Cytology images: decoy cells with enlarged nuclei and homogenized chromatin due to viral inclusions - #1; #2; SV40+
An endoscopic term
Edematous bladder mucosa
Edema usually is due to chronic irritation
Gross: heaping of mucosa; red, friable, ulcerated mucosa
Micro: chronic inflammatory cell infiltrate; fibrous thickening of muscularis propria
Cytology: nuclei are enlarged with prominent nucleoli; variable cytoplasmic vacuoles
Cytology images: reactive urothelial cells #1; #2; #3; #4
Cystitis cystica and cystitis glandularis
Common incidental findings
Referred to together as cystitis cystica et glandularis
Associated with longstanding chronic cystitis, bladder exstrophy, ureteral reimplantation, neurogenic bladder or other causes of mucosal irritation; may regress if cause of bladder irritation is removed
Cystitis cystica: Brunn’s nests that grow into lamina propria and are transformed into urothelium lining slitlike or cystic spaces with pink fluid; present in up to 60% of bladders
Cystitis glandularis of common type: glands in lamina propria lined by columnar or cuboidal epithelium; more common than intestinal type
Cystitis glandularis of intestinal type: also called intestinal metaplasia; goblet cells present in cystitis cystica that resemble colonic epithelium; also called colonic metaplasia, often in bladder neck and trigone, may present as papillary or polypoid mass, usually confined to lamina propria, may have mucin extravasation with dissecting mucin pools and be misdiagnosed as adenocarcinoma, but no significant atypia, no glandular disarray, no desmoplasia, no muscular invasion, no signet ring cells, no necrosis, no/minimal mitotic activity, no carcinoma in situ, no single cells floating in mucin; patients with extensive intestinal metaplasia have higher risk for adenocarcinoma
Case reports: 41 year old man with bladder tumor consisting of cystitis glandularis of intestinal type with mucin extravasation (Archives 2004;128:e89)
Gross: irregular papillary lesions resembling papillary urothelial carcinoma; in trigone, also ureter and renal pelvis
Micro images: cystitis cystica; cystitis glandularis of common type #1; #2; #3 mixed with cystitis glandularis of intestinal type; cystitis glandularis of intestinal type #1; #2; #3; #4; cystitis glandularis of intestinal type with mucin extravasation; figure 1: edematous mucosa; 2/3: proliferation of glands in lamina propria lined by columnar epithelium, including goblet cells and Paneth cells; 4: prominent mucin production with focal mucin extravasation into stroma
Cytology images: cystitis glandularis
Positive stains: neuroendocrine markers focally, PSA, PAP in some cases
References: AJSP 1996;20:1462 (florid cases resembling adenocarcinoma), Archives 1988;112:734 (PSA/PAP+)
Due to gas forming bacteria (Clostridium perfringes, E. coli, Enterobacter aerogenes) producing gas filled cysts in bladder wall
Associated with diabetes (50% of cases), chronic cystitis, neurogenic bladder, leukemia/lymphoma
Treatment: antibiotics, relieve bladder obstruction
Micro: cysts often lined by multinucleated giant cells
Rare; women or children with allergic disorders and peripheral eosinophilia, older men with prostate/bladder disorders, or parasitic infestation
Recurrent episodes of dysuria and hematuria
Not related to Langerhans cell granulomatosis
Treatment: transurethral resection, steroids, antihistamines
Gross: edematous and erythematous mucosa with polypoid growths resembling allergic polyps of nasal septum
Micro: chronic inflammatory infiltrate with marked eosinophils, also fibrosis, muscle necrosis, variable giant cells
Micro images: eosinophilic cystitis due to schistosomiasis (egg not visible)
References: Archives 1984;108:728, AJCP 1979;72:777
Also called cystitis follicularis
Lymphoid follicles in lamina propria, often with chronic cystitis
Overlying urothelium may have mild atypia
Associated with Salmonella urinary tract infection, intravesical chemotherapy or bcg
Due to tuberculosis, post bcg (bacillus Calmette-Guerin) treatment for papillary urothelial carcinoma or prior biopsy / resection
Heals by fibrous scarring
Tuberculosis: rare in most countries; bladder lesions near trigone, smaller lesions merge over time into large ulcers; may involve prostate or vagina; often secondary infection from kidney; caseating granulomas with Langerhans giant cells, mostly in lamina propria with mucosal ulceration
Bcg: used to treat high grade papillary carcinoma or carcinoma in situ of bladder; induces chronic inflammation, superficial ulceration and noncaseating granulomas with active and chronic inflammation; changes may extend into prostate (AJCP 1993;99:244)
Post-biopsy / resection: present in 14% with 2 surgical procedures; either necrotizing and palisading, resembling rheumatoid nodules, or foreign body type (without foreign material) or both (AJCP 1986;86:430)
Micro images: due to bcg treatment
Irritative voiding symptoms, gross hematuria
Causes: cyclophosphamide, radiation therapy, adenovirus, herpes simplex virus, CMV
May require cystectomy
Gross images: hemorrhagic cystitis
Micro: denuded epithelium with fibrinopurulent exudate, marked edema and hemorrhage in lamina propria
Interstitial (Hunner’s) cystitis
Also called Hunner’s ulcer
Rare; a diagnosis of exclusion
Middle-aged white women with persistent suprapubic, perineal or lower abdominal pain and frequency, due to ulceration and marked submucosal edema of bladder
Does not respond to antibiotics
May have autoimmune cause since associated with systemic lupus erythematosis
Best diagnosed from clinical features, since histologic findings are nonspecific (AJSP 1990;14:969)
Micro: may be normal; mucosal ulceration with overlying fibrinous exudates and necrotic debris; lamina propria contains chronic inflammatory cells, prominent mast cells and fibrosis; usually no bacteria identified
Rare chronic granulomatous condition of all organs, commonly GU tract, particularly bladder (Radiographics 2006;26:1847)
Caused by defects in phagocytic or degradative functions of histiocytes in response to gram negative coliforms (E. coli or Proteus)
More common in immunocompromised (HIV, renal transplant recipients) and women
Rarely associated with calcified plaques (encrusted cystitis, Ir J Med Sci 2006;175:74) and renal failure (Nat Clin Pract Urol 2008;5:516)
Case reports: Case of the Week #131
Treatment: antibiotics that concentrate in macrophages (quinolones or trimethoprim-sulfamethoxazole), antibiotics directed against E. coli plus surgery; possibly bethanechol (may correct decreased cGMP levels that may interfere with complete bacterial killing, eMedicine).
Gross: multiple 3-4 mm soft, yellow plaques or nodular thickenings of bladder wall near trigone that resemble carcinoma
Micro: foamy epithelioid histiocytes with PAS+ granular eosinophilic cytoplasm in lamina propria, some lymphocytes and occasional giant cells; histiocytes have increased number of phagosomes containing non-digested bacteria (usually E coli or Proteus), contain Michaelis-Gutmann bodies (iron containing, cytoplasmic laminated mineralized concretions); late-fibrosis and scarring
Micro images: malakoplakia #1 (arrows at Michaelis-Gutmann bodies); #2; #3; #4; von Kossa calcium stain
case of the week - #1; #2; #3; #4; #5; von Kossa stain; iron stain
EM: macrophages have phagosomes that are packed with undigested bacterial products
Rare
Chronically inflamed bladder with grossly noted polypoid lesions (with edema) or papillary lesions
Often due to bladder catheterization; more common/severe with frequent catheterization
Also associated with Beckwith-Wiedemann syndrome, radiation therapy, malignant tumors
Treatment: remove source of injury
Gross: bullous, polypoid or papillary lesions in dome or posterior bladder wall
Micro: thin, finger-like papillae or broad based polypoid lesions with congestion and edema of lamina propria; mild chronic inflammatory infiltrate; reactive fibroblasts may appear bizarre; covered by normal appearing or metaplastic urothelium with orderly maturation and surface umbrella cells; no hyperchromasia, no coarse chromatin, no abnormal mitotic figures
Micro images: papillary cystitis #1; #2; polypoid cystitis #1; #2; #3
DD: papillary urothelial carcinoma (dysplasia present, usually no/minimal inflammation)
References: AJSP 1988;12:542
Acute or chronic
Time and dose dependent
Toxicity enhanced if given with cyclophosphamide
Similar changes with intravesical chemotherapy, which often affects superficial layer of urothelium and causes denuding cystitis
High threshold for diagnosis of carcinoma after radiation and chemotherapy; if uncertain, do repeat cystoscopy and biopsy after inflammation subsides
Micro: hemorrhage and hemosiderin, fibrin deposition, acute and chronic inflammation, edema and thickened mucosal folds, vascular ectasia, swollen endothelial cells, microvessel thrombi, atypical fibroblasts; degenerative type epithelial changes resembling carcinoma in situ but more bizarre including cytoplasmic ballooning, smudged chromatin, nuclear and cytoplasmic vacuoles, karyorrhectic cellular debris; late changes are blood vessels with myointimal proliferation and hyalinization, scattered atypical fibroblasts, intramural fibrosis with replacement of smooth muscle by collagen
Schistosomiasis-related cystitis
Schistosoma haematobium infection is common in Africa and the Middle East, and the world's leading cause of hematuria
Ova are deposited in veins of muscularis propria, degenerate, incite an inflammatory response; early changes are necrosis and eosinophils with mucosal ulceration; later is fibrosis with lymphocytes, histiocytes, foreign body granulomas, dystrophic calcification
Complications include hydroureter, hydronephrosis, bladder ulcer, polyposis, bacterial urinary tract infection, renal failure, urothelial carcinoma
Complications may occur during inactive phase of disease, when diagnosis is most difficult
Micro images: eggs in muscularis mucosa with granulomatous response; egg surrounded by chronic inflammatory cells
contributed by Drs. Kiran Alam, Anshu Jain, Veena Maheshwari, Farhan A. Siddiqui and Ershadul Haq, J.N. Medical College, India - Schistosoma haematobium - transitional epithelium of ureter with schistosome eggs in submucosa and muscle; schistosome eggs in submucosa; schistosome eggs in muscle layer #1; #2; #3; #4-note terminal spine
References: Hum Path 1986;17:333
Similar to malakoplakia but without Michaelis-Gutmann bodies
Associated with malignancy in some cases
Micro images: lamina propria contains sheets of lipid-laden macrophages #1; #2
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
Rarely involves the bladder, usually by direct extension from genital lesions
Also associated with long-standing cystotomy, indwelling catheters, fistulas, immunosuppression
May recur, but doesn’t progress to carcinoma
Call squamous papilloma if no koilocytosis and HPV negative; rare, usually affects elderly women, p53 negative
Gross: smooth, pink-tan, papillary
Micro: resembles condylomas at other sites with papillary fronds lined by hyperplastic and metaplastic squamous epithelium with koilocytosis (perinuclear halos), wrinkled nuclei and binucleated cells; variable atypia but no anaplasia
Micro images: condyloma #1; #2 with koilocytosis; #3
Positive stains: HPV 6, 11, p53
DD: verrucous carcinoma (invasive margins)
References: AJSP 1988;12:205
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
Also known as high grade intraurothelial neoplasia (HG IUN)
Usually a flat lesion, not papillary
Precursor of invasive cancer in many cases
Occasionally present in prostatic ducts, spreads by intramucosal extension
20-80% of CIS patients develop invasive disease if left untreated
Confers poorer prognosis in patients with coexisting noninvasive papillary urothelial carcinoma
Associated with multifocal high grade invasive carcinoma
Include its presence in pathology reports
Treatment: bcg therapy, local resection or total cystectomy
Gross: flat, grossly erythematous, granular or cobblestone mucosa, no mass, may involve large areas of mucosal surface, ureters, urethra
Micro: flat lesion composed of cells with large, irregular, hyperchromatic nuclei, prominent nuclear pleomorphism, high N/C ratios, mitotic figures in mid to upper epithelium; atypia may not be full thickness; epithelium is often denuded
Nuclear area 5x lymphocytes vs. 2x lymphocytes for normal urothelium (Hum Path 2001;32:997)
Also (but less important) loss of polarity, nuclear crowding, irregular thickness of urothelium; cells are not cohesive, leading to shedding into urine
Note: high grade non-invasive papillary lesions are NOT designated carcinoma in situ to avoid confusion
Patterns: large cells with, or large cells without pleomorphism, small cell, clinging (single layer of atypical cells on denuded urothelium), cancerization of urothelium (pagetoid, undermining or overriding); pattern need not be included in surgical pathology report
Associated microinvasion (2 mm or less) demonstrates invasive cells with retraction artifact mimicking vascular invasion (77% of cases of microinvasion); also nests or irregular cords, rarely as isolated single cells with or without desmoplasia (AJSP 2001;25:356)
Cytology: nuclear changes of carcinoma with minimal pleomorphism; relatively clean background; 95% sensitive, image analysis may be comparable to “expert” review (Mod Path 1997;10:976); numerous high-grade neoplastic cells
Micro images: series of images; markedly atypical cells #1; #2; #3; small cell pattern; clinging pattern #1; #2; involvement of Brunn’s nests; with shedding cells
Micro images: A: H&E; B: diffusely CK20+ throughout urothelial thickness; C: intensely p53+; D: Ki-67+
Positive stains: 34betaE12 labels all urothelial layers vs. basal labeling in dysplasia (Hum Path 2000;31:745); typical pattern is CK20+, p53+, CD44-; E-cadherin positive (Hum Path 2002;33:996); frequent HER2+ amplification (Hum Path 1995;26:970)
DD: denuding cystitis (cells may look malignant), reactive atypia (patchy CK20 in umbrella cells only, p53 weak/negative, CD44 diffusely or focally positive vs. CIS with intense CK20 and p53 positivity in 81% and 57% of cases, CD44 negative in all cases, AJSP 2001;25:1074), post-topical therapy for high grade urothelial carcinoma (still have capillaries), dysplasia, radiation (cells still cohesive, may have distinctive nuclear borders, may resemble pagetoid variant of CIS)
References: Mod Path 2003;16:187 (CK20, p53, Ki-67), Hum Path 1993;24:1199 (pagetoid variant)
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
1-2% of bladder carcinomas
Defined as malignant tumor differentiated towards colonic mucosa
2/3 occur in men; mean age 68 years
Usually present with hematuria
5 year survival is 20-40%; stage is most important prognostic feature
Restrict diagnosis to pure adenocarcinomas
Either in situ, urachal (1/3, not actually part of adult bladder) or non-urachal (2/3), or clear cell
Gross: 2/3 are single lesions; fungating masses invade bladder wall and ulcerate the mucosa; tumor surface is covered by gelatinous material
Micro: glandular component predominates, usually resembles colonic carcinoma; often produces mucin, usually deeply invades muscularis propria; almost all are considered high grade at diagnosis
Cytology: high grade, but often lack features of glandular differentiation; rarely are well differentiated and appear benign
Positive stains: CK7, CEA, EMA, CDX2, membranous staining for beta-catenin
Negative stains: PSA, vimentin; variable PAP, CA-125 and CK20
References: Hum Path 1986;17:939 (PAP staining), AJSP 2003;27:303 (CDX2)
In situ adenocarcinoma
Findings below are for patients without concurrent invasive adenocarcinoma or villous adenoma
Mean age 70 years, 79% male
Associated with urothelial CIS or papillary urothelial carcinoma without invasion
74% had or developed invasive carcinoma, including high incidence of micropapillary and small cell urothelial carcinomas (AJSP 2001;25:892)
Micro: papillary, flat, and cribriform architecture; moderate to severe nuclear pleomorphism, apoptosis, 5+ mitotic figures/10 HPF
Micro images: villous adenoma with atypia approaching carcinoma in situ #1; #2
Urachal adenocarcinoma
Mean 52 years, wide age range; no gender preference
Criteria for urachal origin: centered in anterior wall or dome of bladder, invasion from outside in, bladder mucosa intact or ulcerated, no carcinoma in situ or glandular metaplasia other than cystitis glandularis, presence of urachal remnants is helpful but not always identifiable
Poor prognosis (5 year survival of 50%) since diagnosed late in course of disease due to growth in a clinically silent space (between bladder and umbilicus)
40-50% recur locally; metastasizes to lymph nodes, lungs, peritoneal cavity, liver and bone
Prognostic factors are tumor stage and histologic differentiation (Hum Path 1996;27:240)
Staging may be difficult, since arise in bladder wall
Case reports: 30 year old woman with partial cystectomy for urachal adenocarcinoma and isolated metastasis to thoracic vertebra three years later (Archives 2004;128:1043), signet-ring cell type with linitis plastica growth (Archives 1981;105:203)
Treatment: umbilectomy with partial cystectomy (must excise entire tract of median umbilical ligament)
Gross: arise in dome of bladder or anterior bladder or beneath anterior abdominal wall between umbilicus and bladder dome; tumor occurs anywhere along urachal tract
Micro: epicenter is in bladder wall; sharply demarcated from normal epithelium
Most tumors arise from intramural portion of urachus, grow into bladder wall, may lack mucosal involvement
Usually well-differentiated, mucin-producing adenocarcinomas; may be signet-ring type; often colloid type (tumor cells floating in mucin lakes); often NO intestinal metaplasia
Micro images: (1) colloid type adenocarcinoma; (2) mucin and tumor cells dissecting through muscularis propria; (3) tumor extending to umbilicus; (4) papillary and glandular patterns; (5) figure 1: mucinous adenocarcinoma in muscularis mucosa, no urachal remnants identified; 2: vertebral metastasis on technetium bone scan; (6) vertebral metastasis; figure 4: myxoid material, no tumor; 5: mucinous tumor cells floating in myxoid material; 6: rare tumor cells in myxoid material that has destroyed bone
DD: villous adenoma, metastatic adenocarcinoma, local extension of colonic or other adenocarcinoma, nonurachal adenocarcinoma of bladder (intraluminal mass, carcinoma in situ or extensive glandular metaplasia of adjacent urothelium)
Nonurachal adenocarcinoma
Epicenter is mucosa; treat with radical cystectomy
Patients are older (mean 62 years), and mucusuria is more common than in urachal adenocarcinomas
Usually lateral wall or trigone of bladder
75% male
Causes:
(1) 60% due to progression of extensive intestinal metaplasia (cystitis glandularis), arising at trigone, usually enteric
(2) exstrophy (diffuse intestinalization; 7% develop adenocarcinoma, even after repair)
(3) diverticula (usually develop urothelial carcinoma, occasionally adenocarcinoma)
(4) also endometriosis, pelvic lipomatosis, Schistosoma haematobium
Case reports: 86 year old man with moderately differentiated adenocarcinoma of bladder, also prostatic low grade neuroendocrine carcinoma and Gleason 3+3 prostatic adenocarcinoma (Archives 2004;128:e166), developing at vesicocutaneous edge of vesicostomy 40 years after its creation in patient with cadaveric renal transplant (Archives 2004;128:e58), 77 year old woman with colloid carcinoma after long term cyclophosphamide for Waldenstrom’s macroglobulinemia (AJSP 1996;20:500)
Gross images: mucinous adenocarcinoma
Micro images: (1) with villous adenoma; (2) figure 2A: enteric type adenocarcinoma resembling colonic villous adenoma; 2B: cribriform pattern, lining cells are pseudostratified oval/cigar shaped nuclei; (3) figure 5: strong brush-border staining for villin but no cytoplasmic staining (in contrast to colonic adenocarcinoma); (4) biopsy of cutaneous vesicostomy edge shows moderately differentiated adenocarcinoma
DD:
(a) local extension of prostatic adenocarcinoma: most prostatic adenocarcinomas are PSA+ and PAP+, negative for p63, high molecular weight cytokeratin, thrombomodulin, but bladder adenocarcinomas are opposite
(b) local extension of colonic cancer: no urothelial carcinoma in situ, positive nuclear staining for beta-catenin in 81%, CK20+ in 94%, CK7 negative in 100%, thrombomodulin negative in 100% vs. bladder adenocarcinoma: negative nuclear staining for beta-catenin in 100%, CK20+ in only 53%, CK7+ in 65%, thrombomodulin+ in 59% (AJSP 2001;25:1380, AJSP 1993;17:171)
Colonic tumors are CK7-, CK20+, villin+ vs. CK7+, CK20+, villin- for urothelial carcinoma with glandular differentiation (Archives 2002;126:1057)
(c) metastatic disease: usually associated with known disseminated disease (but see AJSP 1990;14:877), submucosal centered, extensive vascular invasion
(d) colonic metaplasia may mimic well differentiated adenocarcinoma due to widespread involvement with dissecting mucin pools; however minimal atypia, no mitoses, no signet ring cells, usually non-infiltrative, minimal/no muscle invasion (Hum Path 1997;28:1152)
(e) urothelial carcinoma with glandular features (doesn’t differentiate towards colonic mucosa, usually minimal mucin and goblet cells, “glands” are surrounded by urothelial-type cells)
(f) florid cystitis glandularis (no nuclear anaplasia, rarely invades muscularis propria); nephrogenic metaplasia, endocervicosis
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
Very rare
Micro: polygonal cells separated by sinusoids
Positive stains: alpha-fetoprotein, alpha-1-antitrypsin
DD: metastatic carcinoma
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
Lymphoepithelioma-like carcinoma
Rare (<50 cases described), first reported in 1991 in bladder
Adults, mean age 67-69 years, range 52-84 years, 75% males; present with hematuria
Not associated with Epstein Barr virus infection in bladder (Hum Path 1995;26:1207)
Favorable outcome, particularly if >50% of tumor has this pattern (Archives 2001;125:1383)
Gross: relatively small tumor in dome, posterior wall or trigone
Micro: resembles lymphoepithelioma of nasopharynx but EBV negative; LEL component should be >50% for diagnosis; undifferentiated tumor cells in syncytial sheets with minimal cytoplasm, prominent nucleoli, numerous mitoses and lymphocytes; usually muscle invasive; often have coexisting urothelial carcinoma
Micro images: sheets and nests of high grade tumor cells in a syncytial pattern with prominent lymphocytes #1; #2; #3 with AE1/AE3; 1/2: H&E; 3: keratin
Positive stains: cytokeratin and EMA (undifferentiated cells); B and T cell markers (for lymphocytes)
Negative stains: CD45/LCA
DD: lymphoma, florid chronic cystitis (if no tumor cells), small cell carcinoma (on biopsies), undifferentiated urothelial carcinoma
References: AJSP 1994;18:466
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)