Bladder - Printer Friendly Version

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

Normal anatomy

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

Normal histology

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)

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

Arteriovenous malformation

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

Cloacogenic bladder

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

Duplication of bladder

Bladder is separated into compartments

Either double bladder, septal bladder or hourglass bladder

Incomplete emptying causes urinary tract infections

Ectopic prostate

Gross: polypoid mass at bladder base

DD: post-surgical ingrowth of prostatic tissue

Exstrophy

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

Hypoplasia

Normal but small bladder, seen in Potter syndrome

Hyperplasia

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

Urachus

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

Patent urachus

Also called persistent urachus

Rare; leads to urination through umbilicus

May be associated with infections

Acquired non-neoplastic anomalies

Amyloidosis

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

Positive stains: Congo red (apple green birefringence when exposed to polarized light)

EM: non-branching fibrils and associated ground substance

Collagen polyp

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

Cystocele

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

Diverticula

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

Micro: wall consists of fibrous tissue with no/scant muscularis propria; squamous or glandular metaplasia present if inflamed

Endocervicosis

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

DD: adenocarcinoma, adenoma malignum from uterine cervix

References: Hum Path 1996;27:816, AJSP 1992;16:533

Endometriosis

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

Endosalpingiosis

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

Lithiasis (stones)

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

Obstruction

Commonly due to prostatic hypertrophy (men) or cystocele (women); also urethral narrowing/strictures, mechanical obstructions, neurogenic bladder

Gross: trabeculation of bladder wall, diverticula

Tamm-Horsfall protein

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

Treatment effect

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

Urinary diversion

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)

Micro: inflamed, atrophic and partially denuded epithelium; Candida in ileal conduits

Cystitis

Acute 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

BK virus

Due to infection with human polyoma BK virus

Bullous cystitis

An endoscopic term

Edematous bladder mucosa

Edema usually is due to chronic irritation

Chronic cystitis

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

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

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+)

Emphysematous cystitis

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

Eosinophilic cystitis

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

References: Archives 1984;108:728, AJCP 1979;72:777

Follicular cystitis

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

Granulomatous cystitis

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)

Hemorrhagic cystitis

Irritative voiding symptoms, gross hematuria

Causes: cyclophosphamide, radiation therapy, adenovirus, herpes simplex virus, CMV

May require cystectomy

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

Malakoplakia

More common in immunocompromised (HIV, renal transplant recipients)

Also more common in women

Caused by defects in phagocytic or degradative functions of histiocytes in response to gram negative coliforms (E. coli, Proteus)

Bladder is most common site, but also in ureters, urethra, renal pelvis, other body sites

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, which are iron containing, cytoplasmic laminated mineralized concretions; late changes are fibrosis and scarring

EM: macrophages have phagosomes that are packed with undigested bacterial products

Polypoid cystitis

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

DD: papillary urothelial carcinoma (dysplasia present, usually no/minimal inflammation)

References: AJSP 1988;12:542

Radiation cystitis

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

References: Hum Path 1986;17:333

Xanthogranulomatous cystitis

Similar to malakoplakia but without Michaelis-Gutmann bodies

Associated with malignancy in some cases

Metaplasias

Intestinal metaplasia

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)

Nephrogenic metaplasia

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

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