Bladder & Urothelial Pathology
Carcinogens in the urine, two molecular roads to cancer, and the bladder's inflammatory mimics
Urothelial carcinoma: who gets it and why
The tumor. Urothelial (transitional cell) carcinoma accounts for about 90% of bladder cancers and can arise wherever urothelium lines the tract: renal pelvis, ureters, bladder and proximal urethra. The typical patient is a man in his 60s or 70s (male:female about 3:1) with painless gross hematuria.
Carcinogens. Cigarette smoking is the leading risk factor, responsible for roughly half of cases. Aromatic amines such as 2-naphthylamine and benzidine (aniline dye, rubber and leather work), phenacetin, cyclophosphamide, arsenic in drinking water and pelvic irradiation add risk. Many carcinogens are metabolized in the liver and excreted in urine, and the bladder stores that urine for hours, so its mucosa receives the longest exposure.
Field effect. Because the whole urothelial surface is exposed, tumors are often multifocal at diagnosis (synchronous) and recur at new sites after resection (metachronous). Patients need lifelong surveillance cystoscopy, and upper-tract tumors are frequently followed by bladder tumors.
Upper-tract tumors. Carcinoma of the renal pelvis and ureter is linked to aristolochic acid (Aristolochia herbal remedies, Balkan endemic nephropathy), which also causes progressive interstitial fibrosis; to phenacetin analgesic abuse; and to Lynch syndrome (mismatch repair deficiency). It presents with hematuria or flank pain from obstruction.
Two molecular pathways, stage and treatment
| Feature | Low-grade papillary | Flat carcinoma in situ |
|---|---|---|
| Architecture | Exophytic fronds with fibrovascular cores; mild atypia | Flat, high-grade malignant cells confined to the urothelium |
| Driver genes | Activating FGFR3, HRAS | Loss of TP53, RB |
| Behavior | Recurs often, rarely invades muscle | Progresses to invasive carcinoma |
| Cystoscopy and cytology | Visible papillary tumor; cytology often negative (cohesive cells) | May show only red, velvety mucosa; cytology often positive (discohesive cells) |
| Treatment | Transurethral resection and surveillance | Intravesical BCG |
Stage matters most. Depth of invasion is the key prognostic factor, and invasion of the muscularis propria is the critical threshold. Non-muscle-invasive tumors are removed by transurethral resection; high-grade tumors and CIS then receive intravesical BCG, live attenuated Mycobacterium bovis that provokes a local Th1, granulomatous immune attack (macrophages, NK cells, cytokines) on tumor cells. Mitomycin, a DNA crosslinker, is an intravesical alternative. Muscle-invasive disease calls for radical cystectomy with cisplatin-based chemotherapy.
Squamous cell carcinoma and adenocarcinoma
Squamous cell carcinoma. Schistosoma haematobium adults live in the vesical venous plexus and release terminal-spined eggs that lodge in the bladder wall, provoking granulomatous inflammation, fibrosis and calcification. The urothelium undergoes squamous metaplasia and then keratinizing SCC with keratin pearls, historically the dominant bladder cancer in endemic regions such as Egypt. Elsewhere, chronic irritation from long-term catheters or stones is the setting. S. mansoni and S. japonicum instead cause intestinal and hepatic disease.
Adenocarcinoma. Primary bladder adenocarcinoma is rare. It arises at the dome from a urachal remnant (the obliterated allantois that connected the bladder to the umbilicus) or in an exstrophied bladder, whose chronically exposed mucosa undergoes glandular metaplasia (cystitis glandularis). Mucin-producing glands, sometimes with signet-ring cells, can mimic a colorectal metastasis, so colon cancer must be excluded. Urachal remnants also produce a patent urachus (urine leaking from the umbilicus), urachal cyst, urachal sinus or vesicourachal diverticulum.
Nonneoplastic bladder disease
Hemorrhagic cystitis. Cyclophosphamide and ifosfamide are metabolized to acrolein, which is excreted in urine and injures the urothelium. Hydration plus mesna, whose free thiol binds acrolein, prevents it without reducing antitumor activity; long-term cyclophosphamide also raises the risk of urothelial carcinoma years later. Viral causes are adenovirus, which produces self-limited gross hematuria in children, and BK polyomavirus after hematopoietic stem cell transplant.
Do not confuse the protectants: mesna neutralizes acrolein in the bladder, whereas dexrazoxane, an iron chelator, protects the heart from anthracyclines.
Interstitial cystitis (bladder pain syndrome). Mostly women in their 20s–40s have suprapubic pain that builds as the bladder fills and eases after voiding, with frequency and urgency but sterile urine. It is a diagnosis of exclusion (negative culture and cytology); cystoscopy may show Hunner lesions (ulcers) or petechial glomerulations after hydrodistension. Treatment aims to restore the protective glycosaminoglycan layer (oral pentosan polysulfate) and dampen pain (amitriptyline, avoiding dietary triggers).
Malakoplakia. Soft yellow mucosal plaques form in the bladder (sometimes the kidney or colon), usually in immunosuppressed patients with chronic gram-negative, typically E. coli, infection. Macrophages ingest the bacteria but have defective phagolysosomal killing, so partly digested debris accumulates and mineralizes with calcium and iron into laminated, targetoid Michaelis-Gutmann bodies, distinct from the Schaumann and asteroid bodies of sarcoidosis and the psammoma bodies of papillary tumors.