246 CHAPTER 6 Urological neoplasia

Bladder cancer: epidemiology and etiology

Bladder cancer is the second-most common urological malignancy, accounting for 70,980 total cases in men and women with 14,330 total deaths in the United States. This represents 2.3% of all cancer deaths. The majority of patients have localized curable or controllable disease.

Risk factors

•Men are 2.5 times more likely than women to develop the disease and die from it. The reasons for this are unclear but may be associated with greater urine residuals or toxic exposure.

•Age increases risk; it is most commonly diagnosed in the eighth decade and is rare in those <50 years of age.

•Race: Black people have a lower incidence than that of White people, but inexplicably they appear to carry a poorer prognosis.

•Environmental carcinogens, found in urine, are the major cause of bladder cancer.

•Chronic inflammation of bladder mucosa: bladder stones, long-term catheters, and the ova of Schistosoma haematobium (bilharziasis) are implicated in development of squamous cell carcinoma of the bladder.

•Smoking is the major cause of bladder cancer in the developed world. Cigarette smoke contains the carcinogens 4-aminobiphenyl (4-ABP) and 2-naphthylamine (see Fig. 6.5). Slow hepatic acetylation (detoxification) of 4-ABP by N-acetyltransferase and glutathione S-transferase M1 (GST M1), or induction of the cytochrome p-450 1A2 demethylating enzyme, appears to increase urinary carcinogenic exposure of the urothelium. Smokers have a 2- to 5-fold risk compared to that of non-smokers of developing bladder cancer and subsequent recurrences. Estimates suggest that 30–50% of bladder

cancer is caused by smoking. There is a slow (20-year) reduction in risk following cessation of smoking. Passive exposure to cigarette smoke is also implicated.

•Occupational exposure to carcinogens, in particular aromatic hydrocarbons like aniline (see Fig. 6.5), is a recognized cause of bladder cancer. See Box 6.3 for examples of at-risk occupations. A latent period of 25–45 years exists between exposure and carcinogenesis.

•Drugs: phenacetin and cyclophosphamide

•Pelvic radiotherapy for other malignancies such as prostate, rectal or cervical cancer

No evidence for a hereditary genetic etiology exists, though many somatic genetic abnormalities have been identified. The most common cytogenetic abnormality is loss of chromosomes 9p, 9q, 11p 13q, and 17q.

Activation or amplification of oncogenes (p21 ras, c-myc, c-jun, erbB-2), inactivation of tumor suppressor genes (p53 mutations appear to worsen survival after treatment, retinoblastoma, p16 cyclin-dependent kinse inhibitor), and increased expression of angiogenic factors (e.g., vascular endothelial growth factor [VEGF]) are reported in transitional cell carcinomas.

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NH2

NH2

NH2

4-aminobiphenyl

Figure 6.5 Carcinogens known to increase risk of bladder cancer.

Box 6.3 Occupations associated with urothelial carcinoma

•Drivers exposed to diesel exhaust

•Dye manufacture

•Fine chemical manufacture (e.g., auramine)

•Hairdressers

•Leather workers

•Painters

•Plumbers

•Rope and textile manufacture

•Rubber manufacture (e.g., tires or electric cable)

248 CHAPTER 6 Urological neoplasia

Bladder cancer: pathology and staging

Benign tumors of the bladder, including inverted papilloma and nephrogenic adenoma, are uncommon. The vast majority of primary bladder cancers are malignant and epithelial in origin:

•>90% are transitional cell carcinoma (TCC); urothelial carcinoma (UC) is now the preferred term.

•1–7% are squamous cell carcinoma (SCC).

•75% are SCC in areas where schistosomiasis is endemic.

•2% are adenocarcinoma

•Rarities include pheochromocytoma, melanoma, lymphoma, and sarcoma arising within the bladder muscle.

•Secondary bladder cancers are mostly metastatic adenocarcinoma from gut, prostate, kidney, or ovary.

Tumor spread

•Direct tumor growth to involve the detrusor, the ureteral orifices, prostate, urethra, uterus, vagina, perivesical fat, bowel, or pelvic side walls.

•Implantation into wounds/percutaneous catheter tracts

• Lymphatic infiltration of the iliac and para-aortic nodes

•Hematogenous, most commonly to liver (38%), lung (36%), adrenal gland (21%), and bone (27%). Any other organ may be involved.

Histological grading

Grading is divided into well, moderately, and poorly differentiated (abbreviated to G1, G2, and G3, respectively).

Staging

Staging is by the TNM (2002) classification (see Fig. 6.6 and Table 6.8). All rely on physical examination and imaging (prefixed c), the pathological classification (prefixed p) corresponding to the TNM categories.

Urothelial carcinoma (transitional cell carcinoma)

UC may be single or multifocal. Because 5% of patients will have a synchronous upper tract UC and metachronous recurrences may develop after several years, the urothelial field-change theory of polyclonality is favored over the theory of tumor monoclonality with implantation (seeding).

Primary UC is considered clinically as superficial or muscle invasive: 70% of tumors are papillary, usually G1 or G2, exhibiting at least 7 transitional cell layers covering a fibrovascular core (normal transitional epithelium has d5 cell layers). Papillary UC is most often superficial, confined to the bladder mucosa (Ta) or submucosa (T1). 10% of patients subsequently develop muscle-invasive or metastatic disease.

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Figure 6.6 Diagrammatic representation of T staging of bladder urothelial cell carcinoma. Reprinted with permission from Brewster S, Cranston D, Noble J, Reynard J (2001) Urology: A Handbook for Medical Students. Informa Healthcare, p. 97.

Table 6.8 2002 TNM staging of bladder carcinoma

250 CHAPTER 6 Urological neoplasia

However, a subset of superficial UC, G3T1 tumors, are more aggressive, with 40% subsequently upstaging. 10% of UC have mixed papillary and solid morphology and 10% are solid. These are usually G3, half of which are muscle invasive at presentation.

Ten percent of UC is flat carcinoma in situ (CIS). This is poorly differentiated carcinoma, but confined to the epithelium and associated with an intact basement membrane. Half of CIS lesions occur in isolation; the remainder occur in association with muscle-invasive UC.

CIS usually appears as a flat, red, velvety patch on the bladder mucosa; 15–40% of such lesions are CIS, the remainder being focal cystitis of varying etiology. The cells are poorly cohesive, up to 100% of patients with CIS exhibiting positive urine cytology, in contrast to much lower yields (17–72%) with G1/2 papillary UC.

From 40% to 83% of untreated CIS lesions will progress to muscleinvasive UC, making CIS the most aggressive form of superficial UC. 5% of patients with G1/2 UC and at least 20% with G3 UC (including CIS) have vascular or lymphatic spread.

Metastatic node disease is found in 0% Tis, 6% Ta, 10% T1, 18% T2 and T3a, and 25–33% T3b and T4 UC.

Papillary urothelial neoplasm of low malignant potential (PUNLMP)

The World Health Organization (WHO) defines PUNLMP as a papillary urothelial tumor that resembles an exophytic urothelial papilloma but shows increased cellular proliferation exceeding the thickness of normal urothelium. They are typically small (1–2 cm) and have little, if any, cytological atypia.

Treatment and follow-up are the same as for low-grade noninvasive urothelial carcinoma.

Squamous cell carcinoma (SCC)

SCC is usually solid or ulcerative and muscle invasive at presentation. SCC accounts for only 2–5% of bladder cancers in North America and Europe. SCC in the bladder is associated with chronic inflammation (bladder calculi, indwelling catheters) and urothelial squamous metaplasia, rather than CIS.

Bilharzial SCC is the most common form of bladder cancer in East Africa and the Middle East and is related to infection with Schistosoma hematobium. In Egypt, 80% of SCC cases are induced by the ova of Schistosoma hematobium.

Non-bilharzial SCC is the second-most common form of bladder cancer in North America and Europe. 5% of paraplegics with long-term catheters develop SCC. Smoking is also a risk factor for SCC.

The prognosis is better for bilharzial SCC than for non-bilharzial disease, probably because it tends to be lower grade and metastases are less common in these patients.

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Adenocarcinoma

Adenocarcinoma is rare, is usually solid/ulcerative and high grade, and carries a poor prognosis. It is frequently advanced at initial presentation (muscle invasive or metastatic). One-third of cases originate in the urachus, the remnant of the allantois, located deep to the bladder mucosa in the dome of the bladder.

Adenocarcinoma is a long-term (10–20+ year) complication of bladder exstrophy and bowel implantation into the urinary tract, particularly bladder substitutions and ileal conduits after cystectomy. There is association with cystitis glandularis, rather than CIS.

Secondary adenocarcinoma of the bladder may arise as discussed earlier.