Cancer of the Bladder and Urinary Tract¶
Chapter 91 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Bladder cancer is strongly associated with tobacco smoking, with 90% of cases occurring in current or former smokers.
- Urothelial carcinoma (transitional cell carcinoma) is the most common histology (90% of cases), with variants like micropapillary and plasmacytoid associated with worse outcomes.
- Systemic therapies for metastatic renal cell carcinoma (RCC) include antiangiogenic TKIs (e.g., sunitinib, cabozantinib) and immunotherapy (e.g., nivolumab, pembrolizumab).
- Genomic sequencing is critical for personalized treatment, with TCGA identifying five molecular subtypes of bladder cancer.
- EV+P (enfortumab vedotin + pembrolizumab) is the preferred first-line therapy for metastatic urothelial carcinoma, improving median overall survival to 31.5 months.
1. DEFINITION & OVERVIEW¶
Cancers of the urinary tract (bladder, renal pelvis, ureter, urethra) are the second most common genitourinary cancers. Bladder cancer alone accounts for 82,290 new cases/year in the U.S. with 16,710 deaths/year. Urothelial carcinoma is the most common histology (90% of cases), with squamous, glandular, and micropapillary variants also present. Global incidence is highest in developed countries, with ~400,000 new cases/year worldwide.
Table 90-3: Commonly Used Systemic Regimens for Metastatic Renal Cell Carcinoma¶
| CLASS | DRUG | FIRST FDA APPROVAL FOR RCC | CURRENTLY USED FOR | |
|---|---|---|---|---|
| Antiangiogenic: TKIs | Sunitinib | 2006 | Advanced RCC, first line | |
| Antiangiogenic: TKIs | Pazopanib | 2009 | Advanced RCC, first line | |
| Antiangiogenic: TKIs | Axitinib | 2012 | Advanced RCC, pretreated | |
| Antiangiogenic: TKIs | Cabozantinib | 2016 2017 | Advanced RCC, pretreated with antiangiogenic therapy Advanced RCC, first line |
| CLASS | DRUG | FIRST FDA APPROVAL FOR RCC | CURRENTLY USED FOR | |
|---|---|---|---|---|
| Antiangiogenic: TKIs | Tivozanib | 2021 | Advanced RCC, pretreated with two or more prior systemic therapies | |
| Immunotherapy: checkpoint inhibitor | Nivolumab | 2015 | Advanced RCC, pretreated with antiangiogenic therapy | |
| Combination therapies | TKI + mTOR inhibitor | Lenvatinib + everolimus | 2016 | Advanced RCC, pretreated with one antiangiogenic therapy |
| Combination therapies | PD-1 inhibitor + CTLA-4 inhibitor | Nivolumab + ipilimumab | 2018 | Advanced intermediate-risk or poor-risk RCC, first line |
| Combination therapies | PD-1 inhibitor + TKI | Pembrolizumab + axitinib | 2019 | Advanced RCC, first line |
| Combination therapies | Nivolumab + cabozantinib | 2021 | Advanced RCC, first line | |
| Combination therapies | Pembrolizumab + lenvatinib | 2021 | Advanced RCC, first line |
1.1 Histology¶
Urothelial carcinoma (transitional cell carcinoma) is the most common (90% of cases). Squamous, glandular, micropapillary, and plasmacytoid variants are also present. Micropapillary and plasmacytoid variants are associated with worse surgical outcomes. Nonurothelial variants (squamous, adenocarcinoma, small-cell, carcinosarcoma) account for ≤ 10% of cases.
1.2 Molecular Biology¶
Urothelial carcinoma exhibits a biphasic phenotype: low-grade papillary tumors (non-invasive) and high-grade invasive tumors. Key molecular events include loss of 9p/9q heterozygosity, FGFR3 mutations, TP53/RB1 mutations, and microsatellite instability in Lynch syndrome-associated tumors. TCGA identified five molecular subtypes: luminal papillary, luminal infiltrated, luminal, basal squamous, and neuronal.
2. EPIDEMIOLOGY¶
Bladder cancer is the sixth most common cancer in the U.S. (82,290 new cases/year). Global incidence is highest in developed countries, with ~400,000 new cases/year worldwide. Risk factors include smoking (90% of cases), occupational exposures (dyes, chemicals), arsenic, schistosomiasis, and genetic predispositions (Lynch syndrome, Cowden disease, RB1 mutations). Males are 4× more likely to develop bladder cancer than females. Median age at diagnosis is 73 years.
2.1 Demographics¶
Bladder cancer is more common in Caucasians than Asians. Median age at diagnosis is 73 years. Males are 4× more frequently affected than females. Higher incidence in developed countries (U.S., Europe, Australia) compared to Southeast Asia and Africa.
2.2 Risk Factors¶
Smoking (90% of cases), occupational exposures (dyes, chemicals), arsenic, schistosomiasis, and genetic factors (Lynch syndrome, Cowden disease, RB1 mutations). Chronic inflammation from schistosomiasis or catheter use increases squamous bladder cancer risk.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Tobacco smoke contains >70 carcinogens, with 1/3 of bladder cancers potentially preventable by smoking cessation. Environmental toxins (benzidine, β -naphthylamine, arsenic) and occupational exposures (leather, paint, rubber) increase risk. Genetic factors include Lynch syndrome (microsatellite instability), Cowden disease (PTEN mutations), and RB1 mutations. Molecular mechanisms involve FGFR3 mutations, TP53/RB1 alterations, and chromosomal losses (9p/9q).
4. CLINICAL FEATURES¶
Painless hematuria (gross/microscopic) is the most common presenting symptom. In females, hematuria may mimic UTIs or menstruation. Chronic infections or catheter use can lead to squamous bladder cancer. Upper tract tumors may present with flank pain or hydronephrosis. Advanced disease may present with cachexia and metastases.
4.1 Presentation¶
Painless hematuria is the most common symptom. In males, hematuria is almost always abnormal. Chronic infections or catheter use increases risk of squamous bladder cancer. Upper tract tumors may present with flank pain or hydronephrosis.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate between benign causes (UTIs, stones, trauma) and malignant causes. In females, hematuria may mimic menstrual bleeding. Consider other urinary tract cancers (renal pelvis, ureter) and non-malignant conditions (cystitis, tumors).
6. INVESTIGATIONS & DIAGNOSIS¶
Urine cytology (50% sensitivity for high-grade tumors), cystoscopy, CT urogram, and MR urogram (for renal insufficiency). Molecular tests (FISH, ctDNA) detect chromosomal changes. TCGA identified five molecular subtypes (luminal papillary, luminal infiltrated, luminal, basal squamous, neuronal). Genomic sequencing is recommended for all metastatic cases.
Bladder Cancer Prognosis According to Stage¶
| T N M Stage | 5-yr Survival |
|---|---|
| Tis/Ta N0 M0 0is/0a | 96% |
| T1 N0 M0 1 | 90% |
| T2 N0 M0 2 | 70% |
| T3 N0 M0 3 | 50% |
| T1-T4 N1-N3 M0 3 | 36% |
| Any T Any N M1 4 | 5% |
6.1 Diagnostic Tests¶
Urine cytology, cystoscopy, CT urogram, MR urogram, FISH, and ctDNA analysis. TCGA findings reveal five molecular subtypes with distinct prognostic and therapeutic implications.
7. MANAGEMENT & TREATMENT¶
NMIBC: TURBT with intravesical BCG (50-29% recurrence reduction). MIBC: Cystectomy (50% cure rate) or bladder-sparing chemoradiation (65% cure rate). Metastatic disease: EV+P (enfortumab vedotin + pembrolizumab) as first-line (31.5 mo median OS). Second-line options include platinum-based chemo, FGFR inhibitors (erdafitinib), and sacituzumab govitecan. Adjuvant nivolumab improves DFS in high-risk patients.
Table 91-2: Treatment Approaches to MIBC Patients¶
| TREATMENT | PATIENT SELECTION | CLINICAL OUTCOMES |
|---|---|---|
| Bladder-sparing chemoradiation | No CIS, no hydronephrosis, maximal TURBT required | 65% cure, 55% bladder intact, highly dependent on patient selection |
| Cystectomy | Any MIBC patient | 50% cure with surgery alone, highly dependent on pathologic stage |
| Adjuvant cisplatin-based chemotherapy | Cisplatin-eligible, high-risk, postcystectomy MIBC patients (pT3-4, N+) | Similar improvement as neoadjuvant treatment, data less robust, many patients not suitable for adjuvant treatment |
| Adjuvant nivolumab | Postsurgery, high-risk MIBC and UTUC patients (pT3-4, N+, cisplatin-eligible after neoadjuvant therapy OR pT2-4, N+, cisplatin-ineligible who did not receive neoadjuvant therapy) | 30% improvement in disease-free survival compared to surgery alone |
Table 91-1: Non–Muscle-Invasive Bladder Cancer Recurrence Risk Groups¶
| RISK GROUP | CHARACTERISTICS |
|---|---|
| Low risk | Initial tumor, solitary tumor, low grade, <3 cm, no CIS |
7.1 Non-Muscle-Invasive Bladder Cancer¶
TURBT with intravesical BCG (50-29% recurrence reduction). Low-risk: mitomycin C, epirubicin, or gemcitabine. Intermediate/high-risk: 6-week BCG regimen. Recurrent cases may require repeat BCG or surgical cystectomy.
7.2 Muscle-Invasive Bladder Cancer¶
Cystectomy (50% cure rate) or bladder-sparing chemoradiation (65% cure rate). Neoadjuvant cisplatin-based chemo improves survival. Adjuvant nivolumab improves DFS by 30% in high-risk patients.
8. PROGNOSIS & COMPLICATIONS¶
5-year survival rates: 96% (Tis/Ta), 90% (T1), 70% (T2), 50% (T3), 36% (T1-T4 N1-N3), 5% (M1). Complications include cachexia, nutritional deficiencies (B12), and treatment-related toxicities (neuropathy, myelosuppression, immune-related adverse events).
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Avoid chemotherapy; consider BCG. Pediatrics: Monitor for congenital anomalies. Elderly: Consider less aggressive therapies. Lynch syndrome: Test for MLH1, MSH2, MSH6 mutations in patients <60 with upper tract tumors or family history.
10. KEY POINTS & CLINICAL PEARLS¶
- Smoking cessation prevents 1/3 of bladder cancers. 2. BCG is the gold standard for NMIBC. 3. EV+P improves OS in metastatic urothelial carcinoma. 4. Genomic sequencing guides personalized therapy. 5. Bladder-sparing chemoradiation is viable for select MIBC patients.