Cancer of the Bladder and UrinaryTract¶

Chapter 91 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 91

Key Clinical Points¶

Painless hematuria is the primary presentation in 70-90% of cases; 90% of patients are current or former smokers.
Urothelial carcinoma (transitional cell) is the dominant histology (~90%); other variants include squamous, glandular, micropapillary, and plasmacytoid.
NMIBC management relies on TURBT followed by intravesical therapy (Mitomycin C or BCG based on risk).
MIBC treatment typically involves neoadjuvant cisplatin-based chemotherapy followed by cystectomy.
Enfortumab vedotin plus pembrolizumab (EV+P) is the preferred first-line therapy for metastatic disease.
FGFR inhibitors (erdafitinib) are indicated specifically for patients with activating FGFR genomic alterations.
Upper tract urothelial carcinoma requires nephroureterectomy, or segmental ureterectomy if renal function is impaired.
5-year survival rates vary significantly by stage: 96% for non-invasive, 39-50% for stage III, and 8% for metastatic disease.
High-risk NMIBC includes T1 tumors, high-grade tumors, CIS, or large/multiple Ta tumors in patients >70 years old.
Specific mutations: FGFR3 (low-grade), TP53/RB1 (high-grade), and Lynch syndrome (upper tract).

DEFINITION & CLASSIFICATION¶

• Overview: Second most common genitourinary malignancy; bladder cancer is the 6th most common cancer in the U.S.

Histology¶

• Urothelial carcinoma (transitional cell): ~90% of cases. • Variant histologies (10-20%): squamous, glandular, micropapillary, and plasmacytoid; these correlate with worse outcomes. • Non-urothelial variants (<10%): squamous cell carcinoma, adenocarcinoma, and small-cell carcinoma.

EPIDEMIOLOGY¶

• Demographics: Median age at diagnosis is 73 years; males are 4x more likely than females to develop the disease. • Geographic/Ethnic factors: Higher incidence in Caucasians.

Risk Factors¶

• Tobacco use: Primary risk factor (90% of cases in U.S.) due to 70+ carcinogens. • Chemical/Environmental exposure: Arsenic, aromatic amines, and industrial chemicals. • Other factors: Chronic schistosomiasis or indwelling catheters (increase squamous cancer risk); Pioglitazone use may slightly increase risk.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Phenotypic distinction: ◦ Low-grade: Recurrent, non-invasive; associated with FGFR3 mutations. ◦ High-grade: Invasive, metastatic; associated with TP53/RB1 mutations. • Lynch syndrome: Associated with microsatellite instability (MSI); accounts for 10-20% of upper tract urothelial carcinomas.

Molecular Biology¶

• Genomic landscape: 71% of patients have targetable alterations (FGFR3, EGFR, ERBB2). • TCGA Subtypes: luminal papillary, luminal infiltrated, basal squamous, neuronal, and luminal. • Chromatin modification: Mutations in these genes are present in most cases.

CLINICAL FEATURES¶

• Primary Presentation: Painless hematuria (70-90% of cases). • Secondary Symptoms: Flank pain → may indicate upper tract disease or hydronephrosis from bladder obstruction. • Advanced Disease: Cachexia and metastases are rarely present at initial diagnosis.

Diagnostic Workup¶

• Urine cytology: 50% sensitivity for high-grade tumors. • Imaging/Endoscopy: CT urogram, cystoscopy (with blue light/narrow-band imaging to detect flat lesions), and ureteroscopy for suspected upper tract tumors.

DIFFERENTIAL DIAGNOSIS¶

• Common Mimics: Urinary tract infection, menstrual bleeding (females), and benign causes (trauma, stones). • Clinical Rule: Persistent hematuria after antibiotic treatment requires further evaluation.

Molecular Diagnostics¶

• Utility: FISH and bladder tumor antigen may detect recurrence but have limited utility in initial diagnosis.

DIAGNOSTIC APPROACH¶

Initial Screening: Urine cytology, CT urogram, and cystoscopy.
Enhanced Detection: Use of blue light/narrow-band imaging (NBI) to identify flat lesions.
Upper Tract Evaluation: Ureteroscopy for suspected upper tract tumors.
Confirmatory Step: Histologic confirmation via TURBT or endoscopic resection.
Metastatic Workup: Genomic sequencing is recommended for metastatic patients.

MANAGEMENT & TREATMENT¶

Non-Muscle-Invasive Bladder Cancer (NMIBC): a. Risk Stratification (Table 91-1): • Low risk: Initial, solitary, low grade, <3 cm, no CIS. • High risk: T1; high-grade; CIS; or multiple and large (>3 cm) Ta low-grade tumors in patients over age 70 (all conditions must be met for the latter). b. Treatment: TURBT followed by intravesical therapy (Mitomycin C or BCG). c. BCG Efficacy: Reduces recurrence by 50-29% and progression by 27%; maintenance BCG improves outcomes.
Muscle-Invasive Bladder Cancer (MIBC): a. Standard Care: Neoadjuvant cisplatin-based chemotherapy → Cystectomy. b. Bladder-sparing chemoradiation: For patients with no CIS, no hydronephrosis, and maximal TURBT; 65% cure rate, 55% bladder intact. c. Adjuvant Therapy: Cisplatin-based chemotherapy for high-risk postcystectomy (pT3-4, N+); Nivolumab for high-risk MIBC/UTUC (30% improvement in DFS).
Metastatic Disease: a. First-line: Enfortumab vedotin plus pembrolizumab (EV+P) preferred over platinum-based chemotherapy. b. Targeted Therapy: Erdafitinib for patients with activating FGFR mutations.
Urinary Diversion (Post-Cystectomy): a. Options: Ileostomy, continent reservoir (Indiana pouch), or neobladder.

Upper Tract Management¶

Primary Choice: Nephroureterectomy.
Renal Preservation: Segmental ureterectomy for patients with significant renal impairment.
CIS Treatment: BCG via nephrostomy tube to preserve kidney function.

COMPLICATIONS & PROGNOSIS¶

• Survival by Stage (Table 91-2): ◦ Tis/Ta: 96% 5-year survival. ◦ T1: 90% 5-year survival. ◦ T2: 70% 5-year survival. ◦ T3: 50% 5-year survival. ◦ T1-T4 with N1-N3: 36% 5-year survival. ◦ Any M1: 5% 5-year survival. • Clinical Definitions:

Definition (Harrison's 22e): Stage I–II bladder cancer has a 70-90% 5-year survival rate; stage III, 39-50%; stage IV, 8%. • Recurrence: Low risk (<10%), High risk (>70%). • Complications: UTI, metabolic disturbances (hyperphosphatemia with FGFR inhibitors), and immune-related toxicities (pneumonitis, colitis).

SPECIAL POPULATIONS¶

• Upper Tract Urothelial Carcinoma: 1. Neoadjuvant cisplatin improves pathologic complete response (14%). 2. Adjuvant chemotherapy reduces recurrence by 55% after nephroureterectomy.

KEY PEARLS & HIGH-YIELD POINTS¶

• Urgent Workup: Painless hematuria in males requires immediate investigation. • BCG Contraindications: Do not use in patients with prior BCG infection or immunosuppression. • Metastatic Preference: EV+P is the preferred first-line over platinum-based chemotherapy. • FGFR Monitoring: Patients on erdafitinib require ophthalmologic monitoring for central serous retinopathy. • Ureterectomy Rule: Segmental ureterectomy should be reserved for patients with significant renal impairment.

Reference Tables¶

TABLE 90-3 Commonly Used Systemic Regimens for Metastatic Renal Cell Carcinoma CLASS Antiangiogenic: TKIs¶

Harrison's 22e, p.690

CLASS	DRUG	FIRST FDA APPROVAL FOR RCC	CURRENTLY USED FOR
Antiangiogenic: TKIs	Sunitinib	2006	Advanced RCC, first line
	Pazopanib	2009	Advanced RCC, first line
	Axitinib	2012	Advanced RCC, pretreated
	Cabozantinib	2016 2017	Advanced RCC, pretreated with antiangiogenic therapy Advanced RCC, first line
	Tivozanib	2021	Advanced RCC, pretreated with two or more prior systemic therapies
	Nivolumab	2015
Combination therapies
TKI + mTOR inhibitor	Lenvatinib + everolimus	2016	Advanced RCC, pretreated with one antiangiogenic therapy
PD-1 inhibitor + CTLA-4 inhibitor	Nivolumab + ipilimumab	2018	Advanced intermediate-risk or poor-risk RCC, first line
PD-1 inhibitor + TKI	Pembrolizumab + axitinib	2019	Advanced RCC, first line
	Nivolumab + cabozantinib	2021	Advanced RCC, first line
	Pembrolizumab + lenvatinib	2021	Advanced RCC, first line
91	Cancer of the Bladder and Urinary Tract Noah M. Hahn

Table 91-2 are required to In carefully selected patients¶

Harrison's 22e, p.693

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%

TABLE 91-1 Non–Muscle-Invasive Bladder Cancer Recurrence Risk Groups¶

Harrison's 22e, p.693

RISK GROUP	CHARACTERISTICS
Low risk	Initial tumor, solitary tumor, low grade, <3 cm, no CIS
High risk	Any of the following: • T1 tumor • High-grade • CIS • Multiple and large (>3 cm) Ta low-grade tumors in patients over age 70 (all conditions must be met for this point on Ta low-grade tumors)