CHAPTER 52 Urothelial Carcinoma of the Bladder
EPIDEMIOLOGY OF BLADDER CANCER
How many cases of bladder cancer are diagnosed each year in the United States? How many patients die of bladder cancer each year?
According to current estimates, there will be approximately 73,510 new cases of bladder cancer diagnosed in the United States in 2012. There will be an estimated 14,880 deaths from bladder cancer (Siegel et al., 2012).
What are the top 4 causes of cancer death in the United States? How many cases of bladder cancer are diagnosed each year in the United States? How many patients die of bladder cancer each year?
Lung cancer is first, followed by breast/prostate, colorectal and then bladder cancer is fourth. (Pancreatic cancer is fifth.) So 2 of the top 4 cancer killers in men are urological cancers.
What are the main carcinogens linked to bladder cancer formation?
Aromatic amines including benzidine, β-naphthylamine, arsenic, benzopyrene, and 4-aminobiphenyl.
Name some established risk factors for development of urothelial carcinoma.
• Cigarette smoking
• Occupational exposure to arylamines
Textile dying
Rubber workers
Hairdressers
Approximately what percentage of urothelial carcinomas can be attributed to cigarette smoking?
While it is impossible to know the exact number, at most, 50% of bladder cancers can be attributed to cigarette smoking.
Which gender is more likely to develop bladder cancer?
Men have 3 to 4 times a greater risk of developing bladder cancer than women (Siegel et al., 2012).
Which racial group demonstrates the highest incidence of bladder cancer?
Non-Hispanic whites demonstrate twice the incidence of bladder cancer seen in African American men or Hispanic men and nearly 3 times the incidence seen in Asian men. A similar pattern is seen in women (Yuan and Nelson, 2011).
At what age is bladder cancer typically diagnosed?
It is most commonly diagnosed in the 8th decade of life with a median age of diagnosis of 70 in both men and women (Parkin, 2008; Siegel et al., 2012).
DIAGNOSIS OF BLADDER CANCER
What percentage of patients with cystoscopically detectable bladder cancer will have gross or microscopic hematuria?
85% (Varkarakis et al., 1974).
What percentage of patients with gross hematuria are found to have a bladder tumor on evaluation?
12% will have a bladder tumor (Khadra et al., 2000).
What percentage of patients without gross hematuria, but hematuria detected on urine dipstick tests are found to have bladder cancer? How about patients without gross hematuria, but microscopic hematuria confirmed on laboratory microscopic examination?
1.3% (0.4%-6.5%) of patients without gross hematuria, but a positive dipstick will be found to have bladder cancer (Golin and Howard, 1980; Messing and Vaillancourt, 1990; Mohr et al., 1986). 4.1% of patients with true microscopic hematuria confirmed in the laboratory will be found to have bladder cancer (Mishriki et al., 2008).
What percentage of patients with carcinoma in situ (CIS) report irritative voiding symptoms?
The Mayo Clinic reported that 80% of patients with CIS presented with irritative voiding symptoms (Zincke et al., 1985).
URINE CYTOLOGY
What is the sensitivity of a positive voided urine cytology?
• For high-grade disease: sensitivity—70% to 85%.
• For low-grade disease: sensitivity—30% to 40% (Lotan and Roehrborn, 2003).
What are the sensitivity and specificity of urine cytology for CIS?
Approximately 90% sensitivity and specificity (Sylvester et al., 2005).
FLUORESCENT IN SITU HYBRIDIZATION (FISH)—UROVYSION
What does the UroVysion urine FISH assay test for?
It is a locus-specific probe to the 9p21 band on chromosome 9 and the aneuploidy for chromosomes 3, 7, and 17.
What are the sensitivity and specificity of the UroVysion (FISH) test for detecting bladder cancer?
Sensitivity—72% and Specificity—83% (Hajdinjak, 2008). Recent studies have reported that the sensitivity and specificity may be somewhat lower than this, particularly in lower stage tumors (Moonen et al., 2007; Gudjonsson et al., 2008).
What percentage of patients with a positive UroVysion FISH test, but negative cystoscopy and cytology will have bladder cancer?
65% (Yoder et al., 2007).
STAGING AND GRADING OF BLADDER CANCER
What percentage of bladder tumors are urothelial in origin?
The histology of approximately 90% of malignant bladder tumors is urothelial carcinoma. This is was previously referred to as transitional cell carcinoma, but the new terminology also includes other epithelial cell types (Lopez-Beltran, 2008).
How is bladder cancer staged clinically?
Exam under anesthesia (rectal exam and bimanual exam), endoscopic biopsy (transurethral resection of bladder tumor [TURBT] or cystoscopic biopsy), and cytology. Upper tracts should be evaluated with delayed contrast images (eg, intravenous pyelogram, CT urogram, MR urogram) or retrograde pyelogram at time of cystoscopy. Patients with evidence of invasive disease should have chest x-ray to evaluate for pulmonary metastases, and cross-sectional imaging of the abdomen and pelvis to evaluate local extent of disease as well as for the presence of nodal/visceral metastases, comprehensive metabolic panel, and a complete blood count.
Go through 2007 AJCC Staging for bladder cancer:
• T stage:
Tx—Primary tumor cannot be assessed.
T0—No primary tumor.
Ta—Noninvasive papillary carcinoma.
Tis—Carcinoma in situ.
T1—Tumor invasion of subepithelial connective tissue (lamina propria).
T2a—Tumor invasion of superficial muscularis propria (inner half).
T2b—Tumor invasion of deep muscularis propria (outer half).
T3a—Microscopic invasion perivesical tissue.
T3b—Macroscopic invasion of perivesical tissue.
T4a—Invasion of prostatic stroma, uterus, and vagina.
T4b—Invasion of pelvic and/or abdominal wall.
• N stage:
Nx—Lymph nodes cannot be assessed.
N0—No lymph node metastases.
N1—Single regional lymph node metastasis distal to bifurcation of common iliac arteries.
N2—Multiple regional lymph node metastasis distal to bifurcation of common iliac arteries.
N3—Lymph node metastases proximal to the bifurcation of the common iliac arteries, but still within the true pelvis.
• M stage:
M0—No distant visceral or nonregional lymphatic metastases.
M1—Distant visceral or nonregional lymphatic metastases.
When should a bone scan be considered?
When patients have symptoms concerning for skeletal metastases (bone pain, neurologic symptoms), when other staging imaging demonstrates lesions suspicious for metastatic disease, or when alkaline phosphatase is elevated.
What is the typical cystoscopic appearance of low-grade bladder tumors?
Papillary and pedunculated.
How do papillary bladder cancers differ in cystoscopic appearance from benign inflammation?
Papillary tumors will each have a tiny but separate blood supply and blood vessel while inflammatory growths may have generalized erythema, but will lack the extra vascularity.
What is the typical cystoscopic appearance of high-grade bladder tumors?
Flat and velvety (CIS), sessile, and/or nodular. They often tend to lose the papillary appearance and appear more solid. Sometimes tumor necrosis is evident.
Which patients should have repeat resections after TURBT? When should this be performed?
Any patients with bladder cancer, but no muscularis propria in the specimen should undergo re-resection, as their staging is incomplete. Patients with high-grade T1 disease, regardless of whether or not muscularis propria is seen in the specimen, should also undergo re-resection, as initial staging underestimates disease invasion in 30% to 40% of these patients (Dutta et al., 2001; Herr, 1999). Re-resections should be performed 2 to 6 weeks after the initial resection.
What percentage of patients will have residual tumor at re-resection for the above indications?
Herr reported a 76% incidence of residual tumor at re-resection (Herr, 1999).
How can cautery artifact be minimized?
Use of cutting rather than cauterizing current, finer diameter cutting loops, and lower cutting currents.
What phenomenon can account for a T1 tumor being falsely read as a T2 tumor?
Invasion of the muscularis mucosa in the lamina propria rather than the muscularis propria.
Which patients with clinical T1 bladder cancer are at the highest risk for progression?
Those with prior treatment with Bacillus Calmette–Gu
rin (BCG) and persistent T1 disease on restaging TURBT, history of multiple T1 recurrences, multifocal T1 disease, extensive concomitant CIS, and vascular invasion. These patients should be considered for immediate cystectomy rather than intravesical treatment (Dalbagni, 2011; Herr et al., 1989, 2007; Lambert et al., 2007).
How many tiers does the current preferred World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) urothelial carcinoma grading system have?
Two (low or high grade). The previous grading system was 3-tiered (low, intermediate, and high grade) (Epstein, 1998).
What percentage of papillary urothelial neoplasms of low malignant potential (PUNLMP) will recur and how many will progress to invasive disease?
27% to 47% will recur and 0% to 4% will progress to muscle-invasive disease.
What percentage of patients with low-grade noninvasive (Ta)urothelial carcinoma will recur and how many will progress to invasive disease?
48% to 71% will recur. 5% will progress to invasive disease.
What percentage of patients with high-grade papillary noninvasive (Ta)urothelial carcinoma will recur and how many will progress to invasive disease? How many will die from disease?
Approximately 60% to 70% recur and 24% to 40% progress to muscle-invasive disease. Approximately 22% will go on to die of their disease (Lightfoot et al., 2011; Herr, 2000).
Is CIS premalignant or malignant?
Malignant. CIS is noninvasive high-grade urothelial carcinoma confined to the epithelium.
What factors are associated with recurrence and progression in patients with non-muscle-invasive urothelial carcinoma?
Multiplicity, prior recurrences, tumor size, concomitant CIS, female gender, tumor grade, and T-stage (Fernandez-Gomez et al., 2008; Sylvester et al., 2006).
What is the most important factor predicting progression of non-muscle-invasive tumors?
Grade.
What level of bladder tumor invasion does hydronephrosis at staging suggest?
This is a marker for invasion at least into the muscularis propria of the bladder. However, hydronephrosis can also be associated with more advanced disease and might be due to intraluminal ureteral disease.
What percentage of patients with CIS will recur after intravesical BCG or chemotherapy and how many will progress to invasive disease? Will die of disease?
Since CIS is extremely difficult (if not impossible) to completely eradicate with TURBT alone, recurrence rates can really only be assessed after treatment with intravesical therapies. In one review of 12 intravesical therapy trials, van der Meijden et al. (2005) found that at a median follow-up of 3.75 years, patients treated with BCG exhibited a 51% recurrence-free survival rate while those managed with intravesical chemotherapy demonstrated a 27% recurrence free survival rate. Forty to eighty percent of patients with CIS will progress to invasive disease (Hudson and Herr, 1995; Lamm et al., 1998; Solsona et al., 1990). Anywhere from 10% to 40% of patients initially diagnosed with CIS will ultimately succumb to bladder cancer (Gofrit et al., 2009; Jakse et al., 2001; Utz et al., 1970).
A patient has completed a 6-week induction course of BCG therapy and is found to have raised velvety patches on cystoscopy as well as positive high-grade cytology. Random bladder biopsies reveal persistent CIS. What management options should you present to this patient?
Re-induction BCG, maintenance BCG, intravesical chemotherapy (valrubicin), and radical cystectomy. It is possible that this patient will achieve a complete response (CR) with further BCG.
In the above case, what is the expected CR rate to a second 6-week induction course of BCG?
Up to 50% of those receiving a second 6-week induction course of BCG will achieve a CR (van der Meijden et al., 2005).
What is the most important predictor of progression in CIS and what is the recommended treatment for those who fail to achieve a CR with BCG therapy?
Patients who fail to achieve a CR by 6 months should undergo radical cystectomy, as 6-month response to BCG has been shown to be the single most important predictor of progression in CIS patients (Herr et al., 1989).
What percentage of patients undergoing radical cystectomy for clinical CIS only will demonstrate upstaging on final pathologic analysis?
In a study of 243 patients who underwent radical cystectomy for clinical CIS only, 87 patients (36%) demonstrated pathologic upstaging. Additionally, 14 (5.9%) patients demonstrated regional lymph node involvement. The 5-year recurrence-free and cancer-specific survival for the entire study group were 74% and 85%, respectively (Tilki et al., 2010).
How often should patients with high-grade non-muscle-invasive bladder cancer (HG Ta, HG Ta, CIS) undergo upper tract imaging?
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