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Etiology & Epidemiology - Upper Tract Cancers

Background:

  • Upper urinary tract urothelial tumors involving the renal pelvis or ureter account for 5% to 7% of all renal tumors and about 5% of all urothelial tumors.
  • Renal pelvic tumors are not reported separately, so worldwide statistics are not accurate.
  • The highest incidence occurs in Balkan countries, where urothelial cancers represent 40% of all renal cancers.

Epidemiology and Etiology

  • The majority of upper tract tumors are urothelial cancers. The majority of these are transitional cell in origin. 
  • Squamous cell cancers and adenocarcinomas represent a small minority.
  • Transitional Cell Carcinoma (TCC) makes up more than 90% of upper urinary tract tumors.
  • TCC may present as papillary or sessile lesions, and may be unifocal or multifocal.
  • On histologic examination these lesions are similar to TCCs of the bladder, but the relative thinness of the muscle layer of the renal pelvis and ureter makes invasion through the muscle coat an earlier event.
  • Carcinoma in situ (CIS), as in the bladder, can be difficult to identify and can vary in appearance from a whitish plaque to epithelial hyperplasia or a velvety red patch due to increased submucosal vascularity.
  • Progression to muscle invasion or invasion into the renal parenchyma or adventitial tissues may occur.
  • The frequency of urothelial tumors of the upper tract is increasing.
  • Non-TCCs of the upper tracts represent a wide spectrum of lesions, from benign to highly malignant.
  • The most common of these are squamous cell cancers and adenocarcinomas.

Squamous Cell Cancers

  • Squamous cell cancers make up 0.7% to 7.0% of upper urinary tract cancers.
  • They are frequently associated with a condition of chronic inflammation or infection or with analgesic abuse
  • These tumors occur six times more frequently in the renal pelvis than in the ureter and are generally moderately to poorly differentiated and more likely to be invasive at the time of presentation.

Adenocarcinomas

  • Adenocarcinomas account for less than 1% of all renal pelvic tumors and are typically associated with long-term obstruction, inflammation, or urinary calculi.
  • These tumors typically present at advanced stage and display a poor prognosis.

Micropapillary Variant

  • A micropapillary variant of TCC in the bladder is associated with aggressive behavior and poor outcome. 
  • This histologic subtype is rare in the upper urinary tract. 
  • Holmang and colleagues described 26 patients with micropapillary variant of TCC  in the upper urinary tract. 
  • Twenty-two patients had stage T3 disease at presentation, 
  • Carcinoma in situ (CIS) or lymphovascular invasion was noted in 64% and 81% of cases. 
  • Five-year survival was 26.9%, and overall the disease-specific mortality was 77%.

Incidence

  • Account for 7 percent of all renal tumors.
  • Overall, urothelial tumors are distributed as follows:
  • Bladder: 90 percent
  • Urethra: 7 percent
  • Ureter or renal collecting system: 3 percent
  • Men are about twice as likely to develop upper urinary tract tumors as are women. 
  • Whites are about twice as likely as African-Americans to develop upper tract tumors. 
  • SEER data suggest that disease-specific annual mortality is greater in black men than in white men (7.4% vs. 4.9%) and greater in women than in men (6.1% vs. 4.4%). 
  • As is the case with bladder cancer, women who develop upper urinary tract cancer are 25% more likely than men to die of their disease. 
  • Accurate data regarding racial differences in mortality are not available.
  • Patients with a history of bladder cancer have 2 to 4 percent chance of developing upper tract tumors (synchronous or asynchronous).
  • This figure increases up to 25 percent in patients with bladder carcinoma in situ.
  • Patients with a history of an upper tract tumor have a 15 to 50 percent chance of eventually developing TCC of the bladder.
  • Such patients also have a 2 to 4 percent chance of developing a contralateral lesion.
  • After cystectomy, there is an approximately 7 percent chance of developing upper tract TCC.
  • The risk is highest with the presence of carcinoma in situ (CIS) in the cystectomy specimen. The highest risk is within 3 to 4 years following cystectomy.
  • There is evidence to suggest that patients with high-grade superficial bladder tumors undergoing bacillus CalmetteGuerin (BCG) intravesical therapy have an increased tendency to develop upper tract lesions.
  • The entire urothelium must be routinely surveyed for the development of cancer once any part has undergone malignant transformation.

Risk Factors:

  • Tobacco exposure increases risk 2-6 fold
  • Phenacitin abuse associated with significant increase in incidence not noted with other NSAIDS
  • Coffee Consumption; A relative risk of 1.8 times normal has been described in individuals who consumed more than seven cups of coffee per day.  
  • After controlling for cigarette smoking, this risk decreased to 1.3.
  • Excess inorganic arsenic in drinking water from artesian wells is associated with an increased risk of upper tract urothelial tumors in addition to other diseases. (Tan et al, 2008).
  • Balkan nephropathy inflammatory lesion of the renal interstitum endemic to the geographic area
  • Use of Aristolichia fangchi, a Chinese herb for weight loss.
  • A significantly increased risk for upper urinary tract tumors has been reported for persons employed in chemical, petroleum, and plastic industries (relative risk of 4); patients with exposure to coal or coke (relative risk of 4); and patients with exposure to asphalt or tar (relative risk of 5.5). 
  • Aniline dyes, β-naphthylamine, and benzidine have been implicated as causative agents, and tumors can occur at long intervals (up to 15 years or more) after exposure.
  • The development of squamous cell cancer (and less commonly adenocarcinoma) has been shown to be related to chronic bacterial infection associated with urinary stones and obstruction.
  • Exposure to cyclophosphamide, an alkylating agent, also appears to confer an increased risk

References:

  • Blacker EJ, Johnson DE, Abdul-Karim FW, et al: Squamous cell carcinoma of renal pelvis. Urology  1985; 25:124.
  • Greenlee RT, Murray T, Bolden S, Wings PA: Cancer statistics, 2000. CA Cancer J Clin  2000; 50:7.
  • Grollman AP, Shibutani S, Monya M, et al: Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A  2007; 104:12129-12134.
  • Holmang S, Thomsen J, Johansson SL: Micropapillary carcinoma of the renal pelvis and ureter. J. Urol  2006; 175:463-467.
  • Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 2004; 54:8.
  • Jensen OM, Knudsen JB, McLaughlin JK, et al: The Copenhagen case-control study of renal pelvis and ureter cancer: role of smoking and occupational exposures. Int J Cancer 1988; 41:557.
  • Munoz JJ, Ellison LM: Upper tract urothelial neoplasms: incidence and survival the last 2 decades. J Urol  2000; 164:1523-1525.
  • Premoli J, et al: Risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage Ta bladder cancer. J Urol  2006; 175:74-77.
  • Rabbani F, Perrotti M, Russo P, Herr HW: Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. J Clin Oncol  2001; 19:94-100.
  • Radovanovic Z, Krajinovic S, Jankovic S, et al: Family history of cancer among cases of upper urothelial tumours in the Balkan nephropathy area. J Cancer Res Clin Oncol  1985; 110:181.
  • Ross RK, Paganini-Hill A, Landolph J, et al: Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter. Cancer Res  1989; 49:1045.
  • Slaton JW, Swanson DA, Grossman HB, Dinney CP: A stage specific approach to tumor surveillance after radial cystectomy for transitional cell carcinoma of the bladder. J Urol  1999; 162:710-714.
  • Solsona E, Iborra I, Ricos JV, et al: Upper urinary tract involvement in patients with bladder carcinoma in situ (CIS): its impact on management. Urology  1997; 49:347-352.
  • Spires SE, Banks ER, Cibull ML, et al: Adenocarcinoma of renal pelvis. Arch Pathol Lab Med  1993; 117:1156.
  • Stefanovic V, Radovanovic Z: Balkan endemic nephropathy and associated urothelial cancer. Nat Clin Pract Urol  2008; 5:105.
  • Stewart GD, Bariol SV, Grigor KM, et al: Upper tract transitional cell carcinoma is of higher grade and stage than bladder TCC. J Urol  2005; 173:268.
  • Stein A, Sova Y, Lurie M, et al: Adenocarcinoma of the renal pelvis: report of two cases, one with simultaneous transitional cell carcinoma of the bladder. Urol Int  1988; 43:299.
  • Tan LB, Chen KT, Guo HR: Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU Int  2008; 102:48-54.
  • Wright JL, Hotaling J, Porter MP: Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol  2009; 181:1035-1039.