Management of Patients With Upper Urinary Tract Transitional Cell Carcinoma

Jay D Raman; Douglas S Scherr*

Disclosures

Nat Clin Pract Urol. 2007;4(8):432-443. 

In This Article

Genetics and Molecular Markers

Many of the molecular events associated with upper-tract TCC are similar to those seen in the development of bladder cancer. Tumor suppressor gene loci on chromosome 9 (p19 and p16), chromosome 17 (p53), and chromosome 13q (retinoblastoma [RB1] gene) have all been identified through molecular and cytogenetic techniques.[12,13,14,15,16,17] Chromosome 9 losses have been associated with early development of low-grade, superficial tumors, whereas abnormal expression of RB1 occurs more often in aggressive cancers.[12,13,14,15] The p53 gene is the most commonly altered gene in human cancers, and p53 loss or mutation is thought to be a key molecular event associated with the progression of low-grade superficial urothelial carcinoma to a high-grade invasive carcinoma.[16,17]

Although TCC represents a malignant disease of the urothelium, molecular insights suggest variability in the biological mechanisms underlying upper urinary tract and bladder urothelial carcinoma. These genetic differences combined with variability in the anatomic location of lesions might affect tumor phenotype.[18,19] Tumor microsatellite instability (MSI) is an indicator of clonal expansion of neoplasms and was first identified in tumors from patients with hereditary nonpolyposis colorectal carcinoma (HNPCC). Studies have demonstrated contrasting patterns of MSI in urothelial tumors, with low levels of instability detected in bladder cancer and significantly higher levels for upper-tract TCC.[20] Furthermore, high levels of MSI correlate with a better clinical prognosis, particularly for patients under 70 years of age with stage T2–T3/N0 disease.[21,22] Other molecular markers that have been studied include E-cadherin, p27, survivin, MSH2, p63, and p53. Although E-cadherin seems to provide independent prognostic significance for upper-tract TCC, most other markers seem to add little value when controlling for stage and grade.[23,24] Therapies targeted at some of these genetic alterations might have a central role in future therapy for upper-tract TCC.

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