Two molecular pathways to transitional cell carcinoma of the bladder.

TLDR

Bladder transitional cell carcinomas present as either papillary or flat (CIS) lesions, with papillary tumors rarely progressing and flat lesions often becoming invasive, suggesting distinct genetic pathways involving chromosome 9 alterations and p53 mutations. The study analyzed 216 bladder tumors across stages and histologies for chromosome 9 loss and p53 mutations. Chromosome 9 loss occurred in 34% of papillary tumors but only 12% of CIS, whereas p53 mutations were present in 3% of papillary but 65% of CIS, indicating that chromosome 9 alterations may drive papillary initiation and CIS progression while p53 mutations underlie CIS aggressiveness, with some cases showing divergent genetic pathways.

Abstract

Noninvasive transitional cell carcinomas of the bladder can have two distinct morphologies suggesting they contain different genetic alterations. Papillary transitional cell carcinomas (T(a) tumors) are often multifocal and only occasionally progress, whereas flat tumors (carcinomas in situ, CIS), frequently progress to invasive disease. We examined 216 bladder tumors of various stages and histopathologies for two genetic alterations previously described to be of importance in bladder tumorigenesis. Loss of heterozygosity of chromosome 9 was observed in 24 of 70 (34%) T(a) tumors but was present in only 3 of 24 (12%) CIS and dysplasia lesions (P = 0.04). In contrast, only 1 of 36 (3%) T(a) tumors contained a p53 gene mutation compared to 15 of 23 (65%) CIS and dysplasias (P < 0.001), a frequency comparable to that observed in muscle invasive tumors (25 of 49; 51%). The presence of p53 mutations in CIS and dysplasia could explain their propensities to progress since these mutations are known to destabilize the genome. Analysis of several tumor pairs involving a CIS and an invasive cancer provided evidence that the chromosome 9 alteration may in some cases be involved in the progression of CIS to more invasive tumors, in addition to its role in the initiation of T(a) tumors. However, the CIS and secondary tumor were found to contain different genetic alterations in some patients suggesting divergent progression pathways. Bladder carcinogenesis may therefore proceed through two distinct genetic alteration pathways responsible for generating superficial tumors with differing morphologies and pathologies.