Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract

Multifocality and recurrence of urothelial carcinoma may result from either the field effect of carcinogens leading to oligoclonal tumors or monoclona l tumor spread. Previous molecular studies, favoring the monoclonality hypo thesis, are mostly limited to the urinary bladder. We investigated genetic alterations in a total of 94 synchronous or metachronous multifocal tumors from 19 patients with at least one tumor both in the upper and lower urinar y tract. Loss of heterozygosity (LOH) was determined using eight markers on chromosome 9 and one marker on 17p13 (p53). Microsatellite instability was investigated at six loci and protein expression of MSH2 and MLH1 was evalu ated by immunohistochemistry. In addition, exons 5-9 of the p53 gene were s equenced. Deletions at chromosome 9 were found in 73% of tumors and at 17p1 3 in 18% of tumors. There was no significant difference in the frequency of LOH in the upper and lower urinary tract. Deletions at 9p21 were significa ntly correlated with invasive tumor growth. The pattern of deletion reveale d monoclonality of all tumors in nine patients. In five patients there were at least two tumor clones with different genetic alterations. In four of t hese patients the different clones occured in the bladder and subsequently in the ureter and renal pelvis. All four patients with p53 mutations reveal ed identical mutations in all tumors. Thus, multifocal urothelial carcinoma s are frequently monoclonal, whereas others show oligoclonality, providing molecular evidence for field cancerization. Intraluminal tumor cell seeding appears to be an important mechanism of multifocal occurence and recurrenc e of urothelial carcinomas.