Identical clonal origin of synchronous and metachronous low-grade, noninvasive papillary transitional cell carcinomas of the urinary tract.

One of the most important biological features of papillary transitional cell carcinoma (pTCC) of the urinary tract is its multicentricity and its tendency for recurrences. Two possible mechanisms, field effect and intramucosal seeding/spreading, have been proposed. The former theory hypothesizes that carcinogenic agents cause synchronous or metachronous malignant transformation of multiple urothelial cells (independent clonal origin), and the latter speculates that synchronous and metachronous tumors are derived from implantation or direct spreading of tumor cells (identical clonal origin). We tested these hypotheses by analyzing the methylation patterns of the androgen receptor gene (HUMARA) located at the X-chromosome. Thirty-five metachronous and synchronous, low-grade (grade 1 or 2), noninvasive pTCCs of the urinary tract from 10 heterozygous female patients were successfully analyzed using formalin-fixed, paraffin-embedded tissue. These included 16 recurrent bladder tumors from 4 patients, 10 metachronous bladder and ureter/renal pelvis tumors from 4 patients, and 9 multifocal tumors from 2 patients. All tumors are monoclonal as indicated by unbalanced methylation of HUMARA. Furthermore, same methylated allele was detected in multiple recurrent or multifocal tumors from any given patient, indicating their identical clonal origin. We conclude that low-grade, noninvasive pTCCs are monoclonal in nature. Synchronous or metachronous pTCCs have an identical clonal origin, strongly supporting the intramucosal seeding/spreading hypothesis.