Superficial and metachronous invasive bladder carcinomas are clonally related

Abstract

Synchronous and metachronous tumors are frequently observed in the urinary tract and may be explained by the concept of 'field cancerization,' i.e., exposure to carcinogens leading to the independent transformation of many urothelial cells resulting in oncogenetically unrelated tumors. Increasing evidence, however, supports the concept of clonality, i.e., the progeny of a single transformed cell spreads through the urinary system resulting in genetically related tumors. The aim of our study was to investigate the putative clonal origin of invasive urothelial cell carcinomas (UCCs) of the bladder from a prior superficial tumor. We selected 6 patients (5 males and 1 female) with superficial and subsequent invasive UCC tumors. All patients were previously diagnosed with a p53 mutation in their invasive tumor. At least 1 superficial and 1 invasive tumor of the same patient were analyzed for mutations in the p53 tumor suppressor gene by PCR-SSCP and, in case of a band shift, followed by direct sequencing. In all patients the same p53 mutation was found in the superficial and subsequent invasive tumor(s). All tumors arose from the same progenitor cell. These results support the concept of a clonal origin of superficial and metachronous invasive bladder UCCs.

Preoperative positive urine cytology is a risk factor for subsequent development of bladder cancer after nephroureterectomy in patients with upper urinary tract urothelial carcinoma

“…The field-cancerization hypothesis suggests that carcinogen exposure of the entire urothelial layer can lead to independent multifocal tumor development [6]. However, there is increasing evidence from molecular studies over the past decade that the intraluminal seeding and implantation hypothesis represents the predominant mechanism [7][8][9][10][11][12]. According to intraluminal seeding and implantation hypothesis, it is reasonable that preoperative positive urine cytology is the risk factor for bladder recurrence, considering urine cytology is the helpful leads to finding the dropping of cancer cells into the bladder.…”

“…The field-cancerization hypothesis suggests that carcinogen exposure of the entire urothelial layer can lead to independent multifocal tumor development [6]. However, there is increasing evidence from molecular studies over the past decade that the intraluminal seeding and implantation hypothesis, describing multiple tumors as a consequence of clonal evolution from a single transformed cell, represents the predominant mechanism [7][8][9][10][11][12]. While UUT-UC recurrence after treatment for bladder cancer is reported as only 0.7-4% [13,14], the risk of subsequent bladder cancer in patients operated for UUT-UC has been reported to be 15-40%.…”

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

“…5 Studies on the genetic heterogeneity of the premalignant field in patients with urothelial bladder cancer (UBC) have given important insights into the processes behind tumor initiation and favor a clonal origin. [6][7][8][9] The shared clonal origin of nonmuscle invasive bladder cancer (NMIBC) recurrences has been repeatedly demonstrated [10][11][12] even though tumors usually occur in different locations within the bladder. 13 Taken together, a model is supported in which tumors develop semiindependently out of a premalignant field that is usually clonal in nature but has additional heterogeneity that manifests as genetic differences between recurrences.…”

EDTA‐induced urothelial cell shedding for the treatment of superficial bladder cancer in the mouse

“…Recurrence of superficial transitional cell carcinoma of the bladder following transurethral resection constitutes a major problem in the management of bladder cancer 1 . The recurrence rate may reach 70–80%, and is characterized by its frequent clonal nature 2,3 The unsatisfactory high local failure rate can be due to new areas of dysplastic urothel, incomplete removal of the tumor or implanted cancer cells released by the primary lesions at the time of resection. Indeed, various groups have shown the beneficial effect of a single immediate postoperative intravesical chemotherapy 4–6 …”