Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Abstract

In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor compo- Small-cell carcinoma of the urinary bladder histologically resembles that occurring in the lung and has been reported with an increasing frequency in recent years. [1][2][3][4][5][6][7][8][9][10] It has been estimated to represent 0.5% of bladder malignancies and develops more frequently in older men, with hematuria as the most common presenting symptom. 8 Small-cell carcinoma of the urinary bladder behaves aggressively, often with locally advanced or metastatic disease at the time of presentation. 11 Over the years, three principal theories have been proposed to account for the development of small-cell carcinoma in the urinary bladder. The first theory is that small-cell carcinomas originate from multipotential, undifferentiated cells or stem cells in the urothelium. 5,8,12,13 The frequent association of this tumor with coexisting urothelial carcinoma supports this theory. The second theory is that these tumors arise from neuroendocrine cells within normal or metaplastic urothelium. 14 The third theory is that small-cell carcinomas are derived from an undefined population of submucosal neuroendocrine cells. 1 In this study, we investigated the clonal relationships between small-cell carcinoma and coexisting urothelial carcinoma using loss of heterozygosity (LOH) and X chromosome inactivation analysis. Materials and Methods PatientsTwenty patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma were included in our study. Archival materials from the 20 cases

Primary sources of pelvic serous cancer in patients with endometrial intraepithelial carcinoma

“…24,26,36 TP53-mutation analysis well defines the cellular lineage between primary organ sites and potential metastasis including serous endometrial intraepithelial carcinoma and associated extrauterine disease. 16,20,22,27,46 In 10 of the 21 serous endometrial intraepithelial carcinoma cases, multiple TP53 gene mutations were identified and identical mutations were found between the foci of serous endometrial intraepithelial carcinoma and their associated extrauterine disease, supporting that the extrauterine disease represents metastasis from corresponding serous endometrial intraepithelial carcinomas. In contrast, 5 of the 21 serous endometrial intraepithelial carcinoma cases showed discordant TP53 mutations between intrauterine and extrauterine samples, suggesting that associated extrauterine disease in those samples was not derived from the metastatic serous endometrial intraepithelial carcinoma but rather from the tubal origin.…”

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

“…This belief is based on the fact that we found MGMT methylation in only 1 of 14 cases containing pure TCC, but in 9 of 13 TCC samples where the histologies were admixed and genetically related. 9 Our findings may distinguish MGMT methylation as an SCBC-specific epimutation. In this setting, MGMT methylation has a sensitivity of 69% and a specificity of 92% in the detection of SCBC.…”

“…14 Tissues were microdissected and DNA was extracted as previously described. 9,15 This research was approved by the Indiana University Institutional Review Board.…”

“…Although infrequent in occurrence, small-cell bladder cancer (SCBC) may evolve or co-evolve from pre-existing TCC. 9 We hypothesized that DNA methylation of specific genes may underlie the pathogenesis of SCBC. In this study, we quantitatively analyzed the methylation status of RASSF1, MLH1, DAPK1, and MGMT, in cases of SCBC, which coexisted with TCC.…”

Multidisciplinary approach in the treatment of patients with small cell bladder carcinoma

“…In several pathology based retrospective studies small cell histology usually coexists with tumour types such as transitional cell carcinoma 1,5 . The coexistence of distinct tumours in the same pathological sample can be considered as supporting a pluripotent stem-cell origin 5,6 . The risks factors most frequently associated with SCCUB are smoking (65-79% reported) [1,7] , age (median: 66 years) and sex (male: female ratio up to 4:1) 1,5 .…”