Histological and genetic changes in malignant transformation of gallbladder adenoma

Design: Elucidate the histological and genetic changes in malignant transfo rmation of adenoma of the gallbladder. Materials and methods: Forty-three adenomas and 20 intramucosal tumors of c arcinoma-in-adenomas were studied for histological and genetic changes (par ticularly K-ras mutation and p53 protein overexpression by immunohistochemi stry) in malignant transformation. The genetic changes were compared with t hose of 164 carcinomas without anomalous union and 17 carcinomas with anoma lous union of pancreatico-biliary duct. Results: Atypical cell foci, i.e. spindle cell foci, were observed only in the adenoma area, with a frequency of 23% in 39 adenomas, and of 45% in 20 tumors of carcinoma-in-adenoma. 129 of 130 spindle cell foci examined were negative for Ki-67 staining and all the spindle cell foci were negative for p53 slain. K-ras mutation and p53 overexpression were not found in all ade nomas, pure and with carcinoma i.s., and only one carcinoma (1/16, 6%) with adenoma showed p53 overexpression. K-ras mutation was low (10%, 4/40) in c arcinomas without adenoma, but high in carcinomas with anomalous union of p ancreatico-biliary duct. While, p53 overexpression was high and similar in carcinomas with and without anomalous union. Conclusions: These results suggest that there an three distinct pathways in gallbladder carcinogenesis; that is, de novo carcinoma develops from a pre dominant p53 alteration with low K-ras mutation, de novo carcinoma with ano malous union from K-ras mutation and p53 mutation, and carcinoma-in-adenoma from K-ras-, p53-, and probably APC-gene-related, as yet unknown, alterati on.