Molecular pathology

Mutations of TP53 are found in the vast majority of invasive gallbladder carcinomas {2124, 2127}. Loss of heterozygosity (LOH) at chromosomal loci 8p (44%), 9p (50%) and 18q (31%) are also frequently detected {2127}. These genetic alterations are considered early events, while RAS mutations and LOH at 3p, RB, and 5q occur less frequently and are considered late events, probably related to tumour progression. Amplification of the c-erbB-2 gene, that codes for a glycoprotein structurally similar to the epidermal growth factor receptor was detected in 30 of 43 invasive gallbladder carcinomas {1036}. However, no correlation between c-erbB-2 gene amplification and prognosis was found. In contrast to lesions of the gallbladder, the incidence of TP53 mutations in extra-hepatic bile duct carcinomas is lower and appears to be a late molecular event.

Although the frequency of KRAS mutations in gallbladder carcinomas has ranged from 0%-34% in different studies, most investigators have found these mutations to be significantly higher in extrahepatic bile duct tumours than in gallbladder carcinomas {2067}. Depend ing on the study, the Incidence of KRAS mutations In extrahepatic bile duct carcinomas has varied from 0-100% {1586}, but most likely, the true incidence is around 56% {2067}. However, the incidence of KRAS mutations is greater in gallbladder carcinomas associated with an anomalous junction of the pancreati-cobiliary duct than in carcinomas not associated with this congenital anomaly {661}. These molecular pathology findings support the concept that gallbladder carcinogenesis requires a number of genetic alterations involving activation of oncogenes or inactivation of tumour suppressor genes.

The molecular pathology of adenomas of the gallbladder differs from that of carcinomas. None of 16 adenomas showed TP53 or p16 Ink4/CDKN2a gene mutations, which are common in carcinomas {2126}. Four adenomas had KRAS mutations (2 in codon 12 and 2 in codon 61) which are considered rare and late

Fig. 9.20 Papillomatosis of extrahepatic bile duct.

events in the pathogenesis of carcinomas of the gallbladder. Only one adenoma of intestinal type showed loss of heterozygosity at 5q22 {2126}. Intraepithelial neoplasia (both dysplasia and carcinoma in situ) shows a high incidence of loss of heterozygosity at the TP53gene locus. Other molecular abnormalities include loss of heterozygosity at 9p and 8p loci and the 18q gene. These abnormalities are also early events and most likely contributing factors in the pathogenesis of gallbladder carcinoma. However, KRAS mutations were not detected in intraepithelial neoplasia {2125}.

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