Mutations of p53 tumor suppressor gene, apoptosis, and proliferation in intrahepatic cholangiocellular carcinoma of the liver

This study was performed to examine the correlation between mutations of th e p53 tumor suppressor gene, the occurrence of apoptosis, and proliferation in cholangiocellular carcinoma of the liver. The results obtained were com pared with pathohistological stage (according to UICC) and grade and with d isease related survival rate. In 41 curatively (R0-) resected intrahepatic cholangiocellular carcinomas, the status of the p53 gene was determined by direct sequencing of exons 4-9 and immunohistochemically. Apoptosis was ass essed using the in situ end labeling (ISEL) technique in combination with m orphological criteria. Proliferation was analyzed by immunohistochemistry o f MIB-1 (Ki-67), Proliferating cell nuclear antigen (PCNA), and silver-stai ned nucleolar organizer regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), grade, several other his topathological factors, and survival rate. Mutations of p53 were detected i n 15/41 carcinomas examined (37%). The most common change was a G-->C and C -->T transition, changing the hot spot amino acid determined by exons 4-8. Of these 15 tumors, 14 were also p53-positive by immunohistochemistry. In e ach carcinoma examined, we could demonstrate MIB-1, PCNA, and AgNOR dots an d also apoptotic cells in variable proportions. The proliferation markers s howed a significant correlation among themselves. In univariate survival an alysis, the extent of the primary tumor, lymph node status, grade, and p53 were significant factors influencing patient survival. Performing multivari ate Cox regression survival analysis, however, only the extent of primary t umor and lymph node status had an independent prognostic impact. Apoptosis was not related to patient prognosis or to other parameters examined. In co nclusion, these results indicated that p53 could serve as an additional pro gnostic parameter that could provide auxiliary information for patient outc ome. However, tumor stage and lymph node involvement were the strongest pro gnostic factors. We failed to establish apoptosis or other pathological par ameters as factors predicting the prognosis of patients with cholangiocellu lar carcinoma.