A Correlation between Mutation of the p53 Gene and Histological Heterogeneity in Differentiated Adenocarcinomas of the Lung, with Reference to Stepwise Progression and Metastatic Ability

I examined 15 cases of differentiated adenocarcinoma of the lung which showed mutation of the p53 gene and whose primary lesions could be divided into three components (peripheral component, intermediate component and central component). Mutation of the p53 gene in each component was examined by an immunohistochemical method and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis in order to elucidate the correlation between histological types in the adenocarcinoma and mutation of the p53 gene. Furthermore, immunohistochemical detection of Ki-67 antigen and the ploidy pattern were examined for each component of the primary lesions and metastatic lesions. As a result, mutation of the p53 gene was detected mainly in the intermediate and central components, that is, in 13 cases in the intermediate component and in all cases in the central component. Higher proliferative activity as well as a DNA aneuploidy pattern were seen in these areas. In contrast, the peripheral component showed mutation of the p53 gene in only 4 cases. Lower proliferative activity and a normal diploidy pattern were seen in this area. As for the metastatic lesions, mutations of the p53 gene were detected in the metastasis of the lymph nodes and brain, as well as in the intermediate and central components of the primary lesions. Moreover, these metastatic lesions showed a higher proliferative activity which was similar index to the central or intermediate one. In 2 cases the metastasis of the lymph node showed an aneuploidy pattern as well as the intermediate and central components. On the other hand, in two metastatic lung tumors no mutation of the p53 gene was detected and lower proliferative activity was seen as observed in the peripheral one. From these results, I conclude that progression of adenocarcinoma of the lung occurs in the intermediate and central components, and is closely related to mutation of the p53 gene.