Heterogeneous distribution of K-ras-mutated epithelia in mucinous ovarian tumors with special reference to histopathology.

The carcinogenic process of epithelial ovarian carcinomas is still unknown, and both pathways of de novo carcinogenesis from the surface epithelium and malignant transformation of benign cystadenoma have been suggested. Especially in mucinous ovarian tumors, the transition from benign cystadenomas to tumors of low malignant potential (LMP) or carcinomas has been implicated. To elucidate this possibility, we analyzed the presence or absence of heterogeneity of the K-ras mutation corresponding to the histological heterogeneity in 71 epithelial ovarian tumors, including 31 mucinous tumors. K-ras mutation was identified in nine mucinous tumors (4 of 10 carcinomas, 4 of 14 LMP tumors, and 1 of 7 cystadenomas) and in two nonmucinous carcinomas. Microdissection of multiple sites with reference to their histological appearance showed the heterogeneous distribution of K-ras-mutated epithelia in two of the nine mucinous tumors. One mucinous carcinoma showed K-ras mutation in all of the histologically LMP and malignant portions, but not in benign portions. In another LMP tumor, all of the LMP portions and one of the benign portions showed K-ras mutation, whereas the other two benign portions had no mutation. In the remaining seven mucinous tumors with K-ras mutation, however, there was a homogeneous distribution of K-ras-mutated epithelia irrespective of their histological appearance. These findings suggest that the K-ras mutation occurs during the transformation from benign cystadenomas to LMP or malignant lesions, providing molecular genetic support for the hypothesis of the "adenoma-carcinoma sequence" in some mucinous ovarian tumors, but in other cases an alternative pathway may also be possible.