Nuclear markers (star volume, mitotic index, AgNOR and Ki-67) of the primary tumor and its metastasis in non-small cell lung carcinomas

Abstract

Although tumor growth is controlled by growth rate and cell cycle, it is also likely that the proliferative activity of tumor cells can influence the growth rate of the primary cancer and account for their aggressiveness. Variations in growth rate, cell cycle control and proliferative activity could, in part, explain differences in invasive and metastatic properties among non-small cell lung carcinomas (NSLC). The purpose of this report is to: (1) evaluate growth rate by using growth- and cell cycle-regulating markers (mitotic count, nuclear star volume, AgNOR, and Ki-67) as reflections of growth rate and (2) compare the indices of primary NSLC with the indices of their metastasis in a series of patients with advanced disease. Thirty-three patients with non-small cell lung cancer and hematogenous metastases were retrospectively studied by histochemical, immunohistochemical, and morphometrical investigations. Clinical variables were examined for differences in the frequency of histological subtypes, nuclear star volume, mitotic index, AgNOR area, and Ki-67 immunohistochemistry indices of expression in subgroups of patients stratified by primary tumor and hematogenic metastasis. The impact of these factors on overall follow-up was analyzed. In the samples available in this study, consisting of primary-met paired tumors, which are unique and rarely available for studies of lung cancer, we found that nuclear star volume and mitotic index in metastatic tumors were significantly higher than in the primary tumors. Although there was no significant difference between the Ki-67 index of metastatic and primary tumors, the Ki-67 index in metastatic brain tumors was significantly higher than in the corresponding primary tumors. Examination of Kaplan–Meier survival curves demonstrated that patients with metastatic tumors showing AgNOR area higher than 10.82 μm 2 and nuclear star volume lower than 559.50 μm 3 had approximately the same odds ratio (log rank of 4.16 and 3.25, p=0.04 and 0.01, respectively) for survival with a median survival time equal to 17 months for both groups. Analysis of the remaining marker correlation had no impact on survival. We conclude that these results offer future possibilities for more complex studies, including the results of additional immunohistochemical analysis using molecular markers that are known to be important in regulating cell proliferation, e.g., cyclin D1, p27, and cyclin E. These would influence clinical decisions or different therapeutic approaches in advanced stage disease of non-small cell lung cancer.