Study on consecutive light microscopic changes of tumor cells and apoptotic index observed in serial cervical biopsies during neoadjuvant chemotherapy with 5-fluorouracil and cisplatin in locally advanced cervical cancer

Abstract

Objective：To determine the effects of neoadjuvant chemotherapy (5-fluorouracil plus cisplatin) on tumor cell morphology and apoptosis by analyzing the consecutive changes of apoptotic index (AI) and histology observed in the serially obtained cervical cancer tissues during the chemotherapy. Methods：Cervical cancer tissues were obtained by punch biopsy just before starting the each cycle of neoadjuvant chemotherapy from five patients with locally advanced disease (stage IIb-IIIb), but previously untreated squamous cell carcinoma of uterine cervix. All patients were treated with three cycles of 5-fluorouracil (1,000 mg/ at day #1-5) and cisplatin (60 mg/ at day #1) at 3 weeks interval. All H & E stained cervical cancer tissue slides were scored for apoptotic index and observed for microscopic changes of tumor cells by a pathologist. Results：After the first cycle of chemotherapy, AI was significantly increased (from 2 times to 8 times). And widespread injury to cytoplasm was observed and followed by karyorrhexis and karyolysis of nucleus of tumor cells. The size of tumor nests was reduced and it was also noted that fibrosis and infiltration of inflammatory cells were increased. The parts of tumor nests were replaced by mature squamous cells and the changes in nuclear morphologic features pointing in a more differentiated direction. But after the second cycle of chemotherapy, only one patient showed an increase in AI by 1.2 times over that after the first cycle of chemotherapy. The rest showed slight decreases in AI compared to that after the first cycle of chemotherapy. In addition, fewer microscopic morphologic changes of tumor cells induced by chemotherapy were observed after the second cycle of chemotherapy compared to those after the first cycle of chemotherapy. Conclusion：We found that AI hardly increased or rather decreased, and that microscopic changes of tumor cells were fewer after the second cycle of neoadjuvant chemotherapy compared to the situation after the first cycle of chemotherapy. Thus, we could deduce that chemoresistance might rapidly develop in cervical cancer cells after the first cycle of neoadjuvant chemotherapy using 5-fluorouracil and cisplatin. So we need to consider this problem when we treat the locally advanced cervical cancer patients with neoadjuvant chemotherapy using 5-fluorouracil and cisplatin.