Tumor proliferation and apoptosis in human uterine cervix carcinoma I: correlations between variables

Abstract

Purpose: Parameters for tumor proliferation and apoptosis were studied prospectively in 84 previously untreated patients with a diagnosis of carcinoma of the uterine cervix. Materials and methods: Tumor proliferation was assessed by in vivo labeling with bromodeoxyuridine (BrdU), followed by a biopsy of the tumor 4–10 h thereafter during an examination under anesthesia. The potential doubling time ( T pot) was obtained by deriving the BrdU labeling index (LI) and S-phase duration ( T S) using flow cytometry. The LI for BrdU and its staining pattern were also determined immunohistochemically. Apoptosis was assessed histologically using morphological criteria. Results: Seven patients were excluded and the FIGO stages of the remaining 77 patients were as follows: IB and IIA, 20 patients; IIB, 29 patients; IIIB and IV, 28 patients. The median tumor diameter was 6 cm. There were 61 squamous cell, 11 adeno- and five adenosquamous carcinomas. Of the 63 patients in whom the tumor grade could be determined, 37 were well or moderately well differentiated and the remaining 26 were poorly differentiated. The median mitotic index (MI) was 0.7%. There were 43 diploid and 34 aneuploid tumors. Median values for T S and S-phase fraction (SPF) were 9.9 h and 16%, respectively. The median BrdU LI by flow cytometry (LI-fc) was 6.7%. There was a significant correlation between LI-fc and LI by histology, although values for the latter (median 11.1%) were consistently higher than those determined by flow cytometry by a factor of 1.5. The median T pot value was 5.0 days. The median apoptotic index (AI) was 1.0% and AI correlated positively with LI-fc. Median values for LI-fc increased with increasing tumor size and were 5.1%, 6.4%, 7.5% and 11.0% for tumors measuring ≤4 cm, 4–6 cm, 6–8 cm and >8 cm, respectively. The remaining proliferation parameters, however, showed no correlation with tumor size, stage, grade or histologic type. Conclusions: In carcinomas of the cervix, tumor proliferation is positively associated with apoptosis and tumor size. These findings suggest that parameters for tumor proliferation and apoptosis are associated with tumor progression and may thus be predictive of clinical outcome.