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Apoptotic and Mitotic Indices Predict Survival Rates in Lymph Node-negative Colon Carcinomas¹

Departments of Gastrointestinal Medical Oncology [F. A. S., M. L.], Biomathematics [H-A. H.], and Veterinary Medicine and Surgery [L. C. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Departments of Pathology [J. H.] and Surgery [F. M.], University of Chicago Medical Center, Chicago, Illinois 60637

An imbalance between apoptosis and mitosis is believed to underlie colon cancer development and progression. These processes regulate the growth of normal and neoplastic epithelia, and in tumors, may confer prognostic information. To test this hypothesis, we determined apoptotic and mitotic indices (AI, MI) by morphology in H&E sections of 154 lymph node-negative, sporadic colon carcinomas. The relationship of these indices to genetic (p53 and Bcl-2) and biological features (DNA ploidy and cell kinetics) and patient survival rates was determined. Tumor features were compared in proximal and distal tumors, given postulated differences in their pathogenesis. Bcl-2 and p53 proteins were examined using immunohistochemistry and DNA ploidy and proliferative indices (PIs) by flow cytometry. Tumor features were dichotomized for analysis of relapse-free survival and overall survival (OS) rates using a Cox proportional hazards model. Median patient follow-up was 8.8 years. The median AI and MI were 1.2% (0–7.6) and 0.40% (0–1.8), respectively, and did not differ by tumor site. AI correlated with histological grade (P = 0.03); MI correlated with PI (P = 0.02) and inversely with Bcl-2 in distal tumors (P = 0.02). p53 and Bcl-2 expression were detected in 52 and 53% of tumors, respectively. Distal tumor site was associated with aneuploidy (P = 0.001), p53 (P = 0.001), and PI >15% (P = 0.002). In a univariate analysis, colon cancers with high MIs (>0.5%) had a poor prognosis (P = 0.04). Bcl-2 overexpression (>20% + tumor cells) was associated with more favorable OS (P = 0.04). The association of ploidy and PI with outcome was of borderline significance for all tumors; however, diploidy predicted better survival in proximal cancers. In distal cancers, low AIs ( 0.25%) and high MIs (>0.5%) were adverse prognostic markers. After adjustment for other variables, an increased MI predicted shorter OS with a hazard ratio (HR) for death of 2.70; 95% confidence interval (CI) was 1.23–5.91 (P = 0.01). Expression of Bcl-2 was associated with more favorable OS (HR, 0.46; 95% CI, 0.21–1.0; P = 0.06). In proximal cancers, Bcl-2 expression was the most important predictor of OS (HR, 0.17; 95% CI, 0.03–0.85; P = 0.03). In distal tumors, low AIs (HR, 3.33; 95% CI, 1.27–9.09; P = 0.01) and high MIs predicted poor survival. In conclusion, increased mitosis and low or absent Bcl-2 expression are significant risk factors for death in node-negative colon cancers, as are low rates of apoptosis in distal tumors. If validated prospectively, our results may identify patient subsets than can benefit from adjuvant chemotherapy.

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