Schwandner O, Schiedeck T H, Bruch H P, Duchrow M, Windhoevel U, Broll R
Department of Surgery, Medical University of Luebeck, Germany.
Dis Colon Rectum. 2000 Sep;43(9):1227-36. doi: 10.1007/BF02237426.
The aim of this study was to evaluate the prognostic value of the apoptotic index for recurrence and disease-free survival after curative surgery for rectal cancer, particularly in relation to clinicopathologic variables, p53- and bcl-2 expression.
Formalin-fixed, paraffin-embedded tissue samples of rectal carcinomas resected curatively within a five-year period were used (N = 160). Apoptotic cells with fragmented DNA were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase-biotin nick-end-labeling method. The ratio of apoptotic tumor cells (in percent) was classified into low apoptotic index (less than 10 percent) and high apoptotic index (10 percent or more). Immunohistochemical analysis was performed using monoclonal antibodies (DO-1 for p53 and clone 124 for bcl-2). Statistics included univariate and multivariate analysis, and survival was calculated using the Kaplan-Meier method.
Seventy-five percent of tumors showed a low apoptotic index, and 25 percent had a high apoptotic index. No correlation was found between apoptotic index and International Union Against Cancer stage (P > 0.05). However, significant correlations were documented with histologic differentiation (mean apoptotic index, 5.74 percent in moderately vs. 3.98 percent in poorly differentiated carcinomas; P = 0.0173), lymph node involvement (mean apoptotic index, 6.11 percent in pN1 vs. 3.72 percent in pN2; P = 0.0074), p53 status (mean apoptotic index, 6.26 percent in p53- vs. 4.42 percent in p53+; P = 0.0085), and bcl-2 expression (mean apoptotic index, 5.13 percent in bcl-2- vs. 6.51 percent in bcl-2+; P = 0.0418). Tumors of the lower rectum had a lower apoptotic index than those of the upper rectum (P = 0.0277). Neither univariate nor multivariate analysis assessed apoptotic index as predictor of prognosis: Recurrence rates did not differ between tumors related to apoptotic index (22 percent with low apoptotic index vs. 15 percent with high apoptotic index; P > 0.05), and no significant differences were found regarding survival (P > 0.05). On multivariate analysis, International Union Against Cancer stage (P = 0.0002), p53 (P = 0.0002), gender (P = 0.0136), and bcl-2 (P = 0.0243) were independent predictors of recurrence. These variables, except for bcl-2, were also independently related to disease-free survival.
Reflecting tumor biology, apoptotic index as single variable showed no prognostic significance, whereas p53 was an independent predictor for both recurrence and survival, and bcl-2 was independently related to recurrence, but not to survival. Clinically, International Union Against Cancer stage and gender were independent prognostic factors after curative surgery for rectal cancer.
本研究旨在评估凋亡指数对直肠癌根治性手术后复发及无病生存的预后价值，尤其是与临床病理变量、p53和bcl-2表达的关系。
使用五年内根治性切除的直肠癌经福尔马林固定、石蜡包埋的组织样本（N = 160）。通过末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸生物素缺口末端标记法检测DNA片段化的凋亡细胞。凋亡肿瘤细胞的比例（百分比）分为低凋亡指数（小于10%）和高凋亡指数（10%或更高）。使用单克隆抗体（针对p53的DO-1和针对bcl-2的克隆124）进行免疫组织化学分析。统计学分析包括单因素和多因素分析，生存情况采用Kaplan-Meier法计算。
75%的肿瘤显示低凋亡指数，25%具有高凋亡指数。凋亡指数与国际抗癌联盟（UICC）分期之间未发现相关性（P > 0.05）。然而，与组织学分化（中度分化癌的平均凋亡指数为5.74%，低分化癌为3.98%；P = 0.0173）、淋巴结受累情况（pN1时平均凋亡指数为6.11%，pN2时为3.72%；P = 0.0074）、p53状态（p53-时平均凋亡指数为6.26%，p53+时为4.42%；P = 0.0085）以及bcl-2表达（bcl-2-时平均凋亡指数为5.13%，bcl-2+时为6.51%；P = 0.0418）存在显著相关性。直肠下段肿瘤的凋亡指数低于直肠上段肿瘤（P = 0.0277）。单因素和多因素分析均未将凋亡指数评估为预后的预测指标：与凋亡指数相关的肿瘤复发率无差异（低凋亡指数组为22%，高凋亡指数组为15%；P > 0.05），生存情况也无显著差异（P > 0.05）。多因素分析显示，国际抗癌联盟分期（P = 0.0002）、p53（P = 0.0002）、性别（P = 0.0136）和bcl-2（P = 0.0243）是复发的独立预测因素。除bcl-2外，这些变量也与无病生存独立相关。
作为单一变量的凋亡指数反映肿瘤生物学特性，无预后意义，而p53是复发和生存的独立预测因素，bcl-2与复发独立相关，但与生存无关。临床上，国际抗癌联盟分期和性别是直肠癌根治性手术后的独立预后因素。
