Chou Yeh-Pin, Lin Jui-Wei, Wang Chih-Chi, Chiu Yi-Chun, Huang Chao-Cheng, Chuah Seng-Kee, Tai Ming-Hong, Yi Li-Na, Lee Chuan-Mo, Changchien Chi-Sin, Hu Tsung-Hui
Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao-Sung Hsiang, Kaohsiung Hsien 833, Kaohsiung, Taiwan.
Oncol Rep. 2008 Jan;19(1):49-56.
To elucidate the prognostic role and relationship of the p53/p21/PCNA pathway in gastrointestinal stromal tumors (GISTs), a total of 167 resected gastric and small intestinal CD117-positive stromal tumor specimens were collected from January 1987 to December 2000. Immunohistochemical studies were performed on the paraffin sections with antibodies of p53, p21/WAF1, proliferating cell nuclear antigen (PCNA) and Ki-67. The immunoreactivity of four markers was recorded by labeling index (LI, %) for clinicopathologic and survival correlation. The labeling index was 0-83% for p53, 0-81% for p21/WAF1, 0-33% for Ki-67 and 12-92% for PCNA. Completely negative immunostaining (LI<1%) was found in 54.5% of p53, 25.8% of p21/WAF1 and 44.3% of Ki-67. The LI of four markers strongly correlate with each other (p<0.05). Furthermore, the LI of all four markers positively correlate to microscopic tumor mitotic counts (p<0.05). Only the LI of p53 and PCNA positively correlate to tumor sizes. Tumors with non-spindle cell type (versus spindle cell) and high cellular pleomorphism (versus low) exhibited a higher p53, p21/WAF1 and PCNA LI (p<0.05). Increased NIH risk significantly correlates to increased p53, PCNA and Ki-67 (p<0.05) LI. Survival analysis indicated that a large tumor size (> or =5 cm, p=0.003), increased tumor mitosis (> or =5/50 HPF, p<0.001), high NIH risk (p<0.001), non-spindle cell type (p=0.024), high p53 LI (p<0.001), high p21/WAF1 LI (p=0.007), high Ki-67 LI (p<0.001) and high PCNA LI (p<0.001) were prognostic factors for poor disease-free survival. Independent factors are tumor size, NIH risk, p53 and p21/WAF1 LI. We demonstrated the first evidence of the linear relationship and prognostic role of the p53/p21/PCNA pathway in gastrointestinal stromal tumors. Abnormalities of the p53/p21WAF1 pathway lead to increased proliferating states, thereby triggering the progression of GISTs.
为阐明p53/p21/PCNA通路在胃肠道间质瘤（GISTs）中的预后作用及关系，我们收集了1987年1月至2000年12月期间共167例切除的胃和小肠CD117阳性间质瘤标本。对石蜡切片进行免疫组织化学研究，使用p53、p21/WAF1、增殖细胞核抗原（PCNA）和Ki-67抗体。通过标记指数（LI，%）记录这四种标志物的免疫反应性，以分析其与临床病理及生存的相关性。p53的标记指数为0 - 83%，p21/WAF1为0 - 81%，Ki-67为0 - 33%，PCNA为12 - 92%。54.5%的p53、25.8%的p21/WAF1和44.3%的Ki-67免疫染色完全阴性（LI<1%）。这四种标志物的LI彼此之间高度相关（p<0.05）。此外，所有四种标志物的LI均与显微镜下肿瘤有丝分裂计数呈正相关（p<0.05）。只有p53和PCNA的LI与肿瘤大小呈正相关。非梭形细胞类型（相对于梭形细胞）和高细胞异型性（相对于低）的肿瘤表现出更高的p53、p21/WAF1和PCNA LI（p<0.05）。美国国立卫生研究院（NIH）风险增加与p53、PCNA和Ki-67的LI增加显著相关（p<0.05）。生存分析表明，肿瘤大尺寸（≥5 cm，p = 0.003）、肿瘤有丝分裂增加（≥5/50高倍视野，p<0.001）、高NIH风险（p<0.001）、非梭形细胞类型（p = 0.024）、高p53 LI（p<0.001）、高p21/WAF1 LI（p = 0.007）、高Ki-67 LI（p<0.001）和高PCNA LI（p<0.001）是无病生存期不良的预后因素。独立因素为肿瘤大小、NIH风险、p53和p21/WAF1 LI。我们首次证明了p53/p21/PCNA通路在胃肠道间质瘤中的线性关系及预后作用。p53/p21WAF1通路的异常导致增殖状态增加，从而引发GISTs的进展。
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