Huang Hsuan-Ying, Huang Wen-Wei, Lin Ching-Nan, Eng Hock-Liew, Li Shau-Hsuan, Li Chien-Feng, Lu David, Yu Shih-Chen, Hsiung Ching-Yeh
Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Ann Surg Oncol. 2006 Dec;13(12):1633-44. doi: 10.1245/s10434-006-9188-4. Epub 2006 Sep 30.
Inactivation of p16(INK4A) promotes G1/S progression of cell cycle. Minichromosome maintenance protein-2 (Mcm2), a novel cell proliferation marker, is known to better correlate with clinical outcomes than Ki-67 in many carcinomas. Since gastrointestinal stromal tumors (GISTs) sometimes remains challenging in prognostication, we analyzed the utility of these three markers in GISTs.
Immunohistochemistry was performed in tissue microarrays of 277 primary GISTs and correlated with NIH consensus criteria and clinical outcomes.
The increment of NIH risk levels significantly correlated with increasing labeling indices (LI) of both Ki-67 (P <.001) and Mcm2 (P <.001) and loss of p16(INK4A) expression (P <.035). However, the latter aberration did occur in 23% of very low/low-risk GISTs. The relationship between Mcm2 and Ki-67 LIs could be modeled as linear (P <.001, r = 0.697), while Mcm2 LI was considerably higher (P <.001) with a stepwise escalation related to risk levels. Ki-67 LI >5% (P <.0001) and Mcm2 LI >10% (P <.0001) were strongly predictive of inferior disease-specific survival (DSS), while aberrant loss of p16(INK4A) only reached a trend (P = .0954). In multivariate analyses, independent adverse factors of DSS were high-risk category (RR = 16.93, P <.0001), metastatic disease (RR = 4.12, P = .0015), Ki-67 LI >5% (RR = 3.55, P = .001), and presence of epithelioid histology (RR = 2.17, P = .0308).
Prognostic efficacy of NIH consensus criteria is substantiated. P16(INK4A) deregulation can occur early in GIST tumorigenesis and marginally correlates with patient survival. Despite Ki-67 LI being an independent prognosticator, simultaneous detection of Mcm2 is recommended as a prognostic adjunct of GISTs, given its better sensitivity and stepwise escalation with increasing risk levels.
p16(INK4A)失活促进细胞周期的G1/S期进程。微小染色体维持蛋白2（Mcm2）是一种新型细胞增殖标志物，在许多癌症中，它与临床预后的相关性比Ki-67更好。由于胃肠道间质瘤（GIST）的预后有时仍具有挑战性，我们分析了这三种标志物在GIST中的应用价值。
对277例原发性GIST的组织芯片进行免疫组织化学检测，并与美国国立卫生研究院（NIH）共识标准及临床预后相关联。
NIH风险水平的增加与Ki-67（P<.001）和Mcm2（P<.001）的标记指数（LI）增加以及p16(INK4A)表达缺失（P<.035）显著相关。然而，在23%的极低/低风险GIST中确实出现了后者的异常。Mcm2与Ki-67 LI之间的关系可模拟为线性关系（P<.001，r = 0.697），而Mcm2 LI明显更高（P<.001），且与风险水平呈逐步上升关系。Ki-67 LI>5%（P<.0001）和Mcm2 LI>10%（P<.0001）强烈预测疾病特异性生存率（DSS）较差，而p16(INK4A)的异常缺失仅达到一种趋势（P =.0954）。在多变量分析中，DSS的独立不良因素为高危类别（RR = 16.93，P<.0001）、转移性疾病（RR = 4.12，P =.0015）、Ki-67 LI>5%（RR = 3.55，P =.001）以及上皮样组织学表现（RR = 2.17，P =.0308）。
NIH共识标准的预后效能得到证实。p16(INK4A)失调可在GIST肿瘤发生早期出现，且与患者生存率的相关性较小。尽管Ki-67 LI是一个独立的预后指标，但鉴于Mcm2具有更好的敏感性且随风险水平逐步上升，建议同时检测Mcm2作为GIST的预后辅助指标。
