Gafà R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G
Department of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara, Ferrara, Italy.
Cancer. 2000 Nov 15;89(10):2025-37.
Widespread microsatellite instability (MSI) occurs in nearly 15% of sporadic colorectal cancers. Large bowel carcinomas with high-frequency MSI (MSI-H) (instability at > or = 30% of microsatellite loci) are believed to display distinctive pathologic features and to behave less aggressively than microsatellite-stable (MSS) tumors and carcinomas with low-frequency MSI (MSI-L) (instability at < 30% of microsatellite loci). The aim of the current study was to accurately define the clinicopathologic and biologic features of MSI-H sporadic colorectal carcinomas.
MSI status was evaluated in 216 large bowel adenocarcinomas using polymerase chain reaction (PCR) and 6 microsatellite markers. Tumors that showed instability with at least two microsatellite markers were classified as MSI-H, whereas the other tumors were classified as MSI-L (instability at one locus) or MSS (no instability). Expression of p53, hMLH1, and hMSH2 gene products was determined by immunohistochemistry, and DNA ploidy pattern was determined by flow cytometry. The prognostic significance of MSI status was assessed by univariate and multivariate survival analyses.
The significantly different pathologic features of MSI-H carcinomas were proximal location; large size; mucinous and medullary histotype; poor differentiation; expanding pattern of growth; more frequent Crohn-like conspicuous lymphoid reaction; and low incidence of extramural vein invasion. Most MSI-H tumors were DNA diploid (33 of 40 tumors; 82.5%) and p53 negative (34 of 44 tumors; 77.3%). Conversely, DNA aneuploidy and p53 overexpression were observed in 82.3% (130 of 158 tumors; P < 0.0001) and 54.1% (93 of 172 tumors; P = 0.0002) of MSI-L/MSS tumors, respectively. Loss of hMLH1 or hMSH2 expression was detected in a high fraction of MSI-H carcinomas (86. 0%). Patients with MSI-H tumors showed a better clinical outcome than patients with MSI-L/MSS tumors (P = 0.0017). Furthermore, in multivariate analysis that included conventional clinicopathologic parameters, MSI status, and p53 expression as covariates, MSI status was a significant independent prognostic indicator of disease specific survival.
Assessment of MSI status is an essential step in the genetic characterization of large bowel carcinomas and identifies a subset of tumors with distinct clinical, pathologic, and biologic features.
广泛的微卫星不稳定性（MSI）发生在近15%的散发性结直肠癌中。高频MSI（MSI-H）（微卫星位点不稳定率≥30%）的大肠癌被认为具有独特的病理特征，且与微卫星稳定（MSS）肿瘤及低频MSI（MSI-L）（微卫星位点不稳定率<30%）的癌相比，侵袭性较低。本研究的目的是准确界定MSI-H散发性结直肠癌的临床病理及生物学特征。
使用聚合酶链反应（PCR）和6个微卫星标记物对216例大肠腺癌的MSI状态进行评估。至少两个微卫星标记物显示不稳定的肿瘤被分类为MSI-H，而其他肿瘤被分类为MSI-L（一个位点不稳定）或MSS（无不稳定）。通过免疫组织化学检测p53、hMLH1和hMSH2基因产物的表达，通过流式细胞术检测DNA倍体模式。通过单因素和多因素生存分析评估MSI状态的预后意义。
MSI-H癌显著不同的病理特征为近端位置；体积大；黏液性和髓样组织学类型；低分化；膨胀性生长模式；更频繁的克罗恩样显著淋巴反应；以及壁外静脉侵犯发生率低。大多数MSI-H肿瘤为DNA二倍体（40例肿瘤中的33例；82.5%）且p53阴性（44例肿瘤中的34例；77.3%）。相反，在MSI-L/MSS肿瘤中分别观察到82.3%（158例肿瘤中的130例；P<0.0001）的DNA非整倍体和54.1%（172例肿瘤中的93例；P = 0.0002）的p53过表达。MSI-H肿瘤患者的临床结局优于MSI-L/MSS肿瘤患者（P = 0.0017）。此外，在包括传统临床病理参数、MSI状态和p53表达作为协变量的多因素分析中，MSI状态是疾病特异性生存的显著独立预后指标。
评估MSI状态是大肠癌基因特征分析的重要步骤，并可识别出具有独特临床、病理和生物学特征的肿瘤亚组。
