Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients Implications for Universal Versus Selective Screening Strategies for Lynch Syndrome
Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients Implications for Universal Versus Selective Screening Strategies for Lynch Syndrome
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DOI：
10.1097/pas.0000000000000177
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发表时间：
2014-06-01
影响因子：
5.6
通讯作者：
Chen, Lee-may
中科院分区：
文献类型：
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作者：
Rabban, Joseph T.;Calkins, Sarah M.;Chen, Lee-may
虽然有共识的成本效益的一个普遍的方法，筛查所有结直肠癌患者林奇综合征（LS）使用错配修复（MMR）蛋白免疫组化（IHC）和/或微卫星不稳定性（MSI）检测，子宫内膜癌患者的普遍与选择性筛查的问题仍有待解决。我们前瞻性地对新诊断的子宫内膜癌患者实施了选择性筛查算法，由患者年龄50岁或以下，符合Bethesda指南标准的个人/家族癌症谱系和/或存在MMR相关肿瘤形态触发。如果符合任何标准，则进行四蛋白质MMR IHC和MSI检测。该算法排除了没有癌症谱系和肿瘤缺乏MMR形态的老年患者的筛查。本研究的目的是回顾性地确定这些排除标准是否遗漏了任何具有异常MMR的肿瘤。在273例新诊断的子宫内膜癌患者中，181例（66%）缺乏筛查标准。回顾性MMR IHC证实181例未筛查患者中177例（97.8%）MMR完整，1例患者（0.5%）MSH 6缺失，3例患者（1.7%）由于MLH 1启动子高甲基化导致MSH 1/PMS 2缺失。相比之下，41%符合1项或多项筛查标准的患者存在异常MMR IHC/MSI，主要包括MLH 1/PMS 2缺失。MMR形态学有助于92%的异常MMR病例的检测，而癌症谱系有助于其余病例的检测。所有由MSH 2和PMS 2引起的异常均被筛查算法检测到，但4例MSH 6病例中有1例未被检测到。后一个发现与文献一致，即MSH 6子宫内膜癌表现出不同于其他MMR基因的表型。我们的结论是，一个基因型特异性的方法来筛选子宫内膜癌LS可能包括通用测试MSH 6 IHC和选择性测试MLH 1，PMS 2和MSH 2 IHC的基础上的年龄，癌症谱系，和MMR形态。这种混合选择性策略的成本效益值得进一步研究，特别是与通用策略相比。进一步的工作，以确定表型特征的子宫内膜癌与甲基化MLH 1，使他们能够被排除在LS筛选也将有助于成本效益。
Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.