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Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry.

运用错配修复蛋白免疫组化筛查检出的Lynch综合征相关和“Lynch样”子宫内膜癌的临床病理学比较

Mills AM,Sloan EA,Thomas M,Modesitt SC,Stoler MH,Atkins KA,Moskaluk CA

Abstract

Expanded testing for Lynch syndrome (LS) is increasingly recommended for patients with endometrial carcinomas, and immunohistochemistry (IHC) for tumor loss of mismatch-repair (MMR) protein expression is the most common primary screen. This has led to the recognition of MMR-IHC-deficient cases without identifiable mutations on directed germline sequencing. The clinical implications of such "Lynch-like" (LL) cancers are unclear. We here report the clinicopathologic features of putative familial endometrial carcinoma identified on universal MMR-IHC screening with attention to cases with discordant IHC and germline results. The files of the University of Virginia Pathology Department were retrospectively searched for all MMR-deficient endometrial carcinomas identified on screening. Cases were categorized as likely sporadic (MLH1/PMS2 loss, evidence of MLH1 promoter hypermethylation) or putative LS (PLS) (loss of MSH2/MSH6, MSH6, or PMS2). PLS cases were further subdivided into LS and LL groups on the basis of the presence or absence of a confirmatory mutation by germline testing, and the clinicopathologic features of these cases were compared. A deficiency of ≥1 MMR protein was observed in 31.4% (66/210) of endometrial carcinomas, including 26 PLS cases, 15 of which had germline testing. Directed germline sequencing confirmed LS in 46.7% (7/15); the remaining cases were classified as LL. High-grade and/or biphasic morphology was seen in 42.9% (3/7) of LS and 62.5% (5/8) of LL cases; the remaining cases showed low-grade, conventional endometrioid morphology. High level microsatellite instability was observed in 71.4% (5/7) of LL cases. The majority of cases from both groups (LS: 85.7% [6/7]; LL: 87.5% [7/8]) were low-stage (T1a/T1b). Endometrial carcinoma was the presenting malignancy in 85.7% (6/7) of LS patients and 87.5% (7/8) of LL patients. Family history was suggestive of LS in 28.5% (2/7) of LS patients and 12.5% (1/8) of LL patients. Screening algorithms based on age and cancer history would have failed to identify LS patients in 57.1% (4/7) of cases. Although universal MMR-IHC identifies endometrial carcinoma patients with LS who would have been missed using targeted screening algorithms, it also identifies cancers with discordant IHC and germline results for which the somatic versus germline origin of the MMR defect is unclear. Further study of this LL group is required before drawing definitive conclusions about their familial cancer risk.

摘要

扩大检测Lynch综合征(LS)被越来越多推荐用于子宫内膜癌患者,免疫组化(IHC)检测肿瘤错配修复(MMR)蛋白表达丢失是最常用的主要筛查方法。这使人们认识到一些MMR-IHC病例经直接体细胞测序未发现相应突变。这种“Lynch样”(LL)癌的临床意义不明。

我们报告广泛MMR-IHC筛查发现的推测为家族性子宫内膜癌的临床病理学特征,关注IHC和胚系结果不一致的病例。从弗吉尼亚大学病理系的文件中回顾性寻找所有筛查发现的MMR缺陷子宫内膜癌病例。这些病例被分为散发性(MLH1/PMS2丢失,证实为MLH1启动子超甲基化)或推测为LS(PLS)(MSH2/MSH6,MSH6,或PMS2丢失)。依据是否出现胚系检测证实的突变,PLS病例进一步分为LS和LL,并比较这些病例的临床病理学特征。

31.4%(66/210)的子宫内膜癌出现≥1MMR蛋白缺陷,包括26例PLS病例,其中15例进行胚系检测。直接胚系测序证实的LS占46.7%(7/15);其余病例归为LL。LS和LL病例中,高级别和/或双相形态学分别占42.9%(3/7)和62.5%(5/8);其余病例呈低级别,传统子宫内膜样形态。71.4%(5/7)LL病例观察到高水平微卫星不稳定性。两组(LS:85.7%[6/7];LL:87.5%[7/8])中大多数病例为早期(T1a/T1b)。85.7%(6/7)的LS患者和87.5%(7/8)的LL患者子宫内膜癌为先证恶性肿瘤。LS患者中,家族史提示为LS的占28.5%,LL患者中为12.5%(1/8)。基于年龄和患癌史的筛查策略无法识别57.1%(4/7)的LS患者。

虽然广泛MMR-IHC筛查可识别出依据定向筛查策略遗漏的LS子宫内膜癌患者,但也检出一些IHC和胚系结果不一致的癌,这些癌中MMR缺陷是体细胞性还是胚系性起源仍不清楚。在得出这些家族的患癌危险性明确结论以前,需进一步研究这类LL病例。

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