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The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy.

Lynch综合征相关卵巢癌的组织形态学:特异性亚型筛查策略

Chui MH,Ryan P,Radigan J,Ferguson SE,Pollett A,Aronson M,Semotiuk K,Holter S,Sy K,Kwon JS,Soma A,Singh N,Gallinger S,Shaw P,Arseneau J,Foulkes WD,Gilks CB,Clarke BA

Abstract

Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.

摘要

Lynch综合征女性发生上皮性卵巢癌(OC)的危险性增加。类似于先前BRCA1/2突变携带者的研究,有证据表明LS相关OCs(LS-OC)具有特异性组织亚型相关性。高级别浆液性癌的诊断是BRCA1/2种系检测的指征,但目前还没有基于组织学亚型的筛查指南用于OC患者分类以进行LS检测。我们对20例已经证实的种系突变LS-OCs病例集中进行肿瘤亚型病理学复习,以形态学评估HE染色切片为基础,必要时行免疫组化染色证实。记录错配修复免疫组化(MMR-IHC)和微卫星不稳定性(MSI)表型状态,详细分析患者谱系以明确先前提出的临床标准是否能选择出这些患者做遗传学检测。病理学复习显示所有LS-OCs或为纯子宫内膜样癌(14例),含子宫内膜样成份的混合性癌(4例),或为透明细胞癌(2例)。无高级别或低级别浆液性癌或肠型黏液性癌。仅2例出现显著肿瘤浸润性淋巴细胞(≥40/10HPF)。除1例外,所有行MMR-IHC或MSI检测的肿瘤均出现MMR缺陷表型。这组病例中,依据Amsterdam II修订的Bethesda 指南,SGO 10%-25%和SGO 5%-10%标准,分别有 50%、55%、65%和85%的患者选出做遗传学检测,任何方案检测的病例均少于系列病例的60%。为了进一步支持亚型导向的筛查策略,MMR-IHC反馈性检测了某大学医院2年间诊断为非浆液性OCs的所有连续病例;10/48 (21%)的病例发现 MMR缺陷,均为子宫内膜样或透明细胞组织学。我们推测子宫内膜样或透明细胞卵巢癌与MMR基因突变遗传倾向密切相关。这些发现提示肿瘤亚型在筛查OC患者进一步遗传学检测中的作用并支持反馈性MMR-IHC和/或MSI检测新诊断的子宫内膜样或透明细胞卵巢癌病例。

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