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

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.