title: The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy.
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.
authors.affiliation: Departments of *Laboratory Medicine and Pathobiology ‡Obstetrics and Gynecology, Faculty of Medicine, University of Toronto §Division of Gynecologic Oncology §§Department of Pathology, University Health Network ∥Department of Laboratory Medicine and Pathology ¶Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry ‡‡Division of General Surgery, Mount Sinai Hospital, Toronto, ON ∥∥Department of Medical Genetics, McGill University Health Centre, Montreal, QB #Division of Gynecologic Oncology ¶¶Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada †Department of Pathology, Bon Secours Hospital, Cork, Ireland **Department of Histopathology, King Edward Memorial Hospital for Women, Perth, Australia ††Department of Cellular Pathology, Barts Health NHS Trust, London, United Kingdom.
authors.forename: Michael Herman
authors.initials: MH
authors.lastname: Chui
authors.forename: Paul
authors.initials: P
authors.lastname: Ryan
authors.forename: Jordan
authors.initials: J
authors.lastname: Radigan
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ferguson
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: Kara
authors.initials: K
authors.lastname: Semotiuk
authors.forename: Spring
authors.initials: S
authors.lastname: Holter
authors.forename: Keiyan
authors.initials: K
authors.lastname: Sy
authors.forename: Janice S
authors.initials: JS
authors.lastname: Kwon
authors.forename: Anita
authors.initials: A
authors.lastname: Soma
authors.forename: Naveena
authors.initials: N
authors.lastname: Singh
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Patricia
authors.initials: P
authors.lastname: Shaw
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Arseneau
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001706:Biopsy; D002170:Canada; D018269:Carcinoma, Endometrioid / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D053842:Microsatellite Instability; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D012042:Registries
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human