Endometrial Carcinoma in Lynch Syndrome: Genotype-Phenotype Correlation
P Ryan, AM Mulligan, M Aronson, A Jennings, S Ferguson, S Gallinger, P Shaw, A Pollett, BA Clarke. Mount Sinai Hospital, Toronto, Canada; St Michael's Hospital, Toronto, Canada; University of Toronto, Toronto, Canada; University Health Network, Toronto, Canada
Background: The endometrium is the commonest site of extraintestinal malignancy in Lynch syndrome. To date there have been limited data on genotype-phenotype correlation in these tumors, a question examined in this study.
Design: Endometrial cancer cases meeting Amsterdam II criteria for mismatch repair (MMR) screening were identified from the records of the Familial GI Cancer Registry in Mount Sinai Hospital and pathology departments of participating institutions. Microsatellite instability (MSI), MMR gene product immunohistochemistry (IHC), and gene sequencing results were correlated retrospectively with cell type and specific gross and microscopic features that have been found useful in screening for Lynch syndrome-associated tumors including: tumor location, type and grade; areas of dedifferentiation; tumor-infiltrating lymphocytes (TILs); and peritumoral lymphoid aggregates.
Results: Of 31 cases identified (mean age 49 years, 12 patients > 50 years old, 23 type 1 and 8 type II histology) 15 had germline mismatch repair gene mutations confirmed by sequence analysis (mean 48.8, 5 > 50 years) - 8 MSH2, 4 MLH1, 3 MSH6 - with the other 16 cases being either MSI high, IHC deficient, or both. Detected pathologic features suspicious for Lynch syndrome were: lower uterine segment tumors - 2/31 (1/15 mutation positive); mixed histologic type - 5/31 (2/15); peritumoral lymphocytes - 17/31 (6/15); TILs - 8/31 (2/15). Suspicious pathologic features were seen in 7 of 15 mutation positive cases, and in 3 of 5 patients older than 50. LUS location and tumor heterogeneity were seen only in association with MSH2 mutations, whereas peritumoral lymphoid aggregates were seen in all mutation groups. Six of 8 MSH2 mutations and all 3 MSH6 mutations are predicted to cause protein truncation, with 2 (non-related) MSH6 cases having the same exon 5 mutation (c.1104delT).
Conclusions: This study confirms the preponderance of MSH2 mutations in Lynch syndrome-associated endometrial carcinoma. Pathologic features may identify a large proportion of cases, including those over 50 years old, and should be incorporated along with age and family cancer history into future guidelines for the identification of sentinel tumors.
Category: Gynecologic & Obstetrics
Monday, March 22, 2010 1:30 PM
Platform Session: Section C, Monday Afternoon