Expanding the Spectrum of DNA Mismatch Repair Protein Deficiency in Cutaneous Sebaceous Neoplasia
Chad J Jessup, Mark Redston, Erin Brodell, Julie DR Reimann. Miraca Life Sciences Research Institute, Newton, MA; Tufts University Medical Center, Boston, MA
Background: Muir Torre Syndrome (MTS), a variant of Lynch syndrome, is characterized by the presence of cutaneous sebaceous neoplasia plus one or more visceral malignancies, most commonly colon cancer. The significance of immunohistological detection of DNA mismatch repair (MMR) deficiency in colorectal carcinomas is well-established, and is recommended as a screening tool for Lynch syndrome identification in newly diagnosed colorectal carcinomas. In comparison, the literature on immunohistochemistry (IHC) application to detect MMR protein expression (MLH1, MSH2, MSH6, PMS2) in sebaceous neoplasia has been less well studied, and has been derived almost exclusively from tertiary care centers. In addition, although recent data has supported a two-antibody approach using MSH6 and PMS2 to capture MMR deficient colon cancers, data are limited for this approach in sebaceous neoplasia. Herein we describe the largest series to date characterizing the clinicopathologic features of MMR deficient sebaceous neoplasms (SN), as well as the relative frequencies of MLH1, MSH2, MSH6, and PMS2 deficiency, in a community practice setting.
Design: A total of 216 consecutive SN from 216 patients were analyzed (133 sebaceous adenomas, 68 sebaceomas, and 15 sebaceous carcinomas). Relevant clinical and histopathological information was obtained via database searches. MMR protein expression was assessed by IHC.
Results: Of the 216 SN, 143 were MMR deficient (66%); 90 MSH2/MSH6 deficient (63%), 27 MLH1/PMS2 deficient (19%), 22 MSH6 alone deficient (15%), and 4 PMS2 alone deficient (3%). As in the colon, MMR deficiency was significantly associated with anatomic location, with non-head and neck (NHN) tumors more likely to be MMR deficient (59/62 NHN vs 84/154 head and neck; P<0.00001). In contrast to prior reports, however, MMR status (deficient versus non-deficient) was not associated with age at presentation (median age, 68 vs. 66), presence of tumor infiltrating lymphocytes (TILs), or tumor type.
Conclusions: Non-head and neck tumors are more likely to be MMR deficient; however, this criteria alone has a low sensitivity for MMR deficient tumor detection (sensitivity of only 41%). No other clinicopathologic factors (including age, TILs, and tumor type) were associated with MMR deficiency. We therefore recommend immunohistochemical testing of all SN for MMR deficiency, regardless of clinicopathologic features. In addition, our findings also confirm the utility of a two antibody approach using MSH6 and PMS2 in screening for MMR deficiency in SN.
Monday, March 4, 2013 8:30 AM
Proffered Papers: Section F, Monday Morning