Screening for Germline Mismatch Repair Mutations Following Diagnosis of Sebaceous Neoplasm

Abstract

Importance Sebaceous neoplasms (SN) define the Muir-Torre syndrome (MTS) variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality. Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SN can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis is limited. Objective To characterize the utility of IHC screening of SN in identification of germline MMR mutations confirming LS Design Retrospective study Setting Two academic cancer centers Participants 86 adult patients referred for clinical genetics evaluation after diagnosis of SN Main Outcomes and Measures Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and MTS, and family history characteristics were compared between mutation carriers and non-carriers. Results 25 (29.1%) of 86 patients with SN had germline MMR mutations confirming LS. Among 77 patients with IHC testing on SN, 38 (49.4%) had loss of staining of one or more MMR proteins, and 14 had germline MMR mutations. IHC correctly identified 13/16 MMR mutation carriers, corresponding to 81.3% sensitivity. Ten of 12 (83.3%) patients with > 1 SN had MMR mutations. 52% of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 44% did not meet the clinical definition of MTS. Conclusions and Relevance IHC screening of SN is effective in identifying patients with germline MMR mutations and can be used as a first line test when LS is suspected. Abnormal IHC, including absence of MSH2, is not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has significant limitations, suggesting that universal IHC screening of SN merits further study. Clinical genetics evaluation is warranted for patients with any of the following: abnormal IHC, normal IHC with personal or family history of other LS-associated neoplasms, or multiple SN.

Sebaceous neoplasms and the immunoprofile of mismatch-repair proteins as a screening target for syndromic cases

“…A similar view has previously been advanced by others [10,14,17] and was most recently formulated by Everett et al [5], who proposed a practical algorithm for patients with sebaceous neoplasms, including IHC as a first-line screening. Additionally, Everett et al commented on the limited utility of family history alone.…”

“…Though mismatch-repair (MMR)-protein proficiency does not exclude MTS [4,5], the immunohistochemistry (IHC) analysis of MMR-proteins remains an approach to be considered in the workup of sebocytic lesions. The prevalence of MMR-protein deficiency among neoplasms with sebocytic differentiation as a group has been addressed in several unselected series [4][5][6][7][8][9][10], the reported values ranging from roughly 25% to 80%.…”

“…The prevalence of MMR-protein deficiency among neoplasms with sebocytic differentiation as a group has been addressed in several unselected series [4][5][6][7][8][9][10], the reported values ranging from roughly 25% to 80%. Additionally, in a series of 25 patients with sebaceous neoplasms, examined for microsatellite instability (MSI), 60% were found to be MSI-high (MSI-H) [11].…”

“…Additionally, in a series of 25 patients with sebaceous neoplasms, examined for microsatellite instability (MSI), 60% were found to be MSI-high (MSI-H) [11]. Some MMR-protein IHC studies of sebaceous neoplasms were based on MLH1-and MSH2 status only [6,[12][13][14][15], others added MSH6 to the staining panel [4,[7][8][9][10]16], and some of these communications additionally report the PMS2-protein status [4,5,[7][8][9][10]17].…”

“…The interpretation of the MMR-protein immunostainings of the sebaceous neoplasms has by some investigators been reported as straight forward [9], whereas others experienced equivocal and/or weak expression, especially with MSH6 [4,5,8,15]. For this reason, the implementation of a 2-panel approach, confined to MSH6 and PMS2, previously addressed [8] as a cost-effective alternative in screening for MMR-protein deficiency among sebaceous neoplasms, might prove problematic.…”