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.
To characterize the utility of IHC screening of SN in identification of germline MMR mutations confirming LS
Two academic cancer centers
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.
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.