Screening for Muir‐Torre Syndrome Using Mismatch Repair Protein Immunohistochemistry of Sebaceous Neoplasms

Abstract

Screening for the Muir-Torre variant of Lynch Syndrome (LS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. To date, research into the clinical utility of MMR IHC for this indication is limited. We conducted a retrospective chart review of 90 patients with MMR IHC completed on at least one SN from January 2005 to May 2010. SNs included were adenomas, epitheliomas, carcinomas and basal and squamous cell carcinomas with sebaceous differentiation. Of the 90 patients, 13 (14 %) had genetically confirmed or fulfilled clinical criteria for a diagnosis of MTS and 51 patients (57 %) presented with an abnormal MMR IHC result (loss of one or more MMR proteins) on at least one SN. Abnormal IHC had a sensitivity of 85 %, specificity of 48 %, positive predictive value (PPV) of 22 % and negative predictive value (NPV) of 95 % when evaluating for MTS. When personal or family history of colorectal cancer (≥2 family members with a history of colorectal cancer) was taken into consideration, ignoring IHC results, sensitivity was 92 %, specificity was 99 %, PPV was 92 % and NPV was 99 %. MMR IHC on SNs when used to screen for MTS has poor diagnostic utility. We recommend that MMR IHC not be performed routinely on SNs when the patient does not have either personal or family history of colorectal cancer.

A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir–Torre variant of Lynch syndrome

“…Previously, we reported on a group of 90 patients who had at least one pathologically confirmed SN. 1 MMR IHC had much lower sensitivity and specificity for LS compared with MMR IHC done on colon tumors (85% vs. 92-94% and 48% vs. 88-100%, respectively). [2][3][4] The specificity of MMR IHC on colon tumors varies depending on whether the loss of MLH1 and PMS2 due to epigenetic silencing (sporadic hypermethylation) of the hMLH1 promoter is taken into consideration.…”

Muir-Torre Syndrome

“…29 Thus, germline microsatellite instability testing is required to confirm the diagnosis of MTS. Given the vagaries of MMR protein IHC results, Roberts et al 29 When a sebaceous tumor shows abnormal MMR IHC, the patient should be referred to a genetic counselor for microsatellite instability testing. If a sebaceous tumor shows intact MMR proteins by IHC, genetic counseling may still be indicated for patients with a personal or family history of colorectal cancer.…”

Genetic Counseling for Cancer: Technology Promises Better Screening for Hereditary Cancer Patients

“…Additionally, the falsepositive rates associated with the other two proteins, MSH2 and MSH6, will likely increase as well. This is supported by reports in the dermatopathology literature which have recently suggested a sporadic etiology for the absence of MSH2 and MSH6 in sebaceous neoplasms [43]. The larger the number of older-onset and isolated cases of colon and endometrial tumors evaluated by programs like universal Lynch syndrome screening, the higher the likelihood of identifying other sporadic tumor etiologies.…”