Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series
Authors: Philip R Cohen, Razelle Kurzrock
Journal: Cureus (2023)
Keywords: adenoma, carcinoma, epithelioma, germline, microsatellite instability, mismatch repair, muir-torre syndrome, neoplasm, sebaceous, somatic
MeSH terms: Case Reports

Muir-Torre syndrome, a subtype of Lynch syndrome, is characterized by a germline mutation of one or more mismatch repair genes such as MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2, mismatch repair system component (PMS2) resulting in microsatellite instability and at least one malignancy and a minimum of one syndrome-associated sebaceous neoplasm such as a sebaceous adenoma, epithelioma, or carcinoma. The syndrome has an autosomal dominant mode of inheritance detectable with germline sequencing of normal body elements such as blood, saliva, or normal skin for a mismatch repair gene mutation. Sebaceous neoplasms can occur before, concurrent with, or following Muir-Torre syndrome-related cancer. Immunohistochemistry, microsatellite instability testing, and next-generation sequencing of tumor tissue can evaluate malignancies such as colorectal and endometrial cancer and sebaceous neoplasms for somatic mismatch repair gene defects. However, these tests cannot differentiate somatic (acquired) versus germline alterations, and immunohistochemistry and microsatellite stability assessment can produce false negatives. Finally, the Mayo Muir-Torre syndrome risk score algorithm cannot always reliably determine which patient with a new sebaceous neoplasm should have germline testing. We report three men who presented with a Muir-Torre syndrome-associated sebaceous neoplasm: a 67-year-old male with no personal or family history of cancer who presented with a chest sebaceous carcinoma with MSH2 and MSH6 gene expression loss on immunohistochemistry and a Mayo Muir-Torre syndrome risk score of 0 who declined germline testing; a 74-year-old male with Janus kinase 2 (JAK2)-related myelodysplastic syndrome, yet no history of a Lynch syndrome-associated cancer, who developed a sebaceous epithelioma on his leg with PMS2 gene expression loss by immunohistochemistry and, although Mayo Muir-Torre syndrome risk score was only 1 (suggests no likelihood of a Lynch syndrome germline mismatch repair gene mutation), germline testing demonstrated a PMS2 alteration; and a 59-year-old male with a germline-confirmed MLH1-associated Lynch syndrome and a prior colon carcinoma, who developed a sebaceous adenoma on his nostril that unexpectedly demonstrated preservation of normal MLH1 staining (reflecting a false negative) by immunohistochemistry. In summary, these cases are consistent with the literature suggesting that tumor immunohistochemistry and microsatellite stability testing can miss germline alterations. Hence, we recommend that the initial evaluation of a patient with even a single new Muir-Torre syndrome-associated sebaceous neoplasm should include germline mismatch repair gene mutation testing. Finding a mismatch repair gene germline mutation should prompt genetic counseling, initial and future cancer screening recommendations, and germline testing of family members.