Microsatellite instability and loss of mismatch repair proteins in nonmelanoma skin cancer and treatment-resistant phenotypically distinct precancerous lesions in Muir-Torre/Lynch syndrome: a multicentre retrospective study

Abstract DNA mismatch repair (MMR) gene mutations resulting in microsatellite instability (MSI) are associated in the pathogenesis of Muir–Torre syndrome (MTS), a variant of Lynch syndrome (LS). It is characteristically defined by the association of at least one sebaceous skin neoplasm and/or keratoacanthoma and a visceral malignancy. The presence of cutaneous lesions plays a vital role in the early detection and preventive cancer screening of the disease; however, nonmelanoma skin cancers (NMSCs) and their precursors are seldom reported. We conducted a retrospective multicentre study between 2011 and 2022 of adults with a confirmed genetic diagnosis of MTS/LS across two specialist institutions presenting with phenotypically distinct treatment-resistant precancerous skin lesions and/or NMSC with the associated loss of MMR expressions consistent with their germline mutations which are currently not recognized diagnostic features. Median age at the onset of precancerous/NMSC in eight individuals was 57.5 years, with an equal sex distribution. Lesions occurred mostly on the face (n = 14), followed by the forearms (n = 8), dorsum of the hands (n = 9), the legs (n = 4) and the chest (n = 1). Our study histologically and immunohistochemically examined MMR expressions and MSI in 20 precancerous and/or NMSCs. Loss of expression and MSI were found in actinic keratoses (AK) (n = 6/7), disseminated superficial actinic porokeratosis (DSAP; n = 1/2), squamous cell carcinoma (n = 4/5) and basal cell carcinoma (n = 4/4). Additionally, we found sebaceomas with atypia (n = 2/2). In 17 lesions, the loss of MMR expression and MSI were consistent with their germline mutations. We also discovered that all lesions identified with MSI had normal adjacent skin with no loss of MMR expression. Our observations suggest the detection of MSI, and MMR gene abnormality, play a critical role in the development of precancerous and NMSC other than sebaceous neoplasms in this disease. To date, the diagnostic criteria for MTS/LS do not include NMSC and their precursors, and these have rarely been reported. We note a clinically distinct presentation of widespread erythematous scaly lesions resembling AK/DSAP, resistant to multiple treatments, which is an additional recognizable clinical feature in this patient subgroup. This is an important association in cancer-prone individuals and immunohistochemistry testing for MMR genes should be encouraged. This can be a powerful investigative tool as AK/DSAP are easily identifiable, numerous and readily accessible for DNA analysis; therefore, detecting the presence of MSI in the skin may aid in screening individuals promptly. MTS/LS is best managed by a multidisciplinary team with close surveillance for visceral malignancies, highlighting the importance of routine monitoring for precancerous and nonsebaceous skin cancers.