Expanding the Spectrum of Skin Neoplasms in Muir–Torre Syndrome: Beyond Sebaceous Tumours

To the Editor: Muir–Torre syndrome (MTS) is a hereditary disorder characterized by internal malignancies and sebaceous tumours.1 Diagnosis of MTS is based on clinical features, family history, and genetic testing.2 Two cases of MTS-associated actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC) have been reported to date.3,4 We present 2 patients with genetically confirmed MTS who presented with AK and SCC, which had loss of the same DNA mismatch repair genes seen in the patients' internal malignancies and sebaceous tumours. The first patient, a 71-year-old man, consulted for a 6-month erythematous, hyperkeratotic plaque on the right hand (Fig. 1A). He had a pathogenic mutation of MLH1 NM_000249.3(MLH1):c.676C>T (p.Arg226Ter) and had previously been diagnosed with MTS-related 2 colorectal adenocarcinomas, a jejunal adenocarcinoma, and a sebaceous adenoma. Histological examination showed keratinocytic dysplasia of the lower layers of the epidermis, parakeratosis, and solar elastosis and was diagnosed as an AK (Fig. 1B).FIGURE 1.: Patient 1. A, Actinic keratosis in the hand. B, Keratinocytic dysplasia of the lower layers of the epidermis, parakeratosis, and solar elastosis; hematoxylin–eosin, ×100. C, Loss of expression of MLH1. Preservation of the expression in the adnexal duct cells, immunostaining, ×100. D, Loss of expression of PMS2, immunostaining, ×100.The second patient, an 80-year-old woman with a history of MTS-related 2 colorectal adenocarcinomas, an endometrial adenocarcinoma, a sebaceous carcinoma, and 2 keratoacanthomas, presented with a hyperkeratotic plaque on the right forearm (Fig. 2A). The biopsy showed keratinocytic dysplasia, altered maturation and horn pearls with extension into dermis, and was diagnosed as an invasive SCC. No sebaceous differentiation was found. One margin of the lesion showed AK (Fig. 2B).FIGURE 2.: Patient 2. A, Squamous cell carcinoma and actinic keratoses on the arm. B, Keratinocytic dysplasia, parakeratosis, and solar elastosis; hematoxylin–eosin, ×100. C, Loss of expression of MSH6 in atypical keratinocytes; immunostaining, ×100. D, Loss of expression of PMS2. Preservation of expression in adnexal structures; immunostaining, ×100.Immunohistochemistry showed loss of expression of MLH1 and PMS2 repair proteins in the first patient (Figs. 1C–D) and loss of MSH6 and PMS2 (Figs. 2C–D) in the second patient, with normal expression in adnexal structures and normal surrounding skin. p53 expression was normal in both cases. Although Hatta et al3 and Nishizawa et al4 reported 2 Japanese patients with MTS who presented with AK and immunohistochemical studies revealed loss of MSH2 protein expression in the lesions, our cases represent the first reported instances of these lesions in European patients. Reduced DNA mismatch repair (MMR) protein expression in keratinocytes have been related to the development of SCC and precancerous skin lesions in MTS-unrelated skin cancers.5 However, our cases suggest that patients with MTS may be at increased risk of developing AK and SCC. These lesions are not typically associated with MTS and may be overlooked during dermatologic evaluations. Therefore, it may be worthwhile to consider testing skin lesions for MMR gene mutations in patients with a history of cancer or other risk factors for cancer, even if they do not meet the criteria for a specific hereditary cancer syndrome. Future research could establish criteria for identifying patients suitable for MMR protein analysis in AK and SCC based on clinical and familial risk factors. In conclusion, our case reports highlight the importance of regular dermatologic surveillance in patients with MTS and underscores the need for further research to explore the relationship between MMR deficiency and a wide range of tumours. The identification of MMR gene mutations in skin lesions could have important implications for the diagnosis of patients with visceral tumours. Therefore, it is crucial to continue studying MTS and other hereditary cancer syndromes and to develop guidelines for genetic testing and counselling to aid in the diagnosis and management of affected individuals. These findings may ultimately lead to earlier diagnosis, more effective treatments, and improved outcomes for patients with MTS and other hereditary cancer syndromes.