Mismatch Repair Proteins Expression and Microsatellite Instability in Skin Lesions With Sebaceous Differentiation: A Study in Different Clinical Subgroups With and Without Extracutaneous Cancer

Abstract

Muir-Torre syndrome (MTS) is defined as the association of a sebaceous tumor or keratoacanthoma and an extracutaneous neoplasm, mainly from the gastrointestinal or genitourinary tracts. MTS is related to hereditary non-polyposis colorectal cancer (HNPCC), a syndrome with germline mutations in the mismatch repair (MMR) gene(s), leading to microsatellite instability (MSI). In this study, using immunohistochemistry and a microsatellite instability assay, we analyzed the incidence of MMR gene abnormalities in 79 sebaceous lesions from 70 patients, 26 of whom also had an extracutaneous visceral neoplasm. We were unable to investigate the family histories of our patients regarding other tumors in order to assess which of our cases met the Amsterdam criteria. Defective MMR protein expression (MMR-) was found in 18/70 (25.7%) patients, with an identical distribution between those having an isolated skin tumor (11/44, 25.0%) and those with an extracutaneous cancer (7/26, 25.4%). In the sporadic group, MMR negative lesions were significantly more frequent in extrafacial areas (P = 0.03). High concordance was found between MMR expression in sebaceous lesions and the extracutaneous neoplasm in the same patient (20/23, 86.9%), as well as between MMR expression and microsatellite status (18/20, 90%). In conclusion, this study confirms the value of immunohistochemistry to identify MMR defective tumors. However, since only a minority of sebaceous neoplasms in patients who also have an extracutaneous cancer display MMR defects, these techniques are of limited value for the identification of "clinically defined" MTS.

A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas

“…Our results also demonstrate that abnormal mismatch repair protein expression is much more frequent in skin sebaceous tumors located on the trunk or extremities compared with head or neck and in men compared with women, similar to other reports in the literature. 14,19 Gynecologic tract carcinomas have been more frequently studied with immunohistochemical antibodies for all four mismatch repair proteins than skin sebaceous tumors ( Our study was limited to only 10 extracolonic cases outside of the gynecologic tract and skin, and very little data are available in the literature regarding mismatch repair protein immunohistochemistry in these sites. 42 Of the 10 cases in our series, only one small bowel adenocarcinoma demonstrated equivocal MSH6 immunoreactivity, with the remainder demonstrating intact mismatch repair protein expression.…”

“…14,18,[36][37][38] To our knowledge, only one study has analyzed the expression of all four mismatch repair proteins in skin sebaceous neoplasms (Table 5). 19 Orta et al 19 analyzed 27 patients with one or more sebaceous neoplasms and showed abnormal mismatch repair protein expression in 12 (44%) patients (Table 4).…”

“…13 Increasingly, patients with multiple sebaceous neoplasms or family history concerning MTS are being screened for mismatch repair protein abnormalities. [14][15][16][17][18] Recent literature has shown that in these patients, mismatch repair protein immunohistochemistry is a useful screening tool. 19 Historically, microsatellite instability (MSI) testing was considered superior to mismatch repair protein immunohistochemistry in identifying patients with Lynch syndrome.…”

MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir–Torre syndrome

“…3,4,19,20 Several reports attest to the reproducibility of these two methods. 13,21 Briefly, these include studies on patients with Muir-Torre syndrome showing that expression of both MLH-1 and MSH-2 by immunohistochemistry is highly predictive of microsatellite stability (93%) while loss of either is associated with microsatellite instability (100%). 3,4,20 A good correlation between the two methods has been observed in patients with hereditary nonpolyposis colorectal cancer and also in patients with sporadic carcinomas of the colon and the endometrium.…”

Clinical and Immunohistochemical Features of Sebaceous Carcinoma: Focusing on the p53 Tumor Suppressor

“…It is likely that many mutations that may result in benign lesions, result put those cells at risk of SC given certain key mutations. Mismatch repair genes that result in microsatellite instability have been established as one known mechanism, but only capture a subset of patients, and is more likely to be seen in patients with Muir-Torre syndrome (MTS) [41][42][43]. Indeed, patients with eyelid sebaceous carcinoma have been reported in immunocompromised patients with MTS [44].…”