Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review

Abstract

A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.

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

“…Discordant results for immunohistochemistry analysis (preserved expression of MLH1) and germline testing (MLH1 alteration) results were observed for our 59-year-old man in this report with an established germline mutation-confirmed MLH1-associated Lynch syndrome whose sebaceous adenoma has preservation of MLH1 staining (Table 1 ). In addition, researchers have assessed the predictive value of immunohistochemistry screening results of skin sebaceous neoplasm with regard to identifying Lynch syndrome patients; they have compared immunohistochemistry analysis with Lynch syndrome-confirmed diagnosis by germline mutation evaluation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. However, each of these studies has documented several patients with preserved expression of mismatch repair genes and germline documentation of mismatch repair gene mutation; if only immunohistochemistry analysis had been performed, the diagnosis of a mutation in the mismatch repair genes would not have been detected, and these individuals and their families would not have been evaluated for cancer and the possible diagnosis of Muir-Torre syndrome or Lynch syndrome.…”

“…Immunohistochemistry analysis had been done in 253 skin lesions from patients with germline mutation-confirmed Lynch syndrome. Fourteen (5.5%) skin lesions from Lynch syndrome patients were mismatch repair gene proficient; there was no loss of mismatch repair gene expression on immunohistochemistry staining for five sebaceous adenomas (2% of skin lesions) and nine (3.5%) other lesions that included two keratoacanthomas, two squamous cell carcinomas, one melanoma, and four other tumors [ 18 ].…”

“…There is a consensus that immunohistochemistry is a good screening test. However, all the investigators have observed negative immunohistochemistry results in patients who had a mismatch repair gene germline mutation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. Most of the researchers suggested genetics referral and additional evaluation when the immunohistochemistry analysis demonstrates loss of gene expression based on staining absence [ 12 , 13 , 18 ].…”

“…However, all the investigators have observed negative immunohistochemistry results in patients who had a mismatch repair gene germline mutation (Table 2 ) [ 10 , 12 , 13 , 18 , 19 ]. Most of the researchers suggested genetics referral and additional evaluation when the immunohistochemistry analysis demonstrates loss of gene expression based on staining absence [ 12 , 13 , 18 ]. Indeed, one of the group of investigators commented that the standard for diagnosing Muir-Torre syndrome is germline genetic testing [ 10 ].…”

“…They utilize immunohistochemistry staining, microsatellite instability testing, and next-generation sequencing of the paraffin-embedded tumor. In addition, blood, saliva, or normal skin can be used for germline evaluation [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”