An Intrapatient Concordance Study of Mismatch Repair Protein Immunohistochemical Staining Patterns in Patients With Muir-Torre Syndrome

Abstract

ebaceous neoplasms (SNs), including sebaceous adenoma, sebaceous epithelioma, and sebaceous carcinoma, are defining features of Muir-Torre syndrome (MTS), a variant of Lynch syndrome (LS). 1 Universal screening of SNs with mismatch repair protein (MMRP) immunohistochemistry (IHC) has previously been recommended by some physicians to detect potential probands 2 but has been debated given the high costs and variable sensitivities of detecting MTS, ranging from 25% to 85% depending on the IHC panel used. [3][4][5] Sensitivity may increase with targeted screening, such as when a patient (of any age) presents with multiple SNs. 6 Because MTS is caused by germline genetic mutations, it is presumed that individual SNs should harbor the same mutation.However, data evaluating intrapatient concordance of MMRP IHC staining patterns between different SNs are limited. This case series examined patients with MTS who had multiple SNs to determine the concordance of MMRP IHC staining patterns between lesions and with germline mutation. MethodsThis retrospective study was approved by the institutional review board of the University of Pennsylvania (protocol No. 828426). Need for informed consent was waived because the research was deemed to be of minimal risk to participants. IMPORTANCE Appropriate use criteria for Muir-Torre syndrome (MTS) screening suggest that mismatch repair protein (MMRP) immunohistochemical (IHC) testing is usually appropriate in patients with 2 or more sebaceous neoplasms (SNs). While MTS is known to be caused by a germline mutation in mismatch repair genes, data are limited as to whether individual sebaceous tumors in these patients with multiple lesions show identical MMRP IHC staining patterns.OBJECTIVE To determine concordance of MMRP IHC staining patterns in lesions of patients with MTS who have multiple SNs. DESIGN, SETTING, AND PARTICIPANTSThis retrospective single-center case series evaluated 38 SNs in 11 patients with MTS confirmed by genetic testing for MMRP IHC staining patterns. Tumor sites were classified as either facial or extrafacial. Data were collected between

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

“…They performed immunohistochemistry analysis of the 38 sebaceous neoplasms from the 11 patients; two sebaceous adenomas, accounting for 5% of the 38 sebaceous neoplasms, in a single Muir-Torre syndrome patient did not show loss of mismatch repair gene expression. Hence, again similar to the man with sebaceous adenoma in this report, the negative immunohistochemistry analysis from one of 11 (9%) patients did not correlate with his germline mutation-established Muir-Torre syndrome [19].…”

“…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.…”

“…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].…”

Detection of MSH2 Gene Methylation in Extramammary Paget’s Disease by Methylation-Sensitive High-Resolution Melting Analysis

“…For patients with Muir-Torre syndrome (MTS), MSH2 was the most frequently mutated MMR gene, and about 90% of the MMR gene mutations in MTS were found in MSH2 [31,32]. Immunohistochemistry test of MMR and detection of MMR deficiency might be used as a potential tool to assist the diagnosis of MTS [33].…”

Immunotherapy for Non-melanoma Skin Cancer

“…proce ss& ApplNo= 125514. The rationale for assessing MSI status in sebaceous carcinoma is supported by data reporting germline variants in the MMR genes MSH2, MSH6, and MLH1 in 8-29% of patients [43][44][45]. Individuals with sebaceous carcinomas, non-polyposis colorectal cancer, and germline loss of MMRs are characterized as having Muir-Torre syndrome (OMIM 158,320) and their tumors demonstrate microsatellite instability [46].…”