Sebaceous Neoplasm With Defective DNA Mismatch Repair

A woman in her 70s presented with a cutaneous lesion composed of a mixture of basaloid cells and sebocytes arranged in lobules, most consistent with a sebaceous adenoma (Figure 1). Immunohistochemistry for mismatch repair genes showed loss of nuclear expression of MSH2 and MSH6 in the tumor cells. Representative images are depicted in Figure 2. Microsatellite instability testing showed instability in all of the 7 informative markers analyzed, indicative of defective DNA mismatch repair function within the tumor.Figure 2Immunohistochemistry results corresponding to the boxed area in Figure 1 are shown for mismatch repair proteins. A, MLH1. B, MSH2. C, PMS2. D, MSH6.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Based on these findings, which of the following diagnostic work-ups should be pursued for possible hereditary tumor predisposition syndrome?a.Tuberous sclerosis complex; genetic testing for germline alterations of TSC1/TSC2 genesb.Multiple hamartoma syndrome; genetic testing for germline alterations of the PTEN genec.Muir-Torre syndrome; genetic testing for germline alterations of MSH2 and MSH6 genesd.Birt-Hogg-Dubé syndrome; genetic testing for germline alterations of the FLCN gene Answer: c. Muir-Torre syndrome; genetic testing for germline alterations of MSH2 and MSH6 genes Muir-Torre syndrome (MTS), a phenotypic variant of hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), is characterized by neoplasms involving the colon, urogenital tract, and skin. The histopathologic features of the skin biopsy specimen from the patient presented herein were most consistent with a sebaceous adenoma. Lynch syndrome is caused by germline alterations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2), and pathogenic alteration of these genes results in microsatellite instability.1Lee J.B. Litzner B.R. Vidal C.I. Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome–associated neoplasms.J Cutan Pathol. 2017; 44: 931-937Crossref PubMed Scopus (0) Google Scholar Identification of expression patterns of mismatch repair proteins (retained vs lost) using an immunohistochemistry-based panel represents a widespread screening method for HNPCC and MTS.1Lee J.B. Litzner B.R. Vidal C.I. Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome–associated neoplasms.J Cutan Pathol. 2017; 44: 931-937Crossref PubMed Scopus (0) Google Scholar, 2Vidal C.I. Sutton A. Armbrect E.A. et al.Muir-Torre syndrome appropriate use criteria: effect of patient age on appropriate use scores.J Cutan Pathol. 2019; 46: 484-489Crossref PubMed Scopus (12) Google Scholar, 3Cook S. Pethick J. Kibbi N. et al.Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.J Am Acad Dermatol. 2023; 89: 1129-1135Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, such testing does not distinguish between somatic and germline alterations, and the diagnosis of HNPCC or MTS requires germline testing.3Cook S. Pethick J. Kibbi N. et al.Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.J Am Acad Dermatol. 2023; 89: 1129-1135Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Within the context of sebaceous neoplasms, immunohistochemistry-based screening plays a vital role in potentially enabling the early diagnosis of MTS as these tumors may precede the occurrence of other malignant neoplasms.1Lee J.B. Litzner B.R. Vidal C.I. Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome–associated neoplasms.J Cutan Pathol. 2017; 44: 931-937Crossref PubMed Scopus (0) Google Scholar,2Vidal C.I. Sutton A. Armbrect E.A. et al.Muir-Torre syndrome appropriate use criteria: effect of patient age on appropriate use scores.J Cutan Pathol. 2019; 46: 484-489Crossref PubMed Scopus (12) Google Scholar,4Shaker N. Shaker N. Abid A. Shah S. Shakra R.A. Sangueza O.P. Muir-Torre syndrome and recent updates on screening guidelines: the link between colorectal tumors and sebaceous adenomas in unusual locations.J Surg Oncol. 2023; 128: 1380-1384Crossref PubMed Scopus (1) Google Scholar Sebaceous neoplasms arising in the setting of MTS commonly exhibit loss of MSH2 and MSH6 protein expression as a consequence of germline alterations of the MSH2 gene.1Lee J.B. Litzner B.R. Vidal C.I. Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome–associated neoplasms.J Cutan Pathol. 2017; 44: 931-937Crossref PubMed Scopus (0)