Muir-Torre syndrome or phenocopy? The value of the immunohistochemical expression of mismatch repair proteins in sebaceous tumors of immunocompromised patients.

G Ponti,F Crucianelli,G Gorelli,V Desmond Mandel,A Percesepe,G Pellacani,C Ruini,C Longo,A Tomasi

doi:10.1007/s10689-014-9733-4

Abstract

Primary and secondary immunodepressive conditions are associated with an increased incidence of sebaceous tumors. Microsatellite instability (MSI) and lack of expression of mismatch repair (MMR) proteins, typical markers of Muir-Torre/Lynch heredo-familial settings, can be recognized also in immunocompromised patients. We aimed to carry on a systematic examination of clinical, immunohistochemical, biomolecular features of sebaceous tumors arising in immunocompromised and immunocompetent patients between 1986 and 2012. Microsatellite screening, immunohistochemical analysis and genetic testing were performed for hMLH1, hMSH2 and hMSH6. Methylation status of MMR genes was checked in cases with immunohistochemistry (IHC) loss of MMR proteins expression and no germline mutations. Fifteen patients had a personal history of visceral carcinomas fulfilling diagnostic criteria for Muir-Torre syndrome. In this cohort, IHC analysis, MSI status and genetic testing were in agreement, showing eight MSH2 and two MLH1 germline mutations. Five patients were immunosuppressed and their sebaceous tumors showed a lack of MSH2/MSH6 expression, although just one case with positive family history for visceral cancer harbored a germline mutation. In immunosuppressed patients, loss of IHC for MMR proteins is not necessarily secondary to MMR germline mutations. IHC false positives are probably due to epigenetic alterations. MSI and lack of expression of MMR proteins can be recognized also in immunocompromised patients without MMR germline mutations.

Highlights

It is well known that primary and iatrogenic immunodepression is associated to an increased incidence of skin tumors [1,2,3]
Tumors arising in Muir–Torre syndrome (MTS) or Lynch syndrome (LS) patients are featured by the presence of a typical instability at microsatellite loci (MSI), which is caused by germline mutations of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, whose loss of expression can be tested through immunohistochemistry (IHC) [5, 6]
The examination of clinical, immunohistochemical and biomolecular features of sebaceous tumor patients highlighted that, despite the crucial role of IHC for MMR genes in the selection and identification of MTS, the genetic counselor should consider the possibility of a IHC-bias related to the IHC findings showing loss of MMR proteins expression in sebaceous tumors in both MTS-associated and immunodepressive-related lesions can not be ruled out

Summary

Introduction

It is well known that primary and iatrogenic immunodepression is associated to an increased incidence of skin tumors [1,2,3]. Tumors arising in MTS or LS patients are featured by the presence of a typical instability at microsatellite loci (MSI), which is caused by germline mutations of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, whose loss of expression can be tested through immunohistochemistry (IHC) [5, 6]. Some primary and secondary immunodepressive conditions are associated to an increased incidence of rare sebaceous tumors [7], in which, beyond the direct pathogenic effect of oncogenic virus [8, 9], a role for genetic aberrations has been hypothesized [10] and among those for MSI and loss of IHC expression of MMR proteins [8]. The genetic mechanism determining MSI and/or loss of MMR expression in sebaceous tumors in the absence of a germline mutation could be reconducted to a more general mechanism, like de novo methylation of promoters, which has been postulated as a major mechanism of inactivation of tumor suppressor genes [12, 13]

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