Answer of Dermatopathology Case 2

Sebaceous adenoma in a patient with Muir-Torre syndrome

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Abstract:

Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnosticalgorithm. J Cutan Pathol. 2009 Jun;36(6):613-9.
Sebaceous gland neoplasms such as adenoma, epithelioma, and carcinoma areuncommon cutaneous tumors. Although sporadic, their occurrence is clinicallysignificant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceralmalignancies that include gastrointestinal and genitourinary cancers. MTS isusually the result of germline mutation in one or more of the DNA mismatch repair(MMR) genes. MMR genes commonly implicated include MSH-2 and MLH-1 and, morerecently, MSH-6. Recent evidence suggests that immunohistochemistry is verysensitive and effective in detecting these defects in cutaneous tumors in MTS. In addition, the genetic instability of cutaneous and visceral tumors in MTS caused by the defects in MMR genes can also be detected, using polymerase chain reaction(PCR)-based techniques, for microsatellite instability (MSI). Given that somesebaceous neoplasms represent cutaneous markers of MTS, what should we asdermatopathologists be advocating? Should we be looking for absence/loss of MMRs in all sebaceous neoplasms? When should we recommend assaying for MSI? Thisreview attempts to address all of these issues with a view to streamlining thework-up of a patient presenting for the first time with a sebaceous neoplasm and no prior personal or family history of internal malignancies.

MSH-2 and MLH-1 protein expression in Muir Torre syndrome-related and sporadicsebaceous neoplasms. P R Health Sci J. 2008 Dec;27(4):322-7.
BACKGROUND: Muir-Torre Syndrome (MTS) is a rare autosomal-dominant disordercharacterized by the predisposition to both sebaceous neoplasm and internalmalignancies. MTS-associated sebaceous neoplasms reveal mutations in DNA mismatchrepair (MMR) genes and microsatellite instability. A significant part of MTS patients represents a phenotypic variant, the hereditary nonpolyposis colorectal cancer (HNPCC). A strong correlation between microsatellite instability andimmunostaining has been demonstrated. The early recognition of sebaceous neoplasmas part of MTS, and their differentiation from sporadic sebaceous neoplasm mayhave an important application in a clinical setting. The absence of MLH-1 orMSH-2 expression by immunostaining identifies tumors with mismatch repair deficiency. OBJECTIVES: Our aim is to determine whether an immunohistochemicalapproach, targeting DNA repair proteins MSH-2 and MLH-1 in MTS-related sebaceous neoplasm and their sporadic counterparts, can be used for their identification.METHODS: We examined 15 sebaceous neoplasms (including 6 internal malignancy-associated sebaceous neoplasms and 8 sporadic sebaceous neoplasms) from 11 patients for the expression of MSH-2 and MLH-1 by immunohistochemistry. RESULTS: Four of 5 internal malignancy-associated sebaceous neoplasms showed loss ofexpression of MSH-2 or MLH-1. Correlation of the immunostaining pattern of thesebaceous neoplasms and the patients' positive history of colon carcinoma was80%. Seven of 8 sporadic sebaceous neoplasms showed a positive expression ofMSH-2 and MLH-1. The prevalence for loss of expression of MMR proteins in sebaceous neoplasms was 38.5%. MMR immunostaining had 87.5% specificity and 80% sensitivity. LIMITATIONS: This study is limited by a small sample size, and by bias selection due to the use of non nationwide data-base as the resource of cases. CONCLUSIONS: Our findings demonstrate that immunohistochemical testing forinternal malignancy-associated sebaceous neoplasms is a practical approach toconfirm a suspected inherited MMR gene defect, and an accurate method to distinguish between sporadic and MTS-associated sebaceous lesions.

Immunohistochemistry screening of sebaceous lesions for Muir-Torre syndrome in a 26-year period in a Mexican population. Dermatol Online J. 2008 Dec 15;14(12):1.
Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis defined as the association of rare sebaceous gland skin tumors, keratoacanthomas, and a personalor familial history of malignant visceral tumors. Germline mutations in certain mismatch repair genes (MMR) have been identified in MTS families and their identification is a cornerstone for diagnosis of MTS. We reviewed our series of sebaceous neoplasms and performed immunohistochemistry (IHC) in order to screen for new MTS cases. Sebaceous neoplasms and visceral tumors from the same patient diagnosed between 1980-2006 were included. Immunohistochemistry to determine the presence or absence of MMR gene products in skin and visceral tumors was performed with mouse monoclonal antibodies anti-MSH2, anti-MSH6 and anti-MLH1. Six sebaceous neoplasms were identified in six females. Four patients presented alack of expression of at least one of the MMR proteins in visceral and cutaneous neoplasms, thus warranting the diagnosis of MTS. Immunohistochemistry is a useful and accessible technique for the characterization of MMR gene expression in patients with sebaceous neoplasms.