Mismatch Repair Protein Deficiency is Common in Sebaceous Neoplasms and Suggests the Importance of Screening for Lynch Syndrome

Abstract

The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients.

Sebaceous neoplasms and the immunoprofile of mismatch-repair proteins as a screening target for syndromic cases

“…In our SA cohort, MSH6 deficiency was the most prevalent aberration, occurring in combination with MSH2 deficiency in the vast majority of cases. This was also the observation in prior reports that include MSH6 examination [7][8][9][10]. Notably, in two of our 17 MMR-protein deficient SAs, loss of expression was confined to the MSH6, probably indicating MSH6 mutation, as was the case in three of the specimens (sebaceous adenomas and epitheliomas) in Chhibbar's series [7], as well as in 2 of 25 deficient sebaceous neoplasms of Cornejo et al [17], and in one of 26 SAs reported by Mojtahed et al [8].…”

“…We found, as have others [6][7][8][9][10]13,14,17,26] that MSH2/MSH6 deficiency, suggestive of MSH2 germline mutation, overrides other constellations. However, in the study by Entius et al [12], based on eight MMR-protein deficient SCs, the proportion of cases with loss of MSH2 and MLH1 was similar, which, as the authors acknowledged, might reflect bias by familiar clustering.…”

“…A similar view has previously been advanced by others [10,14,17] and was most recently formulated by Everett et al [5], who proposed a practical algorithm for patients with sebaceous neoplasms, including IHC as a first-line screening. Additionally, Everett et al commented on the limited utility of family history alone.…”

“…The prevalence of MMR-protein deficiency among neoplasms with sebocytic differentiation as a group has been addressed in several unselected series [4][5][6][7][8][9][10], the reported values ranging from roughly 25% to 80%. Additionally, in a series of 25 patients with sebaceous neoplasms, examined for microsatellite instability (MSI), 60% were found to be MSI-high (MSI-H) [11].…”

“…Additionally, in a series of 25 patients with sebaceous neoplasms, examined for microsatellite instability (MSI), 60% were found to be MSI-high (MSI-H) [11]. Some MMR-protein IHC studies of sebaceous neoplasms were based on MLH1-and MSH2 status only [6,[12][13][14][15], others added MSH6 to the staining panel [4,[7][8][9][10]16], and some of these communications additionally report the PMS2-protein status [4,5,[7][8][9][10]17].…”