Sebaceous neoplasms are rare skin tumors that may occur sporadically or in association to MTS. The diagnosis of a sebaceous neoplasm should give rise to the suspicion of an inherited MMR gene defect. The distinction between patients with MTS and sporadic sebaceous neoplasms is of paramount importance, particularly in those patients presenting sebaceous neoplasms as an initial manifestation of the syndrome.
MTS-sebaceous neoplasms originate from an inherited germ-line mutation in one allele of MMR genes, in combination with a somatic loss-of-function of the remaining wild type allele (12
). The MMR deficiency leads to an inability to correct mutations, and eventually leads to microsatellites instability. Marcus, Madlensky, Gryfe, et al. (16
) clearly demonstrated that immunostaining can accurately discriminate between microsatellite unstable and microsatellite stable neoplasms. Thus, immunohistochemistry can identify patients affected by an MMR deficiency.
Most studies on MMR defects published so far have concentrated on microsatellite instability analysis, and a 100% correlation between microsatellite instability analysis and immunostaining has been well documented (14
In this study we analyzed MTS-associated sebaceous neoplasms and sporadic counterparts to determine the prevalence of loss of expression of MMR proteins, the specificity, and the sensitivity of the immunohistochemical analysis for sebaceous adenomas, sebaceous carcinomas and sebaceomas.
Considered as a whole, 5 cases (42%) were MMR deficient and 7 (58%) had an intact expression of MMR proteins. This is similar to the findings of Singh, Grayson, Redston, et al. (22
) who found a 35% of the sebaceous neoplasms to be MMR deficient.
Similar to the findings of Popnikolov, Gatalica, Colome-Grimmer and Sánchez (23
), we found a loss of MLH-1/MSH-2 protein in four of five (80%) internal malignancy-associated sebaceous neoplasms. One of the five (20%) internal malignancy-associated sebaceous neoplasms included in our study did not show loss of MLH-1/MSH-2 protein expression (case 1B- sebaceous carcinoma). There is a theoretical chance that the somatic mutation of the second allele of the MSH-2 gene in a patient with a germline mutation may lead to the synthesis of a defective, but still detectable protein (17
). This may explain why discordance between immunostaining and clinical diagnosis of MTS may be seen. Otherwise, there may be a different mutated MMR gene of the MMR complex responsible for the development of this tumor. Further molecular analysis is required to clarify these types of discrepancies.
Loss of MLH-1/MSH-2 proteins was detected in one of eight sporadic sebaceous neoplasms (case 3A-sebaceous adenoma). This lesion may represent the first manifestation of MTS in this patient, and may indicate an increased risk for visceral malignancy.
In our study, the percentage of loss of expression of MMR proteins in internal malignancy associated sebaceous neoplasms was significantly higher (80% versus 36.3%, respectively) than the recently published findings of Cesinaro, Ubiali, Sighinolfi, et al. (24
). In their study, only a minority of cases of sebaceous tumors associated with extracutaneous cancer displayed MMR abnormalities and/or microsatellite instability, arguing that these techniques are limited in their ability to identify patients with “clinically defined” MTS (24
). These discrepancies could be related to differences in the definition of MTS cases. In our study, we strictly defined cases of MTS as those presenting at least one sebaceous neoplasm in addition to internal malignancy, all of them being carcinoma of colon. We did not include sebaceous hyperplasia, nor adenomatous polyps and/or hyperplastic polyps of the colon to identify our MTS cases.
No concurrent loss of both MLH-1 and MSH-2 was observed in our study, similar to previous findings (23
). Overall, we found a strong positive correlation (85%) between the staining pattern and the clinical diagnosis of MTS or sporadic sebaceous neoplasms.
There was an observed difference between sebaceous adenomas, carcinomas, and sebaceomas in the rate of the overall loss of the expression of MMR proteins and a positive correlation to the patients’ history for internal malignancy. In our study, the sebaceoma presented the strongest positive correlation.
Previously, Marcus, Madlensky, et al. (16
) reported that immunohistochemistry for MSH-2 and MLH-1 identifies MMR deficiency with 97% sensitivity and 100% specificity in microsatellite instability-analyzed neoplasms. In our study, MLH-1 and MSH-2 immunohistochemistry identifies MTS patients with 80% sensitivity and 87.5% specificity, supporting that immunohistochemistry can be used with a high degree of accuracy for the identification of those sebaceous neoplasms originated by mutations in MMR genes.
There are some inherent limitations in this study, including the possibility that some patients may have an undiagnosed internal malignancy, leading to an underestimation of MTS cases. Another limitation of this study stems from our inability to generalize our findings of prevalence as a nationwide prevalence, because the selected cases did not come from a nationwide data-base. This study includes a relatively small sample size.
This study supports earlier reports of alterations in mismatch repair gene expression for sebaceous neoplasms in patients with MTS (9
) and brings evidence in favor of immunohistochemical analysis as a practical first-line screening test. In those cases where internal malignancy-associated sebaceous neoplasm presents discordant immunostaining results, microsatellite analysis would be required to identify possible false-negative cases. Also, molecular analysis would be required for those tumors that may be originated from mutations in other genes of the mismatch repair complex (16
In summary, our findings support immunohistochemical testing for internal malignancy-associated sebaceous neoplasms as a reliable and practical screening method with a high predictive value for the diagnosis of MMR deficient neoplams. It is an accurate way to distinguish between sporadic and MTS-associated sebaceous lesion.