These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.
Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.23,35,36
If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.13
One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.37 As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.
Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.38
It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.
Final Thoughts
Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.19