Immunohistochemical Screening for Muir-Torre Syndrome

We are now offering immunohistochemical staining for MLH-1, MSH-2 and MSH-6, which may be employed as an initial screening test to help identify patients who may have Muir-Torre syndrome.
Background
Sebaceous gland neoplasms such as adenoma, epithelioma, and carcinoma may be associated with Muir-Torre syndrome (MTS).  MTS is a rare autosomal dominant genodermatosis characterized by cutaneous sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies, most commonly of the gastrointestinal and genitourinary tracts.  MTS is considered a variant or subset of hereditary non-polyposis colorectal cancer (HNPCC; Lynch Syndrome).  MTS is usually the result of mutations in one or more DNA mismatch repair genes.  The genes most commonly implicated include MLH-1, MSH-2, and MSH-6.  Defects in these genes result in genetic instability that is referred to as microsatellite instability.  Sebaceous neoplasms other than on the head and neck and in patients < 50 years old or that are cystic are especially suspicious for MTS.

Testing

Immunohistochemistry:  There is no standard test or algorithm for DNA mismatch repair gene mutation testing.  However, a synthesis of published data suggests that immunohistochemical staining for MLH-1, MSH-2 and MSH-6 is sufficiently sensitive to be useful as a screening test for defects in these genes.  A negative result is interpreted as a lack of the expression of the gene and indicates a gene mutation.  However, maintenance of expression (positive staining) does not exclude the possibility of a different underlying DNA repair defect.
As an example, please see the attached pathology report of a recent case where the patient demonstrated lack of expression of MSH-2 and MSH-6 in a suspicious sebaceous lesion and had a history of colorectal carcinoma, likely a Muir-Torre syndrome patient.

Microsatellite Instability Analysis:  PCR-based techniques for microsatellite instability testing are considered a second tier screening test and there has been good correlation between these tests and immunohistochemistry.  However, these tests are complex, expensive, take 1-2 weeks and do not indicate the specific gene defect present.

Germline Mutation Analysis:  If immunohistochemistry and/or microsatellite instability analysis are suggestive of a DNA mismatch repair gene mutation, germline mutation analysis of MLH-1, MSH-2, and MSH-6 may be done to confirm the mutation. This is a send out reference test.
It should be emphasized that the absence of detectable mutation by any of these methods does not exclude the possibility of a different underlying DNA repair defect or other forms of Muir-Torre syndrome.

Clinical Implications
Some authors suggest immunohistochemical screening only for sebaceous neoplasms located outside the head and neck in patients <50 years old, although others would argue that any sebaceous neoplasm be tested regardless of the patient’s age or other clinical characteristics.
If immunohistochemistry suggests that mismatch repair genes are intact (positive staining) and there is no family history of visceral malignancy, it has been suggested that no further work-up is required.
If immunohistochemistry indicates mismatch repair gene defects (negative or very weak staining) or microsatellite instability analysis is positive, germline mutational analysis should be done.
Regardless of screening test results, any positive family history in a patient with a suspicious sebaceous neoplasm suggests that germline mutational analysis should be done.
Confirmation of a DNA mismatch repair defect by germline mutational analysis reveals that the patient and his or her first degree family members have an inherited cancer predisposition which will require a preventative cancer screening program.  Screening programs would generally involve a Gastroenterologist and guidelines have been issued by the international collaborative group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC).  Genetic counseling may also be useful in this setting.

References:  Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithm. J Cutan Pathol 2009;36:613.
Abbott JJ, Hernandez-Rios P, Amirkhan RH, Hoang MP.  Cystic sebaceous neoplasms in Muir-Torre Syndrome.  Arch Pathol Lab Med 2003;127:614.
Eisen, DB, Michael DJ. Sebaceous lesions and their associated syndromes: Part II. J Am Acad Dermatol 2009;61:563-78.
Lynch HT, Fusaro RM. The Muir-Torre syndrome in kindreds with hereditary nonpolyposis colorectal cancer (Lynch syndrome): a classic obligation in preventative medicine. J Am Acad Dermatol 1999;41:797.
Orta L, Klimstra DS, Qin J, et al. Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s age or other clinical characteristics. Am J Surg Pathol 2009;33:934.
Singh RS, Grayson W, Redston M, et al. Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol 2008;32:936.