MLH1, IHC with Interpretation [70196X]

This immunohistochemistry (IHC) assay is based on an antibody directed against the DNA mismatch repair (MMR) protein MLH1. MLH1 IHC testing is usually done as part of a panel that assesses expression of 4 MMR proteins (the other 3 are MSH2, MSH6, and PMS2) in resected tumor tissue from patients with newly diagnosed colorectal or endometrial cancer. Loss of expression of 1 or more of these proteins may indicate defective DNA repair processes associated with Lynch syndrome [1,2].

IHC for MMR proteins is generally performed on tissue from certain tumors (eg, colorectal carcinomas and endometrial carcinomas) to screen for Lynch syndrome. IHC testing of MMR proteins identifies approximately 95% of tumors with defective MMR [1]. DNA microsatellite instability (MSI) is another testing methodology that may help screen for patients with Lynch syndrome. MSI-high results and/or loss of expression of any MMR protein (except MLH1) can be followed by germline pathogenic variant testing of the relevant genes to confirm Lynch syndrome [1].

Loss of MLH1 expression may reflect germline mutation in the MLH1 gene (in the setting of Lynch syndrome) or MLH1 promotor methylation and BRAF mutation (in the setting of sporadic tumorigenesis). Therefore, in patients with loss of MLH1 expression, testing tumor tissue for a BRAF mutation or for hypermethylation of the MLH1 promoter may be
performed before proceeding to germline genetic testing for Lynch syndrome. In patients with high suspicion of Lynch syndrome, genetic testing should be considered despite normal screening results [2].

The results of IHC of MMR proteins and MSI may also be useful in evaluating chemotherapy and immunotherapy choices for many solid tumors.

The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.

References
1. Baine MK, et al. Immunohistochemical testing of DNA mismatch repair (MMR) proteins. In: Rekhtman N, et al. Quick
Reference Handbook for Surgical Pathologists. 2nd ed. Springer; 2011:35.
2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines[R]).
Genetic/familial high-risk assessment: colorectal. V1.2021. Accessed November 22, 2021. http://www.nccn.org