Up to 4% of Colorectal Cancers Have Unexplained Positive Immunohistochemistry

Up to 4% of Colorectal Cancers Have Unexplained Positive Immunohistochemistry

Douglas K. Rex, MD, MASGE, reviewing Eikenboom EL, et al. Clin Gastroenterol Hepatol 2021 Apr 21.

Universal screening of colorectal cancers (CRCs) is recommended to increase the diagnosis of Lynch syndrome. Tumor screening can be done by microsatellite instability (MSI) testing, but immunohistochemistry (IHC) staining on the tumor is less expensive, easier, and more available. 

This study is a literature review of IHC testing and its outcomes. Among 58,580 unselected CRCs included, about 10% showed mismatch repair deficiency (MMRd) on IHC, and about half of these resulted from hypermethylation of MLH1. Hypermethylation assays were more effective at identifying epigenetic inactivation of MLH1 compared to BRAF mutation analysis. About 6% of all CRCs warranted genetic testing, and an MMR germline variant was found in 38%, corresponding to 2% of all CRCs, 33% of all MMRd CRCs, and increasing to 7.3% of all CRCs in patients younger than age 50 years and 5.0% of patients under 70 years. 

Across all studies, approximately 4% of all CRCs had unexplained MMRd, but when a detailed gene analysis was performed, the rate of unexplained MMRd dropped to 0.61%, with biallelic somatic MMR inactivation as the most common explanation.

Douglas K. Rex, MD, FASGE


This study makes useful points for clinicians looking at pathology reports of CRCs. First, there will be cases with positive IHC and negative germline testing and no apparent explanation for the IHC result. The frequency of this will vary with the type of testing done (eg, less with hypermethylation assays of MLH1 promoter versus more with reliance on BRAF mutations alone). Multipanel gene testing could be useful in these patients, as mutations in genes such as POLE, POLD1, and MUTYH can also inactivate MMR genes.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.


Eikenboom EL, van der Werf-‘t Lam AS, et al. Universal immunohistochemistry for Lynch Syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas. Clin Gastroenterol Hepatol 2021 Apr 19. (Epub ahead of print) (https://doi.org/10.1016/j.cgh.2021.04.021)

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