Systematic immunohistochemistry screening for Lynch syndrome in early age-of-onset colorectal cancer patients undergoing surgical resection

Background: Lynch syndrome (LS), defined by a deleterious (pathogenic) germline mutation in a mismatch repair (MMR) gene, is characterized by early age-of-onset colorectal cancer (CRC). Because clinical criteria for LS, such as the Amsterdam II Criteria, may miss cases, reflex tumor tissue testing of all CRC patients for LS has been proposed. Our study describes the impact of routine immunohistochemistry (IHC) analysis of tumor tissue for loss of MMR protein expression in early age-of-onset CRC patients undergoing resection.

Study design: A prospective institutional program was established to perform IHC analysis on all early age-of-onset (≤50 years) CRC patients undergoing resection. Patients with abnormal IHC analysis were referred to the Clinical Genetics Service for further evaluation. The study cohort excluded patients with other polyposis syndromes and inflammatory bowel disease.

Results: IHC was performed on 198 patients from July 2006 to June 2010. The median age was 42.8 years (range 23.1 to 50.6 years). Abnormal IHC was reported in 38 (19.1%) patients, and 22 (57.8%) with abnormal IHC analysis had germline genetic testing. Seventeen (77.2%) had an alteration detected in an MMR gene: 10 were known to be deleterious mutations and 7 were variants of uncertain significance. Overall, LS was detected in 5.1% of patients. Only 2 of the 10 (20%) with a deleterious mutation actually met the Amsterdam II Criteria.

Conclusions: Reflex IHC testing for LS on early age-of-onset CRC patients undergoing resection is feasible at the institutional level. This strategy identifies a substantial number of LS patients who would have been missed if genetic testing was based on the Amsterdam II Criteria alone.