Lynch Syndrome Related Colorectal Cancer

Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline defects in DNA mismatch repair, principally MLH1, MSH2, MSH6 and PMS2, or EPCAM alterations causing MSH2 silencing.

Colorectal cancers develop through mismatch repair deficiency and microsatellite instability and frequently occur at a younger age than sporadic cancers.

The syndrome also increases risk of endometrial, ovarian, gastric, small bowel and urinary tract malignancies.

The cancer itself presents similarly to sporadic colorectal cancer.

Right sided location, synchronous or metachronous cancers and a strong family history should increase suspicion, but phenotype alone is unreliable.

Universal mismatch repair or microsatellite instability testing of colorectal cancers is therefore more reliable than selecting patients solely by age or family history.

Abnormal tumour mismatch repair testing should trigger appropriate germline assessment after distinguishing sporadic MLH1 loss where relevant.

Known carriers require colonoscopy every 1 to 2 years, generally beginning around age 20 to 25 years or earlier according to the family cancer history.

Oncological treatment follows the same stage principles as sporadic colorectal cancer, but the extent of colectomy requires additional consideration because retained colon remains at substantial risk of a second primary cancer.

For a young fit patient with colon cancer and an MLH1 or MSH2 pathogenic variant, subtotal colectomy with ileorectal or ileosigmoid anastomosis should be seriously considered because it markedly reduces metachronous colon cancer risk.

For MSH6 or PMS2 carriers, segmental oncological colectomy is often reasonable because metachronous risk is lower. Age, baseline bowel function, comorbidity and patient preference remain critical.

A segmental colectomy remains acceptable when functional consequences of extended colectomy outweigh the cancer prevention benefit, but the remaining colon then requires lifelong intensive surveillance.

Primary rectal cancer is usually treated with standard oncological proctectomy. Total proctocolectomy may be considered when previous colon cancer, extensive synchronous neoplasia or future metachronous risk justifies the additional functional cost.

Mismatch repair deficient metastatic colorectal cancer is particularly sensitive to immune checkpoint therapy.