Hereditary nonpolyposis colorectal cancer

Signs and symptoms

In Lynch syndrome, about two-thirds of colon cancers develop in the proximal colon. Common signs include blood in the stool, diarrhea or constipation, and unintended weight loss. For families meeting the Amsterdam criteria, the average age at colorectal cancer diagnosis is 44. Endometrial cancer is the most common sentinel cancer in Lynch syndrome; among women who develop both colon and endometrial cancer, roughly half are diagnosed with endometrial cancer first.

Its most common symptom is abnormal vaginal bleeding, and the average diagnosis age is around 60. Gastric cancer in HNPCC is typically diagnosed at a mean age of 56, with intestinal-type adenocarcinoma being the most frequent pathology. Ovarian cancers linked to HNPCC have an average diagnosis age of 42.5, and about 30% are found before age 40.

Lynch syndrome also raises the risk for small bowel, pancreatic, ureter/renal pelvis, biliary tract, brain, and sebaceous neoplasms. An increased risk for prostate and breast cancer has been associated, though this link is not fully understood. Sarcomas and adrenocortical carcinoma have also been associated, but evidence is insufficient to confirm that Lynch syndrome increases their risk. Cancer rates vary significantly depending on the specific mutation involved.

Genetics

Lynch syndrome is inherited in an autosomal dominant fashion and is characterized by defective DNA mismatch repair, leading to an elevated rate of single nucleotide changes and microsatellite instability (MSI-H). MSI is identifiable in cancer specimens in the pathology laboratory, most often resulting in changes in the lengths of dinucleotide repeats of cytosine and adenine. The four main genes involved are MLH1, MSH2, MSH6, and PMS2, which normally encode proteins that form dimers to function. MLH1 dimerizes with PMS2 to form MutLα, which coordinates binding of other proteins involved in mismatch repair.

MSH2 dimerizes with MSH6 to identify mismatches via a sliding clamp model. Impairment of either gene in a dimer impairs protein function, leading to inability to fix DNA replication errors. People with MSH6 mutations are more likely to be Amsterdam criteria II-negative, and the term MSH6 syndrome has been used for this condition. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria, so families with a deleterious mutation should be considered to have Lynch syndrome regardless of family history.

Diagnosis

Hereditary nonpolyposis colorectal cancer, or HNPCC, is diagnosed based on clinical criteria rather than a lab test. A diagnosis is made automatically when a family includes three or more blood relatives with confirmed colorectal, endometrial, ureteral, kidney cancer of the renal pelvis, or small intestine cancer. At least two of these relatives must be first-degree relatives, the cancers must appear in two or more successive generations, and at least one of the three must have been diagnosed before age 50. Some specialists also count bladder cancer, liver or gallbladder cancers, ovarian adenocarcinoma, glioblastoma, and sebaceous carcinoma toward this total.

Lynch syndrome, a subtype of HNPCC, is diagnosed through genetic testing that finds a germline mutation in one of the MMR genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene. Candidates for testing are identified using clinical criteria like the Amsterdam criteria or Bethesda Guidelines, or through tumor analysis via immunohistochemistry or microsatellite instability testing. Even if these tests suggest Lynch syndrome, a genetic test is still necessary for a definitive diagnosis. A person carrying such a mutation is considered to have Lynch syndrome regardless of whether they ever develop cancer.

Treatment

When colorectal cancer develops in someone with Lynch syndrome, surgery is the main treatment. Options include removing only the cancerous section or the entire colon and connecting the small intestine to the rectum. Because the risk of a new cancer is higher after a partial removal, and quality of life is similar for both procedures, total removal is often recommended, especially for younger patients. For polyps found in the colon, complete removal during a colonoscopy is standard, with a follow-up colonoscopy every two years.

There is debate about whether 5-fluorouracil-based chemotherapy helps for early-stage Lynch-related tumors. For advanced cancers with high microsatellite instability, anti-PD-1 checkpoint inhibitors are now the first choice. Removing the uterus, fallopian tubes, and ovaries before cancer develops is an option to prevent ovarian and endometrial cancer.

Did You Know?

• Henry T. Lynch characterized the syndrome in 1966, initially calling it 'cancer family syndrome'.
• The term 'Lynch syndrome' was coined in 1984; Lynch named the condition HNPCC in 1985.
• National Lynch Syndrome Awareness Day in the US is March 22.