Makindo Medical Notes

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Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome)

Patients with hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch Syndrome, are at increased risk of developing colorectal cancer and various other malignancies due to defects in DNA repair mechanisms.

About

• HNPCC (Lynch Syndrome) is an autosomal dominant disorder with incomplete penetrance, meaning not all individuals with the mutation will develop cancer.
• It accounts for approximately 2-4% of all colorectal cancers.
• The syndrome leads to early onset colorectal cancer, particularly in the proximal colon, often without the presence of hundreds of polyps seen in other hereditary colorectal cancer syndromes like Familial Adenomatous Polyposis (FAP).

Aetiology

• HNPCC is caused by mutations in DNA mismatch repair (MMR) genes, responsible for correcting DNA replication errors.
• Approximately 95% of cases are due to mutations in the hMLH1 and hMSH2 genes, located on chromosomes 3 and 2, respectively.
• Additional genes involved include MSH6 and PMS2, though these mutations are less common.
• The loss of function in these MMR genes leads to microsatellite instability (MSI), a hallmark of Lynch syndrome, resulting in increased mutation rates and tumour development.

Clinical Features

• Colon cancers in Lynch syndrome tend to occur on the right side (proximal colon).
• Average age of colorectal cancer onset is around 45 years, which is younger than in sporadic cases.
• Unlike polyposis syndromes, fewer than 100 adenomas are typically present, and they are more likely to occur in the proximal colon.
• Patients may present with symptoms such as rectal bleeding, changes in bowel habits, or abdominal pain, depending on tumour location.

Increased Risk of Other Malignancies

• Endometrial cancer: Second most common cancer in Lynch syndrome, particularly in women under 50.
• Ovarian cancer: Increased risk alongside endometrial cancer.
• Increased risks for gastric cancer, biliary tract cancer, and small bowel tumours.
• Additional risks for urinary tract cancers (especially ureter and renal pelvis) and brain tumours (gliomas).

Investigations

• Colonoscopy: Recommended every 1-2 years starting from age 20-25 or 2-5 years before the earliest cancer diagnosis in the family.
• Genetic testing: Detects MMR gene mutations (e.g., hMLH1, hMSH2, MSH6, PMS2) and is used to confirm Lynch syndrome in patients and at-risk family members.
• Microsatellite Instability (MSI) testing and immunohistochemistry (IHC): Performed on tumour tissue to assess MMR deficiency.

Modified Amsterdam Criteria for HNPCC (Lynch Syndrome)

• At least two generations are affected by colorectal or Lynch-associated cancers.
• One individual must be a first-degree relative of another affected individual.
• At least one case diagnosed before age 50.
• Cancers include colorectal, endometrial, or small bowel cancers.
• Exclude Familial Adenomatous Polyposis (FAP).
• All tumours confirmed by pathology.

Management

• Colectomy: Surgical resection of the colon may be recommended for individuals with colorectal cancer or high-risk adenomas to reduce the risk of metachronous cancers.
• Surveillance and family screening: Family members should be screened for colorectal, endometrial, and ovarian cancers. Colonoscopy every 1-2 years and consideration of annual gynaecological exams with transvaginal ultrasound and endometrial sampling for women.
• Aspirin therapy: Daily low-dose aspirin has been shown to reduce cancer risk in Lynch syndrome; consider after a risk-benefit assessment with the patient.
• Risk-reducing surgery: For female carriers, prophylactic hysterectomy and bilateral salpingo-oophorectomy may be considered after childbearing, reducing the risks of endometrial and ovarian cancers.

References

• National Cancer Institute - Lynch Syndrome (HNPCC)
• NICE Guideline - Colorectal Cancer