Lynch Syndrome

See Hereditary Colorectal Cancer Syndromes for how this fits among the other hereditary CRC syndromes, and Colorectal Cancer Molecular Pathways for the MSI mutator pathway background. Content below is from a textbook reference chapter (Sabiston Ch52 - Colorectal Neoplasia & Colon Cancer Surgery), not primary literature.

Previously called HNPCC (hereditary nonpolyposis colorectal cancer), but “nonpolyposis” is considered a misnomer since patients can develop polyps/adenomas as well as multiple non-CRC cancers. Accounts for 3–5% of all CRCs and 10–19% of CRCs diagnosed before age 50.

Genetics

Autosomal dominant, caused by a mutation in one of the DNA mismatch repair (MMR) genes — MLH1, MSH2, MSH6, PMS2, EpCAM. These genes maintain DNA fidelity during replication by correcting base mispairs and small insertions/deletions. Mutations in MLH1 and MSH2 account for up to 90% of Lynch syndrome patients. Because of this defect, Lynch tumors are characterized by MSI — mutations at microsatellites are found in the tumor DNA but not in adjacent normal colorectal mucosa or in the normal DNA of individuals with MMR gene defects. MSI is found in most (>90%) colon malignancies in Lynch patients. Immunohistochemistry using antibodies to the MMR gene proteins evaluates for loss of MMR protein expression and assists in identifying Lynch patients. Somatic BRAF mutations are noted in 15% of sporadic CRCs but essentially not in Lynch tumors — a BRAF mutation in an MSI CRC is evidence against Lynch syndrome.

Clinical features

Increased predisposition to CRC and other tumors, developing at early ages. Estimated lifetime CRC risk: 70% for men, 40% for women. Mean age at diagnosis of Lynch-related CRC: 44–61 years, vs. 69 years for sporadic CRC. Lynch-associated CRCs show a predilection for the right colon compared to sporadic CRC, though left-sided colon cancers, rectal cancers, and synchronous lesions at different sites are also common. Among Lynch patients whose initial CRC was treated with less than a total colectomy, risk of metachronous CRC: 16% at 10 years, 41% at 20 years, 62% at 30 years.

Compared with FAP/AFAP/MAP patients, Lynch patients develop few colorectal adenomas by age 50 (usually fewer than 3). But adenoma may progress to carcinoma within 2–3 years — a markedly accelerated adenoma-carcinoma sequence compared with 4–10 years in the general population. Histologic features: poor differentiation, mucinous or signet-ring cell histology, tumor-infiltrating lymphocytes, and lymphoid host response.

Extracolonic cancers: endometrial adenocarcinoma is the most common (lifetime risk 32–45%). Ovarian, gastric, small bowel, urinary tract, brain, and pancreas cancers are also frequently seen. Sebaceous adenomas/carcinomas of the skin and keratoacanthomas are seen in the Muir-Torre variant of Lynch syndrome.

Diagnosis

Germline sequencing of the MMR genes is the “gold standard” for confirming the causative mutation. Patients are initially identified using clinical criteria:

• Amsterdam II criteria — 3+ relatives with an HNPCC-associated cancer (colorectal, or endometrial/small bowel/ureter/renal pelvis) plus all of: one affected patient is a first-degree relative of the other two; 2+ successive generations affected; cancer diagnosed before age 50 in at least one affected relative; FAP excluded; pathologic diagnosis of cancer verified.
• Bethesda criteria (for testing tumors for MSI) — any of: CRC diagnosed before age 50; synchronous/metachronous CRC or HNPCC-related tumors; CRC with MSI-suggestive histology diagnosed before age 60; CRC diagnosed in a first-degree relative with an HNPCC-related tumor, one of which was diagnosed before 50; CRC diagnosed in 2+ first/second-degree relatives with HNPCC-related tumors, regardless of age.

Screening

• Colorectal: recommended every 1–2 years for at-risk individuals (first-degree relatives of a known MMR mutation carrier, or those affected with Lynch without genetic testing), starting age 20–25, or 2–5 years before the youngest CRC diagnosis age in the family if diagnosed before 25. MMR germline mutation-positive patients: consider annual colonoscopy.
• Endometrial: pelvic exam plus endometrial sampling annually starting age 30–35 for at-risk or affected women.
• Ovarian: screening offered starting at the same age. Hysterectomy and bilateral salpingo-oophorectomy should be offered to women with Lynch undergoing colectomy, in all women over 40 or who have finished childbearing.
• Gastric: EGD with gastric antral biopsy considered starting age 30–35, subsequent surveillance every 2–3 years based on individual risk factors.
• Urinary tract: consider for at-risk/affected persons, with annual urinalysis starting age 30–35.

Surgical management

Three issues distinguish surgical decision-making in Lynch-associated colon cancer from sporadic colon cancer: (1) appropriate treatment of the primary tumor, (2) whether to reduce future risk with prophylactic removal of non-neoplastic colon, and (3) morbidity and quality of life after colectomy.

There is no clear consensus on the extent of resection. The choice (partial vs. total colectomy) should be discussed with the patient, factoring in age, comorbidities, and cancer stage — there is no prospective RCT comparing extended resection with limited resection. The cumulative risk of metachronous CRC after segmental colectomy (16% at 10 years, 41% at 20 years, 62% at 30 years, as above) is the key data point cited in favor of more extensive resection; based on currently available evidence, cancer risk reduction is felt to be superior with total colectomy, and total abdominal colectomy with ileorectal anastomosis is the preferred treatment for most patients. Consideration for less extensive (segmental) surgery is reasonable in patients older than 60–65, and in those with underlying sphincter dysfunction. Annual colonoscopy is recommended after segmental resection.

For patients with Lynch syndrome and rectal cancer, the rectal cancer itself should be treated per standard oncologic principles, as in sporadic rectal cancer (see the forthcoming rectal cancer chunk). The decision to also remove the rest of the colon in these patients is made on an individual basis after discussion with the patient.

Open items / gaps

• No primary RCT data on extended vs. limited colectomy for Lynch-associated colon cancer — the chapter explicitly notes this gap in the literature itself.
• No detail yet on chemoprevention (e.g. aspirin) for Lynch syndrome, which is a real and studied area not covered in this chapter chunk.