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Condition created 2026-08-19 · updated 2026-08-24
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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 — MSI and IHC testing of the tumor itself evaluate the tumor's phenotype and do not, by themselves, confirm a diagnosis of Lynch syndrome; LS is confirmed only by finding a germline MMR mutation on subsequent genetic testing. 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.

Per ASCRS Ch22 - Sporadic and Inherited Colorectal Cancer: clinically, MMR gene function is assessed either by MSI measurement (PCR) or IHC staining for MMR proteins — comparable sensitivity/ specificity, with IHC generally less expensive and more widely used. Specific patterns of MMR protein loss have diagnostic significance: loss of both MLH1 and PMS2 (a heterodimer pair) indicates either MLH1 somatic promoter methylation (sporadic) or an MLH1 germline mutation (LS) — distinguished by testing for a BRAF V600E mutation (found in 69% of hypermethylated tumors; if present, LS is unlikely; if BRAF-negative, germline mutational analysis should follow). Functional loss of MSH2, MSH6, or PMS2 typically arises from germline mutations directly. The NCCN and American Gastroenterological Association now recommend universal screening (MSI or IHC) for all resected CRC and endometrial cancer specimens, largely supplanting reliance on family-history criteria alone. An emerging near-term alternative is next-generation sequencing of the tumor biopsy itself, which in a prospective cohort demonstrated equivalent specificity and superior sensitivity for LS compared to traditional sequential MSI/IHC-then-germline testing, with the added benefit of detecting other actionable mutations (KRAS/NRAS, DPYD) that may influence chemotherapy decisions and shorten time to a final LS diagnosis.

Two online/downloadable risk-prediction models (PREMM5 and MMRpro) help assess an unaffected individual's likelihood of carrying an LS mutation based on personal/family history — of particular use when a suggestive family history exists but no affected relative's tumor tissue is available for testing, reducing unnecessary germline testing.

Lynch syndrome variants

  • Turcot syndrome — in addition to CRC, patients develop CNS tumors ("brain tumor polyposis syndrome," BTPS). Can be MMR-deficient as in classic Lynch (type 1) or related to biallelic loss of APC as seen with FAP (type 2 — see Familial Adenomatous Polyposis (FAP)). Glioblastoma multiforme is the most common neurologic cancer in type 1; medulloblastoma in type 2.
  • Muir-Torre syndrome (MTS) — skin structure-related neoplasms, predominantly sebaceous gland tumors; most commonly caused by loss of LS genes, though ~1/3 of MTS may relate to MUTYH-associated polyposis instead (see Familial Adenomatous Polyposis (FAP)'s MAP section). Sebaceous adenomas/carcinomas are rarely seen outside MTS; genetic counseling should be considered for any patient diagnosed with a sebaceous tumor. Immunosuppressant medications may unmask MTS as an underlying condition.
  • Familial CRC type X — patients meeting HNPCC clinical criteria (e.g. Amsterdam) by family history/age but with microsatellite-stable (MSS) tumors. Present later than LS patients; colon cancers occur more distally; do not appear to share LS's elevated extra-colonic malignancy risk. While the exact genetic mechanism is unknown, familial CRC X tumors have stable chromosomal length but a high degree of chromosomal instability more similar to sporadic cancers — genetically distinct from true LS despite the similar clinical presentation.

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.

Large population-based retrospective studies suggest routine biannual colonoscopy reduces LS CRC incidence, though surveillance still fails to prevent a substantial number of cancers; conversely, other studies show cancer-specific survival in screened LS patients is similar to unaffected family members. A recent meta-analysis found surveillance colonoscopy was associated with decreased CRC incidence (OR 0.23) and decreased CRC mortality (OR 0.06) vs. no screening; on average, screening increased life expectancy by 7 years. For MLH1/MSH2 mutation carriers specifically, the estimated risk of developing CRC over the subsequent 5 years increases from 1 in 71 (males)/1 in 102 (females) in their 20s to 1 in 7 (males)/1 in 12 (females) by age 50 — the basis for the age-graded colonoscopy-start recommendations above (age 20–25 for MLH1/MSH2 carriers, no later than age 30 for MSH6, no later than 35 for PMS2, per NCCN/ASCRS guidelines). Aspirin chemoprevention: the CAPP2 randomized controlled trial investigated 600mg/day aspirin in LS patients and found a 50% reduction in cancer incidence in the intervention arm over 4 years — notably, 7% of non-aspirin study participants still developed CRC despite regular endoscopic surveillance. Routine aspirin use is recommended by the American Gastroenterological Association, while the American College of Gastroenterology makes it only a conditional recommendation pending further evidence.

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 Rectal Cancer. The decision to also remove the rest of the colon in these patients is made on an individual basis after discussion with the patient. Total proctocolectomy with IPAA is an alternative to segmental rectal resection for LS patients with rectal cancer, though it carries a pronounced functional difference from restorative proctectomy; the risk of a second colorectal malignancy after segmental proctectomy ranges 15–27% within the first decade postoperatively, even with regular endoscopic surveillance.

The most recent US Multi-Society Task Force on CRC and ASCRS Clinical Practice Guidelines both recommend total abdominal colectomy with ileorectal anastomosis over segmental resection in LS patients. Corroborated by ASCRS Ch25 - Colon Cancer Surgical Treatment (Herzig et al. 2017, the same ASCRS guideline), which briefly covers this same recommendation from the colon-resection- technique side — see Colon Cancer Resection for that page's short cross-link back here. A large registry-based cohort study found the risk of metachronous CRC after segmental colectomy increases to over 60% at 30 years; this risk was reduced with subtotal colectomy at index diagnosis, and a meta-analysis of almost 1000 LS patients found metachronous cancers developed more commonly after segmental vs. total colectomy (23.5% vs. 6.8%, OR 3.7) — though no difference in overall survival between the two approaches has been demonstrated in other series. Factors favoring less radical (segmental) resection: tumor stage, age, fecal continence status, anticipated reliability with surveillance, and patient preference — there is little benefit to prophylactic colectomy in patients with incurable stage IV disease. Total abdominal colectomy leads to significantly greater stool frequency and adversely impacts social function vs. segmental resection; subtotal colectomy with ileosigmoid anastomosis is another reasonable option, expected to offer nearly the same risk reduction as total colectomy while preserving better bowel function and allowing surveillance via flexible sigmoidoscopy. Given the ongoing metachronous-CRC risk, regular colonoscopy (annually) is recommended lifelong after colectomy, regardless of extent — though no clear survival benefit has been demonstrated for such intensive surveillance, it may still detect malignancy at an earlier stage.

Medical treatment

Stage III MMR-deficient CRCs are treated with oxaliplatin-based adjuvant chemotherapy (e.g. FOLFOX — see Sporadic & Young-Onset Colorectal Cancer), similar to sporadic tumors; however, single-agent 5-FU-based chemotherapy appears less efficacious in LS patients, and no survival benefit is seen from adjuvant chemotherapy in stage II MMR-deficient disease, even with other high-risk features. Interestingly, despite MMR-mutated CRCs more commonly showing poor differentiation/mucinous features, LS patients experience better stage-matched survival and fewer recurrences than sporadic patients, particularly for proximal-colon cancers — plausibly related to the greater tumor-related- antigen expression and tumor-infiltrating-lymphocyte response in high-mutational-burden LS tumors.

Immune checkpoint inhibitors — pembrolizumab and nivolumab (anti-PD-1) and ipilimumab (anti- CTLA-4) — are FDA-approved for treating metastatic MSI-H CRCs; evidence suggests most MMR-deficient tumors respond to immunotherapy while most MMR-proficient tumors do not. A confirmatory phase III trial is underway comparing overall survival from adjuvant FOLFOX alone vs. FOLFOX plus atezolizumab (a PD-L1 antibody) in resected colon cancers with deficient mismatch repair.

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 (though several large registry/ meta-analysis series are now cited above).
  • CAPP2 aspirin trial and the PREMM5/MMRpro risk models are cited from the textbook chapter's synthesis, not independently verified against primary publications.