Lynch syndrome

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Diagnosis is made by genetic testing of the index patient and their family members. Management consists of an earlier screening of individuals with defective MMR genes, as well as total colectomy if colorectal neoplasia is discovered. Prophylactic hysterectomy plus salpingo-oophorectomy are recommended for women beyond reproductive age.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Epidemiology

  • Prevalence: 1 in 279 people carry defective mismatch repair (MMR) genes.
    • The most common inherited colon cancer syndrome 
    • Accounts for 2%–4% of colorectal cancers
    • Increased risk for endometrial cancer and many other cancers
  • Malignancies occur earlier than in general population (5th decade).
  • General lifetime cancer risks in Lynch syndrome (LS) (approximate midpoints of broad ranges):
    • Colorectal cancer: 50% (right colon > left colon)
    • Endometrial cancer: 38% 
    • Ovarian cancer: 19% 
    • Stomach cancer: 7% 
  • Sex ratio: women = men

For people with Lynch syndrome, the lifetime cancer risk is also increased to a lesser extent for other cancers, including: renal pelvis, ureters, bladder, brain, small bowel, hepatobiliary tract, pancreas, prostate, and skin. In the figure, the upper ranges of the individual risks are given.

Image by Lecturio.

Etiology

Lynch syndrome patients inherit one or more mutant MMR genes and the respective normal allele/alleles; the 2nd allele then becomes mutated or loses function by epigenetic silencing so often that the inheritance pattern is effectively autosomal dominant.

  • MMR genes that can become mutated: MLH1, MSH2 (an EpCAM (epithelial cell adhesion molecule) gene mutation can also cause loss), MSH6, and PMS2 
  • Mutations then occur at rates up to 1,000 times higher than normal, mostly in regions of repetitive sequences called microsatellites. 
  • The protein products of mismatch repair (MMR) genes are important in “spell-checking” DNA during duplication by detecting and repairing DNA defects.
  • Loss of MMR activity causes an accumulation of DNA replication errors, particularly in repetitive sequences (“tandem repeats”).
    • Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs.
    • A cancer-driver mutation is eventually created by one of the uncorrected errors made during DNA replication.
  • MMR mutations can also occur as sporadic somatic mutations.

Pathogenesis and Pathology

Pathogenis

  • Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma.
  • The MMR pathway of colon carcinogenesis is the 2nd-most common pathway of colorectal cancer (CRC), after the adenoma-carcinoma pathway of colon carcinogenesis.

Pathology

  • Characteristics of CRCs arising via the MMR (MSI-H) pathway: tend to show more mucinous features and reactive tumor-infiltrating lymphocytes
  • Characteristics of endometrial carcinomas in LS: increased frequency of non-endometrioid carcinoma histologies
  • Slightly higher number of adenomatous polyps than the general population, but a higher rate of progression to CRC than typical polyps.

Clinical Presentation and Diagnosis

Clinical Presentation

  • Patients are asymptomatic until they develop malignancy.
  • Colorectal adenocarcinomas:
    • LS manifests with only a low or slightly higher-than-usual number of polyps.
    • Right-side carcinomas (more common): iron deficiency anemia due to bleeding
    • Left-sided carcinomas: changes in bowel habits or stool caliber
  • Endometrial carcinomas: abnormal endometrial bleeding

Diagnosis

  • 1 or more germline mutations in the mismatch repair (MMR) genes or EPCAM gene are needed for a definitive diagnosis of Lynch syndrome.
  • 2 pathways are used to establish the diagnosis: Test the tumor first, or base testing on family history.
  • Suspect Lynch syndrome in any patient who has:
    • CRC prior to 50 years of age, or if more than 1 CRC
    • Endometrial carcinoma < 60 years of age
    • A 1st-degree relative with known LS 
    • Fulfilled accepted criteria for LS (Amsterdam criteria or Bethesda guidelines)
  • Amsterdam II criteria (poor sensitivity, suspect LS if the following criteria are met):
    • 3 or more relatives (at least 1 first-degree) have LS–associated cancers; familial adenomatous polyposis (FAP) excluded.
    • LS–associated cancers involving at least 2 generations
    • 1 or more cancers diagnosed before the age of 50 years
  • Bethesda guidelines, revised (better sensitivity and specificity than Amsterdam criteria):
    • CRC diagnosed < 50 years of age
    • 2 or more LS-associated cancers
    • CRC with MSI-H–like histology in patient < 60 years of age
    • CRC in patient with a 1st-degree relative with LS–associated cancer < 50 years
    • CRC in patient with 2 1st-degree relatives with LS–associated cancer, any age

Management

Surveillance and screening tests

  • For CRC: annual colonoscopy starting at 20–25 years of age, or 2–5 years prior to the earliest age of CRC diagnosis in the family
  • For endometrial cancer: annual endometrial biopsy, starting at 30 years of age
  • Annual skin examinations to detect: sebaceous tumors (benign and malignant) and cutaneous keratoacanthomas associated with Muir-Torre syndrome (a variant of LS)
  • Reproductive counseling: LS patients of reproductive age should be offered carrier testing.

Surgical management

For CRC:

  • Total abdominal colectomy instead of segmental resection for CRC
  • If rectal cancer: total proctocolectomy

For endometrial cancer: 

  • Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) if cancer diagnosed
  • Prophylactic TAHBSO when childbearing is complete

Medical management

Chemoprevention:

  • Estrogen-progestin contraceptives reduce risk of endometrial and ovarian cancers
  • Aspirin: may reduce the risk of CRC 

Immunotherapy:

  • Pembrolizumab or nivolumab 
  • Used in MSI-H–/MMR–deficient tumors

Differential Diagnosis

  • FAP: presents with hundreds of adenomatous polyps and typically results in CRC in the distal colon. Lynch syndrome typically manifests with CRC in the proximal colon and only a low number of polyps. Genetic testing can distinguish between the 2 conditions.
  • Familial colorectal cancer type X (FCCTX): Amsterdam I criteria are met but the tumors lack the MSI seen in LS. No increased risk of other LS–associated cancers.

References

  1. Win, A.K. (2019). Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis. UpToDate. Retrieved November 10, 2020, from https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis
  2. Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). (2020). Small Intestine and Colon. Robbins & Cotran Pathologic Basis of Disease. (10th ed. pp. 814-816). Elsevier, Inc.
  3. Lynch syndrome. (2020). Cancer.Net. https://www.cancer.net/cancer-types/lynch-syndrome
  4. Li, K., Luo, H., Huang, L., Luo, H., & Zhu, X. (2020). Microsatellite instability: A review of what the oncologist should know. Cancer Cell International, 20(1), 16. https://doi.org/10.1186/s12935-019-1091-8
  5. Checkpoint inhibitor immunotherapy delays colorectal cancer progression. (n.d.). News.Cancerconnect.Com. Retrieved November 11, 2020, from https://news.cancerconnect.com/colon-cancer/checkpoint-inhibitor-immunotherapy-delays-colorectal-cancer-progression-cKTur5yY-k-yUY3aHZCjEw
  6. Oiseth, S. J., & Aziz, M. S. (2017). Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. Journal of Cancer Metastasis and Treatment, 3, 250–261. https://doi.org/10.20517/2394-4722.2017.41
  7. Mardis, E. R. (2019). Neoantigens and genome instability: Impact on immunogenomic phenotypes and immunotherapy response. Genome Medicine, 11(1), 71. https://doi.org/10.1186/s13073-019-0684-0
  8. Therkildsen, C., Ladelund, S., Smith-Hansen, L. et al. (2017). Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types. Br J Cancer, 117, 1702–1710. https://doi.org/10.1038/bjc.2017.348 
  9. Kalady, M. F., Kravochuck, S. E., Heald, B., Burke, C. A., & Church, J. M. (2015). Defining the adenoma burden in lynch syndrome. Diseases of the colon and rectum, 58(4), 388–392. https://doi.org/10.1097/DCR.0000000000000333
  10. Burn J, Sheth H, Elliott F, et al (Eds.) (2020). Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet (London, England), 395(10240), 1855–1863. https://doi.org/10.1016/S0140-6736(20)30366-4
  11. Peltomäki, P., Olkinuora, A., & Nieminen, T. T. (2020). Updates in the field of hereditary nonpolyposis colorectal cancer. Expert Review of Gastroenterology & Hepatology, 14(8), 707–720. https://doi.org/10.1080/17474124.2020.1782187
  12. Møller, P. (2020). The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care. Hereditary Cancer in Clinical Practice, 18. https://doi.org/10.1186/s13053-020-0138-0

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details