familial nonpolyposis colon cancer; hereditary nonpolyposis colorectal cancer (HNPCC); Lynch syndrome; cancer family syndrome
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Introduction
Hereditary nonpolyposis colon cancer (HNPCC) is one of the most common inherited cancer susceptibility syndromes.
Epidemiology
- from 3-15% of sporadic colon cancers in western nations have been attributed to HNPCC
- the exact frequency of HPNCC mutations is not known
- most common hereditary colorectal cancer syndrome
- prevalence is 1 in 440[2]
- of 65 cases of Lynch syndrome, 58 identified < 70 years old[17]
Pathology
- colon tumors are the most common types of tumors seen in HNPCC families
- colon cancer occurs in 50-80% of patients with Lynch syndrome by age 44[2]
- colon cancer occurs at unusually high frequency in the proximal colon (predominance of right-sided colon cancer)[15]
- generally larger but less aggressive cancers than seen in adenomatous polyposis coli
- poor differentiation, may include mucinous features, infiltrating lymphocytes
- 35-40% of family members develop other types of tumors;
- endometrial cancer & ovarian camcer are the most common
- lifetime risk of endometrial cancer is 40-60%, with a median age at onset of 48 years
- also gastric cancer, small intestinal cancer, pancreatic cancer, liver cancer, biliary cancer, brain tumor, & upper urinary tract cancer (urothelial carcinoma)
- tumors from patients with HNPCC show microsatellite instability which results from a failure to repair insertion/deletion mispairs
- response to neoantigens generated by a high mutational burden
- colon polyps much less common than in familial adenomatous polyposis
Genetics
- autosomal dominant with high penetrance
- four different genes have been identified (including genes on chromosomes 2 & 3; all participate in mismatch DNA repair
- germline deletion in EpCAM leading to epigenetic inactivation of MSH2[15]
History
- family history of colon cancer (3-2-1 rule)[2]
- 3 affected family members
- 2 generations affected
- 1 under age 50 years
Diagnostic criteria
3-2-1 rule
- three or more relatives with colorectal carcinoma; one affected patient is 1st degree relative of another affected patient
- two generations of the family with colorectal carcinoma
- one case of colorectal carcinoma diagnosed in a patient < 50 years of age
- familial adenomatous polyposis excluded
- tumors verified by histopathology
Laboratory
- HNPCC gene mutations after genetic counseling
- genotyping is NOT yet clinically useful
- urine cytology
- see ARUP consult[5]
Diagnostic procedures
- surveillance colonoscopy every 1-3 years (1-2 years)[9]
- begin at age 25 or 2-5 years prior to the earliest age of colon cancer diagnosis in the family
- for carriers of MSH6, surveillance colonoscopy every 1-2 years beginning at age 30[15]
- for carriers of PSM2, surveillance colonoscopy every 1-2 years beginning at age 35[15]
- tumors frequently occur in the proximal colon making sigmoidoscopy of limited usefulness
- upper GI endoscopy (genetically-confirmed Lynch syndrome)[2]
- capsule endoscopy not recommended[2]
- transvasginal ultrasound
Radiology
- CT urography for post-glomerular hematuria (without pyuria, bacteriuria)
Differential diagnosis
Management
- genetic counseling[20] (NEJM)
- aspirin 600 mg QD
- lifelong therapy[9]
- for at least 2 years decreases the incidence of colorectal cancer after 4 years in carriers of Lynch syndrome[4][18]
- exercise reduces cancer risk[21]
- decreases inflammatory markers (prostaglandin E2) in colon & blood
- increases colonic mucosa natural killer cells & CD8+ T cells[21]
More general terms
More specific terms
- familial nonpolyposis colon cancer type 1 (Lynch-1 syndrome)
- familial nonpolyposis colon cancer type 2 (Lynch-2 syndrome)
- familial nonpolyposis colon cancer type 3
- familial nonpolyposis colon cancer type 4
- familial nonpolyposis colon cancer type 5
- familial nonpolyposis colon cancer type 6
- familial nonpolyposis colon cancer type 7
- hereditary ovarian cancer syndrome
- Muir-Torre syndrome
Additional terms
- DNA mismatch repair; post-replication repair; DNA loop repair
- intestinal polyposis syndrome
- microsatellite or variable number of tandem repeat (VNTR)
- MLH1 gene
- MSH2 gene
- PMS1 gene
- PMS2 gene
References
- ↑ Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8533151
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018.
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 514
- ↑ 4.0 4.1 Burn J et al Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011 Oct 27 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22036019
- ↑ 5.0 5.1 ARUP Consult: Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/lynch-syndrome
ARUP Consult (Algorithm) Lynch Syndrome (HNPCC) Testing Algorithm https://arupconsult.com/algorithm/lynch-syndrome-hnpcc-testing-algorithm
ARUP Consult: Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer https://arupconsult.com/ati/lynch-syndrome
ARUP consult: Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome. https://arupconsult.com/ati/Hereditary-Gastrointestinal-Cancer-Panel - ↑ Goodenberger M, Lindor NM. Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 2011 Jul;45(6):488-500 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21325953
- ↑ Umar A, Boland CR, Terdiman JP et al Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18;96(4):261-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/14970275
- ↑ Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10348829
- ↑ 9.0 9.1 9.2 Rubenstein JH et al American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology. July 28, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26226577 <Internet> http://www.gastrojournal.org/article/S0016-5085%2815%2901031-8/fulltext
- ↑ Koornstra JJ, Mourits MJ, Sijmons RH et al Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol. 2009 Apr;10(4):400-8 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19341971
- ↑ Dana-Farber Cancer Institute Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) PREMM1,2,6 Model: Prediction Model for MLH1, MSH2, and MSH6 Gene Mutations. http://premm.dfci.harvard.edu
- ↑ Giardiello FM, Allen JI, Axilbund JE et al Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi- Society Task Force on colorectal cancer. Gastroenterology. 2014 Aug;147(2):502-26. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25043945
- ↑ Hegde M, Ferber M, Mao R et al ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014 Jan;16(1):101-16. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24310308
- ↑ Lynch HT, de la Chapelle A Hereditary Colorectal Cancer. N Engl J Med 2003; 348:919-932. March 6, 2003 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/12621137 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMra012242
- ↑ 15.0 15.1 15.2 15.3 15.4 Rothaus C Lynch Syndrome-Associated Colorectal Cancer. NEJM Resident 360. Aug 22, 2018 https://resident360.nejm.org/content_items/lynch-syndrome-associated-colorectal-cancer
- ↑ Silva FC, Valentin MD, Ferreira Fde O, Carraro DM, Rossi BM. Mismatch repair genes in Lynch syndrome: a review. Sao Paulo Med J. 2009 Jan;127(1):46-51. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19466295 Free Article
- ↑ 17.0 17.1 Li D, Hoodfar E, Jiang SF et al. Comparison of universal versus age-restricted screening of colorectal tumors for Lynch syndrome using mismatch repair immunohistochemistry: A cohort study. Ann Intern Med 2019 Jun 11; PMID: https://www.ncbi.nlm.nih.gov/pubmed/31181578
- ↑ 18.0 18.1 Burn J et al. 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 2020 Jun 13; 395:1855. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32534647 PMCID: PMC7294238 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30366-4/fulltext
- ↑ NEJM Knowledge+ Nephrology/Urology
- ↑ 20.0 20.1 Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Engl J Med. 2018;379:764-773. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30134129
- ↑ 21.0 21.1 21.2 Deng N, Reyes-Uribe L, Fahrmann JF et al Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome. Clin Cancer Res 2023 Sep 19. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37724990
Patient information
familial nonpolyposis colon cancer (Lynch syndrome) patient information