Colon tumor
Familial polyposis syndromes
Lynch syndrome

Author: Jennifer Findeis-Hosey, M.D. (see Authors page)
Editorial Board review: Raul Gonzalez, M.D.

Revised: 26 August 2015, last major update August 2015

Copyright: (c) 2002-2015, PathologyOutlines.com, Inc.

PubMed Search: Lynch syndrome [title] colon
Definition / General
  • Autosomal dominant hereditary disorder due to mutation in a mismatch repair (MMR) gene
  • Most common hereditary colorectal carcinoma syndrome (accounts for 2-5% of all colorectal carcinomas)
  • 80% of patients develop colorectal carcinoma; also increased risk of endometrial carcinoma (33%), ovarian carcinoma (5%), and cancers of small bowel, stomach, upper urinary tract, and brain (Fam Cancer 2005;4:245)
  • Terminology
  • Initially known as hereditary non-polyposis colon cancer (HNPCC), but this terminology has been criticized (World J Gastroenterol 2006;12:4943)
  • Epidemiology
  • Patients with Lynch Syndrome tend to develop carcinomas at an earlier age than the general population (average age: 44 years old)
  • Sites
  • Colon cancers more likely to occur in the proximal colon
  • Pathophysiology / Etiology
  • Mutation in MMR gene results in defective repair of DNA sequence mismatches, which most frequently occur in long, repetitive DNA sequences (such as seen in microsatellite regions, hence the term microsatellite instability[MSI])
  • Accumulation of DNA mismatches lead to increased risk of developing malignant neoplasms
  • Etiology
  • Typically due to mutation in an MMR gene: most commonly due to a germline mutation in MSH2 or MLH1; less frequently due to germline mutations in MSH6 or PMS2
  • Mutations in EPCAM (Epithelial Cellular Adhesion Molecule) / TACSTD1 (Tumor Associated Calcium Signal Transducer 1) gene may result in Lynch Syndrome: EPCAM gene is adjacent to MSH2, and mutations in EPCAM may result in MSH2 promoter hypermethylation and subsequent inactivation of MSH2
  • Rarely due to inactivation through germline promoter hypermethylation of MLH1; differs from the somatic MLH1 hypermethylation which may be seen in sporadic colon cancers
  • Rarely the result of inactivation of CHEK2 (Cell Cycle Check Point Kinase 2)
  • Diagnosis
  • Amsterdam I screening criteria (all 4 must be met):
    • 3 or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
    • 2 successive affected generations
    • 1 or more colon cancers diagnosed before age 50
    • Familial adenomatous polyposis has been excluded (Dis Colon Rectum 1991;34:424)
    • These criteria are relatively sensitive but not specific for Lynch syndrome, since these patients may lack MMR gene mutations
  • Amsterdam II criteria (all 4 must be met):
    • 3 or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two
    • 2 successive affected generations
    • 1 or more HNPCC-related cancers diagnosed before age 50
    • Familial adenomatous polyposis has been excluded (Gastroenterology 1999;116:1453)
  • Revised Bethesda criteria (any criteria must be met; these are guidelines for when tumors should be tested for MSI):
    • Colorectal cancer diagnosed before age 50 years
    • Presence of synchronous or metachronous colorectal cancers or other HNPCC-associated tumors, regardless of age
    • Colorectal cancer with MSI-H histology (see below) diagnosed before age 60 years
    • Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed before age 50 years
    • Colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors, regardless of age (J Natl Cancer Inst 2004;96:261)
  • Recommended screening for patients with Lynch Syndrome:
    • Full colonoscopy every 1-2 years beginning at age 20-25 years
    • Annual screening for endometrial cancer beginning at age 25-35
    • Annual urinalysis and cytologic examination beginning at age 25
    • Annual skin surveillance, and upper GI endoscopy beginning at age 35 when gastric cancer is part of the family spectrum (JAMA 2006;296:1507)
    • At colonscopic screening, patients have similar rate of adenomas as non-syndrome patients, but much higher incidence of carcinoma (Gastroenterology 2006;130:1995)
  • Laboratory
  • Germline testing for mutations can be performed
  • Microsatellite Instability testing of tumor specimens via PCR is widely utilized; this typically consists of a panel of 5 mono/dinucleotide repeats which are analyzed, and a shift in PCR product size of tumor versus normal indicates instability; designation of MSI-H requires instability in at least 30% of examined loci
  • Immunohistochemical testing panel for 4 MMR proteins (MLH1, MSH2, PMS2, MSH6) is widely utilized
  • BRAF V600E mutation analysis may be performed on cases with loss of MLH1 and PMS2 IHC staining: if mutation is present, then Lynch Syndrome is virtually excluded
  • MLH1 gene promoter hypermethylation may be utilized to determine sporadic vs. Lynch Syndrome-related colon cancers
  • Prognostic Factors
  • Syndromic cancers have better survival than non-syndromic
  • Case Reports
  • 53 year old man with duodenal follicular lymphoma and hereditary nonpolyposis colorectal cancer (Mod Pathol 2000;13:586)
  • 64 year old woman with hereditary nonpolyposis colorectal cancer syndrome (Arch Pathol Lab Med 2003;127:E60)
  • History and molecular genetics of Lynch syndrome in family (JAMA 2005;294:2195)
  • Treatment
  • 5-FU chemotherapy does not appear to be helpful (Isr Med Assoc J 2005;7:520, Eur J Cancer 2009;45:1890)
  • Risk of endometrial carcinoma and ovarian carcinoma is reduced by prophylactic surgery (N Engl J Med 2006;354:261)
  • Gross Description
  • Usually proximal colon; 18% multiple and 40% metachronous (multiple separate occurrences)
  • Micro Description
  • Tumoral features suggestive of MSI-H etiology include: tumor infiltrating lymphocytes and peritumoral lymphocytes, Crohn's-like lymphoid reaction, mucinous features, medullary features, tumoral heterogeneity, and absence of dirty necrosis
  • Micro Images
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    Various images

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    Various images

    Negative Stains
  • Defective mismatch repair genes can be reliably detected (negative staining) by immunohistochemistry (Am J Clin Pathol 2004;122:389, N Engl J Med 2005;352:1851)
    • Loss of only PMS2 staining is suggestive of PMS2 mutation
    • Loss of only MSH6 staining is suggestive of MSH6 mutation
    • Loss of MLH1 and PMS2 staining may be seen in MLH1 mutation (although sporadic colon cancers may also have this profile; if this profile is observed, follow-up with BRAF V600E mutation analysis or MLH1 hypermethylation studies is warranted)
    • Loss of MSH2 and MSH6 staining may be seen in MSH2 mutation
  • Molecular / Cytogenetics Description
  • Defect in mismatch repair genes (caretaker genes that proofread DNA replication): typically MLH1 or MSH2, while MSH6 and PMS2 are less common (Gastroenterology 2006;130:312)
  • Rarely due to EPCAM mutation, germline promoter hypermethylation of MLH1, inactivation of CHEK2 (Cell Cycle Check Point Kinase 2)
  • Associated with microsatellite instability (MSI; microsatellites are dinucleotide repeat sequences, such as (CA)n, normally present in human genome), although MSI is not specific (World J Gastroenterol 2006;12:4745)
  • Additional References