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Colon tumor

Familial polyposis syndromes

Lynch syndrome


Reviewers: Charanjeet Singh, M.D. (see Reviewers page)
Revised: 18 October 2011, last major update September 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
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● Also known as hereditary non-polyposis colon cancer (HNPCC), because patients have hereditary colon carcinoma but fewer polyps than familial adenomatous polyposis
● “HNPCC” terminology has been criticized (World J Gastroenterol 2006;12:4943)
● Hereditary disorder due to mutation in mismatch repair gene (see JAMA 2005;294:2195 for report on family tracked for 100 years)
● Most common hereditary colorectal carcinoma syndrome (2-5% of all colorectal carcinomas)
● Autosomal dominant
● 80% develop colorectal carcinoma; also increased risk of endometrial carcinoma (33%), ovarian carcinoma (5%), cancers of small bowel, stomach, urinary tract and brain (Fam Cancer 2005;4:245)
● Risk of endometrial carcinoma and ovarian carcinoma is reduced by prophylactic surgery (N Engl J Med 2006;354:261)

Molecular description
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● Defect in mismatch repair genes (caretaker genes) MLH1 or MSH2 (90%), MSH6 (7-10%) or PMS2 (less common, Gastroenterology 2006;130:312), which proofread DNA replication
● 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)
● MSI is detected by instability at 2 or more of 5 microsatellite markers (MSH2, MLH1 are most common)
● 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)

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; two successive affected generations; one 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 mismatch repair 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; two successive affected generations; one 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): 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 the MSI-H histology 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; or 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)

Screening: 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, have similar rate of adenomas as non syndrome patients, but much higher incidence of carcinoma (Gastroenterology 2006;130:1995)

Case reports
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● Colorectal carcinoma and duodenal follicular lymphoma (Mod Pathol 2000;13:586)
● Urothelial carcinoma of ureter (Arch Pathol Lab Med 2003;127:E60)

Prognosis/treatment
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● Better survival than other adenocarcinomas
● 5 FU chemotherapy does not appear to be helpful (Isr Med Assoc J 2005;7:520, Eur J Cancer 2009;45:1890)

Gross description
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● Usually proximal colon, 18% multiple and 40% metachronous (multiple separate occurrences)

Micro description
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● Tumors tend to be poorly differentiated with abundant mucin and marked lymphocytic infiltration

Additional references
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OMIM 120435

End of Colon tumor > Familial polyposis syndromes > Lynch syndrome


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