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Emerging Concepts in Colorectal Cancer: Hereditary Non-Polyposis Cancer (Lynch Syndrome)

Emerging Concepts in Colorectal Cancer: Hereditary Non-Polyposis Cancer (Lynch Syndrome). APMG. Pathologist, MD FCAP. Colorectal Cancer: Molecular Pathways. Molecular Pathways in Colon Cancer. What value is there in recognizing MSI-H colorectal tumors?. Prognosis Response to chemotherapy

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Emerging Concepts in Colorectal Cancer: Hereditary Non-Polyposis Cancer (Lynch Syndrome)

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  1. Emerging Concepts inColorectal Cancer:Hereditary Non-Polyposis Cancer(Lynch Syndrome) APMG. Pathologist, MD FCAP

  2. Colorectal Cancer:Molecular Pathways

  3. Molecular Pathways in Colon Cancer

  4. What value is there in recognizing MSI-H colorectal tumors? Prognosis Response to chemotherapy Screen for Lynch Syndrome (HNPCC)

  5. Prognostic significance of MSI-H in sporadic CRC Gryfe,R et al, NEJM 2000; 342:69-77

  6. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer Ribic, C.R., et al. New Engl J Med 349:247-57 (2003)

  7. Colorectal Cancer:Molecular Pathways

  8. Lynch Syndrome (HNPCC) • HNPCC – Hereditary Non-Polyposis Colon Cancer • Historically: • Lynch Syndrome I – restricted to colon • Lynch Syndrome II – colon and extracolonic sites • Accounts for 3-4% of all colon cancers • Accounts for 15-20% of MSI tumors • Inherited predisposition to many different cancers, including colon cancer

  9. Lynch Syndrome: Cardinal Features • Autosomal dominant inheritance • Gene penetrance for CRC of 85-90% • Develop CRC at an early age - 45 yrs • Most CRC (70%) proximal to splenic flexure • Multiple CRC’s common - synchronous and metachronous • Prognosis better than sporadic CRC • Associated pathologic features • Increased risk for other malignancies

  10. Lynch Syndrome:Extracolonic Tumors

  11. Lynch Syndrome: Cumulative cancer risk in LS carriers by age 70 Aarnio M, et al, Int J Cancer 1999; 81:214-218.

  12. Lynch Syndrome:Cumulative cancer risk by age 70 Aarnio, M et al, Int J Cancer 1999; 81:214-18 By age 70, the risk for endometrial cancer exceeds that of colon cancer:

  13. Lynch Syndrome:Pathological features of colorectal cancer Poor differentiation Increased signet cells Medullary features Peritumoral lymphocyte infiltration Crohn’s like reaction Tumor infiltrating lymphocytes (TIL’s)

  14. How to recognizeLynch Syndrome • Amsterdam Criteria • Clinical guidelines for when to suspect Lynch Syndrome • Bethesda Guidelines • Guidelines for when to do MSI testing • Screen all new colon cancers?

  15. Lynch SyndromeAmsterdam Criteria II (1999) Vasen et al, Gastroenterology 1999;116:1453-56 At least three family members with a Lynch Syndrome-associated cancer, two of whom are first-degree relatives. At least two generations represented. At least 1 individual younger than 50 years at diagnosis. FAP should be excluded. Tumors should be verified by pathologic examination.

  16. Revised Bethesda Guidelines for testing colorectal tumors for MSI - 2004 Umar, et al., J Natl Cancer Inst 2004; 96:261-8 Tumors from individuals should be tested for MSI in the following situations: • Colorectal cancer in a patient less than 50 years of age. • Presence of synchronous, metachronous colorectal, or other HNPCC associated tumors, regardless of age. • Colorectal cancer with the MSI-H histology diagnosed in a patient less than 60 yr. • Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 yr. • Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

  17. Lynch Syndrome:Mismatch repair gene mutations

  18. Immunohistochemistryfor MMR Protein Expression MSH2 MLH1 MSH6 PMS2 • Loss of expression • Due to mutation Lynch Syndrome • Due to methylation Sporadic MSI CRC

  19. Universal screening Genetics in Medicine 11:35-41 (2009) Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives Evaluation of Genomic Applications in Practice and Prevention Working Group

  20. Significance of Lynch Syndrome The patient is at risk for other cancers and needs appropriate surveillance. The patient’s relatives will also be at increased risk if they carry the same mutation, and will need appropriate surveillance. Relatives can be tested to determine their risk, and level of surveillance.

  21. Summary • MSI-H tumors account for about 20% of all colon cancers. • Lynch Syndrome tumors account for 15 - 20% of MSI-H colon cancers, and about 4% of all colon cancers. • MSI-H colon cancers are biologically distinctive in their behavior. • MSI testing should be performed if indicated by Bethesda Guidelines. • MSI testing can be performed on fixed tissue. • Patients with MSI-H tumors are candidates for genetic counseling and further genetic testing.

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