Upload
miranda-norris
View
214
Download
0
Embed Size (px)
Citation preview
Emerging Concepts in Colorectal Cancer:
Hereditary Non-Polyposis Cancer(Lynch Syndrome)
Short Presentations in Emerging Concepts (SPEC)
Colorectal Cancer:Molecular Pathways
HypermutabilityPathway
ChromosomalInstability Pathway
Molecular pathways in colon cancer
What value is there in recognizing MSI-H colorectal tumors?
1. Prognosis
2. Response to chemotherapy
3. Screen for Lynch Syndrome (HNPCC)
Prognostic significance of MSI-H in sporadic CRC
Gryfe,R et al, NEJM 2000; 342:69-77
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)
Colorectal Cancer:Molecular Pathways
Hypermutability Pathway
Chromosomal Instability Pathway
APC
Lynch
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
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
Lynch Syndrome:Extracolonic Tumors
Site Features
Endometrium Second most common
Stomach Older generations
Small bowel Risk 25X in HNPCC
Hepatobiliary tract 5% risk
Ureter and pelvis 14-20% risk
Skin Muir-Torre Syndrome
Pancreas Trend for increase
Brain GBM in some HNPCC (Turcot’s)
Hematologic Case reports
Soft tissue Case reports
Larynx Case report
Lynch Syndrome: Cumulative cancer risk in LS carriers by age 70
Aarnio M, et al, Int J Cancer 1999; 81:214-218.
Site of tumor Finnish population (%) HNPCC families (%)
Colon/rectum 1.6 82
Endometrium 1.3 60
Stomach 0.8 13
Ovary 1.3 12
Bladder, ureter, urethra 0.7 4.0
Brain 0.9 3.7
Kidney 0.8 3.3
Biliary tract, gallbladder 0.2 2.0
Lynch Syndrome:Cumulative cancer risk by age 70
By age 70, the risk for endometrial cancer exceeds that of colon cancer:
Aarnio, M et al, Int J Cancer 1999; 81:214-18
Site Incidence by age 70 in women
Endometrium 60%
Colon 54%
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)
How to recognize Lynch 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?
Lynch Syndrome - Amsterdam Criteria II (1999)
• 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.
Vasen et al, Gastroenterology 1999;116:1453-56
Revised Bethesda Guidelines for testing colorectal tumors for MSI - 2004
Tumors from individuals should be tested for MSI in the following situations:
1. Colorectal cancer in a patient less than 50 years of age.2. Presence of synchronous, metachronous colorectal, or other HNPCC
associated tumors, regardless of age.3. Colorectal cancer with the MSI-H histology diagnosed in a patient less
than 60 yr.4. 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.
5. Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.
Umar, et al., J Natl Cancer Inst 2004; 96:261-8Umar, et al., J Natl Cancer Inst 2004; 96:261-8
Lynch Syndrome:Mismatch repair gene mutations
Gene Frequency in HNPCC
MSH2 ~39%
MLH1 ~32%
PMS1 Rare
PMS2 ~14%
GTBP/MSH6 ~14%
Other ?
Immunohistochemistryfor MMR Protein Expression
MLH1
MSH6
MSH2
PMS2
Loss of expressionDue to mutation Lynch SyndromeDue to methylation Sporadic MSI CRC
Universal screening
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
Genetics in Medicine 11:35-41 (2009)
Significance of Lynch Syndrome
1. The patient is at risk for other cancers and needs appropriate surveillance.
2. The patient’s relatives will also be at increased risk if they carry the same mutation, and will need appropriate surveillance.
3. Relatives can be tested to determine their risk, and level of surveillance.
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.
Selected Resources
Lynch HT, et al. Hereditary nonpolyposis colorectal carcinoma and HNPCC-like families: problems in diagnosis,m surveillance, and management. Cancer .2004 ;100:53-64.
EGAPP Working Group. 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. Genet Med. 2009 ;11(1):35-41.
Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch Syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812-823.
Additional Free Resource for CAP Members NOTE: please remove this page before presenting.CAP Member Exclusive: CAP Pathology Resource GuidesFocused on a specific hot-topic technology, thesecomprehensive guides highlights current resources, selectjournal articles, as well as CAP and non-CAP educationalopportunities. And don’t miss the “Insights From EarlyAdopters” section in each guide to gain perspective frompioneering colleagues.AVAILABLE NOW:• Molecular Pathology (single gene test, small panel)• Genomic Analysis (large panel, exome, genome)Learn more: go to cap.org and type Pathology Resource Guides in the
“search” field located at the top of your screen.
“Extremely well done,of high practical andeducational value.”
“An outstanding overviewof basic materials,including the technologyand links to a number ofindividuals and centersthat can assist.”