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

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Emerging Concepts inColorectal
CancerHereditary Non-Polyposis Cancer(Lynch
Syndrome)

• APMG. Pathologist, MD FCAP

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Colorectal CancerMolecular Pathways
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Molecular Pathways in Colon Cancer
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What value is there in recognizing MSI-H
colorectal tumors?

1. Prognosis
2. Response to chemotherapy
3. Screen for Lynch Syndrome (HNPCC)

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Prognostic significance of MSI-H in sporadic CRC
Gryfe,R et al, NEJM 2000 34269-77
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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 349247-57 (2003)
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Colorectal CancerMolecular Pathways
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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

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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 CRCs common - synchronous and
  metachronous
• Prognosis better than sporadic CRC
• Associated pathologic features
• Increased risk for other malignancies

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Lynch SyndromeExtracolonic 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 (Turcots)
Hematologic Case reports
Soft tissue Case reports
Larynx Case report
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Lynch Syndrome Cumulative cancer risk in LS
carriers by age 70
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
Aarnio M, et al, Int J Cancer 1999 81214-218.
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Lynch SyndromeCumulative cancer risk by age 70

• By age 70, the risk for endometrial cancer
  exceeds that of colon cancer

Site Incidence by age 70 in women
Endometrium 60
Colon 54
Aarnio, M et al, Int J Cancer 1999 81214-18
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Lynch SyndromePathological features of
colorectal cancer

• Poor differentiation
• Increased signet cells
• Medullary features
• Peritumoral lymphocyte infiltration
• Crohns like reaction
• Tumor infiltrating lymphocytes (TILs)

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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?

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Lynch SyndromeAmsterdam 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 19991161453-56
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Revised Bethesda Guidelines for testing
colorectal tumors for MSI - 2004

• 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.

Umar, et al., J Natl Cancer Inst 2004 96261-8
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Lynch SyndromeMismatch repair gene mutations
Gene Frequency in HNPCC
MSH2 39
MLH1 32
PMS1 Rare
PMS2 14
GTBP/MSH6 14
Other ?
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Immunohistochemistryfor MMR Protein Expression
MSH2
MLH1
MSH6
PMS2
Loss of expression Due to mutation Lynch
Syndrome Due to methylation Sporadic MSI CRC
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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 1135-41 (2009)
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Significance of Lynch Syndrome

1. The patient is at risk for other cancers and
   needs appropriate surveillance.
2. The patients 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.

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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.