Transcript Microsatellite Instability (MSI), Cancer, and HNPCC

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?
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
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
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; 81:214-218.
Lynch Syndrome:
Cumulative 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
Colon
60%
54%
Aarnio, M et al, Int J Cancer 1999; 81:214-18
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; 96:261-8
Lynch Syndrome:
Mismatch repair gene mutations
Gene
Frequency in HNPCC
MSH2
~39%
MLH1
~32%
PMS1
Rare
PMS2
~14%
GTBP/MSH6
~14%
Other
?
Immunohistochemistry
for MMR Protein Expression
MLH1
MSH6
MSH2
PMS2
Loss of expression
Due to mutation
Lynch Syndrome
Due 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.