About these slides
SPEC – Short Presentation in Emerging Concepts
• Provided by the CAP as an aid to pathologists to
facilitate discussion on the topic
• Content has been reviewed by experts at the
CAP, but does not necessarily reflect the official
opinion of the College of American Pathologists.
• Non-CAP material with identified copyright source
may only be copied or distributed under a license
(permission) from the copyright holder, or under
the doctrine of fair use.
• Version 1.0fc2, rev. 12/31/2013
Emerging Concepts in Colorectal
Hereditary Non-Polyposis Cancer
Short Presentations in Emerging
Molecular pathways in colon cancer
What value is there in recognizing MSI-H
2. Response to chemotherapy
3. Screen for Lynch Syndrome (HNPCC)
Prognostic significance of MSI-H in sporadic
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
Ribic, C.R., et al. New Engl J Med 349:247-57 (2003)
Lynch Syndrome (HNPCC)
• HNPCC – Hereditary Non-Polyposis Colon Cancer
• 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
– Prognosis better than sporadic CRC
– Associated pathologic features
• Increased risk for other malignancies
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
Cumulative cancer risk in LS carriers by age
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.
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
Aarnio, M et al, Int J Cancer 1999; 81:214-18
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
• 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
• 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
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
Mismatch repair gene mutations
Gene Frequency in HNPCC
for MMR Protein Expression
Loss of expression
Due to mutation Lynch Syndrome
Due to methylation Sporadic MSI CRC
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
3. Relatives can be tested to determine their
risk, and level of surveillance.
• MSI-H tumors account for about 20% of all colon
• 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
• MSI testing should be performed if indicated by
• MSI testing can be performed on fixed tissue.
• Patients with MSI-H tumors are candidates for genetic
counseling and further genetic testing.
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
CAP Member Exclusive: CAP Pathology Resource Guides
Focused on a specific hot-topic technology, these
comprehensive guides highlights current resources, select
journal articles, as well as CAP and non-CAP educational
opportunities. And don’t miss the “Insights From Early
Adopters” section in each guide to gain perspective from
• 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.
“An outstanding overview
of basic materials,
including the technology “Extremely well done,
and links to a number of of high practical and
individuals and centers educational value.”
that can assist.”