Lynch Syndrome and
Colorectal Cancer
Steven G. Proshan, M.D.
Annapolis Colon and Rectal Surgeons
Anne Arundel Medical Center
November 8, 2014
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Lynch Syndrome (LS)
 Familial Predisposition to Colorectal and other
cancers
 Autosomal Dominant
 Henry Lynch, MD 1966
 Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
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Colorectal Cancer in LS
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

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Cancers more frequently
Cancers at younger age (40’s)
Right sided cancers
Adenoma to carcinoma sequence more rapid
Synchronous and Metachronous Cancers
Lifetime Risk 10-74% (vs. 5.5% without)
Better Prognosis
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Genetics of CRC
Sporadic
(65%–85%)
Rare CRC
syndromes
(<0.1%)
MYH associated
polyposis (MAP)
(1%)
Familial adenomatous
polyposis (FAP) (1%)
Familial
(10%–30%)
Lynch syndrome
(3%)
Other LS Cancers
Cancer
Endometrium
Incidence (%)
Incidence LS (%)
2.7
14-71
<1
0.2-13
1.6
4-20
Hepatobiliary Tract
<1
0.02-4
Urinary Tract
<1
0.2-25
Small Bowel
<1
0.4-12
Brain/CNS
<1
1-4
Sebaceous Neoplasm
<1
1-9
Pancreas
1.5
0.4-4
Prostate
16.2
9-30
Breast
12.4
5-18
Stomach
Ovary
A Classic HNPCC/Lynch Family
CRC
dx 50s
CRC
dx 45
CRC
dx 61
CRC
dx 48
CRC
dx 52
Endometrial
Ca, dx 59
CRC
dx 75
45
CRC
dx 42
Ovarian
Ca, dx 64
Clinical Diagnosis of LS
Amsterdam I Criteria (1991)
1. Three or more relatives with histologically verified
colorectal cancer, 1 of which is a first-degree relative of
the other two. Familial adenomatous polyposis should
be excluded.
2. Two or more generations with colorectal cancer.
3. One or more colorectal cancer cases diagnosed
before the age of 50 years.
Clinical Diagnosis of LS
Amsterdam II Criteria (1999)
1. Three or more relatives with histologically verified
HNPCC-associated cancer (colorectal cancer, cancer of
the endometrium, small bowel, ureter, or renal pelvis), 1
of which is a first-degree relative of the other 2. Familial
adenomatous polyposis should be excluded.
2. Cancer involving at least 2 generations.
3. One or more cancer cases diagnosed before the age
of 50 years.
Clinical Diagnosis of LS
Revised Bathesda Guidelines (2004)
1. CRC diagnosed at younger than 50 years.
2. Presence of synchronous or metachronous CRC or other LS-associated
tumors.*
3. CRC with MSI-high pathologic-associated features (Crohn-like lymphocytic
reaction, mucinous/signet cell differentiation, or medullary growth pattern)
diagnosed in an individual younger than 60 years old.
4. Patient with CRC and CRC or LS-associated tumor* diagnosed in at least 1
first-degree relative younger than 50 years old.
5. Patient with CRC and CRC or LS-associated tumor* at any age in 2 first-degree
or second-degree relatives.
* LS-associated
tumors include tumor of the colorectum, endometrium,
stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel,
sebaceous glands, and kerotoacanthomas.
LS Genetic Alterations
 Microsatellite Instability (MSI)
 MSI - High
 MSI - Low
 MS - Stable
 MSI – High Better Prognosis
 Most MSI Colorectal Cancers are not LS (12% of
sporadic CRC)
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Microsatellite Instability
Normal Cells
-CG-CGCGCGCG
-CG-CGCGCGCG
-CG
-CGCGCGCG-
-CG-CGCGCGCG
Normal Microsatellites
Tumor Cells
-CG-
-CG-
-CGCGCGCGCG-
-CGCGCG-
-CG-CGCG-
-CG-CGCG-CGCGCG-CGCGCGCGCG-
Microsatellite Instability
Mismatch Repair (MMR) Genes and
Proteins

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Proofread Replicated DNA
Problem will be most obvious in repetitive sequences
Defect in both copies leads to cancer
If already carries one defect, at high risk to develop a
second defect – Lynch Syndrome
 LS is Autosomal Dominant
Autosomal Dominant Inheritance
Carrier Parent
Non-carrier Parent
Aa
aa
Aa
Aa
Carrier
Carrier
1/2
aa
aa
Non-carrier
Non-carrier
1/2
Mismatch Repair (MMR) Genes
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MLH1
MSH2
MSH6
PMS2
EPCAM (Promotor for MSH2)
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MSH2
MSH6
MLH1
PMS2
Universal Tumor Testing for LS
 MSI Testing
 Inexpensive
 Prognostic and Treatment Information
 MMR Protein Testing
 Inexpensive
 Directs which gene to look at
 Confirm Positive Results with Gene Analysis
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Followup
 Genetic Counseling
 Gene Testing Appropriate Family Members
 Familial Colorectal Cancer Type X (FCRCTX)
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Treatment of Colon Cancer in LS
Patients
 Partial Colectomy
 Risk of Metachronous Cancer 16-19% at 10 years
 Total or Subtotal Colectomy with
Ileorectal/Ileosigmoid Anastomosis
 Risk of Metachronous Cancer 0-3.4% at 10 years
 Diarrhea
 Need to consider age and sphincter function
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Treatment of Rectal Cancer in LS
Patients
 Resection of Rectum with Anastomosis
 Risk of Metachronous Cancer 69% at 30 years with
colonoscopy every 1.6 years
 Total Proctocolectomy with Ileal Pouch-Anal
Anastomosis (IPAA)
 Standard of Care for cancer with UC or FAP
 LS patients older
 Total Proctocolectomy with End Ileostomy
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CRC Screening in LS Patients
 Colonoscopy every 1-3 years leads to fewer CRC and at
a later age than unscreened
 Colonoscopy every 1-3 years leads to similar CRC
mortality compared to those without LS, although
more CRC diagnosed
 More frequent colonoscopy (≤ 2 years) better
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CRC Screening in LS Patients
Guideline: Screening for CRC by colonoscopy is
recommended in persons at risk (first-degree relatives
of those affected) or affected with LS every 1 to 2 years,
beginning between ages 20−25 years or 2−5 years
before the youngest age of diagnosis of CRC in the
family if diagnosed before age 25 years.
May need to adjust based on exact family history and
which gene is mutated.
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Endometrial Cancer in LS
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Second most common cancer
75% Stage I and 88% 5 year survival
Hard to prove screening helps
Annual Pelvic Exam and Endometrial Sampling
Offered Starting at Age 30-35
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Ovarian Cancer in LS
 No data as to screening
 Transvaginal Ultrasound and CA-125 Screening does
not seem to help with BRCA1 and BRCA2 patients
 Annual Transvaginal Ultrasound Offered Starting at
Age 30-35
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Prophylactic Hysterectomy and
Oophorectomy in LS
 Retrospective analysis of 315 women with MMR
mutations
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33% Uterine cancer without surgery
No uterine cancer with surgery
5.5% Ovarian cancer without surgery
No ovarian cancer with surgery
 Guideline: Hysterectomy and Oophorectomy after
childbearing or at age 40
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Gastric Cancer in LS
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Lifetime Risk 0.2-13%
EGD every 2-3 years beginning age 30-35
Treat H.pylori if found
Modify based on family history and gene mutation
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Urinary Cancers in LS
 Not much data screening (urinalysis, urine cytology)
helps
 Inexpensive
 Noninvasive
 Easy
 Consider annually starting age 30-35
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Other Cancers in LS
 No screening or no increased screening beyond that
for usual population
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Pancreatic
Small Intestine
Prostate
Breast
 Either no clear increased risk or no good screening
test
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Questions?
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