History
Making the diagnosis of Lynch syndrome is usually a three-stage process, including review of the family cancer history, tumor testing, and genetic testing.
A considerable number of patients diagnosed with colorectal cancer have a family history of this disease; however, most patients do not have any of the known colorectal cancer syndromes. When a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) or other familial colon cancer syndrome is considered, a pedigree should be drawn of each patient.
When a pedigree is analyzed, the family’s size is an important consideration. For instance, a small family with two cases of colorectal cancer among first-degree relatives is more likely to indicate HNPCC than a large family with two cases of similar diagnosis. Patients must be asked about colorectal cancer or polyps in family members and about other associated neoplasms (see Table 2 in the Mortality/Morbidity section).
The following history findings should raise the suspicion for HNPCC:
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Multiple cases of colorectal cancer or numerous adenomatous polyps diagnosed in different generations
-
People younger than 50 years affected
-
The combination of syndrome-related tumors in other organs
-
Synchronous or metachronous tumors in one person
Significant suspicion for HNPCC should prompt further evaluation of the patient and his or her family.
Guidelines
In 1990, following a conference in Amsterdam, the International Collaborative Group (ICG) first proposed clinical criteria to identify patients at risk of developing HNPCC. These criteria, now known as the ICG or Amsterdam I criteria are predicated on an accurate family history of colorectal cancer that includes the number of affected relatives, degree of closeness, and age at diagnosis.
Amsterdam Criteria I
The Amsterdam criteria I include the following [13] :
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Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first-degree relative (parent, child, sibling) of the other two
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Two successive affected generations (one of the patients is a first-degree family member of the other patients)
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One or more colon cancers diagnosed in a relative younger than 50 years
-
FAP has been excluded.
In 1999, the Amsterdam I criteria were revised to include extracolonic cancers, known as Amsterdam II criteria.
Amsterdam Criteria II
The Amsterdam criteria II include the following [2] :
-
Three or more family members with HNPCC-related cancers,* one of whom is a first-degree relative of the other two
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Two successive affected generations (one of the patients is a first-degree family member of the other patients)
-
One or more of the HNPCC-related cancers diagnosed younger than 50 years
-
FAP has been excluded.
* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome)
Less stringent guidelines, such as the modified Bethesda criteria were established in 1997. These guidelines, for appropriate microsatellite instability (MSI) testing on colorectal tumor specimens, were used to identify families likely to have an MMR gene mutation.
The revised Bethesda guidelines for testing colorectal tumors for MSI
The revised Bethesda criteria regarding MSI testing for colorectal tumors include the following [14] :
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Colorectal cancer diagnosed in a patient who is younger than 50 years
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Presence of the synchronous or metachronous colorectal cancer or other HNPCC-associated tumors,* regardless of age
-
Colorectal cancer with the MSI-H,† histology, diagnosed in a patient who is younger than 60 years
-
Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor,* with one of the cancers diagnosed in a patient younger than 50 years
-
Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age
* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).
† MSI-H in tumors refers to changes in two or more of the five National Cancer Institute (NCI)-recommended panels of MSI markers.
The Bethesda criteria may be more sensitive than either form of the Amsterdam criteria in identifying families with HNPCC, but they are not diagnostic of HNPCC, because MSI also occurs in 15% of sporadic tumors. These patients should undergo a DNA test for confirmation (see image below).
Hereditary Nonpolyposis Colorectal Cancer. Diagnostic approach for patients with colorectal tumors.
Criteria for referral to genetic counseling have also been developed, as follows. [15] Endoscopic surveillance should be performed if genetic testing is refused, unavailable, or offers no information.
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Adenomatous polyps in patients younger than 40 years
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Greater than 10 or greater than 100 adenomatous polyps in the classic FAP
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Multiple colorectal carcinomas or other HNPCC-related tumors,* in one individual
-
Colorectal cancer or endometrial cancer diagnosed in a patient younger than 50 years
-
Two first-degree relatives with colorectal carcinoma or HNPCC-related tumor,* independent of age at diagnosis
* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome)
Physical Examination
Despite the term hereditary nonpolyposis, people with hereditary nonpolyposis colorectal cancer (HNPCC) actually do have polyps. However, these individuals tend to have less than 100; the number is usually much higher in other forms of inherited colorectal cancers.
Polyp formation starts in the late second and early third decade of life. Although these cancers are often asymptomatic in their early stages, the following signs and symptoms may develop as the cancer advances:
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Changes in bowel habits (eg, constipation or diarrhea that persists for longer than several days)
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Visible or occult blood in stool (positive fecal occult blood test)
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Black, tarry stool (may represent bleeding above the ligament of Treitz)
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Iron deficiency without an identifiable cause
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Abdominal pain, cramps, or frequent feeling of distention (or bloating)
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Fatigue or weakness
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Decline in appetite
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Unexplained weight loss
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Hereditary Nonpolyposis Colorectal Cancer. Example of an autosomal dominant pedigree.
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Hereditary Nonpolyposis Colorectal Cancer. Diagnostic approach for patients with colorectal tumors.
Tables
- Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair, identified with the frequencies below.
- Table 2. Incidence of different types of cancers in individuals with Lynch syndrome and those in the general population.
- Table 3. IHC staining findings.
- Table 4. Netherlands surveillance protocol for carriers of an MMR-gene mutation.
- Table 5. Dukes classification.
Mismatch Excision Repaired MMR |
Chromosome Location |
Frequency of HNPCC Cases |
MSH2 |
2p16 |
45-50% |
MLH1 |
3p22.3/A> |
20% |
MSH6 |
2p16 |
10% |
PMS2 |
7p22.1 |
1% |
PMS1 |
2q32.2 |
Rare |
MSH3 |
5q14.1 |
Rare |
EXO1 |
1q43 |
Rare |
Other genes not yet discovered |
|
20-25% |
Type of Cancer |
General Population Risk (by age 70 y) |
Lynch Syndrome Risk (by age 70 y) |
Endometrial |
1.5% |
30-40% |
Ovarian |
1% |
9-12% |
Upper Urinary Tract* |
Less than 1% |
4-10% |
Stomach |
Less than 1% |
13% (higher in Asians) |
Small Bowel |
Less than 1% |
1-3% |
Brain |
Less than 1% |
1-4% |
Biliary Tract |
Less than 1% |
1-5% |
MMR Mutations |
Protein Staining |
|||
MLH1 |
MSH2 |
MSH6 |
PMS2 |
|
MLH1 |
- |
+ |
+ |
+ |
MSH2 |
+ |
- |
- |
+ |
MSH6 |
+ |
+ |
- |
+ |
PMS2 |
+ |
+ |
+ |
- |
Surveillance |
MLH1, MSH2, MSH6 (males) |
MSHG (females) |
Colon |
Colonoscopy, every 1-2 years, starting at age 20-25 years |
Colonoscopy, every 1-2 years, starting at age 30 years |
Endometrium |
|
Ultrasonography and CA-125, every 1-2 years, starting at age 30-35 years; consider hysterectomy after age 50 years |
Upper Urinary Tract* |
Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Stomach |
Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Stage |
Tumor |
Node |
Metastasis |
Dukes |
|
|
|
|
|
Stage 1 |
T1 |
N0 |
M0 |
Dukes A |
|
T2 |
N0 |
M0 |
|
|
|
|
|
|
Stage II |
T3 |
N0 |
M0 |
Dukes B |
|
T4 |
N0 |
M0 |
|
|
|
|
|
|
Stage III |
Any T |
N1 |
M0 |
Dukes C |
|
Any T |
N2, N3 |
Mo |
|
|
|
|
|
|
Stage IV |
Any T |
Any N |
M1 |
Dukes D |
