Lynch Syndrome

AUTHOR: Fred F. Ferri, MD

Definition

Lynch syndrome is a hereditary predisposition to malignancy of the colon that is explained by a germline mutation in a DNA mismatch repair gene. The Lynch syndrome phenotype is characterized by a predominance of cancers on the right side of the colon and a propensity for synchronous and metachronous colorectal cancers.

Synonyms

Hereditary nonpolyposis colorectal cancer

HPNCC

Hereditary site-specific colon cancer

ICD-10CM CODE
C18.9		Malignant neoplasm of colon, unspecified

Epidemiology & Demographics

The lifetime risk for developing colon cancer in the U.S. is approximately 6%. Up to 30% of colon cancer is inherited, and 3% may be attributable to Lynch syndrome. The incidence of Lynch syndrome is estimated to be between 1:660 and 1:2000. Lynch syndrome is the most common form of hereditary colon cancer. The average age of diagnosis for Lynch syndrome is 45 yr, although diagnosis can occur as early as the second decade or as late as the seventh decade.

Risk Factors

Family history of colon cancer or other hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers such as endometrial (up to 40% of women with Lynch syndrome may develop endometrial cancer), biliary tract, ovarian, stomach, upper urinary tract, or brain. Table E1 summarizes the risk of Lynch syndrome.

TABLE E1 Risk of Lynch Syndrome

Condition		Risk (%)
Endometrial cancer at any age		1.8
Endometrial cancer diagnosed before 50 yr of age		9
Endometrial and colon cancer at any age		18
Endometrial and colon cancer before 50 yr of age		43
Endometrial and ovarian cancer		7

From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2017, Elsevier.

Genetics

Autosomal-dominant inheritance pattern

Physical Findings & Clinical Presentation

Changes in bowel habits (prolonged constipation)
Melena
Hematochezia
Abdominal pain
Unexplained weight loss
Decreased appetite
Right-sided colon cancer (70% to 85% of cases)

Etiology

Lynch syndrome is thought to be secondary to germline mutations in DNA mismatch repair genes. The predominant genes involved are MSH2 and MLH1, which are tumor suppressor genes, although other genes have documented involvement (PMS1, PMS2, MSH6, and EpCAM). Mutations in these genes prevent repair of DNA mismatches during DNA replication. This is most prevalent in regions of DNA called microsatellites, causing DNA microsatellite instability and leading to an increased risk for malignancy, especially colon cancer. MSH6 mutations are associated with a markedly lower cancer risk than MLH1 or MSH2 mutations.

Diagnosis ⬆ ⬇

Differential Diagnosis

Familial adenomatosis polyposis
Peutz-Jeghers syndrome
Juvenile polyposis
Nonhereditary colorectal cancer. Table E2 compares Lynch syndrome and sporadic colorectal cancer
Gardner syndrome

TABLE E2 Comparison of Clinical Features in Lynch Syndrome and Sporadic Colorectal Cancer

Clinical Feature	Lynch Syndrome	Sporadic Colorectal Cancer
Mean age at diagnosis (year)	45	67
Multiple colon cancers	35%	4%-11%
Synchronous colon cancers	18%	3%-6%
Metachronous colon cancers	24%	1%-5%
Proximal location of the initial cancer ∗	72%	35%
Increased risk of malignant tumors at other sites	Yes	No
Mucinous and poorly differentiated colon cancers	Common	Infrequent
Prognosis	Favorable ^†	Variable

^∗Proximal to the splenic flexure.

^†Patients whose tumors demonstrate microsatellite instability have a more favorable prognosis than those with microsatellite-stable tumors.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Workup

If an individual presents with numerous adenomatous polyps or has multiple relatives with cancer at a young age, a family history complete with pedigree must be obtained. Clinical diagnosis of the Lynch syndrome can be made with the Amsterdam or Bethesda criteria (Box E1) as well as newer models such as prediction model for gene mutations 5 (PREMM5).

Revised Amsterdam (II) criteria (must meet all criteria):
1. HNPCC-associated carrier diagnosis in at least three individuals in the family
2. One of the patients is a first-degree family member of two other patients
3. Involved patients occur in at least two successive generations with diagnosis of HNPCC
4. At least one diagnosis in family of HNPCC was made before age 50
5. The diagnoses are histologically confirmed
6. Familial adenomatous polyposis is excluded
Bethesda criteria (must meet all criteria):
1. Colorectal cancer before age 50
2. Multiple colorectal cancers or other HNPCC-related cancers such as biliary tract, endometrial, stomach, or ovarian
3. Colorectal cancer with microsatellite instability histology <60 yr of age
4. Colorectal cancer or HNPCC-related cancer in first-degree relative <50 yr of age
5. Colorectal cancer or HNPCC-related cancer in at least two first- or second-degree relatives, any age
If criteria for the Lynch syndrome are not met, no further analysis is necessary (although a genetic syndrome cannot be definitively excluded and genetic referral may be warranted).

BOX E1 Amsterdam II Criteria for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome)

Criteria defined by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer

At least three relatives with CRC (one must be a first-degree relative of the other two) or Lynch syndrome-associated cancer ^∗

CRC involving at least two successive generations

One or more cancer cases before age 50 yr

Familial adenomatous polyposis should be excluded

Tumors should be verified by histologic examination

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Laboratory Tests

If a patient meets criteria for Lynch syndrome, immunohistochemistry can be performed for the presence or absence of mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Rarely, MLH3 is identified.
Microsatellite instability analysis should also be performed if criteria for Lynch syndrome are met.

∗Endometrium, ovary, stomach, ureter/renal pelvis, pancreas, brain, hepatobiliary tract, small intestine, and multiple sebaceous adenomas and carcinomas and keratoacanthomas in the Muir-Torre variant of Lynch syndrome.

Treatment ⬆ ⬇

If the mutation has been identified in a family member, screening for this mutation can be performed via genetic testing. Informed consent must be obtained after a thorough explanation has been provided to each individual. Criteria for referral to a genetic counselor for suspected Lynch syndrome is summarized in Box E2.
Surveillance using colonoscopy can be performed in individuals who screen positive, while those who screen negative can be discharged. The mismatch repair gene that is mutated guides screening.
According to the Netherlands Surveillance Protocol, for example, individuals with mutations in MLH1, MSH2, or MSH6 should have colonoscopies every 1 to 2 yr starting at age 20 to 25 yr; urine cytology every 1 to 2 yr starting at age 30 to 35 yr; esophagogastroduodenoscopy every 1 to 2 yr starting at age 30 to 35 yr; and, in females, ultrasound of endometrium and CA-125 every 1 to 2 yr starting at age 30 to 35 yr.
Helicobacter pylori testing is also indicated in patients with Lynch syndrome or at high risk for it.
Aspirin may be protective against colorectal cancer in Lynch syndrome patients.

BOX E2 Criteria for Referral to a Genetic Counselor for Suspected Lynch Syndrome

Bethesda Guidelines

Amsterdam Criteria fulfilled

Persons with two relatives with Lynch syndrome

Colorectal cancer and first-degree relative with a Lynch cancer before 45 yr or a first-degree relative with an adenoma before 40 yr of age

Colorectal cancer or endometrial cancer before 45 yr of age

Right-sided, undifferentiated colon cancer before 45 yr of age

Signet ring colon cancer before 45 yr of age

Adenoma before 40 yr of age

Referrals

To gastroenterology for surveillance colonoscopies
To genetic counselor if patient satisfies Bethesda criteria
To psychologist as necessary for psychologic support

Pearls & Considerations ⬆

Before genetic testing is instituted, informed consent must be obtained because consequences of this testing include the necessity of lifelong screenings such as colonoscopies.
The risk of pancreatic cancer is increased in families with Lynch syndrome compared with the U.S. population.
Familial Colorectal Cancer Type X refers to patients who meet the Amsterdam criteria for HPNCC but have no molecular evidence of a mismatch repair (MMR) deficiency. These patients have a lower risk of colon cancer and no increased risk of extracolonic cancer compared to those with Lynch syndrome.

Patient & Family Education

For information on local genetic counselors, visit the National Society of Genetic Counselors website at http://www.nsgc.org/.
For information on Lynch syndrome, visit http://www.mayoclinic.com/health/lynch-syndrome/DS00669.

Related Content

Colorectal Cancer (Related Key Topic)

Familial Adenomatous Polyposis and Gardner Syndrome (Related Key Topic)

Peutz-Jeghers Syndrome and Other Polyposis Syndromes (Related Key Topic)

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆