HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (LYNCH SYNDROME)

Morning Report May 20, 2009Bridger Clarke

Henry T Lynch, MD Born in Lawrence, Massachusetts, on 4

January 1928. Dropped out of high school at the age of

fourteen and joined the Navy during WWII. Discharged from the Navy in 1946, he

became a professional boxer in upper New York State

Obtained his GED and attended the University of Oklahoma, graduating in 1951.

Eventually attended medical school at UT Galveston and residency at University of Nebraska, completed in 1964.

History In 1962, Charles Magnuson, a gastroenterologist

at the Omaha VA, asked Lynch to consult on a patient with a strong family history of CRC.

Lynch presumed FAP, but discovered a strong familial predilection for CRC in the absence of multiple polyps.

He presented his findings at a meeting of the American Society of Human Genetics in 1964.

History The story goes that his presentation reminded

Marjorie Shaw, a medical geneticist at the University of Michigan, of another family with similar characteristics.

In 1966, she and Lynch published their first report of these two families, family N from Nebraska, and family M from Michigan.

Initially called “cancer family syndrome” (CFS), it is now kn0wn as Lynch Syndrome.

Lynch Syndrome Most common of the inherited colon cancer

susceptibility syndromes (FAP, JP).

“HNPCC” can be misleading as the disorder predisposes to a variety of other cancers.

The designation of “Lynch Syndrome I and II” is also going out of favor.

Mean age of diagnosis is 47 years old, as opposed to 64 years old in patients without the syndrome.

10% have multiple tumors at the time of diagnosis

Accounts for 2-3% of colorectal cancers and ~2% of uterine cancers.

Approximately 4,000 new cases of Lynch Syndrome each year.

CRC in Lynch Syndrome Lifetime risk of colorectal cancer is ~70%

CRCs in Lynch Syndrome evolve from adenomas, but differ from sporadic cancers: More proximal Larger Flatter More high grade dysplasia and villous histology

The adenoma-carcinoma sequence progresses more rapidly, and new cancers can occur within 2-3 yrs of a negative colonoscopy.

Extra-colonic Cancers Endometrial cancer is the most common,

occurring in up to 70% of women who are gene carriers.

Other sites include: Ovarian, gastric, small bowel, renal pelvis,

ureter, pancreatic, and brain cancers.

Debate about whether prostate and breast cancer are part of Lynch Syndrome.

Genetics Caused by a mutation in one of several DNA

mismatch repair (MMR) genes (MLH-1, MSH-2, MSH-6).

The MMR system recognizes base-pair mismatches that occur during DNA replication and repairs them.

DNA mismatches commonly occur in repetitive sequences called microsatellites.

Loss of MMR leads to expansion/contraction of microsatellite region, termed ‘microsatellite instability’, and an increased rate of mutation.

Amsterdam II Criteria: Three or more family members with HNPCC-

related cancers, one of whom is a first degree relative of the other two

Two successive affected generations

One or more of the HNPCC-related cancers

Diagnosed under age 50 years

FAP has been excluded.

Who should be tested? 1. CRC in pt <50 years old.

2. Any patient with synchronous/metachronous CRC or HNPCC-associated tumors, regardless of age.

3. CRC with the MSI-H-like histology in a pt <60 yo.

4. CRC in a patient with one or more first-degree relatives with a HNPCC-related tumor diagnosed <50 yo.

5. CRC in a patient with >1 first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Screening and Surveillance

Screening recommendations for patients with MMR gene mutations:

Colonoscopy every 1-2 years beginning at age 20, or 10 years earlier than the youngest age of colon cancer diagnosis in the family (whichever comes first).

In families with MSH6 mutations, recommendation is to start at age 30 since the age of onset of colon cancer is later in these families

Screening and Surveillence Endometrial and Ovarian cancer:

Annual screening at age 30, or 5 to 10 years before the earliest age of diagnosis in the family (whichever is earlier). Pelvic exam and endometrial aspirate and transvaginal ultrasound are recommended.

Discussion of prophylactic TAH-BSO at 35 years old.

Annual urinalysis with cytology at age 25-35.

Annual skin exam Periodic upper endoscopy