Case Study # 31

Hereditary Nonpolyposis Colorectal Cancer
- Hillary Bownik, BA
- David Jager, MD
- Marie L. Borum, MD, EdD, MPH

Learning Objectives

1)Explain the epidemiology and prevalence of Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
2) Describe the typical presentation and disease progression of HNPCC
3) Name the diseases or medical problems that HNPCC place a patient at increased risk
4) Describe how HNPCC is diagnosed
5) Name the genes involved and mode of inheritance of HNPCC
6) Create a genetic counseling plan for a patient and the family members of a person with HNPCC
7) Describe the screening recommendations and treatment for patients with HNPCC
8) Name and describe the variations of HNPCC

Pretest Questions

1) Which tumor maker correlates with progression and regression colorectal tumors?

 a.) CEA
 b.) CA-125
 c.) PSA
 d.) AFP (alpha-fetoprotein)
 e.) HCG

2) In the United States, what percentage of the total colorectal cancer risk does HNPCC account?

a) 15-25%
b) 80-90%
c) 10-15%
d) 40-45%
e) 2-3%

3) What percentage of HNPCC patients will develop colorectal adenomas?
           
a) 66%
b) 95%
c) 50%
d) 80%
e) 7%

4)Which malignancy is a patient with HNPCC at higher risk for compared to the general population?

a) Endometrial Cancer
b) Ovarian Cancer
c) Colorectal Cancer
d) Upper Urinary Tract Cancer
e) Gastric Cancer
f) Glioblastoma
g) Skin Cancer
h) all of the above

5. Which of the following genes plays a role in the development of Familial HNPCC?

a) ApoA2 and ApoE4
b) BA4 and NF2
c) BRCA 1 and BRCA 2
d) hMLH1 and hMSH2
e) APC

Answers: 1) a 2) e 3) d 4) h 5) d

Case Study

An anxious 34 year old female is seen at your office for her annual routine physical. Her uncle died from colon cancer last month at the age of 52. Upon further investigation, she reports that her mother also died of colon cancer at age 50. She believes two of her cousins, with whom she is not close, also have been diagnosed with cancer. After she obtained further information about her cousins’ diagnosis, a subsequent appointment reveals that her two cousins were diagnosed with colorectal cancer and endometrial cancer, at 37 and 40 respectively. The patient demands to be thoroughly screened for all possibilities of malignancy. Physical exam reveals no abnormalities. Labs were found to be within normal limits, and fecal occult blood testing was negative. How should you proceed? 

Explain the epidemiology and prevalence of HNPCC:

    Colorectal cancer is the third leading cause of cancer and the second leading cause of cancer related deaths in the United States. There are an estimated 136,000 new cases and over 56,000 deaths expected from the disease this year alone.  The etiology of colon cancer appears to be heterogenous with 80% of patients diagnosed with sporadic disease and no evidence of an inherited disorder. In the remaining 20% of cases, family history and certain genetic predisposition places patients at increased risk for developing colon cancer.  One such disease is hereditary nonpolyposis colorectal cancer (HNPCC). It accounts for 3-5% of the total colon cancer risk and 0.8-1.4% of total endometrial cancers. The disease also places individuals at higher risk for developing ovarian, gastric, hepatobiliary, upper urinary tract, brain, and skin cancer.
Explain the Disease Progression in a Patient with HNPCC:

Patients with HNPCC have an overall lifetime risk of developing colorectal cancer of 70-80%.  Unlike patients with FAP, the precursor to colorectal cancer in HNPCC patients is usually one discrete, proximal adenoma containing high-grade dysplasia. Compared with the general population, these lesions occur at a younger age (average age 44), occur more often on the right side of the colon (60-80% proximal to the splenic flexure), and are more villous in nature.

Although HNPCC predisposes patients to a number of other malignancies, patient’s risk is most increased for endometrial and ovarian cancers. By 70 years of age, female patients with HNPCC have a 39% lifetime risk of endometrial cancer and 9% lifetime risk of ovarian cancer. In fact, 50% of females with HNPCC present first with endometrial cancer at the mean age of 46 years old.  The mean age of ovarian cancer diagnosis is 43 years old. However, it is important to remember that 30% of HNPCC patients with ovarian cancer are diagnosed before the age of 40.

What diseases or medical problems does HNPCC place a patient at increased risk?
The following are is a list of malignancies in which HNPCC increases the risk in comparison to the general population:

1. Gastric Cancer- HNPCC increases the risk to 11-19% in comparison to <1% risk found in the general population. The mean age of onset is 56 years old. At the time of diagnosis, intestinal-type adenocarcinoma is the most commonly reported pathology.
2. Upper Urinary Tract-HNPCC increases risk to 4-5% compared to a <1% risk found in the general population. The mean age of onset is 55 years old.  Most commonly, transitional cell tumors are found in the ureter and renal pelvis.
3. Hepatobiliary Tract- HNPCC increases risk to 2-7% in comparison to < 1% risk found in the general population. The mean age of onset is not reported.
4. Small Bowel- HNPCC increases risk to 1-4% compared to a <1% found in the general population. The mean age of onset is 55 years old.  Tumors most often adenocarinoma of the duodenum and jejunum.
5. Brain- HNPCC increases risk to 1-3% in comparison to <1% found in the general population. The mean age of onset is 50 years old. The most common type of CNS tumor found is glioblastoma.

Diagnosis of HNPCC:
Physicians can use the Amsterdam or Amsterdam II guidelines for a clinical diagnosis of HNPCC.
Amsterdam Criteria- all of the following must be included to make a diagnosis:
1) Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first-degree relative of the other two.
2) Two successive generations affected
3) One or more colon cancers diagnosed under the age of 50.
4) Familial Adenomatous Polyposis must be excluded
These criteria were thought to be too restrictive for clinical purposes, and were later modified to include the other HNPCC-related cancers.
Amesterdam II Criteria-all of the following must be included to make a diagnosis:

1. Three or more family members with HNPCC-related cancers, one of whom is a first-degree relative of the other two
2. Two successive affected generations
3. One or more of the HNPCC-related cancers diagnosed under the age of 50
4. Familial Adenomatous Polyposis has been excluded

When a patient meets the criteria of either of the above guidelines, the diagnosis is then confirmed by molecular genetic testing for germline mutations in one of several mismatch repair genes.
Is HNPCC genetic? If so, what genes are involved with inherited forms of HNPCC? What genetic counseling could you offer HNPCC patients and their family members?
HNPCC is acquired through autosomal dominant inheritance. It is caused by a germline mutation in one or more of the following DNA mismatch repair genes: hMLH1 located on chromosome 3p21, hMSH2 located on 2p22-p21, hPMS2 located on 7p22, and hMSH6 located on 2p16.  However, over 95% of mutations causing HNPCC are found on mismatch repair genes hMSH2 and hMLH1. Another identifying genetic factor found in 90% of colorectal DNA of HNPCC patients but lacking in normal colorectal mucosa is microsatellite instability (MSI). MSI is the contraction or expansion of short repeated DNA sequences caused by the deletion or insertion of repeated units. As a result, MSI testing using Bethesda markers is now used as a screening test on the tumor tissue of individuals possibly infected with HNPCC. If this test shows high MSI in tumor DNA, mutations in hMSH2 an hMLH1 genes are tested for by using confirmational sensitive gel electrophoresis (CSGE) or single-strand conformation polymorphism (SSCP). Once a specific genetic mutation is found in the tumor of an individual with HNPCC, then other members of the patient’s family can be tested. However, if a patient has low MSI markings, then further testing is usually not pursued.
“At risk relatives” are considered to be first-degree relatives of a known individual with HNPCC. The majority of individuals diagnosed with HNPCC have inherited the condition from one of their parents. If clinical and family history cannot identify from which parent the inherited mutation occurred, molecular genetic testing should be offered to both parents to determine which one has the gene mutation. However, multiple characteristics of the disease result in not all patients with an HNPCC gene mutation having a parent with the disease. These characteristics include: incomplete penetrance, variable age of cancer development, cancer screening and prophylactic surgery, and early death in individuals not tested for the disease.

Siblings of an HNPCC patient have a 50% risk of inheriting the mutation. Thus, once the mutation has been identified in an HNPCC  individual, molecular genetic testing for the identified mutation should be offered to all siblings. Keep in mind, siblings should still be considered at risk even if the parents have not had cancer because most cases of HNPCC are inherited.

Offspring of an individual with HNPCC also have a 50% chance of inheriting the mutation. All offspring should undergo molecular genetic testing after a specific genetic mutation in an HNPCC patient has been identified.

In summary, what individuals should be offered testing?
Bethesda Guidelines recommend that MSI testing should be offered to colon cancer patients meeting one or more of the following criteria:

1. Family history meeting the Amsterdam diagnostic criteria for HNPCC
2. Two HNPCC-related cancers, including synchronous and metachronous colorectal cancer or associated extracolonic cancers 
3. Colorectal cancer and a first-degree relative with colorectal cancer or HNPCC-related extra-colonic cancer or colorectal adenoma; one of the cancers diagnosed before age 45 years or the adenoma diagnosed before age 40 years
4. Colorectal cancer or endometrial cancer diagnosed before age 45 years (now revised to age 50 years) 
5. Right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology diagnosed before age 45 years 
6. Signet-ring cell type colorectal cancer diagnosed before age 45 years 
7. Adenomas before age 40 years

What are the screening and treatment recommendations for HNPCC?

First degree relatives of HNPCC individuals who decline or have not undergone genetic testing should receive a colonoscopy every one to two years beginning at age 25. They should received annual colonoscopies beginning at age 40. Individuals with a known genetic mutation should received annual colonoscopies at the age of 25 or 5 years before the youngest known case of colon cancer, whichever occurs first. Screening for endometrial cancer should be performed annually in females beginning at age 25 to 35. However, the optimal approach to screening for endometrial cancer continues to be disputed. As a result, transvaginal ultrasonography or endometrial aspiration are often used. There is insufficient evidence in recommending a prophylactic hysterectomy and oophorectomy in females with HNPCC. However, female patients should be properly counseled that this is an available option.

When colorectal cancer develops in a patient with HNPCC, a subtotal colectomy with ileorectal anastomosis is recommended. Surgical resection is recommended because of the high recurrence rates found in these patients.

What are the different variations of HNPCC?

1. Turcot’s Syndrome-  is defined as colorectal cancer or colorectal adenomas in addition to tumors of the central nervous system or brain. A definitive association between both HNPCC and FAP and brain tumors has been observed.  The clinical presentation varies from numerous colonic polyps to a single polyp or colorectal cancer. The pathology of the CNS tumor can actually help distinguish between the underlying genetic cause. APC mutations are more commonly associated with medulloblastomas. On the otherhand, mismatch repair mutations are more commonly associated with glioblastoma. These tumors also exhibit MSI.
2. Muir-Torre syndrome.- is defined by HNPCC in addition to the presence of sebaceous neoplasms such as: adenomas, epitheliomas, carcinomas, and keratoacanthomas. These sebaceous neoplasms exhibit MSI. Patients sometimes exhibit café au lait spots in addition to the sebaceous gland tumors and keratoacanthomas.
3. Homozygous mismatch repair mutations-  Rare cases have documented homozygous mutations in MLH1, MSH2, and PMS2. Affected individuals present with earlier onset of colon cancer, usually prior to the second decade of life. [

What tumor markers are used for evaluation of the recurrence of colorectal cancer?

    Carcinoembryonic Antigen is an oncofetal glycoprotein that is expressed in mucosal cells and overexpressed in adenocarcinoma, especially colorectal cancer. Because the glycoprotein is only elevated in 25% of patients with colorectal cancer confined to the colon, it should not be used as a screening method for colon cancer. It is also elevated in benign disease such as: inflammatory bowel disease, pancreatitis, hypothyroidism, biliary obstruction, peptic ulcer disease, and cirrhosis. Usually, levels greater than 10 ng/mL are rarely caused by benign disease. However, it is a useful tool in screening patients who are at higher risk for developing colorectal recurrence after surgical resection, usually defined as stage II or above at time of diagnosis. CEA levels typically return to normal 6 weeks after surgical resection. Thus, a CEA level should be ordered every 2-3 months in patients for at least 2 years after surgery to monitor for colorectal cancer recurrence.

HNPCC Patient Internet Resources:

1. HNPCC SUPPORT GROUP http://www.generations.hk.com/background/SHG_Intro.php3
   
   
2. HNPCC PATIENT FACT INFORMATION       

www.internalmedicine.osu.edu/genetics/5290.cfm
or
www.cdc.gov/genomics/famhistory/famhist.htm

RESOURCES:

1. Wee, CC, McCathy EP, Phillips RS. Factors associated with colon cancer screening: the role of patient factors and physician counseling. Preventative Medicine. 2005;41(1):23-29.
2. Burt, RW, DiSario JA, Cannon-Albright, L. Genetics of Colon Cancer: Impact of inheritance on colon cancer risk. Annu Rev Med 1995; 46:371.
3. Lindor, NM, Green MH, and the Mayo Familial Cancer Program. The concise handbook of family cancer syndromes. J Natl Cancer Inst 1998; 90:1039
4. Giardiello, FM, Brensinger, JD, Peterson GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001; 121:198.
5. Lynch, HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: An updated review. Gastroenterology 1993; 104:1535.
6. AGA technical review: Hereditary Colorectal Cancer and Genetic Testing. Retrieved from Up to Date on August 18, 2006.