Hereditary Non-Polyposis Colorectal Cancer
Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant condition that accounts for about 2-5 % of colorectal tumors. “Non-polyposis” means that it may present without polyps unlike another inherited condition Familial Adenomatous Polyposis. Patients with HNPCC will present with colon cancer at an earlier age about 44 years than the general population about 60-65 years. The cancer usually occurs over at the right sided colon.
Dr Henry T Lynch first described this syndrome in 1966 and hence HNPCC is also known as Lynch Syndrome. Lynch Syndrome 1 refers to familial colon cancer whereas Lynch Syndrome II refers to HNOCC associated with other cancers of the reproductive system or the gastrointestinal tract.
Before genetic diagnosis is available in the 1990s, diagnosis is usually based on a comprehensive and detailed family history.
Cancer Risks for patients with HNPCC
Cause of HNPCC
The main cause is due to the inherited mutation of one of the DNA mismatch repair gene (MMR) genes. Usually MMR genes will produce proteins that identify and rectify any sequence mismatches during DNA replication. However in HNPCC, the mutation inactivates MMR resulting in more cell mutations and increase cancer transformation in otherwise normal cells.
The MMR genes involved include hMMSH2 and hMSH6 on band 2p16, hMLH1 on band 3p22, hPMS1 on 3p32, hPMS2 on band 7q22, hMSH3 on band 5q14.1 and EXO1 on band 1q43.
Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant condition that accounts for about 2-5 % of colorectal tumors. “Non-polyposis” means that it may present without polyps unlike another inherited condition Familial Adenomatous Polyposis. Patients with HNPCC will present with colon cancer at an earlier age about 44 years than the general population about 60-65 years. The cancer usually occurs over at the right sided colon.
Dr Henry T Lynch first described this syndrome in 1966 and hence HNPCC is also known as Lynch Syndrome. Lynch Syndrome 1 refers to familial colon cancer whereas Lynch Syndrome II refers to HNOCC associated with other cancers of the reproductive system or the gastrointestinal tract.
Before genetic diagnosis is available in the 1990s, diagnosis is usually based on a comprehensive and detailed family history.
Cancer Risks for patients with HNPCC
- They have a 70-80% risk of developing colorectal tumor as compared to the general population. They also have an increased risk of developing a second primary colorectal cancer.
- Female patients have 30-40% lifetime risk of developing endometrial cancer and 9-12% lifetime risk of ovarian cancer.
- Patients may also develop other cancers such as Stomach (13% lifetime risk), hepatobiliary tract (Bile Duct and liver about 1-5% lifetime risk), small intestine (1-3% lifetime risk), urinary tract (4-10% lifetime risk), brain (1-4 % lifetime risk) as well as skin tumors.
- Skin tumors include sebaceous adenomas, sebaceous carcinomas, keratoacanthomas and epitheliomas. Patients who develop sebaceous gland tumors belong to the Muir-Torre variant of Lynch Syndrome.
Cause of HNPCC
The main cause is due to the inherited mutation of one of the DNA mismatch repair gene (MMR) genes. Usually MMR genes will produce proteins that identify and rectify any sequence mismatches during DNA replication. However in HNPCC, the mutation inactivates MMR resulting in more cell mutations and increase cancer transformation in otherwise normal cells.
The MMR genes involved include hMMSH2 and hMSH6 on band 2p16, hMLH1 on band 3p22, hPMS1 on 3p32, hPMS2 on band 7q22, hMSH3 on band 5q14.1 and EXO1 on band 1q43.
Inheritance of HNPCC
Everyone inherit one copy of gene from the mother and one from the father. HNPCC is autosomal dominant meaning only one gene mutation in either copy inherited is sufficient enough to cause HNPCC to be inherited. This means that a patient with Lynch syndrome has 50% chance of passing the mutation to the children. The inheritance does not skip generation and both males and females have equal chance of inheriting it.
Some patients may not have any affected parent. These patients have spontaneous gene mutations. Once acquired this mutation, they will pass it down to their children.
Even if the patient has undergone operation they will still pass down the genes to their children.
Everyone inherit one copy of gene from the mother and one from the father. HNPCC is autosomal dominant meaning only one gene mutation in either copy inherited is sufficient enough to cause HNPCC to be inherited. This means that a patient with Lynch syndrome has 50% chance of passing the mutation to the children. The inheritance does not skip generation and both males and females have equal chance of inheriting it.
Some patients may not have any affected parent. These patients have spontaneous gene mutations. Once acquired this mutation, they will pass it down to their children.
Even if the patient has undergone operation they will still pass down the genes to their children.
Clinical Presentation of HNPCC
1. Colorectal tumor : patients may present with rectal bleeding, change in bowel habit, change in stool consistency, abdominal pain, iron deficiency anemia, loss of appetite and loss of weight.
2. Endometrial cancer: Patients may present with abnormal vaginal bleeding (prolonged periods, heavy periods or inter-menstrual bleeding), post-menopausal bleeding or a bulky uterus.
3. Ovarian Cancer: Patients may have no specific symptoms. They may present at later stages with an abdomen mass, abdomen distension or change in bowel and urinary habits when the cancer has spread to the colon or bladder.
Diagnosis of HNPCC
In 1990, the International Collaborative Group (ICG) proposed the AMSTERDAM I criteria to identify patients at risk of developing HNPCC.
Amsterdam Criteria I
1. 3 or more family members who has confirmed colorectal cancer, one of whom is the first degree relative (child, sibling, parent) of the other 2.
2. 2 successive affected generations of which 1 of the patients are a 1st degree family member of other patients.
3. One or more colon cancers diagnosed in patients younger than 50 years old.
4. Familial Adenomatous Polyposis has been excluded
In 1999, Amsterdam I criteria has been modified to include other non- colon cancers and is known as Amsterdam II Criteria.
Amsterdam II Criteria
1. 3 or more family members who has HNPCC related cancers (Colorectal cancer, endometrial cancer, ovarian cancer, small bowel cancer, transitional cell carcinoma of upper urinary tract, brain cancer, stomach cancer and sebaceous gland skin cancer), one of whom is the 1st degree relative of the other 2.
2. 2 successive affected generations of which 1 of the patients are a 1st degree family member of other patients.
3. One or more colon cancers diagnosed in patients younger than 50 years old.
4. Familial Adenomatous Polyposis has been excluded
Modified Bethesda criteria established in 1997 is a less stringent guideline for appropriate microstatellite instability (MSI) testing on colorectal tumor specimens and is used to identify families that are likely to have MMR gene mutation. It is more sensitive than Amsterdam criteria in identifying families with HNPCC but they are not diagnostic of HNPCC as MSI may occur in 15% of sporadic cancers.
Revised Bethesda Guidelines
1. Colorectal cancer diagnosed in patient younger than 50 years old.
2. Presence of colorectal tumor or other HNPCC related tumors regardless of age.
3. Colorectal tumor with MSI-H, HNPCC related tumors diagnosed in patients younger than 60 years old.
4. Colorectal cancer diagnosed in one or more 1st degree relatives with HNPCC related tumors, with one of the cancers diagnosed in patient younger than 50 years.
5. Colorectal cancer diagnosed in 2 or more 1st or 2nd degree relatives with HNPCC related cancers, regardless of age.
Genetic counseling and genetic testing are then recommended for families who fulfill the Amsterdam criteria.
1. Colorectal tumor : patients may present with rectal bleeding, change in bowel habit, change in stool consistency, abdominal pain, iron deficiency anemia, loss of appetite and loss of weight.
2. Endometrial cancer: Patients may present with abnormal vaginal bleeding (prolonged periods, heavy periods or inter-menstrual bleeding), post-menopausal bleeding or a bulky uterus.
3. Ovarian Cancer: Patients may have no specific symptoms. They may present at later stages with an abdomen mass, abdomen distension or change in bowel and urinary habits when the cancer has spread to the colon or bladder.
Diagnosis of HNPCC
In 1990, the International Collaborative Group (ICG) proposed the AMSTERDAM I criteria to identify patients at risk of developing HNPCC.
Amsterdam Criteria I
1. 3 or more family members who has confirmed colorectal cancer, one of whom is the first degree relative (child, sibling, parent) of the other 2.
2. 2 successive affected generations of which 1 of the patients are a 1st degree family member of other patients.
3. One or more colon cancers diagnosed in patients younger than 50 years old.
4. Familial Adenomatous Polyposis has been excluded
In 1999, Amsterdam I criteria has been modified to include other non- colon cancers and is known as Amsterdam II Criteria.
Amsterdam II Criteria
1. 3 or more family members who has HNPCC related cancers (Colorectal cancer, endometrial cancer, ovarian cancer, small bowel cancer, transitional cell carcinoma of upper urinary tract, brain cancer, stomach cancer and sebaceous gland skin cancer), one of whom is the 1st degree relative of the other 2.
2. 2 successive affected generations of which 1 of the patients are a 1st degree family member of other patients.
3. One or more colon cancers diagnosed in patients younger than 50 years old.
4. Familial Adenomatous Polyposis has been excluded
Modified Bethesda criteria established in 1997 is a less stringent guideline for appropriate microstatellite instability (MSI) testing on colorectal tumor specimens and is used to identify families that are likely to have MMR gene mutation. It is more sensitive than Amsterdam criteria in identifying families with HNPCC but they are not diagnostic of HNPCC as MSI may occur in 15% of sporadic cancers.
Revised Bethesda Guidelines
1. Colorectal cancer diagnosed in patient younger than 50 years old.
2. Presence of colorectal tumor or other HNPCC related tumors regardless of age.
3. Colorectal tumor with MSI-H, HNPCC related tumors diagnosed in patients younger than 60 years old.
4. Colorectal cancer diagnosed in one or more 1st degree relatives with HNPCC related tumors, with one of the cancers diagnosed in patient younger than 50 years.
5. Colorectal cancer diagnosed in 2 or more 1st or 2nd degree relatives with HNPCC related cancers, regardless of age.
Genetic counseling and genetic testing are then recommended for families who fulfill the Amsterdam criteria.
Genetic testing
Genetic testing is performed on a blood sample. It is used to look for the mutation in the MisMatch Repair genes (MMR) that is responsible for HNPCC. Families of patient tested positive should be screened as well. Note that genetic testing only identifies who has inherited the gene mutation but it does not detect any colon polyps or cancer.
Another screening test that conducts test on the dissected colon tumor tissue is called Microstatellite Instability (MSI) testing. If positive, the cancer is most likely due to HNPCC gene mutations.
Colon examinations
Colonic examinations allow physicians to identify colonic polyps as well as tumors. There are few ways where by the colon can be visualized.
1. Colonoscopy: It is a diagnostic procedure whereby a tube with a video camera is inserted through your anus upwards to visualize the whole colon. If a polyp is seen, biopsy of the polyp and removal can be done during this procedure.
2. Flexible sigmoidoscopy: a shorter version of the colonoscopy that examines the lower one third of the colon. The disadvantage is that it does not examine the ascending colon, transverse colon and the proximal part of the descending colon; as such cancer may be missed if it occurs in areas mentioned above. Also HNPCC tumors usually occur in the ascending colon so this test is not recommended unless in combination with a barium enema.
3. CT Colonograghy (Virtual colonoscopy): It is a minimally invasive CT imaging of the colon and rectum using CT scan imaging. It is superior to barium enema and is suitable for patients when colonoscopy is contraindicated or incomplete. It does not carry the risk of colonoscopy such as perforation and sedation. However, if polyp detected it cannot be removed and send for histology.
4. Barium enema: Barium a contrast dye is given to a patient via enema form and is captured by x-ray to visualize the entire colon including the caecum which may not be reachable at times by colonoscopy. However, it may miss up to 50% of polyps smaller than 1 cm. Hence it is often coupled with a flexible sigmoidoscopy. Any lesions detected on barium enema require a full colonoscopy evaluation.
Genetic testing is performed on a blood sample. It is used to look for the mutation in the MisMatch Repair genes (MMR) that is responsible for HNPCC. Families of patient tested positive should be screened as well. Note that genetic testing only identifies who has inherited the gene mutation but it does not detect any colon polyps or cancer.
Another screening test that conducts test on the dissected colon tumor tissue is called Microstatellite Instability (MSI) testing. If positive, the cancer is most likely due to HNPCC gene mutations.
Colon examinations
Colonic examinations allow physicians to identify colonic polyps as well as tumors. There are few ways where by the colon can be visualized.
1. Colonoscopy: It is a diagnostic procedure whereby a tube with a video camera is inserted through your anus upwards to visualize the whole colon. If a polyp is seen, biopsy of the polyp and removal can be done during this procedure.
2. Flexible sigmoidoscopy: a shorter version of the colonoscopy that examines the lower one third of the colon. The disadvantage is that it does not examine the ascending colon, transverse colon and the proximal part of the descending colon; as such cancer may be missed if it occurs in areas mentioned above. Also HNPCC tumors usually occur in the ascending colon so this test is not recommended unless in combination with a barium enema.
3. CT Colonograghy (Virtual colonoscopy): It is a minimally invasive CT imaging of the colon and rectum using CT scan imaging. It is superior to barium enema and is suitable for patients when colonoscopy is contraindicated or incomplete. It does not carry the risk of colonoscopy such as perforation and sedation. However, if polyp detected it cannot be removed and send for histology.
4. Barium enema: Barium a contrast dye is given to a patient via enema form and is captured by x-ray to visualize the entire colon including the caecum which may not be reachable at times by colonoscopy. However, it may miss up to 50% of polyps smaller than 1 cm. Hence it is often coupled with a flexible sigmoidoscopy. Any lesions detected on barium enema require a full colonoscopy evaluation.
Treatment
Surgical removal of the entire colon is the only way to treat an existing colorectal tumor as well as completely prevent the development of colon cancer.
Removal of an organ before cancer occurs is called prophylaxis surgery. Prophylactic colectomy (Removing the colon and rectum) or prophylactic hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus and ovaries) is controversial and is best discussed with the specialists first.
The surgical options will be to remove all of the colon or colon plus rectum. Surgery can now be performed via laparoscopy which involves small incisions in your abdomen instead of the traditional open abdomen laparotomy. Even though the colon and rectum are removed, one must remember that HNPCC also involve other organs hence continuous surveillance is important.
Surgical Options
Total colectomy with ileoanal anastomosis
If there are only few polyps in the rectum, this procedure is favorable. The surgeon will remove the colon and about 5 inches of the rectum. The end part of the small intestine known as the ileum is then joined to the remnant rectum.
Surgical removal of the entire colon is the only way to treat an existing colorectal tumor as well as completely prevent the development of colon cancer.
Removal of an organ before cancer occurs is called prophylaxis surgery. Prophylactic colectomy (Removing the colon and rectum) or prophylactic hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus and ovaries) is controversial and is best discussed with the specialists first.
The surgical options will be to remove all of the colon or colon plus rectum. Surgery can now be performed via laparoscopy which involves small incisions in your abdomen instead of the traditional open abdomen laparotomy. Even though the colon and rectum are removed, one must remember that HNPCC also involve other organs hence continuous surveillance is important.
Surgical Options
Total colectomy with ileoanal anastomosis
If there are only few polyps in the rectum, this procedure is favorable. The surgeon will remove the colon and about 5 inches of the rectum. The end part of the small intestine known as the ileum is then joined to the remnant rectum.
Total Colectomy with ileoanal Pouch
Surgeon will remove the colon plus the rectum leaving just the anal canal and its sphincter muscles. The small intestine is then used to create a “rectum” which is connected to the anus. There may be a temporary diversion of fecal wastes through an ileostomy or stoma which is created and brought to an opening in the abdomen and connected to the stoma bag. After surgery when the first operation has healed the ileostomy is closed up.
Surgeon will remove the colon plus the rectum leaving just the anal canal and its sphincter muscles. The small intestine is then used to create a “rectum” which is connected to the anus. There may be a temporary diversion of fecal wastes through an ileostomy or stoma which is created and brought to an opening in the abdomen and connected to the stoma bag. After surgery when the first operation has healed the ileostomy is closed up.
Proctocolectomy with Ileostomy
This is reserved for patients with rectal cancer. The whole colon and rectum is removed by the surgeon and a permanent ileostomy for diversion of wastes to an opening in abdomen is performed.
This is reserved for patients with rectal cancer. The whole colon and rectum is removed by the surgeon and a permanent ileostomy for diversion of wastes to an opening in abdomen is performed.
Possible Preventive Medications
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may shrink and decrease the number of polyps. However it has not been approved by FDA as a treatment drug since polyps will still recur and best managed surgically. However for patients who have undergone colectomy with ileoanal anastomosis, these drugs may reduce the number and size of polyps in the rectum. NSAIDs also have side effects like gastric ulcer and also risk of upper gastrointestinal bleeding.
COX-2 Inhibitors like Arcoxia and Celebrex has lesser side effects on the gastrointestinal system and reduce risk of bleeding. However there may be an increased risk of coronary artery disease with usage of Celebrex. It is also more useful in patients with FAP.
Aspirin in one randomized controlled trial is found to have reduced long term risk of colorectal cancer in people with a positive family history of colon cancer. Like NSAIDs it carries the risk of upper gastrointestinal bleeding and ulcers.
Folic Acid usage for more than 15 years in one observational study is associated with lower rates of colorectal cancers. One hypothesis suggests that since folate is necessary in the DNA synthesis, suboptimal levels may result in DNA synthesis and repair abnormalities.
Calcium in one randomized control trial suggested reduces risk of recurrent adenomas in average risk people. This does not apply to high risk people with genetically inherited predisposition to colorectal cancer. Hypothesis suggests that as calcium binds to bile acids in the bowel, it reduces their carcinogenic effects.
Estrogen – some studies suggest that it is associated with lower incidence of colorectal tumors in average risk people. This does not apply to patients with genetically predisposition to colon cancer.
Cancer Surveillance in patients with HNPCC
1. Those with family history of Hereditary NonPolyposis Colorectal Cancer (HNPCC) should undergo genetic testing and counseling. Colonoscopy should start from age 20-25 years (or 10 years younger than the earliest age of colon cancer diagnosed in the family) at least every 1-2 years.
2. Women beginning from age 30-35 should have annual pelvic examination, transvaginal ultrasound, Ca125 tumor marker assay and an endometrial biopsy if necessary.
3. Urine analysis and cytology is recommended especially for those with family history of transitional cell carcinoma of the urinary tract. It should start about age 30 years onwards and conducted every 1 to 2 years.
4. For families with a strong history of stomach cancer, annual upper oesophagogastroduodenoscopy (OGD) may be recommended.
5. Depending on the family history, screening for other HNPCC related cancers may be necessary.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may shrink and decrease the number of polyps. However it has not been approved by FDA as a treatment drug since polyps will still recur and best managed surgically. However for patients who have undergone colectomy with ileoanal anastomosis, these drugs may reduce the number and size of polyps in the rectum. NSAIDs also have side effects like gastric ulcer and also risk of upper gastrointestinal bleeding.
COX-2 Inhibitors like Arcoxia and Celebrex has lesser side effects on the gastrointestinal system and reduce risk of bleeding. However there may be an increased risk of coronary artery disease with usage of Celebrex. It is also more useful in patients with FAP.
Aspirin in one randomized controlled trial is found to have reduced long term risk of colorectal cancer in people with a positive family history of colon cancer. Like NSAIDs it carries the risk of upper gastrointestinal bleeding and ulcers.
Folic Acid usage for more than 15 years in one observational study is associated with lower rates of colorectal cancers. One hypothesis suggests that since folate is necessary in the DNA synthesis, suboptimal levels may result in DNA synthesis and repair abnormalities.
Calcium in one randomized control trial suggested reduces risk of recurrent adenomas in average risk people. This does not apply to high risk people with genetically inherited predisposition to colorectal cancer. Hypothesis suggests that as calcium binds to bile acids in the bowel, it reduces their carcinogenic effects.
Estrogen – some studies suggest that it is associated with lower incidence of colorectal tumors in average risk people. This does not apply to patients with genetically predisposition to colon cancer.
Cancer Surveillance in patients with HNPCC
1. Those with family history of Hereditary NonPolyposis Colorectal Cancer (HNPCC) should undergo genetic testing and counseling. Colonoscopy should start from age 20-25 years (or 10 years younger than the earliest age of colon cancer diagnosed in the family) at least every 1-2 years.
2. Women beginning from age 30-35 should have annual pelvic examination, transvaginal ultrasound, Ca125 tumor marker assay and an endometrial biopsy if necessary.
3. Urine analysis and cytology is recommended especially for those with family history of transitional cell carcinoma of the urinary tract. It should start about age 30 years onwards and conducted every 1 to 2 years.
4. For families with a strong history of stomach cancer, annual upper oesophagogastroduodenoscopy (OGD) may be recommended.
5. Depending on the family history, screening for other HNPCC related cancers may be necessary.