Hereditary NonPolyposis Colorectal Cancer


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
-         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.




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.




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. 


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.


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.


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.

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.


References
1.      www.cancer.net
4.      Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med. Mar 30 1995;332(13):839-47. [Medline]. [Full Text].
5.      Lothe RA, Peltomaki P, Meling GI, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. Dec 15 1993; 53(24):5849-52. [Medline].
6.      Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst. Aug 2 1995;87(15):1114-25. [Medline].



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What is Colorectal Tumor?

Colorectal Tumor is cancer involving the colon (ascending colon, transverse colon, descending colon), rectum to the anus. It is one of the top leading cancer involving both men and women. Internationally, more than 1 million people are diagnosed with colorectal tumor every year. When detected early and treated in early stages, the prognosis is good.

Colorectal cancer is mostly adenocarcinomas. Other rarer cancers involving the colon are carcinoid tumors, melanomas, lymphomas and sarcomas. Most colorectal cancers derived from small noncancerous adenomatous polyps which may turn cancerous with time. If the polyps are greater than 1 cm, has villous features or has high grade dysplasia, the chance of malignancy (cancer) increases. Hence when detected and removed early, risk of colorectal cancer decreases.

Causes

75% of colon cancer patients have no known predisposing factors. So what leads to the development of colorectal tumor?

1. About 85% of sporadic colon cancer arises from noncancerous benign polyps which look like mushrooms found on the lining of the colon. There is a loss of tumor suppressor genes and activation of oncogenes which leads to malignant transformation of normal cells to cancerous cells.

2. About 10-20 % of colon cancers arise from serrated polyps which involves the inactivation of DNA mismatch repair gene MLH1which eventually activates the mutations of BRAF gene. These mutations in turn lead to cancerous transformation of cells.

3. 5 % of colon cancers arise from inherited germline mutations resulting in Familial Adenomatosis Polyposis (FAP), Lynch Syndrome and Hereditary NonPolyposis Colorectal Cancer (HNPCC). These hereditary syndromes results in thousands of polyps lining the colon and rectum which increase one’s risk of colorectal tumor. These syndromes are detectable through genetic testing. Colorectal screenings for these patients are highly recommended.


Risk factors of developing colorectal tumor

1. Age: The incidence of colon cancer increase sharply after age 45. 90% of cancer patients are diagnosed at age 50 and above.

2. Family History of Colon Cancer or polyps: If your first degree family members (child, siblings or parents) have colon cancer, your risk of colon cancer is 2 times more than general population. Your risk increased to 4 fold if your family member is diagnosed at < 45 years of age. Your lifetime risk of colon cancer is about 25-50% if more than one family member has the disease.

3. Inflammatory Bowel Disease: Chronic inflammatory disease of the colon such as ulcerative colitis and Crohn’s disease increases your risk of colon cancer. The risk begins to rise after 7-10 years after the disease onset and continues to rise as the disease progresses.

4. Race: African- Americans are at higher risk as compared to other races.

5. Personal history of colon cancer or polyps: If you have a history of colon cancer or polyps, the risk of recurrence is higher.

6. Inherited Syndromes: Familial Adenomatous Polyposis (FAP) and Hereditary NonPolyposis Colorectal Cancer also known as Lynch syndrome puts you at higher risk of colorectal tumor. Genetic Screening and colorectal cancer screening is advisable for families with these syndromes.

7. Diet and Lifestyle activities: Diet rich in fats and red meats and low in fiber is associated with increased risk of colorectal cancer. Smoking and alcohol intake, sedentary lifestyle, pre-existing diabetes and obesity also put you at higher risk of colorectal tumor.

8. Previous radiotherapy: Previous radiation therapy targeted at the abdomen for previous cancer treatment also increases the risk of developing of colorectal cancer.

Clinical symptoms

The symptoms of colon cancer depend on its location and whether it has metastasis (spread).

1. Fatigue and weakness which is the result of chronic blood loss which leads to iron deficiency anemia.

2. Change in bowel habits: These include changes in stool frequency, stool consistency or constipation alternating with diarrhea.

3. Per rectal bleeding: Blood stained stools or passing out frank blood during defecation.

4. Abdomen pain will occur when there is severe obstruction and maybe accompanied with abdomen distension, vomiting and constipation.

5. Unintentional weight loss

6. Tenesmus : Feeling of incomplete emptying of stools

Right sided colon cancer usually causes chronic blood loss resulting in anemia hence patients will feel fatigue. Obstruction is less likely due to the larger diameter of the colon.

Left sided colon being smaller in diameter will often cause obstruction symptoms like abdomen pain, constipation alternating with diarrhea and blood stained stools.

Rectal tumors will result in patients experiencing tenesmus, urgency and recurrent bleeding per rectal.

Anal tumors may present as an external mass, ulcers, and polyps or as an internal mass. Rectal bleeding may be inconsistent. Pain is usually absent.

Physical clinical findings

The doctor will do a physical examination of your abdomen and a digital examination of your rectum. If the cancer is in advance stages, there may be a mass upon palpation of your abdomen as well as area of tenderness. The liver maybe enlarged if the tumor has spread to the liver. Digital examination through the anus will determine if there is any mass at the distal rectum, blood in stools and also whether the anal sphincter and pelvic floor is involved.

Investigations to confirm diagnosis

1. Blood tests

- Full blood count may reveal iron deficiency anemia

- Liver function tests if elevated especially the alkaline phosphatase marker may mean possibility of cancerous spread to liver

- CEA tumor marker is not recommended for screening as it can be elevated in other cancers or in other benign conditions like liver cirrhosis, ulcerative colitis as well as among smokers. It is usually done pre-operation as a prognostic indicator; a level > 5ng/ml is a poorer prognostic indicator. After surgical resection, CEA level should normalize if it is elevated it may indicate recurrence or persistent disease.

2. Fecal testing

- Fecal Occult Blood Test (FOBT): it detects small amounts of blood in stools; if positive a colonoscopy is highly recommended.

3. 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.

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.

5. Imaging

- Chest, abdomen and pelvic CT scan: imaging is done to identify possible metastases (spread of cancer to other organs).

- 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.

- MRI of pelvis or endorectal ultrasonography: This is useful for rectum tumor as it can allow physician to know the depth of penetration of the cancer through the rectal wall, lymph nodes involved and whether pre-operative chemoradiotherapy is necessary.

- Positron Emission Tomography (PET) scan: Like CT scan it is used for staging but not routinely used.

Staging of colorectal tumor

The TNM system is used to classify and stage colon cancer. It depends on the Tumor invasion depth into the wall of colon, the number of lymph Nodes the cancer has spread to and lastly Metastasis whether the cancer has spread to other organs.

Staging is important as it correlates with patient’s long term survival. It also help the physician decide the management plan and also if pre-operative chemoradiotherapy is necessary to shrink the tumor before operation. It also determines if patient require adjuvant therapy like chemotherapy or radiotherapy.

Stage 0: The tumor is in very early stage and only involves the innermost layer of the colon. Also known as carcinoma in situ.

Stage 1: The tumor has grown through the mucosa colon wall (superficial lining) but has not invaded into the wall.

Stage 2: The tumor has invaded through the colon wall but has not spread to any lymph nodes.

Stage 3: The tumor has invaded through the colon wall and has spread to lymph nodes.

Stage 4: The tumor has spread beyond the colon to other organs such as liver and lungs.

Treatment Options

The treatment for colorectal tumor depends on the stage of the cancer.

1. Surgery: Colectomy which means resection of the primary colon or rectal cancer and also the involved lymph nodes is the treatment of choice for localized colon cancer stage 1-3. For stage 4 colorectal tumors where the cancer has spread to other organs, surgery is usually palliative to relieve symptoms such as intestinal obstruction, bleeding and pain. The treatment of choice for such advanced disease is usually systemic chemotherapy.

As medicine advances, colectomy may be done with laparoscopy which is less invasive and speed up recovery as compared with previous open colectomy.

In some patients, a colostomy which is a bag connected to a section of the colon (stoma) that is brought to an opening in the abdomen may be necessary to divert the body wastes while waiting for the operated site of the colon to heal. Most of the time this is temporary however if the cancer involves the rectum outlet it may be permanent.

2. Chemotherapy: Adjuvant Chemotherapy which is post operation chemotherapy is standard treatment for patients with Stage 3 colon cancer and also in some patients with stage 2 colon cancer. Chemotherapy drugs commonly used are fluorouracil in combination with other drugs such as levamisole and leucovorin. These drugs are used to kill the remnant cancer cells and to relieve symptoms. If the colorectal tumor is too large to operate, chemotherapy may be given prior to operation to shrink the tumor first. This is known as neo-adjuvant chemotherapy. Medical Oncologist will decide the chemotherapy regime and frequency.

3. Biologic Agents: Monoclonal antibodies such as cetuximab (Erbitux), panitumumab (Vectibix), bevacizumab (Avastin) are anti-angiogenesis drugs that act on specific defects that allow cancer cells to proliferate. They can be given alone or together with chemotherapy. They are reserved for people with very advanced stage of colon cancer.

4. Radiation therapy: It is standard treatment for patients with rectal cancer. Role of radiation therapy in colon cancer patients is limited. However it is sometimes used with chemotherapy to shrink large tumors before operation. Radiation uses powerful energy sources like x-rays to kill cancer cells. It is also useful if cancer cells have spread to the bone and brain.

5. Treatment options if cancer has spread to liver: Radiofrequency Ablation of the liver lesion (burning the cancer), surgical resection of the tumor, cryotherapy (freezing the tumor) or chemotherapy and radiation therapy targeted at the liver.

Prognosis

The stage of the cancer at presentation is important determining factor of long term survival. 5 year survival rate means the percentage of patients that survive at least 5 years after diagnosis.

Stage 1: > 90%

Stage 2: 70-85%

Stage 3: with less than 4 positive lymph nodes: 67%

Stage 3: with more than 4 positive lymph nodes: 33 %

Stage 4: 5-7% due to cancer having spread to other organs

At each stage, cancer of the rectum has poorer outcomes.

Prevention of colorectal cancers

1. Colorectal cancer screening has proven to save lives and reduce mortality. This is because detection of early stages of cancer with improved treatment as well as prevention by removing polyps has deterred cancers being diagnosed at a later stage which has poorer outcomes.

The screening tests recommended depend on the risk an individual has in developing in cancer. It will be covered in greater details in the next page.

2. Dietary and Lifestyle changes:

- Increase intake of fruits, vegetable and whole grains that are rich in minerals, vitamins and fibers that act as antioxidants which play a role in cancer prevention

- Stop smoking and cut down on alcohol

- Exercise at least every 30 minutes most days of the week

- Maintain a Normal BMI and healthy weight

3. Medications like aspirin, Nsaids and Celebrex: Some studies have found that these drugs may reduce the risk of colorectal cancer. However they do carry increased risk of gastrointestinal bleeding, stomach ulcers and heart problems (especially in COX2 inhibitors). The risks and benefits must be weighed and discussed with your doctor before taking such medications.

4. Surgery: In patients with inherited conditions like Familial Adenomatosis polyposis, Hereditary NonPolyposis Colorectal Cancer and inflammatory bowel disease like Ulcerative Colitis, the risk of developing cancer is many times higher than a normal person. Hence, your doctor may recommend prophylactic surgical removal of the whole colon and rectum to prevent cancer to develop.

Differential Diagnosis

After having discussed all about colorectal tumors, you should know there are some conditions that may present similarly to the symptoms of colorectal cancer. The conditions include:

1. Irritable Bowel Disease

2. Diverticular disease

3. Ischemic Colitis

4. Inflammatory Bowel Disease

5. Infectious Colitis

6. Hemorrhoids

7. Carcinoid tumors

8. Arteriovenous Malformation (AVM)

9. Gastrointestinal lymphoma

In conclusion, if you have symptoms suggestive of colorectal tumor, do seek a doctor’s advice and carry out the necessary tests to determine the actual cause. It could be any of the above conditions instead of the cancer. Also lead a healthy lifestyle balanced with the right diet and adequate amount of exercise as general prevention of cancer.

References

1. Cornett PA et al. “Cancer”. In: Current Medical Diagnosis & Treatment, Fifty-Second Edition, 2013: Chapter 39. * Advanced web edition 2013.

2. www.emedicine.medscape.com

3. www.mayoclinic.com

4. MOH. Cancer Screening. MOH CPG 1/2010.