Familial Adenomatous Polyposis 

What is FAP?

Familial Adenomatous Polyposis (FAP) is a rare inherited genetic colorectal cancer syndrome which accounts for about 1 % of all colorectal cancers. “F” familial means that it runs in the families and is an autosomal dominant inherited disease. “A” Adenomatous means the type of polyps found in the colon which can turn into cancer. “P” polyposis is a condition whereby there are multiple polyps in the colon. The gene mutation involved in causing FAP is the APC gene found on the chromosome 5. The frequency of FAP varies from 1 in 7000 to 1 in 31000 persons.

The polyps (benign noncancerous growths) may start to form starts from age 16 in those with classical FAP. If left untreated, the average age when these polyps turn cancerous is around age 39. Hence for these patients, they may need prophylactic resection of the colon and rectum to prevent it from turning cancerous. If left untreated, there is almost 100% chance a person will develop colorectal cancer.

A variant form of FAP is attenuated familial adenomatous polyposis in which the polyps’ growth is all delayed. Hence the onset of colorectal cancer is delayed till from age 55 for these group of patients.

The polyps can also be found in the stomach, duodenum (starting part of small intestine), skin, bones, eyes, thyroid and abdomen (Desmoid Tumors). Gardner syndrome refers to patients who have colonic polyps as well as polyps outside the colon. 

FAP not only increase the risk of colon cancer, it is also associated with other cancers. The cancers involved include stomach cancer, small intestines cancer, papillary thyroid cancer, pancreatic cancer, adrenal gland cancer, bile duct cancer, medulloblastoma (a type of brain cancer) and also a hepatoblastoma (a form of liver cancer in young children).

The estimated risk of cancers associated with FAP

·       Colorectal Cancer: almost 100% if untreated
·       Small bowel cancer : 4-12%
·       Papillary Thyroid Cancer : 2 %
·       Pancreatic Cancer : 2%
·       Hepatoblastoma : 1.5%
·       Brain Tumor : < 1%
·       Stomach Cancer : < 0.5 %
·       Adrenal gland cancer: small risk
·       Bile Duct Cancer : Small risk 

How is FAP inherited?


Every single cell has two sets of each gene; one from the mother and one from the father. In patients with autosomal dominant FAP inheritance, the mutation in APC gene occurs in one of the gene which means one gene mutation is enough to cause the disease. So a parent with this gene mutation can pass down either a normal gene or a mutated gene. Therefore, the child has 50% of inheriting this disorder.

How is FAP diagnosed?

The classical FAP is usually diagnosed clinically meaning more based on symptoms rather than by laboratory tests. Anyone with more than 100 intestinal colon polyps is considered to have FAP. Genetic testing to detect mutation in genes is advisable in patients with strong family history. 

Clinical presentation

About 30% of patients have spontaneous mutation and acquire FAP although they do not have family history of FAP. These patients may not know they have FAP until symptoms of colon cancer or polyps occur.
Patients may present with bleeding per rectum, if chronic blood loss present they may be anemic resulting in fatigue, dizziness, breathlessness and even fainting spells.

They may also present with non-specific symptoms like weight loss, change in bowel habit, abdomen pain or a mass in the abdomen.
Upon examination, the patient may appear pale. Abdomen examination may not be significant unless when there is cancerous spread to the liver causing the liver to be enlarged. Rectum examination may reveal blood stained stools.

For patients with FAP they may have pigmented lesions on the retina also known as “CHRP” congenital hypertrophy of the retinal pigment epithelium. As a form of FAP called Gardner’s Syndrome is associated with multiple cysts, patients may have multiple sebaceous cysts, jaw cyst, dental abnormalities and bone osteomas (painless bony overgrowth often at skull and mandible). 

Investigation
1.    Blood tests

• Full blood Count: may reveal iron deficiency anemia from chronic blood loss
• Liver Function Test: maybe deranged if cancer has spread to the liver
• Alpha-Fetoprotein (AFP): As part of screening for hepatoblastoma for children up to age 5.

2.    Scopes

• Flexible sigmoidoscopy: Visualization of more than 100 polyps confirms diagnosis of FAP. However Sigmoidoscopy has limited access to just the left sided colon it is inferior to colonoscopy.
• 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.
• OGD (oesophagogastroduodenoscopy): In patients with established FAP, this is necessary as duodenum cancer is the second most common cancer.

3.    Imaging

• Dental and skull x-rays: For patients with Gardner’s FAP should have these x-rays to identify any osteomas and dental abnormalities
• 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.
• Ultrasound abdomen/CT abdomen: In young children as surveillance for hepatoblastoma. Also to survey for pancreatic cancer and other intra-abdominal tumors.
• Ultrasound thyroid: Besides thyroid examination, ultrasound maybe necessary as FAP is associated with increased risk of papillary thyroid cancer.

4.    Genetic Testing

• Blood can be taken for genetic testing for the APC gene mutation present in FAP patients. It can be detected in 80% of patients with FAP meaning that 20% of patients with FAP may not have the gene abnormality detected in blood tests.
• Genetic testing can only confirm the APC gene mutation and identify people with FAP, it cannot detect cancer or polyps.
• The three genetic tests that can be done are In-vitro protein synthesis assay, Linkage testing and APC gene sequencing.

5.    Histology
Polyps removed during scopes can be sent for histology. The polyp in FAP is characteristically a tubular adenoma. 

Treatment

As FAP always present with hundreds to thousands of polyps in the intestines, it is not practical to remove them one by one during colonoscopy. Also due to the inevitable development of colorectal tumor by age 40, prophylactic surgery is usually recommended by age 25. 

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 FAP also involve other organs like thyroid, stomach, duodenum and bones hence continuous surveillance is important.

Surgical Options

Total colectomy with ileoanal anastomosis

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.

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 for FAP 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.
Anti-estrogen medications like tamoxifen may be helpful for desmoid tumors in the abdomen since estrogen may promote their growth.

Prognosis

If FAP is left untreated the average life expectancy is about 42 years. For those who underwent colectomy (removal of colon), life expectancy is extended greatly.

Causes of death in those who had undergone Colectomy are usually from Desmoid tumors and upper gastrointestinal cancers. Hence continuous surveillance is very important.

The cumulative risk of developing non colorectal tumor especially periampullary tumors is about 11% by age 50 and 52% by age 75. 

Differential diagnosis

After having discussed all about FAP, you should know there are some conditions that may present similarly to the symptoms of FAP. The conditions include: Peutz- Jeghers Syndrome, Hereditary Non-polyposis Colorectal Cancer, MUTYH Polyposis, Juvenile polyposis and Hereditary mixed polyposis. 

Cancer screening and surveillance

1.    Those with family history of familial adenomatous polyposis should have genetic counseling and testing. They should have annual flexible sigmoidoscopy starting 10-12 years from puberty. If there are adenoma polyps present then they should have annual colonoscopy instead. Post-surgery flexible sigmoidoscopy should be continued yearly for surveillance of rectal cancer if rectum is not removed.

2.    For children till age 5, screening for hepatoblastoma should be carried out. This includes yearly liver ultrasound, physical examination and also blood alpha fetoprotein levels.

3.    Upper oesophagogastroduodenoscopy (OGD) should begin from age 25 or after polyps are detected. It is done every 1-3 years.

4.    CT scan of the abdomen if polyps are detected on scopes or during surgery. This is to detect any small bowel tumors. It can be repeated every 1-3 years depending on symptoms.

5.    Yearly thyroid examination as FAP has been associated with papillary thyroid cancer.

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