What is familial adenomatous polyposis (FAP)?
Familial adenomatous polyposis (FAP) is a rare, hereditary condition in which a person develops numerous precancerous polyps called adenomas in the large intestine (colon and rectum).
Polyps develop in teen years or early 20s. The number of polyps varies from less than 100 to thousands, and with increasing age the polyps get larger and more problematic. Eventually, one or more of these adenomas will become cancerous.
Without treatment, patients with FAP have a nearly 100% lifetime risk of colorectal cancer. The chance of developing colorectal cancer increases with age; the average age at which people are diagnosed with cancer is 39.
Symptoms and Causes
What causes familial adenomatous polyposis (FAP)?
FAP occurs in 1 in 10,000 people. It is caused by mutations in the APC gene that interfere with the function of the protein made by the gene. This allows cells to grow in an uncontrolled way and predisposes them to becoming cancers. Most patients with FAP inherited a mutation in APC from one of their parents, who were also affected with FAP. About 25% of the time the mutation happens when a patient is conceived and in this case there is no family history of FAP in the parents.
Because patients who are born with an APC mutation have the mutation in every cell in their colon, they develop hundreds and even thousands of these potentially precancerous adenomas. Because the mutation is in every cell in the patients body, other organs are susceptible to growths, either benign or malignant.
These other organs include:
- Bones (osteomas are benign bony tumors usually affecting the skull and jaw).
- The mouth (unerupted teeth, extra teeth and odontomas [benign tumors]).
- The retinas of the eyes (congenital hypertrophy of the retinal pigment epithelium [pigmented lesions on the retinas that usually do not interfere with vision]).
- The soft tissue (tumors such as epidermoid cysts and fibromas on the skin).
- Fibrous tissue, such as in scars (desmoid tumors).
- The stomach. About 90% of patients with FAP will have polyps in the stomach. The most common stomach polyps are benign fundic gland polyps. Stomach cancer occasionally develops from stomach polyps (less than 2% of the time).
- The duodenum (the first part of the small intestine). Nearly all patients who have FAP will develop polyps in the duodenum, and a small percentage of these patients may have duodenal cancer as a result.
- The small intestine. Sometimes polyps develop in the small intestine and very occasionally these become cancers. This is very rare.
- Thyroid gland. Thyroid cancer is more common in patients with FAP than the general population, and twice as common in women than men. It is a very benign version of the cancer (papillary cancer) and is almost always cured.
- The brain. The most common brain cancers in FAP include medulloblastoma, astrocytoma and ependymoma. These are rare, even in FAP. FAP and brain cancer is a type of Turcot’s syndrome.
Desmoid tumors are overgrowths of fibrous tissue that are rare in the general population but happen in 15% of patients with FAP. Sometimes hard white sheets of desmoid tissue develop, causing problems without being a tumor. Another 15% of patients get this version. 50% of desmoid tumors grow inside the abdomen, 45% in the abdominal wall and 5% outside the abdomen altogether. Inside the abdomen, they generally follow an abdominal surgery and tend to grow around the arteries (blood vessels) to the bowel. This makes it difficult or impossible to remove them, unless a great deal of the small bowel is also removed. Even after they are removed, desmoid tumors tend to come back.
Desmoid disease is the second most common cause of death in patients who have FAP.
The risk of desmoid tumors varies. Risk factors include:
- A family history of desmoid tumors (other members of the family have desmoid tumors).
- Female gender.
- Having Gardner’s syndrome.
- Having an APC mutation beyond codon 1400 (a unit of genetic code).
Desmoids are assigned a stage, depending on their size, the symptoms they are causing, and the rate at which they grow:
- Stage I desmoids usually do not need to be treated, or are treated with sulindac (Clinoril®), an anti-inflammatory drug.
- Stage II desmoids are usually treated either with sulindac alone or in combination with an estrogen-blocking drug like raloxifene (Evista®).
- Stage III desmoids are treated with mild chemotherapy.
- Stage IV desmoids are treated with extreme chemotherapy.
Because 80% of FAP-associated desmoids develop within three years of an abdominal surgery, patients who are at high risk of desmoids should delay or avoid surgery. Laparoscopic surgery (surgery performed through very small "keyhole" incisions in the abdomen), can minimize trauma and reduce the risk of desmoid tumors.
Desmoid disease gets milder as patients get older. In about 12% of patients, the desmoids disappear all by themselves. Unfortunately, in 7% of patients with desmoids, the disease is fatal.
How is familial adenomatous polyposis (FAP) inherited?
FAP is inherited in an “autosomal dominant” manner:
- Everyone has two copies of the APC gene.
- People who have FAP have a mutation (change) in one copy of the APC gene.
- The copy of the gene with the mutation can be passed on to future generations.
- The chance that a child of someone with FAP will inherit the copy of the gene with the mutation is 50%.
People who are diagnosed with FAP should tell their family members about their diagnosis and encourage them to undergo genetic counseling. This evaluation includes their personal history, family history and genetic testing for the APC gene mutation. The patient will also receive recommendations to keep the family healthy and to prevent cancer.
Diagnosis and Tests
How is familial adenomatous polyposis (FAP) diagnosed?
A doctor may suspect FAP when multiple adenomatous polyps are found in the patient’s gastrointestinal tract.
Anyone who has more than 20 adenomatous polyps in their large intestine should have genetic testing and genetic counseling. Genetic testing uses blood or a cheek swab to obtain DNA that is then tested to determine if there is an APC gene mutation. Once a mutation is identified in an individual, his or her family members can be screened for that mutation. Patients and families with FAP will benefit by joining a hereditary colon cancer registry.
Management and Treatment
How is familial adenomatous polyposis (FAP) treated?
Because FAP cannot be cured, the aim of treatment is to prevent cancer and preserve a healthy, unaffected lifestyle for the patient.
People who have FAP will need examinations of the gastrointestinal tract and other at-risk organs for the rest of their lives. They will receive medical care by a healthcare team that may include:
- Gastroenterologists (specialists in diseases of the digestive system).
- Colorectal and general surgeons.
- Endocrinologists (specialists in metabolism and diseases of the endocrine system).
- Primary care physicians.
- Genetic counselors.
- Oncologists (cancer specialists).
Patients with FAP are diagnosed either by symptoms if they have no family history to warn them of their risk, or on screening if they are in a family affected by FAP, or have been identified by a positive genetic test. Symptomatic patients are at high risk for cancer and usually need surgery relatively quickly. Screened patients have no symptoms and treatment timing depends on how severe the FAP is.
Children who have inherited the APC mutation normally start yearly colonoscopy when they are 10 or 11. Children who have FAP and develop colon symptoms such as, blood in bowel movements, abdominal pain and/or diarrhea are checked immediately. Examination of the stomach and duodenum usually starts between ages 20 and 25.
Surgery is the standard treatment to prevent colorectal cancer in FAP. The timing and type of colon surgery depend on the number and size of the polyps in the large bowel. If the patient does not have a large number of colon polyps, surgery may not be recommended until later in his or her life.
If there are too many polyps or if they are growing too quickly to be controlled by colonoscopy, it might be necessary to remove the colon and/or rectum with surgery. The bowel is reconstructed by joining the small intestine to the rectum (an ileorectal anastomosis) or making a J pouch out of the small intestine to replace the rectum, so that the patient can avoid having a permanent stoma (bag). While the prospect of surgery may be upsetting, it is important to realize that without it, the risk of colorectal cancer is very high.
The timing and choice of colon surgery depend on several factors, but in particular the number and size of the polyps. Laparoscopic surgery has made removal of the colon less painful and less disabling.
Laparoscopic surgery is performed through very small "keyhole" incisions in the abdomen. A laparoscope -- a small, telescope-like instrument containing a camera -- is placed through an incision near the bellybutton in order to see the inside of the abdomen. The surgery is done using instruments placed via these small incisions. Even after surgery, the remaining bowel is checked every year.
Medications can also reduce the burden of polyps in the colon and rectum. This is known as chemoprevention, and it is prescribed for selected patients by an expert in chemoprevention.
Two medications — sulindac (Clinoril®) and celecoxib (Celebrex®) — have been shown to reduce the number of colorectal polyps and delay the timing of the first surgery. These medications can also control polyps in the pouch or rectum after surgery, or the need for additional surgeries. These medications do not prevent the need for colonoscopy, however, and have not been proven to prevent colon cancer.
Upper gastrointestinal endoscopy
Since adenomatous polyps can develop in the duodenum, an upper endoscopy along with a biopsy (removal of cells or tissue for examination) of the polyps should be done beginning around the age of 20, and then every 1-3 years. In an upper endoscopy, a physician uses an endoscope (a long, thin, flexible instrument about 1/2 inch in diameter) to examine the inside of the upper digestive system.
If the patient has a large number of polyps in the duodenum, surgery to prevent duodenal cancer may be recommended. The duodenum is removed and the intestinal tract is reconnected internally. Patients with advanced stage duodenal polyposis may be treated with celecoxib.
The upper part of the stomach may become carpeted with thick mounds of polyps of various types. In this case, an upper endoscopy and removal of the stomach polyps may need to be done every 3-6 months to make sure that cancer is not developing. If cancer or high-grade dysplasia (abnormal growth) is found in stomach polyposis, removal of the stomach and reconnection of the intestinal tract is recommended.
The thyroid is checked every year with an ultrasound scan at the time of diagnosis or in the mid-teen years, whichever is earlier. Abnormalities in the thyroid, such as cysts or calcifications (hardenings), are usually biopsied at the time of ultrasound. If cancer is detected, the thyroid gland is removed, and the function of the thyroid gland is replaced with medications.