Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, all patients with this syndrome will develop colon cancer by age 35-40 years. In addition, an increased risk exists for the development of other malignancies. See the image below.

See Benign or Malignant: Can You Identify These Colonic Lesions?, a Critical Images slideshow, to help identify the features of benign lesions as well as those with malignant potential.

The genetic defect in FAP is a germline mutation in the adenomatous polyposis coli (APC) gene. Syndromes once thought to be distinct from FAP are now recognized to be, in reality, part of the phenotypic spectrum of FAP.[1]

Syndromes with a germline mutation in the APC gene include FAP, Gardner syndrome, some families with Turcot syndrome, and attenuated adenomatous polyposis coli (AAPC). Gardner syndrome is characterized by colonic polyposis typical of FAP, along with osteomas (bony growth most commonly on the skull and the mandible), dental abnormalities, and soft tissue tumors. Turcot syndrome is characterized by the colonic polyposis that is typical of FAP, along with central nervous system tumors (medulloblastoma). AAPC is characterized by fewer colonic polyps (average number of polyps, 30-35) as compared with the classic FAP. The polyps also tend to develop at a later age (average age, 36 y), and they tend to involve the proximal colonic area.[2]

In considering the spectrum of polyposis syndromes, patients with multiple adenomatous polyps most likely have FAP (or one of its variants), AAPC, or MYH-associated polyposis (MAP). If a patient with a suspected polyposis syndrome undergoes genetic testing and does not have an APC gene mutation, MYH gene testing should be performed to assess for MAP, as 10%-20% of patients who do not have an APC gene mutation have biallelic MYH gene mutations.[3]

The phenotype of MAP is often indistinguishable from FAP or AAPC, with patients having usually 10-100 polyps but sometimes more than 100. The age of onset of MAP is usually in patients older than 45 years, and patients often present symptomatically, with colorectal carcinoma commonly found at the time of the diagnosis. This is in part because there is usually no family history given the autosomal recessive inheritance pattern of MAP. Duodenal polyps can be found in up to one fifth of patients.[4] There is no increased risk of other types of cancers associated with this syndrome.

The APC gene is a tumor suppressor gene that is located on band 5q21.[5] Its function is not completely understood but has been shown to play a part in metaphase chromosome alignment.[6] Normal APC protein promotes apoptosis in colonic cells. Its most important function may be to sequester the growth stimulatory effects of b-catenin, a protein that transcriptionally activates growth-associated genes in conjunction with tissue-coding factors. Mutations of the APC gene result in a truncated/nonfunctional protein.

The resultant loss of APC function prevents apoptosis and allows b-catenin to accumulate intracellularly and to stimulate cell growth with the consequent development of adenomas. As the clonal expansion of cells that lack APC function occurs, their rapid growth increases the possibility for other growth-advantageous genetic events to occur. This causes alterations in the expression of a variety of genes, thereby affecting the proliferation, differentiation, migration, and apoptosis of cells.

Ultimately, enough genetic events transpire that allow the adenomatous polyps to become malignant in patients with FAP. This process is similar to that which occurs in sporadic adenomas. As a result, APC is considered the gatekeeper of colonic neoplasia. Its mutation/inactivation is the initial step in the development of colorectal cancer in patients with FAP.

Germline (ie, inherited) mutations of the APC gene, as is the case with FAP, result in cells containing one mutated copy and one normal copy of the gene. Patients inherit one mutated APC allele from an affected parent, and adenomas develop as the second allele from the unaffected parent becomes mutated or lost. Consequently, every colonic epithelial cell in patients with FAP has one mutated APC allele. Inactivation of the remaining normal copy of the APC gene, by deletion or mutation, completely removes the tumor suppressive function of APC, thus initiating the growth of adenomatous polyps. Inactivation of the second APC allele occurs frequently in the colon, resulting in the development of numerous adenomas.

A retrospective study of outcomes in 492 patients with polyposis found that the age at polyposis onset and years of survival differed significantly by genotype, although the age of onset of colorectal cancer did not.[7] Patients with a mutation in APC 0-178 or 312-412 developed polyposis later and survived longer, whereas patients with mutations in APC 1249-1549 developed polyposis earlier and did not survive as long.

FAP is caused by a germline mutation of the APC tumor suppressor gene, located on band 5q21. Most mutations of the APC gene are nonsense or frameshift mutations, leading to truncation of the APC protein (nonfunctional protein).

More virulent forms of FAP are associated with a mutation in exon 15 between codons 1250 and 1464, the middle portion of the gene.[8]

In patients with AAPC, mutations of the APC gene occur at the extreme amino terminus of the protein.

United States data

Estimates vary from 1 case in 6,850 persons to 1 case in 31,250 persons.

International data

The frequency is constant worldwide.

Race-, sex-, and age-related demographics

FAP has been described in all races, and males and females are equally affected (1:1).

The average age of onset of polyposis in FAP is 16 years, whereas the average age of onset for colorectal cancer is 39 years.

The average age of onset for polyps in AAPC is 36 years, and the average age of onset for cancer in AAPC is 54 years. These patients have fewer polyps (approximately 30 polyps) compared to patients with FAP.

Patients with untreated FAP have a median life expectancy of 42 years. Life expectancy is extended greatly in those treated with colectomy.

Upper gastrointestinal cancers and desmoid tumors are the most common causes of death in patients who have undergone colectomy. This is why surveillance programs, especially after colectomy, are essential. Colectomy only addresses the risk of colon cancer development.

The cumulative probability of developing any type of noncolorectal cancer, mostly periampullary tumors, is 11% by age 50 years and 52% by age 75 years.

Morbidity/mortality

The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. The mean age at which colorectal cancer develops in patients with classic FAP is 39 years. Patients with adenomatous polyposis itself often are asymptomatic.

The second reported lethal complication of FAP is diffuse mesenteric fibromatosis and is referred to as a desmoid tumor. It involves intra-abdominal organs and vessels, causing gastrointestinal obstruction and constriction of veins, arteries, and ureters. Desmoid tumors are reported in 4%-32% of patients. Even after the appropriate surgical treatment of FAP, 20% of patients may develop desmoid tumors after colectomy. Studies have not found a correlation between specific APC mutation sites and desmoid tumor development.[9]  Risk factors include a positive family history. The mortality from these tumors is 10%-50%. The second most common malignancy in patients with FAP is adenocarcinoma of the duodenum and the papilla of Vater. It affects as many as 12% of patients.

Rarer cancers associated with FAP include medulloblastomas (Turcot syndrome), hepatoblastoma, thyroid cancer, gastric cancer, pancreatic cancer, and adrenal cancer.[10]

Complications

Complications of FAP include the following:

• Colorectal cancer (100% in untreated patients)

• Duodenal or periampullary adenocarcinoma (4%-12%)

• Desmoid formation (as many as 20%, typically postcolectomy)

• Other cancers, including medulloblastoma, hepatoblastoma, thyroid cancer, gastric cancer, pancreatic cancer, and adrenal cancer

• Development of rectal cancer in patients with a retained rectum

Most patients with FAP are asymptomatic until they develop cancer. As a result, diagnosing presymptomatic patients is essential.

Of patients with FAP, 75%-80% have a family history of polyps and/or colorectal cancer at age 40 years or younger.

Nonspecific symptoms, such as unexplained rectal bleeding (hematochezia), diarrhea, or abdominal pain, in young patients may be suggestive of FAP.

One study suggested a potential association between FAP and type 2 diabetes, but further studies are needed to confirm this association.[11]

Congenital hypertrophy of the retinal pigment epithelium is highly specific for FAP and is best seen by slit-lamp examination. These are discrete flat pigmented lesions of the retina. These are often multiple (63%) and bilateral (87%). They do not cause any clinical problems.

They indicate that a family member has inherited the gene that causes FAP and is at risk. As a result, they precede polyposis and correlate with mutations between exons 9 and 15 of the gene that causes FAP.

Some lesions are indicative of a Gardner variant of FAP, including the following:

• Osteomas (painless bony overgrowth) of the skull and the mandible may be present. They usually precede the clinical or radiologic diagnosis of intestinal polyposis.

• Dental abnormalities, often diagnosed by using x-ray films, may include supernumerary teeth, impacted teeth, dentigerous cysts, and odontomas.

• In prepubescent patients, epidermoid cysts on the legs, face, scalp, and arms may be present. They are the most common cutaneous manifestation of Gardner syndrome. These cysts are benign and mainly pose a cosmetic concern.

• Fibromas may be present, located on the scalp, shoulders, arms, and back.

Desmoid tumors are discussed in the Mortality/morbidity section under Prognosis.

Juvenile nasopharyngeal angiofibromas (JNA) are a rare, invasive, destructive tumors of the nasopharynx that can be sporadic or associated with FAP.[12]

Fundic gland polyps (FGP) are found in most patients, half of whom will also have dysplastic polyps.[13]  Dysplasia is associated with increased severity of antral gastritis and duodenal polyposis. Acid-suppressive therapy appears to be protective against dysplasia. Helicobacter pylori association is rare.

A palpable abdominal mass in a young patient is suggestive of FAP.

A palpable mass upon rectal examination in a young patient is suggestive of FAP.

2015 ACG guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes

The American College of Gastroenterology (ACG) released the following recommendations for the management of patients with hereditary gastrointestinal cancer syndromes—and they specifically discuss genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer[14] :

• The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer.

• Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives.

• When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives.

• Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making.

• Patients who meet the clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers.

The International Society for Gastrointestinal Hereditary Tumors (InSIGHT) has proposed a staging system and stage-specific interventions for FAP.[15]  

Flexible sigmoidoscopy: Visualization of more than 100 polyps usually establishes the diagnosis because of the diffuse nature of the polyposis.

Colonoscopy is usually reserved for patients thought to have AAPC because of the higher incidence of right-sided polyps (proximal colonic involvement).

Front- and side-viewing esophagogastroduodenoscopy is recommended if sigmoidoscopy or colonoscopy establishes the diagnosis of FAP. It is an essential component of the surveillance program in FAP, especially in that the second most common cancer involves the duodenum. This test helps to evaluate the presence of gastric, duodenal, and periampullary adenomas. It is recommended every 1-3 years. Benign gastric polyps are part of the spectrum of FAP. They are usually confined to the fundus.

Dental and skull x-ray films are recommended in patients thought to have a Gardner variant of FAP. The films help to detect osteomas and dental abnormalities.

Barium studies may be performed to visualize intestinal polyposis.

Periodic ultrasounds or abdominal computed tomography scans are used to check for intra-abdominal desmoid tumors and pancreatic cancer.

Periodic ultrasound of the thyroid: This imaging study is considered because of the increased risk of thyroid cancer. It can supplement the recommended annual physical examination of the thyroid.

Laboratory tests include the following:

• Complete blood cell (CBC) count

• Alpha-fetoprotein (AFP) blood test - For children with FAP until age 5 years as part of a screening program for hepatoblastoma

Genetic testing

Three genetic tests are available.[13] Patients should receive genetic counseling from a trained individual prior to the performance of these tests.

In vitro protein synthesis assay

This is the genetic test of choice for the proband patient (patient with FAP). This test is commercially available. DNA from peripheral blood is analyzed for a truncated APC gene product.

Because of the size of the APC protein, it is analyzed in five overlapping segments. If the proband has a mutation, other family members can be tested (after genetic counseling) for the identical mutation. The test generally has 100% accuracy in detecting other gene carriers in the family.

Gene sequencing

APC gene sequencing is the most accurate test. However, it is hard logistically and, hence, is only reserved for research purposes.

Linkage testing

DNA markers near or in the APC locus are used to identify mutant gene carriers. This test requires two affected family members to achieve an appropriate linkage relationship resulting in 90% accuracy. As a result, this is not appropriate logistically

Genetic testing for a germline mutation in the APC gene should be considered in individuals with 10-20 adenomas in their lifetime, furthermore in patients with a strong family history of polyposis; larger numbers of adenomas is associated with a greater likelihood of FAP.[8, 16, 17, 18]

Counseling and screening of first-degree relatives

Offer genetic counseling before any genetic testing is performed. The patients and their family members should be made aware of the limitations of genetic testing and the associated consequences. Genetic counseling should be performed by someone familiar with FAP and the genetic tests available.

A few patients with clinical FAP have a genetic mutation that cannot be identified, and their first-degree relatives cannot be screened genetically and will require life-time clinical screenings.[19]

Representative polyps should be removed by endoscopic polypectomy to confirm the diagnosis by histologic examination.[2, 20, 21]

The characteristic pathology of a polyp from patients with FAP is a tubular adenoma.

Medical care is mainly based on endoscopic surveillance to detect the onset of polyposis. Consequently, surgery would prevent the development of colon cancer. However, in view of the increased risk for the development of other cancers, continued medical follow-up is required with a number of surveillance tests, as colectomy would only address the potential risk of colon cancer.

Failure to obtain a relevant family history of FAP and providing information to family members on their risk and need for follow-up screenings to prevent cancers can be considered medical negligence. At the same time, identifying an asymptomatic person at risk and needing a diagnosis and follow-up treatment could lead to denial of medical and life insurances.[20, 22, 23] Failure to adequately follow up and monitor for the development of other cancers (eg, rectal pouch, duodenum) may lead to legal problems. Surveillance programs are important.

During pregnancy, the rate of desmoid and adenoma development is increased in the mother, owing to endogenous growth factors. Definitive treatment should ideally be deferred until delivery, if possible.[19]

A number of drugs (eg, celecoxib, sulindac) have been used successfully to reduce the number and the size of polyps in patients with FAP. However, they are insufficient as a primary modality of therapy.

Endoscopic surveillance

Note the following:

• Flexible sigmoidoscopy should be performed every 1-2 years starting at age 10-12 years in patients with FAP to document the onset of polyposis.

• Sigmoidoscopic surveillance and ablation of any polyps in the retained rectum or ileal pouch should be performed every 3-6 months in patients with FAP who have undergone colonic (total or subtotal) resection. There is an increased risk for adenomas and carcinomas in the ileal pouch, as there is increased epithelial cell proliferation at this site as compared to the afferent ileal loop.[23, 24]

• Once polyps are detected, colonoscopic surveillance is recommended to remove large polyps in patients who have not had an operation. This is important because surgery (colectomy) is usually deferred until an appropriate psychological age is reached (usually late teenaged years to early twenties). However, if the polyps have advanced histologic features, then early surgery is recommended.

• Front- and side-view esophagogastroduodenoscopy should be performed every 1-3 years once the diagnosis is made and after surgical therapy. The front-view esophagogastroduodenoscopy allows for the detection of gastric and duodenal polyps. The side-view duodenoscope allows for the examination of the ampulla of Vater.

• Capsule endoscopy is useful for the surveillance of jejunal-ileal polyps in selected patients but is not recommended for duodenal or ampullary surveillance. Some patients who are at high risk may benefit from screening with endoscopic ultrasound for periampullary and ampullary tumors.[19, 25]

Drugs used in the treatment of FAP include sulindac and celecoxib

Note the following:

• Because of the association between cyclooxygenase 2 (COX-2) inhibitors (celecoxib is a member of this drug family) and coronary artery disease, celecoxib is no longer widely used.

• These drugs have no primary role as sole therapy for patients with FAP who have not had surgical therapy. However, in patients with FAP who have had colectomy with ileoanal anastomosis, sulindac or celecoxib may be beneficial in reducing the size and the number of adenomatous polyps in the remaining rectum.

• The use of other nonsteroidal anti-inflammatory drugs (NSAIDs) and similar drugs is being studied.

• Cancers of the rectum (in patients who have had subtotal colectomy with ileorectal anastomosis) have been reported despite treatment with sulindac and celecoxib therapy. Because of the inability to control polyps medically, eventual rectal resection is usually necessary. This is why subtotal colectomy with ileorectal anastomosis (IRA) is not the preferred surgical procedure.

Screening of family members of patients with FAP should begin by age 12 years. Flexible sigmoidoscopy every 1-2 years until the patient is aged 35 years is adequate, then every 3 years thereafter. Genetic testing may eliminate the need for surveillance in some family members.

Desmoid tumors (intra-abdominal) may respond to antiestrogen therapy (tamoxifen) and sulindac because estrogen appears to promote their growth.

Chemotherapy with doxorubicin and dacarbazine may be attempted if no response is observed with other therapies.

A randomized trial suggested potential for aspirin to reduce colorectal adenoma growth or development in patients with FAP. However, it was a small study and patients have to be closely monitored for adverse events.[26]

In a murine model, low-dosage ursodiol together with sulindac prevented adenomas with less toxicity than if each had been given alone in full dosage. Interestingly, one study looked at the role of ursodeoxycholic acid on duodenal adenomas in FAP but found no effect on the development of duodenal adenomas[27, 28]

Dietary considerations

Patients with colectomy often have a change in bowel habits, for which changes in diet can lead to vitamin-mineral deficiencies. Vitamin B-12 deficiency occurs from rapid intestinal transit, ileal resection, and ascending bacterial overgrowth.[19]

Because of the diffuse nature of the polyposis and the inevitability of colorectal cancer, surgical therapy is ultimately required. Surgical therapy should be performed before the onset of cancer.[24]

Note the following:

• Colectomy with mucosal proctectomy and ileoanal pouch pull-through (proctocolectomy with ileal pouch-anal anastomosis/IPAA) is the procedure of choice at many centers. This procedure allows retention of the rectal function. Other options include subtotal colectomy with ileoanal anastomosis and total proctocolectomy with ileostomy.

• If medical therapy and endoscopic therapy do not control polyp growth, rectal resection may be needed in patients who have a retained rectum (such as in subtotal colectomy). Desmoid tumors may be resected with adequate margins. This generally is reserved for patients with ureteral or intestinal obstruction.

In a study to determine whether surgical treatment outcomes vary between patients with FAP (168 patients) and those with the sporadic form of the disease (110 patients), Johnson et al concluded that for both disorders, endoscopic and local surgical management of duodenal polyps are each followed by a high rate of local recurrence.[29, 30] Their results also indicated that for patients with either disease, definitive resection via pancreaticoduodenectomy, pancreas-sparing duodenectomy, or segmental duodenectomy are the best means of eradicating polyps and preventing carcinoma.

Pouchitis appears to be a common complication in patients with medically refractory FAP who undergo ileal pouch-anal anastomosis (IPAA).[31] In a retrospective cohort study of 113 patients with FAP who were treated with IPAA over 23 years (1992-2015), nearly one quarter (22.1%) developed pouchitis. In addition, affected patients appeared to develop pouch-related complications (56.0%) 3 months or later following the procedure. However, more than two thirds of patients treated for pouchitis (69.6%) responded well to antibiotic management.[31]

Outpatient follow-up

Adenomas of ileal pouch

It has been reported that following restorative proctocolectomy, the incidence of adenomas in the ileal pouch is high in patients older than 50 years and in those with more than 1000 polyps at colectomy. Moreover, terminal ileal malignancy appears not to follow the classic adenoma-carcinoma sequence. Additionally, adenomas were rarely found in the afferent loop. No relationship has been found between APC mutation and ileal pouch adenomas.[28, 32]

Educate patients about the need for cancer surveillance after colectomy.[17]  Inform family members so that they may undergo screening.

Consultations are recommended for the following:

• A gastroenterologist familiar with FAP should supervise follow-up care. This is important because appropriate surveillance should be pursued to detect and treat other cancers/complications of FAP after surgery.

• Appropriate genetic counseling for both the patients and their family members should be initiated. The patients and their family members should be made aware of the limitations of genetic testing and the associated consequences. Genetic counseling should be performed by someone familiar with FAP and the genetic tests available

• It has been reported that patients with incontinence after colectomy reported lower psychosocial functioning and experienced greater distress; these patients would benefit from added psychological interventions.[33]

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Class Summary

These agents are used to reduce the number and the size of adenomatous polyps that remain in the rectum or ileal pouch after colectomy in patients with FAP. Celecoxib is not widely used because of the association between COX-2 inhibitors (celecoxib is a member of this drug family) and coronary artery disease.

Sulindac (Clinoril)

Sulfoxide is a nonsteroidal anti-inflammatory agent that is metabolized to the anti-inflammatory sulfide metabolite and a sulfone metabolite. Sulfide metabolite is now known to have apoptotic activity on colonic epithelial cells and is presumed to be responsible for the regression of adenomatous polyps.

Celecoxib (Celebrex)

Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. COX-2 is overexpressed in colonic adenomas, which may contribute to adenoma growth, and inhibition of COX-2 may be the mechanism for polyp regression.