About Us Physicians Education Members Patient and Public Corporate Partners DCR Research Foundation
Home > Physicians > Education > Core Subjects > Familial Adenomatous ...
Print

Familial Adenomatous Polyposis (FAP)

David W Dietz, MD
Assistant Professor of Surgery
Washington University
St. Louis, MO

INTRODUCTION

Familial adenomatous polyposis (FAP) is a dominantly inherited cancer syndrome caused by inactivation of the tumor suppressor gene APC. Patients with classic FAP will typically develop hundreds to thousands of colorectal adenomas by the age of 20 years and will progress to invasive cancer by age 40 years. This can be prevented, in most cases, by timely surgical prophylaxis. The choice of operation is dependent on many factors, including well-described genotype-phenotype relationships (attenuated FAP). After colectomy, however, other manifestations of the syndrome continue to put patients at risk of death. Duodenal adenomas develop in the vast majority of FAP patients and progress to invasive cancer in up to 10%. Periampullary cancer is the 3rd most-common cause of death in FAP. Desmoid tumors also account for significant morbidity and are the 2nd leading cause of mortality. Treatment of these locally invasive tumors can be extremely difficult and typically involves treatment with NSAIDs and/or anti-estrogen agents. Surgical resection of desmoid tumors is usually avoided. Other manifestations of FAP include congenital hypertrophy of the retinal pigment epithelium (CHRPE), osteomas, epidermal cysts, dental abnormalities, thyroid cancer, hepatoblastomas, and tumors of the small bowel, brain, adrenal glands, pancreas, and biliary tree. The newest development in the field of FAP is the description of the closely related syndrome known as “MYH-associated polyposis”. Mutation of the base excision repair gene MYH results in a phenotype very similar to attenuated FAP and is probably causative in up to 10% of polyposis patients who test negative for a mutation in APC.

EPIDEMIOLOGY

FAP is a rare disorder with a birth frequency of 1 in 10,000. Fewer than 1% of colorectal cancers are due to FAP but the cumulative risk of colorectal cancer in these patients exceeds 50% by age 40. The “classic” timeline for the development of colorectal neoplasia in FAP is polyps at age 20-30 years and cancer at age 40-45 years. This varies considerably, however, as the severity of the disease ranges widely. At its worst, thousands of polyps develop during the early teenage years followed by cancer around age 20 years. At the other end of the spectrum are patients with the “attenuated” form of the disease where adenomas will number <100, the rectum is typically spared, and the development of cancer is a late or rare occurrence.

GENETICS

FAP is caused by a mutation in the tumor suppressor gene known as APC (adenomatous polyposis coli). There have been >700 different mutations in the APC gene reported, the most common of which lead to creation of premature stop codon which causes truncation of the APC protein product in the C-terminal region. One method of genetic diagnosis relies on detection of this truncated protein. It is also thought that other modifier genes, as well as epigenetic and environmental factors, also play a role in the development and expression of FAP.

The APC protein participates in the Wnt/Wingless signaling pathway by binding with axin to invactivate beta catenin, a key stimulator of intra-cellular growth cascades. APC also binds to E-cadherin, a facilitator of cell-cell adhesion, and plays an essential role in segregation of chromosomes during cell division. Mutations of the APC gene that stop production of its protein product predispose cells to neoplasia by loss of these multiple functions. When other tumor suppressor genes lose function due to various genetic events, progressive loss of control of cell growth and differentiation occurs. Activation of proto-oncogens (genes coding for proteins that stimulate cell growth) is also part of the cascade of genetic events that eventually produce cancer.

DIAGNOSIS, GENETIC TESTING, AND SCREENING OF AT-RISK PATIENTS

APC mutations are inherited in 80% of FAP patients and occur during conception as spontaneous germ cell mutations in 20%. Some patients have no apparent family history of the disease due to adoption, non-paternity, or lack of knowledge. However, 80% of FAP patients will be part of a family with the disease and, therefore, have the chance for screening and early diagnosis.

The diagnosis of FAP is usually made in one of three ways. 1) By symptoms, typically in patients with either a spontaneous mutation or in those from established FAP families who haven’t undergone screening due to non-compliance. These patients are at very high risk for having an advanced cancer at presentation. 2) By endoscopy, in patients from a known FAP family who are enrolled in a screening program. 3) By genetic testing, again in patients from a known FAP family who undergo genetic analysis prior to the onset of endoscopic screening.

Genetic testing historically relied on the “protein truncation test” (PTT) for diagnosis. However, this test was negative in up to 20-30% of FAP patients, in many cases due to the presence of a non-truncating missense mutation which rendered the APC protein non-functional without altering its size. Today, PTT has been replaced as the first-line test by other techniques, the most common of which is direct DNA sequencing. Other methods which can be used as second-line tests are monoallelic mutation analysis (MAMA), conversion analysis, and multiplex ligation-dependent probe amplification (MLPA). The use of these newer methods has increased the sensitivity of testing in FAP to >95%.

Once a patient is identified as being a member of a FAP family, annual sigmoidoscopy should be performed for screening beginning at age 10-12 years. This simple approach has reduced the incidence of colorectal cancer at diagnosis by 55% and has led to improved survival in all patients. Upper endoscopy is also an important part of the screening program given the high incidence of gastroduodenal polyps and periampullary cancer. EGD should be performed every 6 months to 4 years, depending on the severity of the upper GI manifestations of the disease in the particular patient. Some experts also advise yearly thyroid palpation or ultrasound as well as screening for hepatoblastoma in children by alpha-feto protein measurements or liver imaging.

SURGICAL TREATMENT

Prophylactic colectomy in classic FAP is usually performed shortly after polyps are discovered on surveillance colonoscopy. When polyps are diagnosed in the early teenage years, surgery can be deferred until the patient reaches maturity in their late teens or early twenties. Four options exist; total abdominal colectomy with ileorectal anastomosis (TAC+IRA), total proctocolectomy with ileal pouch anal anastomosis (TPC+IPAA), total proctocolectomy with end ileostomy (EI), and total proctocolectomy with continent ileostomy (TPC+CI) . The choice of operation depends on many factors and should be individualized. The most important determinants are rectal polyp burden, presence of cancer or severe dysplasia, age, symptoms, continence, genotype, and patient compliance.

Patients and their surgeon will typically be faced with the choice between TAC+IRA and TPC+IPAA. While both operations preserve continence, the resultant bowel function is inferior to what the patient had experienced prior to surgery. The advantage of TAC+IRA is that this change in function is less severe than that resulting from TPC+IPAA. The advantage of the latter is that removal of the rectum virtually eliminates the risk of rectal cancer, although several cases following IPAA have been reported worldwide.

TAC+IRA can be performed safely, and should therefore be favored, in the following situations:

1.In patients with mild to moderate colonic polyposis and <20 polyps in the rectum.

2.In genotyped patients with mutations in exons 3,4, or the 3’end of exon 15. These mutations are associated with the “attenuated” form of FAP, where the development of severe rectal polyps or rectal cancer is extremely rare.

3.In teenaged patients where the relatively poor function of an IPAA may have severe social ramifications and where the pelvic dissection associated with proctectomy may alter both male and female sexual function and fertility. In these cases, the patient can be followed closely with annual or bi-annual proctoscopy with proctectomy deferred until rectal polyposis can no longer be controlled with the combination of endoscopic polypectomy and NSAIDs.

In addition, all patients being offered TAC+IRA must have adequate sphincter function and should be willing to enter a surveillance proctoscopy program. Studies in patients with FAP have shown perioperative morbidity rates to be lower following TAC+IRA compared to TPC+IPAA. In addition, patients undergoing TAC+IRA have fewer stools (both daily and nighttime), less incontinence, and wear pads less often than those treated with TPC+IPAA. Rates of rectal cancer following TAC+IRA in FAP have varied widely (5% to 37%) and are clearly related to patient selection and the availability of surgical options. This is best illustrated by a study from the Cleveland Clinic which looked at outcomes in patients having TAC+IRA in the era before the availablility of IPAA and compared it to those having surgery after IPAA became available at that institution. Thirteen percent of patients having TAC+IRA in the pre-IPAA era developed rectal cancer versus none in the post-IPAA era. Likewise, the proctectomy rate following TAC+IRA was much higher in the pre-IPAA era patients (32%) compared to those in the post-IPAA era (2%).

TPC+IPAA is required in the following situations:

1.Patients with severe polyposis

2.Patients with >20 polyps in the rectum

3.Patients with cancer or severe dysplasia

4.Patients with the exon 15G mutation (predicts severe disease)

An area of controversy in the management of FAP patients is whether or not to perform a mucosectomy and handsewn IPAA. Data from patients with ulcerative colitis has shown that functional outcomes are worse in patients undergoing mucosectomy (M) compared to those having preservation of the anal transitional zone by the more common double-stapled IPAA (DS). In FAP, the benefit of improved function must be balanced against the risk of developing adenomas (25-30%) or rectal cancer in the retained anal transitional zone/low rectal mucosa. We tend to perform M in most patients with FAP, reserving DS for women who have had previous vaginal deliveries or patients where body habitus (tall/obese/long, narrow anal canal) may make the extra several centimeters of pouch reach needed after M difficult to obtain.

Another area of controversy is the patient with FAP who presents with rectal cancer. The decision to offer the patient IPAA versus permanent end ileostomy (EI) should be made following sound oncologic principles. If a clear distal and radial margin can be obtained and sphincter function is adequate, then IPAA can be pursued. In these cases, radiation therapy should always be given pre-operatively as radiating an existing pelvic pouch will lead to poor pouch function and eventual pouch excision in most cases. It is for this reason that we tend to treat all rectal cancers in FAP patients with neoadjuvant therapy, regardless of stage, in order to avoid the dilemma of post-operative radiation in a patient whose tumor was understaged by endorectal ultrasound.

TPC+EI is reserved for patients with poor sphincter function, those not willing to undergo yearly adenoma surveillance following IPAA, or those favoring the convenience and low morbidity of an ileostomy over a restorative procedure. It is also the procedure of choice when an intra-abdominal desmoid tumor precludes IPAA or IRA.

FOLLOW-UP OF TREATED CARRIERS

Consistent follow-up of patients after both TAC+IRA and TPC+IPAA is mandatory to avoid the development of cancer in the rectum, anal transitional zone, or ileal pouch. Following TAC+IRA, the recommended surveillance is proctoscopy every 6 months with destruction of all polyps >5 mm in diameter. No formal guidelines exist for surveillance after IPAA, but it is clear that these patients must be followed closely. In addition to the risk of adenomas in the ATZ, polyps can develop in the ileal pouch itself. The published risk of pouch adenomas is 7% after 5 years, 35% after 10 years, and 75% after 15 years. Although rare, cancers have been reported following IPAA and have been found at the IPAA, in the ATZ, and in the ileal pouch. Mucosectomy does not fully protect against cancer as cases have been reported, presumably arising from retained rectal or transitional mucosa.

MEDICAL TREATMENT

Sulindac, a non-steroidal anti-inflammatory drug, and celecoxib, a COX-2 antagonist, have both been shown to cause regression of colorectal adenomas in FAP. Unfortunately, the response is rarely complete and in most cases all that is seen is a modest reduction in the number and size of polyps. No protective effect against the development of cancer has yet been definitively demonstrated and these drugs cannot replace the role of prophylactic colectomy in FAP. Their best use is in controlling pouch or ATZ polyposis after prophylactic surgery. Several small studies have shown a reduction in polyp load ranging from 12% to 44%.

GASTRODUODENAL POLYPS AND CANCER

Duodenal adenomas develop in over 90% of patients with FAP with the median age at diagnosis being 38 years. Two-thirds of duodenal adenomas are found on or near the ampulla of Vater and random biopsies of a normal appearing ampulla will show microadenomas in 10-15% of cases. The danger of duodenal adenomas is progression to invasive cancer; this is the third most-common cause of death in FAP patients. The mean age of cancer diagnosis is 50 years and 3-10% of FAP patients will develop duodenal cancer by age 60-70 years.

Duodenal surveillance should begin before age 30 and the best yield will be obtained using a side-viewing endoscope. The Spigelman stage is used to guide treatment of duodenal polyps and to determine the frequency of surveillance. This classification system places patients into stages 0-IV based on polyp number, size, histology, and presence of dysplasia. Patients with stage 0-I duodenums should have EGD q5 years, those with stage II disease q3 years, and those with stage III disease q1-2 years. Strong consideration of prophylactic duodenectomy should be given to patients with stage IV disease. If duodenal cancer develops, the outcome is generally poor. A randomized study has shown that a six month course of celecoxib 800 mg/day can reduce the severity of duodenal polyposis.

DESMOID TUMORS

Desmoid tumors are neoplastic proliferations of myofibroblasts that occur in 10-15% of FAP patients. They seem to be incited by surgical trauma as the incidence of desmoids found at index surgery is only 3% compared to 36% at second surgery. These locally aggressive tumors have two different morphologies; a sheet-like form known as “desmoplastic reaction” or “desmoid precursor”, or the more-recognizable mass form. There is a slight female predominance associated with desmoid tumors, and their growth seems to be stimulated by estrogen. Half of desmoid tumors will be found within the abdomen with most of these occurring in the mesentery of the small bowel. While 80% follow an indolent course, some become locally aggressive and do not respond to treatment. These tumors can cause chronic abdominal pain, bowel obstruction, and can also lead to intestinal ischemia. Desmoid tumors are the second-leading cause of death in FAP.

Desmoid tumors may also prevent the creation of an IPAA or an IRA as they can tether and shorten the small bowel mesentery. This possibility should always be discussed with patients preoperatively and CT scans may be useful for planning surgery in patients from desmoid families or those with a mutation in the “desmoid region” of the APC gene (distal to codon 1399).

The primary treatment for desmoids is medical. Surgical resection is usually difficult due to the mesenteric location of most intra-abdominal tumors. Attempts at complete excision typically result in morbidity, mortality, and tumor recurrence and should only be utilized in highly selected patients. Sulindac (200-400 mg/day) and antiestrogen therapy (tamoxifen 20-40 mg/day or toremifen 180 mg) are first line therapy. Small studies have shown response rates of 25-50%. A recently described regimen combining sulindac with high-dose tamoxifen (120 mg/day) has shown promise in patients with refractory disease and some groups now use this as second line therapy. If patients fail to respond to these regimens, options are limited. Cytotoxic chemotherapy can be utilized, primarily involving sarcoma-type regimens (i.e. doxorubicin and dacarbazine). Success is limited, however, and mortality rates are high.

MYH-ASSOCIATED POLYPOSIS

A recently described mutation in the human MutY homologue (MYH) produces a colorectal phenotype indistinguishable from attenuated FAP. Termed “MYH-associated polyposis”, this disease may account for up to one-third of cases of FAP in which no APC mutation is identified. MYH functions as a base excision repair gene, preventing mutations resulting from products of oxidative damage. MYH-associated polyposis is inherited in an autosomal recessive fashion. Patients with a biallelic mutation will usually have <100 colonic polyps but have a risk of developing colorectal cancer that approaches 100% at age 65 years. The significance of monoallelic mutation is less clear, with fewer polyps developing and a lower risk of cancer. MYH testing should be performed in any polyposis patient who is not found to carry a mutation in APC.

REFERENCES

  1. Church J. Familial Adenomatous Polyposis: Core Subjects Update. ASCRS 2003.
  2. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol 2006;101:385-398.
  3. Knudsen AL, Bisgaard ML, Bulow S. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2003;2:43-55.
  4. Hartley JE, Church JM, Gupta S, et al. Significance of incidental desmoids identified during surgery for familial adenomatous polyposis. Dis Colon Rectum 2004;47:334-340.
  5. Knudsen AL, Bulow S. Desmoid tumour in familial adenomatous polyposis. A review of literature. Fam Cancer 2001;1:111-119.
  6. Wu J, Philip P, McGannon EA, Church JM. APC genotype, polyp number, and surgical options in familial adenomatous polyposis. Ann Surg 1998;227(1):57-62.
  7. Aziz O, Athanasiou T, Fazio VW, et al. Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 2006;93:407-417.
  8. Phillips RKS, Wallace MH, Lynch PM, et al. A randomized, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002;50:857-860.
  9. Groves CJ, Saunders BP, Spigelman AD, Phillips RKS. Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 2002;50:636-641.
  10. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH. N Engl J Med 2003;348:791-799.