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Familial Adenomatous Polyposis (FAP)

James M. Church, MD
Director, David G. Jagelman Inherited Colorectal Cancer registries
Cleveland Clinic Foundation
Cleveland, Ohio

Introduction

Familial Adenomatous Polyposis (FAP) is a dominantly inherited growth disorder due to an inactivating mutation in the tumor suppressor gene APC. The disease is highly penetrant and is universally expressed as colorectal adenomatous polyposis. Ultimately colorectal cancer will develop unless prophylactic colectomy or proctocolectomy is performed. Extra-colonic expressions of the disease include benign and malignant tumors of several tissues and organs. The first case of FAP was described in 1859 and the first note of a familial association was in 1882. Lockhart-Mummery performed the first recorded operation for FAP at St Marks Hospital in London, in 1918, and founded the first registry for families with this syndrome at the same hospital in 1927. Since then centers for this disease have developed throughout the world, working to define the best management of patients and their families.

Molecular Genetics

FAP is caused by a mutation of an important tumor suppressor gene (APC) on the long arm of chromosome 5. Tumor suppressor genes hold the genetic code for proteins that suppress cell growth. APC is a large cytoplasmic protein that participates in the Wnt/Wingless signaling pathway by binding with axin to inactivate beta catenin, a key stimulator of intra-nuclear 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 APC that stop production of its protein 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-oncogenes (genes coding for proteins that stimulate cell growth) is also part of the cascade of genetic changes that eventually produce cancer.

APC mutations are inherited in 80% of FAP patients and occur during conception as germ cell mutations in 20%. Some patients have no apparent family history because of adoption, non-paternity, or lack of knowledge. However 80% of FAP patients will be part of a family with the disease, and have the chance for screening and early diagnosis. The twenty percent with no family history are usually diagnosed when symptoms occur or when extracolonic manifestations are recognized serendipitously.

Epidemiology

FAP is rare, occurring approximately 1 in 8,000 live births. It affects each gender equally and all races. FAP accounts for less than 1% of all colorectal cancers, meaning that about 1,000 to 1,300 new cases occur each year in the United States.

Presentation

FAP presents with a spectrum of severity, manifested by the age of presentation and the number of adenomas in the colon. At one end of the spectrum are patients who have thousands of polyps in their early teens and develop cancer in their early twenties. At the other end are patients with attenuated FAP, who reach their 60's with less than 100 small adenomas. The severity of the FAP is a major determinant of the timing of surgery and the selection of the procedure to be used.

FAP patients are diagnosed in one of three ways.

  1. By symptoms: Patients may be the first in a family with FAP (a 'spontaneous' mutation). They may not know their family history (adopted, or separated from affected relatives), or they may choose to ignore it. Screening is not performed and diagnosis is made when symptoms prompt investigations. These patients tend to present late and may already have a cancer.
  2. By endoscopy: Patients are part of a recognized family and are usually diagnosed by screening endoscopy.
  3. By genetics: patients are diagnosed by genetic analysis, without undergoing endoscopy at all.

Once a diagnosis is made the severity of the polyposis is determined by estimating the number and size of rectal polyps and colonic polyps. The presence of adenomas is confirmed by biopsy. Lesions suspicious for malignancy are noted and specifically biopsied.

Patients are then examined for evidence of other manifestations of the syndrome.

Registries

FAP families are best managed in the context of a Registry for Inherited Colorectal Cancer. The most important aspect of management is diagnosis of the condition by genetic or endoscopic screening, and appropriate prophylactic treatment. This can minimize death from colorectal cancer and restore life expectancy almost to normal. Registries promote screening by educating families, facilitating testing and coordinating appointments. Counseling is provided as part of the protocol. Registries also serve roles in educating health care professionals and in performing research.

Medical treatment of FAP

Sulindac, a non-steroidal anti-inflammatory medication, consistently ablates adenomas in FAP. Although there have been 3 case reports of rectal cancers occurring in rectums rendered polyp free by Sulindac, other studies have used the drug to achieve prolonged remission of polyps with no sign of cancer. Currently, Sulindac is not a routine treatment replacing surgery, but is under investigation. It has no noticeable effect on duodenal adenomas, but is useful for desmoid tumors.

Celecoxib, a COX-2 specific antagonist, has not proved as effective as sulindac in suppressing polyps but it is the only agent to receive FDA approval for use in chemoprevention in FAP.

Aptosyn is derivative of sulindac (sulindac sulfone, a metabolite with no COX inhibiting effect at all) and is not as effective as sulindac in adenoma suppression.

NSAIDs should not be used as definitive treatment for FAP. They may be useful in temporizing treatment, when surgery needs to be delayed for some reason and there is concern about the adenomas. They may also have a role in controlling pouch polyposis or rectal polyposis after initial prophylactic surgery

Prophylactic Colonic Surgery for FAP

The aim of the surgical treatment of FAP is to intervene in the polyp-cancer sequence by removing the polyps before the transformation to malignancy occurs. This is done by prophylactic colectomy or proctocolectomy. Because FAP is a mucosal disease, it is analogous to ulcerative colitis. The surgical options are similar:

  1. Colectomy and ileo-rectal anastomosis(IRA)
  2. Proctocolectomy with mucosectomy and handsewn ileal pouch-anal anastomosis (IPAAh)
  3. Proctocolectomy without mucosectomy and stapled ileal pouch-anal anastomosis (IPAAs)
  4. Proctocolectomy and ileostomy

IRA is a simple operation with quick recovery, low complication rates and minimal lifestyle interference. It is especially good for asymptomatic teenagers and young adults. The risk of cancer in the retained rectum mandates yearly surveillance and later proctectomy may be necessary. IPAA minimizes this risk but adenomas develop in the ileal pouch so surveillance is still necessary. A handsewn IPAA has more complications and poorer function than a stapled IPAA. Stapled IPAA allows avoidance of a diverting stoma.

Choosing the operation

The way in which a FAP patient presents has a strong effect on the choice of surgery.

  1. When the disease is discovered on screening, the patient is usually young and asymptomatic, just entering or about to enter adulthood. To take such a patient and make them incontinent, or slave to an abnormal bowel habit, is to do them a disservice. Even total proctocolectomy does not cure FAP, nor does it remove the need for regular surveillance. In such patients, colectomy and ileorectal anastomosis will allow a good quality of life during their formative years, while substantially reducing the risk of large bowel cancer. Preoperative discussions focus on the need for regular postoperative surveillance of the rectal stump, and the possibility of further surgery being needed.
  2. A patient who is experiencing symptoms from the large number of colorectal adenomas needs total proctocolectomy. Almost all these patients are suitable for an ileal pouch-anal anastomosis (IPAA). The critical decision is not which operation to perform, but which sort of IPAA to use, hand-sewn or stapled. Because the low rectum appears to be a "hot spot" for polyps after IRA, in most cases this area should be removed by mucosectomy with hand-sewn ileo-anal anastomosis. In some patients (e.g. the very young, those with relatively few low rectal polyps or those in whom an ultra-low stapled anastomosis is possible) a stapled anastomosis may be performed, with the residual anal mucosa kept under surveillance.
  3. If a patient presents with FAP and cancer, the top priority is to cure the cancer. Restorative proctocolectomy (with IPAA) is still possible as long as chances of cancer cure are not compromised. If a colon cancer is incurable and surgery is palliative, ileorectal anastomosis is a good choice.
  4. Patients who present with a desmoid tumor or a strong family history of desmoid tumors deserve special consideration. Such patients are at risk of developing an intra-abdominal desmoid after their colectomy, a desmoid that may make future abdominal surgery difficult or even impossible. Patients with a desmoid should be warned that an IPAA might not be possible. They can choose between a permanent end ileostomy or an ileal-low rectal anastomosis. If the polyposis is severe a complete proctocolectomy with ileostomy makes the most sense.

    For patients with a family history of desmoids let the severity of the colonic disease determine the choice of colorectal surgery. One option (albeit unproven) is to premedicate these patients with sulindac (150mg, twice daily) for 3 months, if circumstances permit.

    A family history of desmoid tumors may make laparoscopic surgery more desirable, in that surgical trauma is minimized. This theory remains to be tested.

  5. Genotype/phenotype studies in FAP have shown that attenuated disease is associated with mutations in exons 3 and 4, mild disease with mutations at the 3' end of exon 15, and extremely severe disease with mutations in exon 15G (including codon 1309, the "hot spot" for mutations in the gene). Such relationships can be used to guide surgical decision-making. Patients in families with 15G mutations are extremely likely to lose their rectums if they are not removed at the inital surgery; IPAA is their best choice. Patients in families with mutations in exons 3 and 4 almost never need proctectomy; they can have an IRA.

The patient makes the choice of surgery after talking with their surgeon, who presents a full range of options, with advantages and disadvantages of each. Only then can the patient make an informed choice. In a disease like FAP, the patient's choice is often influenced by the experience of other family members. If this experience has been bad the Polyposis Registry Coordinator can have a role in counselling, and resolving fears and apprehensions. We recommend IRA to patients with mild disease (i.e. <1,000 polyps in the colon, <20 polyps in the rectum, no cancer, no severe dysplasia in the rectum). In a patient with severe disease, in a family with uniformly severe disease, or with an exon 15G mutation IPAA(s) is recommended. IPAA (h) is reserved for patients with large anal polyps or adenomas down to the dentate line. The indication for total proctocolectomy and ileostomy is for patients with low rectal cancers or severe disease in whom a pouch-anal anastomosis is impossible (e.g. desmoids) or impractical (e.g. poor sphincters).

Laparoscopy in FAP

Because most patients with FAP do not have a cancer at the time of prophylactic colectomy they are good candidates for laparoscopic surgery. The teenagers who are diagnosed on screening stand to benefit most from such minimally invasive surgery. The lack of a large midline incision minimizes time away from school and from the sort of physical activities teenagers do. The colectomy part of total proctocolectomy and ileal pouch-anal anastomosis can also be done in this way, although a Pfanennstiel incision is necessary to make the pouch. If this option can be offered, surgery is a less scary prospect for the patient before the operation, and a more comfortable experience afterwards.

Timing of Surgery

The preoperative colonoscopy in FAP patients is important in helping determine the choice of operation, it's timing, and even the techniques of resection. Large numbers of polyps in a symptomatic patient mean early surgery, as soon as it is convenient. Suspicion of a cancer means very early surgery, and a radical colectomy performed with oncologic technique. An asymptomatic patient with modest numbers of small polyps may be able to wait one or two years for surgery, as long as endoscopic surveillance is performed yearly. In such patients the timing of surgery is a matter of convenience for the family, with school, vacations, sport and insurance coverage all factors in the decision.

Postoperative Surveillance

  1. Post IRA:
    Patients who have had an IRA need yearly proctoscopy to monitor the rectum and to remove adenomas over 5mm in diameter. This is a commitment patients make before the surgery. A prime role for FAP registries is to monitor patient's attendance and to ensure and facilitate follow-up. Financial concerns should not be allowed to limit attendance.
  2. Post IPAA:
    Patients who have had IPAA need yearly examinations, whether they have had a mucosectomy or not. If there is residual rectal mucosa, this is a 'hot spot' for recurrent neoplasia and may need to be stripped out if persistent neoplasia occurs. Mucosectomy does not guarantee complete excision of rectal epithelium and neoplasia can still occur in these patients. The pouch itself may develop adenomas. The natural history of ileal-pouch neoplasia in FAP patients is unknown and deserves study. As time from pouch construction increases, and as pouches become more like colons, the significance of pouch adenomas may increase. Remember, these are patients in whom the colorectal manifestation of FAP was severe enough to warrant total proctocolectomy.

The effect of Desmoid Tumors on Surgery for FAP

Desmoid tumors can have a profound influence on the type of operation that is, or can be, performed. There are 3 scenarios in which desmoid tumors influence surgery.

  1. A family history of desmoid tumors alerts the surgeon to a higher than usual (10%) risk of a desmoid developing in a patient.
  2. At laparotomy for colectomy or proctectomy, an unsuspected desmoid tumor is seen. Under these circumstances it may not be possible to proceed with an IPAA because of the extra tension on the mesentery due to the tightening of the desmoid. If a desmoid-like reaction is seen, where there is a whitish, plaque-like mesenteric reaction without a mesenteric mass or sclerosis, it may be reasonable to proceed with an IPAA. The natural history of this desmoid-type reaction is unknown and the risk of a symptomatic desmoid developing postoperatively is likely to be low, as long as the patient is not in a "desmoid family".

    If the rectum is relatively mildly affected, IRA is an option. If the patient has severe polyposis and an IPAA is not possible, proctectomy and ileostomy is done. A continent ileostomy is contra-indicated. Postoperatively the desmoid must be closely monitored and treated if it enlarges.

    Make sure you discuss the possibility of desmoid tumors and their effect on surgical strategy with the patient before the operation.

  3. A desmoid tumor develops in a patient who has had their surgery for FAP. This is by far the most common scenario; symptomatic intra-abdominal desmoid tumors present after abdominal surgery 80% of the time.

The Stomach and Duodenum

Prospective studies with side-viewing endoscopes show that over 90% of FAP patients develop duodenal adenomas and fundic gland polyps: 10% have gastric adenomas. While fundic gland polyps are harmless, periampullary cancer is the third most common cause of death in FAP. Patients begin EGD surveillance in their twenties. The status of the duodenum can be staged according to the Spigelman Staging System and surveillance designed accordingly. A normal-looking papilla often has adenomatous tissue in it. For a normal or mildly affected duodenum, EGD can be repeated every 3 to 5 years. When there are large (>1cm) adenomas, EGD is indicated every 1 to 2 years. For severe dysplasia, EGD is repeated in 6 months and surgery must be considered.

Endoscopic treatment of duodenal adenomas, whether by laser, electrocautery or snare, is only temporarily effective. The polyps just grow back. Transdudodenal polypectomy is also only a temporary measure. Pancreas-preserving duodenectomy is a more conservative way of achieving lasting remission than a Whipple procedure.

Desmoid Tumors

Desmoid tumors are benign tumors of fibro-aponeurotic tissue that occur in 12% of patients with FAP and are the second most common cause of death. They may occur within the abdomen, in the abdominal wall or in extra-abdominal sites. In FAP, 80% occur within the mesentery of the small bowel and 80% arise after an abdominal surgery. 10% of FAP-associated desmoid tumors grow relentlessly and are fatal. Most (80%) follow an indolent course with periods of growth and remission and a few regress completely. Intra-abdominal desmoid tumors cause symptoms because of pressure on adjacent structures (e.g. ureter), or by obstructing the small bowel. They may make ileal pouch surgery impossible, or cause ulcerations in an existing pouch. Attempts at complete surgical excision are associated with a high recurrence rate and an almost prohibitive morbidity. Long-term therapy with Sulindac may provide some benefit while tamoxifen and anti-sarcoma chemotherapy are used in symptomatic or progressive disease.

Other Tumors in FAP

The constellation of FAP with epidermal cysts, desmoids, osteomas and dental anomalies is given the eponym "Gardner's Syndrome" and is associated with mutations at the 3' end of exon 15. The polyposis itself is usually relatively mild.

The association of FAP with glioblastoma is referred to as Turcot's syndrome. Patients with medulloblastoma also may have Turcot's syndrome but here the colorectal cancer risk is due to a germline mutation of a mismatch repair gene.

Papillary thyroid cancer is associated with FAP, especially in younger women. Hepatoblastoma is associated with FAP but is uncommon. Routine screening of infants by abdominal exam is indicated.

Congenital hypertrophy of the retinal pigmented epithelium (CHRPE, pronounced "chirpy") occurs in families with mutations in exons 5 to 10. This accounts for about 66% of families with FAP. CHRPE has no clinical significance except for its use as a cheap, non-invasive screening test in families where its presence is established.

New developments in FAP

  1. Genetic testing: Genetic testing has come of age for FAP. Although concerns exist about following correct testing protocol, families may now be accurately triaged according to genotype and endoscopic surveillance can be used more appropriately. Genotype-phenotype associations may offer clues to the etiology of various extra-colonic manifestations and may ultimately lead to specific treatments. The effect of a diagnosis of FAP on insurability is a concern.
  2. Laparoscopy: Laparoscopy is an ideal option for young, asymptomatic patients with a benign colonic disease. It promotes quick recovery, unaltered lifestyle and minimizes fear of surgery in a family.
  3. Sulindac: While not a new development, more mature data are showing that Sulindac may be a effective long-term treatment of adenomatous polyposis. It is the best option for pouch polyposis. Other chemotherapeutic agents with less side effects (COX-2 inhibitors, sulindac sulfone) may offer alternatives.

Conclusion: The "State of the Art"

Today a patient with FAP may be diagnosed by genetic testing, have a laparoscopic colectomy and have rectal adenoma suppression with low-dose sulindac. He/she loses minimal time from work or school and moves his bowels 2 or 3 times a day. His family can be tested accurately and simply. This patient still faces potential problems however. We cannot stop or reliably treat a desmoid tumor. We cannot treat high-grade duodenal adenomas without major surgery and we cannot stop discrimination by his insurance company. These are issues for the future.

References

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