Familial Adenomatous Polyposis (FAP)
Familial Adenomatous Polyposis (FAP) is a rare (1 in 8,000) inherited (autosomal dominant) disorder due to an mutation of the tumor suppressor gene APC on the long arm of chromosome and expressed by the phenotype of multiple adenomatous polyps; it accounts for <1% of all colorectal cancers. Approx. 20% occur during germ cell mutations. Extra-colonic expression of FAP includes several tumor sites. It was first described in 1859 and the first familial association was reported in 1882.
FAP presents with a spectrum of severity, manifested by the age of presentation and the number of colonic adenomas (polyps). At one end of the spectrum are the group of patients who develop thousands of polyps in their early teens and go on to 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.
What is attenuated FAP?
An attenuated form of familial adenomatous polyposis (AFAP) has been identified. Individuals with AFAP develop fewer than 100 adenomatous polyps (average of 30 polyps) and the polyps are more likely to occur on the right side of the colon. Whilst the risk of developing cancer is increased the average age at diagnosis is much older (50-55) than in the classic form of the disease. Congenital hypertrophy of the retinal pigment (CHRPE) and desmoid tumors are rarely seen.
Mutations in three specific areas of the APC gene have been associated with the AFAP phenotype. The polyp burden (number of polyps developed) and the risk of other FAP manifestations varies depending on in what area the mutation is located. One of these three areas of the gene is associated with a very variable number of polyps (ranging from two to 500). In families with such mutations, some relatives may have the AFAP phenotype whereas others have classic FAP.
Unlike FAP, not all persons with an AFAP-associated APC mutation will develop polyps, and the lifetime chance to develop polyps is unknown. The incidence of AFAP is also unknown, but thought to be about the same or less than classic FAP.
Sulindac, a non-steroidal anti-inflammatory (NSAID) ablates adenomas. However, there are 3 case reports of rectal cancers developing in rectums rendered polyp free by its use. Sulindac is not a replacement for surgery. It has no effect on duodenal adenomas. NSAIDs may have a role in desmoids and in controlling pouch polyposis or rectal polyposis after surgery.
Surgery intervenes in the polyp-cancer sequence by removing the polyps before their transformation to malignancy. As FAP is a mucosal (lining of the bowel) disease its surgical treatment is analogous to ulcerative colitis.
Proctocolectomy with mucosectomy and handsewn ileal pouch-anal anastomosis
Proctocolectomy without mucosectomy and stapled ileal pouch-anal anastomosis
Proctocolectomy and ileostomy
- Colectomy and ileo-rectal anastomosis (IRA) (see above)
Choosing the operation?
The way in which an individual FAP patient presents and their immediate family's past experience has a strong effect on their choice of surgery.
Screen detected patients are by definition young and asymptomatic. To take such a patient and make them slave to an abnormal bowel habit or worse still incontinent is we believe to do them a disservice particularly as total proctocolectomy neither cures FAP, nor does it remove the need for regular surveillance. IRA (see above) the simpler of the four operations, followed by rectal surveillance will allow for a good quality of life during their formative years, while substantially reducing the risk of large bowel cancer. Future proctectomy may be necessary. The postoperative appearance at 2 weeks when patient reurned to work (seen above).
Symptomatic patients (large number of adenomas) need a total proctocolectomy; almost all are suitable for an ileal pouch-anal anastomosis (IPAA). As the lowermost rectum appears to be a "hot spot" for polyp development after IRA, in most patients this area should be removed by mucosectomy with a hand-sewn IPAA.
Genetic studies 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. As patients from families with 15G mutations are extremely likely to lose their rectums following an IRA; IPAA is their best choice. Patients in families with mutations in exons 3 and 4 almost never need proctectomy; they can have an IRA and follow-up surveillance.
We recommend IRA to patients with mild disease i.e. <1,000 polyps in the colon, <20 polyps in the rectum and no evidence of either cancer or severe dysplasia in the rectum. In a patient with severe disease, from a family with uniformly severe disease, or with an exon 15G mutation IPAA is recommended. Hand sewn IPAA are reserved for patients with adenomas growing at the dentate line. Total proctocolectomy and ileostomy is reserved 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.
FAP patients are good candidates for laparoscopic surgery; teenagers diagnosed on screening stand to benefit most. The lack of a large midline incision minimizes time away from school and from the sort of physical activities teenagers do. If this option can be offered, surgery is a less scary prospect for the patient and a more comfortable experience afterwards.
Colonoscopy is important in helping determine the choice of operation and it's timing. Large numbers of polyps in symptomatic patients warrants early surgery, as soon as its convenient. A suspicion of a cancer requires urgent surgery. Asymptomatic patients with modest numbers of small polyps may be able to wait one or two years provided endoscopic surveillance continues; timing is a matter of convenience for the family, with school, exams, vacations and sport all factors to consider.
Stomach and duodenal polyps?
Prospective studies show that over 90% of FAP patients develop duodenal adenomas and fundic gland polyps: 10% have gastric adenomas. Whilst fundic gland polyps are harmless, periampullary cancer is the third commonest cause of death in FAP patients. Patients begin OGD 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, OGD can be repeated every 3 to 5 years. When there are large (>1cm) adenomas, OGD is indicated every 1 to 2 years. For severe dysplasia, OGD is repeated in 6 months and surgery considered.
Endoscopic treatment of duodenal polyps is only temporarily effective. The polyps just grow back.
Desmoids are benign tumors of fibro-aponeurotic tissue and occur in 12% of FAP patients. They may develop within the abdomen, the abdominal wall or in extra-abdominal sites. The majority, 80% occur within the mesentery of the small bowel. 80% arise after abdominal surgery. 10% grow relentlessly and are fatal. Fortunately, the majority (80%) follow an indolent course with periods of growth and remission; a few can regress completely.
They cause symptoms through pressure on adjacent structures e.g. ureter and bladder, or by obstructing the small bowel. They can make ileal pouch surgery impossible. Attempts at surgical excision are associated with high recurrence rates and high morbidity. Long-term therapy with Sulindac and Tamoxifen may provide some benefit. Anti-sarcoma chemotherapy is used in symptomatic or progressive disease.
Other tumor sites?
FAP, epidermal cysts, desmoids, osteomas and dental anomalies is called "Gardner's Syndrome" and is associated with mutations at the 3' end of exon 15. The polyposis is usually relatively mild. The association of FAP with glioblastoma is referred to as Turcot's syndrome.
Papillary thyroid cancer is associated with FAP, especially in younger women. Hepatoblastoma is associated with FAP but is uncommon.
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.