Familial adenomatous polyposis

Abstract

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program.

Figure 1

Relative and approximate contributions of familial causes to the incidence of colorectal cancer. FAP - Familial adenomatous polyposis, JP - Familial juvenile polyposis, PJ - Peutz-Jeghers syndrome, HNPCC - Hereditary nonpolyposis colorectal cancer (Lynch Syndrome). Note the very small contribution of FAP to the etiology of cancer.

Figure 2

Panel A shows the endoscopic appearance of early FAP adenomas; panel B shows the endoscopic appearance of established, multiple, FAP adenomas.

Figure 3

Panel A illustrates the extracolonic upper gastrointestinal polyp manifestations of FAP (Used with permission and adapted from the American Gastroenterology Association Institute's Clinical Teaching Unit 11, copyright). Fig. B is a schematic illustration of a "J-pouch", formed from the distal small intestine and attached to the anal sphincter. The shorter limb of the "J" acting as a fecal reservoir; Fig. C is an x-ray demonstration of this pouch (Figures provided by Dr. A. Deutsch, Petach Tikva and reproduced, with permission of the publishers, from reference [70]: Rozen P, Levin B, Young GP: Who are at risk for familial colorectal cancer and how can they be managed? In Colorectal Cancer in Clinical Practice: Prevention, Early Detection and Management Edited by: Rozen P, Young GP, Levin B, Spann SJ. London, Ed 2, Taylor and Francis 2002:55-66).

Figure 4

Panel A illustrates the extraintestinal manifestations of FAP (Used with permission and adapted from the American Gastroenterology Association Institute's Clinical Teaching Unit 11, copyright). Panel B is a panoramic jaw X-ray showing mandibular areas of osteoslerosis that can be found in some FAP patients but is not diagnostic of FAP. Panel C shows retinal pigmentation (CHRPE) that can be found in some FAP patients but is not diagnostic of FAP.

Figure 5

Panel A shows the endoscopic appearance of early FAP and the difficulty in identifying adenomas; Panel B shows the endoscopic appearance after spraying with dilute Indian ink contrast chromoendoscopy; note the easier identification of small polyps (Figures reproduced from reference [85]: P Rozen, F Macrae, Familial adenomatous polyposis: The practical applications of clinical and molecular screening. Familial Cancer, 2006; 5:227-335, with kind permission of Springer Science and Business Media). Panel C shows the occasional adenoma seen in attenuated FAP and the difficulty in making the endoscopic diagnosis of FAP. Panel D demonstrates the usefulness of taking random biopsies in attenuated FAP and finding an intramucosal microadenoma, consistent with the diagnosis of FAP. Note the appearance of dark stained and elongated dysplastic nuclei in a distorted crypt that does not protrude above the surrounding normal surface epithelium (Figures reproduced, with permission of the publishers, from reference [70]: Rozen P, Levin B, Young GP: Who are at risk for familial colorectal cancer and how can they be managed? In Colorectal Cancer in Clinical Practice: Prevention, Early Detection and Management Edited by: Rozen P, Young GP, Levin B, Spann SJ. London, Ed 2, Taylor and Francis 2002:55-66.

Figure 6

Relationship between Wnt signaling and the APC tumor-suppressor gene in activating the β-catenin to enter the nucleus (no APC activity) for promoting genes expression and polyamine metabolism (ODC) in the colonic epithelium; or (with APC activity) for the proteasomal degradation in the colonic epithelium.

Figure 7

APC protein functional domains, several of the common mutations and their locations, in relation to the different FAP phenotypes.

Figure 8

Diagram of the MUTYH protein in scale; known functional domains (the filled boxes) data derived from Sampson et al, 2005 [43]; and three types of well known typical mutations - missense or in-frame, splice and truncation. APE1, apurinic endonuclease 1; HhH, helix-hairpin-helix; PCNA, proliferating-cell nuclear antigen; RPA, replication protein A.

Figure 9

Panel A shows flat and elevated duodenal adenomas in a FAP patient. These were proven by biopsy and endoscopic ultrasound to be free of cancer. Panel B - the polyps were removed by submucosal resection and polypectomy. Panel C - the polyp remnants had been destroyed by argon plasma coagulation (figures provided by Dr. M. Santo, Tel Aviv). Panel D shows a large polyp that developed, during pregnancy, in the ileo-anal pouch of a FAP patient. Panel E - the polyps had been removed by submucosal resection and polypectomy and remnants destroyed by argon plasma coagulation (figures provided by Dr. Z. Halpern, Tel Aviv).

Figure 10

Change in number of colorectal polyps in FAP patients receiving placebo or celecoxib (Celebrex^R) for 6 months. The reduction in polyp burden, versus placebo, was significant (*P = 0.003) with the dosage of 400 mg twice a day (data for figure derived from reference [107]).