Familial Adenomatous Polyposis (FAP)
Ronald Bleday, M.D.
Chief, Division of Colorectal Surgery
Beth Israel Deaconess Medical Center, Boston, MA
Colorectal cancer has recently been shown to be caused by at least two distinct molecular pathways. One pathway is characterized by a mutation on the Adenomatous Polyposis Coli (APC) gene which causes the appearance of hundreds to thousands of adenomatous polyps in the large bowel and is the cause of the autosomally dominantly inherited Familial Adenomatous Polyposis (FAP) and related syndromes.1 The molecular alterations that occur in this pathway largely involve deletions of alleles of tumor suppressor genes (i.e., loss of heterozygosity or LOH) in APC, p53, and the Deleted in Colorectal Cancer (DCC) gene2 combined with mutational activation of proto-oncogenes, especially c-Ki-ras.3,4 In contrast, mutation of the human homologues of the bacterial mutHLS complex (hMSH2, hMLH1, hPMS1, and hPMS2) causes the DNA mismatch repair defects that appear to be the cause of Hereditary non-polyposis colorectal cancer (HNPCC).5-8 The mutations in DNA mismatch repair enzymes lead to genetic instability that is reflected in errors in accurate replication of the repetitive nucleotide repeats that are scattered throughout the genome. As a result, the genomic instability identified in HNPCC is commonly referred to as either replication error positive (RER+) or, since microsatellite regions in the genome contain the nucleotide repeats, as microsatellite instability (MIN). Although these replication errors produce mutations in many of the same tumor suppressor genes and proto-oncogenes as the FAP pathway, there is a significantly lower frequency of LOH in the HNPCC pathway.9
The Molecular Biology of the Familial Adenomatous Polyposis Syndromes and the APC gene
Familial adenomatous polyposis (FAP) syndrome is associated with loss of APC, a tumor suppressor gene on chromosome 5q21.10-14 The affected gene is the earliest identified primary genetic change in development of adenomas and is present in adenomatous polyps of 5 mm diameter.15 The gene is also mutated in sporadic tumors, as well as in other familial syndromes, e.g., Gardner's syndrome.12 The function of APC gene product is not completely understood, but parts of the genetic sequence are homologous with the sequence for such structural proteins as myosin and keratin.14 Mutations of APC are generally either point mutations or insertions of mobile genetic elements that lead to chain termination and production of truncated proteins.16 Different phenotypes are seen with the APC gene. For example, extracolonic tumors can develop in addition to adenomatous polyps. Yet identical genetic mutations are found in the classic familial adenomatous polyposis syndromes and with Gardner's syndrome.
Cloning and Screening
The cloning of the APC gene presents powerful diagnostic opportunities, particularly for individuals with a family history of colon cancer. Because of the early stage at which this gene is altered, future screening will provide important information concerning the risk of an individual to develop colon cancer, and if alterations exist, will indicate the need for frequent colonoscopy. This screening will involve simply collecting peripheral blood cells to detect APC mutations in potential members of the FAP families since the inherited mutation is present in all the cells of the body and is currently based on the in vitro synthesis of a truncated APC gene product. However, screening for the mutated APC gene will not help identify patients who are at risk for developing sporadic bowel adenomas. Results of screening FAP family members has an accuracy of approximately 80%. Therefore, endoscopic screening cannot be eliminated completely even with a negative result on genetic analysis. In a review by Petersen and Brensinger,17 they recommend that sigmoidoscopic screening should be performed in an individual with a positive family history for FAP and with a negative test for the APC gene product at 18, 25 and 35 years of age. With a positive test result, after prophylactic colectomy, endoscopic and clinical surveillance needs to continue for upper gastrointestinal polyps and for desmond tumors. The recommended frequency of upper endoscopic screening is not clear, however, screening every one to three years is probably advisable until more long term data becomes available.
If an FAP patient does not undergo a resection of their colon then eventually they will develop a colorectal cancer. Using the concept "no end organ, no end organ disease", the following surgical options have evolved to treat the colon and rectum in patients with FAP: A total proctocolectomy with permanent ileostomy, a total colectomy with ileorectal anastomosis, a total proctocolectomy with ileal pouch anal anastomosis (IPAA), and a total proctocolectomy with continent ileostomy (Koch pouch).
If an FAP patient presents with poor continence or with a physical disability that does not allow the patient to get to the bathroom in a timely manner to evacuate, then the total proctocolectomy with permanent ileostomy is the best option. The procedure is one stage and usually done in a synchronous fashion. An intersphincteric proctectomy is preferred to minimize postoperative morbidity. The major problem with this procedure is that it does lead to a permanent ileostomy. Many young patients prefer to avoid a permanent ileostomy if possible, and studies have shown that there is a higher quality of life if a permanent ileostomy can be avoided.
A total proctocolectomy can be performed and the anus preserved. The operation was first described by Ravich and Sabiston.18 The operation has since been modified especially by Parks and Nicholls,19 who added a terminal ileal pouch which provided a reservoir. This reservoir decreased stool frequency and improved overall functional results. The procedure is usually done in two stages with the colon and rectum removed at the first stage. The lining of the anus is oftentimes removed from the dentate line up to the resection margin on the distal rectal cuff. The "neorectal" pouch is then created either in the form of a J or S and then hand sewn to the internal sphincter just above the dentate line. A temporary loop ileostomy is usually created in order to protect the patient from pelvic sepsis secondary to microscopic leaks along the suture and staple lines of the pouch and ileoanal anastomosis. The temporary ileostomy is taken down approximately six to twelve weeks after the initial operation after a limited barium enema has shown there to be no evidence of any leaks from the diverted segment. Although the operation is more difficult than the total proctocolectomy with end ileostomy, as mentioned, quality of life has generally been measured as higher for the pouch procedure when compared to the permanent ileostomy. Compared to patients who undergo this procedure for ulcerative colitis, pouchitis is quite rare. Fortunately, sexual dysfunction is minimal, although not zero, following this procedure since the dissection is carried close to the rectum avoiding significant injury to the parasympathetic and sympathetic nerves of the pelvis.
There is some controversy of whether to do a rectal mucosectomy in all patients with familial polyposis or whether to perform a double-stapled anastomosis which leaves 0-3 cm of mucosa above the dentate line and below the ileum. The advantages of the stapled technique is that it is easier to perform providing several centimeters of distal rectum to decrease the tension on the ileoanal anastomosis. The procedure can usually be done in a faster and more efficient manner than the hand sewn anastomosis. In retrospective studies, individuals have shown that it may provide better continence, particularly by allowing the patient to discriminate between the passage of flatus versus liquid stool. The problem with leaving this small segment of mucosa is that it is at risk for developing tubular adenomas. If a double-stapled anastomosis is performed then this strip of mucosa needs to be followed every 6-12 months with proctoscopy and removal of any residual polyps.
A total colectomy with ileorectal anastomosis is an alternative to total proctocolectomy. This procedure removes all of the colon but leaves the rectum. It allows the surgeon to avoid a permanent or temporary ileostomy, and usually eliminates the risk of postoperative sexual or urinary dysfunction. The main disadvantage of the operation is that it leaves a relatively long segment of columnar mucosa that will be at risk for developing tubular adenomas.
The risk of developing carcinoma in the rectal remnant after ileorectal anastomosis has been documented in four separate series: 13% at 25 years,20 12% at 20 years,21 20% at 20 years,22 and 25% at 20 years.23 In each of these studies, patients were selected because of the limited number of polyps in their rectum. Despite this limited involvement and the postoperative surveillance program, cancer was not eliminated although most patients with a cancer were salvaged with a proctectomy.
Total Proctocolectomy vs. Total Colectomy and Ileorectal Anastomosis
What is the best choice of procedure for an individual presenting with FAP? The primary goal of a surgical treatment should be the avoidance of the patient dying of colorectal cancer. In patients with multiple polyps in the rectum a total proctocolectomy should be performed with or without an ileal pouch anal anastomosis. In a patient with minimal rectal polyps that can be easily removed and who is compliant with a postoperative surveillance program, an ileorectal anastomosis should be considered. If one risk factor is "life years remaining" then the ileorectal would be favored anastomosis for older individuals. However, Philips argues that the risk of cancer is dependent upon the age of the patient and not on the age at presentation or life years remaining.24 I still favor the total colectomy and ileorectal for late presenting patients (> 40 yrs) with minimal rectal polyps because of the decreased perioperative and long term morbidity. Further clinical and molecular studies will be needed to determine whether age of onset of the polyps or overall age of the patient is more critical in the adenoma to carcinoma sequence of these late presenting FAP patients.
Medical Therapy for Tubular Adenomas
Medical treatments for tubular adenomas, especially non-steroidal antiinflammatory drugs (NSAID), have been shown to decrease the size and number of polyps, especially in FAP patients who have undergone a total colectomy with ileorectal anastomosis and who undergo surveillance of the rectal remnant. The mechanism of action is related to inhibition of prostaglandin synthase enzymes that decrease prostaglandin levels in tissues. In particular suppression of a specific cyclooxygenase isozyme (COX 2) has the best polyp inhibitor effects in experimental models.25 Currently Sulindac at 150 mg p.o. b.i.d. is the treatment of choice for polyp suppression, however, rectal cancer risk is not eliminated with the NSAID treatment and surveillance must continue.
Extraintestinal Tumors: Desmoids
Post-colectomy FAP patients are at risk for developing aggressive fibromas or desmoid tumors. Surgery is a risk factor for the development of these tumors with even small laparoscopic wounds having been reported as having developed tumors.26 Treatment of desmoids should be offered when tumors are enlarging or symptomatic. Surgical excision can be performed for many lesions but some lesions may be unresectable because of proximity to major blood vessels or other organs. Chemotherapy treatments have had some success. Antiestrogen and NSAID combinations have been used with some response. More aggressive chemotherapy regimens have also been tried. A doxorubicin/dacarbazine regimen has been used with good responses by the M.D. Anderson Group27 while we have had success using a vinblastine/methotrexate combination that was first reported in 1989.28 An individualized approach needs to be used for each patient with a desmoid tumor with excision and medical therapy considered in all patients.
Familial Adenomatous Polyposis is a genetic disease that is one of the molecular paradigms for the adenoma to carcinoma sequence. Surgical removal of some or all of the large intestine minimizes the mortality from colorectal cancer but each surgical option carries its own risks and benefits. Medical therapy of polyps with NSAIDS has shown some benefits of decreasing polyp size and frequency but does not eliminate cancer risk. Extra colonic manifestations of FAP require patients to follow a lifelong surveillance program for the diagnosis and treatment of upper adenomas or desmoids.
1. Bodmer WF, Bailey CJ, Bodmer J, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328:614-616.
2. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988; 319:525-532.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759-767.
4. Jessup JM, Steele Jr G, Thomas P, et al. Molecular biology of neoplastic transformation of the large bowel: Identification of two etiologic pathways. Surg Oncol Clinics N America 1996.
5. Fishel R, Lescoe MK, Rao MRS, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1215-1225.
6. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75:1215-1225.
7. Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homolog hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994; 368:258-261.
8. Papadopoulos N, Nicolaides NC Wei YF, et al. Mutation of a muttL homolog in hereditary colon cancer. Science 1994; 263:1625-1629.
9. Peltomaki P, Aaltonen LA, Sistonen P, et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993; 260:810-812.
10. Aoki T, Takeda S, Yanagisawa A, et al. APC and p53 mutations in de novo colorectal adenocarcinomas. Hum Mutat 1994; 3:342-346.
11. Blank M, Klussmann E, Kruger-Krasagakes S, et al. Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histologic types. Int J Cancer 1994; 59:301-306.
12. Herrera L, Kakati S, Gibas L, et al. Brief clinical report: Gardner syndrome in a man with interstitial deletion of 5q. Am J Med Genet 1986; 25:473-476.
13. Nishisho I, Nakamura Y, Miki Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253:665-669.
14. Kinzler KW, Nilbert MC, Su L-K, et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253:661-665.
15. Groden J, Thilveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66:589-600.
16. Miki M, Nishisho I, Horii A, et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in colon cancer. Cancer Res 1992; 52:643-645.
17. Petersen GM, Brensinger JD. Genetic testing and counselling in familial adenomatous polyposis. Oncology 1996; 10:89-94.
18. Ravich MM, Sabiston DC. Anal ileostomy with preservation of the sphincter: A proposed operation in patients requiring total colectomy for benign lesions. Surg Gynecol Obstet 1947; 84:1095-1099.
19. Parks AG, Nicholls RJ. Proctocolectomy without ileostomy for ulcerative colitis. Br Med J 1978; 2:85-91.
20. Bussey HJR. Familial polyposis coli: Family studies, histopathology, differential diagnosis and results of treatment. Johns Hopkins University Press, Baltimore, 1975.
21. Sarre RG, Jagelman DG, Beck GJ, et al. Colectomy with ileorectal anastomosis for familial adenomatous polyposis: The risk of rectal cancer. Surgery 1987; 101:20-26.
22. Bess MA, Adson MA, Elveback LR, et al. Rectal cancer following colectomy for polyposis. Arch Surg 1980; 115:460-467.
23. Heiskanen I, Jarvinen HJ. Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Int J Colorectal Dis 1997; 12:9-13.
24. Nugent KP, Phillips RKS. Rectal cancer risk in older patients with familial adenomatous polyposis and ileorectal anastomosis: A cause for concern. Br J Surg 1992; 79:1204-1206.
25. Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in APC delta 716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 86:803-809.
26. Lynch HT, Fitzgibbons Jr R. Surgery, desmoid tumors and familial adenomatous polyposis: Case report and literature review. Am J Gastroent 1996; 91:2598-2601.
27. Patel SR, Evans HL, Benjamin RS. Combined chemotherapy in adult desmoid tumors. Cancer 1993; 72:3244-3247.
28. Weiss AJ, Lackman RD. Low dose chemotherapy of desmoid tumors. Cancer 1989; 64:1192-1194.