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Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps are benign, they may become malignant, predisposing patients to colorectal cancer. more...

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Signs and symptoms

From the age of 16 onward, patients develop hundreds to thousands of polyps. These may bleed, leading to admixture of blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even with metastasis in the liver or elsewhere.

The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina ("congenital hypertrophy of the retinal pigment"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring).

Diagnosis and treatment

In patients with a strong family of colorectal cancer and symptoms suggestive of polyposis, colonoscopy is indicated, with biopsy of a number of polyps (especially of those that appear dysplastic). In severe cases, a full or partial colectomy is required.

Blood tests (liver enzymes) and ultrasound of the abdomen are often performed to rule out metastasis to the liver.

Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.

Pathophysiology

FAP is due to mutations in the APC gene, which is located on the fifth chromosome (5q21-q22), or in the MUTYH gene located on chromosome 1 (p34.3-p32.1).

APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.

Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.

The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.

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Sulindac in Managing Familial Adenomatous Polyposis - Brief Article
From American Family Physician, 7/15/02 by Richard Sadovsky

Familial adenomatous polyposis (FAP) is inherited by transmission of a mutation of the APC gene on chromosome 5. The most common manifestations of FAP are multiple colorectal adenomas early in life, with later development of colorectal cancer. Treatment often includes total colectomy, which offers significantly lower morbidity and mortality and a functional outcome; however, cancer of the remaining rectal stump has been reported. Sulindac, a nonsteroidal anti-inflammatory drug, has been found to reduce the size and quantity of rectal adenomatous polyps. Cruz-Correa and associates used a prospective study to examine the long-term use of sulindac in patients with FAP who have had total colectomy with ileorectal anastomosis (IRA).

Twelve patients with FAP who had undergone colectomy with IRA and who had five or more rectal adenomas were included in the study. Subjects who did not have specific contraindications received 150 mg of sulindac twice a day. The number and size of the rectal polyps were assessed at baseline and at follow-ups every four months using flexible sigmoidoscopy. At each examination, biopsy of two adenomas was taken. Sulindac dosing was reduced to 150 mg per day following each sigmoidoscopy that demonstrated a polyp-free rectum. Higher dosing was resumed if the polyps recurred. When more than two polyps were found in the rectum, the two largest were biopsied. Monthly telephone calls were used to monitor for adverse effects, and routine chemistry evaluations were obtained at each four-month visit.

The main end points were the number of polyps and histologic changes with sulindac treatment. Seven of the 12 participants were in the study for a mean of 76.9 months, with six of these patients being essentially polyp-free (fewer than five polyps) on their last visit. Five patients were withdrawn from the study early because of development of rectal cancer, progression of histology, increase in the number of polyps, refractory rectal mucosal erosions, or poor compliance. After the initial 12 months, all patients had a significant regression in polyp number. At final follow-up, there was a significant decrease in the recurrence of higher-grade adenomas. Few adverse effects of sulindac use were noted, although in six of the 12 patients, rectal mucosal erosions were reported at the IRA site.

The authors conclude that both short-term and long-term use of sulindac reduce adenomas in the rectal segments of post-surgical patients with FAP. Higher-grade adenoma recurrence was also significantly decreased. There were no major adverse effects or changes in laboratory chemical tests. Patients receiving sulindac who develop rectal mucosal erosions should reduce the medication dosage. Treatment with sulindac requires regular endoscopic examination to (1) follow polyp response, (2) adjust sulindac dosing appropriately, and (3) identify the occasional cases of rectal cancer.

COPYRIGHT 2002 American Academy of Family Physicians
COPYRIGHT 2002 Gale Group

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