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Gardner's syndrome

Gardner's syndrome is a condition affecting the digestive tract. It is a syndrome of multiple polyposis that predisposes a patient to colon cancer. Other abnormalities, such as osteomas of the skull, epidermoid cysts, and fibromas, are also associated with this syndrome. Gardner's Syndrome displays autosomal dominant inheritance, as it is caused by a mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. As such, it bears resemblance to familial adenomatous polyposis (FAP).

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Sulindac suppression of colorectal polyps in Gardner's Syndrome
From American Family Physician, 3/1/90 by William G. Friend

Sulindac Suppression of Colorectal Polyps in Gardner's Syndrome Sulindac (Clinoril) has been reported to cause the regression of existing colonic polyps and the prevention of new polyps in 14 patients with familial polyposis coli and Gardner's syndrome. [1-4] Associated gastric and duodenal polyps have not been observed to undergo this regression. No reports on the effects of sulindac on nonhereditary polyps of the colon have yet been published. This article describes the favorable effects of sulindac in three patients with Gardner's syndrome.

In Gardner's syndrome, unlike in familial polyposis coli, superficial tumors (e.g., sebaceous cysts, lipomas, fibromas, desmoid tumors) and discrete osteomas of the facial bones may occur in association with multiple adenomatous polyps of the colon. Following abdominal surgery, some patients with this syndrome tend to develop extensive, dense peritoneal adhesions that may take the form of desmoid tumors. Extracolonic gastrointestinal and endocrine tumors may also occur. Inheritance of Gardner's syndrome is autosomal dominant. The colonic adenomas, like those in familial polyposis, eventually cause colorectal cancer in virtually all patients.

Illustrative Cases

CASE 1

A 47-year-old woman with a family history of Gardner's syndrome (Figure 1) referred herself for subtotal colectomy. Air-contrast barium enema showed a myriad of polyps located predominantly in the ascending colon (Figure 2). The patient agreed to postpone surgery and try sulindac in a dosage of 150 mg once daily (half the usual adult dose). Three months later, no polyps were seen on repeat air-contrast barium enema (Figure 3).

CASE 2

On sigmoidoscopy, a 12-year-old boy exhibited dozens of small polyps of the rectum. (At age 12, the patient's father had had a substotal colectomy for Gardner's syndrome.) The patient was placed on sulindac, 150 mg once daily. Within six weeks, all of the rectal polyps had disappeared. The patient is now taking 75 mg of sulindac every other day, but a few small polyps have recurred on this low dosage.

CASE 3

Sixteen years previously, a woman with Gardner's syndrome had a subtotal colectomy with ileorectal anastomosis. Since then, she has been followed at six-month intervals; a few dozen small polyps usually have been evident at each examination of the rectum. The patient, now age 42, agreed to a three-month trial of sulindac, 150 mg twice daily. At the end of this trial, no polyps were evident on sigmoidoscopy. She is currently taking 150 mg of sulindac once daily and is without recurrence.

Discussion

Patients with untreated familial polyposis coli usually die from adenocarcinoma of the colon by the fourth decade. Given the validity of the widely accepted theory on the polyp-cancer sequence, [5] Waddell and Loughry's initial observation that sulindac caused the regression of polyps in a patient with familial polyposis coli is truly significant. [1]

The medical literature describes 14 patients (eight with familial polyposis coli and six with Gardner's syndrome) who have demonstrated polyp regression and suppression with sulindac therapy. [1-4] In three of these patients, discontinuance of sulindac was associated with the return of polyps. With the reinstitution of therapy polyps regressed in two of the patients. [4] Thus far, no patient has developed colorectal cancer while taking sulindac.

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) with an active sulfide metabolite that undergoes extensive enterohepatic circulation. In animals, some NSAIDs have been shown to inhibit neoplastic activity in experimentally induced colon tumors. [6]

Long-term use of sulindac is not without risks. In a recent publication, the Food and Drug Administration [7] warns that sulindac may cause gastrointestinal bleeding, ulceration and perforation, as well as the possible formation of kidney stones, gallstones and bile duct sludge. Gastric and duodenal ulcers are present in up to 20 percent of patients on long-term NSAID therapy. Hepatitis, jaundice and renal decompensation have also occurred. A reduction in dosage is presumed to decrease the risk of side effects from sulindac therapy, although this has not yet been proved. [8]

Conventional surgical treatment for polyposis coli requires total or subtotal colectomy soon after the diagnosis is made. Postoperative fibrous dysplasia is a serious complication leading to mechanical obstruction of the small intestine (or ureters) in about one of five patients following surgery for Gardner's syndrome. [9] Rarely, death may occur from the relentless growth of benign desmoid tumors within the mesentery of the small intestine. This strange desmoid reaction appears to be triggered by surgical removal of the colon.

The patients in cases 1 and 3 have siblings who experienced postoperative complications; one of the siblings died from giant intramesenteric benign desmoid tumors. In another series, [4] four of the five patients with Gardner's syndrome who underwent subtotal colectomy developed mesenteric desmoid tumors during sulindac therapy.

In the absence of cancer, physicians may choose to counsel patients with familial polyposis coli and Gardner's syndrome about the use of sulindac as at least a temporary medical alternative to surgical removal of the colon. With sulindac therapy, existing polyps can be expected to regress within a few months. It is possible that the risk of colorectal cancer will also decrease, although this is not yet known. Sulindac, however, does not appear to alter potential neoplastic activity in the stomach and the duodenum.

Final Comment

Sulindac has not yet been approved by the FDA for use in patients with hereditary polyps of the colon. nonetheless, physicians and informed patients may choose to try sulindac instead of surgery. A suggested starting dosage is 150 mg once daily. When polyps have disappeared, the dosage may be reduced to 75 mg once daily, or even less, because the half-life of sulindac sulfide is 16.4 hours. Patients with hereditary polyposis syndromes are typically reevaluated for growth of polyps at six-month intervals.

Complications of sulindac therapy increase with long-term use of the drug. Reducing the dosage has not been proved to decrease the incidence of complications. Misoprostol (Cytotec) may be advised in selected cases; this drug has recently been approved by the FDA for use in the prevention of gastric ulcers in patients taking NSAIDs.

The effect of sulindac and other NSAIDs on the more commonly seen adenomatous polyps of the colon is unknown. Statements made in this article should in no way be construed to mean that sulindac can or should be used to treat polyps of the colon and rectum except in the hereditary conditions described. Polypectomy is the standard of care for all other polyps.

Clinical and laboratory research on this subject is currently being conducted in multiple medical centers.

REFERENCES

[1.] Waddell WR, Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol 1983;24:83-7.

[2.] Gonzaga RA, Lima FR, Carneiro S, Maricel J, Amarante Jr M. Sulindac treatment for familial polyposis coli [Letter]. Lancet 1985;1(8431):751.

[3.] Labayle C, Fischer D, Hagege JP. Efficacy of sulindac in the treatment of rectocolic polypsis [Letter]. Gastroenterol Clin Biol 1986;10:436.

[4.] Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg 1989;157:175-9.

[5.] Fleischer DE, Goldberg SB, Browning TH, et al. Detection and surveillance of colorectal cancer. JAMA 1989;261:580-5.

[6.] Narisawa T, Sato M, Tani M, Kudo T, Takahashi T, Goto A. Inhibition of development of methylnitrosourea-induced rat colon tumors by indomethacin treatment. Cancer Res 1981;41:1954-7.

[7.] Labeling revisions for NSAIDs. FDA Drug Bull 1989;19(1):3-4.

[8.] Lanza FL. Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other nonsteroidal anti-inflammatory agents. Am J Med 1984;77(1A):19-24.

[9.] Lee YT. Gardner's syndrome: a case to study many diseases. Contemp Surg 1986;29:27-38.

The Author

WILLIAM G. FRIEND, M.D. is a director of colon and rectal surgery training at the Swedish Hospital Medical Center, clinical associate professor of surgery at the University of Washington School of Medicine and director of medical research for the Friend Foundation, all in Seattle. Dr. Friend received his medical degree from Columbia University College of Physicians and Surgeons, New York City.

COPYRIGHT 1990 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group

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