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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3641-3642 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.7056
Total Gastrectomy for Gastric Dysplasia in a Patient With Attenuated Familial Adenomatous Polyposis SyndromeRoswell Park Cancer Institute, Buffalo, NY; Department of Surgery, University at Buffalo, State University of New York, Buffalo, NY
Roswell Park Cancer Institute, Buffalo, NY
Roswell Park Cancer Institute, Buffalo, NY; Department of Surgery, University at Buffalo, State University of New York, Buffalo, NY
Rochester Institute for Digestive Diseases and Sciences, Rochester, NY
Roswell Park Cancer Institute, Buffalo, NY; Department of Surgery, University at Buffalo, State University of New York, Buffalo, NY A 31-year-old woman was referred to our institution in June 2007 for evaluation of moderate gastric dysplasia in the setting of numerous fundic gland polyps. The patient's family is known to carry a mutation associated with attenuated familial adenomatous polyposis (AFAP), and her siblings and mother have clinical manifestations of the disease.1 Before her referral, the patient had annual screening colonoscopy and upper endoscopy starting at age 17 years. Her surveillance colonoscopies never demonstrated more than a single adenomatous polyp that was resected endoscopically. In contrast, on initial upper endoscopy, she was found to have numerous small polyps involving the majority of her stomach. Biopsy of these small polyps demonstrated fundic gland-type polypsis characterized by cystically dilated and irregularly budded fundic glands. Subsequently, an upper endoscopy in April 2007 showed at least three dominant polypoid lesions within this carpet of small fundic gland polyps along the greater curvature of the stomach, each measuring approximately 3 cm in diameter. Pathological analysis of these areas revealed multiple fundic gland polyps with adenomatous features and mild to moderate dysplasia. Computed tomography of the abdomen and pelvis revealed thickening of the anterior wall of the stomach and antrum, but found no other appreciable lesions within the peritoneal cavity. (Fig 1, white arrow) After preoperative evaluation, she underwent a total gastrectomy with roux-en-y esophagojejunostomy with feeding jejunostomy in early July 2007. Exploratory laparotomy revealed no evidence of extra-gastric disease. After resection, the stomach was found to have a 17 x 16 cm area with numerous small polyps studding the mucosal surface. (Fig 2) She had an uneventful postoperative course and was discharged 10 days after the operation requiring jejunostomy tube-feeding. Final pathologic evaluation showed fundic gland-type gastric polyposis with multiple areas of high grade dysplasia in a background of patchy low grade dysplasia. (Fig 3, 400x) Fortunately, there were no areas containing invasive carcinoma.
Familial adenomatous polyposis (FAP) is a rare, but well-characterized autosomal dominant condition in which affected individuals develop hundreds of colonic polyps beginning in adolescence and early adulthood (age 20 to 30 years). FAP is caused by mutations in the adenomatous polypsis coli (APC) tumor suppressor gene on chromosome 5q.2 AFAP differs from FAP in that patients clinically develop fewer colonic polyps (< 100) and at a later age (30 to 40 years) than patients with full-blown FAP.3,4 Genetically, germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9 or in the 3' half of the coding region are associated with this attenuated form of the disease.5-7 However, while adenomas in AFAP usually appear 10 to 15 years later than patients with FAP, AFAP still carries the nearly 100% significant risk of colon cancer similar to FAP. Fundic gland polyps are small (2 to 5 mm), sessile hamartomatous polyps arising in the gastric acid-secreting mucosa. These lesions have been reported both sporadically8,9 and in association with FAP and AFAP.10,11 In the sporadic form, fundic gland polyps are thought to arise from mutations in the beta-catenin gene, whereas in FAP or AFAP, the cause is believed to be mutational inactivation of the APC gene.12 Although most sporadic fundic gland polyps are thought to have little or no potential for malignant transformation,10,11,13 there have been several reports of high grade dysplasia and gastric adenocarcinoma in patients with AFAP.14-16 In this patient's family, a maternal aunt and maternal uncle were both diagnosed with gastric adenocarcinoma that was believed to have arisen in a fundic gland polyp.17,18 Despite knowledge of fundic gland polyps in the aunt and an aggressive endoscopic screening regimen in the uncle, both presented with advanced metastatic cancer without any obvious primary gastric tumor on upper gastrointestinal endoscopy. On autopsy of both patients, gastric adenocarcinoma was found to be intimately associated with fundic gland polyposis and was thought to arise from a dysplastic focus within a polyp. This family history prompted us to offer our patient prophylactic gastrectomy. In this report, we describe successful surgical treatment of an AFAP patient with gastric dysplasia in the background of fundic gland polypsis by total gastrectomy. Extrapolating from this patient and her family, we suggest that prophylactic gastrectomy may be beneficial in FAP and AFAP patients with dysplastic changes in fundic gland polyps. It has been argued that gastric fundic glands require only surveillance with upper endoscopy every 1 to 3 years to determine the progression of these polyps since there have been no reports of cancer associated with the sporadic condition and only a small cancer risk in the inherited syndromes.12 However, there is data to suggest that the severity of the upper gastrointestinal disease in these patients may be related to the location of the mutation on the APC gene. A recent study demonstrated that germline mutations in the APC gene after codon 1400 were associated with a more severe duodenal polyposis.19 Hopefully, genetic information will help us to identify and manage those patients with FAP or AFAP that have a higher risk for severe upper gastrointestinal disease. We believe that without gastrectomy, the diagnosis of carcinoma may be difficult to confirm due to possible multifocality of the disease and sampling errors in the presence of numerous fundic gastric polyps. Moreover, one could speculate that early surgical intervention might have prevented the early metastases seen in our patient's relatives. Therefore until genetic testing is refined enough to identify those AFAP patients that will have upper gastrointestinal cancer, we recommend that prophylactic gastrectomy be considered in patients with AFAP found to have dysplasia within their fundic gland polyposes. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Leppert M, Burt R, Hughes JP, et al: Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322:904-908, 1990[Abstract] 2. Bullard K, Rothenberger D: Colon, Rectum and anus, in Brunicardi C: Schwartz's Principles of Surgery (ed 8). New York, NY, McGraw Hill, 2004, pp1087 3. Lynch HT, Smyrk T, McGinn T, et al: Attenuated familial adenomatous polyposis (AFAP): A phenotypically and genotypically distinctive variant of FAP. Cancer 76:2427-2433, 1995[CrossRef][Medline] 4. Spirio L, Olschwang S, Groden J, et al: Alleles of the APC gene: An attenuated form of familial polyposis. Cell 75:951-957, 1993[CrossRef][Medline] 5. van der Luijt RB, Meera Khan P, Vasen HF, et al: Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet 98:727-734, 1996[CrossRef][Medline] 6. Su LK, Kohlmann W, Ward PA, et al: Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15. Hum Genet 111:88-95, 2002[CrossRef][Medline] 7. Spirio LN, Samowitz W, Robertson J, et al: Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps. Nat Genet 20:385-388, 1998[CrossRef][Medline] 8. Declich P, Isimbaldi G, Sironi M, et al: Sporadic fundic gland polyps: An immunohistochemical study of their antigenic profile. Pathol Res Pract 192:808-815, 1996[Medline] 9. Jalving M, Koornstra JJ, Gotz JM, et al: High-grade dysplasia in sporadic fundic gland polyps: A case report and review of the literature. Eur J Gastroenterol Hepatol 15:1229-1233, 2003[CrossRef][Medline] 10. Odze RD: Gastric fundic gland polyps: Are they preneoplastic lesions? Gastroenterology 114:422-423, 1998[Medline] 11. Sarre RG, Frost AG, Jagelman DG, et al: Gastric and duodenal polyps in familial adenomatous polyposis: A prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut 28:306-314, 1987 12. Burt RW: Gastric fundic gland polyps. Gastroenterology 125:1462-1469, 2003[Medline] 13. Ranzi T, Castagnone D, Velio P, et al: Gastric and duodenal polyps in familial polyposis coli. Gut 22:363-367, 1981 14. Coffey RJ Jr, Knight CD Jr, van Heerden JA, et al: Gastric adenocarcinoma complicating Gardner's syndrome in a North American woman. Gastroenterology 88:1263-1266, 1985[Medline] 15. Attard TM, Giardiello FM, Argani P, et al: Fundic gland polyposis with high-grade dysplasia in a child with attenuated familial adenomatous polyposis and familial gastric cancer. J Pediatr Gastroenterol Nutr 32:215-218, 2001[CrossRef][Medline] 16. Odze RD, Quinn PS, Terrault NA, et al: Advanced gastroduodenal polyposis with ras mutations in a patient with familial adenomatous polyposis. Hum Pathol 24:442-448, 1993[CrossRef][Medline] 17. Zwick A, Munir M, Ryan CK, et al: Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 113:659-663, 1997[CrossRef][Medline] 18. Hofgärtner WT, Thorp M, Ramus MW, et al: Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol 94:2275-2281, 1999[Medline] 19. Groves C, Lamlum H, Crabtree M, et al: Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis. Am J Pathol 160:2055-2061, 2002
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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