Development of an intraductal papillary-mucinous neoplasm of the pancreas in a patient with familial adenomatous polyposis.

To the Editor: Familial adenomatous polyposis (FAP) is a premalignant condition characterized by numerous colorectal adenomas that cause adenomatous polyposis coli (APC) gene inactivation. Patients with FAP frequently develop upper gastrointestinal neoplasms, particularly in the duodenum. Many other extracolonic benign and malignant lesions have been described. However, only 1 other case report has described of intraductal papillary–mucinous neoplasm (IPMN) of the pancreas associated with FAP. The carcinogenic processes in the adenoma–carcinoma sequence of IPMNs and colorectal adenomatous polyps are strikingly similar. The APC protein interacts with b-catenin, and APC mutations play a role in the altered levels of b-catenin expression in colorectal neoplasms with FAP. We report a case of pancreatic IPMNs associated with FAP with immunoexpression of b-catenin in neoplasms of the pancreas, stomach, duodenum, and colon in the patient. A 74-year-old man was admitted in 2003 for further examination of an asymptomatic multilocular cystic lesion in the pancreas, which had been detected by ultrasonography. He had previously undergone a prophylactic colectomy with ileorectal anastomosis after a diagnosis of FAP in 1982, and had not developed colorectal cancer. Eighteen years after the colectomy, he underwent an endoscopic resection for gastric cancer (well-differentiated tubular adenocarcinoma). He had a family history of FAP; his sister and his 2 sons were also affected by FAP. Serum pancreatic enzymes and biochemical hepatic tests were normal, and serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal ranges. Computed tomography showed a multilocular cystic mass, measuring 30 mm, located in the pancreas head with proximal main pancreatic duct dilatation. Endoscopic retrograde pancreatography revealed a polypoid lesion of the Vater ampulla; a dilatation of the main pancreatic duct, measuring 7 mm, with filling defects containing mucus; and the cystic tumor that communicated with the main pancreatic duct. Histologic examination of ampullary biopsies found a tubular adenoma with moderate dysplasia. Three cytologic examinations of the pancreatic juice showed borderline malignancy. After a diagnosis of an IPMN localized in the pancreas head with possible malignant transformation, a subtotal stomach-preserving pancreaticoduodenectomy with pancreaticogastric anastomosis was performed. The resected specimen macroscopically had multilocular cystic dilatations of the branch ducts, containing mucous fluid, in the pancreas head. Pathology examination found that (1) the lesion in branch ducts had papillary configurations and the internal surface consisted of high columnar epithelium with mucin-producing cells with moderate dysplasia (pancreatic IPMN with moderate dysplasia); (2) the ampullary tumor was a tubular adenoma with moderate dysplasia; and (3) microscopic duodenal tubular adenomas with severe dysplasia were present. We did an immunohistochemical test for anti-b-catenin antibody (Transduction Laboratories, Lexington, KY) on the sections of the pancreatic IPMN, ampullary adenoma, duodenal adenomas, gastric adenocarcinoma, and colonic adenomas. We used the streptavidin-biotin complex indirect immunoperoxidase method (DAKO, Carpinteria, CA). Membranous staining for b-catenin was seen at the intercellular borders of the epithelial cells in the ampullary and duodenal adenoma. This staining pattern was also preserved in normal epithelial cells in the pancreatic duct and normal duodenal and colonic mucosa. However, the pancreatic IPMN and colonic adenomas showed cytoplasmic staining for b-catenin with membranous staining, and the gastric adenocarcinoma only showed nuclear localization of b-catenin. Twelve days after surgery, the patient underwent computed tomography– guided percutaneous drainage for intraabdominal fluid collection. Since then, his postoperative course has been uneventful. He is alive 26 months after surgery. FAP is an autosomal dominant disorder caused by inactivating mutations of the APC gene located on chromosome 5q21 and is characterized by the development of hundreds to thousands of colorectal adenomas in young adults. If prophylactic colectomy is not performed, essentially all affected subjects will develop colorectal cancer by the fifth decade of life. FAP can be associated with various extracolonic lesions. Benign extraintestinal manifestations include osteomas, exostoses, epidermoid cysts, dental abnormalities, and pigmented ocular fundic lesions. Up to 90% of patients with FAP also develop adenomas in the upper gastrointestinal tract. The frequency of malignant transformation of duodenal adenomas with FAP is 5%. Extraintestinal cancers have been reported in association with FAP as well. These include malignancies of the thyroid gland, adrenal gland, biliary tree, and pancreas. The lifetime risk of extracolonic lesions is significant in patients who have undergone prophylactic colectomy. Pancreatic tumors that have developed in patients with FAP are rare. In a cohort study of 1391 patients with FAP reported in the Johns Hopkins Registry, the relative risk of pancreatic adenocarcinoma (relative risk, 4.46; 95% confidence limits, 1.2–11.4) was increased, but the absolute lifetime risk (21.4 cases/100,000 person-years) was low. Only a pancreatic islet cell tumor (glucagonoma), a cystic and papillary tumor, and an acinar cell carcinoma have been reported. Maire et al found a loss of heterozygosity in the pancreatic IPMN in association with FAP that causes inactivation of both alleles in the APC gene. They proposed a common carcinogenic process in both pancreatic IPMN and colorectal adenomatous polyps in patients with FAP. Chetty et al reported a case of attenuated FAP together with microscopic pancreatic IPMN, which they chanced on in