High-Grade Pancreatic Intraepithelial Neoplasia in a Patient With Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant disorder that is caused by somatic mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5q21. This gene is ubiquitously expressed in many adult organs and codes for a protein that interacts with a variety of cell-adhesion proteins, including β-catenin, axin, and tubulin.1–3 It is now recognized that mutations of this gene cause both classic FAP and Gardner syndrome.3,4 Patients with FAP classically present with hundreds of polyps in the colon and rectum, which inevitably progress to carcinoma by the third to fourth decade of life if a prophylactic colectomy is not performed. Other gastrointestinal and pancreaticobiliary lesions in this syndrome are thought to parallel mucosal exposure of bile and include small intestinal adenomas and biliary tree tumors.2–5 Pancreatic precancerous lesions have only rarely been described in this syndrome, including 2 cases of pancreatic duct adenomas and 2 of intraductal papillary mucinous pancreatic neoplasms.2,4,6 To the best of our knowledge, based on a search of the world English literature, high-grade pancreatic intraepithelial neoplasia (PanIN-3) has not been previously reported in a patient with FAP.

A 58-year-old woman who had a history of FAP presented for a routine examination. She had a total abdominal colectomy with a permanent ileostomy at age 30 years, according to her self-reported history. Eight years previously, an examination revealed multiple duodenal adenomas and a polyp at the ampulla, which were laser ablated. Biopsies from these duodenal polyps showed villous adenomas on histologic examination. She was lost to further follow-up until this presentation.

An endoscopic examination revealed a normal esophagus; multiple, round, polypoidal lesions in the body of the stomach; and multiple duodenal polyps. The ampulla appeared villiform. There was no mass lesion at the ampulla. Biopsies of the duodenal polyps were obtained for histologic examination. An endoscopic ultrasound performed during the procedure revealed inhomogeneity in the head of the pancreas. The body and tail of the pancreas were normal on ultrasound. The main pancreatic duct appeared normal and was not dilated. The medial aspect of descending duodenal wall appeared thickened. The liver and gallbladder were unremarkable. No regional lymphadenopathy was identified on the ultrasound examination. Histology of the duodenal biopsies revealed multiple fragments of adenomatous epithelium. She was scheduled for an exploratory laparotomy and pancreaticoduodenectomy.

Diffuse adhesions were noted throughout the entire abdominal cavity during laparotomy. There was no evidence of involvement of any venous structures around the duodenum or pancreas. The liver was normal to palpation. The distal portion of stomach, the duodenum, and a portion of the pancreas were resected and submitted for gross and microscopic examination.

Gross examination of the specimen included the resected portion of stomach (5 cm long and 9.5 cm in maximum diameter) with attached segment of duodenum (16 cm long and up to 3 cm in diameter). Attached to the duodenum was the head of the pancreas (3.5 × 3.5 × 3.0 cm). Numerous mucosal polyps were noted involving all but the distal 2 cm of the duodenum. The stomach was free of adenomatous lesions grossly. The ampulla and proximal pancreatic duct appeared dilated. Additional sectioning of the pancreas revealed a fibrotic cut surface surrounding small islands of yellowish pancreatic parenchyma. Several representative sections were submitted for microscopic evaluation.

The smaller pancreatic ducts were surrounded by fibrotic stroma and mild chronic inflammatory cells and contained epithelium with prominent papillary architecture and focal luminal necrosis. Glands were arranged back-to-back in a cribriform pattern. Cytologically, there was loss of nuclear polarity, with nuclear irregularities and prominent nucleoli. Mitotic activity was noted with presence of mitotic figures at all levels of the epithelium. These microscopic findings were consistent with a diagnosis of PanIN-3 (Figures 1 and 2). Other small pancreatic ducts had nuclear abnormalities that fell short of those seen in PanIN-3 and were diagnostic of PanIN-2. Microscopic examination of the sections from the duodenum revealed knoblike and papillary projections of the surface epithelium. The epithelium contained enlarged hyperchromatic nuclei and increased mitotic figures (Figures 3 and 4). These adenomatous changes also were seen in the major pancreatic ducts, with the adenomatous epithelium replacing the normal tall columnar mucinous epithelium. It is not clear if these changes represent adenomatous transformation (nonmucinous) of the major pancreatic ducts in this patient with FAP or represent extension from the adjacent adenomatous duodenal epithelium. No carcinoma was identified in the specimen, despite extensive sampling. All lymph nodes were negative for metastatic carcinoma.

Pancreatic intraepithelial neoplasias involve the smaller pancreatic ducts and are generally too small to be seen grossly or by imaging techniques. While the normal small pancreatic duct epithelium is cuboidal to low columnar, PanIN varies from flat in low-grade lesions (PanIN-1) to papillary, micropapillary, or flat but pseudostratified in higher grade lesions (PanIN-2 to PanIN-3).7 The nuclei in PanIN-1 are small and round to oval, while those in higher-grade neoplasia are progressively enlarged, hyperchromatic, and pseudostratified. PanIN-3 shows dystrophic goblet cells, mitoses, irregular nuclear outlines, and prominent nucleoli. Because these pancreatic lesions are premalignant, surgical excision is warranted when possible.

Extracolonic manifestations in FAP syndrome have rarely involved the pancreas. This may be due to the fact that while FAP is caused by mutations in the 5q21 gene locus, most pancreatic carcinomas are associated with mutations in K-ras (12p12), 17p, 18q (DCC locus), p53 (17p13), p16 (9q21), INK4a (9q21), DPC4/SMAD4 (18q21), and c-myc (8q24), and rarely in BRCA2 (13q12), AKT2 (19q13), and LKB1/STK1 (19p13).8–13 Reports on mutations of the APC gene in human pancreatic cancers are few and have inconsistent findings. While Horii et al14 reported somatic mutations of the APC gene in 4 of 10 pancreatic cancers in their series, Yashima et al15 reported the mutation in only 1 of 39 pancreatic cancers. This difference may be explained in part by the fact that Horii et al examined a much more extensive region of the 5q gene and used an RNase protection method as opposed to the polymerase chain reaction–single-strand conformation polymorphism method used by Yashima et al. However, other authors, including Seymour et al12 (33 cases), McKie et al16 (28 cases), Ding et al17 (10 cases), and Neuman et al18 (3 cases), found no APC mutations in pancreatic carcinomas. Some of these differences may be attributable to the differences in the specimens analyzed. Pancreatic cancers usually have abundant desmoplastic stroma surrounding malignant glands. If this reactive stroma were disproportionately sampled, it would cause a false-negative result. Also, the studies that reported the involvement of the APC gene in human pancreatic cancers have been on Japanese patients, and it may be possible that there are differences in the molecular pathogenesis of pancreatic cancers in that population group.16 

Abraham et al19 described 1 patient with the FAP mutation who presented with a pancreaticoblastoma and concluded that pancreatoblastomas may represent an extracolonic manifestation of FAP. Pancreatoblastomas are clinicopathologically distinct from adult pancreatic ductal carcinomas and do not arise from PanINs. Thus, the significance of this finding is uncertain. Giardiello et al20 examined extraintestinal cancers in FAP patients and at-risk relatives and concluded that the relative risk for pancreatic cancer is increased in FAP, but the absolute lifetime risk remains low. However, it is clear that the APC gene is only rarely involved in the pathogenesis of pancreatic cancers. In addition, pancreatic intraepithelial neoplasias (PanIN-1–PanIN-3) have never, to the best of our knowledge, been examined for mutations in the FAP gene.

Since this is the first reported observation of a high-grade pancreatic intraepithelial neoplasia in a patient with FAP, and only a handful of other preneoplastic pancreatic lesions have been reported in this syndrome, it is not clear if all patients with FAP should be screened for preneoplastic pancreatic lesions. Further studies are required to determine whether patients with FAP are at increased risk for pancreatic premalignant lesions.