Premalignant Gastric Heterotopic Pancreas

Heterotopic pancreas, also known as ectopic pancreas, aberrant pancreas, and pancreatic rest, was first characterized in 1729 by Jean Schultz and refers to ectopic pancreatic tissue that lacks anatomic or vascular connection with the pancreas.¹ Heterotopic pancreas is believed to arise during rotation of the foregut, when fragments of the pancreas become separated from the main body and are deposited at ectopic sites.^2,3 The two best-known histogenic theories are based on fetal migration of pancreatic cells and on the penetration of immature gastric mucosa inside the submucosa followed by its differentiation into pancreatic tissue.³ Malignant transformation is not common. In this case report, we describe a rare case of pancreatic intraepithelial neoplasia-2 (PanIN-2) found in a gastric heterotopic pancreas. PanIN-2, a mucinous ductal lesion of the pancreas, is believed to represent a precursor lesion for the development of ductal adenocarcinoma.

Case Report

A 25-year-old woman presented to the emergency room with a 2-day history of progressive, nonradiating epigastric and right-upper-quadrant pain associated with nausea and bilious emesis. Physical examination revealed a nondistended abdomen with epigastric and right-upper-quadrant tenderness. Laboratory evaluation was significant for an elevated amylase level of 285 U/L (normal, 15–120 U/L) and lipase level of 314 U/L (normal, 16–63 U/L). Computed tomography (CT) scan of the abdomen demonstrated gastric-wall thickening with an ill-defined mass in the fundus and a prominent pancreatic duct without peripancreatic inflammatory changes or focal pancreatic mass (Figure 1). Magnetic resonance cholangiopancreatography was negative for biliary or pancreatic pathology. Esophagogastroduodenoscopy noted a protruding smooth-surfaced submucosal mass in the fundus at the gastric side of the esophagogastric junction (Figure 2). Endoscopic ultrasound (EUS) revealed a 2.4 cm × 1.2 cm submucosal lesion in the fundus with mixed hypoechogenicity and hyperecho-genicity and smooth margins. Perigastric and periesophageal adenopathy were absent, and there was no evidence of invasion. The lesion was soft upon compression with biopsy forceps. The clinical impression was that the lesion represented either a complex lipoma or a carcinoid lesion. Also noted on EUS was a calculus in the gallbladder and a normal pancreas. Based upon the EUS findings, it was recommended that the patient undergo either surgical resection of the lesion or repeat EUS in 12 months, reserving resection for progression in size.

Figure 1.

Computed tomography scan of mass-like lesion in fundus of stomach.

Figure 2.

Esophagogastroduodenoscopy of submucosal lesion in fundus of stomach on retroflexion.

The patient opted for surgery. Cholecystectomy was performed, given her recent bout of pancreatitis and findings of cholelithiasis, as well as a partial gastrectomy to excise the submucosal mass. Surgical findings included a freely movable submucosal gastric mass in the anterior cardia and a chronically inflamed gallbladder.

Gross examination revealed a raised, gray-tan, firm, nodular submucosal mass measuring 2.0 cm ×1.8 cm × 1.7 cm. Upon sectioning the mass, 2 small cystic spaces measuring 0.3 cm × 0.3 cm appeared. The intramural nodular mass was 0.6 cm from the surgical margin.

Microscopic examination identified the mass as pancreatic tissue. Although acinar components appeared unremarkable, the ductal system contained cystically dilated foci (Figure 3), with the largest cystic space measuring approximately 0.8 cm. Histologic examination revealed a predominantly flat, ductal-lining epithelium, with focal papillary architecture and separate foci of nuclear pseudostratification (Figures 4 and 5). Luminal nuclei also displayed some loss of polarization, and some nuclei had open chromatin. Mitoses were rare, and atypicalmitotic figures were not identified (Figure 6). There was an absence of cribriforming, and no luminal necrosis was identified. These findings were consistent with those of PanIN-2.

Figure 3.

Low-power view of cystically dilated ducts in ectopic pancreatic tissue.

Figure 4.

Low-power view of lesion displaying focal papillary architecture.

Figure 5.

High-power view displaying epithelial pseudostratification.

Figure 6.

Mitotic figure with no atypia.

In the year following surgery, the patient has remained healthy during outpatient follow-up.

Discussion

Heterotopic pancreas refers to ectopic pancreatic tissue that lacks anatomic or vascular connection with the pancreas. Heterotopic pancreata are reported in up to 14% of all autopsies.⁴ These lesions can be found virtually anywhere along the gastrointestinal tract, but they are typically found in the stomach, duodenum, or jejunum. In the stomach, they are most commonly located in the distal stomach along the greater curvature of the gastric antrum.⁵

Typically, heterotopic pancreas is clinically silent and benign, and it is found incidentally during surgery or endoscopy. Heterotopic pancreas appears as submucosal nodules, usually with central umbilication. Diagnostic examinations include contrast radiography, CT scan, and EUS; however, the accuracy of these tests is limited by the size of the lesion. Surgical resection should be performed when heterotopic pancreas is found incidentally during surgery or when it is symptomatic, to prevent complications.⁶

Because the heterotopic pancreas functions like a normal pancreas, the same pathology that affects the pancreas can affect the ectopic pancreatic tissue. Pancreatitis, cysts, pseudocysts, and malignant transformation can be seen. Complications due to mass effect such as gastric-outlet or bile-duct obstruction, bleeding from ulcerated mass, and intussusception can also be seen.

Although rare, malignant transformation must be considered when submucosal lesions are identified in the stomach. Only 27 cases have been reported in the literature, with 15 of them involving the stomach.² In order to prove that a malignancy arose from ectopic pancreas, three criteria must be fulfilled, according to Guillou,⁷ the tumor must be within or near the ectopic pancreatic tissue; a direct transition between pancreatic structures and carcinoma must be observed; and the nonneoplastic pancreatic tissue must, at a minimum, comprise fully developed acini and ductal structures.^8,9 There are three precursor lesions that give rise to pancreatic cancer: mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), and pancreatic intraepithelial neoplasia (PanIN).¹⁰

MCNs, the most common type of cystic neoplasm, are mucin-producing epithelia neoplasms with “ovarian-type stroma.”¹⁰ They are found typically in middle-aged women. Patients are asymptomatic or present with vague abdominal pain, anorexia, or sense of fullness. Cystic lesions filled with mucin or hemorrhagic material are found in the body or tail of the pancreas; however, the cysts do not communicate with the pancreatic ducts. The cellular lining is oftentimes denuded, making diagnosis via biopsy or fluid aspiration nondiagnostic. Patients with noninvasive carcinoma have an excellent prognosis. By contrast, those with invasive carcinoma have a 5-year survival rate of 60%.¹⁰ When noninvasive lesions are detected, they should be addressed, as even small invasive cancers usually prove lethal.¹⁰

IPMNs are precancerous lesions that progress to carcinoma. They are usually found in the head of the pancreas that involves the main and/or branch pancreatic ducts. IPMNs are lined by mucous-secreting cells that have a high malignant potential; however, the rate of progression appears to be extremely slow, at approximately 15–20 years. More common in men, IPMNs typically present during the fifth or sixth decade of life. Most patients have a history of recurrent pancreatitis due to mucous plugging of the pancreatic duct. Patients can present with weight loss, abdominal/back pain, steatorrhea, jaundice, or diabetes; however, they are often asymptomatic, and lesions are found incidentally. Endoscopy reveals thick mucous extruding from the ampulla of Vater. The cystic lesions of an IPMN typically communicate with, and extensively involve, the large pancreatic ducts.¹⁰

PanlNs are defined as neoplastic epithelial proliferations in the smaller caliber pancreatic ducts and are divided into three grades based upon the degree of architectural and nuclear atypia present.⁹ There is a histologic and genetic progression from PanIN-1 to PanIN-2 to PanlN-3 to invasive ductal adenocarcinoma in the pancreas. This grading system has been extremely useful to researchers; however, there are problems with it clinically. The assignment of lesions to a category within this grading system has been shown to have poor inter- and intraobserver reproducibility; furthermore, morphologic analyses suggest a 2-tier grading system may more accurately reflect the nuclear changes that occur in PanlNs.¹⁰

Our case is unique because tissue histology revealed PanIN-2, a precursor to ductal adenocarcinoma, embedded in a pancreatic rest. To our knowledge, no such case has been reported in the literature. As the rate or propensity of transformation from PanIN-2 to ductal adenocarcinoma has not yet been determined, it is significant that the mass, identified as PanIN-2, was located in this patient and surgically removed. This patient will be followed with EUS every 6—12 months to screen for the development of future submucosal gastric pancreatic pathologies.