Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features

Abstract

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Figure 1

Overview of sporadic gastrinomas less than 3 mm in size within the submucosa stained with hematoxylin and eosin (A) and gastrin (B).

Figure 2

Morphology of sporadic duodenal gastrinoma stained with HE showing a trabecular and glandular growth pattern (A); strong immunoreactivity for gastrin (B), and expression of the nuclear proliferation antigen MIB1 in more than 2% of NET cells (C).

Figure 3

Overview of sporadic pancreatic gastrinoma surrounded by thickened collagen in the vicinity of normal pancreatic parenchyma stained with hematoxylin and eosin (A) and gastrin (B).

Figure 4

Circumscribed linear and nodular hyperplasia of gastrin cells within the Brunner’s glands in a patient with MEN1.

Figure 5

Tiny MEN1-associated duodenal gastrinoma within the submucosa revealing a diameter of less than 1 mm.

Figure 6

Duodenal NETs in the Kiel tumor archive. Fifty-nine (76.6%) out of the 77 NETs were endocrinologically not active, 20 of them expressed gastrin. These were not associated with ZES. All the functionally active NETs (18; 23.4%) were immunohistochemically positive for gastrin and showed a ZES.

Figure 7

Pancreatic NETs in the Zürich tumor archives. Seventy-five (49.3%) out of the 152 pancreatic NETs were endocrinologically not active, of which 3 expressed gastrin. These 3 gastrin-expressing NETs were not associated with ZES. Eight of the 77 functionally active NETs were immunohistochemically positive for gastrin and associated with ZES.

Figure 8

Pancreatic NETs in the Kiel tumor archives. Two hundred and twenty-five (58.7%) out of the 383 pancreatic NETs were endocrinologically not active. These gastrin-expressing NET were not associated with ZES. Sixteen of the 158 functionally active NETs were immunohistochemically positive for gastrin and showed a ZES.