Gastrinoma (Duodenal and Pancreatic)

Abstract

Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES). ZES is characterized by gastric acid hypersecretion resulting in severe acid-related peptic disease (peptic ulcer disease, PUD; gastro-esophageal reflux disease, GERD) [1,2,3] and diarrhea. In this section ZES, due to both duodenal and pancreatic gastrinomas, will be covered together because clinically they are similar [2, 3]. Specific points related to gastrinomas associated with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1) will also be mentioned. Some specific points related to duodenal gastrinomas will also be covered in the duodenal carcinoid section.The incidence of gastrinomas is 0.5–3/million population/year. They are the most common functional and, malignant pancreatic endocrine tumor (PET) syndrome and comprise up to 30% of these tumors [3, 4]. Duodenal tumors, which were originally thought to be uncommon (i.e. <20%), now make up 50–88% of gastrinomas in sporadic ZES patients and 70–100% of gastrinomas in MEN1/ZES patients. In rare cases, gastrinomas occur in other nonpancreatic, nonduodenal abdominal (stomach, liver, bile duct, ovary) (5–15%) and extra-abdominal (heart, small cell lung cancer) locations [5,6,7,8].The WHO classification [10] subdivides gastrinomas, similar to other gastroenteropancreatic neuroendocrine tumors (GEP-NETs), into three general categories: (1) well-differentiated endocrine tumors with benign or uncertain behavior at the time of diagnosis (10–30%); (2) well-differentiated endocrine carcinomas with low-grade malignant behavior (50–80%), and (3) poorly differentiated endocrine carcinomas with high-grade malignant behavior (1–3%). The 50–80% of gastrinomas of the pancreas and duodenum that fall into the category of well-differentiated endocrine carcinomas are usually larger than 1 cm and show local invasion and/or proximal lymph node metastases [6, 11]. Liver metastases occur much more frequently with pancreatic gastrinomas (22–35%) than duodenal gastrinomas (0–10%) [6, 12]. Pancreatic gastrinomas are generally large in size (mean 3.8 cm, 6% <1 cm), whereas duodenal gastrinomas are usually small (mean 0.93 cm, 77% <1 cm). While the pancreatic gastrinomas may occur in any portion of the pancreas, duodenal gastrinomas are predominantly found in the first part of the duodenum including the bulb [7]. At surgery 70–85% of gastrinomas are found in the right upper quadrant (duodenal and pancreatic head area), the so-called ‘gastrinoma triangle’ [4, 5, 13]. MEN1 is an autosomal-dominant syndrome that is present in 20–30% of patients with ZES [14]. In these patients duodenal tumors are usually (70–100%) responsible for the ZES. The duodenal tumors are almost always multiple [15,16,17] and originate from diffuse gastrin cell proliferations [18].Histologically, most gastrinomas are well-differentiated and show a trabecular and pseudoglandular pattern. Their proliferative activity (i.e. the Ki-67 index) varies between 2 and 10%, but is mostly close to 2%. Immunohistochemically, all gastrinomas stain for gastrin.Approximately one fourth of ZES patients have gastrinomas that pursue an aggressive course and aggressive growth occurs in 40% of patients with liver metastases. At diagnosis, 5–10% of duodenal gastrinomas and 20–25% of pancreatic gastrinomas are associated with liver metastases. Liver metastases are the most important prognostic factor, the 10-year survival being 90–100% without liver metastases and 10–20% with. Poor prognostic factors besides liver metastases include: inadequate control of gastric acid hypersecretion; presence of lymph node metastases (p = 0.03); female gender (p < 0.001); absence of MEN1 (p <0.001); short disease history from onset to diagnosis (p <0.001); markedly increased fasting gastrin levels (p < 0.001); presence of a large primary tumor (>3 cm) (p < 0.001); a pancreatic primary gastrinoma (p < 0.001); development of ectopic Cushing’s syndrome or bone metastases (p < 0.001); the presence of various flow cytometric features, molecular features (high HER2/neu gene expression (p = 0.03), high 1q LOH, increased EGF of IGF1 receptor expression), or histological features including angioinvasion, perineural invasion, >2 mitoses per 20 HPF, Ki-67 index >2 [5, 6,19,20,21,22,23,24].At the onset of symptoms, the mean age of patients with sporadic gastrinomas is 48–55 years; 54–56% are males, and the mean delay in diagnosis from the onset of symptoms is 5.2 years. All of the symptoms except those late in the disease course are due to gastric acid hypersecretion. The majority of ZES patients present with a single duodenal ulcer or GERD symptoms and ulcer complications. Multiple ulcers or ulcers in unusual locations are a less frequent presenting feature than in the past. Abdominal pain primarily due to PUD or GERD occurs in 75–98% of the cases, diarrhea in 30–73%