Chapter 18

In 1955, Zollinger and Ellison1 described two patients with jejunal ulceration, gastric acid hypersecretion, and a non-β pancreatic islet cell tumor. The diagnostic triad of gastric acid hypersecretion, recurrent peptic ulceration in the setting of adequate therapy, and a non-β islet cell tumor of the pancreas was proposed for the syndrome that now bears their names. The subsequent development of a sensitive radioimmunoassay resulted in the identification of gastrin overproduction as the underlying mechanism for this syndrome.

The incidence of gastrinoma is between one and three per 1 million people.2,3 In patients with peptic ulcer disease (PUD), gastrinoma is thought to account for 0.1% to 1.0% of cases. However, these figures may be underestimates because these patients may have symptoms similar to those with typical PUD, attributed to Helicobacter pylori or the use of nonsteroidal antiinflammatory drugs (NSAIDs), and may go undiagnosed. Enteropancreatic neuroendocrine tumors are second in incidence only to insulinoma.

Although 75% to 80% of gastrinomas are sporadic, 20% to 25% are diagnosed in the setting of multiple endocrine neoplasia type 1 (MEN1).2,3 This syndrome includes primary hyperparathyroidism and tumors of the pituitary gland in addition to pancreatic islets cell tumors and duodenal gastinomas. (Thymic carcinoids, adrenal adenomas, and some cutaneous tumors have also been associated.) This distinction is important to make because the diagnostic and management approaches to sporadic and familial disease differ significantly. The penetrance of pancreatic neuroendocrine tumors or duodenal gastrinomas in patients with MEN1 is approximately 60% to 70%. Gastrinoma is the most common of these tumors. In general, these tumors become clinically evident in the fourth or fifth decade of life in these patients.

These tumors arise from enteroendocrine cells found in the pancreas and duodenum. Histologically, they are well-differentiated tumors that resemble other pancreatic neuroendocrine tumors and demonstrate few mitoses with a proliferative (Ki-67) index of 2% to 10%. As with all gastroenteropancreatic neuroendocrine tumors, gastrinomas are classified by World Health Organization guidelines into well-differentiated endocrine tumors (benign), well-differentiated endocrine carcinomas (low malignant potential), and poorly differentiated endocrine carcinomas (high malignant potential).4 The majority of gastrinomas (50% to 80%) fit into the well-differentiated endocrine carcinoma category. Ultimately, more than 60% of these tumors prove to be malignant. This distinction relies on evidence of local invasion or metastatic spread because no histologic feature exists that is diagnostic of malignancy.

Although initially described as a pancreatic neuroendocrine tumor, it is now recognized that the majority of gastrinomas (50% to 88%) arise in the duodenum.2,3 In addition, these tumors are rarely found in the stomach, jejunum, biliary tract, liver, kidney, and ovary. Sporadic tumors of the duodenum are typically small (<1 cm). Despite this, 60% to 80% have metastasized to regional lymph nodes at the time of diagnosis. On occasion, gastrinoma is found in a lymph node when no primary tumor is evident. Most, if not all, of these "primary lymph node gastrinomas" have likely spread from a small duodenal tumor. With careful intraoperative examination, most of these primary tumors can be found. The existence of true lymph node primary tumors is currently controversial. The most common site of metastatic spread is the liver; the second most common is bone. In sporadic duodenal gastrinomas, liver metastases are seen in 10% of patients at the time of diagnosis.

In contrast to tumors in the duodenum, sporadic pancreatic gastrinomas are generally larger (>2 cm). Although spread to regional lymph nodes appears to occur at a similar rate to duodenal tumors, pancreatic gastrinomas are associated ...

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