Pancreatic neuroendocrine tumors: gastrinoma
How is the diagnosis of gastrinoma made?
The diagnosis should be suspected on the basis of the clinical presentation and established in almost all patients by demonstrating elevated basal gastric acid secretion (BAO) and fasting elevations of the protein gastrin, which is produced by the gastrinoma. It is this protein gastrin, which leads to the increased acid secretion causing the ulcer formation. ZES should be suspected in the clinical setting of peptic ulcer with diarrhea, familial peptic ulcer, peptic ulcer in unusual locations, and recurrent or resistant peptic ulcers after treatment. ZES should be particularly suspected in patients with:
- peptic ulcers that persist or recur despite treatment for H. pylori infection or with histamine H2-receptor antagonists
- severe esophagitis
- duodenal ulcers without H pylori.
Gastrinomas may behave in a benign or malignant fashion. The percentage of gastrinomas that are actually malignant is unclear. No visual microscopic (histologic) criteria can predict malignancy. Malignancy can only be established by the behavior of the gastrinoma leading to the presence of metastases. Approximately one half of patients have a malignant behaving gastrinoma at the time of diagnosis. Metastases are usually found in the lymph nodes near the pancreas and in the liver. Bone metastases have been reported in about 30% of patients with metastatic gastrinoma in the liver. A number of cases of gastrinoma localized in lymph nodes have been described with no evidence of primary tumor. Some of these cases have been apparently cured by excision of lymph nodes, which suggests that the gastrinoma was not metastatic but originated as a primary tumor in the lymph node.
The number of gastrinomas found at surgery in the duodenum and in lymph nodes near the head of the pancreas, is greater than 50% such that 65% to 90% of all gastrinomas found at surgery occur in the pancreatic head-duodenal area and not necessarily in the pancreas proper. This fact is critical for the detection and localization of the gastrinoma during surgery. In fact, sporadic duodenal gastrinoma can occur without involvement of the pancreas in 25-50% of patients operated on for ZES. Gastrinomas may also occur in other intra-abdominal sites such as the liver, stomach, jejunum, mesentery, common bile duct and spleen. The early detection of a gastrinoma is important as the size of the primary tumor has been shown to be an important factor in predicting liver metastases. Liver metastases occurred in 4% of gastrinomas less than 1 cm in diameter, in 28% with tumors 1.1 to 2.9 cm, and in 61% greater than 3 cm. Duodenal gastrinomas have been found to be malignant with metastatic spread in 48% to 75% of cases. Most duodenal gastrinomas are small (80% less than 1 cm) and most pancreatic gastrinomas are large (70% at least 3 cm), therefore it remains unclear whether tumor size and location are independent predictors.
Roughly 20% of patients with ZES have a familial form with evidence of MEN-1. MEN-1 is an inherited trait that funs in families and is characterized by tumors of multiple endocrine organs, with hyperparathyroidism being the most common abnormality. Neuroendocrine tumors of the pancreas are the second most common, occurring in 82% of MEN-1 patients with 57% having ZES and 25% a different neuroendocrine tumor called an insulinoma. Pituitary and adrenal adenomas are less common. Patients with MEN-1 and ZES differ from sporadic cases in that they frequently present at a younger age; their tumors are almost always multiple and frequently small, and in some studies, patients with MEN-1 have an increased survival rate compared with sporadic cases.
Gastrinomas are more common in males (60%) than in females; the mean age at diagnosis is 45 to 50 years and approximately 20% have MEN-1. The most common presentation of patients with ZES is abdominal pain in 26% to 58%, which usually cannot be differentiated from pain caused by other common acid-peptic disorders. However, in some studies a significant proportion of individuals (14% to 25%) have no peptic ulcer or abdominal pain at the time of diagnosis. Thirty-seven to 73% of patients have diarrhea as an initial symptom, and in 15% to 18% it is the only symptom. Esophageal symptoms, endoscopic abnormalities, or both, were present in 50 - 70% of patients. Since this grouping of symptoms is non-specific and seen in many more common illnesses than gastrinoma, the diagnosis must be made by a specialist such as a gastroenterologist through a number of studies involving blood tests and endoscopy.