Nonfunctional tumors tend to present at later clinical stages with symptoms attributable to mass effect or metastases. Although nonfunctional tumors do not produce specific clinical syndromes, they may secrete inactive amine and peptide products such as the following:
- Alpha-subunit of human chorionic gonadotropin (alpha-hCG).
- Neuron-specific enolase.
- Pancreatic polypeptide.
- Chromogranin A.
The frequent long delays between initial symptoms and diagnosis and the varied effects of the polypeptides secreted often necessitate involvement of multiple surgical and medical subspecialties. Surgery is the only curative modality. Surgery is often used even in the setting of metastatic disease to alleviate the symptoms of hormonal hypersecretion. Effective palliation may be achieved because of the slow-growing nature of the majority of these tumors and the potential use of antihormonal pharmacologic therapy (e.g., cimetidine in the ulcer-producing Zollinger-Ellison syndrome). In patients with indolent, slow-growing metastatic islet cell tumors, the best therapy may be careful observation, and no treatment until palliation is required. In patients with MEN-1 in which 85% have pancreatic islet cell tumors, 90% have hyperparathyroidism, and 65% have pituitary tumors, and they are less likely to be cured by pancreatic resection than are patients with sporadic islet cell tumors. With the exception of pain relief from bone metastases, radiation therapy has a limited role in this disease.
Tumor localization and staging studies include imaging with computed tomography (CT) with or without magnetic resonance imaging (MRI), and endoscopic ultrasound. In addition, somatostatin-receptor scintigraphy and single-photon emission CT may be useful adjuncts. However, somatostatin-receptor scintigraphy has diminished utility in localizing insulinomas versus other pancreatic NETs, since insulinomas often have a low density of somatostatin receptors. If the noninvasive tests do not reveal a tumor, but clinical suspicion remains high, more invasive and technically demanding tests, such as selective arteriography or selective arterial stimulation (with a secretagogue specific for the suspected tumor type), may be useful.
Some of the tumor types have unique characteristics that require specific approaches in their diagnosis and initial evaluation.
Diagnosis is dependent on elevated serum gastrin and elevated gastric acid levels. Provocative testing with calcium and secretin shows considerable overlap, and the value of these tests is limited. Zollinger-Ellison syndrome (ZES) is a syndrome of unrelenting peptic ulcer disease, diarrhea, and gastric hyperacidity, associated with a gastrin-producing tumor. (Refer to the Diarrhea section in the PDQ summary on Gastrointestinal Complications for more information.) It accounts for less than 1% of all peptic ulcer disease. About 15% to 35% of gastrinomas are associated with the MEN-1 syndrome and up to 50% are malignant. Up to 33% of gastrinomas have liver metastases.