Zollinger-Ellison syndrome (ZES)

Epidemiology of gastrinoma
Gastrinomas are the second-most common functioning pancreatic NETs, constituting ∼20%. The reported incidence is between 0.5 and 4 per million, men are more often affected than women. The majority is sporadic, but as many as 25-30% occur as part of the MEN1 syndrome. Even without a family history all ZES patients should be evaluated for MEN1.

Symptoms of gastrinoma
More than 90% of patients with gastrinoma have dyspepsia and ulcer disease, often without signs of Helicobacter Pylori infection. Diarrhea is another common symptom caused by the increased acid secretion. Pain from ulcer or gastro-oesophageal reflux occur in more than 75% of patients.

Diagnosis of gastrinoma
Gastrin levels are often markedly increased, together with raised basal acid output with low gastric pH; serum gastrin >1000 pg/ml and gastric pH <2 indicates (or is diagnostic of) ZES. In patients with lower gastrin levels a secretin test may be required, which is diagnostic with paradoxal rise in gastrin, 200 pg/ml over baseline, but 15% of patients have negative test. The important differential of diagnosis is atrophic gastritis where patients have high gastrin
without gastric acid and high gastric pH; pH >3 excludes ZES (See section for gastric NETs).

In 1989 it was discovered that duodenal location is the most common site, causing 60% of sporadic ZES, and 90% of MEN1-associated ZES. In MEN1 multiple duodenal tumours are common. The duodenal gastrinomas are typically tiny, submucosal tumours, often only a few mm large (2-8 mm), occurring most frequently in the first and second parts of the duodenum (Fig x). The duodenal gastrinomas have great tendency to cause lymph node metastases (∼45%). Liver metastases tend to occur late and in a minority of patients (∼10%), and this can provide possibility for successful surgical removal. The duodenal tumor entity may represent the primary tumor in patients with “primary lymph node gastrinoma” diagnosed in up to 10% of patients with ZES. In such cases the primary tumour may remain undetected, and may be remarkably slow-growing.

Treatment of gastrinoma
All these symptoms can be controlled by proton pump inhibitors, which the patients typically need to take continuously. At the time of diagnosis 50-60% of gastrinomas from the pancreas are malignant. However, if possible, surgical treatment should be considered.

Gastrinoma is always potentially malignant. Survival is favourable in patients with duodenal gastrinomas, even with lymph node metastases. Removal of lymph node metastases may limit further spread, and few (∼10%) of the duodenal gastrinoma patients develop liver metastases. Prognosis is worse for large primary pancreatic tumours, and in patients with liver or bone metastases or very high serum gastrin.

Preoperative localization of gastrinoma
CT with contrast or MRI is routinely performed in patients with ZES to visualize lymph node and liver metastases prior to surgery.

Octreoscan examination can often (∼90%) reveal lymph node and liver metastases, and occasional larger primary tumors. However, small duodenal tumors are not detectable, and instead larger lymph node metastases around the pancreatic head are easily mistaken to represent the primary tumor. Endoscopic ultrasound (EUS) can detect pancreatic gastrinomas, which often occur in the head of the pancreas. EUS
can also visualize few larger duodenal gastrinomas, and often lymph gland metastases around the pancreatic head, but rarely the smallest duodenal tumors. The selective arterial stimulation (SAS) test (also called the Imamura test) was originally developed with injection of
pentagastrin for visualization of gastrinoma, and may provide tumor regionalization (as described for insulinoma) and also demonstrate liver metastases. PET with 11C-labelled 5-HTP may be informative in some cases (Fig xx, xxx).

Fig xx 11C-5-HTP-PET of a patient with elevated gastrin levels showing a duodenal gastrinoma not detected by other methods.

Fig xxx Computed tomography initially considered negative, but then after comparison with PET-images (with 11C-DOPA and 11C-5-HTP) a pancreatic tumor and a lymph node metastasis were identified.

Even in absence of positive localization diagnosis, the patients with ZES should be liberally submitted to surgery, since especially these patients are likely to have resectable duodenal gastrinomas.

Surgery for gastrinoma
The surgical cure rate in ZES patients increased markedly when it was appreciated that the majority of gastrinomas occur in the duodenum. The duodenal gastrinomas may be
visualized by longitudinal duodenotomy at surgery with inversion of the lumen for careful palpation (Fig.7). The smallest duodenal submucosal tumors can be removed by mucosal dissection, larger tumors require duodenal wall excision. Pancreatico-duodenectomy may be required for gastrinomas in the pancreatic head and occasional larger duodenal tumors. The surgery in gastrinoma patients should include clearance of lymph node metastases around the pancreas and duodenum, and should aim to remove also respectable liver metastases.