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Q1: What is the diagnosis?
The diagnosis is metastatic Zollinger-Ellison syndrome.
Q2: How would you confirm this?
Gastrinoma should be confirmed by measurement of the fasting gastrin concentration. Proton pump inhibitors should be stopped for one week and histamine-2-receptor antagonists for 48 hours before measurement of the gastrin concentration as they can contribute to hypergastrinaemia. If the gastrin is raised it should then be repeated with simultaneous measurement of the gastric fluid pH. If the pH is >2.5 hypergastrinaemia may be due to gastric acid hyposecretion such as in cases of pernicious anaemia and Helicobacter pylori infection, or secondary to the use of acid suppressing drugs. A raised serum gastrin of >1000 ng/l in association with a gastric pH of <2.5 is diagnostic of gastrinoma. In cases where the serum gastrin is only moderately raised at <1000 ng/l a secretin provocation test should be performed. A paradoxical rise in the serum gastrin of 200 ng/l after administration of secretin confirms the diagnosis.
In this case the serum gastrin concentration was 1452 ng/l and metastatic gastrinoma was confirmed on liver biopsy.
Q3: What are the treatment options?
The aims of treatment are twofold. Initially the gastric acid hypersecretion needs to be controlled, which can now be done successfully in virtually all cases with the use of proton pump inhibitors. Gastric acid secretion should be reduced to <5 mmol/hour which often requires high doses. Treatment of the gastrinoma itself is based on the site of the primary tumour, the presence and extent of metastatic disease, and whether the tumour is part of the multiple endocrine neoplasia (MEN) type I syndrome. This requires accurate imaging to determine the appropriate treatment. Somatostatin receptor scintigraphy should be performed in all newly diagnosed cases to assess the extent of the disease. In the absence of metastatic disease stringent attempts should be made to resect the primary tumour. Metastatic disease needs to be treated in accordance with the position and extent of the metastases, along with the rate of growth of the tumour.
The clinical syndrome of peptic ulceration and hypergastrinaemia in the presence of a non-β islet cell pancreatic tumour was first described by Zollinger and Ellison in their landmark paper published in 1955.1 After this, the treatment of choice was total gastrectomy which decreased the mortality from peptic ulceration. However the introduction of potent inhibitors of gastric acid secretion over the last 20 years has changed the natural history of the disease. Increasingly metastatic disease, and in particular the extent of liver involvement, is determining life expectancy as the complications related to gastric ulceration diminish.2 This change in the natural history of gastrinomas has shifted the emphasis in treatment towards earlier diagnosis, more accurate tumour localisation, and more active treatment of metastatic disease.
In most reported series there is a delay in the diagnosis of gastrinoma of three to six years from the onset of symptoms. This may be due to the majority of cases presenting with a solitary peptic ulcer rather than the classical situation of multiple ulcers in unusual sites.3 Furthermore in up to 30% of cases the sole presenting feature is oesophageal reflux or persistent secretory diarrhoea. Thus a high index of suspicion is necessary, especially in cases of peptic ulceration that are H pylorinegative where there is no history of non-steroidal anti-inflammatory drug use, or if the symptoms are resistant to usual measures. As 60%–90% of cases are malignant earlier diagnosis and surgical treatment at a premetastatic stage should increase survival.
The decision as to appropriate treatment depends on accurate knowledge of the site of the primary tumour and the presence and extent of metastatic disease. The advent of somatostatin receptor scintigraphy has improved the detection of these tumours, which are often difficult to image with conventional means. Recent studies have shown it to alter management in up to 47% of cases initially imaged with a combination of ultrasound, computed tomography, and magnetic resonance imaging.4 It is now advocated that somatostatin receptor scintigraphy should replace conventional radiology as the initial imaging study in all cases of gastrinoma.5
The treatment of patients with gastrinomas is dependent on the position and potential for surgical resection of the primary tumour, the presence or absence of metastatic disease, and whether the gastrinoma is part of the MEN type I syndrome.
Patients without metastatic disease or MEN type I who undergo curative resection of the primary tumour have a very good long term prognosis. Therefore patients without evidence of liver or distant metastases on imaging should undergo routine surgical exploration, including a thorough search of the duodenum, with a view to complete surgical excision.
The natural history of Zollinger-Ellison syndrome is changing.
Earlier diagnosis through increased awareness may lead to improved survival.
Somatostatin receptor scintigraphy is the imaging modality of choice in all patients with Zollinger-Ellison syndrome.
Surgical resection should be attempted if possible.
At present there is no definitive treatment for metastatic disease, although a variety of therapeutic interventions are undergoing trials.
Orthotopic liver transplantation should be considered in carefully selected patients with advanced metastatic disease confined to the liver.
When to consider Zollinger-Ellison syndrome
Peptic ulceration in atypical sites.
Peptic ulceration in H pylorinegative patients with no history of non-steroidal anti-inflammatory drug use.
Combination of peptic ulceration and diarrhoea.
Peptic ulceration resistant to medical therapy.
Persistent secretory diarrhoea.
Severe oesophageal reflux or oesophageal strictures.
Patients with a strong familial history of peptic ulceration.
The treatment of patients with metastatic disease without MEN type I is more complicated. At present there is no consensus as to the best treatment despite many papers advocating a multitude of modalities including chemotherapy, chemoembolisation, hepatic cryosurgery, laprascopic thermal ablation, extensive hepatic resection, and liver transplantation. At present only hepatic resection of isolated metastases where the primary can also be removed has been shown to improve five year survival.6 However due to the diffuse nature of the tumour hepatic resection is normally only possible in a limited number of cases. In the remainder, if there is no extrahepatic disease, orthotopic liver transplantation should be considered as recent studies have now indicated that in highly selected patients, liver transplantation can yield long term survival.7
Finally, the 25% of patients whose gastrinoma is part of the MEN type I syndrome need to be approached differently. These cases normally have multiple tumours and as yet surgery has not been shown to offer a survival benefit over medical treatment and as such, cannot be recommended. Acid suppression remains the mainstay of treatment.
In summary, earlier diagnosis through increased awareness, improved detection of metastatic disease, and the aggressive treatment of patients with metastatic disease may improve patient survival. Surgical intervention is the only present treatment that results in a cure and should be undertaken where possible. The optimal medical treatment for patients who do not undergo curative surgery remains to be established. In the future improved tumour localisation with somatostatin receptor scintigraphy may lead to more appropriate treatment and therefore improve patient survival.
In this case, the patient underwent orthotopic liver transplantation and enjoyed three and a half years of good quality life before dying of recurrent disease.
Metastatic Zollinger-Ellison syndrome.