Pharmacotherapy of Zollinger–Ellison syndrome

Introduction: The role of pharmacotherapy in the management of patients with Zollinger–Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients.

Areas covered: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib).

Expert opinion: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.     

Metastatic gastrinoma to the liver 20 years after primary resection

Gastrinoma is a rare endocrine tumor that is frequently associated with liver metastasis. The liver metastasis is usually seen simultaneously or soon after a primary operation. A 47-year-old woman who had had a total gastrectomy 20 years earlier developed liver metastasis. An interval of this length between surgery and metastasis is extremely rare. The total gastrectomy prevented the patient from developing the usual symptoms of hypergastrinemia that would have enabled early diagnosis of the metastasis. Laboratory examinations on admission revealed a high serum gastrin concentration (1500 pg/ml). Computed tomography showed an irregularly enhanced mass lesion with an uneven, low-density central area in the right anterior inferior segment of the liver. An extended right hepatectomy was performed. Intraoperative ultrasonography showed no abnormalities in the remnant pancreas. Examination of the cut surface of the specimen revealed a yellow, firm, elastic tumor, 55 mm in diameter. The interior of the tumor appeared necrotic. Histopathologically, the tumor was composed of cells with hyperchromatic, dysplastic nuclei arranged in a trabecular pattern with nest formation. Gastrin staining was positive. A histologic diagnosis of metastatic gastrinoma was made. The patient's gastrin concentration returned to normal and she was well at 2-year follow-up. Received: August 19, 1999 / Accepted: January 28, 2000     

Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1

Jensen RT (Bethesda, MD, USA). Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 477–88. Zollinger–Ellison syndrome (ZES) is the most common symptomatic pancreatic endocrine tumour in patients with MEN-1. Besides the treatment of the usual endocrinopathies seen in patients with MEN-1, the treatment of the ZES requires attention be paid to controlling the gastric acid hypersecretion, to dealing with the gastrinomas per se which are malignant in 18–60% of cases, and to the diagnosis and treatment of gastric carcinoid tumours, that are increasingly seen in these patients. In this article the current management of each of the areas is reviewed and what is known or uncertain discussed, based on our studies at the NIH and data from others. Data from 231 patients including 45 with MEN-1 and 186 without MEN-1 is contrasted in this report. Gastric acid hypersecretion has been controlled in all patients medically with MEN-1 and ZES at the NIH for up to 22 years. The current drugs of choice are H⁺-K⁺ ATPase inhibitors and twice a day dosing is recommended. Periods of parenteral drug therapy (surgery, etc.) and pregnancy require important modifications. The appropriate surgical therapy of the gastrinoma is controversial. Eighty per cent of patients have a duodenal gastrinoma and 20–30% have a pancreatic tumour. Recent studies suggest gastrinoma enucleation combined with duodenotomy rarely results in cure. Aggressive surgery (Whipple resection) can result in cure of gastrinoma but effect on survival is unclear. There are important differences in gastrinoma location, extent, and percentage with aggressive disease in patients with or without MEN-1, which are discussed. Confusion has occurred because of lack of information on the natural history of the gastrinoma compared to the other pancreatic endocrine tumours that occur in MEN-1 and survival data from patients with and without MEN-1 is contrasted. The occurrence of gastric carcinoids in patients with and without MEN-1 with ZES is contrasted and the areas of certainty and disagreement reviewed.     

A case of jejunal gastrinoma diagnosed by percutaneous transhepatic portal venous sampling

A 63-year-old male was admitted to our department for further examination of hypergastrinemia. Secretin provocation test and calcium infusion test suggested Zollinger-Ellison syndrome and percutaneous transhepatic portal venous sampling (PTPVS) demonstrated gastrinoma in the jejunum, although CT, ultrasonography and angiography could not accurately detect the location of the gastrinoma. Laparatomy findings showed a solid tumor 1.5 cm in diameter in the jejunal mesentery 5 cm distal to the ligament of Treitz, and primary gastrinoma was confirmed in the submucosa of the jejunum immediately adjacent to this tumor. An immunohistochemical study using the PAP method revealed gastrin secreting cells in the tumor. In addition to this case of jejunal gastrinoma, a review of literature in Japan and other countries was presented.     

Polymorphism in the C-reactive protein (CRP) gene affects CRP levels in plasma and one early marker of atherosclerosis in men: The Health 2000 Survey

The gastrointestinal hormone gastrin is measured in plasma in physiological, pathophysiological and diagnostic investigations. In the diagnosis of hypergastrinaemic diseases such as gastrinomas and gastric achlorhydria, measurement of gastrin concentrations in circulation is crucial. Gastrin circulates, however, not as a single peptide but as a mixture of peptides of different lengths and amino acid derivatizations. Moreover, in hypergastrinaemia the peptide pattern changes. Consequently, diagnostic gastrin measurements require immunoassays that recognize the pathological plasma patterns, which are characterized by a predominance of the large peptides (gastrin‐34 and gastrin‐71) and less, if any, of the shorter main form of gastrin in normal tissue, gastrin‐17. Alternatively, and in specific cases, “processing‐independent assays” (PIA) for progastrin may be considered, since hypersecreting gastrin cells also release substantial amounts of biosynthetic precursors and processing intermediates. Recently, gastrin kits that do not take the pathological plasma patterns into account have been marketed and may miss the diagnosis. Therefore, proper diagnosis of gastrinomas and other hypergastrinaemic diseases requires insight into cellular gastrin synthesis and peripheral metabolism, and also into the design of useful immunoassays. This review discusses the art of measuring gastrin in plasma with adequate diagnostic specificity.     

Prognostic factors in patients with endocrine tumours of the duodenopancreatic area

Background—Thedevelopment of endocrine tumours of the duodenopancreatic area (ETDP)is thought to be slow, but their natural history is not well known. Theaim of this study was to determine the factors that influence survivalof patients with ETDP.
Patients/Methods—Eightytwo patients with ETDP (44 non-functioning tumours, 23 gastrinomas,seven calcitonin-secreting tumours, four glucagonomas, threeinsulinomas, one somatostatinoma) followed from October 1991 to June1997 were included in the study. The following factors wereinvestigated: primary tumour size, hormonal clinical syndrome, livermetastases, lymph node metastases, extranodular/extrahepatic metastases, progression of liver metastases, local invasion, complete resection of the primary tumour, and degree of tumoral differentiation. The prognostic significance of these factors was investigated by uni-and multi-variate analysis.
Results—Twenty eightpatients (34%) died within a median of 17 months (range 1-110) fromdiagnosis. Liver metastases (p =0.001), lymph node metastases (p = 0.001), progression of liver metastases (p<0.00001), lack of completeresection of the primary tumour (p = 0.001), extranodular/extrahepaticmetastases (p =0.001), local invasion (p = 0.001), primary tumour size3 cm (p = 0.001), non-functioning tumours (p = 0.02), and poortumoral differentiation (p = 0.006) were associated with anunfavourable outcome by univariate analysis. Multivariate analysisidentified only liver metastases (risk ratio (RR) = 8.3; p<0.0001),poor tumoral cell differentiation (RR = 8.1; p = 0.0001), and lack ofcomplete resection of the primary tumour (RR = 4.8; p = 0.0007) asindependent risk factors. Five year survival rates were 40and 100% inpatients with and without liver metastases, 85 and 42% in patientswith and without complete resection of primary tumour, and 17 and 71%in patients with poor and good tumour cell differentiation respectively.
Conclusion—Livermetastases are a major prognostic factor in patients with ETDP.Progression of liver metastases is also an important factor which mustbe taken into account when deciding on the therapeutic approach. Theonly other independent prognostic factors are tumoral celldifferentiation and complete resection of the primary tumour.

Keywords:prognostic factors; survival; endocrine tumours; gastrinoma; cell differentiation; liver metastases

     

Case for the Panel: Filamentous Bodies in a Squamous Cell Carcinoma

A primary hepatic gastrinoma found in a 13-year-old boy was studied by light microscopy, immunohistochemistry, electron microscopy, and immunoelectron microscopy. Results were consistent with a neuroendocrine neoplasm with abundant gastrin-immunoreactive cells. Unlike all previously reported cases of primary hepatic neuroendocrine tumors, which have been endocrinologically asymptomatic, the patient had a Zollinger-Ellison syndrome apparently cured by surgical resection of the tumor.     

Solitary hepatic gastrinoma treated with laparoscopic radiofrequency ablation.

BACKGROUND: This is a case of a solitary hepatic gastrinoma in a 65-year-old male. The patient was diagnosed with Zollinger-Ellison syndrome in 1991. He had negative radiologic and surgical explorations at that time. He was maintained on proton-pump inhibitors for the next 10 years without symptoms. METHODS: A computed tomographic (CT) scan done in April 2001 demonstrated a 5-cm right hepatic lesion. Radionucleotide scanning with octreotide demonstrated intense activity in the same area in the right hepatic lobe. His serum gastrin was 317 pg/mL. He underwent laparoscopic radiofrequency ablation of the lesion. RESULTS: Treatment resulted in a 6-cm ablative area giving a 1-cm margin on the tumor. One- and 3-month follow-up CT scans demonstrated adequate ablation of the tumor. An octreotide scan done 3 months postoperatively did not reveal any areas of abnormal uptake. CONCLUSION: We report success with laparoscopic radiofrequency ablation as an alternative to major hepatic resection in patients with a solitary hepatic gastrinoma.     

Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test

Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28‐year‐old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra‐arterial calcium injection (SACI) test and 68‐gallium edotreotide positron emission tomography CT (Ga‐DOTATOC PET‐CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga‐DOTATOC PET‐CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton‐pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma.