All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update.

Zollinger-Ellison syndrome (ZES) is a distinct syndrome characterized by hyperchlorhydria-induced peptic ulcer disease and chronic diarrhea. It is the result of a gastrin-excess state caused by a duodenal or pancreatic neuroendocrine tumor referred to as gastrinoma. This gastrin-secreting neuroendocrine tumor is usually sporadic in nature, or part of multiple endocrine neoplasia type 1 syndrome. The high rate of malignancy associated with gastrinomas substantiates the need for early diagnosis. In order to diagnose ZES with laboratory tests, patients under antacid medication are required to stay off proton pump inhibitors for at least one week and H2 receptor antagonists for 48 h. Fasting serum gastrin level measurement serves as an initial and fundamental diagnostic test, boasting a sensitivity of 99%. Gastrinoma patients will present with a gastrin level greater than 100 pg/mL, while a serum gastrin level higher than 1000 pg/mL, in the presence of gastric pH <2, is considered diagnostic. Since more common causes of hypergastrinemia exist in the setting of hypochlorhydria, ruling those out should precede ZES consideration. Such causes include atrophic gastritis, Helicobacter pylori (H. pylori)-associated pangastritis, renal failure, vagotomy, gastric outlet obstruction and retained antrum syndrome. The secretin stimulation test and the calcium gluconate injection test represent classic adjuvant diagnostic techniques, while alternative approaches are currently being introduced and evaluated. Specifically, the secretin stimulation test aids in differentiating ZES cases from other hypergastrinemic states. Its principle is based on secretin stimulation of gastrinoma cells to secrete gastrin, while inhibiting normal G cells. The rapid intravenous infusion of 4 µg/kg secretin over 1 min is followed by gastrin level evaluation at specific intervals post-infusion. Localization of the primary tumor and its metastases is the next diagnostic step when gastrinoma-associated ZES is either suspected or biochemically confirmed. Endoscopic ultrasound has showcased sensitivity as high as 83% for pancreatic gastrinomas and is considered the primary modality in such cases, although its tumor detection rates are substantially lower in duodenal lesions. Gallium-68 radiotracers, especially DOTATOC with positron emission tomography, are currently setting the standard in tumor localization, enhancing traditional imaging techniques and showcasing high sensitivity and specificity. Although gastrinomas have been reported in various anatomic locations, the vast majority arise in a specific site named the "gastrinoma triangle", involving parts of the duodenum, pancreas and extra-hepatic biliary system. Proton pump inhibitors serve as the cornerstone of symptomatic ZES treatment. Surgery is routinely performed in localized sporadic ZES, irrespective of imaging results. ZES in multiple endocrine neoplasia type 1 requires work-up for evaluation and treatment of hyperparathyroidism, while surgery might be an option for selected cases. In cases of advanced and metastatic disease, there is a variety of potential treatments, ranging for somatostatin analogs to chemotherapeutic drugs, liver-directed therapies and liver transplantation, while neither hepatic metastases, nor locally invasive disease necessarily preclude surgical management. This article thoroughly and critically reviews available literature and provides an extensive and multidimensional overview of ZES, along with current controversies regarding management of this disease.

How to treat gastrinomas in patients with multiple endocrine neoplasia type1: surgery or long-term proton pump inhibitors?

In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple, and about 15% of patients have coexisting pancreatic gastrinomas, which can be localized by the selective arterial secretagogue injection test (SASI test). The guidelines (GLs) by the Japanese Neuroendocrine Tumor Society (JNETS) recommend surgical resection for functioning duodenopancreatic neuroendocrine tumors (NETs), including gastrinomas, in patients with MEN1 (Grade A, 100% agreement among members). Conversely, the GLs of the National Comprehensive Cancer Network (NCCN) in the USA recommend observation and treatment with proton pump inhibitors (PPIs) or exploratory surgery for occult gastrinomas. An international Consensus Statement (ICS) from the European Union (EU) also does not recommend resection of gastrinomas in patients with MEN1, despite some surgeons having reported surgery being curative for gastrinomas in MEN1 patients. In this review, we discuss the serious side effects and tumorigenic effects of the prolonged use of PPIs and the safety and curability of surgery, supported by our results of curative surgery for gastrinomas in 20 patients with MEN1 over 30 years. We conclude that surgery should be the first-line treatment for gastrinomas in MEN1 patients.

Métodos de diagnóstico de laboratorio e imagenológicos en el síndrome de Zollinger-Ellison / Laboratory and imaging diagnostic methods in the Zollinger-Ellison syndrome

Introducción: el síndrome de Zollinger-Ellison es un tumor neuroendocrino que produce hipersecreción de ácido gástrico y úlcera péptica. Por lo que se realizó la revisión con el objetivo de describir los principales métodos diagnósticos de laboratorio e imagenológicos en el síndrome de Zollinger-Ellison. Desarrollo: se realizó una revisión bibliográfica con los descriptores en español e inglés síndrome de Zollinger-Ellison, tumor neuroendocrino y gastrinoma, sacados de los descriptores en ciencias de la salud (DeCS/MeSH), en las bases de datos Google Académico, SciELO y National Library of Medicine. Como resultados se obtuvo que los métodos de laboratorio son la gastrina sérica basal en ayunas, la cual no es confiable debido a su alteración en diferentes enfermedades, el pH gástrico, excluye hipergastrinemias secundarias, y la secreción gástrica ácida basal, que diferencia las formas de hipergastrinemia. Estos análisis de laboratorio son complementarios entre sí, y para su realización se debe suspender la toma de los inhibidores de la bomba de protones. Otros estudios son la prueba de estimulación por secretina, que confirma la hipergastrinemia, y la prueba de estimulación por calcio, que diagnostica tumores > 1 mm que expresan receptores de calcio. Los métodos imagenológicos son fundamentales para la localización del tumor. La primera técnica de imagen que se debe realizar debido a su alta sensibilidad y especificidad es la gammagrafía con 111 In-octreótido, esta localiza tumores no detectados con otras exploraciones y permite realizar el diagnóstico diferencial con lesiones hipervascularizadas. Conclusiones: el síndrome de Zollinger-Ellison requiere para un diagnóstico certero la utilización de métodos de laboratorio y de imagen novedosos(AU)

Introduction: Zollinger-Ellison syndrome is a neuroendocrine tumor that produces hypersecretion of gastric acid and peptic ulcer. Therefore, the review was carried out with the objective of describing the main laboratory and imaging diagnostic methods in Zollinger-Ellison syndrome. Development: a bibliographic review was carried out with the descriptors in Spanish and English Zollinger-Ellison syndrome, neuroendocrine tumor and gastrinoma, taken from the descriptors in health sciences (DeCS/MeSH), in Google databases. Academic, SciELO and National Library of Medicine. As results, it was obtained that the laboratory methods are fasting basal serum gastrin, which is not reliable due to its alteration in different diseases, gastric pH, excludes secondary hypergastrinemias, and basal acid gastric secretion, which differentiates the forms of hypergastrinemia. These laboratory tests are complementary to each other, and to perform them, the intake of proton pump inhibitors must be suspended. Other tests include the secretin stimulation test, which confirms hypergastrinemia, and the calcium stimulation test, which diagnoses tumors >1 mm that express calcium receptors. Imaging methods are essential for tumor localization. The first imaging technique to be performed due to its high sensitivity and specificity is 111In-octreotide scintigraphy, which locates tumors not detected with other examinations and allows differential diagnosis with hypervascularized lesions. Conclusions: Zollinger-Ellison syndrome requires the use of novel laboratory and imaging methods for an accurate diagnosis(EU)

A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.

Acute kidney injury following vomiting and diarrhea after endoscopy in a duodenal gastrinoma patient.

A 51-year-old woman complaining of weakness in the limbs was diagnosed as having a duodenal gastrinoma on performing a further evaluation. Surgical resection was performed with selective arterial calcium injection for localization. During preoperative hospitalization, she experienced recurrent severe vomiting and diarrhea after endoscopy, leading to acute kidney injury. To our knowledge, this is the first report of gastrinoma with post-endoscopy symptom exacerbation. Although the etiology is unknown, the findings in this case suggest that sufficient fluid replacement, sedation, and high-dose proton pump inhibitor administration should be taken into consideration when performing endoscopy in gastrinoma patients.

Portal vein embolization using a Histoacryl/Lipiodol mixture before right liver resection.

PURPOSE: The purpose of this retrospective study was to evaluate the efficacy and safety of percutaneous transhepatic portal vein embolization (PVE) of the right liver lobe using Histoacryl/Lipiodol mixture to induce contralateral liver hypertrophy before right-sided (or extended right-sided) hepatectomy in patients with primarily unresectable liver tumors. METHODS: Twenty-one patients (9 females and 12 males) underwent PVE due to an insufficient future liver remnant; 17 showed liver metastases and 4 suffered from biliary cancer. Imaging was performed prior to and 4 weeks after PVE. Surgery was scheduled for 1 week after a CT or MRI control. The primary study end point was technical success, defined as complete angiographical occlusion of the portal vein. The secondary study end point was evaluation of liver hypertrophy by CT and MRI volumetry and transfer to operability. RESULTS: In all the patients, PVE could be performed with a Histoacryl/Lipiodol mixture (n = 20) or a Histoacryl/Lipiodol mixture with microcoils (n = 1). No procedure-related complications occurred. The volume of the left liver lobe increased significantly (p < 0.0001) by 28% from a mean of 549 ml to 709 ml. Eighteen of twenty-one patients (85.7%) could be transferred to surgery, and the intended resection could be performed as planned in 13/18 (72.3%) patients. CONCLUSION: Preoperative right-sided PVE using a Histoacryl/Lipiodol mixture is a safe technique and achieves a sufficient hypertrophy of the future liver remnant in the left liver lobe.

Secretin-receptor and secretin-receptor-variant expression in gastrinomas: correlation with clinical and tumoral features and secretin and calcium provocative test results.

CONTEXT/OBJECTIVES: The diagnosis of Zollinger-Ellison syndrome requires secretin testing in 60% of patients. Even with secretin, the diagnosis may be difficult because variable responses occur, and 6-30% have negative testing. The basis for variability or negative responses is unclear. It is unknown whether the tumor density of secretin receptors or the presence of a secretin-receptor-variant, which can act as a dominant negative, is important. The aim of this study was to investigate these possibilities. PATIENTS/METHODS: Secretin-receptor and variant mRNA expression was determined in gastrinomas using real-time PCR from 54 Zollinger-Ellison syndrome patients. Results were correlated with Western blotting, secretin-receptor immunohistochemistry, with gastrin-provocative test results and tumoral/clinical/laboratory features. RESULTS: Secretin-receptor mRNA was detectible in all gastrinomas but varied 132-fold with a mean of 0.89 +/- 0.12 molecules per beta-actin. Secretin-receptor PCR results correlated closely with Western blotting (r = 0.95; P < 0.0001) and receptor immunohistochemistry (P = 0.0015; r = 0.71). The variant was detected in all gastrinomas, but levels varied 102-fold and were 72-fold lower than the total. Secretin-receptor levels correlated with variant levels, Deltasecretin, but not Deltacalcium and with tumor location, but not growth, extent, or clinical responses. Variant levels did not correlate with the Deltasecretin. Detailed analysis provides no evidence that variant expression modified the secretin-receptor response or accounted for negative tests. CONCLUSIONS: Secretin-receptor and secretin-receptor-variant expressions occur in all gastrinomas. Because the expression of the total, but not variant, correlated with the secretin results and no evidence for dominant negative activity of the variant was found, our results suggest that the total secretin-receptor density is an important determinant of the secretin test response.

The role of radiofrequency ablation in multiple liver metastases to debulk the tumor: a pilot study before alternative therapies.

INTRODUCTION: In this study, our aim was to proceed with the first study of our patients by evaluating different metastatic tumor to the liver to check whether, after debulking the tumor with radiofrequency ablation (RFA), the chemotherapy, could increase the survival in these patients as a pilot study before applying alternative therapies in the future. MATERIALS AND METHODS: We studied 11 patients, 7 male, 4 female; age mean, 68 years (50-84). The tumors considered were carcinoid (3), gastrinoma (3), a new endocrine of unknown origin (2), colorectal (2), and breast (1). RESULTS: All of the patients underwent laparoscopic RFA with a prior confirmatory biopsy and were discharged after 23 hours. No pain, bleeding, or wound infections were reported. One (1) patient with a gastrinoma died 9 months following surgery from a myocardial infarction. All other patients are still alive, although 2 experienced hepatic recurrences. CONCLUSIONS: The 11 patients in this series showed that RFA combined with chemotherapy is a viable therapeutic choice for patients with cancer that has metastasized to the liver. New therapies are still needed.

[Neuroendocrine tumors of the gastrointestinal tract]. / Neuroendokrine Tumoren des Gastrointestinaltraktes.

Neuroendocrine tumors (NET) of the gastrointestinal tract are rare and constitute 0.5-1% of all human malignancies. Based on their endocrine secretion, they are functional active or inactive. They are further classified into fore-, mid-, or hindgut tumors. The recently published WHO-classification grouped the tumors according to their tumor size, angioinvasion and Ki-67 index. NET are mainly diagnosed in an advanced tumor stadium because of the paucity of symptoms or when symptoms occur due to endocrine hypersecretion. NET are diagnosed serologically by their hormone secretion and by measuring Chromogranin A levels. They are further detected by CT, MRI or endoscopy including endoscopic ultrasound. Many NET have somatostatin receptors on their surface and can be diagnosed by somatostatin receptor scintigrafy with high sensitivity and specificity. Only by surgery NET can be cured. Because many tumors are diagnosed late, medical options are of utmost importance. Symptom control can be established by somatostatin analogues and interferon-ot. Diazoxid can further inhibit insulin secretion, proton pump inhibitors are the therapy of choice for acid hypersecretion in Zollinger-Ellison syndrome. Advanced neuroendocrine cancers can be treated with chemotherapy. Recently, radio receptor therapy with 90Y-DOTA Octreotid and 177Lu-DOTA Octreotate was established in advanced neuroendocrine cancers and is further evaluated in studies. Net of the gastrointestinal tract should be treated in a multidisciplinary approach with gastroenterologists, surgeons and experts in nuclear medicine. An overview about epidemiology, clinical features, diagnostic methods and therapy of NET of the gastrointestinal tract will is provided in this article.

Intravenous calcium injection test is a novel complementary procedure in differential diagnosis for gastrinoma.

The current study evaluated efficacy of the intravenous calcium injection test as a new diagnostic approach to clarify the existence of gastrinoma, which often goes undetected with routine testing. Twenty-six patients with hypergastrinemia were studied. For the calcium injection test, blood samples were taken from 12 patients with hypergastrinemia (HG), and three healthy volunteers, and one patient with nonfunctioning endocrine tumor in the pancreas (control). We compared results of the calcium injection test with those of the secretin test and the selective arterial secretagogue injection (SASI) test. The SASI test with secretin was performed in 24 of 26 patients with hypergastrinemia, including 22 of 24 patients with Zollinger-Ellison syndrome (ZES). Accuracy in the diagnosis of tumor localization by the SASI test was 95% (21 of 22) in ZES patients. The secretin test was negative in 3 of 21 patients with ZES (14%). Either the secretin test or the SASI test was positive in 22 of 23 patients (96%). The calcium injection test was administered to 12 patients in the HG group and 4 controls. The HG group showed significantly higher serum gastrin levels than those of the control group in the calcium injection test. Eight of 10 ZES patients (80%) had a positive calcium injection test. We could diagnose gastrinomas in 100% of ZES patients by either the calcium injection test or the secretin test. We have thus confirmed the efficacy of the intravenous calcium injection test in the diagnosis of gastrinoma. The calcium injection test could become an adjunct in the diagnosis of gastrinoma, which often goes undetected with routine testing.

[Interstitial laser hyperthermia of gastrinoma liver metastases in a child]. / Interstitielle Laserhyperthermie von Gastrinomlebermetastasen beim Kind.

Ultrasound-guided, laser-induced thermocoagulation with Nd:YAG laser (1064 nm) was performed in a child with metastatic gastrinoma disease. The emitted laser energy to coagulate a radius of 15-20 mm of metastatic liver tissue was 4 W with a duration time of 300 s. Marked reduction of gastrin was observed after interstitial laser hyperthermia.

[Somatostatin receptor scintigraphy in neuroendocrine tumors exemplified by a patient with hepatic metastases of gastrinoma]. / Somatostatin-Rezeptor-Szintigraphie bei neuroendokrinen Tumoren am Beispiel einer Patientin mit hepatisch metastasiertem Gastrinom.

In a 66-year old woman, who suffered from recurrent melena, diarrhea and hematemesis with multiple untreatable gastric and duodenal ulcers, a markedly increased basal and secretin-stimulated gastrin level, clinically a Zollinger-Ellison syndrome was assumed. The conventional diagnostic procedures (esophago-gastro-duodenoscopy, colonoscopy, endosonography, ERCP, abdominal CT and small bowel enema) had failed to reveal the localisation of any gastrinoma. The thereupon performed scintigraphy with In-111-pentetreotide showed four somatostatin receptor expressing liver lesions: two of them could be detected at first site in the consecutively performed MR scans, another retrospectively bearing in mind the scintigraphic images. Today, the somatostatin receptor imaging seems to be a highly sensitive procedure for detecting and localizing hormonally active gastroenteropancreatic tumors. At the same time it is a method for in vivo evaluation of the somatostatin receptor status of localized GEP tumors, thus delivering a decisive diagnostic step for the evaluation of the effectiveness of a therapy with somatostatin analogues before such an expensive therapy is started.

Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients.

BACKGROUND: Liver metastases of endocrine tumors are of major prognostic significance. The various therapeutic approaches have given disappointing results; however, locoregional treatment has allowed transient control of hepatic tumor growth. METHODS: Twenty-four patients with liver metastases of endocrine tumors (mainly carcinoid tumors [n = 18] and gastrinomas [n = 5]) were included in a Phase II study of hepatic arterial chemoembolization (CE). Metastases were bilateral in all patients and invaded more than 50% of the liver in 12. They were synchronous of the primary tumor in 62.5% of the patients. Seventeen patients had not responded to previous intravenous chemotherapy. CE courses were performed every 3 months using an emulsion of 10 ml of iodized oil and doxorubicin 50 mg/m2 injected into tumor vessels, followed by CE arterial occlusion with gelatin sponge particles. Seventy-one CE courses were performed in 23 patients; there was one technical failure. RESULTS: Among patients with carcinoid tumors, disappearance of diarrhea and/or flushing was observed in 8 of 11. Serotonin and/or its metabolite 5-hydroxyindoleacetic acid levels decreased by more than 50% in 57% of the patients. The size of liver metastases decreased by at least 50% in 6 of 18 patients, i.e., in 33% (range, 12-54%). Two had complete responses. The median duration of the responses was 14 months (range, 6-40). Among patients with noncarcinoid tumors, minor response or stabilization occurred in three of five patients. Major side effects were bleeding peptic ulcer (one patient) and oligoanuric renal failure (one patient). Abdominal pain, fever, and increases in hepatic enzyme levels were common and transient. CONCLUSIONS: These results suggest that CE is effective in patients with liver metastases of endocrine tumors, mainly in carcinoids. In the latter, CE allows control of the carcinoid syndrome and regression or stabilization of the liver tumors in 80% of patients.

Long-term follow up of patients with Zollinger-Ellison syndrome (ZES).

We have followed 14 patients with the Zollinger-Ellison syndrome for a median period of 9 years. All patients have suffered from peptic ulcer disease and six of the 14 have had complications such as bleeding or perforated ulcer. Almost half the patients have had diarrhoea as a dominant symptom and 4 patients suffered from multiple endocrine neoplasia. Before 1978, the year when the H2-receptor antagonists were introduced, the majority of the patients were operated with total gastrectomy. After that year there has been no need for gastrectomies, but all but two patients have undergone an explorative laparotomy. We have been able to localize the gastrinoma in 9 of 12 operated patients; in 7 cases it was localized within the gastrinoma triangle. Three of the patients are considered to have been cured after surgery. Eight patients have needed adjuvant acid-reducing medical therapy. Five of these have been failures to high doses of H2-receptor antagonists and have been successfully treated with omeprazole. Five patients have died during the follow-up period and death in two of these cases was related to tumor progression.