Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies.

Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.

Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome-over a decade of follow-up.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management. CASE PRESENTATION: The patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100-624 pg/mL; current 114 pg/mL). CONCLUSION: Success of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

Síndrome de zolinger - Elison / Syndrome of Zolinger - Elison

Resumen:El síndrome de Zollinger - Ellison es una endocrinopatía que fue descrita en 1955 por los doctores Robert Zollinger y Edwin Ellison, quienes propusieron la triada diagnóstica que incluye hipersecreción gástrica ácida, úlcera péptica y gastrinoma. Esta enfermedad predomina en mujeres entre los 50 y 60 años de edad. Según su etiología, este síndrome se clasifica en una forma esporádica o asociada a neoplasia endocrina múltiple tipo 1 (NEM - 1).Más de la mitad de los gastrinomas se localizan en la pared duodenal, el páncreas es la segunda ubicación en frecuencia. Existen localizaciones ectópicas en ovario, mesenterio, hígado y ducto biliar. A nivel histopatológico se encuentran células tumorales redondas, con núcleos pequeños y nucléolos prominentes. La hipersecreción ácida gástrica está asociada a un defecto en la inhibición del retrocontrol negativo de la somatostatina sobre las células G antrales productoras de gastrina. Clínicamente, los pacientes manifiestan dolor abdominal, diarrea, pirosis, náuseas y vómitos; relacionados principalmente a la formación de úlceras pépticas. El diagnóstico debe incluir una medición en los niveles séricos de gastrina y valores de pH gástrico. El tratamiento de primera línea es la terapia antisecretora, principalmente con inhibidores de la bomba de protones. Los estudios de imágenes son deutilidad para detectar metástasis y evaluar la enfermedad quirúrgicamente resecable. Se debe hacer diagnóstico diferencial con otros tumores neuroendocrinos y causas de hipergastrinemia.

Abstract:Zollinger - Ellison syndrome is an endocrinopathy that was first described in 1955 by doctors Robert Zollinger and Edwin Ellison, who proposed the diagnostic triad that includes gastric acid hypersecretion, peptic ulcer and gastrinoma. This disease predominates in women between 50 and 60 years old. Based on the etiology, the syndrome is classified in sporadic or associated with multiple endocrine neoplasia type 1 (NEM - 1). Over half of gastrinomas are located in the duodenal wall, the pancreas is the second frequency location. There are ectopic locations, such as ovary, mesentery, liver and bile duct. Round cells, small nuclei and prominent nucleoli, are the main hispathologycal characteristics. Gastric acid hypersecretion is associated with a defect in the negative feedback inhibition of somatostatin on G antral gastrin-producing cells. Clinically, patients present abdominal pain, diarrhea, heartburn, nausea and vomiting; primarily related to the development of peptic ulcers. Diagnosis includes a measurement in serum gastrin levels and gastric pH values. The first line treatment is the antisecretory therapy, primarily proton-pump inhibitor. Imaging studies are useful to detect metastases and evaluate the surgically resectable disease. Neuroendocrine tumors and hypergastrinemia causes are the main differential diagnoses, the clinician should consider.

[Evolution of clinical ideas about Zollinger-Ellison syndrome].

The paper gives the current views of the diagnosis and treatment of Zollinger-Ellison syndrome (ZES). It underlines the importance of including ZES in differential diagnosis in patient with frequently recurrent and standard-dose proton pump inhibitor therapy-resistant erosive and ulcerative lesions of the upper gastrointestinal tract. It provides the current stepwise algorithm for the diagnosis of the pathology in question. Relevant and promising treatments in patients with ZES are considered.

Zollinger-Ellison syndrome: classical considerations and current controversies.

Zollinger-Ellison syndrome (ZES) is an endocrinopathy characterized by gastrin-secreting tumors, responsible for causing the formation of multiple, refractory, and recurrent peptic ulcers in the distal duodenum and proximal jejunum. Two main variants have been described, sporadic and those found in association with parathyroid and pituitary tumors, a genetic disorder known as multiple endocrine neoplasia-1 (MEN-1). Biochemical serum evaluation for elevated gastrin, followed by radiological or nuclear localization of the primary lesion, is mandated for establishing diagnosis. The mainstays of treatment include management of hypersecretory state with medical suppression of gastric acid production and surgical resection of primary tumor for the prevention of malignant transformation and metastatic complications. Medical therapy with proton pump inhibitors has virtually eliminated the need for acid-reducing surgical procedures. Surgical approach to sporadic and MEN-1-associated ZES varies based on our understanding of the natural history of the condition and the probability of cure; however, resection to a negative microscopic margin is indicated in both cases. Postoperative surveillance involves measurement of gastrin level, followed by imaging if elevation is detected. Re-excision of recurrent or resection of metastatic disease is a subject of controversy; however, at the present time aggressive cytoreductive approach is favored.

Current management of the Zollinger-Ellison syndrome.

In summary, ZES is a syndrome caused by gastrinoma, usually located within the gastrinoma triangle and associated with symptoms of peptic ulcer disease, GERD, and diarrhea. The diagnosis of ZES is made by measuring fasting levels of serum gastrin, BAO, and the secretin stimulation test. Because of the high association of ZES and MEN1, HPT must be excluded by obtaining a serum calcium and parathyroid hormone level. Treatment of ZES consists of medical control of symptoms with PPIs and evaluation for potentially curative surgical intervention. Noninvasive imaging studies including SRS, CT, and MRI should be performed initially to evaluate for metastases and identify resectable disease. Invasive imaging modalities such as EUS may be performed to further evaluate primary tumors. IOUS, palpation, and duodenotomy are used for intraoperative localization of gastrinomas. In patients with MEN1, surgical resection should be pursued only if there is an identifiable tumor larger than 2 cm and after surgery for the primary hyperparathyroidism (3 1/2-gland parathyroidectomy). All patients with resectable localized sporadic gastrinoma should undergo surgical exploration, even those with biochemical evidence but negative imaging studies. Tumor is most commonly found in the duodenum, and the cure rate is high. In patients with liver metastases, surgery should be considered if all identifiable tumor can be safely removed. A multidisciplinary approach including surgical and nonsurgical therapies should be taken in patients with advanced disease.

Zollinger-Ellison syndrome: recent advances and controversies.

PURPOSE OF REVIEW: To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS: Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY: This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.

Gastric neuroendocrine tumours.

BACKGROUND: Gastric neuroendocrine tumours (NETs) are increasingly recognised, and management decisions may be difficult due to an incomplete understanding of aetiology, natural history and optimum therapy. This article presents a current understanding based on recent advances in epidemiology, classification, molecular profiling, and treatment. METHODS: Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. RESULTS: Gastric NETs may be divided into three clinical prognostic groups: type I is associated with autoimmune atrophic gastritis and hypergastrinaemia, type II is associated with Zollinger-Ellison syndrome, and type III lesions are gastrin-independent, have the greatest metastatic potential and poorest prognosis. There has been an increased frequency of gastric NETs reported. Management approaches have evolved in parallel with advances in endoscopic staging and surgery, as well as improved understanding of the biology and natural history of NETs. CONCLUSIONS: Gastric NETs present a spectrum of activity from indolent tumours to metastatic malignancy. Treatment decisions for patients must be individualised and are best managed by a multidisciplinary team approach. The current evidence base is limited to small series and efforts to treat patients within clinical networks of expertise are warranted.

[Advances in the diagnosis and treatment of Zollinger-Ellison syndrome]. / Postepy w diagnostyce i leczeniu zespolu Zollingera-Ellisona.

Zollinger-Ellison syndrome is a rare disorder caused by tumor secretion of gastrin, which results in gastric acid hypersecretion and secondarily in complicated peptic ulcer and diarrhea. ZES might be associated with multiple endocrine neoplasia type 1. The two main principal therapeutic strategies are to control both the gastric acid hypersecretion and the growth of the tumor. Surgery often fails to be curative and therefore many patients requires medical therapy, mainly treatment with proton pump inhibitors. The aim of this paper was to critically discuss contemporary diagnosis and treatment of this neoplasm on the basis of progress made in recent years.

Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances.

Pancreatic neuroendocrine tumors (pNETs) comprise with gastrointestinal carcinoids, the main groups of gastrointestinal neuroendocrine tumors (GI-NETs). Although these two groups of GI-NETs share many features including histological aspects; over-/ectopic expression of somatostatin receptors; the ability to ectopically secrete hormones/peptides/amines which can result in distinct functional syndromes; similar approaches used for tumor localization and some aspects of treatment, it is now generally agreed they should be considered separate. They differ in their pathogenesis, hormonal syndromes produced, many aspects of biological behaviour and most important, in their response to certain anti-tumour treatment (chemotherapy, molecular targeted therapies). In this chapter the clinical features of the different types of pNETs will be considered as well as aspects of their diagnosis and medical treatment of the hormone-excess state. Emphasis will be on controversial areas or recent advances. The other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, because they are covered in other chapters in this volume.

Costs and risks in the management of patients with gastric acid hypersecretion.

GOALS: To define both risks and costs of optimal care of patients with gastric acid hypersecretion. BACKGROUND: The management of Zollinger-Ellison syndrome and other gastric acid hypersecretory disorders remains challenging. The optimal strategy for follow-up including gastric acid analysis, laboratory studies, and endoscopy is unknown but important given the potential complications from uncontrolled acid secretion. STUDY: Over the last 18 years, patients with gastric acid hypersecretory disorders have been followed prospectively with gastric acid analysis and endoscopy titrating oral lansoprazole and evaluating for complications. Protocol driven charges were calculated using the most recent information available. RESULTS: After 1 year of treatment optimization, 19 of 67 patients had 43 relapses, (once only in 10 patients). Risk markers for relapse included: (1) antrectomy, 67% relapsed versus 21% in unoperated patients; (2) basal acid output >5 mmol/h (risk=5.17); and (3) poor compliance. On treatment, 79% of 58 intact patients (excluding antrectomy) were lesion-free; 11% had only 1 relapse. Thus 90% were well managed with optimized lansoprazole alone. Protocol driven charges exceeded $25,000 the first year and $7000 annually thereafter. CONCLUSIONS: Relapse is infrequent and generally mild with acid secreting status closely monitored. The ideal strategy to balance costs and testing awaits further study.

Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review.

Cushing's syndrome and Zollinger-Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome. In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger-Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis. Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein. On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.

Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature.

OBJECTIVE: To report 3 cases of primary neuroendocrine tumors (PNT) of the extrahepatic biliary tree (EHBT) in patients with Zollinger-Ellison syndrome (ZES), 2 of whom had multiple endocrine neoplasia type 1 (MEN 1). METHODS: Three new cases of gastrin-producing tumors of the EHBT are presented, and the pertinent literature relating to PNT of the EHBT is reviewed. RESULTS: Eighty-one previous cases of PNT of the EHBT have been reported in the world literature, 7 of which were hormonally active and associated with peptic ulcer disease, diarrhea, or ZES. Three additional patients presented to us with ZES due to PNT of the EHBT. One patient with MEN 1 was treated with a Whipple procedure for a common bile duct gastrinoma. A second patient underwent left hepatectomy with resection of the confluence of the right and left hepatic ducts for a primary left hepatic duct gastrinoma. The second patient with MEN 1 under-went resection of a gastrinoma at the junction of the cystic duct and the common bile duct. CONCLUSION: Although PNT of the EHBT are uncommon, the association with ZES is even more so. Often, nonfunctioning tumors are diagnosed late in the course of the disease from symptoms related to biliary obstruction. Patients with ZES may be diagnosed earlier because of symptoms resulting from gastrin excess. Surgical resection is the only chance for cure and is often helpful in the palliation of symptoms.

Zollinger-Ellison syndrome: a personal perspective.

The odyssey of Zollinger-Ellison Syndrome is one of the most interesting in surgery. From the initial recognition of two patients with severe peptic ulcer disease in 1955 sprung an international dialogue on this unique disease culminating in discovery that gastrin was the hormone secreted by these pancreatic and duodenal tumors. The impact was the birth of a new area of science, "gastrointestinal endocrinology." Initially, surgeons were challenged by the complexity of the patients and the need to perform total gastrectomy to prevent death from complications of the severe ulcer disease. Later, after the discovery of proton pump inhibitors, total gastrectomy was no longer needed and the surgeon could focus treatment on tumor removal added by radioimmunoassay for gastrin and new imaging modalities. Today, we recognize that all gastrinomas have malignant potential; early surgical removal can reduce the incidence of metastases and improve survival, independent of biochemical cure, in both sporadic and familial forms of the disease.

[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.