Catching the Zebra: Clinical Pearls and Pitfalls for the Successful Diagnosis of Zollinger-Ellison Syndrome.

Zollinger-Ellison syndrome (ZES) results from an ectopic gastrin-secreting tumor leading to peptic ulcer disease, reflux, and chronic diarrhea. While early recognition portends an excellent prognosis with >80% survival at 15 years, symptoms are often nonspecific making the diagnosis difficult to establish. Diagnosis involves a series of tests, including fasting gastrin, gastric pH, chromogranin A, and secretin stimulation. Performing these tests in the correct sequence and at the proper time is essential to avoid inaccurate results. Tumor localization is equally nuanced. Although providers have classically used 111indium-radiolabeled octreotide with somatostatin receptor scintigraphy to evaluate tumor size and metastases, recent studies have shown superior results with newer imaging modalities. In particular, 68gallium (68Ga)-labeled somatostatin radiotracers (i.e., 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE) used with positron emission tomography/computed tomography can provide excellent results. Endoscopic ultrasound is another useful modality, particularly in patients with ZES in the setting of multiple endocrine neoplasia type 1. This review aims to provide clinicians with an overview of ZES with a focus on both clinical presentation and the proper utilization of the various biochemical and imaging tests available.

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.

Mechanism of acid hypersecretion post curative gastrinoma resection.

BACKGROUND: Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown. AIM: The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome. METHODS: Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors. RESULTS: Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038). CONCLUSIONS: Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown.

Reoperative surgery for the Zollinger-Ellison syndrome.

It is clear that a properly performed initial operation is the key to success in the management of a patient with ZES. However, reoperation is frequently a consideration in the management of patients with ZES because high rates of persistent and recurrent disease are manifest even with modern imaging and surgical approaches. In carefully selected patients, reoperation can result in durable biochemical cure and improved survival and should be considered. A thorough knowledge of the natural history of the sporadic form of ZES and ZES in the context of MEN-1, patterns of presentation, and sites of metastases are necessary to achieve the best outcome in patients with this unusual disease.

Prospective evaluation of quality of life in patients with Zollinger-Ellison syndrome.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is associated with complicated ulcer disease of the upper gastrointestinal tract. While management of ZES has dramatically improved with proton pump inhibitor therapy, quality of life in medically treated patients has not been evaluated. METHODS: Over a 3-year period, 52 patients with ZES were prospectively evaluated at 6-month intervals with upper endoscopy and gastric acid analysis to evaluate the efficacy of current drug therapy and completion of SF36v2 forms. At each 6-month visit, patients' medication and problem lists were reviewed, comorbidities assessed, and any gastrointestinal symptoms recorded. Co-morbidity was represented as a simple illness count for the main analysis. The chronic disease score and the Charlson index were used for sensitivity analyses. RESULTS: The unadjusted norm-based estimate of mental component score (MCS) for 52 patients with ZES (mean age 58, 65% male) was 49.8 (95% CI 46.4, 53.1). The unadjusted estimate of the physical component score (PCS) was 42.3 (95% CI 38.9, 45.7). As the number of illnesses or number of medications increased, there was a monotonic decrease in PCS scores. With multivariable adjustment, the coefficient for number of medications became non-significant. An increase in each of the co-morbidity indexes was associated with a decrease in PCS. Results did not vary by representation of co-morbidity. MCS was not significantly different from the general population. CONCLUSIONS: Patients with medically managed ZES have norm-based estimates of the mental component scores as measured by the SF-36v2 that approximate normal values, while the physical component scores were decreased with this reduction largely explained by co-morbid illness.

Surgical management of Zollinger-Ellison syndrome; state of the art.

Much has been learned about the diagnosis and treatment of Zollinger-Ellison Syndrome (ZES), and certain questions require further investigation. Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated. The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy. Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases. All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure. Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm. The role of Whipple procedure, especially for MEN-1 cases, should be explored further. Laparoscopic and endoscopic treatments are more experimental, but may have a role.

Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features.

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Endocrine tumours of the stomach.

Gastric endocrine tumours (gastric carcinoids) usually grow from enterochromaffin-like (ECL) cells. Three types of tumour may be distinguished on the basis of the background gastric pathology: type I, which develops in atrophic body gastritis (ABG); type II, which is associated with multiple endocrine neoplasia and Zollinger-Ellison syndrome; and the sporadic type III, which is not associated with any background pathology. This classification plays a major role in determining the optimal approach to these diseases. In fact, type I carcinoids can be considered to be benign lesions, with exceptional risk of metastases. Type II, in contrast, may be associated with distant metastases, which are also common in type III carcinoids. The therapeutic approach is based mainly on endoscopic excision and somatostatin analogues in types I and II, or on surgical resection in type III. Both types I and II grow under the stimulus of hypergastrinaemia through a well-described sequence. However, gastrin is sufficient to cause ECL cell hyperplasia and dysplasia, but not transformation, which is due to menin defects in MEN-I patients, or to other unknown alterations in ABG. Several other candidates--including Bcl2, p53 and MMP9--have been linked with carcinoid initiation and progression. The biology of type III tumours which are not associated with hypergastrinaemia is still poorly understood.

Duodenal neuroendocrine tumors: Classification, functional syndromes, diagnosis and medical treatment.

Duodenal neuroendocrine tumors (NETs) comprise 2-3% of all GI endocrine tumors and are increasing in frequency. These include gastrinomas, somatostatinomas, nonfunctional NETs, gangliocytic paragangliomas, and poorly differentiated NE carcinomas. Although, the majority are nonfunctional, these tumors are a frequent cause of Zollinger-Ellison syndrome and can cause other clinical hormonal syndromes (carcinoid, Cushing's, etc.). In this chapter, their epidemiology, clinical aspects, localization, diagnosis and medical treatment are reviewed including the latest advances in each area.

Endocrine tumours of the pancreas.

Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in 100,000 of the population, representing 1-2% of all pancreatic neoplasms. Some of the tumours may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel-Lindau (vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines released. Besides specific markers such as insulin, there are also general tumour markers such as chromogranin A, which is the most valuable marker and has been reported to be increased in plasma in 50-80% of patients with EPTs and correlates with tumour burden. The location of endocrine tumours of the pancreas includes different techniques, from endoscopic investigations to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin analogues and alpha-interferon. None of these can cure a patient with malignant disease. In future, therapy will be custom-made and based on current knowledge of tumour biology and molecular genetics.

Gastrinoma de localización anatómica "normal" / Gastrinoma of "normal" anatomic location

No disponible

Risk factors for esophagitis in extreme acid hypersecretors with and without Zollinger-Ellison syndrome.

BACKGROUND & AIMS: Whereas severe duodenal ulcer is the hallmark of acid hypersecretion in Zollinger-Ellison syndrome (ZE) and similar states, the esophagus also is at high risk. We quantified the incidence of esophagitis and various risk factors that might contribute to it. METHODS: Sixty-eight acid hypersecretors (basal acid output >15 mmol/h), 50 patients with ZE, and 18 patients without ZE with normal gastrin levels were studied by gastric analysis, serum gastrin levels, and endoscopy. In 44 of 68 patients, esophageal manometry was performed after the esophagus had healed. RESULTS: Erosive esophagitis, grade 2 or worse, was found in 65%; an additional 15% had heartburn only, for a total reflux disease incidence of 80%. ZE accounted for 95% of severe esophagitis. Patients with and without esophagitis had the same high overnight fasting gastric residual volume and acidity, as well as basal and peak acid and pepsin outputs. However, patients with esophagitis had a lower median lower esophageal sphincter pressure (LESP) of 15.5 vs. 23 mm Hg in those without symptoms; the critical discriminator threshold was 16 mm Hg. Multivariate analysis further identified frequent vomiting and obesity as positive predictors of esophagitis, whereas Helicobacter pylori was a strong negative predictor (odds ratio, 0.16), possibly related to an elevated LESP in patients infected with H. pylori. CONCLUSIONS: Erosive esophagitis is very common in acid hypersecretors. Identified risk factors that could promote abnormal esophageal exposure to the high acid and pepsin levels in our population of hypersecretors were vomiting, LESP < 16 mm Hg, and obesity, whereas H. pylori appeared to protect the esophagus not by reduced acid, but through an elevated LESP.

Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature.

In patients with multiple endocrine neoplasia type 1 (MEN1), the most common functional pancreatic endocrine tumor (PET) syndrome is Zollinger-Ellison syndrome (ZES). ZES has been well studied in its sporadic form (that is, without MEN1); however, there are limited data on patients with MEN1 and ZES (MEN1/ZES), and the long-term natural history is largely unknown. To address this issue we report the results of a prospective long-term National Institutes of Health (NIH) study of 107 MEN1/ZES patients and compare our results with those of 1009 MEN1/ZES patients in 278 case reports and small series in the literature. Patients were clinically, radiologically, and biochemically evaluated yearly for all MEN1 manifestations (mean follow-up, 10 yr; range, 0.1-31 yr). Compared with patients from the literature, the NIH MEN1/ZES patients more frequently had pituitary (60%) and adrenal (45%) disease and carcinoid tumors (30%), but had equal frequency of hyperparathyroidism (94%), thyroid disease (6%), or lipomas (5%). Twenty-five percent of both the NIH and the literature patients lacked a family history of MEN1; ZES was the initial clinical manifestation of MEN1 in 40%. ZES onset preceded the diagnosis of hyperparathyroidism in 45%. However, ZES was rarely (8%) the only initial manifestation of MEN1 if careful testing was done. ZES occurred before age 40 years in 50%-60% of the current patients, in contrast to older studies. The diagnosis of ZES is delayed 3-5 years from its onset and is delayed as long as in sporadic ZES cases. Pituitary disease and carcinoid tumors (gastric > bronchial, thymic) are more frequent than generally reported, whereas a second functional PET is uncommon. In patients with MEN1/ZES without a family history of MEN1, the MEN1 manifestations are not as severe. This study shows that MEN1/ZES patients differ in many aspects from those commonly reported in older studies involving few MEN1/ZES patients. In this study we have identified a number of important clinical and laboratory features of MEN1/ZES that were not previously appreciated, which should contribute to earlier diagnosis and improve both short- and long-term management.

Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome?

BACKGROUND: Proton pump inhibitors are potent acid suppressants which, at normal doses, can result in hypergastrinaemia in patients with idiopathic oesophageal reflux disease and in the control of symptoms in most patients with gastrinomas. Therefore, their use could delay or mask the diagnosis of gastrinoma. AIM: To investigate whether the widespread use of proton pump inhibitors masks or complicates the diagnosis of gastrinoma. SUBJECTS AND METHODS: Data from two centres with different referral criteria for suspected gastrinomas were analysed (Gastroenterology Unit, Rome, Italy and National Institutes of Health, Bethesda, MD, USA). The number of referrals and the number of new patients with gastrinoma diagnosed in the years prior to the widespread use of proton pump inhibitors (1986-1992) were compared with the numbers since proton pump inhibitors became widely available (1993-1998). RESULTS: The decrease in referral rate (P=0.0009) and the decrease in the annual rate of gastrinoma diagnosis (P=0.0020) at both centres correlated with the increased use of proton pump inhibitors. At the Italian centre, there was a 62% decrease in annual referrals (P < 0.0001) in the post-proton pump inhibitor period, relative to the pre-proton pump inhibitor period, whereas there was an increase in the rate of referral of other gastrointestinal endocrine tumours. The number of new cases of gastrinoma diagnosed decreased by 40%. At the US centre, the referral rate decreased by 28% (P=0.024) in the post-proton pump inhibitor period. There was also a 43% decrease in the number of new cases diagnosed annually in the post-proton pump inhibitor period (P=0.0012). There was a 2.6-fold increase in the post-proton pump inhibitor period in the percentage of referrals with a false diagnosis of gastrinoma as the cause of hypergastrinaemia (P=0.0040). CONCLUSIONS: In both referral centres, less patients have been referred with a possible diagnosis of gastrinoma and fewer new patients with gastrinoma have been diagnosed since proton pump inhibitors became widely available. These data support the conclusion that, since proton pump inhibitors have been released, the diagnosis of gastrinoma has been masked and will probably be delayed, with the result that patients with gastrinoma will be diagnosed at more advanced stages in their disease course.

Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localizations on management in patients with gastrinomas.

UNLABELLED: Somatostatin receptor scintigraphy (SRS) is being increasingly used both for localization and, in some cases, diagnosis of various diseases. There are no prospective studies of its specificity or occurrence of false-positive results and their effects on management. This study was designed to address both of these issues. METHODS: Over a 40-mo period, 146 consecutive patients with Zollinger-Ellison syndrome (ZES) undergoing 480 SRS examinations were studied prospectively. Patients were admitted at least yearly and underwent SRS as well as conventional imaging studies (ultrasonography, CT, MRI) and angiography, if necessary. All admissions were assigned to one of five different clinical categories in which imaging studies had different purposes. SRS localizations were classified as true-positive or false-positive based on preset criteria. A false-positive result was determined to change clinical management based on five preset criteria. RESULTS: Of all SRS examinations, 12% resulted in a false-positive localization for a neuroendocrine tumor or its metastases, resulting in a sensitivity of 71%, specificity of 86% and positive and negative predictive values of 85% and 52%, respectively. Extra-abdominal false-positive localizations (2/3) were more common than intra-abdominal (1/3). Thyroid disease, breast disease and granulomatosis lung disease were the most frequent causes of extra-abdominal false-positive localizations. Accessory spleens, localization to previous operative sites, renal parapelvic cysts and various procedural aspects were the most frequent causes of intra-abdominal false-positive localizations. Of all SRS studies, 2.7% resulted in a false-positive result that altered management. CONCLUSION: False-positive SRS localization occurs in 1 of 10 patients with ZES. By having a thorough understanding of diseases or circumstances that result in false-positive localization and comparing the SRS result with the clinical context, the percentage of patients in whom false-positive localization results in altered management can be reduced to below 3% and the correct diagnosis made in almost every case.

The gastrinoma/Zollinger-Ellison syndrome: statistical evaluation of a Japanese series of 359 cases.

The diagnostic modalities and management of gastrinoma/Zollinger-Ellison syndrome (ZES) have been markedly modified and improved over the past 15 years. To evaluate the present status of this disease, in terms of various clinicopathologic features, we collected 359 Japanese cases of gastrinoma/ZES from the literature. We found a decreasing incidence (from 74.7% in 1965-1980 to 34.2% in 1981-1995) of multiple surgeries and a decreasing rate (from 94.3% in 1965-1980 to 83.5% in 1981-1995) of ZES associated with gastrinoma. There was an increasing rate (from 12.6% in 1965-1980 to 48.9% in 1981-1995) of correct preoperative diagnosis. (All these differences were significant; P < 0.01). In 1981-1995, there was a high incidence (51. 1%) of small tumors (20 mm or less) and a high rate (39.5%) of metastases, and a relatively favorable postoperative outcome (10-year survival rate of 63.7%); P < 0.05. The diagnosis and treatment of gastrinoma/ZES have been markedly improved by increased rates of curative surgery, and more favorable postoperative outcomes will be expected in decades to come.

Processing-independent analysis in the diagnosis of gastrinomas.

BACKGROUND: This study evaluates whether a new analytic principle, processing-independent analysis (PIA), offers better specificity and sensitivity than the conventional gastrin radioimmunoassay in the diagnosis of gastrinomas. METHODS: Plasma concentrations of alpha-amidated gastrins and the total progastrin product were measured with radioimmunoassay and with PIA, respectively, in 512 samples taken for gastrin measurement and in a selected group of gastrinoma patients (n=10). RESULTS: Among the 512 patients were 9 with gastrinomas. In plasma from these patients the median degree of amidation (ratio of alpha-amidated gastrins to total progastrin product) was 75% (range, 25-98%), whereas in the other groups the medians varied from 41% to 86%. In the second group of gastrinoma patients all had a degree of amidation of less than 50%. CONCLUSIONS: In screening for gastrinomas PIA offered no diagnostic advantages in comparison with conventional gastrin radioimmunoassay. However, in selected patients who in spite of normal or slightly increased concentrations of amidated gastrins were still suspected of having gastrinoma, additional measurement of the total progastrin product showed incomplete processing of progastrin and thus proved helpful in establishing the diagnosis.