CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:126 130 EDUCATION PRACTICE Diagnosis of the Zollinger Ellison Syndrome DAVID C. METZ Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania See related article, Poitras P et al on page 199, in this issue of CGH. A Clinical Scenario 42-year-old man is referred to you for evaluation of possible Zollinger Ellison syndrome (ZES). 1 He gives an 8-year history of heartburn, for which he has been receiving increasing doses of proton pump inhibitor (PPI) therapy. Over the past few months he has noted worsening symptoms of heartburn and regurgitation, especially at night or after large meals. His primary care physician increased his maintenance PPI dose of omeprazole from 40 mg once daily to 40 mg twice daily but his symptoms have persisted and now he also is complaining of abdominal pain that wakens him from sleep. Open-access, upper-gastrointestinal endoscopy was unrevealing but his fasting serum gastrin level was 465 pg/ml (normal, 100 pg/ml). When this result was obtained his primary care physician ordered an Octreoscan (Mallinckrodt Inc., St Louis, MO) (which was normal) and a serum chromogranin A level (which was increased at 492 pg/ml [normal, 375 pg/ml]). The patient describes no recent change in bowel habits and there is no history of anemia, weight loss, bleeding, jaundice, or dysphagia. Physical examination is within normal limits. The Problem ZES (or gastrinoma) is a rare neuroendocrine tumor of the pancreas or duodenum with an estimated annual incidence of about 0.5 per million. 2 The disease was first described in 1955 by Zollinger and Ellison as consisting of the following triad: (1) gastric acid hypersecretion in the presence of (2) fasting serum hypergastrinemia with (3) resultant fulminant peptic ulcer disease and diarrhea. 1,2 Although many patients with ZES present with more severe or complicated symptoms of peptic ulcer disease than patients with idiopathic ulceration (eg, approximately 7% present with perforation 3 ), the vast majority of ZES patients are indistinguishable from idiopathic acid-peptic patients. 2 Consequently, with the ubiquitous availability of PPI therapy, many patients with ZES are likely to be treated empirically early on in the disease course, leading to improvement in their symptoms and a potential lost opportunity for diagnosis before the development of metastatic disease. In fact, older studies have shown that the mean time to diagnosis after symptoms develop is well over 6 years, 2,4 and a recent combined study from the National Institutes of Health and Italian investigators revealed a declining rate of diagnosis and referral for ZES, possibly as a consequence of masking resulting from early empiric therapy with acid suppression. 5 As mentioned earlier, the primary danger of delaying the diagnosis of ZES is that, despite control of the hormonal syndrome (which actually may be suboptimal without gastric analysis on therapy 2,6 ), these patients still have a significant risk of tumor progression with the development of metastases and consequently a negative outcome over time. 2,7 It has been well established that early diagnosis and surgical intervention for possible cure in appropriately selected patient has a positive outcome with a roughly 30% to 40% cure rate, 8 and an improved long-term outcome whether biochemical cure is achieved or not. 2,9 In addition, most authorities believe that tumor debulking early on in the disease process also may lead to an improved long-term outcome. 9 Patients who undergo surgical resection with a resultant biochemical cure have a 90% chance of remaining disease-free after 3 years of follow-up evaluation. 10 Patients with ZES and multiple endocrine neoplasia syndrome type 1 (MEN-1), which occurs in about one quarter to one third of patients with ZES, 2 may not necessarily benefit from early surgical intervention because cure is unlikely, although surgical intervention generally is performed if there is a pancreatic mass of 2.5 cm or more in size. 2,11 It also should be noted that certain authorities favor nonsurgical management for the majority of individuals, citing a generally good prognosis for the vast majority of patients without surgical intervention, staging limitations at many institutions that may lack certain imaging modalities, and the failure of surgery to impact on the outcome in most patients unless they receive treatment at a center of excellence by an experienced surgeon or have a symptomatic mass lesion. 12 The challenge, therefore, is to identify patients with ZES as early as possible to allow accurate staging of the disease, hereditary testing as necessary, and then surgical resection for cure or debulking as indicated. 2 Hypergastrinemia Hypergastrinemia (an increased fasting serum gastrin level) is the hallmark of ZES. 2 However, there are a number of causes of this condition, which can be subdivided into 3 large groups: appropriate hypergastrinemia, inappropriate hypergastrinemia, and spurious hypergastrinemia (Table 1). Spurious Abbreviations used in this paper: BAO, basal acid output; MEN-1, multiple endocrine neoplasia syndrome type 1; PPI, proton pump inhibitor; ZES, Zollinger Ellison syndrome. 2012 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.07.012
February 2012 ZOLLINGER ELLISON SYNDROME 127 Table 1. Causes of Hypergastrinemia Appropriate hypergastrinemia Atrophic gastritis with or without pernicious anemia Antisecretory therapy (PPIs or high-dose histamine H 2 -receptor antagonist) Chronic renal failure H pylori pangastritis Vagotomy Inappropriate hypergastrinemia ZES (sporadic or associated with MEN-1) Antral-predominant H pylori infection Retained-antrum syndrome Gastric-outlet obstruction Small-bowel resection Spurious hypergastrinemia Nonfasting patient Inaccurate assay hypergastrinemia results from inaccurate testing conditions such as blood draws in nonfasting patients or the performance of inaccurate assays. 13 Appropriate hypergastrinemia implies a physiologically appropriate increase of fasting serum gastrin in response to hypochlorhydria or achlorhydria in an attempt to restore gastric acid secretory capability. 2 The most common causes of appropriate hypergastrinemia are atrophic gastritis with or without pernicious anemia and pharmacologic inhibition with PPI therapy. 2 ZES is the prototypical cause of inappropriate hypergastrinemia. 2 Under such conditions, the source of the gastrin increase (ie, the gastrinoma tumor that generally arises in the triangle of Stabile in the pancreas or duodenum 14 ; see Figure 1) is distant from the gastric antrum (ie, the usual physiological source of gastrin where it is produced by G cells). The gastrinoma causes gastric acid hypersecretion, which is not suppressed because the normal feedback inhibition pathway does not extend beyond the gastric submucosa. 15 Normally, paracrine secretion of somatostatin from D cells in the gastric submucosa inhibits G-cell release of gastrin and enterochromaffin-like cell release of histamine and switches off the drive for acid production. 15 Table 1 lists other causes of inappropriate hypergastrinemia, which always should be considered in patients with possible ZES before any intervention. It also should be noted that Helicobacter pylori gastritis causes both appropriate and inappropriate hypergastrinemia. 16 Antral predominant infection leads to D-cell dysfunction, which in turn leads to loss of G-cell suppression and inappropriate hypergastrinemia, which predisposes to duodenal ulcer disease that closely mimics ZES. 16,17 On the other hand, H pylori pangastritis causes gastric acid hyposecretion and appropriate hypergastrinemia, which predisposes to gastric ulcer disease and, in its end stages, to antral gastric cancer. 16,18 It is clear from the earlier discussion that to refine the diagnosis of ZES, serum gastrin should be measured together with an assessment of gastric acid secretory capability in the absence of antisecretory therapy and in fasting patients. 2,19 In most cases, this is accomplished easily by aspiration of gastric juice at endoscopy for ph determination using ph paper (limited by Clinical Laboratory Improvement Amendments licensing laws), although ph values that are within the gray zone of 3.0 to 6.0 are unhelpful, requiring formal gastric analysis for accurate assessment as described later in more detail. 2,10,12,20 Patients with hypergastrinemia and a low gastric ph level therefore could have ZES because the hypergastrinemia is inappropriate, whereas those with hypergastrinemia but an increased ph would more likely have an appropriate cause for the gastrin increase. 2,18,20 Thus, in the scenario described earlier, the presence of PPI therapy at a high dose alters the utility of the serum gastrin measurement and fails to provide useful information regarding the presence or absence of ZES. To confirm the presence of inappropriate hypergastrinemia in this patient, careful weaning of the antisecretory therapy will be required with a repeat serum gastrin determination together with a measure of acid secretory capability. 2,19 The moderate degree of hypergastrinemia in the case at hand ( 1000 pg/ml) but clearly well above the upper limit of normal (100 110 pg/ml in most laboratories) is quite typical of ZES. 21 Levels greater than 1000 pg/ml are not more likely to be associated with ZES than more moderately increased levels because atrophic gastritis also may be associated with very high levels of hypergastrinemia, especially in the setting of type 1 gastric carcinoids. 2,21,22 PPI-induced hypergastrinemia may be profound, especially in the setting of H pylori infection, so that the degree of hypergastrinemia per se also has limited use in distinguishing appropriate from inappropriate hypergastrinemia in general. 23 It cannot be stressed forcefully enough that PPI withdrawal to distinguish appropriate from inappropriate hypergastrinemia in patients with possible ZES is a potentially dangerous intervention that needs to be performed carefully. 2,10,12,19 As the disease is developing and before initial therapy with PPIs, gastric acid secretion increases but its potentially deleterious consequences may be mitigated to a large extent by concomitant pancreatic bicarbonate hypersecretion, which buffers the excess gastric acid that is produced. In fact, up to 30% of patients with ZES do not develop peptic ulceration and present purely with Figure 1. The Gastrinoma Triangle (of Stabile) is bound by the junction of 1) the common and cystic ducts (superiorly), 2) the second and third portions of the duodenum (inferiorly), and 3) the head and neck of the pancreas (medially). Most primary (sporadic) gastrinomas are single and arise in the duodenal wall as depicted. In MEN-1 syndrome, duodenal primaries are commonly multiple. Occasionally, solitary sporadic primary lesions develop in the pancreas (within the triangle defined above).
128 DAVID C. METZ CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2 secretory diarrhea, likely as a consequence of buffering of acid. 2,10,20 After the gastric acid hypersecretion has been controlled with PPI therapy, the stimulus for pancreatic hypersecretion may be lost and it reverts to its resting basal state. Acute withdrawal of PPI therapy in ZES patients may therefore lead to a sudden and dramatic increase in gastric acid production without the presence of a concomitant buffering capacity from the pancreas and potentially serious outcomes that can occur rapidly. Therefore, it is essential for the diagnosing physician to educate the patient and also institute a careful wean of PPI therapy under controlled circumstances to safely establish the presence of inappropriate hypergastrinemia and make the diagnosis. 2,19 Establishing Inappropriate Hypergastrinemia PPIs have a short serum half-life but a prolonged duration of action because they concentrate more than a thousand-fold in the low ph milieu of the secretory canaliculus of the parietal cell and bind covalently to actively secreting hydrogen potassium adenosine triphosphatase enzymes. 24 It is generally believed that PPIs should be withdrawn for at least a week and possibly more than 1 week to restore normal levels of gastric acid production, allowing proper measurements of gastrin and ph concomitantly. 10,12,19,20 Unless an alternative method of acid suppression is used during this wean, patients are at extreme risk for the development of severe rebound hypersecretion and peptic ulcer disease with possible complications. 19,20 Histamine H 2 -receptor antagonists have a shorter duration of action than PPIs and they should be started at sufficient doses to control acid hypersecretion as soon as the PPIs are stopped. 10,19,25 I generally prescribe oral ranitidine (or an equivalent histamine H 2 -receptor antagonist) at 450 to 750 mg every 6 hours (dependent on body habitus, degree of hypergastrinemia, and level of suspicion for ZES) 10,19,25 and I always inform the patient to use an alarm clock to ensure that the drug is taken appropriately every 6 hours rather than 4 times a day at meals and at bedtime. This maneuver reduces the period of time during which the patient is at risk from rebound hypersecretion but one cannot avoid stopping all therapy for the last 24 to 30 hours of the wean to properly exclude antisecretory drug effects from impacting on the determination of the type of hypergastrinemia that is present. 2,10,19,25 During the last 24 to 30 hours of the PPI wean, patients may use antacids ad libitum until midnight on the night before their formal serum gastrin and acid secretory measurement and they are warned that if they develop diarrhea, nausea, vomiting, or abdominal pain that they should present to the emergency room for nasogastric aspiration, which will render them safe and still able to be studied rather than for intravenous antisecretory therapy, which will defeat the process of being able to establish whether they have appropriate or inappropriate hypergastrinemia. I also generally provide the patient with a letter documenting the plan in progress for presentation to emergency room personnel if needed. On the day of evaluation patients should have a morning fasting serum gastrin drawn together with a gastric acid aspirate for ph determination or, if available, a formal gastric analysis for basal acid output determination. 2,10,19,20 I generally perform a secretin stimulation test at the same time but, as discussed in more detail later, this also must be performed together with a measurement of acid secretory capability to be most useful. Measuring gastric ph with ph paper on a gastric aspirate obtained endoscopically or after nasogastric tube insertion is performed easily but is subject to CLIA restrictions. ph determination of a gastric aspirate sample is sufficient to establish the presence of inappropriate hypergastrinemia providing that the ph is less than 3.0. 2,10,18,20 Unfortunately, however, a ph of greater than 3.0 does not exclude inappropriate hypergastrinemia and ZES because gastric acid output may still be increased if sufficient volume of gastric juice is produced. 2,19,26 Under such conditions formal gastric acid analysis will be required. A basal acid output (BAO) of greater than 15 meq/h in the presence of any level of hypergastrinemia is pathognomonic of ZES. 2,10,19,20,27 In prior years, gastric acid analysis was refined by measuring maximal acid output after gastric stimulation with subcutaneous pentagastrin (and before this betazole) and a value of greater than 48 meq/h in men and greater than 30 meq/h in women or an increased BAO to maximal acid output ratio of greater than 0.7 was believed to be highly predictive of ZES. 2,10,19,20,27 Unfortunately, pharmacologic gastric stimulants are no longer available in the United States to permit this refinement in the diagnosis of ZES. Proton Pump Inhibitor Withdrawal Is Not Always Required As was alluded to earlier, PPI withdrawal for formal assessment of hypergastrinema does have risks. Patients with a life expectancy of fewer than 10 years because of age or comorbidities or patients who are unlikely to tolerate a surgical exploration owing to comorbidities probably should not be subjected to PPI withdrawal because they are unlikely to benefit from a formal ZES diagnosis. 19 The benefits of a successful surgical intervention (by an experienced surgeon) are really only realized well into the future (beyond 10 years). 2,8,9,20 On the other hand, young healthy patients (as in the patient described in the scenario earlier) may well benefit from an accurate diagnosis and denying such individuals the potential for a surgical attempt at cure (or debulking if not curable) would not be appropriate. The dilemma therefore, is to balance the risks of not making a formal diagnosis with the risks of causing hypersecretion and morbidity. Other Tests for Zollinger Ellison Syndrome Secretin receptors are present on both gastrinoma cells as well as antral G cells. 2,28 When stimulated by intravenous secretin (2 U/kg if using Kabi secretin or 0.4 g/kg if using recombinant secretin), both cell types release gastrin, which then can be measured serially over 30 minutes. 2,10,28,29 Traditionally, ZES is said to be characterized by a paradoxical increase in serum gastrin levels after secretin stimulation (an increase above basal levels of 110 200 pg/ml depending on which criteria are used). 10,28,29 In normal individuals, the gastrin response to secretin stimulation is blunted because the secretin binds to both somatostatin-releasing D cells as well as antral G cells and a lower level increase, or even sometimes a decrease, in serum gastrin levels occurs owing to the paracrine inhibition of G-cell gastrin release by somatostatin (similar to G cells, gastrinoma cells also contain somatostatin receptors but they are not closely associated with D cells and somatostatin is
February 2012 ZOLLINGER ELLISON SYNDROME 129 a paracrine peptide). However, patients with G-cell hyperplasia (individuals with H pylori infection, gastric atrophy, or chronic PPI exposure) also may have a robust response to secretin stimulation leading to false-positive secretin testing. 2,30 In fact, achlorhydria is a well-recognized cause of false-positive secretin testing such that secretin testing (positive in only 87% of patients with ZES anyway 28 ) is unhelpful in confirming or refuting the presence of ZES even if hypergastrinemia is present (without a concomitant measure of acid secretory capability). Gastrinoma cells also show surface somatostatin receptors. 2,31 Somatostatin has a very short serum half-life but octreotide (a synthetic circular octapeptide somatostatin analogue) has a longer half-life, enabling its use therapeutically to reduce hormone secretion or as a carrier molecule for radioreceptor imaging or therapy. 32 Octreotide preferentially binds to type 2 somatostatin receptors, which are densely present on the surface of gastrinoma cells. 31 Although an Octreoscan is the most sensitive test for the localization of both primary and metastatic gastrinomas, 2,32 its sensitivity for identifying a primary tumor is no higher than 70% so that negative testing cannot exclude the presence of ZES. 32 A negative Octreoscan such as occurred in the case in point also should not deter surgical exploration in patients with documented inappropriate hypergastrinemia without other obvious causes for the condition because gastrinomas will be discovered in more than 95% of appropriately worked-up patients by an experienced surgeon. 2,20,29,33 Furthermore, an Octreoscan is an expensive test and, because most patients with hypergastrinemia do not have ZES, this expense often can be averted by assessing the patient for inappropriate versus appropriate hypergastrinemia before submitting them to expensive imaging studies. Endoscopic features of patients with ZES may include hypertrophic folds owing to prolonged stimulation of the oxyntic mucosa by gastrin, gastric (type II) carcinoid tumors in patients with MEN-1 syndrome, and, occasionally, direct visualization of duodenal gastrinomas. 2,4,11,12,21 However, the complete absence of all these features is not at all unusual. In addition, gastric (type I) carcinoids also occur in atrophic gastritis and hypertrophic folds occur in H pylori infection as well as other infiltrating conditions. Consequently, endoscopic features may not be useful in distinguishing ZES from other causes of peptic ulceration or hypergastrinemia. In the case at hand endoscopy was unrevealing. Chromogranin A is believed to be an important marker of neuroendocrine tumors in general and gastrinoma in particular but its measurement also is fraught with problems if the test is performed in an inappropriate context. 34,35 False-positive increase of serum chromogranin A levels are well described in patients with liver disease, renal failure, and G-cell hyperplasia induced by gastric atrophy and, most importantly in the current context, by chronic PPI therapy because G cells are neuroendocrine cells in their own right. 34,35 Much also has been written about the lack of accuracy of certain chromogranin A assays and different normal ranges based on the types of assays performed. 34,35 Recommendations Patients similar to the individual described earlier are likely to benefit from an early diagnosis of ZES and a surgical exploration. The earlier discussion explains why there really is no avoiding a PPI withdrawal to prove inappropriate hypergastrinemia in such patients. An Octreoscan is an expensive alternative first step before PPI withdrawal to document inappropriate hypergastrinemia but secretin and chromogranin A testing are unhelpful. Careful PPI withdrawal with fasting serum gastrin determination concomitantly with gastric acid analysis (ph or BAO determination) and secretin stimulation testing under controlled circumstances to limit the potential for serious adverse events is the mainstay of diagnosis. Once inappropriate hypergastrinemia has been confirmed other conditions, especially antral-predominant H pylori gastritis, should be excluded, the presence or absence of MEN-1 syndrome should be considered, and exploratory surgery should be contemplated after cross-sectional imaging studies are obtained in appropriate (healthy, young) individuals. References 1. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955;142:709 723; discussion, 724 728. 2. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008;135: 1469 1492. 3. Waxman I, Gardner JD, Jensen RT, et al. Peptic ulcer perforation as the presentation of Zollinger Ellison syndrome. Dig Dis Sci 1991;36:19 24. 4. Stage JG, Stadil F. The clinical diagnosis of the Zollinger Ellison syndrome. Scand J Gastroenterol Suppl 1979;53:79 91. 5. Corleto VD, Annibale B, Gibril F, et al. Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger Ellison syndrome? Aliment Pharmacol Ther 2001;15:1555 1561. 6. Maton PN, Frucht H, Vinayek R, et al. Medical management of patients with Zollinger Ellison syndrome who have had previous gastric surgery: a prospective study. Gastroenterology 1988;94: 294 299. 7. Weber HC, Venzon DJ, Lin JT, et al. Determinants of metastatic rate and survival in patients with Zollinger Ellison syndrome: a prospective long-term study. 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130 DAVID C. METZ CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 2 17. Metz DC, Weber HC, Orbuch M, et al. Helicobacter pylori infection. A reversible cause of hypergastrinemia and hyperchlorhydria which may mimic Zollinger Ellison syndrome. Dig Dis Sci 1995; 40:153 159. 18. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404:398 402. 19. Dhillo WS, Jayasena CN, Lewis CJ, et al. Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists. Ann Clin Biochem 2006;43:153 155. 20. Wolfe MM, Jensen RT. Zollinger Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med 1987;317: 1200 1209. 21. Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore) 2006;85:295 330. 22. Borch K, Renvall H, Liedberg G, et al. Relations between circulating gastrin and endocrine cell proliferation in the atrophic gastric fundic mucosa. Scand J Gastroenterol 1986;21:357 363. 23. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996;334:1018 1022. 24. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 2006;23(Suppl 2):2 8. 25. Metz DC, Pisegna JR, Fishbeyn VA, et al. Control of gastric acid hypersecretion in the management of patients with Zollinger Ellison syndrome. World J Surg 1993;17:468 480. 26. Pratha VS, Hogan DL, Lane JR, et al. Inhibition of pentagastrinstimulated gastric acid secretion by pantoprazole and omeprazole in healthy adults. Dig Dis Sci 2006;51:123 131. 27. Roy PK, Venzon DJ, Feigenbaum KM, et al. Gastric secretion in Zollinger Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine (Baltimore) 2001;80:189 222. 28. Frucht H, Howard JM, Slaff JI, et al. Secretin and calcium provocative tests in the Zollinger Ellison syndrome. A prospective study. Ann Intern Med 1989;111:713 722. 29. Metz DC, Buchanan M, Purich E, et al. A randomized controlled crossover study comparing synthetic porcine and human secretins with biologically derived porcine secretin to diagnose Zollinger Ellison syndrome. Aliment Pharmacol Ther 2001;15: 669 676. 30. Feldman M, Schiller LR, Walsh JH, et al. Positive intravenous secretin test in patients with achlorhydria-related hypergastrinemia. Gastroenterology 1987;93:59 62. 31. Reubi JC, Häcki WH, Lamberts SW. Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors. J Clin Endocrinol Metab 1987;65:1127 1134. 32. Gibril F, Reynolds JC, Chen CC, et al. Specificity of somatostatin receptor scintigraphy: a prospective study and effects of falsepositive localizations on management in patients with gastrinomas. J Nucl Med 1999;44:539 553. 33. Norton JA, Doppman JL, Jensen RT. Curative resection in Zollinger Ellison syndrome. Results of a 10-year prospective study. Ann Surg 1992;215:8 18. 34. Goebel SU, Serrano J, Yu F, et al. Prospective study of the value of serum chromogranin A or serum gastrin levels in the assessment of the presence, extent, or growth of gastrinomas. Cancer 1999;85:1470 1483. 35. Vezzosi D, Walter T, Laplanche A, et al. Chromogranin A measurement in metastatic well-differentiated gastroenteropancreatic neuroendocrine carcinoma: screening for false positives and a prospective follow-up study. Int J Biol Markers 2011;26:94 101. Reprint requests Address requests for reprints to: David C. Metz, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, 3rd Floor, Philadelphia, Pennsylvania 19104. e-mail: david.metz@uphs.upenn.edu; fax: (215) 349-5915. Conflicts of interest The author discloses no conflicts.