Sporadic Zollinger-Ellison Syndrome Research Articles

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.

Zollinger-Ellison Syndrome - review

Introduction and purpose&#x0D; Zollinger-Ellison syndrome (ZES) is a constellation of symptoms that includes gastric ulcer, gastroesophageal reflux disease (GERD), and chronic diarrhea. They are caused by the presence of gastrinoma, which is a neuroendocrine tumor that secretes gastrin. Gastrinoma is most often found in the duodenum and pancreas. ZES occurs sporadically in about 80% of cases, while in 20-25% it is a component of multiple endocrine neoplasms (MEN1). It is malignant in 60-90% of cases. The aim of the study is to present the typical clinical course of ZES, the diagnostic path and current therapeutic recommendations.&#x0D; Description of the state of knowledge &#x0D; ZES is present in about 0.1% -1% of patients with peptic ulcer disease. The direct cause of symptoms in patients with ZES is excessive gastric secretion stimulated by ectopic gastrin. Excess gastric acid damages the gastric mucosa and small intestine and disrupts the transport of fats, leading to the development of diarrhea. Other common symptoms include abdominal pain, nausea, or more rarely severe complications of GERD or peptic ulcer disease. Diagnostics include measurement of fasting serum gastrin, measurement of gastric pH, and assessment of basal gastric acid production.&#x0D; Summary &#x0D; In pharmacological treatment, proton pump inhibitors (PPIs) are the first-line drugs to control excessive gastric acid secretion in patients with ZES. Other therapeutic options include histamine receptor antagonists or somatostatin analogues. Surgical intervention remains the only possible causal treatment. In the case of sporadic ZES routine exploratory laparotomy with curative intent is recommended. In the group of patients with coexisting MEN-1 syndrome, surgical intervention is reserved for patients with tumors&gt; 2 cm.

SUN-907 Dual Ectopic Gastrin and ACTH Secretion Leading to Combined Zollinger-Ellison Syndrome and Cushing’s Syndrome in a Patient with Metastatic Neuroendocrine Pancreatic Tumor

Background:Zollinger-Ellison Syndrome (ZES) is caused by ectopic secretion of gastrin from a gastrinoma. The annual incidence of gastrinomas is 0.5 to 2 per million population1. Although 17-30% of gastrinomas will stain positive for both gastrin and ACTH, the clinical manifestation of both ZES and Cushing’s syndrome is rare. In a study by Maton et al., 3 of 59 patients (5%) with sporadic ZES (not MEN1) had Cushing’s syndrome as well2.Clinical Case:A 63yo woman with DM2 presented with persistent diarrhea for 2 years, and was diagnosed with ZES with a gastrin level of 1359 pg/mL (<100 pg/mL). A CT A/P showed a 3.8 cm pancreatic tail mass with multiple liver lesions. These lesions showed positive uptake on octreoscan, and a biopsy was positive a pancreatic neuroendocrine (NE) tumor. Her diarrhea was controlled with a PPI and no other intervention was made.7 months later, she experienced severe worsening of her DM control despite aggressive medication titration. Due to new confusion and lethargy, she presented acutely to the ED. Labs showed metabolic alkalosis and profound hypokalemia with a CO2 38 mmol/L (22 - 31 mmol/L), venous pH 7.58 (7.32 - 7.42) and K 2.1 mmol/L (3.5 – 5.0 mmol/L). Her skin was diffusely hyperpigmented, and she had numerous cushingoid features on exam including supraclavicular fat pads, round face, thin skin and thin extremities. A subsequent cortisol level was found to be 125 mcg/dL (AM [6-10 am] 4.8 – 19.5 mcg/dL) with an ACTH of 1081 pg/mL (6-50 pg/mL).She was not an optimal candidate for adrenalectomy given previous abdominal surgeries. After an octreotide drip (total 1475 mcg in 24 hrs) failed to reduce cortisol levels, metyrapone 250 mg q6h was started which led to an immediate and significant reduction in cortisol (209 to 38 mcg/dL), improved quality of life and significant reduction in her insulin and K supplementation requirement.Conclusion:We present a rare case of a dual gastrin and ACTH-secreting metastatic pancreatic NE cancer, in which overt ZES preceded the relatively abrupt onset of clinical Cushing’s syndrome. Similar to Babu et al., the initial presentation was dominated by worsening DM control3. Despite the octreoscan positivity, cortisol production was not appreciably blocked by octreotide but was well controlled by metyrapone.As seen in other cases, we again highlight the pluripotency of NE tumors and the ability to change hormone production. We also present the unique circumstance this patient faced for treatment options as she was not an optimal candidate for surgery.Reference:1. Oberg K. Pancreatic endocrine tumors. Semin Oncol. 2010 Dec;37(6):594-618.2. Maton PN, Gardner JD, Jensen RT. Cushing’s syndrome in patients with the Zollinger-Ellison syndrome. N Engl J Med. 1986 Jul 3;315(1):1-5.3. Babu AR, Dwarakanathan AA. Cushing’s syndrome from ectopic production of corticotropin by a metastatic gastrinoma. Endocr Pract. 2003 May-Jun;9(3):229-32.

Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies.

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.

Multiple gastrinomas of the duodenum in a patient with sporadic Zollinger-Ellison syndrome

Multiple gastrinomas of the duodenum in a patient with sporadic Zollinger-Ellison syndrome

Value of Surgery in Patients With Negative Imaging and Sporadic Zollinger-Ellison Syndrome

To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies. Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group. Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results. Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival. Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

Importance of Surveillance for Multiple Endocrine Neoplasia-1 and Surgery in Patients With Sporadic Zollinger–Ellison Syndrome

Zollinger-Ellison syndrome (ZES) is a rare disorder characterized by gastrin-secreting tumors of the gastrointestinal tract and gastric acid hypersecretion. There is controversy over the best way to manage these patients; we investigated outcomes of patients with different forms of the disease, who did and did not undergo surgery. We performed a retrospective chart review of patients with ZES associated with multiple endocrine neoplasia type 1 (MEN-1) (n = 16) and those with sporadic ZES (n = 33) seen at a tertiary care center from August 1994 to January 2012. Cox proportional hazards modeling was used to compare survival times among groups, based on treatment with surgery (n = 34) and the presence of MEN-1 (n = 9 with surgery; n = 7 without surgery). Differences were compared using the unpaired Student t test and the Fisher exact test. Patients with MEN-1 syndrome-associated ZES presented at a younger age than patients with sporadic ZES (34.9 vs 45.7 y, respectively; P < .05) and were diagnosed at a younger age (39.3 vs 49.7 y, respectively; P < .01), yet lived a similar number of years (55.9 vs 55.1 y, respectively; P = .91). None of the patients with MEN-1-associated ZES died of progressive disease, compared with 86% of deaths among patients with sporadic ZES (P < .05). Lymph node involvement, detected during surgery, increased the risk of metastasis to liver (P = .13) and lack of cure by surgery (P = .01). Surgery reduced all-cause mortality (hazard ratio, 0.11; 95% confidence interval, 0.2-0.6; P = .011) and disease-related mortality (hazard ratio, 0.14; 95% confidence interval, 0.2-0.84; P = .032) of patients with sporadic, but not MEN-1 syndrome-associated, ZES. The presence of MEN-1 is associated with earlier onset and diagnosis of ZES, but a benign clinical course that rarely results in disease-related death; surgery therefore can be deferred for these patients. However, 86% of deaths among patients with sporadic ZES are attributed to disease-related causes, and mortality is reduced by early surgical intervention. Patients with sporadic ZES should undergo surgery soon after diagnosis.

Surgical Treatment of Zollinger-Ellison Syndrome

Gastrinomas are functional endocrine duodenopancreatic tumors and are responsible for the Zollinger-Ellison-syndrome (ZES). Although most gastrinomas grow slowly, 60–90% are malignant [1]. The natural course of sporadic ZES is more aggressive than of MEN1ZES with 15 years survival rates of 70-80 and 100% [2]. Patients with metastatic sporadic gastrinoma have 5-year survival rates of only 20– 38%. Surgery is the only way to cure ZES. In this editorial the surgical management of sporadic and MEN-1 associated gastrinomas will be discussed.

Zollinger-Ellison syndrome associated with a history of alcohol abuse: Coincidence or consequence?

This 47-year observational study suggests that sporadic Zollinger-Ellison (Z-E) syndrome, particularly duodenal wall gastrinomas (DWG), is associated with a history of alcohol abuse. Thirty-nine consecutive Z-E patients were followed from 1962 through 2010. The drinking patterns of these patients were assessed and compared with 3,786 community controls. Thirty-five patients had extrapancreatic gastrinomas (34 DWG and/or paraduodenal lymph nodes, 1 antral gastrinoma). Total gastrectomy was done in 24; 9 underwent less extensive operations to remove DWG, and 2 patients had no operations. There were no deaths from tumor progression. Four patients presented with pancreatic gastrinoma (PG) and liver metastasis, all died from tumor progression. Alcohol abuse (>50 g/d) was documented in 81% of patients with DWG and/or paraduodenal lymph nodes. The drinking patterns (drinks per day) of DWG patients were significantly different: DWG vs community control-abstainers, 3% vs 24%; 1-2 drinks, 16% vs 62%; 3-5 drinks, 29% vs 12%; and ≥ 6 drinks, 52% vs 2.5% (P < .01). Alcohol abuse is strongly associated with and may be a risk factor for sporadic Z-E with extrapancreatic DWG. Liver metastases and tumor deaths were not observed in this subgroup, supporting the concept that DWG and PG are different tumor entities.

Reoperative Surgery in Sporadic Zollinger-Ellison Syndrome: Longterm Results

Most patients with Zollinger-Ellison Syndrome (ZES), even those in whom gastrinoma is found and resected at initial operation, will suffer from persistent or recurrent disease in longterm followup. There is currently no consensus about managing patients with recurrent or persistent ZES. Our unit has historically maintained an aggressive approach toward monitoring and reoperation for patients with sporadic ZES. We performed a review of a consecutive series of patients evaluated and managed at our institution between 1970 and 2007 for ZES. "Biochemical cure" was defined as normal serum gastrin assays and negative imaging studies. Reoperations were performed for elevations in serum gastrin assays and positive findings on imaging studies. Fifty-two patients with sporadic ZES were analyzed. Median followup was 14 years. Among patients with sporadic ZES, 37 patients underwent operative management. The most common operations were resection of duodenal gastrinoma (n=8) and total gastrectomy (n=7). Nine patients underwent 15 reoperations for recurrent or persistent disease. "Biochemical cure" was obtained in four patients (44%) undergoing reoperation for ZES. Three of these patients remained without evidence of recurrence at 4, 9, and 12 years after their curative re-resection. Only one of nine patients who underwent reoperation died of metastatic gastrinoma. Primary and reoperative surgery in patients with sporadic ZES results in a significant rate of "biochemical cure." In selected patients with recurrent or persistent disease, reoperation for resection of gastrinoma is associated with excellent longterm survival and is warranted.

Pathologie des Insulinoms und des Gastrinoms: Lokalisation, Größe, Multizentrizität, Assoziation mit der multiplen endokrinen Neoplasie Typ I und Malignität

The pathology of insulinoma and gastrinoma was studied in 81 patients (31 men, 50 women, mean age 48.4 years) suffering from persistent hyperinsulinaemic hypoglycaemia, and in 44 patients (28 men, 16 women, mean age 48.5 years) with Zollinger-Ellison syndrome. Insulinomas were seen in the pancreas of all patients with persistent hyperinsulinaemic hypoglycaemia. In 70 of the 81 patients the insulinoma was solitary, whereas six patients had multiple insulinomas. In five patients with multiple endocrine neoplasia type I, multiple endocrine tumours of the pancreas were visible, only one of them in each case being an insulinoma. 75% of all insulinomas were less than 2 cm in size and 15% were malignant. 18 of the 44 Zollinger-Ellison syndrome patients also had multiple endocrine neoplasia type I. Nine of these patients presented with duodenal gastrinomas which were often multiple and smaller than 0.5 cm. The gastrinoma was located in the pancreas of one of the patients with multiple endocrine neoplasia, in two patients in lymph nodes, and no gastrinoma was identified in the specimens from six patients. 33% of the duodenal gastrinomas had metastasised. Solitary gastrinomas were found in all 26 patients with sporadic Zollinger-Ellison syndrome, 14 being located in the pancreas (diameter over 2 cm in eight cases) and ten in the duodenum (diameter less than 1 cm in seven cases). 16 of these gastrinomas were malignant.

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.

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.

Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome?

To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1. DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX. These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

Meningiomas may be a component tumor of multiple endocrine neoplasia type 1.

Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions. Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome. Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age = 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10-15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P = 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus. These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.

Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1).

The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence.

Management and outcome of patients with sporadic gastrinoma arising in the duodenum.

Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized. Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival. There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137). Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group.

Effect of chronic hypergastrinemia on human enterochromaffin-like cells: Insights from patients with sporadic gastrinomas

Background & Aims: The effect of chronic hypergastrinemia alone on gastric enterochromaffin-like (ECL) cells in humans is largely unknown because in the common chronic hypergastrinemic states (atrophic gastritis, chronic proton pump inhibitor use), it is not possible to separate the effect of hypergastrinemia and other factors, such as gastritis or atrophy. Studies of patients with sporadic Zollinger–Ellison syndrome (ZES) allow this separation. Methods: In 106 patients with ZES, gastric biopsies were taken, and the qualitative ECL cell pattern/grade and the α-subunit of human chorionic gonadotropin (α-hCG) expression were determined. Results: In patients with active disease, 99% had ECL hyperplasia and abnormal α-hCG staining. Fifty percent had advanced changes in both of these, with 7% having dysplasia and 0% having carcinoids. Advanced ECL cell and α-hCG changes were most affected by the level of hypergastrinemia. For ECL cell changes, even mild hypergastrinemia had an effect. Advanced ECL change was also affected by the duration of drug treatment, cure status, and presence of atrophic gastritis, but not by sex or previous vagotomy. The α-hCG expression independently predicted dysplasia. Conclusions: In humans, chronic hypergastrinemia alone causes advanced ECL cell change and abnormal expression of mucosal α-hCG. No threshold for this effect was detected, as reported by some, and in contrast to animal studies, sex and vagal tone did not play a major role. The long-term risk of developing gastric carcinoids with chronic hypergastrinemia is low in patients with sporadic gastrinomas (at least 100 times less than in patients with multiple endocrine neoplasia type 1 with ZES) for at least 15–20 years.GASTROENTEROLOGY 2002;123:68-85

Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome.

In patients with Zollinger-Ellison syndrome (ZES) or other conditions requiring oral doses of proton pump inhibitors, it frequently becomes necessary to use parenterally administered gastric acid inhibitors. However, i.v. histamine-2 receptor antagonists are not effective at usual doses and lose their effectiveness because of tachyphlaxis. With the approval in the United States of i.v. pantoprazole, a substituted benzimidazole available in i.v. formulation, it will become possible to acutely manage gastric acid secretion in the acute care setting of a hospital. This study was developed to monitor the safety and establish the efficacy of i.v. pantoprazole as an alternative to oral proton pump inhibitors for the control of gastric acid hypersecretion in patients with ZES. The efficacy of replacing oral PPI therapy with i.v. pantoprazole was evaluated in 14 ZES patients. After study enrollment, patients taking their current doses of oral PPI (omeprazole or lansoprazole) were switched to pantoprazole i.v. for 6 days during an 8-day inpatient period in the clinical research center. Effective control was defined as an acid output (AO) of < 10 mEq/h (< 5 mEq/h in patients with prior gastric acid-reducing surgery). The mean age of the 14 patients enrolled in the study was 52.4 yr (range = 38-67). Mean basal AO was 0.55 +/- 0.32 mEq/h and mean fasting gastrin was 1089 pg/ml (range = 36-3720). Four patients were also diagnosed with the multiple endocrine neoplasia type I syndrome, nine were male, and two had previously undergone acid-reducing surgery. Before study enrollment, gastric acid hypersecretion was controlled in nine of 14 patients with omeprazole (20-200 mg daily) and five of 14 with lansoprazole (30-210 mg daily). In the oral phase of the study all patients had adequate control of gastric acid secretion, with a mean AO of 0.55 +/- 0.32 mEq/h (mean +/- SEM). Thereafter, 80 mg of i.v. pantoprazole was administered b.i.d. for 7 days by a brief (15 min) infusion and the dose was titrated upward to a predetermined maximum of 240 mg/24 h to control AO. A dose of 80 mg b.i.d. of i.v. pantoprazole controlled AO in 13 of 14 of the patients (93%) for the duration of the study (p > 0.05 compared to baseline values for all timepoints). One sporadic ZES patient (oral control value = 0.65 mEq/h on 100 mg of omeprazole b.i.d. p.o.) was not controlled with 80 mg of i.v. pantoprazole b.i.d. and dosage was titrated upward to 120 mg b.i.d. after day 2. There were no serious adverse events observed. Intravenous pantoprazole provides gastric acid secretory control that is equivalent to the acid suppression observed with oral proton pump inhibitors. Most ZES patients (93%) maintained effective control of AO previously established with oral PPIs when switched to 80 mg of i.v. pantoprazole b.i.d.; however, for difficult-to-control patients, doses > 80 mg b.i.d. may be required.

Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

OBJECTIVES: In patients with Zollinger-Ellison syndrome (ZES) or other conditions requiring oral doses of proton pump inhibitors, it frequently becomes necessary to use parenterally administered gastric acid inhibitors. However, i.v. histamine-2 receptor antagonists are not effective at usual doses and lose their effectiveness because of tachyphlaxis. With the approval in the United States of i.v. pantoprazole, a substituted benzimidazole available in i.v. formulation, it will become possible to acutely manage gastric acid secretion in the acute care setting of a hospital. This study was developed to monitor the safety and establish the efficacy of i.v. pantoprazole as an alternative to oral proton pump inhibitors for the control of gastric acid hypersecretion in patients with ZES. METHODS: The efficacy of replacing oral PPI therapy with i.v. pantoprazole was evaluated in 14 ZES patients. After study enrollment, patients taking their current doses of oral PPI (omeprazole or lansoprazole) were switched to pantoprazole i.v. for 6 days during an 8-day inpatient period in the clinical research center. Effective control was defined as an acid output (AO) of <10 mEq/h (<5 mEq/h in patients with prior gastric acid-reducing surgery). RESULTS: The mean age of the 14 patients enrolled in the study was 52.4 yr (range = 38–67). Mean basal AO was 0.55 ± 0.32 mEq/h and mean fasting gastrin was 1089 pg/ml (range = 36–3720). Four patients were also diagnosed with the multiple endocrine neoplasia type I syndrome, nine were male, and two had previously undergone acid-reducing surgery. Before study enrollment, gastric acid hypersecretion was controlled in nine of 14 patients with omeprazole (20–200 mg daily) and five of 14 with lansoprazole (30–210 mg daily). In the oral phase of the study all patients had adequate control of gastric acid secretion, with a mean AO of 0.55 ± 0.32 mEq/h (mean ± SEM). Thereafter, 80 mg of i.v. pantoprazole was administered b.i.d. for 7 days by a brief (15 min) infusion and the dose was titrated upward to a predetermined maximum of 240 mg/24 h to control AO. A dose of 80 mg b.i.d. of i.v. pantoprazole controlled AO in 13 of 14 of the patients (93%) for the duration of the study ( p > 0.05 compared to baseline values for all timepoints). One sporadic ZES patient (oral control value = 0.65 mEq/h on 100 mg of omeprazole b.i.d. p.o.) was not controlled with 80 mg of i.v. pantoprazole b.i.d. and dosage was titrated upward to 120 mg b.i.d. after day 2. CONCLUSIONS: There were no serious adverse events observed. Intravenous pantoprazole provides gastric acid secretory control that is equivalent to the acid suppression observed with oral proton pump inhibitors. Most ZES patients (93%) maintained effective control of AO previously established with oral PPIs when switched to 80 mg of i.v. pantoprazole b.i.d.; however, for difficult-to-control patients, doses >80 mg b.i.d. may be required.