Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns.

PURPOSE: The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors. PATIENTS AND METHODS: Nineteen patients with histologically proven metastatic gastrinoma in the liver with Zollinger-Ellison syndrome were studied. Conventional imaging studies were performed initially and at 4- to 6-month intervals before any treatment. Metastases growth rates were calculated and correlated with laboratory and clinical parameters, as well as tumor extent on initial tumor assessment. RESULTS: Twenty-six percent of patients (five of 19) demonstrated no growth over a mean follow-up time of 29 months, 32% (six of 19) had slow growth (1% to 50% increase in volume per month) over a 19-month period, and 42% (eight of 19) had rapid growth (> 50% volume increase per month) over an 11-month period. In patients with rapid growth, 62% died; 0% of the no-growth or slow-growth group died. No clinical or laboratory parameter correlated with growth rate, except the rate increase in fasting serum gastrin and the presence of bilobar liver or bone metastases. The growth rate was highly predictive of death from tumor. CONCLUSION: The growth rate of metastatic gastrinoma varies markedly in different patients and 26% demonstrate no growth. The growth rate needs to considered in the determination of when and in whom antitumor therapy is initiated, as well as in the assessment of response to tumoricidal therapies.

Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and magnetic resonance image in their detection, frequency, location, and effect of their detection on management.

PURPOSE: To determine whether bone scan, magnetic resonance imaging (MRI), or somatostatin receptor scintigraphy (SRS) is best for identifying bone metastases in patients with gastrinomas, as well as their frequency and location, whether their detection affects management, and what patient subgroups should be examined. MATERIALS AND METHODS: One hundred fifteen patients with gastrinoma were prospectively studied. Patients were examined yearly and those with liver metastases were reexamined every 3 months. Based on clinical history, histology, growth pattern, and development of new bone lesions, possible bone metastases were classified as to whether they were or were not bone metastases. Imaging results were correlated at different times in the disease course and with disease extent. RESULTS: Bone scan was positive in 52 patients, MRI in seven, and SRS in six. Eight patients (7%) were determined to have bone metastases and MRI was correctly positive in seven, SRS in six, and bone scan in five. SRS or MRI was positive in all patients with bone metastases. Bone scan had significantly lower specificity and sensitivity, and a higher rate (P < .02) of false-negative results than MRI or SRS. Bone metastases occurred in 31% of patients with liver metastases and 0% with only lymph node metastases. The initial bone metastases were in the spine or sacrum (75%) followed in descending order by the pelvis or sacroiliac joints (38%), scapula or shoulder, and ribs. In all cases, detection of bone metastases changed the management. CONCLUSION: SRS and MRI, because of high sensitivity and specificity, are recommended over bone scanning to screen for bone metastases in patients with gastrinomas. However, because bone metastases can occur initially outside the axial skeleton, SRS is the recommended initial localization method of choice. Bone metastases occur in 7% of all patients and 31% of patients with liver metastases, only occur in patients with liver metastases, are usually in the axial skeleton initially, and their detection changes management in all cases. Patients with pancreatic endocrine tumors with liver metastases should undergo SRS every 6 months to 1 year to detect bone metastases.

Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.

PURPOSE: The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone state is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. PATIENTS AND METHODS: Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8+/-0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushing's syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. RESULTS: Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing's syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushing's syndrome markedly decreased survival rate. CONCLUSIONS: In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushing's syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches.

Prognostic value of initial fasting serum gastrin levels in patients with Zollinger-Ellison syndrome.

PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas.

The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. To address this question we analyzed the gastrinomas from 44 patients for p16INK4a gene mutations and correlated the results to the tumor's biological behavior, growth pattern, and aggressiveness. No gastrinomas had mutations of exon 1 or exon 2 of the p16INK4a gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastrinomas, hypermethylation of a 5'-CpG island of the p16INK4a gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (computed tomography scan, magnetic resonance imaging, and ultrasound), and since 1994 have been assessed with radionuclide scanning using [111In-diethylenetriamine pentaacetic acid,DPhe1]octreotide. The mean follow-up was 5.1+/-0.4 yr (range, 1.2-11.7). The presence or absence of methylation of the p16INK4a gene did not correlate with clinical characteristics of the gastrinoma, biological behavior (gastrin release and basal or maximal acid output), the presence or absence of known prognostic factors (tumor size, gastrinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16INK4a gene is the most common gene alteration described to date in gastrinomas. Furthermore, because it is independent of disease stage it is probably an early event in the pathogenesis and because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16INK4a gene is probably a central process in the molecular pathogenesis of these tumors.

Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form.

The natural history of pancreatic endocrine tumors (PETs) in patients with MEN1 is largely unknown. Recent studies in patients with sporadic PETs show that in a subset, tumor growth is aggressive. To determine whether PETs in patients with MEN1 show similar growth behavior, we report results from a long-term prospective study of 57 patients with MEN1 and Zollinger-Ellison syndrome. All patients had tumor imaging studies yearly, and the mean follow-up was 8 yr. Only patients with PETs 2.5 cm or larger underwent abdominal surgical exploration. Hepatic metastases occurred in 23%, and in 14% tumors demonstrated aggressive growth. Three tumor-related deaths occurred, each due to liver metastases, and in each, aggressive tumor growth was present. Overall, 4% of the study group, 23% with liver metastases and 38% with aggressive disease, died. Aggressive growth was associated with higher gastrins and larger tumors. Patients with liver metastases with aggressive growth differed from those with liver metastases without aggressive growth in age at MEN1 onset or diagnosis and primary tumor size. Survival was decreased (P = 0.0012) in patients with aggressive tumor growth compared with those with liver metastases without aggressive growth or with no liver metastases without aggressive growth. Based on these results a number of factors were identified that may be clinically useful in determining in which patients aggressive tumor growth may occur. These results demonstrate in a significant subset of patients with MEN1 and Zollinger-Ellison syndrome, aggressive tumor growth occurs and can lead to decreased survival. The identification of prognostic factors that identify this group will be important clinically in allowing more aggressive treatment options to be instituted earlier.

Expression of the calcium-sensing receptor in gastrinomas.

Extracellular calcium levels are able to influence the secretion of gastrin by gastrinomas and possibly affect the growth pattern. The molecular mechanisms of these functions are not known. The purpose of the present study was to investigate the presence of the calcium-sensing receptor (CaR) in 10 gastrinomas and determine the extent of expression in the tumors. The amounts of CaR messenger ribonucleic acid in eight tumors were determined by quantitative RT-PCR. Protein expression was analyzed by Western blot and immunohistochemistry using a monoclonal antibody (ADD). CaR messenger ribonucleic acid was detected in all gastrinomas with levels ranging from 0.04-3.16 times the amount of beta-actin transcripts. The Western blot showed a major immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding to the receptor dimer and monomer, respectively. Immunohistochemistry demonstrated variable membranous staining in all gastrinomas and normal pancreatic islets. No staining was observed in the normal liver, lymph node, or exocrine pancreas. We conclude that the CaR is present in all gastrinomas, with expression varying by 80-fold. It probably contributes to the calcium-stimulated gastrin release by gastrinomas. Whether the density of the CaR is a determining factor of the magnitude of this gastrin release or plays a role in regulating the growth pattern of the gastrinoma, as it does in other cells, remains unclear at present.

Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for disease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large cohort of patients with sporadic gastrinomas to disease activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfinger-printing (ddF) for abnormalities in the 9 coding exons and adjacent splice junctions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequenced for mutations. The findings were correlated with clinical manifestations of the disease, primary tumor site, disease extent, and tumor growth postoperatively. Tumor growth was determined by serial imaging studies. Sixteen different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of the 16 mutations were located in exon 2 compared to 7 of 16 in the remaining 8 coding exons (P = 0.005 on a per nucleotide basis). Primary pancreatic or lymph node gastrinomas with a mutation had only exon 2 mutations, whereas duodenal tumors uncommonly harbored exon 2 mutations (P = 0.011). Similarly, small primary tumors (<1 cm) more frequently contained a nonexon 2 mutation (P = 0.02). There was no difference between patients with or without a mutation with respect to clinical characteristics, primary tumor site, disease extent, or proportion of patients disease free after surgery. Postoperative tumor growth tended to be more aggressive in patients with a mutation (P = 0.09). No correlation in the rate of disease-free status or postoperative tumor growth in patients with active disease to the location of the mutation was seen. These results demonstrate that the MEN1 gene is mutated in 31% of sporadic gastrinomas, and mutations are clustered between amino acids 66-166, which differs from patients with familial MEN1, in whom mutations occur throughout the gene. The presence of an MEN1 gene mutation does not correlate with clinical characteristics of patients with gastrinomas, gastrinoma extent, or growth pattern; however, the location of the mutation differed with gastrinoma location. These data suggest that mutations in the MEN1 gene are important in a proportion of sporadic gastrinomas, but the presence or absence of these mutations will not identify the clinically important subgroups with different growth patterns.

The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndromes.

Carcinoid tumors were identified in the antro-pyloric mucosa of four patients with multiple endocrine neoplasia type 1 (MEN-1)/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic Zollinger-Ellison syndrome (P < 0.001), indicating a prominent role for the MEN-1 gene defects in tumor development. Immunohistochemically the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, two of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT-2), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In one of these patients a second antral VMAT-2-positive carcinoid was seen 21 months after the first diagnosis. The other two antral carcinoids were unreactive for VMAT-2. Multiple ECL cell tumors were found in the gastric body-fundus mucosa of the two patients with VMAT-2-positive, but not in those with VMAT-2-negative, antral carcinoids. In one case, the former tumors were diagnosed 22 months after the detection of the antral tumor. We conclude that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN-1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least two cases, were identified as ectopic ECL cell carcinoids.

Zollinger-Ellison syndrome. Clinical presentation in 261 patients.

We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)

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.

We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and < 60% for BAO > 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of < 15% in patients with no prior acid-reducing surgery. The proposed criterion of BAO/MAO ratio > 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH < or = 1 was met by only 27% of patients, and pH < or = 0.96 by 21% of patients with previous acid-reducing surgery. For patients with MEN1 with no prior acid-reducing surgery, the sensitivities were lower compared with patients with the sporadic form of ZES. The mean gastric volume in patients without prior acid-reducing surgery was 314 +/- 10 mL/hr and 247 +/- 25 mL/hr in patients with prior acid-reducing surgery. A basal volume criteria of > 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.

Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.

BACKGROUND AND AIMS: Long-term treatment with H(+)-K(+)-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. METHODS: In 131 consecutive patients treated with either omeprazole (n = 111) or histamine H2-receptor antagonists (n = 20), serum vitamin B12 and folate levels and complete blood counts were determined after acid secretion had been controlled for at least 6 months. These studies were repeated yearly. Serum vitamin B12 and folate levels were correlated with the type of antisecretory drug and the extent of inhibition of acid secretion. RESULTS: The mean duration of omeprazole treatment was 4.5 years, and for H2-receptor antagonists 10 years. Vitamin B12 levels, but not serum folate levels or any hematological parameter, were significantly (P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced sustained hyposecretion (P = 0.0014) or complete achlorhydria (P < 0.0001). In 68 patients with two determinations at least 5 years apart, vitamin B12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment was inversely correlated with vitamin B12 levels (P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B12 levels during follow-up. CONCLUSIONS: Long-term omeprazole treatment leads to significant decreases in serum vitamin B12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome treated with H(+)-K(+)-ATPase inhibitors should have serum vitamin B12 levels monitored. Furthermore, these results raise the possibility that other patients treated chronically with H(+)-K(+)-ATPase inhibitors may develop B12 deficiency.

Ability of somatostatin receptor scintigraphy to identify patients with gastric carcinoids: a prospective study.

UNLABELLED: Gastric carcinoids are of increasing clinical concern because they may develop in hypergastrinemic states, especially with the increased chronic use of potent acid suppressants that can cause hypergastrinemia. However, gastric carcinoids are difficult to diagnose. Somatostatin receptor scintigraphy (SRS) has a high sensitivity and specificity for localizing carcinoids in other locations. The purpose of this study was to determine whether SRS could localize gastric carcinoids. METHODS: Two groups of patients with Zollinger-Ellison syndrome (ZES) with hypergastrinemia, each having a different increased risk of developing gastric carcinoids, were studied. One hundred sixty-two consecutive patients with ZES were studied prospectively, with 39 having multiple endocrine neoplasia, type 1 (MEN-1) (high increased risk), and 123 not having MEN-1 (low increased risk). Patients were admitted to the hospital initially and then yearly, undergoing SRS with SPECT, upper gastrointestinal endoscopy, and Jumbo Cup biopsies of any gastric abnormalities, as well as random biopsies of the gastric body. Tumor localization studies were also performed. Both the results of the routine SRS interpretation and the results of a masked review, with particular attention to the stomach of high risk MEN-1 patients, were correlated with the gastric biopsy results. RESULTS: Gastric SRS localization was positive in 19 (12%) of 162 patients. Sixteen patients had a gastric carcinoid, and 12 of these patients had SRS localization. The sensitivity of SRS in localizing a gastric carcinoid was 75%, with a specificity of 95%. Positive and negative predictive values were 63% and 97%, respectively. CONCLUSION: SRS is a noninvasive method that can identify patients with gastric carcinoids with a reasonable sensitivity and a high specificity. SRS should prove useful in the treatment of patients with hypergastrinemic states that have an increased incidence of gastric carcinoids. In patients with MEN-1, one must realize that localization in the upper abdomen on SRS may be caused by a gastric carcinoid and not a pancreatic endocrine tumor.

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.

A prospective study of the effectiveness of low dose omeprazole as initial therapy in Zollinger-Ellison syndrome.

BACKGROUND: The proton pump inhibitors (omeprazole and lansoprazole) are the drugs of choice for the medical management of gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES). These drugs are safe for long-term therapy but are acid-labile and high doses are expensive. The recommended starting dose of omeprazole is 60 mg/day. However, it has been shown in recent studies that the maintenance dose of omeprazole could be safely reduced to 20 mg once or twice a day in more than two-thirds of patients with ZES. The purpose of this study is to determine if an initial starting dose of omeprazole 20 mg/day is safe and effective in patients with ZES. METHODS: Forty-nine consecutive patients with ZES being treated with ranitidine for at least 2 weeks were admitted to the NIH. Omeprazole 20 mg was started on day 1 of the admission and ranitidine discontinued 4 h after the first dose. Gastric acid output was measured for 1 h prior to the next omeprazole dose on day 2, then on day 3 if the value was > 10 mmol/h on the previous day. If acid-peptic symptoms developed or the gastric acid output remained > 10 mmol/h on day 3, the patient was considered to have failed omeprazole 20 mg/day initial therapy and the dose titrated daily to achieve adequate control of acid-peptic symptoms and gastric secretion. RESULTS: In 33 of the 49 patients (68%) omeprazole 20 mg/day was successful as initial therapy. Sixteen patients (32%) failed this initial omeprazole dose (eight patients owing to persistent peptic symptoms and eight patients owing to inadequate acid control). The final daily omeprazole dose required in these patients was 40 mg in eight patients (16%), 60 mg in one patient (2%) and 80 mg in seven patients (14%). Basal acid output (BAO) was the only clinical or laboratory feature that was significantly different between the two groups in which low dose initial omeprazole therapy was or was not successful; all patients with basal acid output < 20 mmol/h had a successful outcome. CONCLUSIONS: Because of the need to rapidly control gastric acid hypersecretion owing to the high risk of complications from peptic ulcer disease, patients with ZES should continue to be started on omeprazole 60 mg/day and the dose adjusted by acute titration methods as is currently recommended. After a maintenance dose is established, attempts should be undertaken to reduce the dose to 20 mg/ day once or twice a day. Only the minority of patients with ZES in whom basal acid output is known to be < 20 mmol/h (20% of patients) should be started on a low initial omeprazole dose.

Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy.

BACKGROUND: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores. AIM: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger-Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs. METHODS: One hundred and nine patients with ZES but without previous gastric resections were studied. All patients underwent assessment of acid control on antisecretory agents, determination of tumour extent, evaluation of haematological parameters (Hct, haemoglobin, WBC, MCV, MCHC), and determination of serum iron parameters (iron, ferritin, transferrin, iron/ transferrin ratio). Acid control values for the last 4 years were reviewed, the presence or absence of acid hyposecretion determined using three different criteria and this result correlated with haematological and iron parameters. RESULTS: Eighty-nine patients were taking omeprazole, nine patients were taking histamine H2-antagonists and 11 patients were taking no drugs following curative resection. The mean duration of omeprazole treatment was 5.7 years (range 0.7-12.5 years) and total duration of any treatment was 10.1 years (range 0.7-21 years). Acid hyposecretion was present by at least one criterion in 45% of patients. There were no significant differences between patients with or without acid hyposecretion, taking or not taking omeprazole, having different durations of omeprazole treatment or different durations of total time receiving any antisecretory treatment, for any serum iron parameter, haematological parameter, or for the frequency of iron deficiency. Males and females did not differ in percentage with low ferritin levels or percentage with iron deficiency. CONCLUSIONS: Continuous treatment with omeprazole for 6 years or continuous treatment with any gastric antisecretory drug for 10 years does not cause decreased body iron stores or iron deficiency. These results suggest that, in contrast to recent results which show yearly monitoring of vitamin B12 in such patients is needed, such monitoring for iron parameters is not necessary.

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.

Prospective study of the ability of histamine, serotonin or serum chromogranin A levels to identify gastric carcinoids in patients with gastrinomas.

BACKGROUND: Chronic hypergastrinaemia causes gastric enterochromaffin cell proliferation and carcinoid tumours. The only reliable means to diagnose enterochromaffin cell changes/carcinoids is by biopsy. AIM: To assess whether serum histamine, chromogranin A or serotonin and urinary N-methylimidazoleacetic acid or 5-hydroxyindoleacetic acid correlate with advanced enterochromaffin cell changes or gastric carcinoids in patients with gastrinomas. METHODS: Consecutive patients (n=145) had the above assays and endoscopy with gastric biopsies. RESULTS: Lower N-methylimidazoleacetic acid and chromogranin A levels (P < 0.0001) occurred in disease-free patients. In patients with active disease, the fasting serum gastrin levels correlated (P < 0.0001) with both chromogranin A and N-methylimidazoleacetic acid levels. Chromogranin A (P=0.005), but not N-methylimidazoleacetic acid, serotonin, 5-hydroxyindoleacetic acid or histamine levels, correlated with the enterochromaffin cell index. Carcinoids, but not advanced enterochromaffin cell changes only, were associated with higher chromogranin A and N-methylimidazoleacetic acid levels. CONCLUSIONS: Serum chromogranin A levels and urinary N-methylimidazoleacetic acid levels, but not serum histamine or serotonin or urinary 5-hydroxyindoleacetic acid, correlate with the presence of gastric carcinoids. However, no assay identified patients with advanced enterochromaffin cell changes only with high sensitivity/specificity. Thus, N-methylimidazoleacetic acid and chromogranin A levels are unable to identify patients with advanced changes in enterochromaffin cells and therefore neither can replace routine gastric biopsies.

Intramucosal cysts in the gastric body of patients with Zollinger-Ellison syndrome.

To ascertain the frequency and the clinico-functional correlations of intramucosal cysts in the gastric body of patients with the Zollinger-Ellison syndrome (ZES) and to clarify the relevant mechanism of development, a total of 106 consecutive ZES patients (58 M, 48 F; mean age: 53 yrs, range 19-93 yrs) were investigated with a mean of 7.2 biopsy specimens of the body mucosa per patient proved to be suitable for the study. Biopsies of endoscopically detectable polypoid lesions were not considered. Cystic changes were evaluated with respect to their severity by assessing the cyst grade (0, absent, 1; <30%, 2; 30-60%; 3 >60% of the mucosal area of the biopsy specimen of individual patients showing the most pronounced finding, respectively) and to their intragastric distribution by assessing the ratio of biopsy specimens showing cystic changes over the total number of biopsies examined in each patient. Intramucosal cysts were found in biopsies of non-polypoid gastric body mucosa in 71.7% of 106 patients with Zollinger-Ellison syndrome (ZES) and showed grade 2 and 3 severity in 22 and 8 cases, respectively. The severity of cystic changes correlated with the gastrin levels (p = 0.0005) and was more advanced in patients with active than in those with cured disease (p = 0.037). In the former group, furthermore, advanced cystic changes correlated with age (p = 0.03), male gender (p = 0.014), years of disease from onset (p < 0.02), years of omeprazole treatment (p = 0.033), basal acid output (p < 0.02), severity of ECL cell proliferative changes (p = 0.028), and absence of previous gastrinoma resection (p = 0.039) whereas they did not correlate with MEN-1 status, gastritis, maximal acid output, total duration of any antisecretory drug treatment, daily doses of omeprazole (> 20 mg vs 20 mg), years from surgery, duodenal localization of gastrinoma(s), presence of gastric carcinoid tumor(s) and of liver metastases. In groups of patients subdivided according to three levels of serum gastrin, the duration of omeprazole treatment was not related to the severity of cystic changes. It is concluded that intramucosal cysts in non polypoid gastric body mucosa of ZES patients are by far more common than the already reported fundic gland polyps, to which they likely give raise. Circulating levels of gastrin have an important independent role in their development.

Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger-Ellison syndrome.

To investigate the optimum number of biopsy specimens to be obtained for enterochromaffin-like (ECL) cell monitoring in hypergastrinemic patients and ECL cell regional variations potentially influencing the results, qualitative ECL cell changes were assessed in 149 patients with Zollinger-Ellison syndrome using jumbo biopsy specimens and a systematic sampling procedure of 4 areas each from the lesser or greater curvature of the gastric body. Of 1,176 specimens examined, 1,101 were adequate. The correlation was excellent between different sites within the greater or lesser curvature. In contrast, a normal ECL cell pattern was more frequent in the lesser curvature, whereas linear hyperplasia was more frequent in the greater curvature. Dysplastic lesions and carcinoid tumors in endoscopically unremarkable mucosa were detected in 3.4% and 1.2% of biopsy specimens, respectively, and were equally distributed between the lesser and greater curvature. Their chances of being diagnosed were related to the number of specimens examined. Extensive sampling of both the lesser and greater curvature is recommended for early diagnosis of dysplastic and/or carcinoid lesions in patients at risk. In contrast, limited sampling in the greater curvature seems to be adequate in patients with no risk for carcinoid development.