ABSTRACT
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone-secreting and non-functional GEP-NETs. By combining this approach with in vitro studies of human-derived organoids, we demonstrated the convergence of cell autonomous immune and pro-inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural- and immune-related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal-appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro-inflammatory signaling was confirmed using patient-derived duodenal organoids. Gastrin-secreting and non-functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non-MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro-inflammatory and pro-neural factor IL-17B. Treatment of human duodenal organoids with IL-17B activated NF-κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue-specific neuro-immune signatures in GEP-NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro-inflammatory factors, including tumor-derived IL-17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.
Subject(s)
Duodenal Neoplasms , Gastrinoma , Intestinal Neoplasms , Neuroendocrine Tumors , Pancreatic Neoplasms , Stomach Neoplasms , Humans , Neuroendocrine Tumors/pathology , Gastrinoma/genetics , Gastrinoma/metabolism , Gastrinoma/pathology , Neuroimmunomodulation , Interleukin-17 , Duodenal Neoplasms/genetics , Pancreatic Neoplasms/pathology , Tumor MicroenvironmentSubject(s)
Duodenal Neoplasms/metabolism , Epigenesis, Genetic , Gastrinoma/metabolism , Gene Regulatory Networks , MicroRNAs/metabolism , Multiple Endocrine Neoplasia Type 1/metabolism , Neuroendocrine Tumors/metabolism , Stomach Neoplasms/metabolism , Female , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks/genetics , Humans , Pancreas/metabolismABSTRACT
Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wild-type allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wild-type MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome-related gastrinoma to biochemical prevention.
Subject(s)
Duodenum/metabolism , Gastrinoma/genetics , Hypercalcemia/genetics , Multiple Endocrine Neoplasia Type 1/genetics , Pancreatic Neoplasms/genetics , Parathyroid Glands/metabolism , Alleles , Duodenum/pathology , Gastrinoma/metabolism , Gastrinoma/pathology , Germ-Line Mutation , Humans , Hypercalcemia/metabolism , Models, Genetic , Multiple Endocrine Neoplasia Type 1/metabolism , Multiple Endocrine Neoplasia Type 1/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Parathyroid Glands/pathology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Signal Transduction/geneticsABSTRACT
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
Subject(s)
Gastrins/biosynthesis , Proton Pump Inhibitors/therapeutic use , Stomach Diseases/drug therapy , Stomach Diseases/etiology , Zollinger-Ellison Syndrome/complications , Zollinger-Ellison Syndrome/metabolism , Animals , Carcinoma, Neuroendocrine , Chronic Disease , Gastrinoma/metabolism , Humans , Proton Pump Inhibitors/adverse effects , Risk Factors , Stomach Diseases/metabolism , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.
Subject(s)
Gastrinoma/mortality , Intestinal Neoplasms/mortality , Liver Neoplasms/mortality , Neuroendocrine Tumors/mortality , Pancreatic Neoplasms/mortality , Proto-Oncogene Proteins/metabolism , Stomach Neoplasms/mortality , Cohort Studies , Female , Follow-Up Studies , Gastrinoma/metabolism , Gastrinoma/pathology , Gastrinoma/surgery , Humans , Intestinal Neoplasms/metabolism , Intestinal Neoplasms/pathology , Intestinal Neoplasms/surgery , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Male , Middle Aged , Netherlands , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/surgery , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Survival RateABSTRACT
The existence of primary lymph node (LN) gastrinoma is questionable and controversial. In fact, the presence of gastrinoma in such uncommon site raises the possibility of metastasis from another occult primary site. An extensive evaluation and careful follow-up is always warranted. A female aged 48 years presented with chronic abdominal pain and watery diarrhoea. Her serum gastrin and chromogranin were elevated, and an underlying gastrinoma was suspected. Further evaluation with an octreotide scan, an endoscopic ultrasound and a secretin stimulation test confirmed the diagnosis. Further evaluation for multiple endocrine neoplasia-1 syndrome was negative. She underwent a surgical enucleation near the head of the pancreas. No other lesions were found after careful exploration of the gastrinoma triangle. Histology showed a LN with a neuroendocrine tumour that tested positively with gastrin and chromogranin stains. Her symptoms resolved postoperatively, her serum gastrin normalised and a repeated octreotide scan was negative.
Subject(s)
Diarrhea/etiology , Gastrinoma/diagnosis , Lymph Nodes/pathology , Neuroendocrine Tumors/diagnosis , Chromogranins/blood , Female , Gastrinoma/metabolism , Gastrinoma/surgery , Gastrins/blood , Humans , Lymph Nodes/surgery , Middle Aged , Neuroendocrine Tumors/surgery , Treatment OutcomeSubject(s)
Adrenocorticotropic Hormone/metabolism , Gastrinoma/diagnostic imaging , Gastrinoma/secondary , Pancreatic Neoplasms/diagnostic imaging , Child , Female , Gastrinoma/metabolism , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Magnetic Resonance Imaging , Pancreatic Neoplasms/metabolismABSTRACT
Sporadic gastrin-producing neuroendocrine tumors of the duodenum present either with the Zollinger-Ellison syndrome (ZES) or with unspecific symptoms. While syndromic gastrin-producing neuroendocrine tumors often show metastases at the time of diagnosis, those without a syndrome do not. The aim of the study was to search for clinicopathological features that may distinguish the two categories of gastrin-producing duodenal tumors. In a retrospective study, we analyzed the clinical and pathological data in a series of 41 patients with syndromic (i.e., gastrinomas) or non-syndromic duodenal gastrin-producing neuroendocrine tumors (ns-gas-NETs). Twenty-four (59 %) of the 41 patients had tumors that were associated with a ZES and were classified as gastrinomas. These tumors showed a higher Ki-67 index than that of the ns-gas-NETs (1.74 vs. 0.85 %, p = 0.012). In addition, they had more lymph node metastases (75 vs. 6 %, p < 0.001) and showed liver metastases and thus presented much more frequently in TNM stage ≥III (75 vs. 6 %; p < 0.001) than their non-syndromic counterparts. Gastrinomas were removed surgically, ns-gas-NETs endoscopically. We did not observe any significant differences in overall survival or recurrence of disease. Duodenal gastrinomas show no clear morphological features that distinguish them from their non-syndromic counterparts. However, the patients with gastrinomas present in a more advanced stage of disease and need surgical treatment, while non-syndromic gastrin-producing duodenal NETs may be cured by complete endoscopical removal.
Subject(s)
Duodenal Neoplasms/metabolism , Gastrinoma/metabolism , Gastrins/metabolism , Neoplasm Recurrence, Local/metabolism , Neuroendocrine Tumors/metabolism , Adult , Aged , Aged, 80 and over , Duodenal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Retrospective StudiesSubject(s)
Diarrhea , Digestive System Surgical Procedures/methods , Duodenal Neoplasms , Duodenal Ulcer , Esomeprazole/administration & dosage , Gastrinoma , Peptic Ulcer , Rehydration Solutions/administration & dosage , Diagnosis, Differential , Diarrhea/diagnosis , Diarrhea/etiology , Diarrhea/metabolism , Diarrhea/physiopathology , Diarrhea/therapy , Duodenal Neoplasms/metabolism , Duodenal Neoplasms/pathology , Duodenal Neoplasms/physiopathology , Duodenal Neoplasms/therapy , Duodenal Ulcer/diagnosis , Duodenal Ulcer/drug therapy , Duodenal Ulcer/etiology , Duodenal Ulcer/physiopathology , Duodenum/pathology , Duodenum/surgery , Endoscopy, Digestive System/methods , Fluid Therapy/methods , Gastrinoma/metabolism , Gastrinoma/pathology , Gastrinoma/physiopathology , Gastrinoma/therapy , Humans , Male , Middle Aged , Neoplasm Staging , Osmolar Concentration , Peptic Ulcer/diagnosis , Peptic Ulcer/drug therapy , Peptic Ulcer/etiology , Peptic Ulcer/physiopathology , Proton Pump Inhibitors/administration & dosage , Tomography, Emission-Computed, Single-Photon/methods , Tomography, X-Ray Computed/methods , Treatment Outcome , Water-Electrolyte BalanceABSTRACT
Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.
Subject(s)
Biomarkers, Tumor/metabolism , Gastrointestinal Neoplasms/therapy , Neuroendocrine Tumors/therapy , Pancreatic Neoplasms/therapy , Carcinoid Tumor/metabolism , Carcinoid Tumor/therapy , Gastrinoma/metabolism , Gastrinoma/therapy , Glucagonoma/metabolism , Glucagonoma/therapy , Humans , Insulinoma/metabolism , Insulinoma/therapy , Pancreatic Neoplasms/metabolism , Vipoma/metabolism , Vipoma/therapySubject(s)
Gastrinoma/metabolism , Gastrins/metabolism , Glucagon/metabolism , Glucagonoma/metabolism , Necrolytic Migratory Erythema/etiology , Neuroendocrine Tumors/metabolism , Pancreatic Neoplasms/metabolism , Adult , Female , Gastrins/blood , Glucagon/blood , Glucagonoma/complications , Humans , Neuroendocrine Tumors/complications , Pancreatic Neoplasms/complications , Paraneoplastic Syndromes/etiology , PhenotypeABSTRACT
AIM: The value of chromogranin A (CgA) versus gastrin and progastrin in diagnosis and control of gastrinoma patients is not settled because the peptides circulate as variable mixtures. We have addressed this complexity using defined sequence-specific assays. PATIENTS & METHODS: Six assays were applied to plasma from 40 gastrinoma patients to measure α-amidated gastrins, glycine-extended gastrins, the total progastrin product, and assays for CgA sequence (340-348) and the 'total' CgA product. RESULTS: The gastrin/progastrin parameters did not add to the diagnosis beyond that of α-amidated gastrins, except in one patient. All gastrin parameters correlated otherwise closely. The CgA results differed. Thus, 11 patients had normal CgA concentrations. By contrast, all total CgA concentrations were elevated but correlated only moderately to gastrin. CONCLUSION: Assays measuring α-amidated gastrins have high diagnostic value except for singular patients in whom only progastrin was elevated. By contrast, CgA measurements are not valid in diagnosis or control of gastrinomas.
Subject(s)
Biomarkers, Tumor/blood , Chromogranin A/blood , Gastrinoma/diagnosis , Gastrins/blood , Protein Precursors/blood , Adult , Aged , Female , Gastrinoma/metabolism , Gastrinoma/pathology , Humans , Linear Models , Male , Middle Aged , Peptides/chemical synthesis , Peptides/chemistry , RadioimmunoassayABSTRACT
Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma and resultant hypergastrinemia, which leads to recurrent peptic ulcers. Because gastrinoma is the most common pancreatic endocrine tumor seen in multiple endocrine neoplasia type I (MEN 1), the possibility of gastrinoma should be investigated carefully when patients exhibit symptoms associated with hormonal changes. Ureteral stones associated with hyperparathyroidism in the early course of MEN 1 are known to be its most common clinical manifestation; appropriate evaluation and close follow-up of patients with hypercalcemic urolithiasis can lead to an early diagnosis of gastrinoma. We report a patient with ZES associated with MEN 1, and urolithiasis as the presenting entity. A 51-year-old man visited the emergency department with recurrent epigastric pain. He had a history of calcium urinary stone 3 years ago, and 2 years later he had 2 operations for multiple jejunal ulcer perforations; these surgeries were 9 months apart. He was taking intermittent courses of antiulcer medication. Multiple peripancreatic nodular masses, a hepatic metastasis, parathyroid hyperplasia, and a pituitary microadenoma were confirmed by multimodal imaging studies. We diagnosed ZES with MEN 1 and performed sequential surgical excision of the gastrinomas and the parathyroid adenoma. The patient received octreotide injection therapy and close follow-up.
Subject(s)
Multiple Endocrine Neoplasia Type 1/diagnosis , Urolithiasis/diagnosis , Zollinger-Ellison Syndrome/diagnosis , Gastrinoma/diagnostic imaging , Gastrinoma/metabolism , Gastrinoma/pathology , Gastrins/metabolism , Humans , Immunohistochemistry , Liver/diagnostic imaging , Magnetic Resonance Imaging , Male , Mesenteric Artery, Superior/diagnostic imaging , Middle Aged , Multimodal Imaging , Multiple Endocrine Neoplasia Type 1/complications , Multiple Endocrine Neoplasia Type 1/diagnostic imaging , Pancreas/diagnostic imaging , Pituitary Gland/diagnostic imaging , Positron-Emission Tomography , Radiopharmaceuticals , Thyroid Gland/diagnostic imaging , Tomography, X-Ray Computed , Ultrasonography , Urolithiasis/etiology , Zollinger-Ellison Syndrome/complicationsABSTRACT
Circulating agents cause intestinal secretion or changes in motility with decreased intestinal transit time, resulting in secretory-type diarrhea. Secretory diarrhea as opposed to osmotic diarrhea is characterized by large-volume, watery stools, often more than 1 L per day; by persistence of diarrhea when patients fast; and by the fact that on analysis of stool-water, measured osmolarity is identical to that calculated from the electrolytes present. Although sodium plays the main role in water and electrolyte absorption, chloride is the major ion involved in secretion.
Subject(s)
Diarrhea/etiology , Calcitonin/metabolism , Carcinoma, Medullary/complications , Carcinoma, Medullary/metabolism , Gastrinoma/complications , Gastrinoma/metabolism , Histamine Release , Humans , Hyperthyroidism/complications , Malignant Carcinoid Syndrome/complications , Mast Cells/metabolism , Mastocytosis, Systemic/complications , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/metabolism , Pancreatic Polypeptide/metabolism , Somatostatin/metabolism , Somatostatinoma/complications , Somatostatinoma/metabolism , Thyroid Neoplasms/complications , Thyroid Neoplasms/metabolism , Vipoma/complications , Vipoma/metabolism , Zollinger-Ellison Syndrome/complicationsABSTRACT
BACKGROUND: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production. METHODS: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated. RESULTS: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm. CONCLUSIONS: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.
Subject(s)
Neuroendocrine Tumors/secondary , Pancreatic Neoplasms/pathology , Adult , Aged , Female , Gastrinoma/metabolism , Gastrinoma/pathology , Gastrinoma/secondary , Gastrinoma/surgery , Hormones/biosynthesis , Humans , Lymph Node Excision , Lymphatic Metastasis , Male , Middle Aged , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/surgery , Pancreatectomy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/surgery , Retrospective Studies , Survival Analysis , Young AdultABSTRACT
Chromogranins belong to the family of secretory chromogranin and secretogranin proteins. They are found in secretory vesicles throughout the neuroendocrine system. Chromogranin A (CgA) is the main component. CgA acts as a prohormone submitted to processes of degradation through which active peptides are generated. CgA has auto, para and endocrine functions. It is widely used as an immunohistochemical marker. Despite the lack of international standardization, and the lack of an accurate definition of the diagnostic cut-off levels, some CgA assays are reliable. Numerous studies have suggested that CgA determination may be of interest for the diagnosis and the follow-up of various endocrine tumors. Plasma levels of this general marker are proportional to tumor mass. The localization of the primitive tumor, the presence of associated hormonal secretions and possible renal failure and/or hypergastrinemia must be taken into consideration for proper interpretation of CgA levels. New clinical indications are emerging for the evaluation of stress in intensive care units and the assessment of cardiovascular risk. New assays estimating the concentration of active peptides are under development.
Subject(s)
Biomarkers, Tumor/blood , Chromogranin A/blood , Gastrinoma/diagnosis , Neuroblastoma/diagnosis , Neuroendocrine Tumors/diagnosis , Pheochromocytoma/diagnosis , Adrenal Gland Neoplasms/chemistry , Adrenal Gland Neoplasms/diagnosis , Adrenal Gland Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Chromogranin A/metabolism , Female , Gastrinoma/chemistry , Gastrinoma/metabolism , Humans , Ileal Neoplasms/chemistry , Ileal Neoplasms/diagnosis , Ileal Neoplasms/metabolism , Immunoassay , Male , Neuroblastoma/chemistry , Neuroblastoma/metabolism , Neuroendocrine Tumors/chemistry , Neuroendocrine Tumors/metabolism , Pheochromocytoma/chemistry , Pheochromocytoma/metabolism , Pituitary Neoplasms/chemistry , Pituitary Neoplasms/diagnosis , Pituitary Neoplasms/metabolism , Secretory Vesicles/chemistry , Secretory Vesicles/metabolism , Thyroid Neoplasms/chemistry , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/metabolismABSTRACT
OBJECTIVE: The recent description of dyspepsia in healthy individuals after stopping treatment with proton-pump inhibitors (PPIs) indicates that reflux disease may worsen due to this treatment. The aim of this paper is to review current knowledge of the regulation of gastric acid secretion, including maximal acid secretion, and to improve understanding of the pathogenesis of acid-related conditions. MATERIAL AND METHODS: We reviewed our findings from three decades of studies on gastric acid secretion in the isolated rat stomach and in humans as well as studies by the group of Robert Jensen involving gastrinoma patients. RESULTS: The parietal cell has receptors for histamine and acetylcholine, whereas the gastrin receptor is localized to the enterochromaffin-like (ECL) cell. Gastrin-stimulated histamine release depends on the ECL cell mass, which is regulated by gastrin. The parietal cell mass is also influenced by gastrin. All conditions with hypergastrinemia concomitant with a normal oxyntic mucosa result in an increase in acid secretion. Helicobacter pylori infection in the antral mucosa may induce duodenal ulcers by its effect on acid secretion, as in patients with gastrinoma. Whereas PPIs induce clinically important rebound acid hypersecretion, histamine-2 blockers do not, since they also induce tolerance. CONCLUSION: From a biological and physiological point of view, patients should be given treatment that disturbs the normal physiology as little as possible.
Subject(s)
Dyspepsia/etiology , Enterochromaffin-like Cells/metabolism , Gastric Acid/metabolism , Gastroesophageal Reflux/drug therapy , Proton Pump Inhibitors/administration & dosage , Animals , Gastrinoma/metabolism , Gastroesophageal Reflux/metabolism , Helicobacter Infections/metabolism , Helicobacter pylori , Histamine/metabolism , Histamine H2 Antagonists/administration & dosage , Humans , Parietal Cells, Gastric/metabolism , Rats , Stomach Neoplasms/metabolismSubject(s)
Biomarkers/metabolism , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/metabolism , Biomarkers/blood , Biomarkers/urine , Chromogranin A/blood , Chromogranin A/metabolism , Fasting/metabolism , Gastrinoma/diagnosis , Gastrinoma/metabolism , Humans , Hydroxyindoleacetic Acid/metabolism , Hydroxyindoleacetic Acid/urine , Hypoglycemia/diagnosis , Insulinoma/diagnosis , Insulinoma/metabolism , Neuroendocrine Tumors/therapy , Secretin/metabolismABSTRACT
Prediction of the evolution of endocrine pancreatic tumors remains difficult based on histological criteria alone. We have previously demonstrated that epigenetic changes are an early event in a mouse model developing insulinomas. Particularly, overexpression of the imprinted IGF2 was caused by the hypermethylation of CpGs in the differentially methylated region 2 (DMR2). Here, we investigated whether IGF2 hypermethylation is also observed in human insulinomas and whether this alteration is common to other human endocrine tumors of the pancreas and the digestive tract. We analyzed the methylation status of 40 CpGs located in the DMR0 and DMR2 of the IGF2 as well as in the H19 DMR by pyrosequencing in a cohort of 62 patients with pancreatic or small intestine endocrine tumors. Altered methylation patterns were observed in all tumor types for the different regions of IGF2, but not for H19. However, hypermethylation of the IGF2 DMR2 was specific for insulinomas and did not occur in any of the other types of tumors which were characterized by a loss of methylation in this region. Gain of methylation in the IGF2 DMR2 in insulinomas correlated with loss-of-imprinting and promoter 4 mediated overexpression of IGF2 at the RNA and protein level. Furthermore, a decreasing degree of methylation in the different regions of IGF2 correlated well with increasing degree of malignancy according to the WHO classification of pancreatic endocrine tumors (PETs), suggesting that methylation of IGF2 might be a useful biomarker for classification and staging of PETs.
Subject(s)
DNA Methylation/physiology , Gene Expression Regulation, Neoplastic , Genomic Imprinting/genetics , Insulin-Like Growth Factor II/genetics , Insulinoma/genetics , Pancreatic Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Female , Gastrinoma/classification , Gastrinoma/genetics , Gastrinoma/metabolism , Gene Expression Regulation, Neoplastic/genetics , Humans , Insulin-Like Growth Factor II/metabolism , Insulinoma/classification , Insulinoma/metabolism , Male , Middle Aged , Organ Specificity/genetics , Pancreatic Neoplasms/classification , Pancreatic Neoplasms/metabolism , Promoter Regions, Genetic/physiology , RNA, Long Noncoding , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Up-Regulation , Young AdultABSTRACT
Some 80-90% of gastrinomas are located in the gastrinoma triangle, which includes the duodenum, the pancreatic head, and the hepatoduodenal ligament. The natural history of the tumors depends on their origin. Duodenal gastrinomas are much less aggressive than pancreatic primaries and infrequently develop liver metastases. The reason therefore is unclear. The transcription factor pancreatic-duodenal homeobox 1 (Pdx1) is important in differentiation and development of the pancreas and duodenum. In embryonic development, Sonic hedgehog (Shh) expression establishes a sharp molecular boundary, which allows for the proper patterning of the duodenal and pancreatic epithelium. Pancreatic polypeptide (PP) is expressed in pancreatic islets and is known to be expressed in pancreatic endocrine tumors. This study aims to clarify the expression pattern of Pdx1, Shh, and PP in duodenal and pancreatic gastrinomas. Tissue from 15 patients with duodenal and from 11 patients with pancreatic gastrinomas that underwent surgery between 1987 and 2007 at our institution because of a gastrinoma were evaluated by immunohistochemistry (IHC). Furthermore, tissue from lymph node metastases from two patients with a so far undetected primary gastrinoma was analyzed. IHC revealed strong Pdx1 expression in pancreatic gastrinomas, but not in duodenal gastrinomas. By contrast, there was no Shh expression detectable in pancreatic gastrinomas, but found in all duodenal gastrinomas. This pattern was also true for associated metastases. Shh expression combined with absence of Pdx1 expression in lymph node metastases from patients with an unknown location of the primary suggests a so far undetected duodenal gastrinoma. We show for the first time that only pancreatic, but not duodenal gastrinomas express Pdx1. Moreover, only duodenal gastrinomas express Shh, suggesting a different genetic background of these two tumors. Whereas the expression of Pdx1 in pancreatic gastrinomas might suggest their endocrine origin from islets, duodenal gastrinomas develop from a Pdx1 negative cell cluster. The expression pattern of Pdx1, Shh, and PP in resected metastases can help to locate an otherwise undetected primary gastrinoma.