Gastric neuroendocrine tumors (NETs) are rare neoplasms that originate from enterochromaffin cells in the gastric mucosa and pose a diagnostic dilemma due to their non-specific presentation.

We present a 79-year-old woman, who came with complaints of abdominal pain associated with loss of pain and appetite. Although on the first look multiple differentials could be listed, upon complete evaluation she was diagnosed to have type III Gastric NET. Histopathology and immunohistochemistry allowed diagnostic confirmation of the disease along with strong clinical suspicion. The patient however succumbed to the illness due to advanced disease and lack of established protocol for its management.

The treatment of Gastric NETs primarily involves surgical resection of the tumor and is especially helpful in type I and II cases. For advanced metastatic type III NETs, lines of therapy have not been established although surgical resection can be done if the majority (∼90 %) of the tumor is resectable. Patients should be given a choice in decision making and newer drug therapies should always be considered.

Since gastric NETs are a rarer cause of abdominal pain, it can often be overlooked in favor of other, more common differentials. One should be aware of this disease and the newer diagnostic methods to have any sort of clinical suspicion when presented with such a scenario. The management of the condition although not been established, novel therapies should be considered if the tumor is not resectable.

The diagnosis of gastric neuroendocrine tumors (NETs) is being made with increased frequency likely as a result of more upper endoscopies being done for unrelated reasons. It is therefore vital that gastroenterologists become familiar with the basic work-up and management of patients found to have these tumors. This review describes the classification, pathophysiology, clinical characteristics, and treatment options of the different gastric NETs.

In addition to the three traditional subtypes of gastric NETs, additional cases associated with achlorhydria and appropriate hypergastrinemia may exist. The management of gastric NETs between 1 and 2 cm in size remains controversial and needs to be individualized. Gastric NETs are uncommon but are now diagnosed more frequently. This review highlights the role of hypergastrinemia in their development and the controversies around their management.

Neuroendocrine tumors (NET) previously called carcinoid tumors are neoplasms of enterochromaffin/neuroendocrine cell origin which display neurosecretory capacity that may result in the carcinoid syndrome. The annual incidence of patients with NET is 8.4 per 100000; yet many NET remain asymptomatic and clinically undetected. A majority of NET follows a benign course; however, some will display malignant characteristics. NET most commonly occur in the gastrointestinal tract (67%) and bronchopulmonary system (25%). Gastrointestinal NET occur within the stomach, small intestine, liver, and rectum. We report a retrospective study of 11 subjects: Eight with benign carcinoid tumors: duodenal bulb (n = 2), terminal ileum (n = 1), sigmoid colon (n = 2), and rectum (n = 3); three with malignant carcinoid: liver (n = 1) and intra-abdominal site (n = 2). The diagnosis, endoscopic images, outcome, treatment and review of the literature are presented.

The concept of precursor lesions of endocrine neoplasms is a new and interesting topic in endocrine pathology. A variety of clinicopathological conditions are associated with a sequence of cellular changes from hyperplasia to neoplasia; dysplasia is, in contrast, quite rare. The majority of precursor lesions is associated with familial genetic syndromes. These include C-cell hyperplasia in thyroid that is associated with familial medullary thyroid carcinoma, adrenal medullary hyperplasia as a precursor of phaeochromocytomas in MEN2 syndrome, rare pituitary adenohypophyseal cell hyperplasia in familial syndromes associated with pituitary adenomas, MEN1-related precursor gastric enterochromaffin-like cell (ECL) hyperplasia, and duodenal gastrin producing (G) and/or somatostatin producing (D) cell hyperplasia that give rise to type II gastric neuroendocrine tumours (NETs) and duodenal NETs, respectively, and MEN1- or VHL-related islet hyperplasia, islet dysplasia and ductulo-insular complexes that are associated with pancreatic NETs. Other hyperplasias are not thought to be associated with genetic predisposition. Some are attributed to inflammation; autoimmune chronic atrophic gastritis-related ECL hyperplasia can progress to type I gastric NETs, and EC (enterochromaffin) cell or L cell hyperplasia associated with inflammatory bowel diseases can progress to colorectal NETs. In the lung, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia can give rise to peripherally-located low grade pulmonary NETs and tumourlets (neuroendocrine microtumours <5  mm). Rarely, secondary hyperplasias develop into autonomous neoplasms, as in tertiary hyperparathyroidism or pituitary thyrotroph adenomas in primary hypothyroidism. While some precursor lesions, such as thyroid C cell hyperplasia, represent frankly premalignant conditions, others may represent a sequence of proliferative changes from hyperplasia to benign neoplasia that may also progress to malignancy.

Gastrointestinal (GI) and neuroendocrine tumors (NETs) can be treated by mini-invasive endoscopic resection when localized in the superficial layers of the bowel wall and their size is <20 mm. Endoscopic diagnosis of NETs is usually incidental or suspected after clinical, laboratory or imaging findings. Endoscopic mucosal resection is the most commonly used technique for NET removal, endoscopic submucosal dissection is indicated in selected cases, while papillectomy is feasible for ampullary lesions. Histopathologic assessment of the resection margin (circumferential and deep) is important for staging. Incidence of endoscopic mucosal resection-/endoscopic submucosal dissection-related complications for removal of GI NETs are similar to those reported for other GI lesions. Endoscopic follow-up is based on histopathologic characteristics of the resected NETs and its site. NETs >20 mm in size, with penetration of the muscle layer and/or serosa are at high risk for metastases and surgical approach is recommended when feasible.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 <2%) or G2 (Ki67 2-20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 >20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.

The gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are composed of cells with a neuroendocrine phenotype. Well-differentiated tumors, well-differentiated carcinomas, poorly differentiated carcinomas, functioning tumors (with a hormonal syndrome), and nonfunctioning tumors are identified. To predict their clinical behavior, these neuroendocrine tumors are classified on the basis of their clinicopathological features, including size, local invasion, angioinvasion, proliferative activity, histological differentiation, and metastases, into neoplasms with benign, uncertain, low-grade malignant and high-grade malignant behavior. In addition, a tumor/nodes/metastases classification and a grading system are presented. In the light of these criteria, the various GEP-NET entities are reviewed.

The tumours of the disseminated/diffuse neuroendocrine cell system are a group of neoplasms sharing uniformly appearing cells which differ from each other in their biology, prognosis and genetics. In the lung they are called carcinoid and small/large-cell neuroendocrine carcinomas. In the gastroenteropancreatic compartment they are classified as well-differentiated neuroendocrine tumours or carcinomas and poorly differentiated neuroendocrine carcinomas. Depending on their localization these neoplasms reveal distinct phenotypes with respect to pathology, immunohistochemistry, and hormonal syndromes. Their clinical behaviour--ranging from benign and low-grade to high-grade malignancy--can be predicted on the basis of clinicopathological criteria. Currently extensive work is being performed to unravel the genetic background.

This review focuses on precursor lesions of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs). There are three conditions that are associated with hyperplastic changes in endocrine cells preceding GEP-NETs: autoimmune chronic atrophic gastritis or multiple endocrine neoplasia type 1 (MEN1) with gastric enterochromaffin-like (ECL) cell hyperplasia; MEN1 with gastrin and somatostatin cell hyperplasia in the duodenum and glucagon cell hyperplasia in the islets of the pancreas; and inflammatory bowel disease with endocrine cell hyperplasia in the colon. In gastric ECL cell hyperplasia, it is assumed that hypergastrinemia promotes the growth of the ECL cells of the corpus mucosa and leads to hyperplasia and neoplasia. In the duodenum and the pancreas, the MEN1-associated germline mutation of the menin gene obviously causes hyperplasia of the gastrin and somatostatin cells (duodenum) and the glucagon cells (pancreas), resulting in multifocal development of tumors. These tumors show allelic deletion of the MEN1 gene, whereas the precursor lesions retain their heterozygosity. The endocrine cell hyperplasia in the colon described in inflammatory bowel disease has neither a genetic nor a definite hormonal background.

Gastric carcinoid tumours are rare, but are increasing in incidence.

To discuss tumour pathogenesis and outline current approaches to patient management.

Review of published articles following a Pubmed search.

Although interest in gastric carcinoids has increased since it was recognized that they are associated with achlorhydria, to date there is no definite evidence that humans taking long-term acid suppressing medication are at increased risk. Type I tumours are associated with autoimmune atrophic gastritis and hypergastrinaemia, type II are associated with Zollinger-Ellison syndrome, multiple endocrine neoplasia-1 and hypergastrinaemia and sporadic type III carcinoids are gastrin-independent and carry the worst prognosis. Careful investigation of these patients is required, particularly to identify the tumour type, the source of hypergastrinaemia and the presence of metastases. Treatment can be directed at the source of hypergastrinaemia if type I or II tumours are still gastrin responsive and not growing autonomously. Type III tumours should be treated surgically.

Advances in our understanding of the pathogenesis of gastric carcinoids have led to recent improvements in investigation and management. Challenges remain in identifying the genetic and environmental factors, in addition to hypergastrinaemia, that are responsible for tumour development in susceptible patients.

For a long time, the assessment of malignancy risk and patient outcome in digestive endocrine tumors had to rely on sparse and mostly unconfirmed data. The 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded to be useful for clinical purposes, providing the basis for proper patient management and for designing treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories are considered: 1) well differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; 2) well differentiated endocrine carcinomas, low grade; and 3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the above categories are summarized. The relevance of additional features as for tumor prognostication, chiefly the Ki67 proliferation index and malignancy associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and midgut origin.

The diffuse neuroendocrine cell gives rise to a heterogeneous population of tumours which differ in their morphological and functional features. The term 'carcinoid', although well established in medical terminology, is therefore no longer adequate to cover the entire spectrum of neuroendocrine neoplasms. Here we use the term neuroendocrine tumours (NET), which was suggested in the WHO classification of 2000, and review the most important NET entities that are currently recognised in the gastrointestinal tract, highlighting their distinguishing features.

Gastrointestinal (GI) carcinoids are ill-understood, enigmatic malignancies, which, although slow growing compared with adenocarcinomas, can behave aggressively. Carcinoids are classified based on organ site and cell of origin and occur most frequently in the GI (67%) where they are most common in small intestine (25%), appendix (12%), and rectum (14%). Local manifestations--mass, bleeding, obstruction, or perforation--reflect invasion or tumor-induced fibrosis and often result in incidental detection at emergency surgery. Symptoms are protean (flushing, sweating, diarrhea, bronchospasm), usually misdiagnosed, and reflect secretion of diverse amines and peptides. Biochemical diagnosis is established by elevation of plasma chromogranin A (CgA), serotonin, or urinary 5-hydroxyindoleacetic acid (5-HIAA), while topographic localization is by Octreoscan, computerized axial tomography (CAT) scan, or endoscopy/ultrasound. Histological identification is confirmed by CgA and synaptophysin immunohistochemistry. Primary therapy is surgical excision to avert local manifestations and decrease hormone secretion. Hepatic metastases may be amenable to cytoreduction, radiofrequency ablation, embolization alone, or with cytotoxics. Hepatic transplantation may rarely be beneficial. Chemotherapy and radiotherapy have minimal efficacy and substantially decrease quality of life. Intravenously administered receptor-targeted radiolabeled somatostatin analogs are of use in disseminated disease. Local endoscopic excision for gastric (type I and II) and rectal carcinoids may be adequate. Somatostatin analogues provide the most effective symptomatic therapy, although interferon has some utility. Overall 5-year survival for carcinoids of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colonic carcinoids is 62%, and gastric type III/IV is 33%.

Although well established in medical terminology, the term carcinoid is no longer adequate to cover the entire morphological and biological spectrum of neoplasms of the disseminated neuroendocrine cell system. Therefore, instead of carcinoid, the WHO classification published in 2000 uses the general terms neuroendocrine tumor and neuroendocrine carcinoma. In this review a classification of gastroenteropancreatic neuroendocrine tumors based on the WHO criteria is described. We also classify and comment on the most important tumor entities. On the basis of localization and of various morphological and biological criteria, we distinguish between benign neuroendocrine tumors, tumors with uncertain malignant potential, and tumors showing low-grade and high-grade malignancy.

Activins and inhibins, which belong to the TGF beta family, are composed of different combinations of alpha-, betaA-, and betaB-subunits, resulting in inhibin A (alphabetaA), inhibin B (alphabetaB), activin A (betaAbetaA), activin B (betaBbetaB), and activin AB (betaAbetaB). They regulate several cell functions, acting as paracrine/autocrine factors. Their actions, which depend on binding to specific receptors, are also modulated by follistatin. Gastroenteropancreatic (GEP) endocrine cells and endocrine tumors (ETs) produce several growth factors, but it is not well known whether they express follistatin and the various inhibin/activin subunits. We studied their expression in 65 GEP ETs using immunohistochemistry (IHC) and in situ hybridization (ISH). The alpha-subunit and follistatin were not identified in normal GEP endocrine cells and were poorly expressed in ETs. A betaA-subunit immunoreactivity (IR) was detected in A-, G-, EC-, and GIP-cells, while betaB-chain IR was present only in D-cells. The mRNAs encoding for these molecules were poorly expressed in normal tissues. BetaA- and betaB-subunits were identified in several ETs by both IHC and ISH: betaA-subunit mainly in G-cell and A-cell ETs, and betaB-subunit in D-cell, A-cell, and EC-cell ETs. Our results demonstrate a differential expression of activin/inhibin subunits among different types of GEP endocrine cells and related tumors, suggesting a role in modulation of biological functions of these normal and neoplastic endocrine cells.

Endocrine tumors (ETs) of the digestive system produce several growth factors including acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), which are thought to be involved in the growth of tumor cells and in the proliferation of tumor stromal cells. Their actions depend on binding to four specific receptors--FGFR1, FGFR2, FGFR3, and FGFR4--whose distribution in normal endocrine cells and related tumors of the gastroenteropancreatic (GEP) system has previously been examined. Formalin-fixed, paraffin-embedded normal tissues and 60 well-characterized GEP endocrine tumors were immunostained using specific antibodies directed against various GEP hormones, aFGF, FGFR1, FGFR2, FGFR3, and FGFR4. Acidic FGF immunoreactivity (IR) was found in gut EC cells; FGFR1 immunoreactivity in rare duodenal endocrine cells and in pancreatic A cells; FGFR2 immunoreactivity in gastric and duodenal G cells, pancreatic B cells, and rectal EC cells; FGFR3 immunoreactivity in duodenal G cells; and FGFR4 immunoreactivity in rectal L cells and in pancreatic B, PP, and A cells. Immunoreactivity for at least one of the four FGFRs was found in all tumors, independently of FGFR expression in the putative cell of origin. EC cell tumors, which were all positive for aFGF, were found to express at least three different FGFRs. FGFRs also were localized in the stromal cells of all the tumors examined. The tumor stroma was more abundant in EC cell tumors than in other types of neoplasms. The results suggest that aFGF-FGFR interaction may be involved in the modulation of normal endocrine cell functions and in the regulation of tumor growth and stromal proliferation of EC cell carcinoids.

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53. p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors. p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P =.02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases. Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors.