Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Malignant Enterochromaffinlike Cell Carcinoid of the Gastric Stump: An Ultrastructural Study

A metastasizing carcinoid of the gastric stump found 25 years after Billroth II gastric resection for duodenal ulcer is described. Electron microscopy and optical endocrine cell staining proved the tumor to be composed of enterochromaffinlike (ECL) cells. This unusual combination further shows that, at variance with most of these tumors, ECL cell carcinoids may develop also in a condition excluding a trophic effect of gastrin. This case emphasizes the malignant behavior of gastrin-independent ECL cell tumors.     

Ghrelin expression in hyperplastic and neoplastic proliferations of the enterochromaffin-like (ECL) cells

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells—a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.     

Neuroendocrine differentiation in gastric adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia

Patients with hypergastrinemia secondary to achlorhydria have an increased risk of developing ECL cell carcinoids and gastric adenocarcinomas. Hypergastrinemia is central in the pathogenesis of ECL cell carcinoids, but the link between gastrin and gastric carcinomas is controversial. During neoplastic transformation ECL cells may, however, lose many of their neuroendocrine characteristics, making them difficult to recognise as neuroendocrine with conventional immunohistochemical techniques. Neuroendocrine differentiation was therefore examined in eight gastric adenocarcinomas found in seven patients with severe hypergastrinemia and/or pernicious anemia using a monoclonal antibody towards chromogranin A and immunohistochemistry without and with a sensitive signal amplification technique. The Sevier-Munger method was used as a more specific marker of ECL cells. Seven of the carcinomas contained scattered neuroendocrine tumour cells. When using signal amplification, an increase in the number of immunoreactive neoplastic cells was seen. In many tumours, clusters or confluent sheets of such cells were disclosed, suggesting a neuroendocrine and ECL cell origin. These tumours may therefore be ECL cell carcinomas and hypergastrinemia may thus be involved in the tumourigenesis.     

Smooth Muscle Cell Abnormalities Associated with Gastric ECL Cell Carcinoids

The histologic and immunohistochemical study of 45 ECL cell gastric carcinoids and of the extratumoral gastric mucosa revealed four variants of smooth muscle cell abnormalities: (1) hypertrophy of muscularis mucosae trapped within the tumors, a finding occurring in 76.5% of cases; (2) proliferation of stromal smooth muscle cells originating from the muscularis mucosae and mostly associated with tumor invasion of the submucosa (seen in 93.9% of cases with abundant stromal component of the tumors); (3) occurrence of frequent, prominent aggregates of smooth muscle cells in the lamina propria of the antral (but not of the fundic) mucosa of the stomach (found in 41.7% of cases); and (4) increased thickness of the extratumoral muscularis mucosae in the fundic (but not in the antral) mucosa of patients with gastric carcinoids. In addition, localized muscle cell proliferation was also associated with foci of micronodular hyperplasia of endocrine cells in the extratumoral mucosa. These findings were neither observed in control cases of gastric adenocarcinoma, gastric peptic ulcer, and duodenal peptic ulcer (10 unselected cases from each group) nor were they observed in 10 subjects with normal gastric mucosa collected at autopsy. With the possible exception of the increased thickness of the extratumoral fundic muscularis mucosae, which may be influenced by the mucosal inflammatory process, it is suggested that the present findings represent a proliferative response of smooth muscle cells to basic fibroblastic growth factor whose production by gastric carcinoids and their precursor lesions has recently been demonstrated.     

The regulation of gastric acid secretion – clinical perspectives

The purpose of this review, based upon 40 years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug‐induced hypo‐acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long‐term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet‐ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.     

Development of gastric carcinoids inmastomys during histamine2-receptor blockade

We have investigated the effect of histamine₂-receptor blockade on gastric carcinoid formation inMastomys, a rodent prone to develop gastric carcinoids. During long-term treatment (8–24 weeks) with loxtidine, a 3–5 fold increase in plasma gastrin levels was observed. Oxyntic mucosal histamine and histidine decarboxylase activity were increased 2 times and 4–10 times respectively in loxitidine-treated animals, as compared to controls. An increase in oxyntic mucosal thickness was also noted in all treated animals, while gross tumors were only observed in animals treated for 24 weeks. Immunocytochemical analysis of treated animals revealed a marked proliferation of chromogranin-positive cells in the oxyntic mucosa. These cells were identified as ECL cells because they were labeled by histamine antibodies, but not by gastrin-, somatostatin-or serotonin-antibodies. Hyperplasia of endocrine cells was noted after 8 weeks of treatment, while dysplastic lesions were seen after 16 weeks and the first micro- or macrocarcinoids after 24 weeks of treatment. No tumors, or hyperplastic changes, were observed in control animals. The results demonstrate that histamine₂-receptor blockade significantly enhances the development of gastric carcinoids inMastomys and suggest that hypergastrinemia may be important for the development of these tumors.     

Endocrine neoplasm of the stomach. Study of thirteen cases

A Thirteen patients with primary endocrine neoplasm of the stomach were studied for 20 years. Six patients were male and 7 female with an age range of 33 to 77, mean age 57 years. Nine cases corresponded to well differentiated carcinoids and four to neuroendocrine carcinomas. Of the former, three were sporadic and six were associated with atrophic gastritis. These two forms of neoplasm showed important differences: those associated with atrophic gastritis had hypergastrinemia, all of the multiple small tumors confined to the corpus and fundus were well differentiated carcinoids associated with intestinal metaplasia and G cell hyperplasia in antrum and ECL cell hyperplasia in corpus and fundus. Tumors were clinically benign, with an excellent prognosis. All patients are currently alive with no evidence of neoplasm. In only one of these cases, antiparietal cell antibodies were documented; in three of them, extensive intestinal metaplasia probably due to Helicobacter pylori infection was found. In contrast, sporadic carcinoids were large isolated tumors originating in the antrum or corpus. Two patients died as a consequence of the neoplasm; all of them were moderately differentiated and in none of the cases we found evidence of endocrine hyperplasia. All were positive for generic endocrine markers and were focally positive to some of the specific hormone markers. Al four neuroendocrine carcinomas had a clinical course similar to that of gastric adenocarcinomas and were poorly differentiated large tumors. We conclude that gastric carcinoids associated with atrophic gastritis have an excellent prognosis. On the other hand, neuroendocrine carcinomas have a very poor prognosis with fatal outcome of patients. Sporadic carcinoids have an intermediate prognosis.     

Pattern of gastric endocrine cells in microcarcinoidosis — an immunohistochemical study of 14 gastric biopsies

A total of 14 gastric biopsy specimens from patients with microcarcinoidosis were analysed by immunohistochemical methods to evaluate the pattern of endocrine cell hyperplasia and dysplasia. All the patients had type A gastritis (autoimmune gastritis). Nonantral proliferations of gastric endocrine cells were classifed according to Solcia et al. All 14 cases had hyperplasia and 13 (92.9%) of them, dysplasia of gastric endocrine cells; 9 (64.3%) of the 14 were found to have showed a coexisting invasive gastric carcinoid at the time of diagnosis of microcarcinoidosis. The patients with invasive carcinoids had higher degrees and more complex forms of endocrine dysplasia (precarcinoid lesions). The average size of the foci of the microcarcinoidosis in gastric biopsies was 0.14±0.09 cm in the patients without invasive carcinoid, as against to 0.5±0.24 cm in the group of patients with associated invasive carcinoid. Microcarcinoid gastric biopsies about 0.5 cm in size, are suggestive of adjacent invasive carcinoid. However, even frankly invasive ECL carcinoids seem to be clinically less dangerous than was thought until recently.     

Neuroendocrine tumors of the gastrointestinal tract

Neoplastic proliferations of neuroendocrine cells (NE) may occur throughout the entire GI tract but affect particularly appendix and ileum ("midgut carcinoids"), rectum ("hindgut carcinoids"), as well as stomach and the duodenum ("foregut carcinoids"). Only more exceptionally, they arise in the esophagus, jejunum and colon. The NE tumors encompass a heterogeneous gross and microscopic structural spectrum, ranging from inconspicuous microproliferations ("mucous membrane nevi") to bulky tumor masses. Their growth patterns are usually characteristic and easily recognized. In doubtful cases their NE differentiation becomes established by a characteristic silver affinity, by the ultrastructurally observed presence of characteristic "endocrine" secretion granules, and by immunohistochemically detectable occurrence of "pan-NE markers" (neuron-specific enolase, chromogranins, and synaptophysin), biogenic amines (mainly serotonin), and neurohormonal peptides. Foregut carcinoids usually contain serotonin, gastrin, and somatostatin, midgut carcinoids often only serotonin and tachykinins, whereas the hindgut carcinoids as a rule are multihormonal with a wide spectrum of hormonal peptides, including even insulin. Most GI NE tumors are found in the appendix (50%) and the ileum (30%). Practically all (98%) of the appendiceal NE tumors are benign. They have recently been proposed as arising from apparently Schwann-cell-related NE cells in the submucosa, whereas the ileal--and probably also all the other non-appendiceal NE tumors--are derived from the totipotential cells in epithelial crypts of the mucosa. Among the ileal NE neoplasms a large number can metastasize and result in a fatal outcome. The ability to metastasize is related to the size and to the multiplicity of the primary tumors at the time of initial diagnosis and, to some extent, to their histopathologic growth pattern. Now, some relationship between the prognosis and the cytochemically assessed nuclear DNA content of the NE tumor cells has also been established; not less than about 1/4 to 1/3 seem to be aneuploid. Almost 90% of the rectal carcinoids are benign. Exceptionally, a highly malignant NE neoplasms can arise from the colon/rectum--as well as from the esophagus--composed of NE cells of small and intermediate size. The NE tumors of the stomach are often composed of ECL (enterochromaffin-cell-like) cells; such ECL cell carcinoids are related to atrophic gastritis with pernicious anemia; experimentally, they can be induced by hypergastrinemia in rats. Duodenal carcinoids often contain psammoma bodies and can be associated with neurofibromatosis.     

Ultrastructural characterization of fundic endocrine cell hyperplasia associated with atrophic gastritis and hypergastrinaemia

Summary Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D₁ cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D₁ cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D₁ and P cells, if any, remains obscure.Abbreviations EC enterochromaffin cells, producing 5-hydroxytryptamine - ECL enterochromaffin-like cells - D somatostatin producing cells - D₁ cells with small granules showing some characteristics of granules of D cells - P cells with small granules similar to those of pulmonary (P) endocrine cells - X gastric endocrine cells with large, dense granules. Unless specified, the secretory product of these cells is unknown Supported by grants from the Italian Ministry of Public Education and from the A.I.R.C. (Associazione Italiana per la Ricerca sul Cancro)     

Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors

The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent accumulation of biogenic amine inside the secretory granules of endocrine cells and neurons and was demonstrated in the histamine-producing enterochromaffin-like (ECL) cells of the stomach. In the present investigation, VMAT2 immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated (neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2 parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2 immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12 of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach (differentiated cells only). No VMAT2 immunoreactivity was observed in five gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths, and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2 immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell tumors, separating them from all other endocrine tumors arising in the gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of which proved essentially negative. Received: 28 June 1999 / Accepted: 20 October 1999     

The origin of subdural neomembranes. I. Fine structure of the dura-arachnoid interface in man.

A patient with atrophic gastritis and excessively raised serum gastrin concentrations (4000 to 5000 pg/ml) was found to have multiple polypous tumors of the gastric corpus mucosa. Following gastrectomy, serum gastrin concentrations decreased to undetectable levels. The tumors consisted of a mixed population of endocrine cells. The majority of tumor cells were of the ECL type, but, in addition, enterochromaffin cells of various subtypes as well as agranular cells were found. The tumors were locally invasive and invaded the walls of submucosal blood vessels. The surrounding mucosa showed a severe atrophic gastritis with intestinalization and contained numerous goblet cells, enterochromaffin cells, and cholecystokinin cells. Cholecystokinin cells do not occur in the normal oxyntic mucosa. Hence, the observation of this cell type in intestinalized gastric epithelium suggests that "intestinalization also is associated with changes in endocrine cell populations. Gastrin has been shown to affect the function of the ECL cells. Indications for a trophic action of gastrin on these cells have been obtained. It is discussed whether greatly raised serum gastrin levels in patients with atrophic gastritis may be associated with increased risks for the development of certain types of gastric tumors.     

ECL‐cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H+K+ATPase alpha subunit

A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H⁺K⁺ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL‐cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL‐cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL‐cell differentiation.     

Neuroendocrine Pathology of the Stomach: The Parma Contribution

The current knowledge on gastric neuroendocrine pathology essentially developed in the last four decades. The historical evolution of the concepts and of the relevant clinical implications is described from the perspective of a group actively participating in this research domain. The histamine-producing enterochromaffin-like (ECL) cells have been recognized as the leading cell type involved in the most significant alterations of gastric neuroendocrine cells. The trophic stimulus exerted by circulating gastrin has been demonstrated to have a crucial role on proliferative changes of ECL cells through a sequence of hyperplasia-dysplasia-neoplasia described by Solcia et al. (Digestion 41:185-200,1988). The development of ECL cell tumors in rats treated with toxicological doses of inhibitors of gastric acid secretion prompted appropriate anatomoclinical investigations proving the lack of tumor risk in humans when therapeutic dosages of the drugs are used. Moving from the comprehensive concept of gastric carcinoid, different types of neuroendocrine tumors have been identified in the stomach with substantial variations in prognosis and treatment options. In general, ECL cell tumors developed in hypergastrinemic conditions were found to behave better than those originating outside the setting of hormonal stimulation. Pathological features highly predictive of patient survival have been described. The genetic changes involved in tumor development and progression have revealed substantial overlapping with those of neuroendocrine tumors of other foregut derivatives (i.e., pancreas, duodenum, lung) delineating a family of neuroendocrine tumors genetically distinct from those of the distal parts of the digestive system.     

Clinical and histopathological tumour progression in ECL cell carcinoids ("ECLomas")

AIMS: The aims of this study were to illustrate the malignant potential of gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) associated with hypergastrinemia, and the gradual neoplastic progression of such tumours. In addition, we examined whether the tyramide signal amplification (TSA) technique could visualize immunohistochemical (IHC) neuroendocrine (NE) features in the dedifferentiated neoplastic ECL cells which were not detected by conventional methods. METHODS: Conventional histopathological and IHC methods for visualizing ECL cells and cell proliferation were used in addition to the TSA technique. OBSERVATIONS: Our patient was followed for 5 years. During that period, her ECLoma displayed all the signs of classical tumour progression, ultimately with the appearance of metastases in the regional lymph nodes, the liver and the skin. The neoplastic ECL cells became progressively dedifferentiated with an increasing number of Ki-67 immunoreactive (IR) cell nuclei. In addition, there was a substantial decrease in argyrophil and IR NE cells that could be visualized by conventional methods. By applying the TSA technique, however, the number of IR tumour cells increased considerably. CONCLUSIONS: ECLomas secondary to hypergastrinemia should be closely followed for signs of clinical and histopathological tumour progression. Such ECLomas deserve early, active, radical surgical treatment. The TSA technique is a valuable tool for visualizing the characteristic IHC features in dedifferentiated NE cells.     

Galectin-4 expression in carcinoid tumors

Galectins (Gal) are an evolutionarily conserved family of 15 carbohydrate-binding proteins (lectins) that are widely distributed in normal and neoplastic cells in a wide range of organisms. They have roles in inflammation, cell adhesion, tumor progression, and metastasis. The function and distribution of Gal-3 and Gal-1 are well characterized, but less information is available about Gal-4. Recent studies have localized Gal-4 in the enterochromaffin cells of the porcine and murine small intestine. We examined the expression of Gal-4 in primary and metastatic human ileal carcinoid tumors as well as in carcinoid tumors of the stomach, lung, and rectum. A total of 44 primary and 42 ileal metastatic carcinoid tumors were examined by immunohistochemistry using tissue microarrays (TMA) with monoclonal antibodies to Gal-4, Gal-3, and Gal-1. Pulmonary (n=7), rectal (n=6), and gastric (n=6) carcinoids were examined with larger tissue sections. A total of 18 pancreatic neuroendocrine tumors were also examined with larger tissue sections. Western blots of three ileal carcinoids were also done. Gal-4 was most highly expressed in the ileal carcinoids and the levels of expression tended to be higher in primary ileal carcinoids compared to the metastatic tumors (p=0.069). All 18 pancreat neuroendocrine tumors were negative for Gal-1, Gal-3, and Gal-4. Western blot showed a 32 kDa band for Gal-4 in the ileal carcinoids. Gal-3 and Gal-1 were not detected in the metastatic ileal carcinoids by Western blotting. Gastric carcinoids also expressed Gal-4, but very few pulmonary or rectal carcinoids were positive for Gal-4 (p=0.002). Lower levels of Gal-1 and Gal-3 expression were present in ileal carcinoids compared to primary pulmonary and rectal tumors. These results show a differential distribution of Gal-4 in carcinoid tumors in different locations of the gastrointestinal tract and the lungs.     

Endocrine Precursor Lesions of Gastroenteropancreatic Neuroendocrine Tumors

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.     

Expression of the alpha subunit of human chorionic gonadotropin in normal and neoplastic neuroendocrine cells. An immunohistochemical study

The alpha subunit of human chorionic gonadotropin (HCG) was localized Immunohistochemically in paraffin sections of normal human tissues and neuroendocrine tumors. A small subset of dispersed neuroendocrine cells was positive in normal adult tissues, including gastric antrum, urachal remnant, anal glands and prostate. Positive cells were consistently present in perinatal lung but rare in adult lung. In contrast, the beta subunit was absent from these cells. Seventy-two of 151 extrapituitary neuroendocrine tumors (48%) were alpha subunit-positive. Thirty-three of 37 bronchial carcinoids (92%) were immunoreactive, with a high percentage of the tumors (54%) containing moderate to large numbers of positive cells. The alpha subunit was further demonstrated in 9 of 45 small cell lung carcinomas (20%), 19 of 35 extrapulmonary carcinoids (54%), 3 of 11 islet cell tumors (27%) and 8 of 13 medullary thyroid carcinomas (62%). Two of three malignant islet cell tumors were positive. Positive cells were usually few in number, except for two small cell lung carcinomas, two rectal carcinoids, one thymic carcinoid and one malignant islet cell tumor. Pheochromocytomas (n = 10) were negative. Eleven of 19 pulmonary tumorlets (58%) were alpha subunit-immunoreactive. A few beta subunit-positive cells were detected in only 6 lung lesions. The physiological significance of the imbalance of expression of HCG subunits by certain neuroendocrine cells and their tumors remains unknown.