gastrins and Pheochromocytoma

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Apudoma; Dehydration; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Parathyroid Neoplasms; Pheochromocytoma; Postgastrectomy Syndromes; Somatostatin; Syndrome; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Blood Glucose; Calcium; Endocrine System Diseases; Gastrins; Humans; Insulin; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Pheochromocytoma; Pituitary Neoplasms; Radioimmunoassay; Syndrome; Thyroid Neoplasms; Zollinger-Ellison Syndrome

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Using sequence-specific radioimmunoassays before and after cleavage with trypsin and carboxypeptidase B, we have examined the occurrence and molecular nature of cholecystokinin (CCK) and gastrin peptides in bioactive (i.e. alpha-carboxyamidated) as well as non-amidated precursor forms in extracts from 13 human pheochromocytomas. All but one tumour contained amidated CCK, but only in moderate amounts (less than or equal to 20 pmol/g tissue). In contrast to the complete sulphation in tissues which normally produce CCK (the brain and small intestine), the amidated adrenal CCK peptides were poorly sulphated (less than or equal to 17%). Four pheochromocytomas, including the one without amidated CCK, contained between 28 and 0.2 pmol amidated gastrin/g, mainly in the form of sulphated gastrin-17. In addition, all tumours contained biosynthetic precursors of both CCK and gastrin. In most extracts there was more precursor than bioactive peptide(s), the progastrin concentration ranging up to 338 pmol/g. The results show that pheochromocytomas synthesize CCK and gastrin. The posttranslational processing differs, however, markedly from that of the principal CCK and gastrin producing tissues, with respect to both proteolytic cleavages and amino acid derivatization. This emphasizes that accurate quantitation in tumours requires assays which measure the translation products irrespective of their degree of processing.

Topics: Adrenal Gland Neoplasms; Amides; Amino Acid Sequence; Cholecystokinin; Chromatography, Gel; Gastrins; Humans; Pheochromocytoma; Radioimmunoassay; Sulfates

A 30-year-old man presenting with watery diarrhea, hypokalemia, and hypochlorhydria (Verner-Morrison syndrome, WDHH syndrome) had raised plasma levels of vasoactive intestinal polypeptide (VIP), somatostatin (SRIF), calcitonin, and gastrin, as well as high urinary excretion of vanillylmandelic acid. A right adrenal pheochromocytoma was found and excised. The neoplastic cell population was immunohistochemically shown to contain VIP, SRIF, and calcitonin. Gross, histologic, and immunohistochemical evaluation of the pancreas revealed no abnormalities, whereas a marked hyperplasia of the gastrin-producing cells of the gastric antral mucosa was demonstrated. Postoperatively, the patient recovered from his symptoms and the plasma hormone levels returned to normal values. The clinical and histogenetic implications of this most unusual tumor of neural crest derivatives are discussed.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adult; Calcitonin; Gastrins; Histocytochemistry; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Male; Pheochromocytoma; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms

The relationship between serum catecholamines and serum gastrin in the basal state and in response to a liquid test meal was investigated in 6 patients with histologically proven pheochromocytoma before and after surgical removal of the tumor. Serum catecholamines were measured by a high performance liquid-chromatography technique, and serum gastrin was determined by radioimmunoassay. In patients with normal serum adrenaline, no increase in serum gastrin level in the basal state or after ingesting a test meal was found. In contrast, in those with abnormally high serum adrenaline, the serum gastrin levels in the basal state and in response to a test meal were significantly higher than in patients with a normal serum adrenaline level and in normal subjects. Surgical removal of the tumor resulted in a significant decrease in both the serum adrenaline concentration and serum gastrin secretion in the basal state and after meal stimulation. These results indicate that adrenaline stimulates serum gastrin secretion not only in the basal state, but also in response to a test meal.

Topics: Adrenal Gland Neoplasms; Adult; Chromatography, High Pressure Liquid; Eating; Epinephrine; Female; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Norepinephrine; Pheochromocytoma; Radioimmunoassay

Topics: Adrenal Gland Neoplasms; Adult; Animals; Catecholamines; Female; Gastrins; Humans; Male; Pheochromocytoma; Rats

A 51 year old man was found to have a malignant gastrinoma. A phaeochromocytoma had been diagnosed and removed previously. The occurrence of these two rare tumours in a single patient suggests the possibility of a crossover between MEA I and MEA II. Reported cases of the "crossover syndrome" are reviewed and the status of this phenomenon as a syndrome is discussed.

Topics: Adrenal Gland Neoplasms; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms, Multiple Primary; Pheochromocytoma; Stomach Neoplasms; Syndrome

Topics: Adrenal Gland Neoplasms; Carbohydrate Metabolism; Catecholamines; Gastrins; Glucose Tolerance Test; Humans; Insulin; Lipid Metabolism; Male; Middle Aged; Pheochromocytoma

Topics: Adrenergic alpha-Antagonists; Epinephrine; Gastrins; Humans; Phentolamine; Pheochromocytoma

Topics: Anemia, Pernicious; Bicarbonates; Duodenal Ulcer; Endocrine System Diseases; Esophagitis, Peptic; Esophagus; Gastric Juice; Gastrins; Humans; Hyperplasia; Intestines; Kidney Failure, Chronic; Pancreas; Pheochromocytoma; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

Serum gastrin radioimmunoassay (RIA) is a sensitive and specific method suitable for measurement of circulating concentrations of this peptide hormone, which is a major regulator of gastric acid secretion. When performed under optimal conditions this RIA permits measurement of low and normal serum gastrin levels and changes that occur after physiologic stimulation. Hypergastrinemia may be secondary to atrophy of the acid-secreting gastric mucosa. This form of pypergastrinemia is appropriate and leads to no seriousequences. Hypergastrinemia associated with gastric acid hypersecretion is inappropriate. The major cause is a gastrinsecreting tumor (gastrinoma) that produces the clinical picture of the Aollinger-Ellison syndrome. The differential diagnosis of inappropraite hypergastrinemia includes antral G-cell hyperplasia and ISOLATED RETAINED ANTRUM. Accurate diagnosis of these conditions may be aided by ancillary studies including feeding, secretin, and calcium stimulation tests. Distinction among these conditions is important in planning appropriate surgical tratment.

Topics: Antibody Specificity; Arthritis, Rheumatoid; Catecholamines; Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Kidney Failure, Chronic; Pentagastrin; Pheochromocytoma; Pyloric Antrum; Radioimmunoassay; Stimulation, Chemical; Stomach Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Animals; Catecholamines; Dogs; Epinephrine; Female; Gastrins; Humans; Kidney Neoplasms; Methods; Phenoxybenzamine; Pheochromocytoma; Radioimmunoassay; Time Factors

Topics: Adenoma, Islet Cell; Anemia, Pernicious; Cross Reactions; Duodenal Ulcer; Fasting; Gastrins; Humans; Peptides; Pheochromocytoma; Radioimmunoassay; Stomach Ulcer; Zollinger-Ellison Syndrome