gastrins and Ovarian-Neoplasms

Gastrin producing ovarian tumor is a rare cause of the Zollinger-Ellison syndrome. We report the case of an ovarian carcinoma showing increased plasma gastrin concentration. A 60-yr-old woman presented with epigastric pain and diarrhea. Physical examination showed a large mass in the lower abdomen. Computed tomography revealed a large multilocular ovarian cyst. Upper gastrointestinal endoscopy examination showed multiple ulcerations of the stomach and duodenum. The plasma gastrin level was 1500 pg/ml. No tumors were found in the pancreas and duodenum, and salpingo-oophorectomy was performed. Histologic examination revealed a mucinous tumor of borderline malignant potential. Immunoperoxidase studies for gastrin showed many gastrin-producing cells within the epithelium of the tumor. There have been 11 cases (including our patient) of gastrin-producing ovarian tumor reported in the literature. We review here the relevant literature. Although ovarian gastrinoma is extremely rare, it should be considered as a possible cause of the Zollinger-Ellison syndrome in women.

Topics: Adenocarcinoma, Mucinous; Female; Gastrins; Hormones, Ectopic; Humans; Middle Aged; Ovarian Neoplasms; Zollinger-Ellison Syndrome

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

Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

Topics: Cell Line; Cell Line, Tumor; Cells, Cultured; Female; Fenofibrate; Fluorescent Antibody Technique; Gastrin-Secreting Cells; Gastrins; Humans; Immunohistochemistry; Ovarian Neoplasms; Phytohemagglutinins; PPAR alpha; Pyloric Antrum; Receptors, Dopamine D1; RNA, Messenger; Sodium Chloride

We report a rare case of an ovarian mucinous cystadenoma in which there were peculiar neuroendocrine micronests composed of gastrin-immunoreactive cells. There was no clinical evidence of hypergastrinemia. The mucinous component of the neoplasm was represented by columnar cells mostly expressing a gastric phenotype with MUC5AC and claudin 18 positivity, which was consistent with the presence of interspersed gastrin cells. The tumoral stroma displayed areas of luteinization with cells intensely positive for α-inhibin, MART-1 and calretinin.

Topics: Biomarkers, Tumor; Cystadenoma, Mucinous; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Middle Aged; Neuroendocrine Cells; Ovarian Neoplasms

Gastrin-secreting tumors have been identified in ectopic locations including the ovary; the mechanisms regulating gastrin gene expression, its distribution, and signaling pathways in these ectopic tissues are not known. The purpose of our present study was to determine: (1) whether the gastrin gene and peptide could be detected in ovarian cancer cell lines, (2) if functional gastrin releasing peptide receptors (GRP-R) are present, and (3) whether gastrin gene expression is altered by GRP. Five ovarian cancer cell lines (SW626, OVCA 420, OVCA 429, OVCA 432, and OVCA 433) were analyzed. We identified gastrin gene and peptide expression in the SW626 cell line but not in the OVCA lines. SW626 cells express a functional GRP-R that is correctly coupled to the Ca2+ signaling pathway. Treatment of SW626 cells with bombesin, the amphibian equivalent of GRP, inhibited expression of the gastrin gene in a time- and dose-dependent fashion. The SW626 ovarian cancer cell line will provide a useful model to further define regulation and expression of both the gastrin gene and peptide in ectopic (nongastrointestinal) tissues.

Topics: Blotting, Northern; Blotting, Southern; Bombesin; Cystadenocarcinoma; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Ovarian Neoplasms; Polymerase Chain Reaction; Radioimmunoassay; Receptors, Bombesin; Tumor Cells, Cultured

Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.

Topics: Autoradiography; Breast Neoplasms; Carcinoma, Small Cell; Cholecystokinin; Female; Gastrins; Humans; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Thyroid Neoplasms

Gastrin synthesis in ovarian tumors has been described in a few isolated cases associated with the Zollinger-Ellison syndrome. Consequently, ovarian gastrin synthesis has been considered exceptional. In order to evaluate whether expression of gastrin in ovarian tumors indeed is rare, we examined the expression and processing of progastrin in 16 malignant and 5 benign ovarian tumors and 4 normal postmenopausal ovaria. Using a library of sequence specific radioimmunoassays, cleavage by processing-like enzymes, and gel chromatography, we found that one-half of the malignant tumors expressed significant concentrations of amidated gastrins [6.7 +/- 2.7 (SEM) pmol/g; range, 1.4-20.0 pmol/g, n = 7]. The concentrations of glycine-extended gastrins and progastrins were low (0.25 +/- 0.03 and 1.4 +/- 0.4 pmol/g, respectively) but higher than in controls and benign tumors. Chromatography showed that the majority of the bioactive gastrins was unsulfated gastrin-17. The other half of the malignant tumors expressed glycine-extended gastrins and progastrins (0.2 +/- 0.03 and 0.6 +/- 0.1 pmol/g; n = 9), but the amidation of the peptides was impaired (0.1 +/- 0.03 pmol/g). Low concentrations of glycine-extended gastrins and progastrins were detected in the normal ovarian tissues (0.2 +/- 0.05 pmol/g tissue and 0.2 +/- 0.06 pmol/g, respectively, n = 4) and in the benign tumors (0.1 +/- 0.02 pmol/g and 0.5 +/- 0.03 pmol/g; n = 5). Amidated gastrins were undetectable, except in low amounts in a single benign tumor (0.2 pmol/g tissue). The results show that postmenopausal ovaria and neoplastic ovarian tissues express the gastrin gene at peptide level. The synthesis and processing of progastrin increase considerably in malignant tumors.

Topics: Cholecystokinin; Female; Gastrins; Humans; Ovarian Neoplasms; Protein Precursors

Our experience with 47 sporadic gastrinomas suggests that no less than 85% of these tumors are located to the right of the superior mesenteric artery. This finding is unexpected because approximately 75% of insulinomas and glucagonomas are located to the left of the superior mesenteric artery. All of our extrapancreatic gastrinomas have been located to the right. These observations prompted us to determine if other extrapancreatic gastrinomas were also predominantly located to the right side. We searched the world's literature and found 10 cases of ovarian gastrinomas and one case of a renal gastrinoma. Nine of these remote extrapancreatic gastrinomas were located on the right side. This distribution of remote extrapancreatic gastrinomas is similar to our experience with peripancreatic gastrinomas. This unexpected right-sided preponderance of both remote and peripancreatic gastrinomas suggests a common origin for both.

Topics: Adult; Aged; Female; Gastrinoma; Gastrins; Humans; Kidney Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Ovarian Neoplasms; Secretin

A Zollinger-Ellison syndrome due to an ovarian mucinous cystadenoma of borderline malignancy is reported in a 76-year-old woman. Immunostaining procedures showed reactivity for gastrin in neoplastic cells. After operation, the patient has remained without symptoms for 6 years. This is the fifth case reported in the literature. All of these ovarian tumors were considered mucinous cystadenomas histologically.

Topics: Aged; Cystadenoma; Female; Gastrins; Hormones, Ectopic; Humans; Ovarian Neoplasms; Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome in a 76-year-old woman is reported. The source of the hypergastrinemia proved to be an ovarian cystadenocarcinoma. Resection was performed and the diagnosis was confirmed histologically, immunohistochemically and by determination of gastrin in tumor tissue and in serum. The long-term result was good.

Topics: Aged; Cystadenocarcinoma; Female; Gastrins; Hormones, Ectopic; Humans; Ovarian Neoplasms; Zollinger-Ellison Syndrome

We report a patient with severe peptic ulcer disease and a right ovarian mass that was found to be a gastrin-producing cystadenocarcinoma. Gastrin production by the tumor was stimulated by secretin and inhibited by the long-acting somatostatin analogue SMS 201-995. Following resection of the tumor, serum gastrin levels and the gastrin response to secretin returned to normal. Histologic examination, including Alcian blue staining for mucin and immunoperoxidase staining for gastrin, revealed gastrin at the base and mucin at the apex of the tumor cells. This report demonstrates secretin stimulation and somatostatin inhibition of gastrin secretion from a cell that is apparently not of endocrine origin.

Topics: Cystadenocarcinoma; Female; Gastrins; Humans; Immunoenzyme Techniques; Middle Aged; Octreotide; Ovarian Neoplasms; Ovary; Peptic Ulcer; Secretin; Staining and Labeling

Zollinger-Ellison syndrome is usually caused by a gastrin-secreting tumor in or near the pancreas. We describe a patient in whom an ovarian cystadenocarcinoma was the cause of the syndrome. The patient presented with a short history of peptic ulceration and development of a large pelvic mass. Investigations demonstrated a basal acid output of 37.8 mEq/h and a maximal acid output of 36.0 mEq/h, and the plasma concentration of gastrin was 830 pg/ml (normal less than 100). Secretin and calcium infusion tests were positive, and a meal test was compatible with Zollinger-Ellison syndrome. Imaging studies demonstrated a normal liver and pancreas but a large cystic right ovarian mass. Resection of the mass resulted in a marked reduction in gastric acid output, a fall in plasma gastrin concentration to normal, negative calcium and secretin tests, and a normal (positive) meal test. Histology of the mass showed it to be a mucinous cystadenocarcinoma. The tumor stained with immunoperoxidase technique was positive for gastrin, and the cyst fluid contained high concentrations of gastrin and calcitonin. One year later, the patient has no biochemical or imaging evidence of tumor. Ovarian, gastrin-producing tumors and pancreatic gastrinomas cannot be distinguished by provocative tests, and negative imaging studies do not exclude a pancreatic tumor. Patients with an ovarian mass and Zollinger-Ellison syndrome should have a bilateral oophorectomy and a careful exploration of the pancreatic area.

Topics: Cystadenocarcinoma; Female; Gastric Acid; Gastrins; Humans; Immunoenzyme Techniques; Middle Aged; Ovarian Neoplasms; Ovary; Zollinger-Ellison Syndrome

An ovarian gastrinoma would appear to be an extremely rare cause of the Zollinger-Ellison syndrome. Nevertheless, two consecutive cases of Zollinger-Ellison syndrome seen at our institution each proved to be caused by a gastrin-producing ovarian mucinous cystadenoma. That the ovarian tumor was the source of gastrin production was established by preoperative and postoperative gastrin and gastric secretory studies and by specific immunocytochemistry of the excised tissue. After oophorectomy, each patient was apparently cured of the disease. Ovarian gastrinomas may not be as uncommon as is generally believed and should be considered as a possible cause of the Zollinger-Ellison syndrome in any female patient in whom a primary gastrointestinal or pancreatic tumor cannot be located.

Topics: Adult; Cystadenoma; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Ovarian Neoplasms; Zollinger-Ellison Syndrome

We report a case of a clinically and biologically typical hypergastrinemia syndrome due to ovarian mucinous cystadenoma. When examined under histoimmunofluorescence, this "border-line" tumor was shown to contain a polymorphous endocrine cell proliferation, composed primarily of G cells and, to some degree, of D cells. Electron microscopic study further evidenced a small amount of prolactin containing cells, which coincided with elevated prolactin-levels in blood. Ovariectomy combined with vagotomy and pyloroplasty resulted in a prompt disappearance of both clinical and biological abnormalities. Ovarian mucinous cystadenomas have been known for a long time to contain endocrine cells, but only five cases, including the present one, have been described with fully developed endocrine expression. We suggest that this particular condition could be more frequent than generally admitted, and could justify systematic screening for mucinous cystadenoma in the case of peptide hormone dysfunction.

Topics: Adult; Cystadenoma; Female; Gastrins; Humans; Hyperprolactinemia; Ovarian Neoplasms; Syndrome

The localization of peptide hormones and serotonin in ovarian mucinous and endometrioid tumors with argyrophil cells was examined by immunohistochemistry. All of the 15 mucinous tumors had argyrophil cells which resemble the enterochromaffin cells seen in the gastrointestinal tract, and peptide hormones such as gastrin and somatostatin were found in 3 of 5 benign, in 3 of 5 borderline, and in all of 5 malignant tumors. Serotonin was found in 4 benign, 3 borderline and 2 malignant tumors. Of 19 endometrioid adenocarcinomas, type I argyrophil cells which resemble enterochromaffin cells were found in 4 tumors, type II argyrophil cells which contain argyrophil granules mainly in the apical portion or throughout the whole cytoplasm were found in 14, and mixed type cells were found in one. Somatostatin-positive cells were found only in type I cells of a tumor with mixed type argyrophil cells. Serotonin-positive cells were found in 3 tumors containing type I cells. The results obtained were discussed in the comparison with those of cervical and endometrial adenocarcinomas of the uterus. In conclusion, the present study suggests that type I or similar argyrophil cells in ovarian tumors may have endocrine activity.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antibodies, Monoclonal; Endometriosis; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Ovarian Neoplasms; Serotonin; Somatostatin

Examples of mucinous tumors from retroperitoneum (2) and pancreas (1) were studied. These tumors share many morphological similarities with ovarian mucinous tumour and adenoma malignum of uterine cervix. They have a similar spectrum of endocrine cells; serotonin, somatostatin, gastrin and pancreatic polypeptide cells were characterized. In nonproliferative areas was found a well-differentiated mucinous columnar epithelium with scarce endocrine cell. In more proliferative areas were found either a mucinous columnar lining with infolds and secondary glands or a less well-differentiated intestinal-type epithelium with papillary formations; both linings were well supplied in endocrine cells.

Topics: Adenocarcinoma; Adult; Endocrine Glands; Epithelium; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Humans; Ovarian Neoplasms; Pancreatic Neoplasms; Pancreatic Polypeptide; Retroperitoneal Neoplasms; Serotonin; Somatostatin; Uterine Cervical Neoplasms

Topics: Adult; Cystadenoma; Female; Gastrins; Humans; Ovarian Neoplasms; Secretory Rate; Zollinger-Ellison Syndrome

Forty-five cases of mucinous tumors of the ovary were studied for argyrophilia. Argyrophil cells were identified in seven of the 22 cystadenomas (32%), five of the 11 borderline tumors (45%), and two of the 12 carcinomas (17%). These 14 tumors and two additional mucinous tumors known to contain argyrophil cells were studied further by immunohistochemical methods for the localization of calcitonin, gastrin, somatostatin, adrenocorticotropin (ACTH), serotonin, neurotensin, and lysozyme. Serotonin immuno-reactivity was identified in 15 of the 16 cases. Among the peptide hormones, there was a high frequency of positivity for ACTH, gastrin, and somatostatin. Despite the demonstration of reactivity for these hormones, there was no clinical evidence of syndromes of hormone excess in the patients. Lysozyme was present in all but one of the benign and borderline tumors, but was not identified in the carcinomas. Lysozyme was also found in normal and neoplastic gastric and endocervical epithelium, indicating that its presence is not useful in differentiating gastrointestinal and müllerian-type epithelium. The results of this study confirm the previously recognized intestinal characteristics of the epithelium of many mucinous tumors, but also raise the question whether the simple, uniformly mucinous epithelium that is most common within these tumors and is generally regarded as endocervical in type may occasionally be gastric in nature.

Topics: Adrenocorticotropic Hormone; Calcitonin; Cystadenocarcinoma; Cystadenoma; Endothelium; Female; Gastrins; Humans; Immunoenzyme Techniques; Muramidase; Neurotensin; Ovarian Neoplasms; Serotonin; Silver; Somatostatin; Staining and Labeling

We report a patient with abdominal pain, diarrhea, and edema of the small intestine all of which disappeared after resection of an ovarian mucinous cystadenoma of borderline malignancy. Preoperatively, the serum gastrin level was high and it decreased to normal afterwards; subsequent immunohistochemical studies of the tumor revealed cytoplasmic hormone granules containing gastrin-like immunoreactivity. We believe that the symptoms in our patient were the result of an ectopic ovarian gastrin-producing tumor.

Topics: Adult; Cystadenoma; Female; Gastrins; Hormones, Ectopic; Humans; Ovarian Neoplasms

Topics: Adenocarcinoma, Mucinous; Adolescent; Adult; Child; Female; Gastrins; Histocytochemistry; Humans; Immunoenzyme Techniques; Microscopy, Electron; Ovarian Neoplasms; Serotonin; Silver; Somatostatin; Staining and Labeling

Topics: Adult; Aged; Cholecystokinin; Cystadenocarcinoma; Cystadenoma; Enkephalins; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Middle Aged; Neurotensin; Ovarian Neoplasms; Somatostatin

Topics: Cystadenocarcinoma; Female; Gastrins; Humans; Middle Aged; Ovarian Neoplasms; Zollinger-Ellison Syndrome

Techniques for evaluating ectopic gastrin production associated with the Zollinger-Ellison syndrome are described. The site of gastrin production in this example was a mucinous cystadenoma of the ovary confirmed by immunoperoxidase localization of gastrin within the ovarian tumor cells and by radioimmunoassay of the tumor's gastrin content. These methods, localizing the source of ectopic gastrin, permitted conservative management of the ulcer diathesis with surgical resection of the mucinous cystadenoma. After oophorectomy the patient's serum gastrin level returned to normal, and the ulcer diathesis ceased.

Topics: Cystadenoma; Female; Gastrins; Hormones, Ectopic; Humans; Middle Aged; Ovarian Neoplasms; Ovary; Radioimmunoassay; Zollinger-Ellison Syndrome

Topics: Cystadenoma; Female; Gastrins; Humans; Middle Aged; Ovarian Neoplasms; Radioimmunoassay; Zollinger-Ellison Syndrome