Metastatic Islet Cell Tumor Research Articles

Cholecystokinin expression in tumors: biogenetic and diagnostic implications.

Cholecystokinin (CCK) is a classic gut hormone. CCK is also a complex system of peptides expressed in several molecular forms in enteroendocrine I cells, in cerebral and peripheral neurons, in cardiac myocytes and spermatozoa. CCK gene expression has now been found at protein or peptide level in different neuroendocrine tumors; cerebral gliomas and astrocytomas and specific pediatric tumors. Tumor hypersecretion of CCK was recently reported in a patient with a metastatic islet cell tumor and hypercholecystokininemia resulting in a novel tumor syndrome, the cholecystokininoma syndrome. This review presents an overview of the cell-specific biogenesis of CCK peptides, and a description of the CCK expression in tumors and of the cholecystokininoma syndrome. Finally, assays for the diagnosis of CCK-producing tumors are reviewed.

GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP-NETs) - APPROACH TO DIAGNOSIS AND MANAGEMENT.

Neuroendocrine tumors comprise heterogeneous group of neoplasms which originate from endocrine cells, both within endocrine organs and within the cells of diffuse endocrine system. These tumors have variable clinical behavior ranging from well-differentiated, slow growing tumors to poorly-differentiated, highly invasive malignancies. These tumors generally fall into two broad categories; A group of neuroendocrine tumors that has the biology and natural history of a high grade malignancy and a characteristic small cell with undifferentiated or anaplastic appearance by light microscopy. WHO classifies this group of tumors as poorly differentiated neuroendocrine carcinomas. A typical example is the small cell lung cancer. The second group has variable but most often indolent biological behavior and characteristic well-differentiated histologic features. The majority of these tumors arise in the gastrointestinal tract and collectively, they are referred to as gastroenteropancreatic neuroendocrine tumors (GEP-NETs)1,2. Gastroenteropancreatic neuroendocrine tumors can also be classified as functioning or non-functioning tumors. The term “non-functioning” refers to the absence of clinical syndromes of hormonal hypersecretion. The functioning tumors include insulinoma, glucagonoma, gastrinoma, VIPoma and somatostatinoma. Clinical Presentation and Natural History The clinical course of patients with GEP-NETs is highly variable. Some patients with indolent tumors remain symptom free for year even without treatment. Most patients with non-functioning tumors due to lack of symptoms related to hormonal hypersecretion are diagnosed late in the course of the disease. Clinical signs and symptoms are due to tumor mass with local invasion and distant metastases. These symptoms may include abdominal pain, weight loss, anorexia, nausea, jaundice, intra-abdominal mass and bleeding. Patients with functioning metastatic islet cell tumors typically manifest with symptoms caused by specific type of hormone produced by the tumor. With metastatic carcinoids, the secretion of serotonin and other vasoactive substances causes the carcinoid syndrome which manifests as episodic flushing, wheezing, diarrhea, pellagra- like skin lesions and eventual right-sided valvular heart disease. The carcinoid syndrome is most commonly seen with mid-gut carcinoid tumors (small intestine, appendix and proximal large bowel) and mostly in the setting of metastatic disease3,4,5,6. Tumor Clinical Syndrome Hormone Insulinoma Hypoglycemia Pro-insulin, Insulin Gastrinoma (ZE Syndrome) Peptic ulcer, diarrhea Gastrin VIPoma (VM Syndrome) Watery diarrhea, hypokalemia VIP Glucagonoma Anemia, diabetes, NME Glucagon Somatostatinoma Diabetes, diarrhea, steatorrhea Gallstones Somatostatin GHFRoma Acromegaly GHFR ACTHoma Cushing’s syndrome ACTH ZE- Zollinger-Ellison, VM-Verner-Morrison, VIP-Vasoactive intestinal peptide, GHFR- Growth hormone releasing factor, ACTH-Adenocorticotropic hormone, NME- Necrolytic migratory erythema.

Intraductal Spread by Metastatic Islet Cell Tumor (Well-differentiated Pancreatic Endocrine Neoplasm) Involving the Breast of a Child, Mimicking a Primary Mammary Carcinoma

Metastases to the breast are rare, accounting for an estimated 1% to 2% of malignant breast neoplasms. The key histopathologic features supporting a metastasis to the breast have been stated to be the absence of elastosis, presence of a pushing border (circumscribed lesion), multiple satellite foci, lymphatic emboli, and, most importantly, the absence of an in situ carcinoma component. We report a unique case of a pancreatic islet cell tumor metastatic to the breast of an 18-year-old girl. Clinically, the patient was thought to have a mammary primary because on her initial biopsy, the metastasis grew within mammary ducts and colonized a complex sclerosing lesion, simulating an in situ component. However, review of slides from the prior pancreatic neoplasm, review of slides from the subsequent mastectomy, and use of immunohistochemistry allowed recognition of the lesion as a metastasis, which proved to be the first clinical manifestation of a systemic relapse. To our knowledge, this is the second case of islet cell tumor reported to metastasize to the breast, and the first report of a metastasis proven to have grown within existing ducts of the breast by immunohistochemistry.

Differences in Survival for Patients With Resectable Versus Unresectable Metastases From Pancreatic Islet Cell Cancer

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

Detection of Photofrin Fluorescence From Malignant and Premalignant Lesions in the Bronchus using a Full‐color Endoscopic Fluorescence Imaging System

Study objectives: To detect invisible lung cancer and to determine field of laser radiation during PDT we developed a full-color fluorescence fiberscopic system. We tested the efficacy of this system in patients with various bronchial malignancies. System design: A fiber-optic endoscope was attached to a camera box containing a color ICCD camera which can detect from 400 to 700nm fluorescence in full-color. Light of average wavelength 405 nm was selected and radiated through the light channel of the fiberscope from a 300W Xenon lamp. Patients and methods: We examined nine consecutive patients with bronchial malignancy admitted in our hospital to receive PDT. Sixteen lesions in these nine patients were observed with white light and excitation light and the results were compared. Histological examinations were done by taking biopsy specimens and samples for pathological and cytological examination. After the diagnosis was confirmed, 2.0 mg/kg Photofrin was injected. Forty eight hours after the administration of Photofrin, observation of the bronchial wall was made using a full-color endoscopic fluorescence imaging system just before PDT. Results: Bright red fluorescence from Photofrin was Observed in 14/14 bronchial malignancies: 3 squamous cell carcinoma, 9 squamous cell carcinoma in situ, 1 metastatic breast cancer and 1 metastatic islet cell tumor. Bright red fluorescence was also detected in 2/2 squamous dysplasia. Green autofluorescence was observed in the normal part of the bronchus. Conclusions: Results of the present study suggest that the full-color endoscopic fluorescence imaging system can be used to detect malignant and premalignant lesions as red fluorescence against green autofluorescence with Photofrin administration, and this system has the potential to detect absence of autofluorescence in cancerous lesions.

Acute and long-term effects of octreotide in patients with ACTH-dependent cushing's syndrome

purpose: Octreotide is of proven efficacy in the management of patients with acromegaly, thyrotropin-secreting pituitary adenomas, and certain gastrointestinal tumors, but its effect in Cushing's syndrome is less clear. patients and methods: We studied 10 patients who presented with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, 3 of whom were previously adrenalectomized. Serum cortisol or ACTH levels were measured before and during the administration of octreotide 50 to 500 μg every 8 hours for 24 to 72 hours. results: Treatment was effective in four patients: serum cortisol levels decreased to within or below the normal range in Patients 1,2, and 3, and ACTH levels were substantially lowered in Patient 4, who had previously been adrenalectomized for a metastatic islet cell tumor. These responses were sustained during long-term treatment for 2 to 72 weeks. All four patients showed no evidence of a pituitary tumor on computed tomographic or magnetic resonance imaging and had proven (Patients 3 and 4) or presumed ectopic disease. Of the six patients who did not respond, four had pituitary tumors and two had presumed ectopic ACTH production. conclusion: We conclude that a short trial of octreotide is warranted in patients with ACTHdependent Cushing's syndrome who have no demonstrable pituitary tumor. A response to treatment should alert the physician to the possibility of an ectopic ACTH source and will identify patients whose disease may be controllable using octreotide.

Zollinger-Ellison Syndrome and Pheochromocytoma

A 49-year-old woman was diagnosed in 1985 as having pheochromocytoma because of hypertension with high levels of plasma catecholamine concentration and 24-hour urine excretion of vanillyl-mandelic acid and metanephrine together with a right adrenal mass. The excised tumor cells had fine granular basophilic cytoplasm with argyrophilic granules by Grimelius' method. Four years later, she was diagnosed as having a duodenal bulb ulcer. Serum gastrin showed an abnormally high level of 1900 pg/ml. Abdominal echogram and computed tomography revealed a hypoechoic lesion in the pancreas and intrahepatic multiple tumors. A needle biopsy specimen of the liver tumor was compatible with the histology of metastatic islet cell tumor. A diagnosis of Zollinger-Ellison syndrome was made due to malignant gastrinoma with multiple liver metastases. The patient had no family history of endocrinological or neoplastic disorders. The present case indicates the possibility that pheochromocytoma and gastrinoma, that is, endocrine tumors characteristic of multiple endocrine neoplasia (MEN) I and MEN II, may be coincident even in a person without MEN. A continued awareness of previously rare or undescribed manifestations is important in patients with islet cell tumors or pheochromocytoma.

Gastrinomas: A 42‐year experience

In 1947, a patient with metastatic islet cell tumor was treated for intractable ulcer disease at the University of Chicago Medical Center. Eight years later, in retrospect, it was recognized that he and another patient had the Zollinger-Ellison syndrome (ZE). From 1947 until the present, 30 patients with the ZE syndrome have been treated at this institution. Twenty-one (70%) were male and 9 (30%) were female. Their ages ranged from 24 to 76 years. Most (79%) had abdominal pain, however, melena (42%), hematemesis (33%), and severe diarrhea (35%) were prominent as well. Symptoms were present for a mean of 5.8 years before diagnosis. Over their entire clinical course, duodenal ulcers occurred in 96% of patients, gastric ulcers in 24%, jejunal ulcers in 29%, esophageal ulcers in 6%, and stomal ulcerations in 58%. Eleven (38%) of all gastrinomas were proved to occur in the duodenum; 10 (34%) were pancreatic in origin, including 3 with the MEN I syndrome; 3 (10%) were extrapancreatic and extraduodenal in origin, and no tumor was found in 5 (17%). Each of the 3 patients with MEN I developed a proven pancreatic islet cell carcinoma with metastases as well as hyperparathyroidism and a pituitary lesion. Of 27 patients who were explored for gastrinoma, tumor was found in 20 (74%). Excluding patients with MEN who had multiple lesions throughout the pancreas, all tumors were found in the "gastrinoma triangle." Total gastrectomy was performed in 10 (37%) of 27 of all patients who were explored, in 5 (71%) of 7 when no tumor was found, and in only 5 (25%) of 20 when tumor was present. Operative mortality was 15% (4 of 27) but no death has occurred since 1974. Long-term survival has followed both tumor resection or total gastrectomy in selected individuals (including 1 patient with known multiple liver metastases who is alive 18 years after liver biopsy and total gastrectomy); however, since malignant gastrinomas were present in 46% of all patients (or 57% in whom tumor was found) and since local metastases can sometimes be removed, we favor an aggressive approach to localization and resection when liver metastases or other distant metastases are not found. Duodenal gastrinomas are particularly favorable for resection for cure. They were malignant in only 36% and their metastases were nodal in each of 4 cases. The major problem is finding them since they are often small and "occult."(ABSTRACT TRUNCATED AT 400 WORDS)

Malignant Islet Cell Tumor with Rhabdomyosarcomatous Differentiation

We present a widely metastatic islet cell tumor of the pancreas with focal areas resembling rhabdomyosarcoma. To our knowledge, this is the first reported case of islet cell/carcinoid tumor exhibiting such differentiation. Desmin was localized to the rhabdoid areas by immunohistochemistry. Cross striations were not seen by light microscopy, but Z-lines and thick filaments were seen on electron microscopy.

Metastatic islet cell tumor in Von Hippel-Lindau disease

A 56-year-old woman with many unusual manifestations of von Hippel-Lindau syndrome is described. In addition to retinal hemangioblastomas, pheochromocytoma, renal cell carcinoma, and multiple organ cysts, she had a cerebellar astrocytoma, pancreatic exocrine insufficiency, diabetes mellltus, thyrotoxicosis, and a metastatic calcitonin-secreting islet cell carcinoma. This case report documents the first example of a metastatic islet cell tumor in a patient with von Hippel-Lindau disease. The possible relationship between this disorder, the other neurocutaneous syndromes, and the multiple endocrine neoplasia syndromes is discussed.

Acute renal failure and renal tubular squamous metaplasia following treatment with streptozotocin

Nephrotoxicity, in the form of transient proteinuria, azotemia, abnormalities of tubular function, and acute renal failure, is the major toxic condition following administration of streptozotocin. The renal morphologic and ultrastructural abnormalities associated with streptozotocin remain poorly defined. We describe a patient with metastatic islet cell tumor of the pancreas who was treated with 16 weekly courses of 1 g/m2 of streptozotocin without marked change in renal function. Following a six-week hiatus without change in renal function, a single course of 1 g/m2 of streptozotocin was administered and resulted in acute renal failure. Light microscopic examination of the kidneys showed irregularly dilated renal tubules lined by low cuboid epithelium. The cells were pleomorphic and showed some mitoses. Nuclei were irregular and variably hyperchromatic. Electron microscopic examination disclosed large aggregates of fine microfilaments in the proximal convoluted tubules and collecting ducts. Microfilament aggregates were both free in the cytoplasm and membrane bound. Microfilaments were proved to be tonofilaments by the demonstration of keratin within the epithelium, using the immunoperoxidase method. These data suggest that squamous metaplasia may be an important part of streptozotocin renal toxicity, and the suggestion is made that they may be an antecedent of neoplastic change.

Remission of hypoglycemia after partial resection of a metastatic islet cell tumor

The course of a malignant islet cell tumor, producing increased levels of both insulin and glucagon, was studied clinically and in vitro for two years. The patient presented with hypoglycemia, and extensive hepatic metastases were present. Instead of biopsy alone, it was elected to remove the primary in the tail of the pancreas, and subtotal pancreatectomy was performed. There followed a six month interval without hypoglycemia, during which immunoreactive insulin (IRI) decreased (though remaining elevated) and immunoreactive glucagon (IRG) increased markedly. The tumor and a liver metastasis contained elevated IRI and IRG with immunofluorescence for insulin, though typical beta and alpha cells were not present on electron microscopy. A preparation of a monolayer culture of a liver metastasis decreased its IRI production with a similar time course to the clinical improvement, though rapid cell growth continued. Streptozotocin in vitro was markedly cytotoxic. In vivo Streptozotocin caused tumor regression, increase in fasting plasma glucose, decrease in plasma IRI and IRG, and improvement of glucose tolerance. Thus, this case showed elevated IRG in plasma and tumor, improvement in glucoregulation upon excision of the primary, and both in vitro cytotoxicity and clinical improvement with Streptozotocin. It is suggested (1) that cases refractory to therapy directed toward suppression of insulin secretion might benefit from removal of the primary and (2) that further use of cultures of such tumors should be initiated to establish whether they might be useful for predicting in vivo effectiveness of cytotoxic agents.

Newer studies in the Zollinger-Ellison syndrome

<h2>Summary</h2> Patients may have metastatic islet cell tumors without elevated basal acid secretions. A period of approximately thirty months occurred before recurrent symptoms and widespread tumor growth became evident. Calcium infusion is a potent stimulus for acid secretion in patients with the Zollinger-Ellison syndrome. Its action may be to cause the release of gastrin from these tumors and/or potentiate the effect of gastrin. Insulin hypoglycemia stimulated acid secretion in three of six vagotomized patients studied. After total gastrectomy serum gastrin levels were low if all gastric tissue was removed. Small remnants of gastric mucosa were associated with elevated gastrin levels.

Arteriographic Demonstration and Successful Removal of Metastatic Islet Cell Tumors in Liver: A Case Report

A patient with organic hyperinsulinism is described. A malignant islet cell tumor in the head of the pancreas was found and removed. Because of persistent hypoglycemia, subtotal pancreatectomy was performed, but no additional tumor was found. A year later, total pancreatectomy, duodenectomy and resection of part of the stomach and jejunum were performed with failure again to find a tumor. Only by means of selective arteriography of the celiac artery were two tumors discovered in the right lobe of the liver. These were removed by resection of the lobe of the liver and histologically confirmed as metastatic islet cell tumor. After this operation there were no further hypoglycemic attacks but persistent diabetes ensued. The resection of the metastatic islet cell tumor took place three and one-half years after the initial hypoglycemic attacks. The patient is symptom-free four years after removal of the metastases.

Effects of Extracts of Primary and Metastatic Pancreatic Islet Cell Tumors on Gastric Secretion

Summary 1.Extracts were made of 13 islet cell tumors by means of a technique described by Gregory and his associates. 2.Extracts of islet cell tumors from 2 patients who had hyperinsulinism contained a substance presumed to be insulin that produced both hypoglycemia and gastric secretion in dogs with vagally innervated pouches. One of these was tested in a dog with a vagally denervated pouch and was inactive. 3.An extract of a nonfunctioning islet cell tumor of the pancreas produced neither hypoglycemia nor gastric secretion. 4.Extracts were made of five primary and five metastatic islet cell tumors from patients who had the Zollinger-Ellison syndrome. A gastric secretagogue was demonstrated in nine of the extracts but was not detected in one of the metastatic tumors. Extracts of two primary tumors produced hypoglycemia in dogs despite the fact that hypoglycemia had not been present clinically. In other cases, a gastric secretagogue was demonstrated that was not insulin, adding to the mounting evidence that islet cell tumors in patients with the ZollingerEllison syndrome produce a stimulant for gastric secretion.

Extraction of a gastric secretagogue from primary and metastatic islet cell tumors in three cases of zollinger-ellison syndrome

Extraction of a gastric secretagogue from primary and metastatic islet cell tumors in three cases of zollinger-ellison syndrome