Insulin-producing Islet Cell Tumors Research Articles

SUN-321 Rare Case of Hypoglycemia Induced by IGF2 Secreted by an Ovarian Tumor

Introduction: Mesenchymal and epithelial tumors can produced un-cleaved IGF-2 molecules known as “big” IGF-2. These tumors are associated with elevated levels of IGF-2, which can mimic hypoglycemic events of insulin-producing islet-cell tumors by binding and activating insulin receptors. Typically plasma levels of insulin, IGF-1, and GH are low. “Big” IGF-2 molecular testing is not commercially available, however diagnosis of IGF-2 mediated hypoglycemia is based on low insulin and proinsulin in association with a IGF-2 to IGF-1 ratio >3. Clinical Case A 62 year old female with no significant past medical problems presented with 20 lb weight loss and a two month history documented symptomatic hypoglycemia episodes . Her PCP palpated a firm, non-painful mass occupying nearly her entire abdomen on physical exam. CT revealed a pelvic mass measuring 23.4 cm thought to originate from the ovary. Biopsy of the mass showed a well-differentiated neuroendocrine tumor grade 3, Ki 67 of 15%. Lab work by Endocrinology was significant for a serum glucose of 46 mg/dl, insulin <5 uIU/ml, C-peptide <1 ng/ml, cortisol 43 ug/dl, IGF-1 18 ng/ml, IGF-2 163 ng/ml (IGF1:IGF2: 9), pro-insulin 1.7 pmol/L, sulfonyl urea screen was negative, Ca 125: 230 U/ml, Ca 19-9: 7 U/ml, CEA <1 ng/ml, and chromogranin-A 598 ng/ml. Ga DOTATE scan revealed a 21 cm intra-abdominal mass with multiple peritoneal soft tissue implants consistent with a neuroendocrine tumor with peritoneal carcinomatosis. Due to persistent episodes of hypoglycemia, the patient was started on octretotide 200 mg q 8 hrs, Dexamethasone 1 mg q 3 hrs and parenteral nutrition. The patient was evaluated by surgery and deemed to inoperable due to multiple metastasis. She was then treated with cepecidobine and temozolomide with significant improvement in her glycemic control. A week later, the patient was able to be weaned off TPN and dexamethasone and was discharged home on oral diet. She was evaluated a month later as outpatient and had infrequent episodes of hypoglycemia. Conclusion This is the first case report of a patient with IGF-2 induced hypoglycemia treated with a combination of cepecidobine, temozolomide, and octreotide. While octreotide helped to improve her glycemic control by generally inhibiting hormonal secretion, likely of both IGF-2 and insulin production, final symptom relief and clinical stabilization occurred with the combination of capecitabine and temozolomide, which in vitro data has is synergistic for induction of apoptosis in neuroendocrine tumor cell lines .

Tumors, IGF-2, and Hypoglycemia: Insights From the Clinic, the Laboratory, and the Historical Archive

Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.

Hyperinsulinemic hypoglycemia due to polyclonal gammopathy with insulin autoantibodies

Insulin-producing islet cell tumors, nesidioblastosis and glycogenosis type 1 have to be considered in cases of endogenous hypoglycemia. In addition, insulin-specific autoantibodies have been described as a cause of hypoglycemia.

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.

Aneuploid islet cell tumor with late metastasis

An unusual case of insulin producing islet cell tumor is reported which recurred after a 16 yr interval. In most instances malignancy of islet cell tumors is impossible to assess morphologically or functionally but depends on the recognition of metastases. Nuclear DNA analysis provides significant prognostic and biological information in a number of solid human tumors. Retrospective computerized nuclear image analysis of the primary tumor in the present case showed an aneuploid DNA profile similar to that seen in the metastasis. It appears that ploidy studies may be useful in predicting malignant potential of islet cell tumors.

Deficient Counterregulatory Hormone Responses during Hypoglycemia in a Patient with Insulinoma*

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.

Nesidioblastosis and endocrine hyperplasia of the pancreas: A secondary phenomenon

Diffuse endocrine cell proliferation (nesidioblastosis) and islet cell hyperplasia are considered causes of organic hyperinsulinism but have not been distinguished (by histometric or immunohistologic methods) from the normally variable pancreatic islet cell population during development and in adults. Therefore, in this study morphologic, immunohistologic (to detect insulin, glucagon, somatostatin, and pancreatic polypeptide), and morphometric features were evaluated in 1) normal pancreases (from fetal to adult; n = 49); 2) pancreases from patients with nesidioblastosis (n = 5); and 3) tumor-associated pancreases (TAP) from patients with insulin-producing islet cell tumors (n = 8). The study of normal postnatal development revealed that all features of fetal development remain present after birth and that the diagnosis of any diffuse endocrine disorder should therefore be based essentially on quantitative histometric parameters (total endocrine area, islet size distribution, distribution of each endocrine cell type). With these parameters endocrine cell hyperplasia was demonstrated in TAP from adults due to increased numbers of A and D cells. However, in the cases previously diagnosed as pathologic nesidioblastosis, all parameters were within the normal range. Thus, nesidioblastosis does not appear to be a pathologic entity. Careful re-examination of the pancreases, prompted by these data, revealed small islet cell tumors in three of these five cases. It is concluded that the endocrine pancreas can react rapidly, both morphologically and functionally, to changes in hormonal feedback, e.g., islet cell tumors. Therefore, the observation of a diffuse islet cell disorder in a patient with hyperinsulinism should not be considered an indication that an islet cell tumor is not present.

Regulation of in Vitro Insulin Release from a Transplantable Syrian Hamster Insulinoma1

An insulin-producing islet cell tumor of the Syrian hamster has been studied in vitro for its capacity to respond to known stimuli of insulin release. Insulin secretion during short term incubation and perifusion of fragments of tumor was detected by radioimmunoassay. Insulin release was increased 2-4 fold by 40 mM potassium in the presence of calcium, glucose (22 mM), glucagon (0.3-3.0 muM), N6,02'-dibutyryl adenosine 3',5'-monophosphate (cAMP; 6mM), and theophylline (10 mM). Concentrations of glucagon that induced insulin release were also effective in activating adenylate cyclase in the membranes of tumor cells. Thus, this tumor appears to possess a cAMP-mediated mechanism for insulin release. Somatostatin (0.8-25 mum) inhibited glucagon-induced insulin release without altering basal or glucagon stimulated adenylate cyclase activity. It would appear that inhibition of glucagon induced insulin release by somatostatin is not mediated by adenylate cyclase. We propose that insulin release by this tumor is sufficiently similar to that found in normal islets so as to make it a suitable model for biochemical studies that require large quantities of homogeneous tissue.

PREOPERATIVE ANGIOGRAPHIC LOCALIZATION OF INSULIN-PRODUCING TUMORS OF THE PANCREAS

The significant morbidity and mortality associated with pancreatic surgery for isletcell tumors indicate the need for accurate, reliable identification and preoperative localization of insulin-producing islet-cell tumors. The results of this study indicate that angiographic examination of the pancreas can detect such tumors with a degree of accuracy greater than 90 per cent, if attention is paid to the technical quality of the examination. This attention is as important for the accurate diagnosis as are the size, location, and vascularity of the tumor. Vascularity of the tumor as assessed histologically may not have as important a role in the diagnosis as previously suggested.Supplementary techniques such as stereoscopy, subtraction, magnification, and selective injections are also important. We were able to demonstrate 6 of 12 occult insulin-producing islet-cell tumors within the pancreas preoperatively by means of such techniques, which otherwise might have resulted in a partial pancreatectomy without i...

Selective Angiography in Localizing Islet-Cell Tumors of the Pancreas

Forty insulin-producing islet-cell tumors of the pancreas excised from 26 patients were studied with preoperative pancreatic angiography. In 14 patients, at least 1 tumor was identified by angiography. Of 24 tumors 1 or more centimeters in diameter, 12 were correctly localized, and of 16 less than 1 cm, 3 were visualized. Overall detection rate was 15 of 40 tumors (38%). Localization was more frequent in tumors with increased vascularity histologically, and in those located in the head of the pancreas. Adenomatosis was associated with tumor in 3 cases but was not apparent angiographically. Super-selective angiography, vasoconstrictive pharmacoangiography, and subtraction techniques were occasionally helpful.

Plasma proinsulin in patients with functioning pancreatic islet cell tumors.

ABSTRACT Plasma levels of proinsulin were determined in 19 patients with benign and in 2 patients with malignant insulin-producing islet cell tumors. Proinsulin accounted for 8–78 (mean 37)% of fasting plasma total immunoreactive insulin (IRI) in patients with islet cell tumors and for 20% or less in 10 healthy subjects. In 12 of 19 patients with benign and in both patients with malignant tumors, the proinsulin component was clearly elevated and exceeded 25% of fasting total IRI. The finding of an elevated fasting plasma level of proinsulin may be helpful in establishing the diagnosis of an insulin-producing islet cell tumor when fasting blood glucose is within the range of normal and/or when the plasma level of total IRI is normal or only slightly elevated. Fasting plasma concentrations of proinsulin were greater in those patients who had greater concentrations of total IRI, most likely reflecting the increased rate of insulin synthesis. In patients with benign tumors, the increases in plasma total IRI e...

Appraisal of selective angiography in localizing islet-cell tumors of the pancreas.

In recent years the problem of accurate preoperative diagnosis of insulin-producing islet-cell tumors of the pancreas has been largely surmounted in adults. Newer technics such as the determination of plasma insulin during the intravenous tolbutamide test (3) or after administration of l-leucine, have contributed to accurate differentiation from other causes of hypoglycemia. Treatment of an islet-cell tumor requires surgical extirpation; yet operative identification of the lesion (or lesions) may pose a difficult problem. The adenomas are generally small, in most cases 1-3 cm in diameter. They are frequently buried within the substance of the pancreas and may not be detected by inspection or palpation. Approximately three-fourths of the tumors occur in the body and tail of the pancreas, but they may be situated in any part of the gland, or even in aberrant pancreatic tissue of the duodenum, spleen, omentum, liver, or elsewhere. Moreover, the tumors are multiple in approximately 10 per cent of cases (4). In his search for the lesion the surgeon may be faced with a prolonged eliotomy, extensive mobilization and manipulation of the pancreas, or progressive empirical partial pancreatectomy with serial sectioning. Therefore, preoperative assessment of the number, size, and location of the lesions would be of material assistance. Since islet-cell tumors of the pancreas may be highly vascular, selective angiography offered promise as a means for preoperative identification of their site and number. In 1963, Olsson reported the first angiographic demonstration of such a tumor (5). Baum et al. (1) identified 4 islet-cell tumors by angiography and Rösch and Bret (6) described 3 additional neoplasms. From the isolated successes reported in the literature, however, one gains no idea of the incidence of diagnostic arteriograms in patients with proved lesions. This paper describes our experience with 6 cases. A correlation between the arteriographic success rate and the histology of the tumors is noted, and, from a review of a larger number of cases, the anticipated success rate from angiography is predicted. Method and Materials Pancreatic arteriography was performed in 6 patients subjected to operative removal of 7 islet-cell tumors. Selective celiac and superior mesenteric arteriography was performed by the Seldinger technic, employing a yellow Kifa catheter in most patients. Twenty-five cubic centimeters of 75 per cent Hypaque was selectively injected into the celiac artery in two seconds, followed by serial filming in the anteroposterior and right posterior oblique projections. The filming program was two exposures per second for four seconds, one exposure per second for four seconds, and one exposure every two seconds for twelve seconds. Twenty-five cubic centimeters of 75 per cent Hypaque was then injected into the superior mesenteric artery, with serial filming in the anteroposterior projection, using the previously described program. It must be emphasized that in all cases the arteriograms were of good to excellent quality, and failure to demonstrate the lesions cannot be ascribed to technical inadequacy. The gross description of the tumors in these patients was as follows: Case I (A.W.): A 1 cm diameter purple tumor in the tail of the pancreas of a 19-year old girl. Case II (R.B.): A 3 cm diameter purple lesion deep in the head of the pancreas in a 48-year-old man who had undergone a prior subtotal pancreatectomy. Case III (H.R.): A 1.5 × 2 cm purple tumor in the tail of the pancreas of a 52-year-old woman. Case IV (R.L.): A white nodule, 3 cm in diameter, in the tail of the pancreas, containing some calcification, in a 19-year-old man. In addition, a 2 mm white lesion was present in the body of the pancreas. Case V (R.B.): A tan, ill-defined lesion, 1.5 cm in diameter, in the tail of the pancreas, which interdigitated with normal tissues. Case VI (H.S.): A 1 cm pale tumor in the tip of the pancreas of a 58-year-old woman.