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© 2000 American Society for Clinical Oncology
Case 1: Hypoglycemic Syncope Due to a Peripheral Neuroectodermal TumorConsultant Editor
Klinikum Grosshadern, Munich, Germany, and University Hospital, Zurich, Switzerland CASE 1. HYPOGLYCEMIC SYNCOPE DUE TO A PERIPHERAL NEUROECTODERMAL TUMOR A 79-year old woman was admitted to the hospital because of syncope. The patient was found unconscious by her fellow nuns in the morning. Emergency treatment consisted of intravenous glucose, which resulted in prompt recovery. The patient had been well until 5 months earlier, when dizziness, sweating, and episodes of disorientation had occurred. The patient did not suffer from any known chronic disease nor did she take any regular medication. On admission, she was fully oriented. Physical examination revealed dullness to percussion and absent breath sounds below the fifth rib on the right side. The examination of the left lung and the upper part of the right lung revealed vesicular breath sounds. Cardiac and abdominal findings were unremarkable. The patient had two hypoglycemic episodes during the first 48 hours of the hospital stay. Blood glucose levels were 1.25 and 1.05 mmol/L, and insulin and c-peptide levels were less than 3 mU/L and less than 0.5 µg/L, respectively. A computed tomography scan showed a large inhomogenous tumor in the right lung. It was displacing the heart to the left and appeared to infiltrate the mediastinum and the left lung (Fig 1). Computed tomography–guided biopsy of the thoracic mass was performed. Morphology showed a small, blue, round-cell tumor that was immunohistochemically unreactive for keratin, CD45, HHF-35, and S100. Therefore, a carcinoma, lymphoma, rhabdomyosarcoma, and neurogenic sarcoma could essentially be ruled out. There was an unequivocal expression of vimentin, neuron-specific enolase, and mic-2 gene product (Fig 2), allowing the diagnosis of a malignant tumor with neuroectodermal differentiation. On the basis of the immunohistochemical profile and the thoracopulmonary localization, a malignant peripheral neuroectodermal tumor (PNET) was diagnosed.1 Results of a full blood count, coagulation tests, and biochemistry analyses were normal. Her insulin-like growth factor (IGF)-1 level was 90 µg/L and her IGF-2 level was 844 µg/L (normal reference range, 170 to 360 and 800 to 1,200 µg/L, respectively). Because of an elevated big IGF-2 level of 325 µg/L (reference range, < 150 µg/L), tumor-associated extrapancreatic hypoglycemia was diagnosed.
PNETs are closely related to Ewing’s sarcoma.2,3 Recommended therapy consists of surgery and combined radio- and chemotherapy.1,4 However, the prognosis remains poor even with this form of treatment. In this patient, several therapeutic options were considered in an effort to reduce the tumor mass, lower the big IGF-2 levels, and prevent hypoglycemia. Chemotherapy and radiotherapy were not used because of significant morbidity and possible mortality in this senile patient. Embolization of the tumor was not feasible because too many blood vessels supplied the tumor. Because octreotide and meta-iodobenzylguanidine scintiscans did not show enrichments in the tumor, they could not be used as a therapeutic option. Glucagon, somatostatin injection, and diazoxide application were ineffective. Therefore, treatment consisted of frequent food administration, which led to a reduced frequency of hypoglycemic episodes but not to normoglycemia. Therefore, a percutaneous endoscopic gastrostomy was performed. Continuous infusion of 20 grams of glucose per hour was necessary to prevent hypoglycemia. Seven months after discharge, the patient died at home because of pulmonary insufficiency, most probably due to tumor progression. Hypoglycemia in nondiabetics and nonalcoholics is a rare clinical problem. Most of the remaining patients experience hyperinsulinism as a factitious problem or due to insulinomas.5 Both conditions could be ruled out in this patient because insulin and c-peptide levels were unmeasurable during hypoglycemic episodes. Hypoglycemia as a paraneoplastic phenomenon is mediated by big IGF-2, an unprocessed form of IGF-2 produced by tumors.6-8 In one series of 64 patients, 20 different malignancies were associated with hypoglycemia. Thirty-three patients had tumors of mesenchymal origin and 21 had tumors of epithelial origin.7 In normal human serum, IGFs are found in three different pools: free IGF contributes less than 1% and has a short half-life of approximately 10 minutes; 20% to 30% of the total circulating IGF is bound to a 50-kd IGF-binding protein complex and has a half-life of about 30 minutes; and 70% to 80% of total IGF is associated with the 150-kd complex, which has a half-life of approximately 12 hours. Nearly all of the patients with extrapancreatic tumor-induced hypoglycemia have abnormal levels of big IGF-2, whereas total IGF-2 is usually within the normal range. However, due to defective formation of the 150-kd complex, most of the big IGF-2 is bound to the 50-kd complex that can pass the capillaries and delivers big IGF-2 to insulin target tissues. It inhibits lipolysis in adipose tissue and gluconeogenesis in the liver and increases glucose uptake in skeletal muscle. These mechanisms underly the biochemical findings of reduced serum-free fatty acids and low blood sugar levels. In addition, increased bioavailability of big IGF-2 by its association with the 50-kd complex leads to suppression of insulin and growth hormone secretion, two other biochemical characteristics found in patients with extrapancreatic tumor hypoglycemia. To our knowledge, this is the first description of tumor-associated extrapancreatic hypoglycemia caused by a big IGF-2–producing PNET in an elderly patient. REFERENCES 1. Llombart-Bosch A, Terrier-Lacombe MJ, Peydro-Olaya A, et al: Peripheral neuroectodermal sarcoma of soft tissue (peripheral neuroepithelioma). Pathol 20:273-280, 1989
2.
Verrill M, Judson I, Harmer C, et al: Ewing’s sarcoma and primitive neuroectodermal tumor in adults: Are they different from Ewing’s sarcoma and primitive neuroectodermal tumor in children? J Clin Oncol 15:2611-2621, 1997
3.
Delattre O, Zucman J, Melot T, et al: The Ewing family of tumors: A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294-299, 1994
4.
Miser JS, Kinsella TJ, Triche TJ, et al: Treatment of peripheral neuroepithelioma in children and young adults. J Clin Oncol 5:1752-1758, 1987
5.
Service FJ: Hypoglycemic disorders. N Engl J Med 332:1144-1152, 1995 6. Daughaday WH: The pathophysiology of IGF II hypersecretion in non-islet cell tumor hypoglycemia. Diabetes Rev 3:62-72, 1995 7. Zapf J: Insulin-like growth factor binding proteins and tumor hypoglycemia. Trends Endocrinol Metab 6:37-42, 1995 8. Zapf J, Futo E, Peter M, et al: Can big insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest 90:2574-2584, 1992
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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