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Journal of Clinical Oncology, Vol 23, No 27 (September 20), 2005: pp. 6809-6811 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.4828
Severe Hypoglycemia Caused by Paraneoplastic Production of IGF-II in Patients With Advanced Gastrointestinal Stromal Tumors: A Report of Two CasesMedizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch; Robert-Rössle-Klink, Charité Campus Buch, Lindenberger, Berlin, Germany
Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Campus Virchow-Klinikum, Berlin, Germany
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch; Robert-Rössle-Klink, Charité Campus Buch, Lindenberger Weg 80, 13125 Berlin, Germany
Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Campus Virchow-Klinikum, Berlin, Germany
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch; Robert-Rössle-Klink, Charité Campus Buch, Lindenberger Weg 80, 13125 Berlin, Germany
Klinik für Innere Medizin I und Kardiologie, Alfried Krupp Krankenhaus, Essen, Germany
Zentrum Innere Medizin, Schwerpunkt Onkologie, Gastroenterologie, Infektiologie, Marienkrankenhaus, Hamburg, Germany
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, HELIOS-Klinikum Berlin-Buch; Robert-Rössle-Klink, Charité Campus Buch, Lindenberger Weg 80, 13125 Berlin; Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité Campus Virchow-Klinikum, Berlin, Germany To the Editor: We report on two patients with advanced gastrointestinal stromal tumors (GIST) presenting with severe non–islet-cell tumor hypoglycemia (NICTH) related to paraneoplastic production of IGF-II. To our knowledge, the association of NICTH and GIST has not been reported before. In June 2001, a 59-year-old male patient with an empty medical history was admitted to the hospital complaining of pain in the right upper abdomen since two months, weight loss of 4 kg, and night sweats. Imaging showed multiple liver lesions of up to 10 cm with central necrosis and a mass in the duodenum. Histology showed a GIST. After several days in the hospital, the patient went into a coma and was admitted to the intensive care unit. Severe hypoglycemia with a glucose level of 14 mg/dL (normal range 60 to 100), hypokalaemia of 3.3 mmol/L, and tachyarrhythmia absoluta were diagnosed. After symptomatic treatment, the patient's condition improved rapidly. To maintain normal glucose blood levels the patient needed 12 g of glucose per hour. Insulin blood levels were repeatedly below normal limits (< 2 mU/L, normal range 5 to 25), C-peptide was normal. Two weeks later the patient was transferred to the Charité, Berlin, due to the availability of investigational imatinib treatment. By this time the patient needed 720 g of intravenous glucose in addition to a normal oral diet to maintain normal glucose blood levels. An NICTH was suspected and IGF-I und IGF-II levels were measured. IGF-II was elevated (1406 ng/mL, age adapted normal range 459 to 1,123) while IGF-I was suppressed (23 ng/mL, normal range 91 to 284). In consistency with suppressed insulin levels, the diagnosis of IGF-II-dependent NICTH was established. The patient was included in European Organisation for Research and Treatment of Cancer trial 62005 and was started on 800 mg imatinib per day. After one week of imatinib treatment, the intravenous glucose infusions could be reduced to 30 g per night with oral glucose treatment during daytime. Four weeks later, IGF-II levels returned to normal and the patient was fully ambulatory. Two months after start of imatinib, the patient was seen for the first follow-up evaluation. He had gained 5 kg of weight and did not need any intravenous glucose support. Imaging showed a partial remission of the liver metastases. The patient has spent 43 months on imatinib in continuous partial remission and living on a normal diet. A 35-year-old male patient was diagnosed with GIST of the small bowel in 2000 that was treated with a segmental resection. Twenty months later, multiple metastases in the liver and peritoneum were detected and treatment with imatinib was initiated. Due to disease progression after 17 months, the dose was increased to 800 mg per day. Ten months later the patient was found in coma by his wife. He was admitted to the intensive care unit and hypoglycemia of 30 mg/dL was diagnosed and treated by glucose infusions. After repeated episodes of hypoglycemia, the patient was transferred to the Charité, Berlin, where progression of the GIST was diagnosed. IGF-I was suppressed (20.3 ng/mL, normal range 90 to 360) while IGF-II was elevated (1,196 µg/L, normal range 242 to 873). Insulin (< 2 mU/L, normal range 6 to 25) and C-peptide (<0.1 nmol/L, normal range 0.33 to 1.2) were undetectably low. Due to rapidly deteriorating general condition and progressive GIST, a debulking operation was performed. Following the operation, imatinib was increased to 1,000 mg per day. No further hypoglycemia occurred. NICTH is a rare condition. Several case reports on patients with underlying malignant disease and secondary NICTH have been published. Systematic evaluations and data on incidence of NICTH are missing. Soft tissue sarcomas have been associated with NICTH in several reports, including the first in 1930.1 The association of GIST and NICTH has not been reported to date. However, most case reports and a systematic review on patients with mesenchymal tumors and NICTH date from the pre-GIST era and might therefore have missed this recently established diagnosis. Seventy of 115 patients with sarcomas and NICTH had abdominal sarcomas of various histologial subtypes, including spindle-cell sarcomas and leiomyosarcomas, which could well represent GISTs.4 NICTH is characterized by elevated IGF-II levels or abnormal high molecular IGF-II-precursor-proteins and normal or decreased levels of IGF1 and insulin.2,3 Increased levels of IGF2-mRNA could be detected in tumor tissues.2 It has been speculated that IGF-II is stimulating tumor cell growth via auto-/parakrine loops since it has been shown to be a growth factor for hematopoietic stem cells.5,6,7 The mechanism of hypoglycemia in NICTH is still unclear. Possible explanations are a disturbed and increased glucose metabolism or a decreased hepatic gluconeogenesis.7 Since clinically detectable hypoglycemia seems to be associated with high tumor burden, auto-/paracrine IGF-II-mediated increased glucose metabolism could also attribute to the hypoglycemia. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES 1. Doege KW: Fibrosarcoma of the mediastinum. Ann Surg 92:955-960, 1930[Medline] 2. Daughaday WH, Emanuele MA, Brooks MH, et al: Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 319:1434-1440, 1988[Abstract] 3. Bertherat J, Logie A, Gicquel C, et al: Alterations of the 11p15 imprinted region and the IGFs system in a case of recurrent non-islet-cell tumour hypoglycaemia (NICTH). Clin Endocrinol (Oxf) 53:213-220, 2000[CrossRef][Medline] 4. Anderson N, Lokich JJ: Mesenchymal tumors associated with hypoglycemia: Case report and review of the literature. Cancer. 44:785-790, 1979[CrossRef][Medline] 5. Schwartz GN, Warren MK, Sakano K, et al: Comparative effects of insulin-like growth factor II (IGF-II) and IGF-II mutants specific for IGF-II/CIM6-P or IGF-I receptors on in vitro hematopoiesis. Stem Cells 14:337-350, 1996[Abstract]
6. Zhang CC, Lodish HF: Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103:2513-2521, 2004 7. Daughaday WH, Deuel TF: Tumor secretion of growth factors. Endocrinol Metab Clin North Am. 20:539-563, 1991[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
