Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report

BACKGROUND: Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it. CASE PRESENTATION: A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, "big" insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT. CONCLUSION: Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established

HOsm inhibits TNFα or IL-1β stimulated mRNA for RANTES (A), IP-10 (B) and MCP-1 (C) chemokines in parallel with overall chemokine release levels.

<p>mRNA levels were measured following stimulation for 6 hours and normalized to constitutive GAPDH production after treatment with TNFα or IL-1β in the presence of 400 mOsm HTS or Sorbitol. No significant differences were seen between any of the HTS and SOR groups.</p

HOsm inhibits IRF-1 localization to the nucleus with either TNFα or IL-1β stimulation.

<p>IRF-1 in the nuclear extract of cells stimulated by TNFα or IL-1β in the presence of 400 mOsm HTS or sorbitol was examined by immunoblotting (A), figure is representative of three separate experiments. The gels were digitized and quantitated for nuclear IRF-1 after TNFα (A) or IL-1β stimulation (C); * p<0.05 for ISO vs. either HTS or SOR at matched time points; no significant differences were found between HTS and SOR groups.</p

Hyperosmolarity inhibits secretion of archetypal cytokines induced by TNFα or IL-1β.

<p>Hyperosmolar effects (400 mOsms, by either NaCl or sorbitol), on 27 inflammation-related gene products secreted by stimulated A549 cells measured by multiplex assay. Chosen from genes clustered on chromosomes 2, 4, 5 and 17 and eight others. Fold increases and inhibition were compiled from three separate experiments. Stimulated responses are bolded, if these measured over 100 ng/ml except for IL-4 (less than 20 ng/ml) <b>and at least >5 fold</b>. >400, >100, >5 The effect of HTS and Sorbitol (both 400 mOsm) are shown as <i>% response</i> of stimulated values and also <u>underlined </u>if these are <u>at least 33% different, </u>><u>75, </u>><u>50, </u>><u>33</u>. NA, not applicable, – indicates undetectable.</p><p>Hyperosmolarity inhibits secretion of archetypal cytokines induced by TNFα or IL-1β.</p