A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor
- 782 Downloads
Non-Islet Cell Tumor Hypoglycemia (NICTH) is a rare paraneoplastic cause of hypoglycemia arising from excess tumor production of insulin-like growth factor. The objective of this report is to describe an unusual case of Extragastrointestinal Stromal Tumor (EGIST) associated NICTH.
A 64 year-old African female was brought to the emergency room with a 1-month history of recurrent syncope, weight loss, and abdominal bloating. Serum blood glucose was discovered to 39 mg/dL, when insulin, proinsulin, and C-peptide were suppressed. Computed tomography scan revealed a diffuse extraintestinal metastatic disease process, and a biopsy confirmed the diagnosis of an Extragastrointestinal Stromal Tumor (EGIST). IGF-I and II levels were 27 ng/ml and 262 ng/ml respectively, and the ratio of IGF-II to IGF-I was calculated as 9.7:1, suggestive of IGF-II-mediated NICTH. Acutely, the patient’s hypoglycemia resolved with dextrose and glucagon infusion. Long-term euglycemia was achieved with prednisone and imatinib therapy.
NICTH should be considered when hypoglycemia occurs in the setting of low serum insulin levels. Whereas definitive treatment of EGIST involves surgical resection, immunotherapy with tyrosine kinase inhibitors and corticosteroids have been shown to alleviate hypoglycemia in cases where surgery is delayed or not feasible.
KeywordsTumor induced hypoglycemia Extragastrointestinal stromal tumor (GIST) Non-islet cell tumor hypoglycemia
Tyrosine kinase receptors c-kit
Hematopoetic progenitor cell antigen CD34
Discovered on GIST-1
Extragastrointestinal stromal tumor
Gastrointestinal stromal tumor
Human recombinant growth hormone
Monoclonal muscle specific actin antibody
Human melanoma black
IGF binding proteins
Insulin like growth factor I
Insulin like growth factor II
Non-islet cell tumor hypoglycemia
Platelet-derived growth factor-α
Tyrosine kinase inhibitor
Tumor induced hypoglycemia can be divided into two broad categories. The first involves insulin hypersecretion from pancreatic islet cell insulinomas. The second, known as Non-Islet Cell Tumor Hypoglycemia (NICTH), is from paraneoplastic production of insulin-like growth factor from a tumor, leading to unrestrained glucose uptake at peripheral tissues [1, 2]. The first description of NICTH dates back to 1929 and involved a patient with metastatic hepatocellular carcinoma. Post-mortem examination of the pancreas was normal. Furthermore, analysis of the tumor failed to reveal the presence of insulin, thus leading to the conclusion that the hypoglycemia was non-insulin mediated . Since this original description, a variety of tumors have been shown to exhibit NICTH. These primarily include tumors of mesenchymal and epithelial origin with hepatocellular carcinomas being among the most frequently implicated.
Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor arising within the gastrointestinal (GI) tract. These tumors express the phenotype of the Interstitial Cells of Cajal or related stem cell-like precursors and are associated with somatic mutations of the tyrosine kinase receptors c-kit (CD117) and platelet-derived growth factor-α (PDGFR-α) [4, 5, 6]. Over the last decade, a handful of case reports have described an association between GIST and NICTH . In extremely rare cases, GIST can arise primarily outside the GI tract, where it is termed Extragastrointestinal Stromal Tumor (EGIST) [6, 7]. Representing less than 10% of all stromal tumors, EGISTs share the same histological features, immunophenotype, and biological behavior as GISTs. Most EGISTs originate in the lesser or greater omentum, the mesentery, or less commonly in the retroperitoneum, with very few cases reported of tumors arising from the abdominal wall itself [6, 8]. While some sources suggest that EGISTs represent peritoneal metastases of undiagnosed GISTs or GISTs that may have detached from the intestinal wall during extensive extramural growth, others consider them to be primary tumors arising from multipotent mesenchymal stems cells of the extra-intestinal tissue [6, 8, 9]. Surgery remains a mainstay for localized GIST/EGIST. However, immunotherapy with tyrosine kinase inhibitors (TKI), especially imatinib, has emerged as a promising neoadjuvant or alternative therapy.
Here, we describe the case of a patient presenting with a rare abdominopelvic EGIST tumor and recurrent episodes of severe symptomatic hypoglycemia. To the best of our knowledge, this is the first reported case linking EGIST and NICTH.
A 64 year-old African female was brought to the emergency room in January 2016 with a chief complaint of recurrent syncope. Her serum blood glucose on arrival was 39 mg/dL. A detailed review of systems was notable for non-specific abdominal bloating and distension and a 50 lb weight loss over the preceding year. Vital signs on presentation were within normal limits; physical exam revealed a firm palpable right lower quadrant mass. Her past medical history revealed a history of pelvic EGIST that had been diagnosed in March 2010 at an outside facility. A computed tomography (CT) scan at that time demonstrated a large pelvic mass involving the right ovary, the mesovarian, and the mesometrium. Pathological analysis of the tumor revealed diffuse staining for c-Kit, CD-34, and the smooth muscle marker caldesmon, while stains for pancytokeratin, S-100, Human Melanoma Black (HMB-45), Melan-A, actin, myogenin and desmin were all negative. The mitotic index was noted to be high at 28/50 high power fields, and tumor necrosis was noted. Following a debulking procedure, all intestinal specimens were found to tumor-free. Hence, the diagnosis of a primary EGIST was made. Post-operatively, she was started on immunotherapy with the TKI, imatinib. Since that time, the patient missed most of her follow-up appointments. During the current admission, she reported discontinuation of imatinib several months ago. She further noted that hypoglycemia had indeed been the initial manifestation of her EGIST in 2010, but this symptom had resolved post-operatively.
Fine needle aspiration and core biopsy of the right lower quadrant mass were performed. H&E staining revealed the typical spindle shaped morphology (Fig. 1c). Immunostaining for CD117 (Fig. 1d) and Discovered on GIST-1 (DOG-1) (Fig. 1e) were diffusely positive. Muscle specific actin (HHF-35), a mesenchymal marker present in 47% of GIST biopsies, was positive, while immunostaining for carcinoma markers were negative (not shown). Hence, a diagnosis of recurrent metastatic EGIST was made. Tumor sections were next stained with an antibody that recognized both big IGF-II and mature IGF-II (Abcam, Cambridge MA). Consistent with the patient’s presentation with severe hypoglycemia, the tumor stained positive for big IGF-II/IGF-II (Fig. 1f).
The true incidence of NICTH is unclear, but has been estimated to be extremely rare at approximately one per one million person years . Hypoglycemia is thought to arise from excessive tumor production of IGF-II or its precursor high molecular weight “big” IGF-II. Hence the term “IGFII-oma” is often used to describe these tumors . Both IGF-I and IGF-II are structurally related to insulin and act at peripheral insulin receptors to mimic insulin action, leading to increased glucose uptake, suppression of lipolysis, and inhibition of glycogenolysis, gluconeogenesis, and ketogenesis in the liver .
Under normal conditions, the liver produces IGF-II, in a growth hormone-independent manner, and IGF-II forms a biologically inactive ternary complex with IGF binding proteins (IGFBP), the most common of which are IGFBP3 and acid labile subunit (ALS) [12, 13]. Tumor-produced IGF-II has an equal affinity for IGFBPs compared to IGFI and II. However, instead of forming an inactive ternary complex, IGF-II forms smaller binary complexes with IGFBP. In NICTH, there is an increase in the quantity of unbound and active IGF-II as well as increased formation of these active binary complexes, which exhibit increased vasculature permeability and significantly increased bioavailability. As a side mechanism, increased IGF-II in turn further suppresses hepatic IGFBP production, thus propagating further insulin like activity and creating a vicious cycle of severe and symptomatic hypoglycemia .
NICTH is typically a diagnosis of exclusion, but should be suspected when hypoglycemia without hyperinsulinemia is present. Biochemically, insulin, proinsulin, C-peptide, growth hormone and β-hydroxybutyrate levels are low at the time of hypoglycemia, as was observed in this patient. In contrast, IGF-II or IGF-II precursor levels are often elevated. Typically an IGF-II:IGF-I ratio of 10:1 is considered pathognomonic, while a normal ratio is around 3:1 [1, 12]. In our patient, the levels were 9.7:1, which were quite high, though perhaps not diagnostic.
The range of tumors associated with NICTH is broad. In recent years, a handful of case reports and case series have described GIST-associated NICTH [4, 9, 11]. GIST tumors arise from the gut wall. In rare instances, they arise outside the GI tract in the omentum, mesentery, and retroperitoneum and are referred to as EGISTs. EGISTs share the same histological and immunotypic features and biological behavior as GISTs [4, 14]. The diagnosis of GIST/EGIST tumors relies on CD117 (c-KIT) positivity on immunohistochemical staining, which remains a highly sensitive and specific marker.
Discovered on GIST-1 (DOG1) protein is another recently discovered tumor marker that has particularly utility in identifying tumors harboring mutations in platelet-derived growth factor-α (PDGFR-α) . Whereas staining for both CD117 and DOG1 were observed in this patient’s tumor, formal mutation analysis was not performed. Surgery remains the mainstay for localized GIST/EGIST. However, immunotherapy with tyrosine kinase inhibitors (TKI), especially imatinib, has emerged as a promising neoadjuvant or alternative therapy. TKIs are especially useful in surgically unresectable or malignant tumors, and the advent of TKIs has increased median survival in such cases by nearly 50% [16, 17].
Use of steroids in the treatment of inoperable NICTH
Number of patients
Glucocorticoid used (and dosages)a
Duration of therapy
Goal of the study
Teale, et al. 1998 
One patient was treated with dexamethasone 4 mg three times a day.
Three patients were treated with prednisolone 30 mg once daily.
6 weeks–7 months
To compare the effectiveness of hGH and glucocorticoid therapy in NICTH by analyzing the molecular distribution of different forms of IGF-II and IGFBP-3.
Teale, et al. 2004 
Five patients were treated with prednisolone. Different regimens included: 20 mg once daily; 30 mg once daily; 5 mg three times a day)
One patient was treated with dexamethasone 4 mg once daily.
To compare the outcome of different treatment options in NICTH
Bourcigaux, et al. 2005 
Three different phases of study: phase 1 with prednisone only, phase 2 with hGH only, phase 3 with both.
The lowest effective dose when steroids were used alone was prednisone 30 mg.
Days (experimental study)
To assess if combination therapy with low dose steroid and hGH is effective in inoperable patients with NICTH.
Perros, et al. 1996 
Prednisone 30 mg once daily given with a combination of hGH and bendrofluazide; steroids were lowered later to 15 mg once daily (only in combination),
Our patient continued to have severe hypoglycemia as an inpatient. This was acutely treated with continuous infusions of both glucagon and dextrose. Once the diagnosis of recurrent NICTH was established, she was successfully transitioned to prednisone 40 mg once daily, and euglycemia was achieved. Since surgical resection was not a viable option given the extent of her disease, imatinib was restarted after discussion with oncology with the aim of decreasing tumor burden. Over the next few months, she was successfully weaned off all steroids and repeat imaging demonstrated some shrinkage of the tumor with TKI therapy.
In summary, NICTH is a rare paraneoplastic phenomenon that has been described in association with a variety of neoplasms. The pathophysiology of NICTH arises from excessive tumor production of both IGF-II and its precursor “big” IGF-II, resulting in an altered IGF-I to IGF-II ratio and insulin-independent stimulation of the insulin receptor. While cases of GIST associated NICTH have been reported, to our knowledge, our patient remains distinctive in having an extremely rare extragastrointestinal GIST tumor with an even more rare presentation of non-islet cell tumor hypoglycemia. While definitive treatment involves tumor resection and/or adjuvant treatment with TKIs, corticosteroids have been shown to successfully alleviate hypoglycemia. The overall consensus from a limited number of published reports suggests initiating steroids at a dose of prednisone 30 mg or higher and then tapering over weeks to months to the smallest dosage required to maintain euglycemia .
The authors acknowledge the support of the Islet and Physiology Core of the Indiana Diabetes Research Center (P30-DK-097512), the editorial assistance of Ms. Marilyn Wales, and the assistance of the Pathology and Radiology Departments at the Sidney and Lois Eskenazi Hospital in Indianapolis, Indiana.
Work in the laboratory of C.E-M is supported by NIH grants UC4 DK104166 and DK093954, VA Merit Award I01 BX001733, and JDFR grant SRA-2014-41 The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs or the United States Government, or the JDRF.
Availability of data and materials
ZS and CE-M analyzed and interpreted patient data. ST performed the histological examination of tumor sections. All authors contributed to the writing the manuscript; all authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written permission to publish this case report was obtained from the patient.
Ethics approval and consent to participate
Reports describing the case of a single patient are exempt from review by the Indiana University School of Medicine Institutional Review Board.
- 5.Rikhof B, van Doorn J, Suurmeijer AJ, Rautenberg MW, Groenen PJ, Verdijk MA, et al. Insulin-like growth factors and insulin-like growth factor-binding proteins in relation to disease status and incidence of hypoglycaemia in patients with a gastrointestinal stromal tumour. Ann Oncol. 2009;20(9):1582–8.CrossRefPubMedGoogle Scholar
- 17.Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26(4):620–5.CrossRefPubMedGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.