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CASE REPORT Table of Contents  
Ahead of print publication
Non-islet cell tumor-related hypoglycemia in a case of metastatic gastrointestinal stromal tumor: A rare paraneoplastic syndrome: A case report


1 Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Submission25-Apr-2022
Date of Decision28-Sep-2022
Date of Acceptance30-Sep-2022
Date of Web Publication17-Nov-2022
 

  Abstract 


Introduction: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Clinical presentations depend upon the site of involvement. It can lead to obstruction, bleeding, perforation, or symptoms due to mass effects. Tumor-induced hypoglycemia (nonislet cell tumor-related hypoglycemia [NICTH]) is a rare manifestation of GIST. Case Report: We herewith present the case of a 46-year-old female who presented with multiple abdominal lumps and recurrent episodes of syncope due to NICTH. On investigations, she was diagnosed to have unresectable GIST on biopsy. Her hypoglycemic episodes could be explained by rare paraneoplastic syndrome due to the raised levels of insulin-like growth factor-2. After treatment with imatinib (800 mg once daily), her hypoglycemic episodes subsided, which supported the diagnosis. Conclusion: NICTH is a rare paraneoplastic manifestation of GIST; targeted therapy can avert neuroglycopenic symptoms.

Keywords: Imatinib, metastatic gastrointestinal stromal tumor, nonislet cell tumor-related hypoglycemia


How to cite this URL:
Ghosh NK, Kumar A, Sharma VK, Verma V. Non-islet cell tumor-related hypoglycemia in a case of metastatic gastrointestinal stromal tumor: A rare paraneoplastic syndrome: A case report. Apollo Med [Epub ahead of print] [cited 2022 Nov 28]. Available from: https://apollomedicine.org/preprintarticle.asp?id=361433





  Introduction Top


Gastrointestinal stromal tumor (GIST) is the most common type of mesenchymal tumor of the gastrointestinal (GI) tract. Usual presentations include intestinal obstruction, bleeding, and perforation. Rare presentations are paraneoplastic symptoms such as hyperpigmentation, mastocytosis, and hypoglycemia.[1] Hypoglycemia is rarely observed in GIST, known as nonislet cell tumor-related hypoglycemia (NICTH). NICTH mimics insulinoma, and diagnosis is suspected in the presence of a bulky or metastatic tumor, biochemical evidence of low insulin, C-peptide, and elevated insulin-like growth factor-2 (IGF-2).[2] The goals of the treatment include management of hypoglycemia and modalities to decrease the tumor burden. There are only 10 case reports in the literature on NICTH in GIST [Table 1]. We present a rare case of metastatic GIST, where the patient presented with hypoglycemic episodes and was managed with Imatinib.
Table 1: Case reports reporting hypoglycemia in gastrointestinal stromal tumor

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  Case Report Top


A 46-year-old female presented with complaints of diffuse abdominal pain for 2 months, which was insidious in onset, mild, and dull aching associated with abdominal distention and constipation. She had no nausea, vomiting, jaundice, GI bleeding, anorexia, or weight loss. History of seizure, bone pain, or respiratory distress was absent. She had intermittent episodes of syncope, which used to improve after food intake. Examination revealed multiple, nontender, firm, mobile lumps over the abdomen. Rectal examination, per-vaginal examination, and other systemic examinations were within normal limits. Abdominal sonography and contrast-enhanced computed tomography revealed multiple heterogeneously enhancing lesions in the peritoneal cavity, mild ascites, and subcentimetric lymph nodes in the external iliac, obturator, and common iliac region [Figure 1]. Percutaneous biopsy and immunohistochemistry revealed a spindle cell tumor positive for CD117 and DOG1. It was negative for desmin. There were 1–2 mitotic figures per 50 high-power fields, and the Ki-67 proliferation index was 2%–3% [Figure 2]. Hematological and biochemical parameters were normal. She had multiple hypoglycemic episodes. Blood sample collected during the episode of hypoglycemia revealed serum glucose level to be 36 mg/dl, blood ketones 0.5 mmol/l (≤0.5 mmol/l), insulin levels <1.39 pmol/l (17.8–173 pmol/l), C-peptide 0.026 nmol/l (0.37–1.47 nmol/l), growth hormone 0.542 ng/ml (0.4–10 ng/ml), and serum cortisol 1059 nmol/l (138–550 nmol/l) which ruled out hyperinsulinism or adrenal insufficiency. NICTH is usually diagnosed based on evidence of tumor and hypoglycemia after ruling out other possible etiologies. Thus, a clinical diagnosis of NICTH was made in this patient. Serum levels of IGF-2 could not be estimated due to limited laboratory facility. She was advised a high dose (800 mg) of imatinib based on previously reported cases. In the first 24 h of treatment, there were no hypoglycemic episodes [Figure 3]. Hence, the diagnosis of GIST-induced hypoglycemia was ascertained. The further plan was to continue imatinib and assess response. The patient remained euglycemic for 4 weeks; however, she succumbed to her illness.
Figure 1: CECT shows multiple heterogeneously enhancing lesions in the peritoneal cavity. CECT: Contrast-enhanced computed tomography

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Figure 2: Histopathology slides of GIST with markers. (a) An intersecting fascicle of plump spindled tumor cells, ×100. (b) Tumor cells, ×400. (c) Tumor cells, ×1000. (d) Vimentin. (e) CD117. (f) DOG1. (g) No staining for Desmin. (h) Ki-67 index (2%–3%). GIST: Gastrointestinal stromal tumor

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Figure 3: Blood sugar trends during admission

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  Discussion Top


Hypoglycemia(NICTH) is a rare presentation of GIST, which is due to increased secretion of IGF-2.[1],[2] A few case reports and small series were published in the literature [Table 1]. The incidence of NICTH is 2.1–15 per million people, and there is no gender preference.[3],[9] It is usually observed in bulky or metastatic tumors of the mesenchymal origin (fibrosarcomas, mesotheliomas, leiomyosarcomas, and hemangiopericytomas) and rarely observed in carcinoid tumors, myelomas, lymphomas, hepatocellular carcinomas, and colorectal cancers.[4],[10],[11],[12] Hypoglycemia in NICTH results from suppressed growth hormone secretion and increased synthesis of incompletely processed IGF-2. IGF-2 stimulates the insulin receptors, improves glucose utilization by skeletal muscles, and simultaneously inhibits glucose release from the liver resulting in hypoglycemia. Daughaday first reported a case of NICTH in association with fibrosarcoma.[11] There are no published guidelines for the diagnosis of this rare entity. Usually, the clinical diagnosis of NICTH is made when a patient has a tumor detected on imaging, confirmed by histological examination, and all other hypoglycemia causes have been ruled out. In our patient, insulin hypersecretion, growth hormone, or cortisol deficiency were ruled out based on biochemical parameters. Serum IGF-2 is generally elevated in these cases; however, diagnosis can also be made based only on clinical suspicion (Singhal et al.), like in our case.[4] Usually, these patients have decreased levels of GH, IGF-1, and increased IGF-2/IGF-1 ratio (>10).[5] Treatment of NICTH includes correction of hypoglycemia and measures to reduce the tumor burden. Tumor-targeted treatment measures include local (selective embolization or radiofrequency ablation) or systemic therapies (chemotherapy). Palliation of symptomatic hypoglycemia is the primary therapeutic goal as it can be lethal; however, the long-term outcome depends upon the response of the tumor to the therapy. Most of these patients have unresectable or metastatic disease at the time of diagnosis, and R0 resection is challenging. Hence, a local tumor ablation therapy or systemic chemotherapy is preferred. Hypoglycemic epsodes are relieved with exogenous glucose, stimulation of glycogenolysis, or gluconeogenesis and the drugs used are glucagon, diazoxide, octreotide, recombinant growth hormone, and glucocorticoids.[13]

GIST is a chemotherapy- and radiotherapy-resistant tumor. It responds to tyrosine kinase inhibitors (TKIs) (e.g., imatinib, sunitinib, and regorafenib). Hypoglycemia induced by GIST responds to TKIs, low-dose steroids, and growth hormones.[14],[15] Some reports suggest that high doses of imatinib can abate hypoglycemic episodes. In our patient, high doses of imatinib (800 mg/day) made her euglycemic. TKIs decrease glucose uptake by tumor cells and relocate the glucose receptors inside the cell resulting in a euglycemic state.[5] Most patients have metastatic disease, and information is limited regarding guidelines for the management and long-term follow-up of such patients. Our patient had metastatic GIST with hypoglycemia and responded to imatinib; however, she succumbed to her illness, probably attributed to metastatic disease. This patient could have been evaluated with mutational analysis and PET scan for formulating a better therapeutic plan, but due to financial constraints, it could not be performed.


  Conclusion Top


NICTH is a rare clinical presentation in association with GIST. Tumor-directed treatment, i.e., surgery or targeted therapy, can decrease tumor burden and improve glycemic status; however, the prognosis is poor. Thus, the awareness of such a rare clinical presentation can suggest advanced disease and dictate further management.

Conflicts of interest

There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Funding

Nil.

Author's contribution

NKG and AK – Concept, design, manuscript writing and critical analysis, and final proofreading. VKS and VV – manuscript writing, information collection, and critical analysis.



 
  References Top

1.
Carballo M, Roig I, Aguilar F, Pol MA, Gamundi MJ, Hernan I, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J Med Genet A 2005;132A: 361-4.  Back to cited text no. 1
    
2.
Pink D, Schoeler D, Lindner T, Thuss-Patience PC, Kretzschmar A, Knipp H, et al. Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: A report of two cases. J Clin Oncol 2005;23:6809-11.  Back to cited text no. 2
    
3.
Escobar GA, Robinson WA, Nydam TL, Heiple DC, Weiss GJ, Buckley L, et al. Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: A case report. BMC Cancer 2007;7:13.  Back to cited text no. 3
    
4.
Singhal A, Hadi R, Mehrotra K, Rastogi S, Masood S. Paraneoplastic hypoglycaemia: A rare manifestation of pelvic gastrointestinal stromal tumour. J Clin Diagn Res 2017;11:D01-2.  Back to cited text no. 4
    
5.
Dimitriadis GK, Gopalakrishnan K, Rao R, Grammatopoulos DK, Randeva HS, Weickert MO, et al. Severe paraneoplastic hypoglycemia secondary to a gastrointestinal stromal tumour masquerading as a stroke. Endocrinol Diabetes Metab Case Rep 2015;2015:150062.  Back to cited text no. 5
    
6.
Rikhof B, van Doorn J, Suurmeijer AJ, Rautenberg MW, Groenen PJ, Verdijk MAJ, 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;20:1582-8.  Back to cited text no. 6
    
7.
Hamberg P, de Jong FA, Boonstra JG, van Doorn J, Verweij J, Sleijfer S. Non-islet-cell tumor induced hypoglycemia in patients with advanced gastrointestinal stromal tumor possibly worsened by imatinib. J Clin Oncol 2006;24:e30-1.  Back to cited text no. 7
    
8.
Beckers MM, Slee PH, van Doorn J. Hypoglycaemia in a patient with a gastrointestinal stromal tumour. Clin Endocrinol (Oxf) 2003;59:402-4.  Back to cited text no. 8
    
9.
Service FJ, McMahon MM, O'Brien PC, Ballard DJ. Functioning insulinoma – Incidence, recurrence, and long-term survival of patients: A 60-year study. Mayo Clin Proc 1991;66:711-9.  Back to cited text no. 9
    
10.
Teale JD, Wark G. The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf) 2004;60:457-60.  Back to cited text no. 10
    
11.
Daughaday WH. Hypoglycemia in patients with non-islet cell tumours. Endocrinol Metab Clin North Am 1989;18:91-101.  Back to cited text no. 11
    
12.
Dogu GG, Dikilitas M, Ozkan M, Karahan OI, araca Z, Gunay N. et al. Hypoglycemia in a patient with metastatic gastrointestinal stromal tumor: Is chemotherapy a reasonable option for symptom control? UHOD-Uluslararasi Hematoloji-Onkoloji Dergisi 2010;20:48-51.  Back to cited text no. 12
    
13.
Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: A clinical review. J Clin Endocrinol Metab 2014;99:713-22.  Back to cited text no. 13
    
14.
Shetty N, Sirohi B, Shrikhande SV. Molecular target therapy for gastrointestinal stromal tumours. Transl Gastrointest Cancer 2015;4:207-18.  Back to cited text no. 14
    
15.
Chen JH, Ho CH, Chen YC, Chao TY, Kao WY, He CT. Prednisolone for therapy of advanced gastrointestinal stromal tumour-induced hypoglycaemia. J Cancer Res Pract 2011;27:165-70.  Back to cited text no. 15
    

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Correspondence Address:
Nalini Kanta Ghosh,
Department Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_67_22



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