A Case of Paraneoplastic Hypoglycemia From Squamous Cell Carcinoma of Undetermined Primary

Abstract

Case: A 57 year old man with squamous cell carcinoma (SCC) of the tongue with complete response to chemoradiation was found unresponsive with a reading of “low” by a POC glucometer. He was treated with an IV dextrose bolus but had recurrent hypoglycemia requiring a continuous dextrose infusion. He was diagnosed with COVID-19 pneumonia, acute hepatitis (elevated liver enzymes), and acute kidney injury (elevated serum creatinine 1.2 mg/dL). Other labs: elevated TSH 8.44 uIU/mL, normal AM cortisol 16.4 ug/dl. A 5.1 cm mass was discovered in the left lung with bilateral nodules, biopsi revealed SCC of unclear origin (either lung or metastatic disease from prior tongue cancer). He was malnourished from prior cancer related dysphagia and nutritional supplements were added. Despite this and improvement in liver and kidney function, he had persistent hypoglycemia. He became hypoglycemic within 4-hrs while performing a 72-hr fast with labs: serum glucose 45 mg/dL, insulin < 2 uU/mL, c-peptide < 0.1 ng/mL, proinsulin < 4 pmol/L, beta hydroxybutyrate 0.17 mmol/L, IGF1 < 16 ng/mL (ref: 50 - 317), IGF2 147 ng/mL (ref: 267-616), negative hypoglycemia panel and insulin antibody. This was consistent with a paraneoplastic hypoglycemia known as non-islet cell tumor hypoglycemia (NICTH). To discontinue the dextrose infusion, he was started on prednisone 20 mg daily titrated up to 60 mg daily, intermittent tube feeds and palliative chemotherapy. With this, hypoglycemia improved, and the dextrose infusion was discontinued. Unfortunately, he had ischemic bowel perforation leading to cardiac arrest and death. Discussion: Our patient had NICTH as suggested by the 72-hr fast (non-insulin mediated hypoglycemia, IGF2/IG1 ratio > 10) and the presence of a tumor. It is mediated by tumor-produced IGF-2 causing increased glucose utilization, decreased gluconeogenesis, glycogenolysis and ketogenesis. Curiously, IGF-2 may not be elevated if the tumor produces a partially processed “big IGF-2” for which there is no commercial assay. Instead, an IGF2/IGF1 ratio close to or more 10 is indicative of NICTH. Mesenchymal and hepatic tumors are the most common cause of this rare entity with an incidence of one per million people years. A literature search showed very few reports of SCC-mediated-NICTH, with one case of esophageal SCC. Our patients’ primary tumor was undetermined (lung vs tongue) - but in either case this could be a novel association. A multidisciplinary approach is required centered around the tumor (surgery, chemotherapy, or radiation). High dose prednisone 30 to 60 mg daily can be used in the interim as it decreases IGF-2 but is not always successful. Recombinant hGH and glucagon are alternatives or can be combined with steroids. In summary IGF2/IGF1 ratio should be calculated, palliative tumor directed therapy should be initiated with prednisone and supplemental nutrition as adjuncts.