Non-islet-cell tumor hypoglycemia as first manifestation of an advanced hepatocellular carcinoma

Non-islet cell tumor hypoglycemia (NICTH) is a rare but severe complication of malignancy. We present the case of 55 year old man who was admitted for severe hypoglycemia. The diagnosis of insulinoma was ruled out. After clinical work-ups, we made the diagnosis of metastatic HCC with production of IGF-2.

Think Outside the Thorax: Doege-Potter Syndrome Presenting as a Retroperitoneal Mass

Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome, occurring less commonly than insulinoma. These tumors produce high molecular weight insulin-like growth factor-2 or “big IGF-2”, resulting in hypoglycemia: big IGF-2 decreases glycogenolysis, gluconeogenesis, and glucagon release as well as increases glucose uptake by adipocytes and skeletal muscle. NICTH specifically associated with a solitary fibrous tumor (SFT) is known as Doege-Potter syndrome. Doege-Potter syndrome is seen most with thoracic SFT’s. This case study details the diagnosis and management of Doege-Potter syndrome due to retroperitoneal SFT. Case Description: Our patient is a 68-year-old, white female who initially presented to an outside facility with a 3-week history of episodic neuroglycopenic symptoms temporarily relieved with eating. She reported night sweats but no weight change or fever. Medical history was notable only for hypertension and GERD. She had no personal or family history of diabetes. She was transferred to our facility for further evaluation of an 18.6 cm multilobular mass seen just inferior to the liver on abdominal CT. Whipple’s triad was confirmed with venous glucose sampling while inpatient. C-peptide, free/total insulin, and pro-insulin were collected during permissive hypoglycemia and were low. Morning cortisol and TSH were unremarkable. Additionally, sulfonylurea screen and insulin antibodies were negative. Ultrasound-guided biopsy of the lesion was positive for CD34 and STAT6, consistent with SFT. Refractory hypoglycemia was treated with D5W infusion until surgical resection of the retroperitoneal mass, after which, she had complete resolution of her hypoglycemia. Discussion: This patient’s serum IGF-2 was within normal limits, consistent with reports of feedback inhibition exerted by increased levels of big-IGF-2. Therefore, the IGF-2:IGF-1 ratio is used to determine increased serum levels of big IGF-2, but this test is not widely available. SFT’s can recur within months to years of resection, necessitating surveillance. Recurrence is also more common with extrathoracic tumors. Surgical pathology noted tumor dimensions of 22 cm and 2270 g; mitotic rate was 1 per 10 hpf. Features typical of malignancy include large size (>15 cm) and mitotic rate >4 mitoses per hpf. This patient’s follow-up CT abdomen at 6 weeks did not show any findings to suggest recurrent or metastatic disease.

A Case of Non-Islet Cell Tumor Hypoglycemia in Metastatic Solitary Fibrous Tumor

Introduction: Insulin like growth factor (IGF-2) mediated hypoglycemia secondary to solitary fibrous tumor (SFT), also known as Doege-Potter syndrome is a rare paraneoplastic syndrome. The tumor cells produce large amounts of high molecular weight IGF 2 precursor protein called “big IGF-2” which binds to insulin and IGF receptors in liver, muscle and other peripheral tissues. This causes reduced gluconeogenesis and increased uptake of glucose by the muscle and other tissues leading to hypoglycemia. Big IGF-2 also exerts central negative feedback of growth hormone causing reduction of IGF-I production. Most SFTs are benign and localized (approximately 78-88%). As a result, tumor excision alone would often lead to resolution of the hypoglycemia. We present a case of metastatic SFT with multiple metastasis managed with oral prednisone. Clinical Case: A 44-year-old man with metastatic SFT presented with bilateral humeral fractures. He has known metastatic disease to the brain, lung, liver, bony lytic lesions over a course of eleven years. It has progressed despite multiple chemotherapy and radiation therapies. Prior to admission, he had multiple syncopal episodes associated with fasting hypoglycemia. He reported capillary blood glucose values ranging between 30-50 mg/dl during these episodes which would improve after drinking juice or eating candy. There was no history of diabetes mellitus or use of oral hypoglycemic agents or insulin. On admission, he had a capillary blood glucose value of less than 20 mg/dl, which was confirmed by a serum glucose value of 18 mg/dl on basic metabolic panel. His renal, liver and thyroid function tests were normal. Significant labs include: serum glucose 17 mg/dl, C-peptide <0.10 ng/ml (n: 1-4 ng/ml), serum insulin <1.6 Uu/ml (n: <20 Uu/ml), beta-hydroxybutyrate <0.2 mmol/L (n: <0.3), cortisol 10.8 ug/dl(n: 5-15 ug/dl) glucagon 6 pg/ml(ref 8-57 pg/ml), insulin-like growth factor-1 (IGF 1) 20 ng/ml (n: 52-328), and IGF-2 level 380 ng/ml (267-616 ng/ml), improvement in blood glucose from 46 to 111 mg/dl after 1-gram glucagon administration. The IGF-2/IGF-1 ratio of 19 confirmed our clinical suspicion of non-islet cell tumor hypoglycemia (NICTH). He was started on prednisone 20 mg twice daily with marked improvement in hypoglycemia. Conclusion: NICTH is a rare cause of hypoglycemia and should be considered in the differential while evaluating hypoglycemia in malignancy. For diagnosing NICTH, assays for big IGF-II are not commercially available. However, the IGF-II:IGF-I ratio is considered to be a surrogate marker of big IGFII concentration. The normal ratio is 3 and ratio >10 is diagnostic of NICTH. In cases like ours where tumor resection is not possible, glucocorticoids are most effective in management of hypoglycemia by inhibiting big IGF2 production and stimulating gluconeogenesis.

Doege-Potter Syndrome with a Benign Solitary Fibrous Tumor: A Case Report and Literature Review

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up.