Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib
A 46-year-old woman was carried to the emergency room with sudden loss of consciousness before breakfast. During transfer in the ambulance, her blood glucose level was measured as 20 mg/dL. After intravenous infusion of dextrose solution, she regained consciousness.\nHer medical history included a 7-mm size neuroendocrine carcinoma in the pancreas (), with metastases to retroperitoneal lymph nodes, left supraclavicular lymph nodes and liver (). The patient had received this diagnosis 4 months prior, after presenting with right flank pain. Needle biopsy and immunohistochemical (IHC) staining of the supraclavicular lymph node had been positive for CD56, chromogranin, and synaptophysin, and negative for glucagon and insulin. One month later, she started taking sunitinib 37.5 mg per day because the disease progressed and the right flank pain increased. After 2 months of sunitinib treatment she felt severe fatigue from which she was diagnosed with hypothyroidism, a common adverse event of sunitinib. She began levothyroxine, but even after normalization of thyroid hormone levels, she experienced intermittent weakness, dizziness, and hunger. To relieve fatigue and hunger, she increased oral intake and experienced weight gain of 10 kg over a month. Her medications included oxycodone to relieve flank pain and famotidine for epigastric soreness. She reported having no personal or family history of thyroid disease or diabetes mellitus.\nOn physical examination, she appeared well. Her vital signs were within the normal range, height 156.5 cm and body weight 53 kg. There were two palpable, hard, and nontender lymph nodes of less than 1 cm each in the left supraclavicular area. Goiter was not found. She had tenderness in the right flank on percussion, but hepatosplenomegaly was not noted. Grade 1 hand-foot syndrome (mild erythema), a skin-related side effect of sunitinib was observed. The blood cell count, urinalysis, and serum chemistry and electrolytes were within normal range. A1c at admission was 5.6%. An electrocardiogram revealed a normal sinus rhythm and chest X-ray showed no abnormality. Computed tomography of the abdomen demonstrated an increase in the size of the liver mass from 1.8 to 2.8 cm.\nOvernight fasting plasma glucose was 16 mg/dL with C-peptide and insulin levels of 6.1 ng/mL and 27.2 µIU/mL, respectively. These inappropriately elevated fasting insulin and C-peptide levels compared to the glucose level confirmed that the patient's hypoglycemia resulted from endogenous hyperinsulinemia. Differential diagnosis of endogenous hyperinsulinemia was based on negative titers for insulin antibody and insulin receptor antibody. We performed a liver biopsy to obtain metastatic tissue, and the histologic examination revealed diffuse infiltration of the cancer cells in the liver. IHC staining positive for CD56, chromogranin, and synaptophysin confirmed metastatic neuroendocrine carcinoma. In addition, the metastatic lesion in the liver which had been negative at the initial diagnosis () was strongly positive for insulin (). We concluded that the nonfunctional neuroendocrine carcinoma that metastasized to the liver changed into an insulin-producing tumor after 2 months of administration of sunitinib.\nSince sunitinib may have played a role in the transformation, it was discontinued. However, even with frequent dietary intake, the patient required more than 500 g of glucose per day via the central vein to prevent hypoglycemia. High-dose glucocorticoid and glucagon administration were not effective in relieving the severe hypoglycemia. Eighteen days after discontinuation of sunitinib, severe hypoglycemia persisted and she underwent transarterial chemoembolization (TACE) for the metastatic lesions in the left lobe of her liver. TACE showed extensive and multiple staining of liver nodules, which suggested successful embolization. Intravenous glucose infusion was slowly tapered to 200 g per day during the 2 weeks after TACE. Then a β-cell toxin, streptozotocin (500 mg/m2), and adriamycin (50 mg/m2) were administrated intravenously. Intravenous glucose infusion was stopped 1 week after this infusion. The patient underwent another round of TACE for the right lobe of the liver and intravenous streptozotocin/adriamycin, and she was successfully discharged. One month after the final treatment, her fasting blood glucose was 101 mg/dL. Local control of metastatic carcinoma and systemic administration of β-cell toxin had reversed her severe hypoglycemia.