Refractory Metastatic Insulinoma Treated with Everolimus, Complicated by Cryptogenic Organizing Pneumonia.

Abstract

Insulinoma is a rare neuroendocrine pancreatic islet cell tumor of which the majority are benign and solitary. Its estimated incidence is 2 to 4 cases per 1 million person-years. We report the case of an 82-year-old female who presented with metastatic insulinoma to the liver and retroperitoneal lymph nodes. It was diagnosed based on positive Whipple’s triad, elevated insulin, elevated C-peptide, and negative insulin auto-antibody. Her disease was initially managed with diazoxide 100 mg orally every 8 hours, octreotide LAR 30 mg intramuscularly every month, and sunitinib 12.5 mg orally three times a day. However, patient had recurrent symptoms and imaging consistent with worsened metastatic insulinoma; and thus, treatment was changed to everolimus 10 mg PO daily. Over the subsequent 10 months, the patient developed progressive shortness of breath and hypoxemia with and oxygen saturation (SpO2) of 89% on room air. Computerized tomography (CT) and lung biopsy were consistent with cryptogenic organizing pneumonia (COP) temporally associated with the initiation of everolimus. She was started on prednisone 1 mg/kg/day and within 48 hours, her symptoms and hypoxemia improved to SpO2 of 98–99% at room air and her repeat CT chest showed marked disease improvement. Given her good response with everolimus, it was continued in conjunction with the prednisone and to this day, patient has had a significant therapeutic response with normoglycemia and stable, well-controlled symptoms. This case is unique because to our knowledge, it is the first reported case of a patient with metastatic insulinoma complicated by the development of cryptogenic organizing pneumonia. It reaffirms the causal association between everolimus and cryptogenic organizing pneumonia that has been reported numerous times in literature. However, there has been no reported cases showing that the COP can be managed with prednisone concurrently with everolimus for the metastatic insulinoma without diminished clinical benefit. While pulmonary complications have been cited as reasons for discontinuation of everolimus therapy, our case report highlights the use of steroids as a viable therapeutic strategy that allows successful therapy with everolimus to be continued. In addition to presenting this case, we will also do a thorough review of the literature surrounding the available therapeutic options of metastatic insulinoma. This will include surgery, somatostatin analogs, antimicrobials, potassium channel activators, VEGF-A inhibitors, alkylating agents and mTOR inhibitors to provide a more in-depth picture of how we treat metastatic insulinoma.