Discussion
A literature review reveals a limited number of case reports that describe the conversion of a non-functional NET into a functional one. Multiple case series estimate the rate of conversion to be between 3.4% and 6.8%, but this date is mostly observational [11,12]. The mechanism behind this conversion remains unclear, although some studies have shown secondary conversion post-therapy with sunitinib or traditional chemotherapy [13,14]. These studies suggest epigenetic conversion of the primary NET, which may occur because of treatment, but the mechanism is not well described. Among the few treatment options for malignant insulinoma are Everolimus and Sunitinib. Everolimus inhibits the MTOR pathway that is a part of insulin-related gluconeogenesis and is effective as an adjunctive therapy in patients who are not a candidate for surgical treatment [15]. Sunitinib is a tyrosine kinase inhibitor that directly inhibits tumor growth, thereby reducing insulin production, but it can sometimes cause paradoxical hypoglycemia on its own [13,16].
Our patient was already diagnosed with metastatic pancreatic NET in the outpatient setting prior to presentation. She had known metastases to the liver and lungs when she was admitted for management of acute pulmonary embolism. This tumor had tested positive for NET tumor markers of synaptophysin and chromogranin on initial evaluation. It is not common for functional testing to occur for tumors unless the patient demonstrates any clinical signs of a functional tumor, which is what this case report describes. While hospitalized, the patient developed symptomatic hypoglycemia with decreased blood glucose levels that improved with glucose administration. These three clinical findings, also known as Whipple’s triad [4], strongly raised the suspicion for conversion of the primary pancreatic NET into an insulinoma. Subsequent measurements of fasting insulin and c-peptide levels confirmed this diagnosis. Interestingly, our patient did not receive any treatment prior to conversion and had a much shorter time of conversion than is described in the literature, 3 months vs. a median of 15 months in other reports [11]. Due to her metastatic disease prior to conversion, treatment options remained limited, and our patient’s prognosis was poor. She was hospitalized numerous times for insulin-related complications and was not a candidate for any aggressive therapy.
Our case describes one of the few instances of conversion from a non-functional NET into an insulinoma without any prior treatment and over a much shorter time frame. It also describes an aggressive clinical course in these patients due to uncontrolled symptoms related to hypoglycemia and a paucity of treatment options therein. Traditional insulinoma treatments, including surgical resection, could have been utilized, but metastatic disease made this impossible. Newer drugs such as Everolimus and Sunitinib could have been an option for our patient but were not an option as the patient declined these treatments. There may have been some hesitation due to the novelty of these treatments and a lack of strong evidence in their favor.