For Insulinomas, No Place to Hide

Abstract

What a splendid idea to use the receptor for glucagonlike peptide-1 (GLP1), which is widely expressed onhealthys-cells, tovisualize their tumorous counterpart, insulinomas! After the preliminary report of this novel technique in animals (1) and in two patients (2), Christ et al. (3) now report in a series of six consecutive insulinoma patients that they could localize the typically small insulinomas in all cases. Inspired by the finding that GLP-1 receptors are commonly expressed in insulinoma cells, this observation was based on a sound hypothesis. This novel approach certainly extends our armamentarium of imaging techniques (transabdominal ultrasound, endoscopic ultrasound, intraoperative ultrasound, computed tomography scan, magnetic resonance imaging, angiography, somatostatin receptor scintigraphy, selective arterial calcium injection/insulin stimulation, and portal venous sampling), which have traditionally been used with mixed success. This less than optimal success is due to the small size of a typical insulinoma often being below the detection limit of the respective methods. In the absence of a more reliable direct imaging method, the diagnosis of an insulinoma, and thus the recommendation for explorative laparotomy, has often been based solely on the biochemical evidence for an insulin-producing tumor. However, by this traditional approach, patients with other causes of hyperinsulinemia (e.g. factitious hypoglycemia due to sulfonylureas) may also be subjected to surgery, and the intraoperative detection of the tumor solely depends on the experience of the surgical team. Finally, extrapancreatic insulinomas may remain undetected even during an exploratory laparotomy. The evidence for an insulinoma based on this novel imaging approach will certainly facilitate the decision of patients and physicians to undergo and to accept the potential risks of surgery. Despite the results presented by Christ et al. (3) certainly being promising, a couple of questions related to the potential future role for GLP-1 receptor scintigraphy in the diagnostic workup of insulinoma patients remain. How does this method perform in selected patients in whom other methods did not clarify the site of the insulinoma? The standard to be compared against probably should be endoscopic ultrasound, which identifies the greatest percentage of insulinomas [ 90% (4)] compared with other methods. Even more challenging would be a group of patients with firm biochemical proof of hyperinsulinemic hypoglycemia, but an unsuccessful surgical exploration by an experienced surgeon, and especiallywhenintraoperativeultrasoundwasemployed(5). Such patients will most likely benefit from being referred to the authors of the current study or other sites that can offer this method in the future. Anotherquestionof interest iswhether false-positive findings could potentially be observed. This would be particularly deleterious in cases of sulfonylurea-induced factitious hypoglycemia (6), a condition that can be biochemically difficult to discern from an insulinoma. Furthermore, will metastases, which occur in approximately 10% of insulinomas with malignant features (7), be reliably detected, or is it possible that malignant insulinoma cells dedifferentiate and lose GLP-1 receptor expression? The fact that in the present report “difficult to localize” insulinomas were included, especially one residing in an extrapancreatic site, certainly provides a rationale for positive expectations. Technically speaking, a rather large dose of exendin-4 (30 g per injection) was used for GLP-1 receptor scintigraphy in the study of Christ et al. (3) published in this issue of JCEM (3). It was not surprising that this dose was associated with nausea (8). More surprising, however,