To the Editor: The precise localization of some insulinomas(islet-cell adenomas that secrete insulin) with the use of conventionalimaging techniques, such as computed tomography (CT), magneticresonance imaging (MRI), endosonography,1 and indium-111 (111In)–labeledpentetreotide scintigraphy (OctreoScan),2 is a challenging clinicalproblem. In vitro studies have demonstrated that receptors forglucagon-like peptide 1 (GLP-1) are highly overexpressed inalmost all insulinomas.3,4 Therefore, GLP-1-like radioligandsretaining high binding affinity to GLP-1 receptors have beendeveloped. One such radioligand, [Lys40(Ahx-DTPA-111In)NH2]exendin-4,successfully targeted insulinomas in the Rip1-Tag2 mouse.5 Weevaluated the diagnostic value of GLP-1–receptor scintigraphyin two patients with insulinomas that either were not localized(Patient 1) or were unsatisfactorily localized (Patient 2) withthe use of conventional imaging methods.
The radioligand was labeled with 111In and was administeredintravenously (90 MBq) during a 5-minute period.4 Whole-bodyplanar imaging and single-photon-emission CT (SPECT) imagingof the abdomen were performed at various times. The resultsprovided proof of concept that a GLP-1–receptor scan canidentify barely detectable insulinomas that express GLP-1 receptor.Histologic analysis of surgically removed tissues that correspondedto the tumor "hot spots" identified in both patients confirmedthat the lesions were insulinomas containing GLP-1 receptorsin high density.
In Patient 1, a 64-year-old man with neuroglycopenia and endogenoushyperinsulinism, the tumor could not be localized with any ofthe conventional preoperative imaging methods (including CT,endoscopic ultrasonography, octreoscan scintigraphy, and selectivearterial calcium stimulation and hepatic venous sampling), whereasGLP-1–receptor scintigraphy precisely identified the lesion,which was confirmed on removal as an ectopic insulinoma (Figure 1and the Supplementary Appendix, available with the full textof this letter at www.nejm.org). In Patient 2, a 31-year-oldwoman with endogenous hyperinsulinism, the tumor location onthe GLP-1–receptor scan (Figure 2) was found to overlapwith that of a suspicious lesion seen on endosonography. Allother imaging methods had been unsuccessful. In both patients,the GLP-1–receptor scan enabled the surgeon to localizeand resect the tumor. Not only were the SPECT images decisive,but the large accumulation of radioactivity in these small tumorsalso permitted in situ localization with a probe during surgery.
Figure 1. GLP-1–Receptor Imaging of an Insulinoma in Patient 1.
In Patient 1, a 64-year-old man with symptomatic neuroglycopenia and biochemically confirmed endogenous hyperinsulinism, whole-body planar scans show an insulinoma (arrow) with a tumor-to-background ratio of 5.8 at 4 hours after injection of a radioligand (Panel A) and of 13.4 at 4 days after injection (Panel B). Because of urinary excretion of the radioligand, the kidney and bladder labeling are less prominent on day 4 than at 4 hours, so late scans (2 to 4 days after injection) are recommended. Transaxial single-photon-emission CT (SPECT) that was performed 4 days after the injection of a radioligand shows uptake in a small nodule between the duodenum and the superior mesenteric artery (Panel C, arrow). A glucagon-like peptide 1 (GLP-1)–receptor autoradiograph shows total binding of iodine-125–labeled GLP-1(7-36) amide in tumor tissue (Panel D); an autoradiograph with nonspecific binding is shown for comparison (Panel E). The bar represents 1 mm.
Figure 2. GLP-1–Receptor Imaging of an Insulinoma in Patient 2.
In Patient 2, a 31-year-old woman with biochemically confirmed endogenous hyperinsulinism who presented with a 2-week history of fainting, endosonography showed a suspicious lesion in the transition zone between the pancreatic body and tail. Transaxial single-photon-emission CT (SPECT) that was performed 23 hours after the injection of a radioligand reveals an insulinoma (Panel A, arrow). A glucagon-like peptide 1 (GLP-1)–receptor autoradiograph shows total binding of iodine-125–labeled GLP-1(7-36) amide in the tumor (Tu) but not in the pancreas (P) (Panel B); an autoradiograph with nonspecific binding is shown for comparison (Panel C). The bar represents 1 mm.
These findings indicate that GLP-1–receptor scanning mayoffer a new diagnostic approach that permits the successfullocalization of small insulinomas. Since virtually all insulinomasexpress GLP-1 receptors,3 we speculate that the rate of successof such diagnostic scintigraphy would be high.
Damian Wild, M.D. Helmut Mäcke, Ph.D. University Hospital 4031 Basel, Switzerland
Jean Claude Reubi, M.D. University of Bern 3010 Bern, Switzerland reubi{at}pathology.unibe.ch
Supported by a grant (OCS-01778-08-2005) from Oncosuisse anda grant (SNF-PBBSB-118838) from the Swiss National Science Foundation.
References
McAuley G, Delaney H, Colville J, et al. Multimodality preoperative imaging of pancreatic insulinomas. Clin Radiol 2005;60:1039-1050. [CrossRef][ISI][Medline]
Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716-731. [ISI][Medline]
Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 2003;30:781-793. [ISI][Medline]
Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007;48:736-743. [Free Full Text]
Wild D, Behe M, Wicki A, et al. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 2006;47:2025-2033. [Free Full Text]
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