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Previous Volume 359:766-768 August 14, 2008 Number 7 Next

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To the Editor: The precise localization of some insulinomas (islet-cell adenomas that secrete insulin) with the use of conventional imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), endosonography,¹ and indium-111 (¹¹¹In)–labeled pentetreotide scintigraphy (OctreoScan),² is a challenging clinical problem. In vitro studies have demonstrated that receptors for glucagon-like peptide 1 (GLP-1) are highly overexpressed in almost all insulinomas.^3,4 Therefore, GLP-1-like radioligands retaining high binding affinity to GLP-1 receptors have been developed. One such radioligand, [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]exendin-4, successfully targeted insulinomas in the Rip1-Tag2 mouse.⁵ We evaluated the diagnostic value of GLP-1–receptor scintigraphy in two patients with insulinomas that either were not localized (Patient 1) or were unsatisfactorily localized (Patient 2) with the use of conventional imaging methods.

The radioligand was labeled with ¹¹¹In and was administered intravenously (90 MBq) during a 5-minute period.⁴ Whole-body planar imaging and single-photon-emission CT (SPECT) imaging of the abdomen were performed at various times. The results provided proof of concept that a GLP-1–receptor scan can identify barely detectable insulinomas that express GLP-1 receptor. Histologic analysis of surgically removed tissues that corresponded to the tumor "hot spots" identified in both patients confirmed that the lesions were insulinomas containing GLP-1 receptors in high density.

In Patient 1, a 64-year-old man with neuroglycopenia and endogenous hyperinsulinism, the tumor could not be localized with any of the conventional preoperative imaging methods (including CT, endoscopic ultrasonography, octreoscan scintigraphy, and selective arterial calcium stimulation and hepatic venous sampling), whereas GLP-1–receptor scintigraphy precisely identified the lesion, which was confirmed on removal as an ectopic insulinoma (Figure 1 and the Supplementary Appendix, available with the full text of this letter at www.nejm.org). In Patient 2, a 31-year-old woman with endogenous hyperinsulinism, the tumor location on the GLP-1–receptor scan (Figure 2) was found to overlap with that of a suspicious lesion seen on endosonography. All other imaging methods had been unsuccessful. In both patients, the GLP-1–receptor scan enabled the surgeon to localize and resect the tumor. Not only were the SPECT images decisive, but the large accumulation of radioactivity in these small tumors also permitted in situ localization with a probe during surgery.

View larger version (73K): [in this window] [in a new window]   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.

 

View larger version (47K): [in this window] [in a new window]   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 may offer a new diagnostic approach that permits the successful localization of small insulinomas. Since virtually all insulinomas express GLP-1 receptors,³ we speculate that the rate of success of such diagnostic scintigraphy would be high.

Damian Wild, M.D.
Helmut Mäcke, Ph.D.
University Hospital
4031 Basel, Switzerland

Emanuel Christ, M.D., Ph.D.
Beat Gloor, M.D.
University Hospital
3010 Bern, 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 and a grant (SNF-PBBSB-118838) from the Swiss National Science Foundation.

References

1. McAuley G, Delaney H, Colville J, et al. Multimodality preoperative imaging of pancreatic insulinomas. Clin Radiol 2005;60:1039-1050. [CrossRef][Web of Science][Medline]
2. 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. [Web of Science][Medline]
3. 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. [Web of Science][Medline]
4. 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]
5. 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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