Correspondence

Glucagon-like Peptide 1–Receptor Scans to Localize Occult Insulinomas

N Engl J Med 2008; 359:766-768August 14, 2008

Article

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 1Figure 1GLP-1–Receptor Imaging of an Insulinoma in Patient 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 2Figure 2GLP-1–Receptor Imaging of an Insulinoma in Patient 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.

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@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.

5 References

1. 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. 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
   CrossRef | Medline

3. 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
   CrossRef | Web of Science | Medline

4. 4

   Korner M, Stockli 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
   CrossRef | Web of Science | Medline

5. 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
   Web of Science | Medline

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1. 1

   Helle-Brit Fiebrich, Sophie J. van Asselt, Adrienne H. Brouwers, Hendrik M. van Dullemen, Milan E.J. Pijl, Philip H. Elsinga, Thera P. Links, Elisabeth G.E. de Vries. (2012) Tailored imaging of islet cell tumors of the pancreas amidst increasing options. Critical Reviews in Oncology/Hematology 82:2, 213-226
   CrossRef

2. 2

   Vittoria Rufini, Richard P. Baum, Paola Castaldi, Giorgio Treglia, Anna Maria Gaetano, Cecilia Carreras, Daniel Kaemmerer, Merten Hommann, Dieter Hörsch, Lorenzo Bonomo, Alessandro Giordano. (2012) Role of PET/CT in the functional imaging of endocrine pancreatic tumors. Abdominal Imaging
   CrossRef

3. 3

   Melpomeni Fani, Helmut R. Maecke. (2012) Radiopharmaceutical development of radiolabelled peptides. European Journal of Nuclear Medicine and Molecular Imaging
   CrossRef

4. 4

   Peter Laverman, Jane K. Sosabowski, Otto C. Boerman, Wim J. G. Oyen. (2012) Radiolabelled peptides for oncological diagnosis. European Journal of Nuclear Medicine and Molecular Imaging
   CrossRef

5. 5

   K. P. Koopmans, A. W. J. M. Glaudemans. (2012) Rationale for the use of radiolabelled peptides in diagnosis and therapy. European Journal of Nuclear Medicine and Molecular Imaging
   CrossRef

6. 6

   Yifan Zhang, Wengen Chen. (2012) Radiolabeled glucagon-like peptide-1 analogues. Nuclear Medicine Communications 33:3, 223-227
   CrossRef

7. 7

   Maarten Brom, Lieke Joosten, Wim J. G. Oyen, Martin Gotthardt, Otto C. Boerman. (2012) Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas. Contrast Media & Molecular Imaging 7:2, 160-166
   CrossRef

8. 8

   Dale O. Kiesewetter, Haokao Gao, Ying Ma, Gang Niu, Qimeng Quan, Ning Guo, Xiaoyuan Chen. (2011) 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. European Journal of Nuclear Medicine and Molecular Imaging
   CrossRef

9. 9

   Otto C. Boerman, Martin Gotthardt. (2011) 18F-Labelled exendin to image GLP-1 receptor-expressing tissues: from niche to blockbuster?. European Journal of Nuclear Medicine and Molecular Imaging
   CrossRef

10. 10

    Haokao Gao, Gang Niu, Min Yang, Qimeng Quan, Ying Ma, Eunice N. Murage, Jung-Mo Ahn, Dale O. Kiesewetter, Xiaoyuan Chen. (2011) PET of Insulinoma Using ¹⁸ F-FBEM-EM3106B, a New GLP-1 Analogue. Molecular Pharmaceutics 8:5, 1775-1782
    CrossRef

11. 11

    Yi Wang, Keunpoong Lim, Marc Normandin, Xiaojian Zhao, Gary W. Cline, Yu-Shin Ding. (2011) Synthesis and evaluation of [18F]exendin (9–39) as a potential biomarker to measure pancreatic β-cell mass. Nuclear Medicine and Biology
    CrossRef

12. 12

    M Tomaszuk, A Sowa-Staszczak, W Lenda-Tracz, B Glowa, D Pach, M Buziak-Bereza, A Stefanska, B Janota, D Pawlak, R Mikolajczak, A B Hubalewska-Dydejczyk. (2011) Dosimetry of exendin-4 based radiotracer for glucagonlike peptide-1 receptor imaging: an initial report. Journal of Physics: Conference Series 317, 012011
    CrossRef

13. 13

    Zhanhong Wu, Ivan Todorov, Lin Li, James R. Bading, Zibo Li, Indu Nair, Kohei Ishiyama, David Colcher, Peter E. Conti, Scott E. Fraser, John E. Shively, Fouad Kandeel. (2011) In Vivo Imaging of Transplanted Islets with ⁶⁴ Cu-DO3A-VS-Cys ⁴⁰ -Exendin-4 by Targeting GLP-1 Receptor. Bioconjugate Chemistry 22:8, 1587-1594
    CrossRef

14. 14

    Eugene P. Ceppa, Duykhanh P. Ceppa, Philip A. Omotosho, James A. Dickerson, Chan W. Park, Dana D. Portenier. (2011) Algorithm to diagnose etiology of hypoglycemia after Roux-en-Y gastric bypass for morbid obesity: case series and review of the literature. Surgery for Obesity and Related Diseases
    CrossRef

15. 15

    Wouter A.P. Breeman, Erik de Blois, Ho Sze Chan, Mark Konijnenberg, Dik J. Kwekkeboom, Eric P. Krenning. (2011) 68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives. Seminars in Nuclear Medicine 41:4, 314-321
    CrossRef

16. 16

    Beatrice Waser, Jean Claude Reubi. (2011) Value of the radiolabelled GLP-1 receptor antagonist exendin(9–39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans. European Journal of Nuclear Medicine and Molecular Imaging 38:6, 1054-1058
    CrossRef

17. 17

    Aaron I. Vinik, Michael Raymund C. Gonzales. (2011) New and Emerging Syndromes due to Neuroendocrine Tumors. Endocrinology & Metabolism Clinics of North America 40:1, 19-63
    CrossRef

18. 18

    João D. G. Correia, António Paulo, Paula D. Raposinho, Isabel Santos. (2011) Radiometallated peptides for molecular imaging and targeted therapy. Dalton Transactions 40:23, 6144
    CrossRef

19. 19

    J. C. Reubi, A. Perren, R. Rehmann, B. Waser, E. Christ, M. Callery, A. B. Goldfine, M. E. Patti. (2010) Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass. Diabetologia 53:12, 2641-2645
    CrossRef

20. 20

    Emanuel Christ, Damian Wild, Jean Claude Reubi. (2010) Glucagonlike Peptide-1 Receptor: An Example of Translational Research in Insulinomas: A Review. Endocrinology & Metabolism Clinics of North America 39:4, 791-800
    CrossRef

21. 21

    Kjell Öberg. (2010) Pancreatic Endocrine Tumors. Seminars in Oncology 37:6, 594-618
    CrossRef

22. 22

    Aaron I. Vinik, Eugene A. Woltering, Richard R. P. Warner, Martyn Caplin, Thomas M. O'Dorisio, Gregory A. Wiseman, Domenico Coppola, Vay Liang W. Go. (2010) NANETS Consensus Guidelines for the Diagnosis of Neuroendocrine Tumor. Pancreas 39:6, 713-734
    CrossRef

23. 23

    Maarten Brom, Wim J. G. Oyen, Lieke Joosten, Martin Gotthardt, Otto C. Boerman. (2010) 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. European Journal of Nuclear Medicine and Molecular Imaging 37:7, 1345-1355
    CrossRef

24. 24

    Jean-Marc Guettier, Phillip Gorden. (2010) Insulin secretion and insulin-producing tumors. Expert Review of Endocrinology & Metabolism 5:2, 217-227
    CrossRef

25. 25

    Robert T. Jensen, Jeffrey A. Norton. 2010. Endocrine Tumors of the Pancreas and Gastrointestinal Tract. , 491-522.
    CrossRef

26. 26

    Klaas P. Koopmans, Oliver N. Neels, Ido P. Kema, Philip H. Elsinga, Thera P. Links, Elisabeth G.E. de Vries, Pieter L. Jager. (2009) Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results. Critical Reviews in Oncology/Hematology 71:3, 199-213
    CrossRef

27. 27

    Margret Schottelius, Hans-Jürgen Wester. (2009) Molecular imaging targeting peptide receptors. Methods 48:2, 161-177
    CrossRef

28. 28

    Ritika R Kapoor, Chela James, Khalid Hussain. (2009) Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nature Clinical Practice Endocrinology & Metabolism 5:2, 101-112
    CrossRef