Generic placeholder image

Current Radiopharmaceuticals


ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Review Article

Physiopathological Premises to Nuclear Medicine Imaging of Pancreatic Neuroendocrine Tumours

Author(s): ">Vincenzo Cuccurullo*, "> Giuseppe Danilo Di Stasio and ">Luigi Mansi

Volume 12, Issue 2, 2019

Page: [98 - 106] Pages: 9

DOI: 10.2174/1874471012666190206094555

Price: $65


Background: Pancreatic Neuroendocrine Tumors (P-NETs) are a challenge in terms of both diagnosis and therapy; morphological studies need to be frequently implemented with nonstandard techniques such as Endoscopic Ultrasounds, Dynamic CT, and functional Magnetic Resonance.

Discussion: The role of nuclear medicine, being scarcely sensitive F-18 Fluorodeoxyglucose, is mainly based on the over-expression of Somatostatin Receptors (SSTR) on neuroendocrine tumor cells surface. Therefore, SSTR can be used as a target for both diagnosis, using radiotracers labeled with gamma or positron emitters, and therapy. SSTRs subtypes are capable of homo and heterodimerization in specific combinations that alter both the response to ligand activation and receptor internalization.

Conclusion: Although agonists usually provide efficient internalization, also somatostatin antagonists (SS-ANTs) could be used for imaging and therapy. Peptide Receptor Radionuclide Therapy (PRRT) represents the most successful option for targeted therapy. The theranostic model based on SSTR does not work in insulinoma, in which different radiotracers such as F-18 FluoroDOPA or tracers for the glucagon-like peptide-1 receptor have to be preferred.

Keywords: Pancreatic neuroendocrine tumors, nuclear medicine, Pet, SSTR, PRRT, NETs, P-NETs.

Graphical Abstract
Shi, C.; Klimstra, D.S. Pancreatic neuroendocrine tumors: Pathologic and molecular characteristics. Semin. Diagn. Pathol., 2014, 6, 498-511.
Liu, I.H.; Kunz, P.L. Biologics in gastrointestinal and pancreatic neuroendocrine tumors. J. Gastrointest. Oncol., 2017, 3, 457-465.
Rindi, G.; Petrone, G.; Inzani, F. The 2010 WHO classification of digestive neuroendocrine neoplasms: A critical appraisal four years after its introduction. Endocr. Pathol., 2014, 2, 186-192.
Reid, M.D.; Balci, S.; Saka, B.; Adsay, N.V. Neuroendocrine tumors of the pancreas: Current concepts and controversies. Endocr. Pathol., 2014, 1, 65-79.
Sundin, A. Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours. Best Pract. Res. Clin. Gastroenterol., 2012, 6(26), 803-818.
Janson, E.T.; Sorbye, H.; Welin, S.; Federspiel, B.; Gronbaek, H.; Hellman, P.; Ladekarl, M.; Langer, S.W.; Mortensen, J.; Schalin-Jantti, C.; Sundin, A.; Sundlov, A.; Thiis-Evensen, E.; Knigge, U. Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncologica, 2014, 53, 1284-1297.
Jacobs, M.A.; Weinstein, S.; Hope, T.A.; Aslam, R.; Yee, J.; Coakley, F. Neuroendocrine tumors: Beyond the abdomen. J. Comput. Assist. Tomogr., 2014, 38, 898-8914.
Cloyd, J.M.; Poultsides, G.A. Non-functional neuroendocrine tumors of the pancreas: Advances in diagnosis and management. World J. Gastroenterol., 2015, 21, 9512-9525.
Toumpanakis, C.; Kim, M.K.; Rinke, A.; Bergestuen, D.S.; Thirlwell, C.; Khan, M.S.; Salazar, R.; Oberg, K. Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology, 2014, 99, 63-74.
de Herder, W.W. GEP-NETS update: Functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs). Eur. J. Endocrinol., 2014, 170, R173-R183.
Cuccurullo, V.; Faggiano, A.; Scialpi, M.; Cascini, G.L.; Piunno, A.; Catalano, O.; Colao, A.; Mansi, L. Questions and answers: What can be said by diagnostic imaging in neuroendocrine tumors? Minerva Endocrinol., 2012, 37, 367-377.
Cascini, G.L.; Cuccurullo, V.; Tamburrini, O.; Rotondo, A.; Mansi, L. Peptide imaging with somatostatin analogues: More than cancer probes. Curr. Radiopharm., 2013, 6, 36-40.
Patel, Y.E. Somatostatin and its receptor family. Front. Neuroendocrinol., 1999, 20, 157-198.
Reubi, J.C.; Waser, B.; Laissue, J.A.; Gebbers, J-O. Somatostatin and vasoactive intestinal peptide receptors in human mesenchymal tumors: in vitro identification. Cancer Res., 1996, 56, 1922-19231.
Reubi, J.C. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr. Rev., 2003, 24, 389-427.
Mansi, L.; Cuccurullo, V. Diagnostic imaging in neuroendocrine tumors. J. Nucl. Med.: Official publication. Soc. Nucl. Med., 2014, 55, 1576-1577.
Reubi, J.C.; Waser, B.; Schaer, J.C.; Laissue, J.A. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur. J. Nucl. Med., 2001, 28, 836-846.
Reubi, J.C.; Laissue, J.A.; Waser, B.; Steffen, D.L.; Hipkin, R.W.; Schonbrunn, A. Immunohistochemical detection of somatostatin sst2a receptors in the lymphatic, smooth muscular, and peripheral nervous systems of the human gastrointestinal tract: Facts and artifacts. J. Clin. Endocrinol. Metab., 1999, 84, 2942-2950.
Reubi, J.C.; Waser, B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptortumour targeting. Eur. J. Nucl. Med. Mol. Imaging, 2003, 30, 781-793.
Barnett, P. Somatostatin and somatostatin receptor physiology. Endocrine, 2003, 20, 255-264.
Cascini, G.L.; Cuccurullo, V.; Mansi, L. The non tumour uptake of (111)In-octreotide creates new clinical indications in benign diseases, but also in oncology. Q. J. Nucl. Med. Mol. Imaging, 2010, 54, 24-36.
Vezzosi, D.; Bennet, A.; Rochaix, P.; Courbon, F.; Selves, J.; Pradere, B.; Buscail, L.; Susini, C.; Caron, P. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur. J. Endocrinol., 2005, 152, 757-767.
Reubi, J.C.; Schar, J.C.; Waser, B.; Wenger, S.; Heppeler, A.; Schmitt, J.S. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur. J. Nucl. Med., 2000, 27, 273-282.
Lesche, S.; Lehmann, D.; Nagel, F.; Schmid, H.A.; Schulz, S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J. Clin. Endocrinol. Metab., 2009, 94, 654-661.
Baum, R.P.; Kulkarni, H.R.; Carreras, C. Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms. Seminars Nucl. Med., 2012, 42, 190-207.
Kwekkeboom, D.J.; Kam, B.L.; van Essen, M.; Teunissen, J.J.; van Eijck, C.H.; Valkema, R.; de Jong, M.; de Herder, W.W.; Krenning, E.P. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr. Relat. Cancer, 2010, 17, R53-R573.
Krenning, E.P.; de Jong, M.; Kooij, P.P.; Breeman, W.A.; Bakker, W.H.; de Herder, W.W.; van Eijck, C.H.; Kwekkeboom, D.J.; Jamar, F.; Pauwels, S.; Valkema, R. Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy. Ann. Oncol., 1999, 10(Suppl. 2), S23-S239.
Cescato, R.; Schulz, S.; Waser, B.; Eltschinger, V.; Rivier, J.E.; Wester, H.J.; Culler, M.; Ginj, M. Liu. Q.; Schonbrunn, A.; Reubi, J.C. Internalization of sst2, sst3 and sst5 recep- tors: effects of somatostatin agonists and antagonists. J. Nucl. Med., 2006, 47, 502-511.
Bodei, L.; Ferone, D.; Grana, C.M.; Cremonesi, M.; Signore, A.; Dierckx, R.A.; Paganelli, G. Peptide receptortherapies in Neuroendocrine tumors. J. Endocrinol. Invest., 2009, 32, 360-369.
Kitson, S.L.; Cuccurullo, V.; Moody, T.S.; Mansi, L. Radionuclide antibody-conjugates, a targeted therapy towards cancer. Curr. Radiopharm., 2013, 6, 57-71.
Fani, M.; Nicolas, G.P.; Wild, D. Somatostatin receptor antagonists for imaging and therapy. J. Nucl. Med., 2017, 58, 61S-66S.
Kliewer, A.; Reinscheid, R.K.; Schulz, S. Emerging paradigms of G protein-coupled receptor dephosphorylation. Trends Pharmacol. Sci., 2017, 38, 621-636.
Lee, M.H.; Appleton, K.M.; Strungs, E.G.; Kwon, J.Y.; Morinelli, T.A.; Peterson, Y.K.; Laporte, S.A.; Luttrell, L.M. The conformational signature of β-arrestin2 predicts its trafficking and signalling functions. Nature, 2016, 31, 665-668.
O’Toole, D.; Saveanu, A.; Couvelard, A.; Gunz, G.; Enjalbert, A.; Jaquet, P.; Ruszniewski, P.; Barlier, A. The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies. Eur. J. Endocrinol., 2006, 155(6), 849-857.
Smit Duijzentkunst, D.A.; Kwekkeboom, D.J.; Bodei, L. Somatostatin Receptor 2-Targeting Compounds. J. Nucl. Med., 2017, 58(Suppl. 2), 54S-60S.
Tornesello, A.L.; Buonaguro, L.; Tornesello, M.L.; Buonaguro, F.M. New insights in the design of bioactive peptides and chelating agents for imaging and therapy in oncology. Molecules, 2017, 2, 22-28.
Cuccurullo, V.; Prisco, M.R.; Di Stasio, G.D.; Mansi, L. Nuclear medicine in patients with net: Radiolabeled somatostatin analogues and their brothers. Curr. Radiopharm., 2017, 10(2), 74-84.
Van der Lely, A.J.; de Herder, W.W.; Krenning, E.P.; Kwekkeboom, D.J. Octreoscan radioreceptor imaging. Endocrine, 2003, 20, 307-311.
Kwekkeboom, D.J.; Kam, B.L.; van Essen, M.; Teunissen, J.J.; van Eijck, C.H.; Valkema, R.; de Jong, M.; de Herder, W.W.; Krenning, E.P. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr. Relat. Cancer, 2010, 29, R53-R73.
Rambaldi, P.F.; Cuccurullo, V.; Briganti, V.; Mansi, L. The present and future role of (111)Inpentetreotide in the PET era. Q. J. Nucl. Med. Mol. Imaging, 2005, 49, 225-235.
Cuccurullo, V.; Mansi, L. Toward tailored medicine (and beyond): the phaeochromocytoma and paraganglioma model. Eur. J. Nucl. Med. Mol. Imaging, 2012, 39(8), 1262-1265.
Upadhyay, B.; Lu, S.J.; Navalkissoor, S.; Gnanasegaran, G.; Buscombe, J. The imaging of neuroendocrine tumors using single photon emission computed tomography/computed tomography. Q. J. Nucl. Med. Mol. Imaging, 2015, 59, 140-151.
Rufini, V.; Calcagni, M.L.; Baum, R.P. Imaging of neuroendocrine tumors. Semin. Nucl. Med., 2006, 36, 228-247.
Briganti, V.; Matteini, M.; Ferri, P.; Vaggelli, L.; Castagnoli, A.; Pieroni, C. Octreoscan SPET evaluation in the diagnosis of pancreas neuroendocrine tumors. Cancer Biother. Radiopharm., 2001, 16, 515-524.
Rambaldi, P.F.; Cuccurullo, V.; Cascini, G.L.; Mansi, L. Our experience in thymic hyperplasia using 67Ga-citrate, 111In-pentetreotide and 201Tl-chloride. Eur. J. Nucl. Med. Imaging, 2010, 37(8), 1616.
Cascini, G.L.; Cuccurullo, V.; Tamburrini, O.; Mansi, L.; Rotondo, A. Nuclear medicine in multiple myeloma - more thandiagnosis. Nucl. Med. Review, 2010, 13(1), 32-38.
Cuccurullo, V.; Mansi, L. Toward tailored medicine (and beyond): the phaeochromocytoma and paraganglioma model. Eur. J. Nucl. Med. Mol. Imaging, 2012, 39, 1262-1265.
Binderup, T.; Knigge, U.; Loft, A.; Mortensen, J.; Pfeifer, A.; Federspiel, B.; Hansen, C.P.; Hojgaard, L.; Kjaer, A. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET. J. Nucl. Med., 2010, 51, 704-712.
Mansi, L.; Cuccurullo, V.; Ciarmiello, A. From Homo sapiens to Homo in nexu (connected man): Could functional imaging redefine the brain of a “new human species”? Eur. J. Nucl. Med. Mol. Imaging, 2014, 41, 1385-1387.
Cuccurullo, V.; Cascini, G.L.; Tamburrini, O.; Rotondo, A.; Mansi, L. Bone metastasesradiopharmaceuticals: An overview. Curr. Radiopharm., 2013, 6, 41-47.
Cuccurullo, V.; Cascini, G.L.; Tamburrini, O.; Mansi, L.; Rotondo, A. Less frequent requests for In-111 pentreotide and its brothers of endocrinological interest. Minerva Endocrinol., 2011, 36, 41-52.
Mikołajczak, R.; Maecke, H.R. Radiopharmaceuticals for somatostatin receptor imaging. Nucl. Med. Rev. Cent. East. Eur., 2016, 19, 126-132.
Kitson, S.L.; Cuccurullo, V.; Ciarmiello, A.; Mansi, L. Targeted Therapy Towards Cancer-A Perspective. Anticancer. Agents Med. Chem., 2017, 17(3), 311-317.
Cuccurullo, V.; Di Stasio, G.D.; Evangelista, L.; Castoria, G.; Mansi, L. Biochemical and pathophysiological premises to positron emission tomography with choline radiotracers. J. Cell. Physiol., 2017, 232(2), 270-275.
Cuccurullo, V.; Di Stasio, G.D.; Schillirò, M.L.; Mansi, L. Small-animal molecular imaging for preclinical cancer research: PET and SPECT. Curr. Radiopharm., 2016, 9(2), 102-113.
Velikyan, I. 68Ga-Based radiopharmaceuticals: Production and application relationship. Molecules, 2015, 20, 12913-12943.
Kulkarni, H.R.; Baum, R.P. Theranostics with Ga-68 somatostatin receptor PET/CT: monitoring response to peptide receptor radionuclide therapy. PET Clin., 2014, 9, 91-97.
Eberlein, U.; Lassmann, M. Dosimetry of [(6)(8)Ga]-labeled compounds. Applied Radiation and Isotopes: Including data, instrumentation and methods for use in agriculture, industry and medicine 2013, 76, 70-74.
Ambrosini, V.; Morigi, J.J.; Nanni, C.; Castellucci, P.; Fanti, S. Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]tracers, [11C]/[18F]-HTP). Q. J. Nucl. Med. Mol. Imaging, 2015, 59(1), 58-69.
Win, Z.; Al-Nahhas, A.; Rubello, D.; Gross, M.D. Somatostatin receptor PET imaging with Gallium-68 labeled peptides. Q. J. Nucl. Med. Mol. Imaging, 2007, 51, 244-250.
Ambrosini, V.; Nanni, C.; Fanti, S. The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. PET Clin., 2014, 9, 323-329.
Kayani, I.; Conry, B.G.; Groves, A.M.; Win, T.; Dickson, J.; Caplin, M.; Bomanji, J.B. A comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in pulmonary neuroendocrine tumors. J. Nucl. Med., 2009, 50(12), 1927-1932.
Prasad, V.; Ambrosini, V.; Hommann, M.; Hoersch, D.; Fanti, S.; Baum, R.P. Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT. Eur. J. Nucl. Med. Mol. Imaging, 2010, 37(1), 67-77.
Goldsmith, S.J. Update on nuclear medicine imaging of neuroendocrine tumors. Future Oncol., 2009, 5(1), 75-84.
Ginj, M.; Chen, J.; Walter, M.A.; Eltschinger, V.; Reubi, J.C.; Maecke, H.R. Preclinical evaluation of new and highly potent analogues of octreotide for predictive imaging and targeted radiotherapy. Clin. Cancer Res., 2005, 11, 1136-1145.
Ginj, M.; Zhang, H.; Eisenwiener, K.P.; Wild, D.; Schulz, S.; Rink, H.; Cescato, R.; Reubi, J.C.; Maecke, H.R. New pansomatostatin ligands and their chelated versions: affinity profile, agonist activity, internalization, and tumor targeting. Clin. Cancer Res., 2008, 14(7), 2019-2027.
Beyer, T.; Hacker, M.; Schubiger, A.; Virgolini, I.; Wester, H.J. Nuclear medicine 2013: From status quo to status go. European journal of nuclear medicine and molecular imaging, 2013, 40, 1794-1796.
Virgolini, I.; Innsbruck, T. Peptide receptor radionuclide therapy (PRRT): clinical significance of re-treatment? Eur. J. Nucl. Med. Mol. Imaging, 2015, 42, 1949-1954.
Bodei, L.; Cremonesi, M.; Kidd, M.; Grana, C.M.; Severi, S.; Modlin, I.M.; Paganelli, G. Peptide receptor radionuclide therapy for advanced neuroendocrine tumors. Thorac. Surg. Clin., 2014, 24(3), 333-349.
Sowa-Staszczak, A.; Hubalewska-Dydejczyk, A.; Tomaszuk, M. PRRT as neoadjuvant treatment in NET. Recent Results Cancer Res., 2013, 194, 479-485.
Del Gobbo, A.; Pellegrinelli, A.; Gaudioso, G.; Castellani, M.; Zito Marino, F.; Franco, R.; Palleschi, A.; Nosotti, M.; Bosari, S.; Vaira, V.; Ferrero, S. Analysis of NSCLC tumourheterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas. Histopathology, 2016, 68, 746-751.
Bakker, W.H.; Breeman, W.A.; Kwekkeboom, D.J.; De Jong, L.C.; Krenning, E.P. Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q. J. Nucl. Med. Mol. Imaging, 2006, 50, 265-2671.
Taieb, D.; Garrigue, P.; Bardies, M.; Abdullah, A.E.; Pacak, K. Application and dosimetric requirements for gallium-68-labeled somatostatin analogues in targeted radionuclide therapy for gastroenteropancreatic neuroendocrine tumors. PET Clin., 2015, 10, 477-486.
Fani, M.; Mueller, A.; Tamma, M.L.; Nicolas, G.; Rink, H.R.; Cescato, R.; Reubi, J.C.; Maecke, H.R. Radiolabeled bicyclic somatostatin-based analogs: A novel class of potential radiotracers for SPECT/PET of neuroendocrine tumors. J. Nucl. Med., 2010, 51(11), 1771-1779.
Tatsi, A.; Maina, T.; Cescato, R.; Waser, B.; Krenning, E.P.; de Jong, M.; Cordopatis, P.; Reubi, J.C.; Nock, B.A. 111In-DOTA-Somatostatin-14 analogs as potential pansomatostatin-like radiotracers - first results of a preclinical study. EJNMMI Res., 2012, 2(1), 25-28.
Maina, T.; Cescato, R.; Waser, B.; Tatsi, A.; Kaloudi, A.; Krenning, E.P.; de Jong, M.; Nock, B.A.; Reubi, J.C. [111In-DOTA]LTT-SS28, a first pansomatostatin radioligand for in vivo targeting of somatostatin receptor-positive tumors. J. Med. Chem., 2014, 57(15), 6564-6571.
Tatsi, A.; Maina, T.; Cescato, R.; Waser, B.; Krenning, E.P.; de Jong, M.; Cordopatis, P.; Reubi, J.C.; Nock, B.A. [DOTA]Somatostatin-14 analogs and their (111)In-radioligands: effects of decreasing ring-size on sst1-5 profile, stability and tumor targeting. Eur. J. Med. Chem., 2014, 12, 30-37.
Schillaci, O.; Massa, R.; Scopinaro, F. 111In-pentetreotide scintigraphy in the detection of insulinomas: Importance of SPECT imaging. J. Nucl. Med., 2000, 41, 459-462.
Prasad, V.; Sainz-Esteban, A.; Arsenic, R.; Plöckinger, U.; Denecke, T.; Pape, U.F.; Pascher, A.; Kühnen, P.; Pavel, M.; Blankenstein, O. Role of (68)Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: An explorative study. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43, 1593-1600.
Sowa-Staszczak, A.; Pach, D.; Mikołajczak, R.; Mäcke, H.; Jabrocka-Hybel, A.; Stefańska, A.; Tomaszuk, M.; Janota, B.; Gilis-Januszewska, A.; Małecki, M.; Kamiński, G.; Kowalska, A.; Kulig, J.; Matyja, A.; Osuch, C.; Hubalewska-Dydejczyk, A. Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC- 99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma. Eur. J. Nucl. Med. Mol. Imaging, 2013, 40, 524-531.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy