Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1189 word(s) 1189 2020-12-16 09:26:40 |
2 format correct Meta information modification 1189 2020-12-23 03:17:25 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Liberini, V. Neuroendocrine Neoplasms. Encyclopedia. Available online: (accessed on 24 June 2024).
Liberini V. Neuroendocrine Neoplasms. Encyclopedia. Available at: Accessed June 24, 2024.
Liberini, Virginia. "Neuroendocrine Neoplasms" Encyclopedia, (accessed June 24, 2024).
Liberini, V. (2020, December 22). Neuroendocrine Neoplasms. In Encyclopedia.
Liberini, Virginia. "Neuroendocrine Neoplasms." Encyclopedia. Web. 22 December, 2020.
Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies represented by different histological subtypes, primary locations and functional status. NENs range from well-differentiated neuroendocrine tumors (NETs), which are mainly indolent neoplasms, to poorly differentiated neuroendocrine carcinomas (NECs), which are highly aggressive cancers with poor prognosis.

peptide receptor radionuclide therapy PRRT 68Ga-

1. Introduction

NENs originated in the gastroenteropancreatic (GEP) tract are graded according to Ki-67 index and mitotic count, which represents features of the proliferative activity of the tumor (Table 1).

Table 1. Classification and grading criteria for GEP-NENs, according to the WHO 2019 Grading Classification.

The mutational status also has an important impact on NEN behavior. Several studies have demonstrated a strong correlation between well-differentiated NETs and MEN1, DAXX and ATRX mutations, whereas NECs usually carry TP53 or RB1 mutations [1][2][3]. According to the National Cancer Institute’s Surveillance, Epidemiology and Results (SEER) Program, the incidence of NENs increased 6.4-fold from 1973 (1.09 per 100,000) to 2012 (6.98 per 100,000) [4], owing to an increasing awareness of NEN occurrence and also due to a more effective identification of these tumors. A remarkable feature of NENs is the expression of somatostatin receptors (SSTRs) in well-differentiated tumors, with SSTRs type 1 and type 2 being present in the vast majority of GEP-NENs, while SSTRs type 3 and type 5 are expressed by approximately 60% of cases, and SSTR type 4 only rarely [5]. The knowledge of histopathological and molecular characteristics of NENs as well as the availability of more accurate diagnostic tools and therapeutic options, allows for a personalized approach to these diseases, with potential benefits in treatment response and survival.

In vivo imaging of SSTR expression in NENs has become feasible since the development of [123I]I-labelled tyr-3-octreotide in 1989 [6][7], when Krenning et al. documented for the first time positive [123I]I-labelled tyr-3-octreotide scans obtained for two meningiomas, two gastrinomas and one carcinoid [7]. In the last decade, the accuracy in NEN detection by [111In]In-pentetreotide (Octreoscan®) single-photon emission computed tomography (SPECT)/computed tomography (CT) has been surpassed by [68Ga]Ga-DOTA-labelled somatostatin analogue positron emission tomography (PET)/CT. Compared to SPECT radiopharmaceuticals, somatostatin analogue PET/CT also has the advantage of lower radiation exposure, earlier and shorter acquisition times, higher spatial resolution and the possibility of tracer uptake quantitation [8][9]. The main [68Ga]Ga-DOTA-labelled somatostatin analogues clinically available today are [68Ga]Ga-DOTA-TATE (DOTA, Tyr(3)-octreotate), [68Ga]Ga-DOTA-NOC (DOTA,1-Nal(3)-octreotide) and [68Ga]Ga-DOTA-TOC (DOTA, D-Phe1, Tyr (3)-octreotide).

Peptide receptor radionuclide therapy (PRRT) has been proven to be an effective systemic treatment in the clinical management of patients with advanced, metastatic or inoperable, slowly progressing NENs with high somatostatin receptor expression. The principle behind PRRT efficacy is the dual component of the radiopeptide: (1) the somatostatin receptor ligand that binds the specific receptor (SSTR1-5, especially SSTR2) overexpressed on the surface of neuroendocrine tumor cells, allowing its internalization into the tumor cells and (2) the high energy of the radioactive β-particle (90Y or 177Lu) labeled to a somatostatin receptor (SSTR) ligand, yielding cell apoptosis through direct or indirect DNA damage of target cells (self-dose) or neighboring cells (cross-fire effect) [10]. In the last few years, DOTATATE (DOTA, Tyr(3)-octreotate), labeled either with [117Lu]Lu or [90Y]Y as radionuclides, was the peptide most widely used, owing to its higher SSTR2 affinity compared to DOTATOC (DOTA, D-Phe1, Tyr (3)-octreotide) and DOTANOC (DOTA, 1-Nal(3)-octreotide), which is present in the vast majority of GEP-NENs. These two radiopeptides share similar radiobiology and pharmacokinetic aspects, such as fast blood clearance and urinary elimination, low whole-body radiation exposure and a high absorbed dose to the spleen, the kidney and the liver, but they have different toxicity profiles. An important advantage of [117Lu]Lu is its partial decay into γ photons (E = 113 KeV and 208 KeV), allowing the acquisition of SPECT/CT images, which is useful for dosimetry and immediate therapy response assessment [11][12][13].

As of today, [117Lu]Lu-DOTA-TATE has almost completely replaced [90Y]Y-DOTA-TATE and [90Y]Y-DOTA-TOC. In 2017, the phase III NETTER-1 trial showed that [117Lu]Lu-DOTA-TATE treatment resulted in longer progression-free survival and a higher response rate compared to high dose somatostatin analogues in patients with advanced midgut neuroendocrine tumors (NETs) and disease progression after first-line somatostatin analogue therapy [14]. Owing to this result, [117Lu]Lu-DOTA-TATE (Lutathera®) was approved by the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) in the year 2018 for the treatment of inoperable or metastatic well-differentiated gastroenteropancreatic) NETs with disease progression. More recently, α particle (i.e., actinium-225 (225Ac) or bismuth-213 (213Bi) labeled somatostatin receptor (SSTR) ligand through a chelator (dodecane tetra-acetic acid (DOTA)) have been applied in clinical trials [15]. An overview of characteristics of theragnostic radionuclides in patients with NENs is given in Table 2.

Table 2. Characteristics of theragnostic radionuclides used in patients with NENs.

In order to achieve a clinical benefit, both appropriate patient selection and accurate response assessment to PPRT are essential. In fact, disease progression during therapy is reported in approximately 20–30% of patients, and in approximately 10% of them within 6 months to 1 year after PPRT [14][19]. Furthermore, PRRT treatment is not exempt from toxicity. The critical organs are the bone marrow and the kidneys. More specifically, the kidneys are the dose-limiting organs. Therefore, an intravenous administration of an amino acid solution consisting of lysine and arginine, prior to PRRT, can partially protect the kidneys from radiation damage [15]. In 2018, Baum et al. [20] presented the outcome of personalized [117Lu]Lu and/or [90Y]Y PRRT in a cohort of 1048 patients with NENs. According to the Common Terminology Criteria for Adverse Events (CTACAE criteria), grade 3 and 4 adverse events were recorded in <1% of patients. However, myelodysplastic syndrome (MDS) or leukemia and chronic kidney disease developed in 22 (2%) and 5 (0.4%) patients, respectively. In a cohort of 807 patients with NENs, Bodei et al. [21] reported grade 3 and 4 hematological toxicity, myelodysplastic syndrome and grade 4 renal failure in approximately 10%, 2–4% and <1% of patients, respectively.

The identification of biomarkers to assess PRRT efficacy and avoid patient toxicity is crucial but also challenging in a heterogeneous group of tumors such as NENs. The current parameters (biomarkers, such as chromogranin A, and RECIST 1.1) used for PRRT response assessment are considered suboptimal based upon the Delphic consensus assessment for GEP-NENs [22], owing to the variability in somatostatin receptor expression, histology and the characteristic slow growth of these tumors. Functional imaging in particular and new approaches in image analysis could play a key role as prognostic biomarkers and for the therapy response assessment. Hence, standardization is needed.


  1. Uccella, S.; La Rosa, S.; Volante, M.; Papotti, M. Immunohistochemical Biomarkers of Gastrointestinal, Pancreatic, Pulmonary, and Thymic Neuroendocrine Neoplasms. Endocr. Pathol. 2018, 29, 150–168. [Google Scholar] [CrossRef] [PubMed]
  2. Simbolo, M.; Barbi, S.; Fassan, M.; Mafficini, A.; Ali, G.; Vicentini, C.; Sperandio, N.; Corbo, V.; Rusev, B.; Mastracci, L.; et al. Gene Expression Profiling of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Transcriptomic Subtypes with Specific Genomic Alterations. J. Thorac. Oncol. 2019, 14, 1651–1661. [Google Scholar] [CrossRef]
  3. Scarpa, A.; Chang, D.K.; Nones, K.; Corbo, V.; Patch, A.M.; Bailey, P.; Lawlor, R.T.; Johns, A.L.; Miller, D.K.; Mafficini, A.; et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017, 543, 65–71. [Google Scholar] [CrossRef]
  4. Dasari, A.; Shen, C.; Halperin, D.; Zhao, B.; Zhou, S.; Xu, Y.; Shih, T.; Yao, J.C. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017, 3, 1335–1342. [Google Scholar] [CrossRef]
  5. Papotti, M.; Bongiovanni, M.; Volante, M.; Allìa, E.; Landolfi, S.; Helboe, L.; Schindler, M.; Cole, S.; Bussolati, G. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors: A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 2002, 440, 461–475. [Google Scholar] [CrossRef]
  6. Lamberts, S.W.J.; Reubi, J.C.; Krenning, E.P. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors. Acta Oncol. (Madr.) 1993, 32, 167–170. [Google Scholar] [CrossRef]
  7. Krenning, E.P.; Breeman, W.A.P.; Kooij, P.P.M.; Lameris, J.S.; Bakker, W.H.; Koper, J.W.; Ausema, L.; Reubi, J.C.; Lamberts, S.W.J. Localisation of Endocrine-Related Tumours with Radioiodinated Analogue of Somatostatin. Lancet 1989, 333, 242–244. [Google Scholar] [CrossRef]
  8. Geijer, H.; Breimer, L.H. Somatostatin receptor PET/CT in neuroendocrine tumours: Update on systematic review and meta-analysis. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 1770–1780. [Google Scholar] [CrossRef]
  9. Pauwels, E.; Cleeren, F.; Bormans, G.; Deroose, C.M. Somatostatin receptor PET ligands - the next generation for clinical practice. Am. J. Nucl. Med. Mol. Imaging 2018, 8, 311–331. [Google Scholar] [PubMed]
  10. Zaknun, J.J.; Bodei, L.; Mueller-Brand, J.; Pavel, M.E.; Baum, R.P.; Hörsch, D.; O’Dorisio, M.S.; O’Dorisiol, T.M.; Howe, J.R.; Cremonesi, M.; et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 800–816. [Google Scholar] [CrossRef] [PubMed]
  11. Huizing, D.M.V.; de Wit-van der Veen, B.J.; Verheij, M.; Stokkel, M.P.M. Dosimetry methods and clinical applications in peptide receptor radionuclide therapy for neuroendocrine tumours: A literature review. EJNMMI Res. 2018, 8. [Google Scholar] [CrossRef] [PubMed]
  12. Sabet, A.; Ezziddin, K.; Pape, U.F.; Reichman, K.; Haslerud, T.; Ahmadzadehfar, H.; Biersack, H.J.; Nagarajah, J.; Ezziddin, S. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. Eur. J. Nucl. Med. Mol. Imaging 2014, 41, 505–510. [Google Scholar] [CrossRef]
  13. Stolniceanu, C.R.; Nistor, I.; Bilha, S.C.; Constantin, V.; Simona, V.; Matovic, M.; Stefanescu, C.; Covic, A. Nephrotoxicity/renal failure after therapy with 90Yttrium- A nd 177Lutetium-radiolabeled somatostatin analogs in different types of neuroendocrine tumors: A systematic review. Nucl. Med. Commun. 2020, 41, 601–617. [Google Scholar]
  14. Strosberg, J.; El-Haddad, G.; Wolin, E.; Hendifar, A.; Yao, J.; Chasen, B.; Mittra, E.; Kunz, P.L.; Kulke, M.H.; Jacene, H.; et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N. Eng. J. Med. 2017, 376, 125–135. [Google Scholar] [CrossRef]
  15. Pencharz, D.; GnanaseGaran, G.; Navalkissoor, S. Theranostics in neuroendocrine tumours: Somatostatin receptor imaging and therapy. Br. J. Radiol. 2018, 91. [Google Scholar] [CrossRef]
  16. A. Scheinberg, D.; R. McDevitt, M. Actinium-225 in Targeted Alpha-Particle Therapeutic Applications. Curr. Radiopharm. 2012, 4, 306–320. [Google Scholar] [CrossRef]
  17. Morgenstern, A.; Apostolidis, C.; Kratochwil, C.; Sathekge, M.; Krolicki, L.; Bruchertseifer, F. An Overview of Targeted Alpha Therapy with 225 Actinium and 213 Bismuth. Curr. Radiopharm. 2018, 11, 200–208. [Google Scholar] [CrossRef]
  18. Müller, C.; Van Der Meulen, N.P.; Benešová, M.; Schibli, R. Therapeutic radiometals beyond 177Lu and 90Y: Production and application of promising α-particle, β-particle, and auger electron emitters. J. Nucl. Med. 2017, 58, 91S–96S. [Google Scholar] [CrossRef]
  19. Kwekkeboom, D.J.; Kam, B.L.; Van Essen, M.; Teunissen, J.J.M.; Van Eijck, C.H.J.; 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. [Google Scholar] [CrossRef] [PubMed]
  20. Baum, R.P.; Kulkarni, H.R.; Singh, A.; Kaemmerer, D.; Mueller, D.; Prasad, V.; Hommann, M.; Robiller, F.C.; Niepsch, K.; Franz, H.; et al. Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms. Oncotarget 2018, 9, 16932–16950. [Google Scholar] [CrossRef] [PubMed]
  21. Bodei, L.; Kidd, M.; Paganelli, G.; Grana, C.M.; Drozdov, I.; Cremonesi, M.; Lepensky, C.; Kwekkeboom, D.J.; Baum, R.P.; Krenning, E.P.; et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: The value and limitations of clinical factors. Eur. J. Nucl. Med. Mol. Imaging 2015, 42, 5–19. [Google Scholar] [CrossRef] [PubMed]
  22. Oberg, K.; Krenning, E.; Sundin, A.; Bodei, L.; Kidd, M.; Tesselaar, M.; Ambrosini, V.; Baum, R.P.; Kulke, M.; Pavel, M.; et al. A delphic consensus assessment: Imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocr. Connect. 2016, 5, 174–187. [Google Scholar] [CrossRef]
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 433
Revisions: 2 times (View History)
Update Date: 23 Dec 2020
Video Production Service