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Neuroendocrine Tumors: Challenges and Future Perspectives

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 22894

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Dr. Anna La Salvia

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National Center for Drug Research and Evaluation, National Institute of Health (ISS), Rome, Italy
Interests: neuroendocrine tumors; drug development; clinical research; translational research; precision oncology
Special Issues, Collections and Topics in MDPI journals

Dr. Giuseppe Lamberti

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Department of Medical or Surgical Sciences (DIMEC), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Interests: neuroendocrine tumors; small-cell lung cancer; immunotherapy; clinical research; precision oncology
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Neuroendocrine tumors (NETs) are a family of neoplasms of increasing incidence and prevalence worldwide. Their heterogeneity in terms of biological aggressiveness, their variegated site of origin (although they are most commonly gastro-entero-pancreatic in about 60% of cases and pulmonary in approximately 30% of cases) and their capability to potentially produce hormonally active substances poses unique challenges for clinical management. NETs are characterized by the peculiar and frequent expression on cell surfaces of somatostatin receptors, which represents the ideal target for therapy (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Few chemotherapy schemes (such as streptozotocin/5-FU or the association of Capecitabine and Temozolomide) are currently part of the therapeutic armamentarium. However, regardless of the huge number of clinical trials and many promising new drugs, the only approved targeted agents for advanced progressive NETs are everolimus and sunitinib (the second one only for those of pancreatic origin). Additionally, despite a great effort in the search for innovative biomarkers, only few validated biomarkers are available so far. The aim of this Special Issue is to highlight recent advances in the context of diagnosis, treatment, and the prediction of prognosis for NETs.

Dr. Anna La Salvia
Dr. Giuseppe Lamberti
Guest Editors

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Keywords

neuroendocrine tumors
clinical challenges
innovative biomarkers
novel agents
personalized oncology

Related Special Issue

Neuroendocrine Tumors: Challenges and Future Perspectives (Second Volume) in Journal of Clinical Medicine

Published Papers (10 papers)

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Editorial

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4 pages, 200 KiB

Open AccessEditorial

Neuroendocrine Tumors: Challenges and Future Perspectives

by Giuseppe Lamberti and Anna La Salvia

J. Clin. Med. 2022, 11(15), 4351; https://doi.org/10.3390/jcm11154351 - 27 Jul 2022

Cited by 1 | Viewed by 1121

Abstract

The awareness and interest of the scientific community towards Neuroendocrine tumors (NETs) has progressively increased in the last few decades [...] Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

Research

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12 pages, 1258 KiB

Open AccessArticle

Inflammatory Cytokines Associated with Diagnosis, Tumor Grade and Prognosis in Patients with Neuroendocrine Tumors

by Lukas Geisler, Teresa Hellberg, Joeri Lambrecht, Henning Jann, Jana Knorr, Johannes Eschrich, Sven H. Loosen, Alexander Wree, Linda Hammerich, Andreas Krieg, Tom Luedde, Frank Tacke, Christoph Roderburg and Raphael Mohr

J. Clin. Med. 2022, 11(20), 6191; https://doi.org/10.3390/jcm11206191 - 20 Oct 2022

Cited by 1 | Viewed by 1331

Abstract

Background and aims: Inflammatory cytokines represent diagnostic and prognostic biomarkers in manifold cancers. Recent data suggest a pivotal role of these cytokines in different biological processes involved in the development of neuroendocrine tumors (NETs). However, their role as biomarkers in NETs is only poorly understood. Methods: We analyzed serum concentrations of 13 inflammation-related cytokines at different time points in 43 patients with well-differentiated gastroenteropancreatic NETs (G1/G2) treated at Charité Berlin and compared them to 40 healthy controls. The results were correlated with clinical records. Results: Serum concentrations (Median (Interquartile Range (IQR)) in pg/mL) of IL-1β (124 (82) vs. 68 (61) pg/mL; p = 0.0003), IL-6 (111(122) vs. 88 (32) pg/mL; p = 0.0086), IL-8 (1058 (768) vs. 210 (90) pg/mL; p < 0.0001), IL-18 (2936 (1723) vs. 1590 (704) pg/mL; p < 0.0001), and TNF (271 (260) vs. 42 (25) pg/mL; p < 0.0001) were significantly elevated in NET patients, whereas IL-10 (43 (44) vs. 105 (48) pg/mL; p < 0.0001) showed lower concentrations in NETs when compared to controls. Cytokine levels significantly correlated with tumor grade (IL-6; p = 0.0070), prevalence of distant metastasis (IL-18; p = 0.0313), and disease progression over time (IL-10; p = 0.0033) but not tumor location. Chromogranin A (CgA) and the NETest are currently used to monitor treatment response. A more accurate prediction could possibly be achieved by employing a subset of cytokines. Our data clearly warrants further functional investigation into the role of the immune response and cytokine release in NETs. Conclusion: A biologically plausible panel of cytokines might be added to the diagnostic and prognostic tools currently employed in patients with NETs. Combining different markers into a score would elevate diagnostic accuracy compared to single markers. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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13 pages, 1589 KiB

Open AccessArticle

Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma

by Anna La Salvia, Raffaella Carletti, Monica Verrico, Tiziana Feola, Giulia Puliani, Massimiliano Bassi, Franz Sesti, Angelina Pernazza, Rossella Mazzilli, Giuseppe Lamberti, Alessandra Siciliani, Massimiliano Mancini, Chiara Manai, Federico Venuta, Mohsen Ibrahim, Silverio Tomao, Giulia D’Amati, Cira Di Gioia, Elisa Giannetta, Federico Cappuzzo and Antongiulio Faggiano Show full author list Hide full author list

J. Clin. Med. 2022, 11(19), 5958; https://doi.org/10.3390/jcm11195958 - 9 Oct 2022

Cited by 4 | Viewed by 1663

Abstract

Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39–81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs’ location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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9 pages, 257 KiB

Open AccessArticle

Prevalence of Selected Single-Nucleotide Variants in Patients with Neuroendocrine Tumors—Potential Clinical Relevance

by Anna Kurzyńska, Dorota Pach, Anna Elżbieta Skalniak, Agnieszka Stefańska, Marta Opalińska, Elwira Przybylik-Mazurek and Alicja Hubalewska-Dydejczyk

J. Clin. Med. 2022, 11(19), 5536; https://doi.org/10.3390/jcm11195536 - 21 Sep 2022

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Abstract

Introduction: The genetic basis of neuroendocrine tumors (NETs), whose incidence is continuously increasing, is still not fully defined. The majority of NETs are sporadic, and only a small percentage occur as part of hereditary genetic syndromes. However, the associations of multiple genetic variants have been found as clinically relevant in several neoplasms. The aim of this study was to evaluate whether selected, literature-based genetic variants may have a potential role in NET susceptibility and clinical outcome in Polish patients. Materials/methods: A total of 185 patients recruited from one clinical center were enrolled. In the first part of the study, the molecular analysis including four single-nucleotide variants (rs8005354 (DAD1, NM_001344 intronic T/C substitution), rs2069762 (T/G substitution in the promoter region of the IL2 NM_000586), rs3731198 (CDKN2A, NM_000077 intronic A/G substitution), and rs1800872 (C/A substitution in the promoter region of the IL10 NM_000572)) was performed in 107 participants (49 patients with NETs with different primary site NETs and a control group of 58 healthy adult volunteers). In the second stage, the same single-nucleotide polymorphisms (SNPs) were assessed in 127 patients with NET and analyzed in terms of clinical data (primary site, serum CgA concentration, and metastatic disease). Results: The analysis of homozygotes revealed a statistically significant higher prevalence of TT homozygotes of variant rs3731198 in the control group (p = 0.0209). In NET patients, there was a statistically significant higher prevalence of GG homozygotes of variant rs1800872 (p = 0.003). There was a statistically significant correlation between the rs3731198 variant and lymph node metastases (p = 0.0038 with Bonferroni correction). Conclusions: Our study indicates that GG homozygotes of variant rs1800872 are more often observed in NET patients, while TT homozygotes of variant rs3731198 are less frequent in this group. The rs3731198 variant may be related to an increased risk of lymph node metastasis. Further, larger multicenter studies are warranted to evaluate the potential genetic factors of sporadic NETs. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

8 pages, 1623 KiB

Open AccessArticle

Usefulness of 68-Gallium PET in Type I Gastric Neuroendocrine Neoplasia: A Case Series

by Maria Rinzivillo, Francesco Panzuto, Gianluca Esposito, Edith Lahner, Alberto Signore and Bruno Annibale

J. Clin. Med. 2022, 11(6), 1641; https://doi.org/10.3390/jcm11061641 - 16 Mar 2022

Cited by 7 | Viewed by 1523

Abstract

Background: Type I gastric neuroendocrine neoplasia (gNEN) is a rare and low-grade tumor in which the therapeutic strategy is almost always endoscopic. For this reason, the use of radiology or nuclear medicine imaging is not recommended by guidelines. Conversely, in a small number of cases, locoregional or distant metastases may develop, thus suggesting a role for imaging techniques. This retrospective study was performed to explore the usefulness of [⁶⁸Ga]Ga-DOTA-SST PET/CT in the management of patients with T1gNENs. Patients and Method: Single-center retrospective analysis, in an ENETS Center of Excellence, of patients with type I gNEN who underwent [⁶⁸Ga]Ga-DOTA-SST PET/CT. The indication for performing [⁶⁸Ga]Ga-DOTA-SST PET/CT was generally based on the presence of at least one of the following criteria: (1) polyps > 10 mm; (2) endoscopic positive (R1) margin after previous endoscopic resection; and (3) Ki-67 > 3%. Results: A total of 120 patients with T1gNEN were evaluated. Overall, 15 out of 120 (13%) patients had performed [⁶⁸Ga]Ga-DOTA-SST PET/CT. The median Ki-67 value was 6% (IQR 1–9): 9 out of 15 (60%) were G1 tumors, and 6 out of 15 (40%) were G2 tumors. Ninety-three percent of patients were treated by tumor endoscopic resection, whereas surgery was performed in two patients (13%) after incomplete endoscopic resection; the remaining patients (6.6%) received somatostatin analogs due to the presence of multiple recurrent tumors. Overall, [⁶⁸Ga]Ga-DOTA-SST PET/CT was positive in 8 out of 15 patients (53%). Following the [⁶⁸Ga]Ga-DOTA-SST PET/CT findings, the clinical management was modified in 6 out of 15 (40%) patients. Conclusion: [⁶⁸Ga]Ga-DOTA-SST PET/CT can be useful in a restricted and selected group of patients with gastric neuroendocrine neoplasia with relevant risk factors to establish the most appropriate therapeutic strategy. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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10 pages, 265 KiB

Open AccessArticle

A Multinational Pilot Study on Patients’ Perceptions of Advanced Neuroendocrine Neoplasms on the EORTC QLQ-C30 and EORTC QLQ-GINET21 Questionnaires

by Rachel S. van Leeuwaarde, Angélica M. González-Clavijo, Marc Pracht, Galina Emelianova, Winson Y. Cheung, Christina Thirlwell, Kjell Öberg and Francesca Spada

J. Clin. Med. 2022, 11(5), 1271; https://doi.org/10.3390/jcm11051271 - 25 Feb 2022

Cited by 1 | Viewed by 1717

Abstract

Among the available neuroendocrine neoplasm (NEN)-specific HR-QoL scales, only the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires have been validated in several languages. We aim to assess patients’ perceptions of these questionnaires. A cross-sectional qualitative pilot study was conducted among 65 adults from four countries with well-differentiated advanced gastro-entero-pancreatic (GEP) or unknown primary NENs. Patients completed the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires and then a survey containing statements concerning the questionnaires. The majority of patients had a small intestine NET (52%). Most tumors were functioning (55%) and grade 2 NET (52%). Almost half of the patients identified limitations in the questionnaires, with nine (14%) patients scoring the questionnaires as poor and 16 (25%) patients as moderate. Overall, 37 (57%) patients were positive towards the questionnaires. Approximately a quarter of patients considered the questionnaires not suitable for all ages, missing some of their complaints, not representative of their overall HR-QoL regarding the treatment of their NET and too superficial. The current validated EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires may show some limitations in the design of questions and the patients’ final satisfaction reporting of the questionnaire. Large-scale, high-quality prospective studies are required in HR-QoL assessment regarding NETs. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

Review

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19 pages, 699 KiB

Open AccessReview

Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review

by Arianna Zappi, Irene Persano, Linda Galvani, Elena Parlagreco, Elisa Andrini, Davide Campana, Maria Pia Brizzi, Giuseppe Lamberti and Anna La Salvia

J. Clin. Med. 2023, 12(2), 717; https://doi.org/10.3390/jcm12020717 - 16 Jan 2023

Cited by 4 | Viewed by 3162

Abstract

Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts’ opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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18 pages, 1678 KiB

Open AccessReview

Management of Pheochromocytomas and Paragangliomas: A Case-Based Review of Clinical Aspects and Perspectives

by Bartosz Kamil Sobocki, Adrian Perdyan, Olga Szot and Jacek Rutkowski

J. Clin. Med. 2022, 11(9), 2591; https://doi.org/10.3390/jcm11092591 - 5 May 2022

Cited by 4 | Viewed by 6198

Abstract

Paraganglioma and pheochromocytoma are rare medical conditions. Thus, there are still a small number of studies, clinical trials, and evidence-based data in this field. This makes clinical decisions more difficult. In this study, we present a case report enriched with a short review of available essential clinical data, indicating the need for constant metoxycatecholamine level observation and a proper diagnostic imaging approach, especially in terms of ongoing pandemics. Our research also provides a summary of the molecular background of these diseases, indicating their future role in clinical management. We analyzed the ClinicalTrials.gov dataset in order to show future perspectives. In this paper, the use of the PET-CT before MRI or CT is proposed in specific cases during diagnosis processes contrary to the guidelines. PET-CT may be as effective as standard procedures and may provide a faster diagnosis, which is important in periods with more difficult access to health care, such as during the COVID-19 pandemic. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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15 pages, 264 KiB

Open AccessReview

Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?

by Sergio Di Molfetta, Tiziana Feola, Giuseppe Fanciulli, Tullio Florio, Annamaria Colao, Antongiulio Faggiano and NIKE Group

J. Clin. Med. 2022, 11(4), 1019; https://doi.org/10.3390/jcm11041019 - 16 Feb 2022

Cited by 7 | Viewed by 2119

Abstract

Lung carcinoids are well-differentiated and low-/intermediate-grade neuroendocrine neoplasms of the lung. Given their relative rarity, and the paucity of data available from prospective studies, no global consensus exists on the systemic treatment of these tumours. In recent years, immune checkpoint inhibitors have revolutionized cancer management and are under evaluation in patients with diverse types of neuroendocrine neoplasms. The aim of this narrative review is to analyse all available data for the use of approved immune checkpoint inhibitors in patients with lung carcinoids. We performed an extensive search for relevant data sources and found five published articles, one meeting abstract, and nine registered clinical trials indicating a growing interest of researchers in this field, and providing preliminary evidence of efficacy for combined nivolumab plus ipilimumab and durvalumab plus tremelimumab regimens in the treatment of advanced and/or metastatic lung carcinoids. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

Other

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12 pages, 1239 KiB

Open AccessSystematic Review

Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis

by Antonella Lucia Marretta, Alessandro Ottaiano, Domenico Iervolino, Alessandra Bracigliano, Ottavia Clemente, Francesca Di Gennaro, Roberto Tafuto, Mariachiara Santorsola, Secondo Lastoria and Salvatore Tafuto

J. Clin. Med. 2023, 12(4), 1494; https://doi.org/10.3390/jcm12041494 - 13 Feb 2023

Cited by 6 | Viewed by 1560

Abstract

Introduction. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC showed efficacy in the metastatic setting of pheocromocytomas (PCCs) and paragangliomas (PGLs) where no standard therapies have been established. Background. A search of peer-reviewed and English articles reporting on 177Lu-DOTATATE and 90Y-DOTATOC efficacy was performed through Medline and Scopus. A subsequent meta-analysis was performed to evaluate the pooled effect size on disease control rate (DCR) with PRRT. Secondary endpoints were description of patients’ genetic characteristics, hematologic toxicity, and time-to-outcome. The pooled effect was estimated with both a mixed-effects model and a random-effects model. Results. Twelve studies met the criteria for this meta-analysis: ten with 177Lu- and two with 90Y-PRRTs (213 patients). The largest one included 46 patients. Median ages ranged from 32.5 to 60.4 years. When reported, mutations of SDHB were the most frequent genetic alterations. The pooled DCRs were 0.83 (95% CI: 0.75–0.88) and 0.76 (95% CI: 0.56–0.89) for 177Lu- and 90Y-PRRT, respectively. The pooled DCR for PRRT was 0.81 (95% CI: 0.74–0.87). Conclusions. We report an updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs, showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)

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