Neuroendocrine Neoplasms: Current Challenges and Advances in the Biological Aspects, Diagnostic and Therapeutic Management

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 28993

Special Issue Editors

Department of Abdominal Cancer, ENETs Center of Excellence, Istituto Nazionale Tumori, IRCCS, Fondazione “G. Pascale”, Naples, Italy
Interests: management of soft tissue sarcomas and osteosarcomas from diagnosis to the cure; medical approach of the GIST; predictive factors of outcome and prognosis; epigenetic and genetic changes in soft-tissue sarcomas
Special Issues, Collections and Topics in MDPI journals
Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
Interests: abdominal cancers; colorectal cancer; immunotherapy; genomic landscape; neuroendocrine tumors
Special Issues, Collections and Topics in MDPI journals
Division of Cardiology, Istituto Nazionale Tumori, IRCCS, Fondazione “G. Pascale”, Naples, Italy
Interests: microenvironment; chemokines; chemoresistance; inflammation
Special Issues, Collections and Topics in MDPI journals
Department of Breast and Thoracic Oncology, Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS, Fondazione “G. Pascale”, Naples, Italy
Interests: neuroendocrine tumors; genomic landscape; immune signature; tumor microenviroment; copy number signatures; Axl; immunotherapy; CAR-T cells; STR; PRRT
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with increasing incidence and prevalence. NENs clinical management requires a multidisciplinary approach, which has a positive impact on the survival of the patients.

NENs heterogeneity is linked to both biological and clinical characteristics. In recent years, the better understanding of NENs biology and the efforts of different specialists and researchers in investigating NENs treatment and diagnosis strategies have continually evolved NENs management as a field of investigation. As a result, many preclinical studies and phase II and phase III clinical trials have been completed, that have allowed the improvement of the treatment strategy and diagnostic tools for NENs. However, many other studies are ongoing and are expected to further improve our understanding of the biology of NENs as well as treatment and diagnosis.

This Special Issue aims to gather research on the biological, diagnostic, and therapeutic aspects that can offer real progresses in the management of NENs patients. Original research and review articles should present new data from basic or clinical research and/or analyze and discuss previous research in an innovative and original way.

Dr. Salvatore Tafuto
Dr. Alessandro Ottaiano
Dr. Vincenzo Quagliariello
Dr. Claudia von Arx
Guest Editors

Manuscript Submission Information

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Keywords

  • neuroendocrine neoplasms
  • carcinoid syndrome
  • multidisciplinary team in NENs
  • somatostatin analogs
  • targeted therapies
  • peptide receptor radionuclide therapy (PRRT)

Published Papers (10 papers)

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Research

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13 pages, 4154 KiB  
Article
Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT
Cancers 2021, 13(9), 2035; https://doi.org/10.3390/cancers13092035 - 23 Apr 2021
Cited by 8 | Viewed by 2228
Abstract
(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response [...] Read more.
(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of 177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in 177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT. Full article
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15 pages, 1517 KiB  
Article
Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE; Differences in Tumor Dosimetry, Vascularity and Lesion Metrics in Pancreatic and Small Intestinal Neuroendocrine Neoplasms
Cancers 2021, 13(5), 962; https://doi.org/10.3390/cancers13050962 - 25 Feb 2021
Cited by 22 | Viewed by 2658
Abstract
Dosimetry during peptide receptor radionuclide therapy (PRRT) has mainly focused on normal organs and less on the tumors. The absorbed dose in one target tumor per patient and several response related factors were assessed in 23 pancreatic neuroendocrine neoplasms (P-NENs) and 25 small-intestinal [...] Read more.
Dosimetry during peptide receptor radionuclide therapy (PRRT) has mainly focused on normal organs and less on the tumors. The absorbed dose in one target tumor per patient and several response related factors were assessed in 23 pancreatic neuroendocrine neoplasms (P-NENs) and 25 small-intestinal NEN (SI-NENs) during PRRT with 177Lu-DOTATATE. The total administered activity per patient was (mean ± standard error of mean (SEM) 31.8 ± 1.9 GBq for P-NENs and 36 ± 1.94 GBq for SI-NENs. The absorbed tumor dose was 143.5 ± 2 Gy in P-NENs, 168.2 ± 2 Gy in SI-NENs. For both NEN types, a dose–response relationship was found between the absorbed dose and tumor shrinkage, which was more pronounced in P-NENs. A significant drop in the absorbed dose per cycle was shown during the course of PRRT. Tumor vascularization was higher in P-NENs than in SI-NENs at baseline but equal post-PRRT. The time to progression (RECIST 1.1) was similar for patients with P-NEN (mean ± SEM 30 ± 1 months) and SI-NEN (33 ± 1 months). In conclusion, a dose response relationship was established for both P-NENs and SI-NENs and a significant drop in the absorbed dose per cycle was shown during the course of PRRT, which warrants further investigation to understand the factors impacting PRRT to improve personalized treatment protocol design. Full article
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8 pages, 549 KiB  
Article
Evolution of the Mesenteric Mass in Small Intestinal Neuroendocrine Tumours
Cancers 2021, 13(3), 443; https://doi.org/10.3390/cancers13030443 - 25 Jan 2021
Cited by 12 | Viewed by 2467
Abstract
Background: A metastatic mesenteric mass is a hallmark of small intestinal neuroendocrine tumours (SI-NETs). However, little is known on its development over time. Therefore, we conducted a study to assess the evolution of a SI-NET-associated mesenteric mass over time. Methods: Retrospectively, 530 patients [...] Read more.
Background: A metastatic mesenteric mass is a hallmark of small intestinal neuroendocrine tumours (SI-NETs). However, little is known on its development over time. Therefore, we conducted a study to assess the evolution of a SI-NET-associated mesenteric mass over time. Methods: Retrospectively, 530 patients with proven SI-NET were included. The presence and growth of a mesenteric mass was assessed using RECIST 1.1 criteria on every consecutive CT-scan until the end of follow-up or resection. Results: At baseline, a mesenteric mass was present in 64% of the patients, of whom 13.5% showed growth of the mesenteric mass with a median time to growth of 40 months. Male gender was the only independent predictor of growth (OR 2.67). Of the patients without a mesenteric mass at the first evaluation, 2.6% developed a pathological mesenteric mass. Treatment with peptide receptor radionuclide therapy (PRRT; N = 132) resulted in an objective size reduction of the mesenteric mass in 3.8%. Conclusion: The metastatic mesenteric mass in SI-NETs has a static behavior over time. Therefore, site-specific growth behavior should be taken into account when selecting target lesions and assessing disease progression and therapeutic response. PRRT appears not to be effective for size reduction of the mesenteric mass. Full article
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15 pages, 1523 KiB  
Article
A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study
Cancers 2020, 12(5), 1235; https://doi.org/10.3390/cancers12051235 - 14 May 2020
Cited by 12 | Viewed by 2603
Abstract
Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study [...] Read more.
Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival. Full article
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12 pages, 2025 KiB  
Article
Neuroendocrine Carcinoma of the Uterine Cervix: A Clinicopathologic and Immunohistochemical Study with Focus on Novel Markers (Sst2–Sst5)
Cancers 2020, 12(5), 1211; https://doi.org/10.3390/cancers12051211 - 12 May 2020
Cited by 27 | Viewed by 5400
Abstract
Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2–2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center ( [...] Read more.
Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2–2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). Results. All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell–neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell–neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2–3, in 9 cases); SST2 in 8 (50%, score 2–3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. Conclusions. P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs. Full article
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Review

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18 pages, 557 KiB  
Review
From the Magic Bullet to Theragnostics: Certitudes and Hypotheses, Trying to Optimize the Somatostatin Model
Cancers 2021, 13(14), 3474; https://doi.org/10.3390/cancers13143474 - 12 Jul 2021
Cited by 2 | Viewed by 2090
Abstract
The first “theragnostic model”, that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and [...] Read more.
The first “theragnostic model”, that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the “DOTA-Ga-68/Lu-177”, used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted. Full article
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28 pages, 1149 KiB  
Review
Large Scale Molecular Studies of Pituitary Neuroendocrine Tumors: Novel Markers, Mechanisms and Translational Perspectives
Cancers 2021, 13(6), 1395; https://doi.org/10.3390/cancers13061395 - 19 Mar 2021
Cited by 14 | Viewed by 2978
Abstract
Pituitary neuroendocrine tumors (PitNETs) are non-metastatic neoplasms of the pituitary, which overproduce hormones leading to systemic disorders, or tumor mass effects causing headaches, vertigo or visual impairment. Recently, PitNETs have been investigated in large scale (exome and genome) molecular analyses (transcriptome microarrays and [...] Read more.
Pituitary neuroendocrine tumors (PitNETs) are non-metastatic neoplasms of the pituitary, which overproduce hormones leading to systemic disorders, or tumor mass effects causing headaches, vertigo or visual impairment. Recently, PitNETs have been investigated in large scale (exome and genome) molecular analyses (transcriptome microarrays and sequencing), to uncover novel markers. We performed a literature analysis on these studies to summarize the research data and extrapolate overlapping gene candidates, biomarkers, and molecular mechanisms. We observed a tendency in samples with driver mutations (GNAS, USP8) to have a smaller overall mutational rate, suggesting driver-promoted tumorigenesis, potentially changing transcriptome profiles in tumors. However, direct links from drivers to signaling pathways altered in PitNETs (Notch, Wnt, TGF-β, and cell cycle regulators) require further investigation. Modern technologies have also identified circulating nucleic acids, and pinpointed these as novel PitNET markers, i.e., miR-143-3p, miR-16-5p, miR-145-5p, and let-7g-5p, therefore these molecules must be investigated in the future translational studies. Overall, large-scale molecular studies have provided key insight into the molecular mechanisms behind PitNET pathogenesis, highlighting previously reported molecular markers, bringing new candidates into the research field, and reapplying traditional perspectives to newly discovered molecular mechanisms. Full article
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13 pages, 436 KiB  
Review
Neuroendocrine-Related Circulating Transcripts in Small-Cell Lung Cancers: Detection Methods and Future Perspectives
Cancers 2021, 13(6), 1339; https://doi.org/10.3390/cancers13061339 - 16 Mar 2021
Cited by 3 | Viewed by 1735
Abstract
No well-established prognostic or predictive molecular markers of small-cell lung cancer (SCLC) are currently available; therefore, all patients receive standard treatment. Adequate quantities and quality of tissue samples are frequently unavailable to perform a molecular analysis of SCLC, which appears more heterogeneous and [...] Read more.
No well-established prognostic or predictive molecular markers of small-cell lung cancer (SCLC) are currently available; therefore, all patients receive standard treatment. Adequate quantities and quality of tissue samples are frequently unavailable to perform a molecular analysis of SCLC, which appears more heterogeneous and dynamic than expected. The implementation of techniques to study circulating tumor cells could offer a suitable alternative to expand the knowledge of the molecular basis of a tumor. In this context, the advantage of SCLC circulating cells to express some specific markers to be explored in blood as circulating transcripts could offer a great opportunity in distinguishing and managing different SCLC phenotypes. Here, we present a summary of published data and new findings about the detection methods and potential application of a group of neuroendocrine related transcripts in the peripheral blood of SCLC patients. In the era of new treatments, easy and rapid detection of informative biomarkers in blood warrants further investigation, since it represents an important option to obtain essential information for disease monitoring and/or better treatment choices. Full article
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20 pages, 1674 KiB  
Review
Modelling Pancreatic Neuroendocrine Cancer: From Bench Side to Clinic
Cancers 2020, 12(11), 3170; https://doi.org/10.3390/cancers12113170 - 28 Oct 2020
Cited by 9 | Viewed by 3214
Abstract
Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise [...] Read more.
Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise and patient outcomes, although variable, have been linked with 5-year survival rates as low as 40%. Improvement of diagnostic and treatment modalities strongly relies on disease models that reconstruct the disease ex vivo. A key constraint in pNET research, however, is the absence of human pNET models that accurately capture the original tumour phenotype. In attempts to more closely mimic the disease in its native environment, three-dimensional culture models as well as in vivo models, such as genetically engineered mouse models (GEMMs), have been developed. Despite adding significant contributions to our understanding of more complex biological processes associated with the development and progression of pNETs, factors such as ethical considerations and low rates of clinical translatability limit their use. Furthermore, a role for the site-specific extracellular matrix (ECM) in disease development and progression has become clear. Advances in tissue engineering have enabled the use of tissue constructs that are designed to establish disease ex vivo within a close to native ECM that can recapitulate tumour-associated tissue remodelling. Yet, such advanced models for studying pNETs remain underdeveloped. This review summarises the most clinically relevant disease models of pNETs currently used, as well as future directions for improved modelling of the disease. Full article
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12 pages, 1682 KiB  
Review
Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis
Cancers 2020, 12(8), 2246; https://doi.org/10.3390/cancers12082246 - 11 Aug 2020
Cited by 4 | Viewed by 2255
Abstract
The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, [...] Read more.
The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle–Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53–1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24–3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease. Full article
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