Heterogeneity of Neuroendocrine Tumors: Impact on Biology and Response to Treatments

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 21349

Special Issue Editors

Beaujon Hospital, Université de Paris, Paris, France
Interests: neuroendocrine tumors; digestive oncology; pancreatic diseases; pancreatic cancer
Beaujon Hospital, Université de Paris, France
Interests: pancreatic tumor; neuroendocrine tumor; tumor heterogeneity; tumor molecular subtyping

Special Issue Information

Dear Colleagues, 

Neuroendocrine neoplasms (NEN) are rare malignancies with increasing prevalence that mostly arise from the digestive and bronchopulmonary systems. They are characterized by a marked heterogeneity regarding their clinical presentation and prognostic characterization, which mainly depend on tumor stage, pathological differentiation and grade, and evolutive slope. In addition, recent efforts have been made to better characterize the molecular features of NEN. Their spectrum is wide, ranging from localized benign lesions to diffuse metastatic spreading, and from slowly growing tumors with limited molecular events to highly aggressive carcinomas with molecular alterations similar to other carcinomas.

Recent advances in the understanding of NEN biology have resulted in a rising number of available treatments, including surgery, somatostatin analogs, chemotherapy, targeted therapies, liver-directed therapies, and peptide receptor radionuclide therapy. However, most of these treatments are used based on a low level of evidence, and comparisons between them have been scarce. In particular, the impact of the heterogeneity of NEN on treatment efficacy has been poorly explored. Because factors predictive of treatment efficacy are lacking, therapeutic decision-making is essentially influenced by prognostic factors.

This Special Issue aims to gather cutting-edge research on the characterization and therapeutic advances in NEN, with a focus on the impact of their heterogeneity on tumor biology and treatment efficacy. Original research and review articles should present new data from basic or clinical research and/or provide an innovative and critical appraisal of previous research. Papers exploring novel clinical or molecular biomarkers impacting prognosis and treatment efficacy are particularly welcome.

Dr. Louis de Mestier
Prof. Jérôme Cros
Guest Editors

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Keywords

  • neuroendocrine neoplasms
  • neuroendocrine tumors
  • biomarkers
  • tumor heterogeneity
  • treatment efficacy

Published Papers (10 papers)

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Research

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14 pages, 1832 KiB  
Article
Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications
by Michele Simbolo, Giovanni Centonze, Luca Giudice, Federica Grillo, Patrick Maisonneuve, Anastasios Gkountakos, Chiara Ciaparrone, Laura Cattaneo, Giovanna Sabella, Rosalba Giugno, Paola Bossi, Paola Spaggiari, Alessandro Del Gobbo, Stefano Ferrero, Luca Mastracci, Alessandra Fabbri, Martina Filugelli, Giovanna Garzone, Natalie Prinzi, Sara Pusceddu, Adele Testi, Valentina Monti, Luigi Rolli, Alessandro Mangogna, Luisa Bercich, Mauro Roberto Benvenuti, Emilio Bria, Sara Pilotto, Alfredo Berruti, Ugo Pastorino, Carlo Capella, Maurizio Infante, Michele Milella, Aldo Scarpa and Massimo Milioneadd Show full author list remove Hide full author list
Cancers 2022, 14(19), 4653; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194653 - 24 Sep 2022
Cited by 1 | Viewed by 2254
Abstract
Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 [...] Read more.
Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. Results: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. Conclusions: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC. Full article
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12 pages, 2032 KiB  
Article
Frequency and Prognostic Significance of Intertumoural Heterogeneity in Multifocal Jejunoileal Neuroendocrine Tumours
by Moritz Jesinghaus, Jelte Poppinga, Bettina Lehman, Elisabeth Maurer, Annette Ramaswamy, Albert Grass, Pietro Di Fazio, Anja Rinke, Carsten Denkert and Detlef K. Bartsch
Cancers 2022, 14(16), 3963; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14163963 - 17 Aug 2022
Cited by 3 | Viewed by 1095
Abstract
Background: A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient [...] Read more.
Background: A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival. Methods: We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival. Results: Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival (p = n.s.). Discussion: Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required. Full article
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10 pages, 533 KiB  
Article
[68Ga]Ga-DOTANOC Uptake at Pancreatic Head/Uncinate Process: Is It a Persistent Diagnostic Pitfall Over Time?
by Elena Tabacchi, Emilia Fortunati, Giulia Argalia, Lucia Zanoni, Diletta Calabrò, Silvi Telo, Davide Campana, Giuseppe Lamberti, Claudio Ricci, Riccardo Casadei, Stefano Fanti and Valentina Ambrosini
Cancers 2022, 14(14), 3541; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143541 - 21 Jul 2022
Cited by 6 | Viewed by 1707
Abstract
Purpose: [68Ga]Ga-DOTA-peptide uptake in the pancreatic head/uncinate process (UP) is a frequent PET/CT finding. Although mostly physiologic, it can represent a pitfall in PET/CT reading, especially when focal. An increased frequency of UP uptake has been reported in patients (pts) affected by diabetes [...] Read more.
Purpose: [68Ga]Ga-DOTA-peptide uptake in the pancreatic head/uncinate process (UP) is a frequent PET/CT finding. Although mostly physiologic, it can represent a pitfall in PET/CT reading, especially when focal. An increased frequency of UP uptake has been reported in patients (pts) affected by diabetes mellitus (DM). The aim of the study is to describe the frequency of [68Ga]Ga-DOTANOC UP uptake to evaluate its variations over time and its possible correlation with DM. Methods: In September 2017, a monocentric prospective observational electronic archive was initiated at our center to collect clinical and imaging data of pts undergoing [68Ga]Ga-DOTANOC PET/CT. Among the pts enrolled in the first 6 months (Sept 2017 to Feb 2018), those presenting [68Ga]Ga-DOTANOC PET/CT uptake at UP level were included. Pts with UP lesions already documented on CT/MRI or those that underwent surgical excision of UP before PET/CT were excluded from the analysis. [68Ga]Ga-DOTANOC UP uptake was classified as diffuse or focal and compared with the pattern observed in previous PET/CT scans performed at our center. An increased frequency of UP uptake was also correlated with the presence of DM. Results: In the first 6 months, 253 pts were enrolled in the archive and 172 out of them were included in the analysis. UP increased uptake was frequently observed (77/172, 44.8%) and was mostly diffuse (62/77). In 75/172 pts (43.6%), previous [68Ga]Ga-DOTANOC PET/CT scans were available (overall 268 scans; number of previous PET per pt range: 1–20) and were retrospectively reviewed. Despite the fact that, in most pts, the uptake pattern was stable over time (54/75 pts, 72%), it changed in approximately one third of cases (21/75, 28%). Among DM pts (29/172), only 10/29 (34.4%) presented increased UP uptake. Conclusions: UP [68Ga]Ga-DOTANOC uptake is a frequent non-malignant finding (slightly higher than previously reported), mostly presenting with a diffuse pattern. However, contrary to previous reports, our data show that the pattern of uptake may vary over time in approximately one third of the cases and it is not more frequently observed in pts with DM. Full article
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11 pages, 597 KiB  
Article
Heterogeneity of Small Intestinal Neuroendocrine Tumors Metastasis: Biologic Patterns of a Series with Virchow’s Node Involvement
by Maria Wedin, Marina Tsoli, Göran Wallin, Eva Tiensuu Janson, Anna Koumarianou, Gregory Kaltsas and Kosmas Daskalakis
Cancers 2022, 14(4), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040913 - 12 Feb 2022
Cited by 2 | Viewed by 1624
Abstract
Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow’s node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of [...] Read more.
Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow’s node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of 230 SI-NET patients treated at two tertiary referral centers, we found nine patients with VM (prevalence 3.9%). Among those, there were 5 females and median age at SI-NET and VM diagnosis was 61 and 65 years, respectively. Two patients had G1 tumors and five G2, while two tumors were of unspecified grade (median Ki67: 7%, range 2–15%). Four patients presented with synchronous VM, whereas five developed metachronous VM after a median of twenty-four months (range: 4.8–117.6 months). Hepatic metastases were present in seven patients, extrahepatic metastases (EM) in eight (six para-aortic distant lymph node metastases, one lung and one pancreatic metastasis), whereas peritoneal carcinomatosis (PC) in two patients. We used a control group of 18 age- and sex-matched SI-NET patients from the same cohort with stage IV disease but no extra-abdominal metastases. There was no difference in best-recorded response to first line treatment according to RECIST 1.1 as well as progression-free survival (PFS) between patients with VM and those in the control group (Chi-square test p = 0.516; PFS 71.7 vs. 106.9 months [95% CI 38.1–175.8]; log-rank p = 0.855). In addition, median overall survival (OS) of SI-NET patients with VM did not differ from those in the control group (138.6 [95% CI 17.2–260] vs. 109.9 [95% CI 91.7–128] months; log-rank p = 0.533). In conclusion, VM, although relatively rare in patients with SI-NETs, is more often encountered in patients with G2 tumors and established distant para-aortic lymph node metastases. The presence of VM in SI-NET patients does not seem to impact patients’ survival outcomes and treatment responses, when compared to age- and sex-matched SI-NET patients with stage IV disease confined in the abdomen. Full article
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19 pages, 5745 KiB  
Article
Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms
by Matteo Bulloni, Giada Sandrini, Irene Stacchiotti, Massimo Barberis, Fiorella Calabrese, Lina Carvalho, Gabriella Fontanini, Greta Alì, Francesco Fortarezza, Paul Hofman, Veronique Hofman, Izidor Kern, Eugenio Maiorano, Roberta Maragliano, Deborah Marchiori, Jasna Metovic, Mauro Papotti, Federica Pezzuto, Eleonora Pisa, Myriam Remmelink, Gabriella Serio, Andrea Marzullo, Senia Maria Rosaria Trabucco, Antonio Pennella, Angela De Palma, Giuseppe Marulli, Ambrogio Fassina, Valeria Maffeis, Gabriella Nesi, Salma Naheed, Federico Rea, Christian H. Ottensmeier, Fausto Sessa, Silvia Uccella, Giuseppe Pelosi and Linda Pattiniadd Show full author list remove Hide full author list
Cancers 2021, 13(19), 4875; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194875 - 29 Sep 2021
Cited by 6 | Viewed by 2043
Abstract
Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based [...] Read more.
Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs. Full article
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13 pages, 11596 KiB  
Article
The Microenvironment of Small Intestinal Neuroendocrine Tumours Contains Lymphocytes Capable of Recognition and Activation after Expansion
by Tobias Hofving, Frank Liang, Joakim Karlsson, Ulf Yrlid, Jonas A. Nilsson, Ola Nilsson and Lisa M. Nilsson
Cancers 2021, 13(17), 4305; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174305 - 26 Aug 2021
Cited by 5 | Viewed by 2173
Abstract
Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering [...] Read more.
Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET. Full article
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15 pages, 2413 KiB  
Article
Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?
by Melissa Frizziero, Alice Durand, Rodrigo G. Taboada, Elisa Zaninotto, Claudio Luchini, Bipasha Chakrabarty, Valérie Hervieu, Laura C. L. Claro, Cong Zhou, Sara Cingarlini, Michele Milella, Thomas Walter, Rachel S. Riechelmann, Angela Lamarca, Richard A. Hubner, Wasat Mansoor, Juan W. Valle and Mairéad G. McNamara
Cancers 2021, 13(16), 4152; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164152 - 18 Aug 2021
Cited by 5 | Viewed by 1990
Abstract
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” [...] Read more.
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide. Full article
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14 pages, 1878 KiB  
Article
Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms
by Caroline Lacombe, Ophélie De Rycke, Anne Couvelard, Anthony Turpin, Aurélie Cazes, Olivia Hentic, Valérie Gounant, Gérard Zalcman, Philippe Ruszniewski, Jérôme Cros and Louis de Mestier
Cancers 2021, 13(4), 643; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040643 - 05 Feb 2021
Cited by 20 | Viewed by 1864
Abstract
Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our [...] Read more.
Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11–15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value. Full article
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Review

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14 pages, 2460 KiB  
Review
Neuroendocrine Neoplasms of the Breast: The Latest WHO Classification and Review of the Literature
by Yukinori Ozaki, Sakiko Miura, Ryosuke Oki, Teppei Morikawa and Keita Uchino
Cancers 2022, 14(1), 196; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010196 - 31 Dec 2021
Cited by 4 | Viewed by 3161
Abstract
Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 [...] Read more.
Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 defined neuroendocrine neoplasms (NENs) of the breast (Br-NENs) as tumors in which >90% of cells show histological evidence of NE differentiation, including NETs (low-grade tumors) and NEC (high-grade). Due to the low prevalence of these tumors and successive changes in their diagnostic criteria over the years, only limited evidence of these tumors exists, derived mainly from case reports and retrospective case series. Breast tumors with NE differentiation are usually treated like the more commonly occurring IBC-NSTs. Immunohistochemistry (IHC) of breast tumors with NE differentiation usually shows a hormone receptor (HR)-positive and human epidermal growth factor type 2 (HER2)-negative profile, so that hormonal therapy with cyclin-dependent kinase (CDK)4/6 inhibitors or other targeted agents would be reasonable treatment options. Herein, we present a review of the literature on breast tumors with NE differentiation as defined in the latest WHO 2019 classification, and discuss the clinical management of these tumors. Full article
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Other

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25 pages, 2339 KiB  
Systematic Review
Perioperative Carcinoid Crisis: A Systematic Review and Meta-Analysis
by Aileen Xu, Pilar Suz, Tea Reljic, Abhirup C. Are, Ambuj Kumar, Benjamin Powers, Jonathan Strosberg, Jason W. Denbo, Jason B. Fleming and Daniel A. Anaya
Cancers 2022, 14(12), 2966; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122966 - 16 Jun 2022
Cited by 9 | Viewed by 2086
Abstract
Background: Surgery is the only curative option for patients with neuroendocrine tumors (NET) and is also indicated for debulking of liver metastasis. Intraoperative carcinoid crisis (CC) is thought to be a potentially lethal complication. Though perioperative octreotide is often recommended for prevention, recent [...] Read more.
Background: Surgery is the only curative option for patients with neuroendocrine tumors (NET) and is also indicated for debulking of liver metastasis. Intraoperative carcinoid crisis (CC) is thought to be a potentially lethal complication. Though perioperative octreotide is often recommended for prevention, recent NET society guidelines raised concerns regarding limited data supporting its use. We sought to evaluate existing evidence characterizing CC and evaluating the efficacy of prophylactic octreotide. Methods: A systematic review was performed on studies including patients having surgery for well-differentiated NET and/or NET liver metastasis (2000–2021), and reporting data on the incidence, risk factors, or prognosis of CC, and/or use of prophylactic octreotide. Meta-analysis was performed using random-effects models. Results: Eight studies met inclusion criteria (n = 943 operations). The pooled incidence of CC was 19% (95% CI [0.06–0.36]). Liver metastasis (odds ratio 2.85 [1.49–5.47]) and gender (male 0.58 [0.34–0.99]) were the only significant risk factors. The occurrence of CC was associated with increased risk of major postoperative complications (2.12 [1.03–4.35]). The use of prophylactic octreotide was not associated with decreased risk of CC (0.73 [0.32–1.66]). Notably, there was no standard prophylactic octreotide strategy used. Conclusions: Intraoperative carcinoid crisis is a common complication occurring in up to 20% of patients with midgut NET and/or liver metastasis undergoing surgery. Prophylactic octreotide may not provide an efficient way to prevent this complication. Future studies should focus on prospective evaluation of well-defined prophylactic protocols using a standardized definition for CC. Full article
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