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Angerilli V, Sabella G, Simbolo M, Lagano V, Centonze G, Gentili M, Mangogna A, Coppa J, Munari G, Businello G, Borga C, Schiavi F, Pusceddu S, Leporati R, Oldani S, Fassan M, Milione M. Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms. Br J Cancer 2024; 131:159-170. [PMID: 38729995 PMCID: PMC11231306 DOI: 10.1038/s41416-024-02705-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 04/20/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND High-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55). METHODS We analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1. RESULTS Frequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival. CONCLUSIONS This study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.
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Affiliation(s)
| | - Giovanna Sabella
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Lagano
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marco Gentili
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute of Pathological Anatomy, Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giada Munari
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Chiara Borga
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Sara Pusceddu
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Rita Leporati
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Simone Oldani
- Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy
| | - Massimo Milione
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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Liu Y, Cui R, Wang Z, Lin Q, Tang W, Zhang B, Li G, Wang Z. Evaluating Prognosis of Gastrointestinal Metastatic Neuroendocrine Tumors: Constructing a Novel Prognostic Nomogram Based on NETPET Score and Metabolic Parameters from PET/CT Imaging. Pharmaceuticals (Basel) 2024; 17:373. [PMID: 38543159 PMCID: PMC10975134 DOI: 10.3390/ph17030373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 01/06/2025] Open
Abstract
INTRODUCTION The goal of this study is to compare the prognostic performance of NETPET scores, based on gallium-68 DOTANOC (68Ga-DOTANOC) and fluorine-18 fluorodeoxyglucose (18F-FDG) Positron Emission Tomography-Computed Tomography (PET-CT), and PET-CT metabolic parameters in metastatic gastrointestinal neuroendocrine tumors (GI-NET), while constructing and validating a nomogram derived from dual-scan PET-CT. METHODS In this retrospective study, G1-G3 GI-NET patients who underwent 68Ga-DOTANOC and 18F-FDG PET scans were enrolled and divided into training and internal validation cohorts. Three grading systems were constructed based on NETPET scores and standardized uptake value maximum (SUVmax). LASSO regression selected variables for a multivariable Cox model, and nomograms predicting progression-free survival (PFS) and overall survival (OS) were created. The prognostic performance of these systems was assessed using time-dependent receiver-operating characteristic (ROC) curves, concordance index (C-index), and other methods. Nomogram evaluation involved calibration curves, decision curve analysis (DCA), and the aforementioned methods in both cohorts. RESULTS In this study, 223 patients (130 males; mean age ± SD: 52.6 ± 12 years) were divided into training (148) and internal validation (75) cohorts. Dual scans were classified based on NETPET scores (D1-D3). Single 68Ga-DOTANOC and 18F-FDG PET-CT scans were stratified into S1-S3 and F1-F3 based on SUVmax. The NETPET score-based grading system demonstrated the best OS and PFS prediction (C-index, 0.763 vs. 0.727 vs. 0.566). Nomograms for OS and PFS exhibited superior prognostic performance in both cohorts (all AUCs > 0.8). CONCLUSIONS New classification based on NETPET score predicts patient OS/PFS best. PET-CT-based nomograms show accurate OS/PFS forecasts.
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Affiliation(s)
- Yifan Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Ruizhe Cui
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Zhixiong Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Qi Lin
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Wei Tang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Bing Zhang
- Department of Nuclear Medicine, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China;
| | - Guanghua Li
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
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Sugawara T, Rodriguez Franco S, Franklin O, Kirsch MJ, Colborn KL, Del Chiaro M, Schulick RD. Management of Localized Small- and Large-Cell Pancreatic Neuroendocrine Carcinoma in the National Cancer Database. J Am Coll Surg 2023; 237:515-524. [PMID: 37146214 DOI: 10.1097/xcs.0000000000000735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
BACKGROUND The role of curative-intent resection and perioperative chemotherapy for nonmetastatic pancreatic neuroendocrine carcinoma (PanNEC) remains unclear due to their biological aggressiveness and rarity. This study aimed to evaluate the association of resection and perioperative chemotherapy with overall survival for nonmetastatic PanNEC. STUDY DESIGN Patients with localized (cT1-3, M0), small- and large-cell PanNEC were identified in the National Cancer Database from 2004 to 2017. The changing trends in terms of the annual proportions of resection and adjuvant chemotherapy were assessed. The survival of patients who received resection and those who received adjuvant chemotherapy were investigated using Kaplan-Meier estimates and Cox regression models. RESULTS In total, 199 patients with localized small- and large-cell PanNEC were identified; 50.3% of those were resected, and 45.0% of the resected patients received adjuvant chemotherapy. Rate of resection and adjuvant treatment has trended upward since 2011. The resected group was younger, was more often treated at academic institutions, had more distal tumors, and had a lower number of small-cell PanNEC. The median overall survival was longer in the resected group compared to the unresected group (29.4 months vs 8.6 months, p < 0.001). Resection was associated with improved survival in a multivariable Cox regression model adjusting for preoperative factors (adjusted hazard ratio 0.58, 95% CI 0.37 to 0.92), while adjuvant therapy was not. CONCLUSIONS This nationwide retrospective study suggests that resection is associated with improved survival in patients with localized PanNEC. The role of adjuvant chemotherapy needs more investigation.
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Affiliation(s)
- Toshitaka Sugawara
- From the Division of Surgical Oncology, Department of Surgery (Sugawara, Rodriguez Franco, Franklin, Colborn, Del Chairo), University of Colorado School of Medicine, Aurora, Colorado
- the Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Sugawara)
| | - Salvador Rodriguez Franco
- From the Division of Surgical Oncology, Department of Surgery (Sugawara, Rodriguez Franco, Franklin, Colborn, Del Chairo), University of Colorado School of Medicine, Aurora, Colorado
| | - Oskar Franklin
- From the Division of Surgical Oncology, Department of Surgery (Sugawara, Rodriguez Franco, Franklin, Colborn, Del Chairo), University of Colorado School of Medicine, Aurora, Colorado
- the Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden (Franklin)
| | - Michael J Kirsch
- the Department of Surgery (Kirsch, Schulick), University of Colorado School of Medicine, Aurora, Colorado
| | - Kathryn L Colborn
- From the Division of Surgical Oncology, Department of Surgery (Sugawara, Rodriguez Franco, Franklin, Colborn, Del Chairo), University of Colorado School of Medicine, Aurora, Colorado
- the Department of Biostatistics and Informatics (Colborn), University of Colorado School of Medicine, Aurora, Colorado
- the Surgical Outcomes and Applied Research Program (Colborn), University of Colorado School of Medicine, Aurora, Colorado
| | - Marco Del Chiaro
- From the Division of Surgical Oncology, Department of Surgery (Sugawara, Rodriguez Franco, Franklin, Colborn, Del Chairo), University of Colorado School of Medicine, Aurora, Colorado
- the University of Colorado Cancer Center (Del Chiaro, Schulick), University of Colorado School of Medicine, Aurora, Colorado
| | - Richard D Schulick
- the Department of Surgery (Kirsch, Schulick), University of Colorado School of Medicine, Aurora, Colorado
- the University of Colorado Cancer Center (Del Chiaro, Schulick), University of Colorado School of Medicine, Aurora, Colorado
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D’Agosto S, Fiorini E, Pezzini F, Delfino P, Simbolo M, Vicentini C, Andreani S, Capelli P, Rusev B, Lawlor RT, Bassi C, Landoni L, Pea A, Luchini C, Scarpa A, Corbo V. Long-term organoid culture of a small intestinal neuroendocrine tumor. Front Endocrinol (Lausanne) 2023; 14:999792. [PMID: 37082125 PMCID: PMC10112019 DOI: 10.3389/fendo.2023.999792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 03/02/2023] [Indexed: 04/22/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.
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Affiliation(s)
- Sabrina D’Agosto
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Elena Fiorini
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Francesco Pezzini
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Pietro Delfino
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Caterina Vicentini
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
| | - Silvia Andreani
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
| | - Paola Capelli
- Azienda Ospedaliera Integrata dell’Università di Verona, Verona, Italy
| | - Borislav Rusev
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
| | - Rita T. Lawlor
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
| | - Claudio Bassi
- Pancreas Institute, Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Luca Landoni
- Pancreas Institute, Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Antonio Pea
- Pancreas Institute, Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
| | - Vincenzo Corbo
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
- Centre for Applied Research on Cancer (ARC-Net) Research Centre, University of Verona, Verona, Italy
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Reccia I, Pai M, Kumar J, Spalding D, Frilling A. Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2023; 15:1861. [PMID: 36980746 PMCID: PMC10047148 DOI: 10.3390/cancers15061861] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/10/2023] [Accepted: 03/18/2023] [Indexed: 03/22/2023] Open
Abstract
Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.
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Affiliation(s)
- Isabella Reccia
- General Surgical and Oncology Unit, Policlinico San Pietro, Via Carlo Forlanini, 24036 Ponte San Pietro, Italy
| | - Madhava Pai
- Division of Surgery, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | - Jayant Kumar
- Division of Surgery, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | - Duncan Spalding
- Division of Surgery, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
| | - Andrea Frilling
- Division of Surgery, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK
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Gao C, Fan Z, Yang J, Shi M, Li Y, Zhan H. Diagnostic role and prognostic value of tumor markers in high-grade gastro-enteropancreatic neuroendocrine neoplasms. Pancreatology 2023; 23:204-212. [PMID: 36710224 DOI: 10.1016/j.pan.2023.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 01/09/2023] [Accepted: 01/16/2023] [Indexed: 01/31/2023]
Abstract
OBJECTIVES High-grade gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors of two different types: well differentiated neuroendocrine tumors grade 3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). This study aimed to explore the value of eight common preoperative markers in differentiating NETs G3 from NECs and the prognosis prediction of high-grade GEP-NENs. METHODS Seventy-two patients diagnosed with high-grade GEP-NENs who underwent surgery at our institution were recruited for this study. Demographic and clinicopathological characteristics, preoperative serum tumor markers, and survival data were collected and analyzed. Kaplan-Meier methods were used to analyze survival rates, and a Cox regression model was used to perform multivariate analyses. RESULTS Serum carcinoembryonic antigen (CEA) was dramatically higher in NECs than in NETs G3 (P = 0.025). After follow-up, 57 of the 72 patients remained for survival analysis. Elevated serum carbohydrate antigen 19-9 (CA19-9), CEA, cancer antigen 125 and sialic acid (SA) levels indicated poorer survival of high-grade GEP-NEN patients. Only CA19-9 (HR: 6.901, 95% CI: 1.843 to 25.837, P = 0.004) was regarded as an independent risk factor for overall survival. Serum CA19-9 (HR: 4.689, 95% CI: 1.127 to 19.506, P = 0.034) was also regarded as an independent factor for overall survival in NECs. CONCLUSIONS Serum CEA levels can be used to distinguish NETs G3 from NECs. Preoperative CA19-9, CEA, cancer antigen 125 and SA levels have predictive value in the prognosis of high-grade GEP-NENs. Preoperative CA19-9, neuron-specific enolase, and SA levels can predict the prognosis of NECs.
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Affiliation(s)
- Changhao Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Jian Yang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Ming Shi
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Yongzheng Li
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
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Popa Ilie IR, Georgescu CE. Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia. Neuroendocrinology 2023; 113:262-278. [PMID: 34348340 DOI: 10.1159/000518106] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/25/2021] [Indexed: 11/19/2022]
Abstract
The worldwide prevalence and incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and of NENs, in general, have been increasing recently. While valuing the considerable progress made in the treatment strategies for GEP-NEN in recent years, patients with advanced, metastasized disease still have a poor prognosis, which calls for urgent novel therapies. The immune system plays a dual role: both host-protecting and "tumor-promoting." Hence, immunotherapy is potentially a powerful weapon to help NEN patients. However, although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Studies led to their approval in NEN of the lung and Merkel cell carcinoma, whereas results in other settings have not been so encouraging. Oncolytic viruses can selectively infect and destroy cancer cells, acting as an in situ cancer vaccine. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype. Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to checkpoint inhibitors alone. Future efforts should focus on finding the best way to include immunotherapy in the GEP-NEN treatment scenario. In this context, this study aims at providing a comprehensive generalized review of the immune checkpoint blockade and the oncolytic virotherapy use in GEP-NENs that might improve GEP-NEN treatment strategies.
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Affiliation(s)
- Ioana Rada Popa Ilie
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Carmen Emanuela Georgescu
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Henzinger H, Brcic I. From morphology to molecular targets—the pathologist’s view in diagnosing gastroenteropancreatic neuroendocrine neoplasms. MEMO - MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2022; 15:287-293. [DOI: 10.1007/s12254-022-00850-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/05/2022] [Indexed: 12/12/2022]
Abstract
SummaryIn the last decade, a number of genetic alterations in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have been identified. In addition, differences in tumor morphology as well as proliferation index (Ki-67) or number of mitoses have led to changes in the classification of these neoplasms. According to the new World Health Organization (WHO) classification, GEP-NENs are now divided into two genetically and prognostically different categories: (i) well-differentiated neuroendocrine tumors (NET) subdivided into low (G1), intermediate (2) and high (G3) grade tumors, and (ii) poorly differentiated neuroendocrine carcinomas (NEC). In addition, a group of mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN) has been defined. This review focuses on the clinical, morphological, immunohistochemical and molecular findings of the GEP-NENs and their key diagnostic features that can help the pathologist to differentiate between tumors in this heterogeneous group. In challenging cases, additional immunohistochemical and/or molecular analysis can be helpful to determine the correct diagnosis and proper treatment for the patient.
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Kong G, Hicks RJ. PRRT for higher-grade neuroendocrine neoplasms: What is still acceptable? Curr Opin Pharmacol 2022; 67:102293. [PMID: 36195008 DOI: 10.1016/j.coph.2022.102293] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/25/2022] [Accepted: 09/01/2022] [Indexed: 01/25/2023]
Abstract
Peptide receptor radionuclide therapy (PRRT) is a widely accepted treatment for progressive grade 1 and 2 (G1-2) gastroenteropancreatic neuroendocrine tumors (NET). There is increasing evidence that PRRT is effective for selected patients with well-differentiated (WD) G3 NET, which are now separated from neuroendocrine carcinoma (NEC). These preliminary data have led to prospective PRRT trials currently in progress. This article provides an update of the current role of PRRT for patients with WD-G3 NET, highlighting the importance of patient selection based on molecular imaging phenotype, as well as outlining some potential future directions in this field. Upcoming prospective trials will help define the role, sequencing, and optimization of PRRT to improve outcomes of patients with WD-G3 NET.
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Affiliation(s)
- Grace Kong
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
| | - Rodney J Hicks
- The University of Melbourne Department of Medicine, St Vincent's Hospital, Melbourne, Australia.
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10
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Centonze G, Maisonneuve P, Prinzi N, Pusceddu S, Albarello L, Pisa E, Barberis M, Vanoli A, Spaggiari P, Bossi P, Cattaneo L, Sabella G, Solcia E, La Rosa S, Grillo F, Tagliabue G, Scarpa A, Papotti M, Volante M, Mangogna A, Del Gobbo A, Ferrero S, Rolli L, Roca E, Bercich L, Benvenuti M, Messerini L, Inzani F, Pruneri G, Busico A, Perrone F, Tamborini E, Pellegrinelli A, Kankava K, Berruti A, Pastorino U, Fazio N, Sessa F, Capella C, Rindi G, Milione M. Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis. Neuroendocrinology 2022; 113:457-469. [PMID: 36417840 DOI: 10.1159/000528186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/17/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.
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Affiliation(s)
- Giovanni Centonze
- 1st Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Natalie Prinzi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Albarello
- Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Eleonora Pisa
- Division of Pathology, European Institute of Oncology (IEO), Milan, Italy
| | - Massimo Barberis
- Division of Pathology, European Institute of Oncology (IEO), Milan, Italy
| | - Alessandro Vanoli
- Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Paola Spaggiari
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Paola Bossi
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Laura Cattaneo
- 1st Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- 1st Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Enrico Solcia
- Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy
| | - Federica Grillo
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
| | - Giovanna Tagliabue
- Lombardy Cancer Registry, Varese Province Cancer Registry Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Aldo Scarpa
- ARC-NET Research Center for Applied Research on Cancer, Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Marco Volante
- Department of Oncology, University of Turin, Turin, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
| | - Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Biomedical Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Luigi Rolli
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Elisa Roca
- Thoracic Oncology - Lung Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
| | - Luisa Bercich
- Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Mauro Benvenuti
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Luca Messerini
- Diagnostic and Molecular Pathology, Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Frediano Inzani
- Anatomic Pathology Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Giancarlo Pruneri
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Adele Busico
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Perrone
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elena Tamborini
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Pellegrinelli
- Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Brescia, Italy
| | - Ketevani Kankava
- Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia
| | - Alfredo Berruti
- Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science, Brescia, Italy
- Public Health, University of Brescia, Brescia, Italy
| | - Ugo Pastorino
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Nicola Fazio
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology (IEO), Milan, Italy
| | - Fausto Sessa
- Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy
| | - Carlo Capella
- Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy
| | - Guido Rindi
- Section of Anatomic Pathology, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore/Unit of Anatomic Pathology, Rome, Italy
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS/Roma European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Rome, Italy
| | - Massimo Milione
- 1st Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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11
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Borbon LC, Tran CG, Sherman SK, Ear PH, Chandrasekharan C, Bellizzi AM, Dillon JS, O'Dorisio TM, Howe JR. Is There a Role for Surgical Resection of Grade 3 Neuroendocrine Neoplasms? Ann Surg Oncol 2022; 29:6936-6946. [PMID: 35802214 PMCID: PMC10399278 DOI: 10.1245/s10434-022-12100-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are aggressive tumors with poor survival outcomes for which medical management is generally recommended. This study sought to evaluate outcomes of surgically treated G3 GEP-NEN patients. METHODS A single-institutional prospective NEN database was reviewed. Patients with G3 GEP-NENs based on World Health Organization (WHO) 2019 definitions included well-differentiated neuroendocrine tumors (G3NET) and poorly differentiated neuroendocrine carcinomas (G3NEC). Clinicopathologic factors were compared between groups. Overall survival from G3 diagnosis was assessed by the Kaplan-Meier method. RESULTS Surgical resection was performed for 463 patients (211 G1, 208 G2, 44 G3). Most had metastatic disease at presentation (54% G1, 69% G2, 91% G3; p < 0.001). The G3 cohort included 39 G3NETs and 5 G3NECs, 22 of pancreatic and 22 of midgut origin. Median overall survival (mOS; in months) was 268.1 for G1NETs, 129.9 for G2NETs, 50.5 for G3NETs, and 28.5 for G3NECs (p < 0.001). Over the same period, 31 G3 patients (12 G3NETs, 19 G3NECs) were treated non-surgically, with mOS of 19.0 for G3NETs and 12.4 for G3NECs. CONCLUSIONS Surgical resection of G3 GEP-NENs remains controversial due to poor prognosis, and surgical series are rare. This large, single-institutional study found significantly lower mOS in patients with resected G3NENs than those with G1/G2 tumors, reflecting more aggressive tumor biology and a higher proportion with metastatic disease. The mOS for resected G3NETs and G3NECs exceeded historical non-surgical G3NEN series (mOS 11-19 months), suggesting surgery should be considered in carefully selected patients with G3NENs, especially those with well-differentiated tumors.
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Affiliation(s)
- Luis C Borbon
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Catherine G Tran
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Scott K Sherman
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Po Hien Ear
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | | | - Andrew M Bellizzi
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Joseph S Dillon
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Thomas M O'Dorisio
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - James R Howe
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
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12
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Que QY, Zhang LC, Bao JQ, Ling SB, Xu X. Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:397-408. [PMID: 35734618 PMCID: PMC9160682 DOI: 10.4240/wjgs.v14.i5.397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/19/2022] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
Over the last 40 years, the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have continued to increase. Compared to other epithelial neoplasms in the same organ, GEP-NENs exhibit indolent biological behavior, resulting in more chances to undergo surgery. However, the role of surgery in high-grade or advanced GEP-NENs is still controversial. Surgery is associated with survival improvement of well-differentiated high-grade GEP-NENs, whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers. Additionally, surgery also plays an important role in locally advanced and metastatic disease. For locally advanced GEP-NENs, isolated major vascular involvement is no longer an absolute contraindication. In the setting of metastatic GEP-NENs, radical intended surgery is recommended for patients with low-grade and resectable metastases. For unresectable metastatic disease, a variety of surgical approaches, including cytoreduction of liver metastasis, liver transplantation, and surgery after neoadjuvant treatment, show survival benefits. Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control, prolonged survival, and improved sensitivity toward systemic therapies. Although there is no established neoadjuvant or adjuvant strategy, increasing attention has been given to this emerging research area. Some studies have reported that neoadjuvant therapy effectively reduces tumor burden, improves the effectiveness of subsequent surgery, and decreases surgical complications.
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Affiliation(s)
- Qing-Yang Que
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, Zhejiang Province, China
- Zhejiang University Cancer Center, Hangzhou 310006, Zhejiang Province, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310006, Zhejiang Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
| | - Lin-Cheng Zhang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, Zhejiang Province, China
- Zhejiang University Cancer Center, Hangzhou 310006, Zhejiang Province, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310006, Zhejiang Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
| | - Jia-Qi Bao
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, Zhejiang Province, China
- Zhejiang University Cancer Center, Hangzhou 310006, Zhejiang Province, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310006, Zhejiang Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
| | - Sun-Bin Ling
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, Zhejiang Province, China
- Zhejiang University Cancer Center, Hangzhou 310006, Zhejiang Province, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310006, Zhejiang Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, Zhejiang Province, China
- Zhejiang University Cancer Center, Hangzhou 310006, Zhejiang Province, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310006, Zhejiang Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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13
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Feng LH, Su T, Lu Y, Ren S, Huang L, Qin X, Liao T. A model for predicting the overall survival of gastroenteropancreatic neuroendocrine neoplasms after surgery. Scand J Gastroenterol 2022; 57:581-588. [PMID: 35001789 DOI: 10.1080/00365521.2021.2024247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The increase in the incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NENs) and refined morphological imaging techniques have led to a rise in the number of patients undergoing surgery. However, there is still a paucity of objective, clinically reliable and personalized tools to evaluate patient prognosis. MATERIALS AND METHODS We identified patients from the Surveillance, Epidemiology, and End Results (SEER) database who underwent surgery for GEP-NEN from 1975 to 2018. The predictors associated with OS were investigated by Multivariate Cox proportional hazards (PHs) regression analysis in the primary cohort; a prognostic nomogram was then built based on the multivariate analysis results. The performance of the nomogram was assessed by Harrell's concordance index (C-index) and calibration curve and compared with the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS A total of 45,889 patients were enrolled in our study; 32,321 were included in the primary cohort, and 13,568 were included in the validation cohort. A nomogram incorporating Age, Differentiation, M staging, and AJCC staging was subsequently built based on the multivariate analysis. The C-index (0.833 for the primary cohort and 0.845 for the validation cohort) and calibration curves indicated good discriminative ability and calibration of the nomogram. Further analysis demonstrated that the nomogram had superior discriminatory ability than the AJCC staging system (C-index= 0.706). CONCLUSION The proposed nomogram showed excellent prediction with good calibration and discrimination, which can be used to make well-informed and individualized clinical decisions regarding the clinical management of GEP-NENs.
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Affiliation(s)
- Lu-Huai Feng
- Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Tingting Su
- Department of ECG Diagnostics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yang Lu
- Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Shuang Ren
- Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Lina Huang
- Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Xiuyu Qin
- Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Tianbao Liao
- Department of President's Office, Youjiang Medical University for Nationalities, Baise, China.,Philippine Christian University Center for International Education, Manila City, Philippine
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14
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Couvelard A, Cros J. An update on the development of concepts, diagnostic criteria, and challenging issues for neuroendocrine neoplasms across different digestive organs. Virchows Arch 2022; 480:1129-1148. [PMID: 35278097 DOI: 10.1007/s00428-022-03306-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/11/2022] [Accepted: 02/27/2022] [Indexed: 12/16/2022]
Abstract
Digestive neuroendocrine neoplasms (NENs) are a group of heterogeneous neoplasms found throughout the digestive tract, with different behaviour and genetic background. In the last few years, nomenclature and WHO/UICC classifications of digestive NENs have changed, and molecular classifications have emerged, especially in pancreatic locations. Increasing patho-molecular details are needed to diagnose the different categories of NEN, including the use of helpful immunohistochemical markers. In this review, we address these topics in three successive chapters. We first briefly review recent updates in classifications, discuss important grading and proliferating issues and advances in the molecular understanding of NEN. Then, we provide an update on diagnosis, including the most important differential diagnoses of NEN, with a focus on high-grade neoplasms and mixed tumours. Finally, we highlight a variety of currently used and next-generation predictive and prognostic biomarkers as well as biomarkers of tumour origin and describe some site specificities of gastrointestinal NEN. We specifically focus on biomarkers available to pathologists with the potential to change the way patients with NEN are diagnosed and treated.
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Affiliation(s)
- Anne Couvelard
- Department of Pathology of Bichat and Beaujon AP-HP Hospitals, ENETS Centre of Excellence, Université Paris Cité, 46 Rue Henri Huchard, 75018, Paris, France.
| | - Jérôme Cros
- Department of Pathology of Bichat and Beaujon AP-HP Hospitals, ENETS Centre of Excellence, Université Paris Cité, 46 Rue Henri Huchard, 75018, Paris, France
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15
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Keutgen XM. First Differentiate and Then Operate (Or Not) : Editorial on "Surgical Treatment of Patients with Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: An NCDB Analysis". Ann Surg Oncol 2022; 29:3371-3372. [PMID: 35230582 DOI: 10.1245/s10434-022-11490-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 11/18/2022]
Affiliation(s)
- Xavier M Keutgen
- Neuroendocrine Tumor Program, University of Chicago Medicine, Chicago, IL, USA.
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16
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Liao T, Su T, Huang L, Li B, Feng LH. Development and validation of a novel nomogram for predicting survival rate in pancreatic neuroendocrine neoplasms. Scand J Gastroenterol 2022; 57:85-90. [PMID: 34592854 DOI: 10.1080/00365521.2021.1984571] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Over the past decades, the incidence and prevalence of pancreatic neuroendocrine neoplasms (pNENs) have steadily increased. However, accurate prediction of the prognosis and treatment of this condition are currently challenging. This study aims to develop and validate a personalized nomogram to predict the survival of patients with pNENs. MATERIALS AND METHODS A total of 9739 patients with pNENs were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Subsequently, the patients were randomly assigned to a derivation cohort (n = 6874) and a validation cohort (n = 2865). The survival of patients was assessed using the Cox proportional hazards (PHs) regression analysis. Then, the nomogram that predicted 3-and 5-year survival rates were developed in the derivation cohort. Further, the predictive performance of the nomogram was evaluated through discrimination and calibration. RESULTS The Cox regression analysis revealed that age, differentiation, the extent of tumor, M staging, and surgery were independent prognostic predictors for pNENs. The nomogram showed superior discrimination capability than AJCC staging in both derived and validation cohorts (C-index: 0.874 versus 0.721 and 0.833 versus 0.721). The calibration curves showed that the practical and predicted survival rates effectively coincided, specifically for the 3-year survival rate. CONCLUSION Our nomogram is a valuable tool for the prediction of the survival rate for patients with pNENs; this may promote individualized prognostic evaluation and treatment.
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Affiliation(s)
- Tianbao Liao
- Department of President's Office, Youjiang Medical University for Nationalities, Baise, China.,Philippine Christian University Center for International Education, Manila City, Philippine
| | - Tingting Su
- Department of ECG Diagnostics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Lina Huang
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bixun Li
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu-Huai Feng
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
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17
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Neuroendocrine Carcinomas of the Digestive Tract: What Is New? Cancers (Basel) 2021; 13:cancers13153766. [PMID: 34359666 PMCID: PMC8345167 DOI: 10.3390/cancers13153766] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.
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18
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La Rosa S. Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms. Endocr Pathol 2021; 32:245-257. [PMID: 33786701 PMCID: PMC8116295 DOI: 10.1007/s12022-021-09676-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
The growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.
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Affiliation(s)
- Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.
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19
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Pellat A, Cottereau AS, Palmieri LJ, Soyer P, Marchese U, Brezault C, Coriat R. Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions. Cancers (Basel) 2021; 13:2448. [PMID: 34070035 PMCID: PMC8158108 DOI: 10.3390/cancers13102448] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 02/06/2023] Open
Abstract
Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.
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Affiliation(s)
- Anna Pellat
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Anne Ségolène Cottereau
- Department of Nuclear Medicine, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Lola-Jade Palmieri
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Philippe Soyer
- Department of Radiology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Ugo Marchese
- Department of Surgery, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Catherine Brezault
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Romain Coriat
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
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Abdel-Rahman O, Rahbari N, Reissfelder C, Oweira H. Outcomes of non-metastatic poorly differentiated gastroenteropancreatic neuroendocrine neoplasms treated with surgery: a real-world population-based study. Int J Colorectal Dis 2021; 36:941-947. [PMID: 33145607 DOI: 10.1007/s00384-020-03793-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2020] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To assess the outcomes of non-metastatic poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with radical surgery. METHODS Surveillance, Epidemiology, and End Results (SEER) database (1998-2015) was accessed, and patients with non-metastatic poorly differentiated/undifferentiated GEP-NENs were reviewed. Multivariable Cox regression analysis was used to evaluate factors affecting overall survival (OS) and cancer-specific survival (CSS). Patients treated with radical surgery were matched to those who did not undergo surgery through propensity score matching and Kaplan-Meier survival estimates were used to evaluate the impact of surgery in the post-propensity cohort. RESULTS A total of 1517 patients were included. Within multivariable Cox regression models and compared to no surgery, radical surgery was associated with improved OS (HR: 0.41; 95% CI: 0.34-0.50) and CSS (HR: 0.37; 95% CI: 0.29-0.47). A total of 233 patients who underwent no surgery were then matched to 233 patients who underwent radical surgery. Within the post-propensity cohort, radical surgery was associated with improved OS (P < 0.001). CONCLUSIONS Radical surgery is associated with improved survival outcomes in patients with non-metastatic poorly differentiated GEP-NENs. Further studies are required to better identify the best timing of radical surgery within the context of multimodal management.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T4G1Z2, Canada.
| | - Nuh Rahbari
- Department of Surgery, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Reissfelder
- Department of Surgery, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Hani Oweira
- Department of Surgery, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
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21
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Abdel-Rahman O, Fazio N. Outcomes of small-cell versus large-cell gastroenteropancreatic neuroendocrine carcinomas: A population-based study. J Neuroendocrinol 2021; 33:e12971. [PMID: 33870570 DOI: 10.1111/jne.12971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 11/29/2022]
Abstract
The recent World Health Organization classification for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) classified poorly differentiated GEP-NENs into small cell and large cell categories. The present study aimed to assess the differences in outcomes between patients with both histological categories. The Surveillance, Epidemiology and End Results (SEER) database (1975-2016) was accessed and patients with small cell and large cell GEP-neuroendocrine carcinomas (NECs) were extracted. Differences in survival outcomes were explored through Kaplan-Meier survival estimates and multivariable Cox regression models. In total, 2204 patients with GEP-NEC were identified in the survival cohort, including 1698 patients with small cell NEC (77%) and 506 patients with large cell NEC (23%). Using Kaplan-Meier analysis/log-rank testing, large cell GEP-NEC was associated with better overall survival compared to small cell NEC (P < 0.01). Using multivariable Cox regression analysis, large cell GEP-NEC was associated with better overall survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.77; 95% confidence interval = 0.68-0.86) and cancer-specific survival (large cell GEP-NEC versus small cell GEP-NEC, hazard ratio = 0.79; 95% 95% confidence interval = 0.69-0.91). Patients with small cell GEP-NEC have worse survival outcomes compared to those with large cell GEP-NEC. Further efforts are needed to identify biological differences and treatment sensitivities between both histological categories.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO); IRCCS, Milan, Italy
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22
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Wang WQ, Zhang WH, Gao HL, Huang D, Xu HX, Li S, Li TJ, Xu SS, Li H, Long J, Ye LY, Wu CT, Han X, Wang XH, Liu L, Yu XJ. A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors. J Gastroenterol 2021; 56:395-405. [PMID: 33742253 DOI: 10.1007/s00535-021-01777-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/08/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. METHODS We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. RESULTS PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76-39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors. CONCLUSION We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.
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Affiliation(s)
- Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Dan Huang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuai-Shuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Long
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Long-Yun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Han
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiao-Hong Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Brazg Ferro L, Wolf I, Peleg Hasson S, Golomb I, Osher E, Berlin A, Gutfeld O, Ospovat I, Soyfer V. Extrapulmonary Small Cell Cancer: A New Insight into a Rare Disease. Oncology 2021; 99:373-379. [PMID: 33774637 DOI: 10.1159/000514520] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/13/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Extrapulmonary small-cell cancer (EPSCC) is a relatively rare malignancy. The management of EPSCC is usually extrapolated from small-cell lung cancer (SCLC). In spite of the morphological similarity of the 2 malignancies, there are many differences in clinical features, prognosis, and recommendations of treatment of these disorders. The data on the correlation of clinical-pathological characteristics of EPSCC and treatment results is scarce. MATERIALS AND METHODS This retrospective analysis of 41 consecutively treated patients diagnosed with EPSCC in 2015-2018 was performed in a tertiary medical center. The correlation between the clinical and pathological characteristics and the treatment outcome (response rate, disease-free interval, and overall medial survival) was done using the standard statistics, Kaplan-Meier method, and multivariate analyses. The stratification was done on the stage of the disease, Ki-67 proliferative index, the location of the tumor, and smoking. RESULTS Forty-one patients were included with a median age of 66.3 years. The most common primary site was the gastrointestinal tract (28, 68.3%) including the pancreas. The most common distant metastasis site was the liver (23, 56.1%). Only 2 patients (4.9%) had brain metastases. Unlike in SCLC, most patients did not have any history of smoking (23, 56.1%). Nineteen patients with metastatic disease received systemic treatment, mostly cisplatin-based chemotherapy, with a response rate of 57.9%. The results of treatment were significantly better in patients with disseminated EPSCC with Ki-67 <55%, while its role in limited disease was nonsignificant. DISCUSSION The results of our study show the unique entity of EPSCC. The rarity of brain metastases proves that prophylactic brain irradiation should not be recommended in practice. The provocative idea of prophylactic liver irradiation in limited-stage EPSCC of gastrointestinal origin can be evaluated in future studies. The predictive role of Ki-67 is important in metastatic EPSCC. There is probably no role of smoking in developing EPSCC.
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Affiliation(s)
- Leora Brazg Ferro
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ido Wolf
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shira Peleg Hasson
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Inbal Golomb
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ester Osher
- Institute of Endocrinology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alla Berlin
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Orit Gutfeld
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Inna Ospovat
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Viacheslav Soyfer
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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24
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Albertelli M, Grillo F, Lo Calzo F, Puliani G, Rainone C, Colao AAL, Faggiano A, NIKE group AltieriBarbaraBarreaLuigiBottiglieriFilomenaCampioneSeveroDe CiccoFedericaDi MolfettaSergioDicitoreAlessandraDolciCarlottaFeolaTizianaFanciulliGiuseppeFeroneDiegoFerraྟrancescoGalloMarcoGiannettaElisaGrossrubatscherErikaGuadagnoEliaGuarnottaValentinaIsidoriAndrea M.LaniaAndreaLenziAndreaMalandrinoPasqualeMessinaErikaModicaRobertaMuscogiuriGiovannaPesLucaPizzaGenoveffaPofiRiccardoRazzorePaolaRizzaLauraRubinoManilaRuggieriRosa MariaSbardellaEmiliaSestiFranzVenneriMary AnnaVitaleGiovanniZatelliMaria Chiara. Pathology Reporting in Neuroendocrine Neoplasms of the Digestive System: Everything You Always Wanted to Know but Were Too Afraid to Ask. Front Endocrinol (Lausanne) 2021; 12:680305. [PMID: 33967966 PMCID: PMC8104083 DOI: 10.3389/fendo.2021.680305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals.
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Affiliation(s)
- Manuela Albertelli
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy
- *Correspondence: Federica Grillo,
| | - Fabio Lo Calzo
- Department of Clinical Medicine and Surgery, Division of Endocrinology, Federico II University, Naples, Italy
- Internal Medicine Unit, Frangipane Hospital, Ariano Irpino, Italy
| | - Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy
- Oncological Endocrinology Unit, Regina Elena National Cancer Institute, Roma, Italy
| | - Carmen Rainone
- Department of Clinical Medicine and Surgery, Division of Endocrinology, Federico II University, Naples, Italy
| | - Annamaria Anita Livia Colao
- Department of Clinical Medicine and Surgery, Division of Endocrinology, Federico II University, Naples, Italy
- UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Roma, Italy
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25
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Arakelyan J, Zohrabyan D, Philip PA. Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): Opportunities for personalized therapies. Cancer 2020; 127:345-353. [PMID: 33270905 DOI: 10.1002/cncr.33354] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine neoplasms (panNENs) are the second most common epithelial tumors of the pancreas. Despite improvements in prognostic grading and staging systems, it remains a challenge to predict the clinical behavior of panNENs and the response to specific therapies given the high degree of heterogeneity of these tumors. Most panNENs are nonfunctional and present as advanced disease. However, systemic therapies provide modest benefits. Therefore, there is a need for predictive biomarkers to develop personalized treatment and to advance new drug development. The somatostatin receptors remain the only clinically established prognostic and predictive biomarkers in panNENs. Oncogenic drivers are at a very low frequency. Commonly mutated genes in panNENs include MEN1, chromatin remodeling genes (DAXX and ATRX), and mammalian target of rapamycin pathway genes. In contrast, poorly differentiated neuroendocrine carcinomas (panNECs), which carry a very poor prognosis, have distinctive mutations in certain genes (eg, RB1 and p53). Ongoing research to integrate epigenomics will provide tremendous opportunities to improve current understanding of the clinical heterogeneity of pancreatic neuroendocrine tumors and provide invaluable insight into the biology of these tumors, new drug development, and establishing personalized therapies.
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Affiliation(s)
- Jemma Arakelyan
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Adult Solid Tumor Chemotherapy Clinic, Professor Yeolan Hematology Center, Yerevan, Armenia
| | - Davit Zohrabyan
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Adult Solid Tumor Chemotherapy Clinic, Professor Yeolan Hematology Center, Yerevan, Armenia
| | - Philip A Philip
- Department of Oncology, Yerevan State Medical University, Yerevan, Armenia.,Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan.,Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan.,Barbara Ann Karmanos Cancer Center, Detroit, Michigan
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26
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Cavalcanti E, Galleggiante V, Coletta S, Stasi E, Chieppa M, Armentano R, Serino G. Altered miRNAs Expression Correlates With Gastroenteropancreatic Neuroendocrine Tumors Grades. Front Oncol 2020; 10:1187. [PMID: 32766159 PMCID: PMC7379872 DOI: 10.3389/fonc.2020.01187] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors that present a wide spectrum of different clinical and biological characteristics. Currently, tumor grading, determined by Ki-67 staining and mitotic counts, represents the most reliable predictor of prognosis. This time-consuming approach fails to reach high reproducibility standards thus requiring novel approaches to support histological evaluation and prognosis. In this study, starting from a microarray analysis of paraffin-embedded tissue specimens, we defined the miRNAs signature for poorly differentiated NETs (G3) compared to well-differentiated NETs (G1 and G2) consisting of 56 deregulated miRNAs. We identified 8 miRNAs that were expressed in all GEP-NETs grades but at different level. Among these miRNAs, miR-96-5p expression level was progressively higher from grade 1 to grade 3; inversely, its target FoxO1 expression decreased from grade 1 to grade 3. Our results reveal that the miRNAs expression profile of GEP-NET is correlated with the tumor grade, showing a potential advantage of miRNA quantification that could aid clinicians in the classification of common GEP-NETs subtypes. These findings could reliably support the histological evaluation of GEP-NETs paving the way toward personalized treatment approaches.
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Affiliation(s)
- Elisabetta Cavalcanti
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Vanessa Galleggiante
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Sergio Coletta
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Elisa Stasi
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Marcello Chieppa
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Raffaele Armentano
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Grazia Serino
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
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27
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Pellat A, Coriat R. Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review. J Clin Med 2020; 9:E1677. [PMID: 32492939 PMCID: PMC7357105 DOI: 10.3390/jcm9061677] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G-3). These lesions show a number of mitosis, or a Ki-67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G-3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G-3 represents about one third of NEN G-3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G-3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G-2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G-3.
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Affiliation(s)
- Anna Pellat
- Department of Gastroenterology and digestive oncology, Cochin Teaching Hospital, AP-HP, 75014 Paris, France;
- Faculté de Médecine, Université de Paris, 75006 Paris, France
- Oncology Unit, Hôpital Saint Antoine, AP-HP, Sorbonne Université, 75012 Paris, France
| | - Romain Coriat
- Department of Gastroenterology and digestive oncology, Cochin Teaching Hospital, AP-HP, 75014 Paris, France;
- Faculté de Médecine, Université de Paris, 75006 Paris, France
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Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer 2020; 122:1309-1314. [PMID: 32152503 PMCID: PMC7188798 DOI: 10.1038/s41416-020-0775-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/18/2020] [Indexed: 12/17/2022] Open
Abstract
Background Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. Methods Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. Results Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. Conclusions Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. Clinical trial registration number NCT02939651 (10/20/2016).
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29
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Nielsen K, Binderup T, Langer SW, Kjaer A, Knigge P, Grøndahl V, Melchior L, Federspiel B, Knigge U. P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms. BMC Cancer 2020; 20:27. [PMID: 31924180 PMCID: PMC6953213 DOI: 10.1186/s12885-019-6498-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Background High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Method Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5–30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). Results In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. Conclusion Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.
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Affiliation(s)
- Kirstine Nielsen
- Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Tina Binderup
- ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. .,Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
| | - Seppo W Langer
- ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Oncology,, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Andreas Kjaer
- ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | - Pauline Knigge
- Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | - Veronica Grøndahl
- Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Linea Melchior
- ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Federspiel
- ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Ulrich Knigge
- Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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Shi H, Chen L, Zhang Q, Lin Y, Jiang C, Yao H, Hou X, Chen M, Lin R, Chen J. Concordance Between the Ki-67 Index Cutoff Value of 55% and Differentiation in Neuroendocrine Tumor and Neuroendocrine Carcinoma in Grade 3 Pancreatic Neuroendocrine Neoplasms. Pancreas 2020; 49:1378-1382. [PMID: 33122528 DOI: 10.1097/mpa.0000000000001693] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE In 2017 and 2019, the World Health Organization defined grade 3 neuroendocrine tumors (G3 NETs) and neuroendocrine carcinoma (G3 NEC) in the pancreas. The validity of this classification remains to be verified. METHODS Clinical data were collected and analyzed for 39 G3 pancreatic neuroendocrine neoplasms (PanNENs) patients between 2009 and 2018. RESULTS The tumor-node-metastasis stage (P = 0.0260), differentiation (P = 0.0115), and Ki-67 index (P = 0.0371) are prognostic factors for G3 PanNENs by Kaplan-Meier survival analysis. Among 39 patients, 18 had a Ki-67 index of less than 55% and well-differentiated morphology (G3 NET) and 16 had a Ki-67 index of 55% or greater and poorly differentiated morphology (G3 NEC). Grade 3 neuroendocrine tumor had a significant better prognosis than G3 NEC (median overall survival time, 25 months [95% confidence interval, 10.854-39.146 months] vs 12 months [95% confidence interval, 6.316-17.684 months], P = 0.0164). Based on Cox regression analyses, tumor-node-metastasis stage (P = 0.016) was identified as the independent prognostic factor for G3 PanNENs. CONCLUSIONS The upper Ki-67 index cutoff of 55% might be the best cutoff value to define G3 NETs and G3 NECs for G3 PanNENs. The World Health Organization 2017 and 2019 classification system for G3 PanNENs can identify high-risk patients with G3 PanNENs.
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Affiliation(s)
- Huiying Shi
- From the Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Luohai Chen
- Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou
| | - Qin Zhang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Yuan Lin
- Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chen Jiang
- From the Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Hailing Yao
- From the Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Xiaohua Hou
- From the Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Minhu Chen
- Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou
| | - Rong Lin
- From the Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Jie Chen
- Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou
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31
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Busico A, Maisonneuve P, Prinzi N, Pusceddu S, Centonze G, Garzone G, Pellegrinelli A, Giacomelli L, Mangogna A, Paolino C, Belfiore A, Kankava K, Perrone F, Tamborini E, Pruneri G, Fazio N, Milione M. Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin. Neuroendocrinology 2020; 110:616-629. [PMID: 31557757 DOI: 10.1159/000503722] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. METHODS In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). RESULTS Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2-89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9-169, p = 0.0007). CONCLUSIONS These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.
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Affiliation(s)
- Adele Busico
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Garzone
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Pellegrinelli
- Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Chiari, Brescia, Italy
| | - Luca Giacomelli
- Department of Surgical Sciences and Integrated Diagnostics, School of Medicine, University of Genoa, Genoa, Italy
- Polistudium SRL, Milan, Italy
| | - Alessandro Mangogna
- Pathology Unit, Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Ospedale di Cattinara, Trieste, Italy
| | - Cinzia Paolino
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
- Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Antonino Belfiore
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Ketevani Kankava
- Teaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia
| | - Federica Perrone
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Elena Tamborini
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giancarlo Pruneri
- School of Medicine, University of Milan, Milan, Italy
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,
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32
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Nikiforchin A, Peng R, Sittig M, Kotiah S. A Rare Case of Metastatic Heterogeneous Poorly Differentiated Neuroendocrine Carcinoma of Ileum: A Case Report and Literature Review. J Med Cases 2020; 11:6-11. [PMID: 34434328 PMCID: PMC8383677 DOI: 10.14740/jmc3401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 12/20/2019] [Indexed: 11/11/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) represent a diverse group of tumors arising from neuroendocrine cells. Current World Health Organization (WHO) classification is based on tumor differentiation and grade defined by mitotic rate and/or Ki-67 index to determine prognosis and treatment options. However, some NENs do not meet WHO pathology criteria due to morphologic heterogeneity and this leads to management challenges. WHO defines poorly differentiated NENs of the gastrointestinal tract as having morphologically large or small cell features with marked elevation of Ki-67. We present a unique clinical case that does not fit either growth pattern and also has heterogeneity with a well-differentiated component. This case report and literature review highlights the current limitations of the WHO classification of small bowel NENs and the subsequent challenges in management decisions for the patients.
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Affiliation(s)
- Andrei Nikiforchin
- Department of Surgical Oncology, Mercy Medical Center, 227 Saint Paul Place, Baltimore, MD, USA
| | - Ruth Peng
- Department of Pathology, Mercy Medical Center, 345 Saint Paul Place, Baltimore, MD, USA
| | - Michelle Sittig
- Department of Surgical Oncology, Mercy Medical Center, 227 Saint Paul Place, Baltimore, MD, USA
| | - Sandy Kotiah
- Department of Medical Oncology and Hematology, Mercy Medical Center, 227 Saint Paul Place, Baltimore, MD, USA
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33
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Scoville SD, Cloyd JM, Pawlik TM. New and emerging systemic therapy options for well-differentiated gastroenteropancreatic neuroendocrine tumors. Expert Opin Pharmacother 2019; 21:183-191. [PMID: 31760823 DOI: 10.1080/14656566.2019.1694003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with a wide range of clinical behavior. Multiple treatment modalities exist, including novel and emerging systemic options, and an understanding of the advantages and disadvantages of each is imperative for optimizing the outcomes of patients with GEP-NETs.Areas covered: While surgical resection remains the preferred treatment for localized well-differentiated GEP-NETs, treatment of unresectable disease depends on its extent, location, and distribution as well as underlying aspects of tumor biology. Isolated hepatic metastases can be successfully treated with liver-directed therapies such as hepatic arterial based therapies or ablation. Diffuse metastatic disease often requires systemic treatments such as molecular-targeted therapeutics, peptide receptor radionuclide therapy (PRRT), or traditional chemotherapy. Somatostatin analogs are often the primary treatment option capable of simultaneously inhibiting hormone production and slowing tumor growth.Expert opinion: Recent advances in systemic treatment options for advanced well-differentiated GEP-NETs have emerged due to an improved understanding of the molecular mechanisms responsible for tumor development and progression. Future research is needed to determine the optimal indications for and sequencing of these novel therapies.
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Affiliation(s)
- Steven D Scoville
- Department of Surgery, Division of Surgical Oncology at The Ohio State University, James Cancer Center, Columbus, OH, USA
| | - Jordan M Cloyd
- Department of Surgery, Division of Surgical Oncology at The Ohio State University, James Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology at The Ohio State University, James Cancer Center, Columbus, OH, USA.,Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research The Ohio State University, Wexner Medical Center, Columbus, USA
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34
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Saller J, Seydafkan S, Shahid M, Gadara M, Cives M, Eschrich SA, Boulware D, Strosberg JR, Aejaz N, Coppola D. EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors. Cancer Genomics Proteomics 2019; 16:309-318. [PMID: 31467225 PMCID: PMC6727072 DOI: 10.21873/cgp.20136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/15/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIM Low-grade pancreatic neuroendocrine tumors (LG-PNETs) behave unpredictably. The aim of the study was to identify biomarkers that predict PNET metastasis to improve treatment selection. PATIENTS AND METHODS Five patients with primary non-metastatic LG-PNETs, six with primary LG-PNETs with synchronous or metachronous metastases (M-PNETs), and six metastatic to liver LG-PNETs (ML-PNETs) from the group of six M-PNET patients were selected. RNA data were normalized using iterative rank-order normalization. Student's t-test identified differentially-expressed genes in LG-PNETs versus M-PNETs. A 2-fold difference in expression was considered to be significant. Results were validated with an independent dataset of LG-PNETs and metastatic LG-PNETs. RESULTS Overall, 195 genes had a >2-fold change (in either direction). A total of 29 genes were differentially overexpressed in M-PNETs. Erythrocyte membrane protein band 4.1-like 5 (EPB41L5) had a 2.07-fold change increase in M-PNETs and the smallest p-value. EPB41L5 was not statistically different between M-PNETs and ML-PNETs. EPB41L5 differential expression between primary and metastatic LG-PNETs was confirmed by immunohistochemistry. CONCLUSION These results support further investigation into whether EPB41L5 is a biomarker of PNETs with high risk for metastases.
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Affiliation(s)
- James Saller
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Shabnam Seydafkan
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Mohammad Shahid
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Manoj Gadara
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Mauro Cives
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Steven A Eschrich
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - David Boulware
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Jonathan R Strosberg
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Nasir Aejaz
- Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, IN, U.S.A
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.
- Department of Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
- Department of Oncological Sciences, University of South Florida, Tampa, FL, U.S.A
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Kitagawa Y, Osumi H, Shinozaki E, Ota Y, Nakayama I, Suzuki T, Wakatsuki T, Ichimura T, Ogura M, Ooki A, Takahari D, Suenaga M, Chin K, Yamaguchi K. Safety and efficacy of amrubicin monotherapy in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract: a single cancer center retrospective study. Cancer Manag Res 2019; 11:5757-5764. [PMID: 31417315 PMCID: PMC6599893 DOI: 10.2147/cmar.s201048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 05/29/2019] [Indexed: 01/25/2023] Open
Abstract
Purpose Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC. Patients and methods Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests. Results In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7–7.4) and 13.8 months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR. Conclusion AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.
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Affiliation(s)
- Yusuke Kitagawa
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yumiko Ota
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Suzuki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Ichimura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akira Ooki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mitsukuni Suenaga
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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36
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Milione M, Miceli R, Barretta F, Pellegrinelli A, Spaggiari P, Tagliabue G, Centonze G, Paolino C, Mangogna A, Kankava K, Pusceddu S, Giacomelli L, Corti A, Cotsoglou C, Mazzaferro V, Sozzi G, de Braud F, Pruneri G, Anichini A. Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2019; 5:217-226. [PMID: 31136102 PMCID: PMC6817832 DOI: 10.1002/cjp2.135] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 12/13/2022]
Abstract
Microenvironment‐related immune and inflammatory markers, when combined with established Ki‐67 and morphology parameters, can improve prognostic prediction in gastro‐entero‐pancreatic neuroendocrine neoplasms (GEP‐NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP‐NENs. For this purpose, formalin‐fixed paraffin‐embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN‐, and fibroblast‐related markers. A total of 314 patients were used to generate overall survival (OS) and disease‐free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5‐year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP‐NENs showed phenotypic divergence with immune‐inflammatory markers. HLA, CD3, CD8, and PD‐1/PD‐L1 IHC expression separated G3 into two sub‐categories with high versus low adaptive immunity‐related features. MoTIFs PI for OS based on COX‐2Tumor(T) > 4, PD‐1Stromal(S) > 0, CD8S < 1, and HLA‐IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12–2.96; p < 0.0001). MoTIFs PI for DFS was based on COX‐2T > 4, PD‐1S > 4, HLA‐IS < 1, HLA‐IT < 2, HLA‐DRS < 6 (HR 1.77; 95% CI, 1.58–1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30–10.15; p < 0.001) and Ki‐67 (HR 11.32; 95% CI, 5.28–24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67–18.47; PI = 5: HR 2.87; 95% CI, 1.21–6.81; p < 0.001) and MoTIFs PI for DFS in well‐differentiated GEP‐NENs (HR 6.21; 95% CI, 2.52–13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune‐inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki‐67 improve 5‐year DFS prediction in GEP‐NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints.
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Affiliation(s)
- Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Rosalba Miceli
- Medical Statistics, Biometry and Bioinformatics, Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Barretta
- Medical Statistics, Biometry and Bioinformatics, Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Pellegrinelli
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.,Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Chiari, Brescia, Italy
| | - Paola Spaggiari
- Department of Pathology, Cancer Center Humanitas Research Hospital, Milan, Italy
| | - Giovanna Tagliabue
- Cancer Registry Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Cinzia Paolino
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.,Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Unit of Pathology, Clinical Department of Medical, Surgical and Health Science, University of Trieste, Ospedale di Cattinara, Trieste, Italy
| | - Ketevani Kankava
- Teaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Giacomelli
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.,Polistudium SRL, Milan, Italy
| | | | - Christian Cotsoglou
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Vincenzo Mazzaferro
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Gabriella Sozzi
- Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.,School of Medicine, University of Milan, Milan, Italy
| | - Giancarlo Pruneri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.,School of Medicine, University of Milan, Milan, Italy
| | - Andrea Anichini
- Department of Research, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
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Gaudenzi G, Vitale G. Transplantable zebrafish models of neuroendocrine tumors. ANNALES D'ENDOCRINOLOGIE 2019; 80:149-152. [DOI: 10.1016/j.ando.2019.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Hamano Y, Moriwaki T, To K, Watahiki T, Yamada T, Sakashita S, Hyodo I. A Neuroendocrine Tumor of Unknown Primary Origin that Responded to Treatment Based on Tumor Grade Progression. Intern Med 2019; 58:1087-1091. [PMID: 30568142 PMCID: PMC6522411 DOI: 10.2169/internalmedicine.1809-18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The standard chemotherapies for neuroendocrine tumors (NETs) are somatostatin analog (SSA) and targeted-agents for NET G1/G2 and platinum-based chemotherapy for neuroendocrine carcinoma (NEC), classified according to the WHO criteria of 2010. We report a case of NET, in which tumors were successfully treated with platinum-containing chemotherapy after remarkable progression with SSA. A 46-year-old man with multiple lymph nodes and liver metastases of unknown primary origin was diagnosed with NET G2 based on the examination of a biopsy specimen. His tumors were stable with SSA for a year, but rapidly became enlarged. A second biopsy revealed NEC. He received cisplatin plus etoposide, and his tumors showed a marked reduction in size.
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Affiliation(s)
- Yukako Hamano
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
| | - Keii To
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
| | - Takahisa Watahiki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
| | - Takeshi Yamada
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
| | - Shingo Sakashita
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Japan
| | - Ichinosuke Hyodo
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Japan
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Yanagihara K, Kubo T, Iino Y, Mihara K, Morimoto C, Seyama T, Kuwata T, Ochiai A, Yokozaki H. Development and characterization of a cancer cachexia model employing a rare human duodenal neuroendocrine carcinoma-originating cell line. Oncotarget 2019; 10:2435-2450. [PMID: 31069007 PMCID: PMC6497432 DOI: 10.18632/oncotarget.26764] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/15/2019] [Indexed: 12/19/2022] Open
Abstract
Cancer cachexia interferes with therapy and worsens patients' quality of life. Therefore, for a better understanding of cachexia, we aimed to establish a reliable cell line to develop a cachexia model. We recently established and characterized the TCC-NECT-2 cell line, derived from a Japanese patient with poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC). Subcutaneous xenograft of TCC-NECT-2 cells in mice resulted in tumor formation, angiogenesis, and 20% incidence of body weight (BW)-loss. Subsequently, we isolated a potent cachexia-inducing subline using stepwise selection and designated as AkuNEC. Orthotopic and s.c. implantation of AkuNEC cells into mice led to diminished BW, anorexia, skeletal muscle atrophy, adipose tissue loss, and decreased locomotor activity at 100% incidence. Additionally, orthotopic implantation of AkuNEC cells resulted in metastasis and angiogenesis. Serum IL-8 overproduction was observed, and levels were positively correlated with BW-loss and reduced adipose tissue and muscle volumes in tumor-bearing mice. However, shRNA knockdown of the IL-8 gene did not suppress tumor growth and cachexia in the AkuNEC model, indicating that IL-8 is not directly involved in cachexia induction. In conclusion, AkuNEC cells may serve as a useful model to study cachexia and D-NEC.
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Affiliation(s)
- Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takanori Kubo
- Department of Life Sciences, Yasuda Women’s University Faculty of Pharmacy, Hiroshima, Japan
| | - Yuki Iino
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Keichiro Mihara
- Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Chie Morimoto
- Department of Living Science Nutrition Course, Matsuyama Shinonome Junior College, Matsuyama, Japan
| | - Toshio Seyama
- Department of Life Sciences, Yasuda Women’s University Faculty of Pharmacy, Hiroshima, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan
| | - Atsushi Ochiai
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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The Significant Influence of the Neuroendocrine Component on the Survival of Patients with Gastric Carcinoma Characterized by Coexisting Exocrine and Neuroendocrine Components. JOURNAL OF ONCOLOGY 2019; 2019:3671268. [PMID: 30992704 PMCID: PMC6434268 DOI: 10.1155/2019/3671268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 01/30/2019] [Accepted: 02/18/2019] [Indexed: 12/14/2022]
Abstract
Background Gastric adenocarcinoma patients with a neuroendocrine (NE) component are frequently observed in routine practice. Several previous studies have investigated the influence of a NE component on the survival of these patients; however, the results were inconsistent. Methods We retrospectively investigated a consecutive series of 95 gastric adenocarcinoma patients with a NE component and 190 gastric adenocarcinoma patients without a NE component. We adopted 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% as the cut-off proportions of the NE component, respectively, and analyzed the patients' overall survival according to the proportion of the NE component. Results The 1-, 3-, and 5-year actual survival rates of the patients with a NE component were 90.1%, 72.3%, and 67.2%, respectively, and for those without a NE component 94.2%, 79.3%, and 75.7%, respectively. The multivariate analysis showed that the patients with NE components >70% (HR: 2.156; 95% CI: 1.011, 4.597; p=0.047) and >90% (HR: 2.476; 95% CI: 1.088, 5.634; p=0.031) had significantly worse survival than those without a NE component. Only the diameter of tumors (>4.64 cm) (HR: 2.585; 95% CI: 1.112, 6.006; p=0.027) and pN3 (HR: 2.953; 95% CI: 1.051, 8.293; p=0.040) were independently associated with worse overall survival for gastric adenocarcinoma patients with a NE component (all p<0.05). Conclusion Gastric adenocarcinoma patients with a NE component >70% and >90% have significantly worse survival than those without a NE component. Only the diameter of tumors and the number of metastatic lymph nodes are independent prognostic factors for gastric adenocarcinoma patients with a NE component.
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Cloyd JM, Konda B, Shah MH, Pawlik TM. The emerging role of targeted therapies for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors. Expert Rev Clin Pharmacol 2019; 12:101-108. [PMID: 30582383 DOI: 10.1080/17512433.2019.1561273] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are unique and complex neoplasms, exhibiting a wide spectrum of diverse clinical behaviors. The contemporary management of well-differentiated GEP-NETs is marked by the availability of a wide range of targeted therapies. Areas Covered: For patients with localized or oligometastatic disease, surgical resection remains the preferred approach and is associated with excellent long-term outcomes. For patients with unresectable but isolated liver metastases, multiple liver-directed therapies, including hepatic arterial based therapies and ablative techniques, exist. For patients with metastatic and progressive disease, a number of systemic therapies exist: molecular targeted agents, peptide receptor radionuclide therapy (PRRT), and systemic chemotherapy. Furthermore, somatostatin analogs (SSA) are an important component of therapy, both effectively controlling symptoms of hormonal overproduction and contributing to slowing tumor progression. Expert Opinion: In the near future, advances in our understanding of tumor biology, genetics, immunology, nanotechnology, and radiation pharmacology should only continue to expand the availability of targeted therapies, improving the outcomes of patients with GEP-NETs. We herein review the management of advanced well-differentiated GEP-NETS with a particular emphasis on the role of targeted therapies.
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Affiliation(s)
- Jordan M Cloyd
- a Surgery Division of Surgical Oncology , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Bhavana Konda
- b Internal Medicine , Division of Medical Oncology , Columbus , OH , USA
| | - Manisha H Shah
- c Internal Medicine , Division of Medical Oncology , Columbus , OH , USA
| | - Timothy M Pawlik
- d Department of Surgery The Urban Meyer III and Shelley Meyer Chair for Cancer Research Professor of Surgery, Oncology, and Health Services Management and Policy , The Ohio State University, Wexner Medical Center , Columbus , OH , USA
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Frizziero M, Spada F, Lamarca A, Kordatou Z, Barriuso J, Nuttall C, McNamara MG, Hubner RA, Mansoor W, Manoharan P, Fazio N, Valle JW. Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas. Neuroendocrinology 2019; 109:100-112. [PMID: 30703770 DOI: 10.1159/000497336] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 01/30/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. OBJECTIVES To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. METHODS Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. RESULTS We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3-4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). CONCLUSIONS CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.
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Affiliation(s)
- Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Francesca Spada
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Zoe Kordatou
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Christina Nuttall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Wasat Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Nicola Fazio
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom,
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom,
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Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances. Adv Anat Pathol 2019; 26:13-30. [PMID: 29912000 DOI: 10.1097/pap.0000000000000201] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.
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Kasajima A, Konukiewitz B, Oka N, Suzuki H, Sakurada A, Okada Y, Kameya T, Ishikawa Y, Sasano H, Weichert W, Klöppel G. Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20. Neuroendocrinology 2019; 108:109-120. [PMID: 30485860 DOI: 10.1159/000495806] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 11/25/2018] [Indexed: 11/19/2022]
Abstract
The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24-36) were significantly lower than those of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.
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Affiliation(s)
- Atsuko Kasajima
- Department of Pathology, Technical University Munich, Munich, Germany,
- German Cancer Consortium (DKTK), Heidelberg, Germany,
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan,
| | - Björn Konukiewitz
- Department of Pathology, Technical University Munich, Munich, Germany
| | - Naomi Oka
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
- National Hospital Organization, Sendai Medical Center, Sendai, Japan
| | - Hiroyoshi Suzuki
- National Hospital Organization, Sendai Medical Center, Sendai, Japan
| | - Akira Sakurada
- Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Kameya
- Division of Pathology, Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
| | - Yuichi Ishikawa
- Department of Pathology, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Wilko Weichert
- Department of Pathology, Technical University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Günter Klöppel
- Department of Pathology, Technical University Munich, Munich, Germany
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Yanagihara K, Kubo T, Mihara K, Kuwata T, Ochiai A, Seyama T, Yokozaki H. Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma. Oncotarget 2018; 9:36503-36514. [PMID: 30559933 PMCID: PMC6284856 DOI: 10.18632/oncotarget.26367] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022] Open
Abstract
Poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC) is a rare cancer with poor prognosis. However, a D-NEC cell line has not yet been established to study the disease. We established a cell line, TCC-NECT-2, from the ascites tumor of a 59-year-old male Japanese patient with D-NEC. TCC-NECT-2 was positive for neuroendocrine markers, chromogranin A (CGA), cluster of differentiation 56 (CD56/NCAM), synaptophysin (SYN/p38), and neuron specific enolase (NSE). Cells exhibited retinoblastoma (RB) protein loss. Orthotopic implantation of TCC-NECT-2 cells into nu/nu mice resulted in tumor formation (incidence = 83.3%) with neuroendocrine characteristics, metastasis, and weight loss. BRAFV600E and TP53 mutations and C-MYC gene amplification were also observed in TCC-NECT-2. BRAFV600E-expressing TCC-NECT-2 cells were sensitive to BRAF inhibitor vemurafenib, and especially dabrafenib, in vitro, and were strongly inhibited in a dose-dependent manner. Dabrafenib treatment (30 mg/kg) in a xenograft model for 14 days significantly suppressed tumor growth (percent tumor growth inhibition, TGI% = 48.04). An enhanced therapeutic effect (TGI% = 95.81) was observed on combined treatment of dabrafenib and irinotecan (40 mg/kg). Therefore, TCC-NECT-2, the first reported cell line derived from D-NEC, might serve as a useful model to study the basic biology of D-NEC and translational applications for treatment.
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Affiliation(s)
- Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan.,Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takanori Kubo
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Keichiro Mihara
- Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan
| | - Atsushi Ochiai
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Toshio Seyama
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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Cavalcanti E, Ignazzi A, De Michele F, Caruso ML. PDGFRα expression as a novel therapeutic marker in well-differentiated neuroendocrine tumors. Cancer Biol Ther 2018; 20:423-430. [PMID: 30346879 PMCID: PMC6422502 DOI: 10.1080/15384047.2018.1529114] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/09/2018] [Accepted: 09/22/2018] [Indexed: 01/14/2023] Open
Abstract
AIMS To evaluate the biological significance of dense vascular networks associated with low-grade NENs, we assessed the impact of PDGFRα tissue expression in 77 GEP/NEN patients, associating PDGFRα expression with the morphological characterization in low-grade tumors. METHODS AND RESULTS Paraffin-embedded specimens of 77 GEP- NEN tissues, collected from January 2006 to March 2018, were evaluated for PDGFRα tissue expression and correlations with clinicopathological characteristics. PDGFRα tissue expression was significantly correlated with grade and the NEN growth pattern (p < 0.001) but not with gender, primary site or lymph nodes metastatic status. PDGFRα staining was mainly localized in the vascular pole of the neuroendocrine cells and in Enterochromaffin (EC) cells. In particular PDGFRα tissue expression was significantly more expressed in G2 (p < 0.001) than G1 and G3 cases (p 0.004; p < 0.0002;) and correlated with an insular growth pattern. PDGFRα tissue expression was associated with the Ki67 index and we found a significant negative trend of association with the Ki67 proliferation index (P < 0.001): thus PDGFRα expression is referred to morphological and not to proliferative data. CONCLUSIONS PDGFRα represents an effective target for new anti-angiogenic treatment in WD- GEP-NENs, in particular in G2 cases, and in G3 cases only when there is a mixed insular-acinar pattern. In this context, it is important to carefully delineate those tumors that might better respond to this type of treatment alone or in combination. Further investigation of the relationship between PD-L1 and PDGFRa is warranted, and may contribute to optimize the therapeutic approach in patients with GEP-NENs.
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Affiliation(s)
- Elisabetta Cavalcanti
- Department of Pathology, IRCCS Gastroenterologico “S. de Bellis”, Castellana Grotte, Bari, Italy
| | - Antonia Ignazzi
- Department of Pathology, IRCCS Gastroenterologico “S. de Bellis”, Castellana Grotte, Bari, Italy
| | - Francesco De Michele
- Department of Pathology, IRCCS Gastroenterologico “S. de Bellis”, Castellana Grotte, Bari, Italy
| | - Maria Lucia Caruso
- Department of Pathology, IRCCS Gastroenterologico “S. de Bellis”, Castellana Grotte, Bari, Italy
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Highly favourable outcomes with peptide receptor radionuclide therapy (PRRT) for metastatic rectal neuroendocrine neoplasia (NEN). Eur J Nucl Med Mol Imaging 2018; 46:718-727. [DOI: 10.1007/s00259-018-4196-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/11/2018] [Indexed: 12/16/2022]
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Impressive Response to Tandem Treatment With [90Y]DOTATOC and [177Lu]DOTATOC in Grade 3 Pancreatic Neuroendocrine Carcinoma. Clin Nucl Med 2018; 43:506-508. [PMID: 29742602 DOI: 10.1097/rlu.0000000000002116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Peptide receptor radionuclide therapy is an effective, well-tolerated, treatment for well-differentiated neuroendocrine tumors, resulting in a significant survival benefit and improvement of quality of life. Very few data are available on peptide receptor radionuclide therapy effectiveness in grade 3 neuroendocrine carcinomas with high somatostatin receptor expression. We report the case of a 70-year-old woman with metastatic pancreatic grade 3 neuroendocrine carcinoma who underwent 6 cycles of tandem treatment with investigational radiopharmaceuticals Y-DOTATOC and Lu-DOTATOC achieving an impressive response.
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Ten-Year Survival After Peptide Receptor Radionuclide Therapy of a Metastatic Well-differentiated G3 Pancreatic Neuroendocrine Neoplasm. Clin Nucl Med 2018; 43:676-678. [DOI: 10.1097/rlu.0000000000002186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Sorbye H, Baudin E, Perren A. The Problem of High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Beyond. Endocrinol Metab Clin North Am 2018; 47:683-698. [PMID: 30098724 DOI: 10.1016/j.ecl.2018.05.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
High-grade gastroenteropancreatic neuroendocrine neoplasms are well-differentiated neuroendocrine tumors or poorly differentiated small/large cell neuroendocrine carcinoma. Distinguishing these entities relies on different genetic backgrounds and resulting different biology. The new classification creates several problems. Almost all clinical treatment data on neuroendocrine neoplasms do not stratify between well and poorly differentiated, providing insufficient help in treatment selection. Treatment of gastroenteropancreatic neuroendocrine neoplasms should separate between well-differentiated neuroendocrine tumors and neuroendocrine carcinoma, and depends on primary tumor site, stage, proliferation rate, and clinical course. This article addresses how to diagnose and treat gastroenteropancreatic neuroendocrine neoplasms, focusing on well-differentiated neuroendocrine tumors versus neuroendocrine carcinomas.
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Affiliation(s)
- Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway; Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway.
| | - Eric Baudin
- Endocrine Oncology, Gustave Roussy, rue Édouard-Vaillant 114, Villejuif 94800, France
| | - Aurel Perren
- Department of Pathology, University of Bern, Murtenstrasse 31, Bern 3008, Switzerland
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