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      A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal

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          The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

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          Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

          As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.
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            Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids.

            Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management.
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              The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms.

              The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.

                Author and article information

                +33 (0) 4 72 73 8447 , creei@iarc.fr
                Mod Pathol
                Mod. Pathol
                Modern Pathology
                Nature Publishing Group US (New York )
                23 August 2018
                23 August 2018
                : 31
                : 12
                : 1770-1786
                [1 ]ISNI 0000 0004 1760 4193, GRID grid.411075.6, Istituto di Anatomia Patologica, , Università Cattolica-Fondazione Policlinico Universitario A. Gemelli, ; Rome, Italy
                [2 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Department of Pathology, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [3 ]ISNI 0000 0004 0386 3928, GRID grid.475637.4, International Agency for Research on Cancer (IARC), , World Health Organization (WHO), ; Lyon, France
                [4 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, University Health Network, , University of Toronto, ; Toronto, ON Canada
                [5 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, University of Lausanne Medical Center, ; Lausanne, Switzerland
                [6 ]ISNI 0000 0001 0792 4829, GRID grid.410529.b, CHUGA, UniversitéUGA, , Centre Hospitalier Universitaire Grenoble Alpes, ; Grenoble, France
                [7 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Pathology, , University Medical Center Utrecht and Princess Máxima Center for Pediatric Oncology, ; Utrecht, The Netherlands
                [8 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Charité - University Hospital Berlin, ; Berlin, Germany
                [9 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [10 ]ISNI 0000000123222966, GRID grid.6936.a, Department of Pathology, , Technical University of München, ; München, Germany
                [11 ]ISNI 0000 0000 9565 2378, GRID grid.412915.a, Department of Pathology, , Belfast Health and Social Care Trust, ; Belfast, UK
                [12 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, University Hospital Zurich, ; Zurich, Switzerland
                [13 ]ISNI 0000 0004 1936 8868, GRID grid.4563.4, University of Nottingham, ; Nottingham, UK
                [14 ]ISNI 0000 0004 0606 0717, GRID grid.422301.6, Beatson West of Scotland Cancer Centre, ; Glasgow, UK
                [15 ]National Cancer Registration and Analysis Service, Fulbourn, UK
                [16 ]ISNI 0000 0001 2248 6943, GRID grid.69566.3a, Department of Pathology, , Tohoku University School of Medicine, ; Sendai, Japan
                [17 ]ISNI 0000 0004 1756 948X, GRID grid.411475.2, Section of Pathology, ARC-Net Research Center and Department of Diagnostics and Public Health, , University and Hospital Trust of Verona, ; Verona, Italy
                [18 ]ISNI 0000 0001 2284 9388, GRID grid.14925.3b, Departement of Pathology, , Gustave Roussy Cancer Campus, ; Villejuif, France
                [19 ]ISNI 0000 0004 1757 1758, GRID grid.6292.f, University Medical Center, , University of Bologna, ; Bologna, Italy
                [20 ]Faculté de Médecine Lyon Est, Lyon, France
                [21 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Radboud University Nijmegen Medical Center, ; Nijmegen, The Netherlands
                © United States & Canadian Academy of Pathology 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funded by: FundRef https://doi.org/10.13039/100008700, Centre International de Recherche sur le Cancer (International Agency for Research on Cancer);
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