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      High-Grade Progression Confers Poor Survival in Pancreatic Neuroendocrine Tumors

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          Abstract

          Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 ( n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, p < 0.001). Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

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          Most cited references 12

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          Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas.

          Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized.
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            Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study

             Guido Rindi (corresponding) ,  Catherine Klersy,  Luca Albarello (2019)
            Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.
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              Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies.

              In this Review, we discuss clinical developments and controversies in the treatment of neuroendocrine tumours (NETs) that are relevant for clinicians and clinical researchers. We describe advances in genetics, blood-based biomarkers, functional imaging, and systemic therapy of advanced NETs and discuss results of recent phase 3 studies, systemic treatment of advanced disease with peptide receptor radionuclide therapy, biotherapy, chemotherapy, and molecularly targeted therapy, and the potential role of immunotherapy in the treatment of NETs. Suggested treatment algorithms for NETs of ileal or jejunal origin and of pancreatic origin are presented.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2020
                October 2020
                29 October 2019
                : 110
                : 11-12
                : 891-898
                Affiliations
                aDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                bDepartment of Medical Oncology, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
                cDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden
                dDepartment of Surgical Sciences, Uppsala University, Uppsala, Sweden
                eAnatomia Patologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
                fAnatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy
                Author notes
                *Joakim Crona, MD, PhD, Department of Medical Sciences, Uppsala University, Onkologisk Endokrinologi, Akademiska Sjukhuset ing 78, SE–75185 Uppsala (Sweden), E-Mail joakim.crona@medsci.uu.se
                Article
                504392 Neuroendocrinology 2020;110:891–898
                10.1159/000504392
                31658459
                © 2019 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 3, Pages: 8
                Categories
                Research Article

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