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      The Ki-67 antigen in the new 2021 World Health Organization classification of lung neuroendocrine neoplasms

      review-article
      1 , 2
      Pathologica
      Pacini Editore srl
      neuroendocrine, neoplasms, lung, carcinoid, carcinoma, Ki-67

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          Summary

          Prof. Rosai’s work has permeated the surgical pathology in many fields, including the 2017 World Health Organization classification on tumors of endocrine organs and pulmonary neuroendocrine cell pathology, with stimulating contributions which have also anticipated the subsequent evolution of knowledge. Among the many studies authored by Prof. Rosai, we would like to recall one of which whose topic has been encased in the new 2021 World Health Organization classification on lung tumors. This is an eminently practical paper dealing with the use of the proliferation antigen Ki-67 in lung neuroendocrine neoplasms. While these neoplasms are primarily ranked upon histologic features and Ki-67 labeling index does not play any role in classification, diagnostic dilemmas may however arise in severely crushed biopsy or cytology samples where this marker proves helpful to avoid misdiagnoses of carcinoids as small cell carcinoma. Another application of Ki-67 labeling index endorsed by the 2021 World Health Organization classification regards, alongside mitotic count, the emerging recognition of lung atypical carcinoids with increased mitotic or proliferation rates, whose biological boundaries straddle a subset of large cell neuroendocrine carcinoma.

          This article focuses on these two practical applications of the proliferation marker Ki-67 in keeping with the 2021 World Health Organization classification, which provides standards for taxonomy, diagnosis and clinical decision making in lung neuroendocrine neoplasm patients.

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          Most cited references81

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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

          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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            Ki-67: more than a proliferation marker.

            Ki-67 protein has been widely used as a proliferation marker for human tumor cells for decades. In recent studies, multiple molecular functions of this large protein have become better understood. Ki-67 has roles in both interphase and mitotic cells, and its cellular distribution dramatically changes during cell cycle progression. These localizations correlate with distinct functions. For example, during interphase, Ki-67 is required for normal cellular distribution of heterochromatin antigens and for the nucleolar association of heterochromatin. During mitosis, Ki-67 is essential for formation of the perichromosomal layer (PCL), a ribonucleoprotein sheath coating the condensed chromosomes. In this structure, Ki-67 acts to prevent aggregation of mitotic chromosomes. Here, we present an overview of functional roles of Ki-67 across the cell cycle and also describe recent experiments that clarify its role in regulating cell cycle progression in human cells.
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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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                Author and article information

                Journal
                Pathologica
                Pathologica
                PATHOL
                Pathologica
                Pacini Editore srl
                0031-2983
                1591-951X
                01 October 2021
                October 2021
                : 113
                : 5
                : 377-387
                Affiliations
                [1 ] Department of Oncology and Hemato-Oncology, University of Milan , Milan, Italy
                [2 ] Department of Pathology, Memorial Sloan-Kettering Cancer Center , New York, USA
                Author notes
                Correspondence Giuseppe Pelosi Servizio InterAziendale di Anatomia Patologica, IRCCS Multimedica, via Gaudenzio Fantoli 16/15, 20138 Milan, Italy Tel.:+ 39 02 5540 6572/6509 Fax.: +39 02 5540 6570 E-mail: giuseppe.pelosi@ 123456unimi.it

                Conflict of interest

                The Authors declare no conflict of interest.

                Article
                10.32074/1591-951X-542
                8720414
                34837096
                fb578704-80b1-48a8-af6c-c22a69640d80
                © 2021 Copyright by Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

                This is an open access journal distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International) license: the work can be used by mentioning the author and the license, but only for non-commercial purposes and only in the original version. For further information: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en

                History
                : 24 October 2021
                : 24 October 2021
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 81, Pages: 11
                Categories
                Review

                neuroendocrine,neoplasms,lung,carcinoid,carcinoma,ki-67
                neuroendocrine, neoplasms, lung, carcinoid, carcinoma, ki-67

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