Combined carcinomas are defined as tumors with both NEC and NSCLC components.
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In this article, the term NE carcinoma (NEC) will be used as an umbrella term for SCLC and LCNEC. Major WHO NE tumor types include typical carcinoid, atypical carcinoid, small cell lung carcinoma (SCLC), and large cell NE carcinoma (LCNEC). The criteria and terminology for lung NE neoplasms in the latest World Health Organization (WHO) classification of thoracic tumors (5 th edition 2021) remains largely unchanged from the prior edition 1, 2. Thoracic WHO classification 5 th edition (2021): terminology and criteria for neuroendocrine neoplasms This article will address the areas of recent progress and persistent challenges in pulmonary NE neoplasms, focusing on the areas relevant to pathologic diagnosis. However, in recent years, there has been several significant breakthroughs in understanding of the molecular characteristics of each major type of lung NE neoplasm, which may set the stage for significant progress in the near future. Conversely, until recently, there has been only limited progress in the identification of clinically relevant biological subsets and the development of personalized approaches in the field of lung neuroendocrine (NE) neoplasms.
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In the last decade, there has been a tremendous progress in identifying molecular subtypes in non-small cell lung carcinoma (NSCLC), forming the basis of increasingly personalized systemic therapies for this disease. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies.
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Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC).