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Orlandi R. Neuroendocrine neoplasms of the lung: The latest updates. World J Clin Oncol 2025; 16:106630. [DOI: 10.5306/wjco.v16.i5.106630] [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: 03/03/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 05/19/2025] Open
Abstract
Neuroendocrine neoplasms are a group of tumors with heterogenous malignancy that evolve from neuroendocrine cells, most frequently in the gastrointestinal tract and in the lung. The latest 2021 World Health Organization (WHO) classification of lung tumors defines neuroendocrine neoplasms of the lung as an independent group of tumors, including typical and atypical neuroendocrine tumors and small cell and large cell neuroendocrine carcinomas. Although the overall nomenclature is essentially unchanged from the fourth WHO classification, there are several clinically relevant updates. In this review article, we discuss the epidemiological, clinical, diagnostic, therapeutic and prognostic features of these fascinating neoplasms, including the latest insights, current challenges and future perspectives.
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Affiliation(s)
- Riccardo Orlandi
- Department of Thoracic Surgery, University of Milan, Milan 20122, Italy
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2
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Trandafir TE, Heijboer FWJ, Akram F, Derks JL, Li Y, Hillen LM, Speel EJM, Megyesfalvi Z, Dome B, Stubbs AP, Dingemans AMC, von der Thüsen JH. Deep Learning-Based Retinoblastoma Protein Subtyping of Pulmonary Large-Cell Neuroendocrine Carcinoma on Small Hematoxylin and Eosin-Stained Specimens. J Transl Med 2025; 105:104192. [PMID: 40345665 DOI: 10.1016/j.labinv.2025.104192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 04/15/2025] [Accepted: 04/30/2025] [Indexed: 05/11/2025] Open
Abstract
Molecular subtyping of pulmonary large-cell neuroendocrine carcinoma (LCNEC) based on retinoblastoma protein (pRb) expression may influence systemic treatment decisions. Current histomorphologic assessments of hematoxylin and eosin-stained tissue samples cannot reliably differentiate LCNEC molecular subtypes. This study explores the potential of deep learning (DL) to identify histologic patterns that distinguish these subtypes, by developing a custom convolutional neural network to predict the binary expression of pRb in small LCNEC tissue samples. Our model was trained, cross-validated, and tested on tissue microarray cores from 143 resection specimens and biopsies from 21 additional patients, with corresponding immunohistochemical pRb status. The best-performing DL model achieved a patient-wise balanced accuracy value of 0.75 and an area under the receiver operating characteristic curve value of 0.77 when tested on biopsies, significantly outperforming the hematoxylin and eosin-based subtype classification by lung pathologists. Explainable artificial intelligence techniques further highlighted coarse chromatin patterns and distinct nucleoli as distinguishing features for pRb retained status. Meanwhile, pRb lost cases were characterized by limited cytoplasm and morphologic similarities with small cell lung cancer. These findings suggest that DL analysis of small histopathology samples could ultimately replace immunohistochemical pRb testing. Such a development may assist in guiding chemotherapy decisions, particularly in metastatic cases.
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Affiliation(s)
- Teodora E Trandafir
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Frank W J Heijboer
- Department of Respiratory Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Farhan Akram
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jules L Derks
- Department of Respiratory Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Yunlei Li
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Lisa M Hillen
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Ernst-Jan M Speel
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Zsolt Megyesfalvi
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Balazs Dome
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Translational Medicine, Lund University, Lund, Sweden
| | - Andrew P Stubbs
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Anne-Marie C Dingemans
- Department of Respiratory Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jan H von der Thüsen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Das S, Samaddar S. Recent Advances in the Clinical Translation of Small-Cell Lung Cancer Therapeutics. Cancers (Basel) 2025; 17:255. [PMID: 39858036 PMCID: PMC11764476 DOI: 10.3390/cancers17020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum-etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes.
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Affiliation(s)
- Subhadeep Das
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907, USA
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907, USA
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Beckert M, Meyer C, Papadopoulos T, Levidou G. Application of the 5th WHO Guidelines for the Diagnosis of Lung Carcinoma in Small Lung Biopsies in a Tertiary Care Center: Is Insecurity of Pathologists for the Accurate Diagnosis Justified? Diagnostics (Basel) 2024; 14:2090. [PMID: 39335769 PMCID: PMC11431320 DOI: 10.3390/diagnostics14182090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/16/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND/OBJECTIVES The diagnosis of lung carcinoma (LC) is currently performed in small biopsies and according to the WHO classification by using limited stains to spare tissue for molecular testing. This procedure, however, often causes diagnostic uncertainty among pathologists. METHODS In this retrospective analysis, we compared the diagnosis made by these guidelines in 288 lung biopsies with that using more stains, as retrieved from our archive. We also compared the results of p63 and p40 immunoexpression and investigated the diagnostic role of p53/Rb1. RESULTS In our investigation, we reached a definite diagnosis with a mean number of one stain compared with six stains in the original diagnostic procedure, with a 97.3% concordance rate. Only in the case of metastases, a clear advantage is proven in the use of more stains, especially in the absence of clinical information. We also found a comparable utility of p40 and p63 for the diagnosis of squamous cell carcinoma, despite the higher p63 expression in other histological types. Moreover, normal p53/Rb1 expression could be utilized for the exclusion of small-cell LC. CONCLUSIONS Our study confirms the diagnostic certainty achieved by the suggestions of the WHO classification and justifies the potential insecurity in the absence of adequate communication with the treating clinician.
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Affiliation(s)
- Manuela Beckert
- Department of Pathology, Nuremberg Clinic, Paracelsus Medical University, 90419 Nuremberg, Germany
| | - Christian Meyer
- Department of Pathology, Nuremberg Clinic, Paracelsus Medical University, 90419 Nuremberg, Germany
| | - Thomas Papadopoulos
- Department of Pathology, Nuremberg Clinic, Paracelsus Medical University, 90419 Nuremberg, Germany
| | - Georgia Levidou
- Department of Pathology, Nuremberg Clinic, Paracelsus Medical University, 90419 Nuremberg, Germany
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Desai N, D'Ambrosio D, Dombrowski KS, Illei PB, Heymann JJ. Pulmonary Cytopathology: Current and Future Impact of Microscopy and Immunohistochemistry. Surg Pathol Clin 2024; 17:411-429. [PMID: 39129140 DOI: 10.1016/j.path.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
With the advancement of tissue procurement techniques, in-depth knowledge of morphology is crucial for cytopathologists to diagnose neoplastic and nonneoplastic lung diseases optimally. Cytopathologists must also be well versed in immunohistochemistry/immunocytochemistry markers and their interpretation for an accurate diagnosis.
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Affiliation(s)
- Niyati Desai
- Department of Pathology and Cell Biology, New York-Presbyterian Hospital-Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA
| | - Danielle D'Ambrosio
- Department of Pathology, New York University Grossman School of Medicine, 560 First Avenue, New York, NY 10016, USA
| | - Katya S Dombrowski
- Department of Pathology, The Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD 21287, USA
| | - Peter B Illei
- Department of Pathology, The Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD 21287, USA
| | - Jonas J Heymann
- Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital-Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
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Vocino Trucco G, Righi L, Volante M, Papotti M. Updates on lung neuroendocrine neoplasm classification. Histopathology 2024; 84:67-85. [PMID: 37794655 DOI: 10.1111/his.15058] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of pulmonary neoplasms showing different morphological patterns and clinical and biological characteristics. The World Health Organisation (WHO) classification of lung NENs has been recently updated as part of the broader attempt to uniform the classification of NENs. This much-needed update has come at a time when insights from seminal molecular characterisation studies revolutionised our understanding of the biological and pathological architecture of lung NENs, paving the way for the development of novel diagnostic techniques, prognostic factors and therapeutic approaches. In this challenging and rapidly evolving landscape, the relevance of the 2021 WHO classification has been recently questioned, particularly in terms of its morphology-orientated approach and its prognostic implications. Here, we provide a state-of-the-art review on the contemporary understanding of pulmonary NEN morphology and the potential contribution of artificial intelligence, the advances in NEN molecular profiling with their impact on the classification system and, finally, the key current and upcoming prognostic factors.
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Affiliation(s)
| | - Luisella Righi
- Department of Oncology, University of Turin, Turin, Italy
| | - Marco Volante
- Department of Oncology, University of Turin, Turin, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
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Chen C, Wang Y, Huang H, He X, Li W. Percutaneous computed tomography-guided core needle biopsy can be used to histologically confirm the clinical features and long-term prognosis of pulmonary neuroendocrine neoplasms. Jpn J Radiol 2023; 41:1414-1419. [PMID: 37395983 DOI: 10.1007/s11604-023-01465-4] [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: 01/17/2023] [Accepted: 06/22/2023] [Indexed: 07/04/2023]
Abstract
PURPOSE We investigated the clinical features and prognosis outcomes of pulmonary neuroendocrine neoplasms (PNENs) which were histologically confirmed after percutaneous computed tomography-guided core needle biopsy (PCT-CNB). MATERIALS AND METHODS We retrospectively investigated 173 patients who had PNENs which were histologically confirmed after PCT-CNB; patients were split into low and intermediate-grade neuroendocrine tumor (LIGNET) (typical carcinoid (TC) and atypical carcinoid (AC)) and high-grade neuroendocrine carcinoma-tumor (HGNEC) groups. In this latter group, patients were further subdivided into large-cell neuroendocrine carcinoma (LCNEC), small-cell lung cancer (SCLC), and high-grade neuroendocrine carcinoma-not otherwise specified (HGNEC-NOS) groups. Complications after biopsy were recorded. We also assessed overall survival (OS) rates using Kaplan-Meier curves, with prognostic factors determined using univariate and multivariate analyses. RESULTS Complications were mainly pneumothorax (22.5; 39/173 patients), chest tube placement (4.0; 7/173 patients), and pulmonary bleeding (33.5%; 58/173 procedures)-no patient mortality was recorded. Definitive diagnoses were ascribed to 102 SCLC, 10 LCNEC, 43 HGNEC-NOS, 7 TC, and 11 AC patients. The 1- and 3-year OS rates in the LIGNET group were 87.5% and 68.1%, respectively, and 59.2 and 20.9% in the HGNEC group, respectively these data were statistically significant (P = 0.010). For SCLC, 1- and 3-year OS rates were 63.3 and 22.3%, 30.0 and 10.0% for LCNEC, and 53.3% and 20.1% for HGNEC-NOS, respectively (P = 0.031). Independent prognostic factors for OS included disease type and distant metastasis. CONCLUSION PNENs may be pathologically diagnosed using PCT-CNB. While differential diagnoses between LCNEC and SCLC are problematic in some patients, a HGNEC-NOS diagnosis was ascribed and PCT-CNB samples were shown to predict NEN OS rates.
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Affiliation(s)
- Chao Chen
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui, 200032, Shanghai, China
| | - Ying Wang
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui, 200032, Shanghai, China
| | - Haozhe Huang
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui, 200032, Shanghai, China
| | - Xinhong He
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui, 200032, Shanghai, China
| | - Wentao Li
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No.270 Dongan Road, Xuhui, 200032, Shanghai, China.
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Song L, Zhou F, Xu T, Zeng L, Xia Q, Wang Z, Deng L, Li Y, Qin H, Yan H, Huang Z, Mi J, Xu Q, Yang N, Zhou C, Zhang Y. Clinical activity of pembrolizumab with or without chemotherapy in advanced pulmonary large-cell and large-cell neuroendocrine carcinomas: a multicenter retrospective cohort study. BMC Cancer 2023; 23:443. [PMID: 37189075 PMCID: PMC10186661 DOI: 10.1186/s12885-023-10952-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC). METHODS We retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC - 37 treatment-naïve and 23 pre-treated - who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed. RESULTS Of the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2-11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0-50.1) for first-line pembrolizumab plus chemotherapy of LCC (n = 27), whereas mPFS was 5.5 months (95%CI: 2.3-8.7) and mOS was 13.0 months (95%CI: 11.0-15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n = 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6-3.4) and mOS was 4.5 months (95% CI: 0.0-9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0-7.6) and mOS was not reached for LCNEC. CONCLUSION Our study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer. TRIAL REGISTRATION NCT05023837(ESPORTA, 27/08/2021).
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Affiliation(s)
- Lianxi Song
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
- Department of Medical Oncology, Yiyang Center Hospital, Yiyang, 413000, China
| | - Fei Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
| | - Tian Xu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Liang Zeng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Qing Xia
- Department of Oncology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200002, China
| | - Zhan Wang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Li Deng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Yizhi Li
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Haoyue Qin
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Huan Yan
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhe Huang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Jinye Mi
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Qinqin Xu
- Department of Medical Oncology, Qinghai Provincial People's Hospital, Xining, 810007, China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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Sung S, Heymann JJ, Politis MG, Baine MK, Rekhtman N, Saqi A. Small Biopsy and Cytology of Pulmonary Neuroendocrine Neoplasms: Brief Overview of Classification, Immunohistochemistry, Molecular Profiles, and World Health Organization Updates. Adv Anat Pathol 2022; 29:329-336. [PMID: 36053019 DOI: 10.1097/pap.0000000000000360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Pulmonary neuroendocrine neoplasms comprise ~20% of all lung tumors. Typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma represent the 4 major distinct subtypes recognized on resections. This review provides a brief overview of the cytomorphologic features and the 2021 World Health Organization classification of these tumor types on small biopsy and cytology specimens. Also discussed are the role of immunohistochemistry in the diagnosis and molecular signatures of pulmonary neuroendocrine tumors.
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Affiliation(s)
- Simon Sung
- Department of Pathology & Cell Biology, Columbia University Irving Medical Center
| | - Jonas J Heymann
- Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital-Weill Cornell Medical College
| | | | - Marina K Baine
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Natasha Rekhtman
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anjali Saqi
- Department of Pathology & Cell Biology, Columbia University Irving Medical Center
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Yang L, Fan Y, Lu H. Pulmonary Large Cell Neuroendocrine Carcinoma. PATHOLOGY AND ONCOLOGY RESEARCH 2022; 28:1610730. [PMID: 36304941 PMCID: PMC9592721 DOI: 10.3389/pore.2022.1610730] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 09/29/2022] [Indexed: 11/30/2022]
Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare subtype of malignant pulmonary tumor. The incidence rate of LCNEC was reported to be 0.3%–3% in lung cancers. Although LCNEC is classified as non-small cell lung cancer (NSCLC), it is more aggressive and malignant than other NSCLC, and its biological behavior is similar to that of small cell lung cancer (SCLC). Most of the LCNEC patients are elderly smoking male and the clinical manifestations are not specific. The imaging manifestations of the tumors are often located in the periphery and the upper lobes, and the enlargement of mediastinal or hilar lymph nodes is common. The diagnosis is mainly based on pathology by the histological features and immunohistochemistry (IHC). Specific neuroendocrine markers such as chromogranin A (CgA), synaptophysin (Syn) and CD56 are usually diffusely positive in LCNEC, and found that insulinoma-associated protein (INSM1) and high rate of Ki-67 are helpful for diagnosis. More differential diagnoses also increase the difficulty of correctly diagnosing LCNEC. The rise of LCNEC molecular typing in recent years may be helpful for diagnosis and subsequent treatment. This review focuses on the epidemiological features, imaging studies, pathology, diagnosis, treatment, and prognosis of LCNEC.
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Affiliation(s)
- Lan Yang
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Ying Fan
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Hongyang Lu
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Hongyang Lu,
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Baine MK, Febres-Aldana CA, Chang JC, Jungbluth AA, Sethi S, Antonescu CR, Travis WD, Hsieh MS, Roh MS, Homer RJ, Ladanyi M, Egger JV, Lai WV, Rudin CM, Rekhtman N. POU2F3 in SCLC: Clinicopathologic and Genomic Analysis With a Focus on Its Diagnostic Utility in Neuroendocrine-Low SCLC. J Thorac Oncol 2022; 17:1109-1121. [PMID: 35760287 PMCID: PMC9427708 DOI: 10.1016/j.jtho.2022.06.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 11/18/2022]
Abstract
INTRODUCTION POU2F3 is a recent marker of a small cell lung carcinoma (SCLC) subtype related to chemosensory tuft cells (SCLC-P). The characteristics of SCLC-P have not been fully defined, and the data on POU2F3 expression in other lung tumors are scarce. METHODS We screened 254 SCLC for POU2F3 expression and comprehensively analyzed histopathologic, genomic, and clinical characteristics of POU2F3-positive tumors. We also explored POU2F3 expression in other major lung cancer types (n = 433) and a targeted set of potential diagnostic mimics of SCLC (n = 123). RESULTS POU2F3 was expressed in 30 of 254 (12%) SCLC and was strongly associated with low expression of standard neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1). Notably, POU2F3 was expressed in 75% of SCLC with entirely negative or minimal neuroendocrine marker expression (15/20) and was helpful in supporting the diagnosis of SCLC in such cases. Broad targeted next-generation sequencing revealed that SCLC-P (n = 12) exhibited enrichment in several alterations, including PTEN inactivation, MYC amplifications, and 20q13 amplifications, but similar rates of RB1 and TP53 alterations as other SCLC (n = 155). Beyond SCLC, POU2F3 expression was exclusively limited to large cell neuroendocrine carcinoma (12%) and basaloid squamous cell carcinoma (22%). CONCLUSIONS This is the largest cohort of SCLC-P clinical samples to date, where we describe the diagnostic utility of POU2F3 in a challenging subset of SCLC with low or absent expression of standard neuroendocrine markers. The distinct genomic alterations in SCLC-P may offer a novel avenue for therapeutic targeting. The role of POU2F3 in a narrow subset of other lung cancer types warrants further study.
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Affiliation(s)
- Marina K Baine
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Jason C Chang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Achim A Jungbluth
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shenon Sethi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William D Travis
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Min-Shu Hsieh
- Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Mee Sook Roh
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Robert J Homer
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jacklynn V Egger
- Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - W Victoria Lai
- Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Charles M Rudin
- Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Natasha Rekhtman
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Rekhtman N. Lung neuroendocrine neoplasms: recent progress and persistent challenges. Mod Pathol 2022; 35:36-50. [PMID: 34663914 PMCID: PMC8695375 DOI: 10.1038/s41379-021-00943-2] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
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). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. 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. 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.
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Affiliation(s)
- Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
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13
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Poté N. Histoséminaire de pathologie onco-thoracique : cas n°4. Ann Pathol 2022; 42:151-155. [DOI: 10.1016/j.annpat.2021.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 10/19/2022]
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14
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The 2021 WHO Classification of Lung Tumors: Impact of advances since 2015. J Thorac Oncol 2021; 17:362-387. [PMID: 34808341 DOI: 10.1016/j.jtho.2021.11.003] [Citation(s) in RCA: 663] [Impact Index Per Article: 165.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/26/2021] [Accepted: 11/01/2021] [Indexed: 11/22/2022]
Abstract
The 2021 World Health Organisation (WHO) Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are 1) broader emphasis on genetic testing than in the 2015 WHO Classification, 2) a chapter entirely dedicated to the classification of small diagnostic samples, 3) continued recommendation to document percentages of histological patterns in invasive non-mucinous adenocarcinomas, with utilization of these features to apply a formal grading system, as well as using only invasive size for T-factor size determination in part lepidic non-mucinous lung adenocarcinomas as recommended by the 8th Edition TNM Classification, 4) recognition of spread through airspaces (STAS) as a histological feature with prognostic significance, 5) moving lymphoepithelial carcinoma to squamous cell carcinomas, 6) update on evolving concepts in lung neuroendocrine neoplasm classification, 7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT) as a new entity within the adenoma subgroup, 8) recognition of thoracic SMARCA4-deficient undifferentiated tumor, and 9) inclusion of essential and desirable diagnostic criteria for each tumor.
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Pelosi G, Travis WD. The Ki-67 antigen in the new 2021 World Health Organization classification of lung neuroendocrine neoplasms. Pathologica 2021; 113:377-387. [PMID: 34837096 PMCID: PMC8720414 DOI: 10.32074/1591-951x-542] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 10/24/2021] [Indexed: 01/14/2023] Open
Abstract
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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Affiliation(s)
- Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - William D. Travis
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
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Guo J, Hou L, Zhang W, Dong Z, Zhang L, Wu C. Improving differential diagnosis of pulmonary large cell neuroendocrine carcinoma and small cell lung cancer via a transcriptomic, biological pathway-based machine learning model. Transl Oncol 2021; 14:101222. [PMID: 34530194 PMCID: PMC8450252 DOI: 10.1016/j.tranon.2021.101222] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 12/21/2022] Open
Abstract
A transcriptomic, biological pathway-based machine learning model was constructed. This classification model can predict LCNEC from borderline samples. The model may help clinicians choose appropriate therapy for pulmonary NETs patients. Background Accurately differentiating between pulmonary large cell neuroendocrine carcinomas (LCNEC) and small cell lung cancer (SCLC) is crucial to make appropriate therapeutic decisions. Here, a classifier was constructed based on transcriptome data to improve the diagnostic accuracy for LCNEC and SCLC. Methods 13,959 genes mapped to 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were included. Gene Set Variation Analysis (GSVA) algorithm was used to enrich and score each KEGG pathway from RNA-sequencing data of each sample. A prediction model based on GSVA score was constructed and trained via ridge regression based on RNA-sequencing datasets from 3 published studies. It was validated by another independent RNA-sequencing dataset. Clinical feasibility was tested by comparing model predicated result using RNA-sequencing data derived from hard-to-diagnose samples of lung neuroendocrine cancer to conventional histology-based diagnosis. Results This model achieved a ROC-AUC of 0.949 and a concordance rate of 0.75 for the entire prediction efficiency. Of the 27 borderline samples, 17/27 (63.0%) were predicted as LCNEC, 7/27 were predicted as SCLC, and the remainder was NSCLC. Only 8 cases (29.6%) with LCNEC were diagnosed by pathologists, which was significantly lower than the results predicted by the model. Furthermore, cases with predicted LCNEC by the model had a significant longer disease-free survival than those where the model predicted SCLC (P = 0.0043). Conclusion This model was able to give an accurate prediction of LCNEC and SCLC. It may assist clinicians to make the optimal decision for patients with pulmonary neuroendocrine tumors in choosing appropriate treatment.
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Affiliation(s)
- Junhong Guo
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Likun Hou
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Wei Zhang
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Zhengwei Dong
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Lei Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, PR China.
| | - Chunyan Wu
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China.
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Yoshimura M, Seki K, Bychkov A, Fukuoka J. Molecular Pathology of Pulmonary Large Cell Neuroendocrine Carcinoma: Novel Concepts and Treatments. Front Oncol 2021; 11:671799. [PMID: 33968782 PMCID: PMC8100606 DOI: 10.3389/fonc.2021.671799] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/31/2021] [Indexed: 01/14/2023] Open
Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an aggressive neoplasm with poor prognosis. Histologic diagnosis of LCNEC is not always straightforward. In particular, it is challenging to distinguish small cell lung carcinoma (SCLC) or poorly differentiated carcinoma from LCNEC. However, histological classification for LCNEC as well as their therapeutic management has not changed much for decades. Recently, genomic and transcriptomic analyses have revealed different molecular subtypes raising hopes for more personalized treatment. Two main molecular subtypes of LCNEC have been identified by studies using next generation sequencing, namely type I with TP53 and STK11/KEAP1 alterations, alternatively called as non-SCLC type, and type II with TP53 and RB1 alterations, alternatively called as SCLC type. However, there is still no easy way to classify LCNEC subtypes at the actual clinical level. In this review, we have discussed histological diagnosis along with the genomic studies and molecular-based treatment for LCNEC.
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Affiliation(s)
| | - Kurumi Seki
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
| | - Andrey Bychkov
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Fukuoka
- Department of Pathology, Kameda Medical Center, Kamogawa, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Raso MG, Bota-Rabassedas N, Wistuba II. Pathology and Classification of SCLC. Cancers (Basel) 2021; 13:cancers13040820. [PMID: 33669241 PMCID: PMC7919820 DOI: 10.3390/cancers13040820] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/03/2021] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Small cell lung carcinoma (SCLC), is a high-grade neuroendocrine carcinoma defined by its aggressiveness, poor differentiation, and somber prognosis. This review highlights current pathological concepts including classification, immunohistochemistry features, and differential diagnosis. Additionally, we summarize the current knowledge of the immune tumor microenvironment, tumor heterogeneity, and genetic variations of SCLC. Recent comprehensive genomic research has improved our understanding of the diverse biological processes that occur in this tumor type, suggesting that a new era of molecular-driven treatment decisions is finally foreseeable for SCLC patients. Abstract Lung cancer is consistently the leading cause of cancer-related death worldwide, and it ranks as the second most frequent type of new cancer cases diagnosed in the United States, both in males and females. One subtype of lung cancer, small cell lung carcinoma (SCLC), is an aggressive, poorly differentiated, and high-grade neuroendocrine carcinoma that accounts for 13% of all lung carcinomas. SCLC is the most frequent neuroendocrine lung tumor, and it is commonly presented as an advanced stage disease in heavy smokers. Due to its clinical presentation, it is typically diagnosed in small biopsies or cytology specimens, with routine immunostaining only. However, immunohistochemistry markers are extremely valuable in demonstrating neuroendocrine features of SCLC and supporting its differential diagnosis. The 2015 WHO classification grouped all pulmonary neuroendocrine carcinomas in one category and maintained the SCLC combined variant that was previously recognized. In this review, we explore multiple aspects of the pathologic features of this entity, as well as clinically relevant immunohistochemistry markers expression and its molecular characteristics. In addition, we will focus on characteristics of the tumor microenvironment, and the latest pathogenesis findings to better understand the new therapeutic options in the current era of personalized therapy.
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Affiliation(s)
- Maria Gabriela Raso
- Correspondence: (M.G.R.); (I.I.W.); Tel.: +1-713-834-6026 (M.G.R.); +1-713-563-9184 (I.I.W.)
| | | | - Ignacio I. Wistuba
- Correspondence: (M.G.R.); (I.I.W.); Tel.: +1-713-834-6026 (M.G.R.); +1-713-563-9184 (I.I.W.)
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Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment. Br J Cancer 2020; 124:925-932. [PMID: 33250511 PMCID: PMC7921668 DOI: 10.1038/s41416-020-01188-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 09/25/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
Background The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME). Methods This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3). Results The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73–6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = −0.648, p = 0.005, stromal: r = −0.490, p = 0.046). Conclusions A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.
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Baine MK, Rekhtman N. Multiple faces of pulmonary large cell neuroendocrine carcinoma: update with a focus on practical approach to diagnosis. Transl Lung Cancer Res 2020; 9:860-878. [PMID: 32676352 PMCID: PMC7354156 DOI: 10.21037/tlcr.2020.02.13] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignancy that is strongly linked to smoking and notoriously difficult to diagnose and treat. Recent molecular data reveal that it represents a biologically heterogeneous group of tumors, characterized by morphologic and genomic diversity that straddles small cell and non-small cell lung carcinomas (NSCLCs), and in a minority of cases atypical carcinoids. This review provides an update on recent molecular and clinical developments in LCNEC with the main focus on practical approach to pathologic diagnosis using illustrative examples of the main differential diagnostic considerations.
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Affiliation(s)
- Marina K Baine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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