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Moyana TN. Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options. World J Gastroenterol 2024; 30:5198-5204. [PMID: 39735276 PMCID: PMC11612703 DOI: 10.3748/wjg.v30.i48.5198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/23/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.
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Affiliation(s)
- Terence N Moyana
- Diagnostic and Molecular Pathology, The Ottawa Hospital and University of Ottawa, Ottawa K1H 8L6, Ontario, Canada
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2
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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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3
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Shi Z, Wei J, Xu M, Song Z. Efficacy and safety of immune checkpoint inhibitors in lung large-cell neuroendocrine carcinoma. J Thorac Dis 2023; 15:4172-4181. [PMID: 37691658 PMCID: PMC10482626 DOI: 10.21037/jtd-23-348] [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: 03/09/2023] [Accepted: 06/30/2023] [Indexed: 09/12/2023]
Abstract
Background Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare and highly aggressive neuroendocrine tumor. There is currently no standard therapeutic regimen, and systemic chemotherapy results in poor prognosis. Due to the rarity of L-LCNEC, the efficacy and safety of immune checkpoint inhibitors (ICIs) remain unclear. Methods This study included 34 L-LCNEC patients administered ICIs at Zhejiang Cancer Hospital, from February 6, 2018 to February 6, 2023. The treatment responses were evaluated. Fisher's exact test was used to compare categorical variables, and the Kaplan-Meier method was used for survival analyses. Cox regression was used for multivariate analysis. Results The objective response rate (ORR) of 34 patients was 29.4%, the disease control rate (DCR) was 82.4%, the median progression-free survival (PFS) was 6.30 months, and the median overall survival (OS) was 14.77 months. The ORRs of combined LCNEC (n=7) and pure LCNEC (n=27) were 14.3% and 33.3%; the DCRs were 100% and 77.8%; the median PFSs were 12.48 and 5.6 months (P=0.032); and the median OSs were 21.27 and 14.73 months, respectively (P=0.233). The observed incidence of immune-related adverse events (irAEs) was 61.8%, primarily occurring in grades 1/2 (58.8%) and grade 3 (5.9%). Elevated aminotransferases (14.7%), pneumonia (8.8%), and fatigue (8.8%) were the most common irAEs. Conclusions ICIs treatment showed efficacy and safety in advanced L-LCNEC, with the potential for greater benefits in the combined LCNEC subtype.
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Affiliation(s)
- Zheng Shi
- Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China
| | - Jingwen Wei
- Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China
| | - Manyi Xu
- Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhengbo Song
- Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
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Ferencz B, Megyesfalvi Z, Csende K, Fillinger J, Poór V, Lantos A, Pipek O, Sólyom-Tisza A, Rényi-Vámos F, Schelch K, Lang C, Schwendenwein A, Boettiger K, László V, Hoetzenecker K, Döme B, Berta J. Comparative expression analysis of immune-related markers in surgically resected lung neuroendocrine neoplasms. Lung Cancer 2023; 181:107263. [PMID: 37270937 DOI: 10.1016/j.lungcan.2023.107263] [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: 01/04/2023] [Revised: 05/20/2023] [Accepted: 05/25/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND Although immunotherapy has led to a paradigm shift in the treatment of lung cancer, the therapeutic approaches for lung neuroendocrine neoplasms (LNENs) are still limited. Our aim was to explore the immunological landscape and the expression of immune checkpoint markers in LNENs. METHODS Surgically removed tumor samples of 26 atypical carcinoid (AC), 30 large cell neuroendocrine carcinoma (LCNEC) and 29 small cell lung cancer (SCLC) patients were included. The immune phenotype of each tumor type was assessed by using a panel of 15 immune-related markers. As these markers are potentially expressed by immune cells and/or tumor cells, they might serve as putative targets for immunotherapy. Expression patterns were measured by immunohistochemistry and correlated with clinicopathological parameters and prognosis. RESULTS Unsupervised hierarchical clustering revealed distinct immunologic profiles across tumor types. Specifically, AC tumors were characterized by high tumor cell CD40 expression and low levels of immune infiltrates whereas SCLC samples had a high CD47 and Inducible T Cell Costimulator (ICOS) expression in tumor cells and immune cells, respectively. High CD70 and CD137 expression by tumor cells as well as elevated expression of CD27, Lymphocyte Activation Gene 3 (LAG3), and CD40 by immune cells were characteristic for LCNEC samples. Overall, SCLC and LCNEC tumors had a more immunogenic phenotype than AC samples. High tumor cell CD47 and CD40 expressions were associated with impaired and improved survival outcomes, respectively. CONCLUSIONS By providing insights into the widely divergent immunologic profiles of LNENs, our results might serve as a basis for the development of novel immunotherapy-related approaches in these devastating malignancies.
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Affiliation(s)
- Bence Ferencz
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Zsolt Megyesfalvi
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
| | - Kristóf Csende
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
| | - János Fillinger
- National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Valentin Poór
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
| | - András Lantos
- National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Orsolya Pipek
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | | | - Ferenc Rényi-Vámos
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Karin Schelch
- Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Christian Lang
- Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
| | - Anna Schwendenwein
- Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Kristiina Boettiger
- Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Viktória László
- National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Balázs Döme
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; Department of Translational Medicine, Lund University, Lund, Sweden.
| | - Judit Berta
- National Korányi Institute of Pulmonology, Budapest, Hungary
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Abstract
BACKGROUND Pulmonary nodule growth is often measured by volume doubling time (VDT), which may guide management. Most malignant nodules have a VDT of 20 to 400 days, with longer VDTs typically observed in indolent nodules. We assessed the utility of VDT in differentiating pulmonary carcinoids and hamartomas. METHODS A review was performed from January 2012 to October 2021 to identify patients with pathologic diagnoses and at least 2 chest computed tomography scans obtained 6 or more months apart. Visualization software was used to segment nodules and calculate diameter and volume. Volume doubling time was calculated for scans with 1-mm slices. For the remainder, estimated nodule volume doubling time (eVDT) was calculated using nodule diameter. Volume doubling times/eVDTs were placed into growth categories: less than 400 days; 400-600 days; and more than 600 days. RESULTS Sixty nodules were identified, 35 carcinoids and 25 hamartomas. Carcinoids were larger than hamartomas (median diameter, 13.5 vs 11.5 mm; P = 0.05). For carcinoid tumors, median VDT (n = 15) was 1485 days, and median eVDT (n = 32) was 1309 days; for hamartomas, median VDT (n = 8) was 2040 days and median eVDT (n = 25) was 2253 days. Carcinoid tumor eVDT was significantly shorter than hamartomas ( P = 0.03). By growth category, 1 of 25 hamartomas and 5 of 35 carcinoids had eVDT less than 400 days and 24 of 25 hamartomas and 27 of 35 carcinoids had eVDT more than 600 days. Of 4 carcinoid tumors with metastases, 2 had eVDT less than 400 days and 2 had eVDT more than 600 days. CONCLUSIONS Growth rate was not a reliable differentiator of pulmonary hamartomas and carcinoids. Slow growing carcinoids can metastasize. Radiologists should be cautious when discontinuing computed tomography follow-up based on growth rates alone.
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Affiliation(s)
- James W Ryan
- From the Brigham and Women's Hospital, Boston MA
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Russ DH, Barta JA, Evans NR, Stapp RT, Kane GC. Volume Doubling Time of Pulmonary Carcinoid Tumors Measured by Computed Tomography. Clin Lung Cancer 2022; 23:e453-e459. [PMID: 35922364 DOI: 10.1016/j.cllc.2022.06.006] [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: 03/21/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Pulmonary carcinoid tumor (PCT) is a rare neuroendocrine lung neoplasm comprising approximately 2% of lung cancer diagnoses. It is classified as either localized low-grade (typical) or intermediate-grade (atypical) subtypes. PCT is known clinically to be a slow-growing cancer, however few studies have established its true growth rate when followed over time by computed tomography (CT). Therefore, we sought to determine the volume doubling time for PCTs as visualized on CT imaging. MATERIALS AND METHODS We conducted a retrospective analysis of all PCTs treated at our institution between 2006 and 2020. Nodule dimensions were measured using a Picture Archiving and Communication System or retrieved from radiology reports. Volume doubling time was calculated using the Schwartz formula for PCTs followed by successive CT scans during radiographic surveillance. Consistent with Fleischner Society guidelines, tumors were considered to have demonstrated definitive growth by CT only when the interval change in tumor diameter was greater than or equal to 2 mm. RESULTS The median volume doubling time of 13 typical PCTs was 977 days, or 2.7 years. Five atypical PCTs were followed longitudinally, with a median doubling time of 327 days, or 0.9 years. CONCLUSIONS Typical pulmonary carcinoid features a remarkably slow growth rate as compared to more common lung cancers. Our analysis of atypical pulmonary carcinoid included too few cases to offer definitive conclusions. It is conceivable that clinicians following current nodule surveillance guidelines may mistake incidentally detected typical carcinoids for benign non-growing lesions when followed for less than 2 years in low-risk patients.
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Affiliation(s)
- Douglas H Russ
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
| | - Julie A Barta
- Division of Pulmonary, Allergy and Critical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA
| | - Nathaniel R Evans
- Division of Thoracic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA
| | - Robert T Stapp
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA
| | - Gregory C Kane
- The Jane and Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, PA
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La Salvia A, Carletti R, Verrico M, Feola T, Puliani G, Bassi M, Sesti F, Pernazza A, Mazzilli R, Lamberti G, Siciliani A, Mancini M, Manai C, Venuta F, Ibrahim M, Tomao S, D’Amati G, Di Gioia C, Giannetta E, Cappuzzo F, Faggiano A. Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma. J Clin Med 2022; 11:5958. [PMID: 36233825 PMCID: PMC9570740 DOI: 10.3390/jcm11195958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022] Open
Abstract
Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39−81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs’ location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs.
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Affiliation(s)
- Anna La Salvia
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Raffaella Carletti
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Monica Verrico
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, 86077 Pozzilli, Italy
| | - Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Massimiliano Bassi
- Department of Thoracic Surgery, Policlinico Umberto I, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Angelina Pernazza
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Rossella Mazzilli
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00185 Rome, Italy
| | - Giuseppe Lamberti
- Department of Specialized, Experimental and Diagnostic Medicine, S. Orsola-Malpighi Hospital, University of Bologna, 40126 Bologna, Italy
| | - Alessandra Siciliani
- Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Massimiliano Mancini
- Division of Morphologic and Molecular Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Chiara Manai
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Federico Venuta
- Department of Thoracic Surgery, Policlinico Umberto I, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Mohsen Ibrahim
- Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Giulia D’Amati
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Cira Di Gioia
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Federico Cappuzzo
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Antongiulio Faggiano
- Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, 00185 Rome, Italy
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Simbolo M, Centonze G, Giudice L, Grillo F, Maisonneuve P, Gkountakos A, Ciaparrone C, Cattaneo L, Sabella G, Giugno R, Bossi P, Spaggiari P, Del Gobbo A, Ferrero S, Mastracci L, Fabbri A, Filugelli M, Garzone G, Prinzi N, Pusceddu S, Testi A, Monti V, Rolli L, Mangogna A, Bercich L, Benvenuti MR, Bria E, Pilotto S, Berruti A, Pastorino U, Capella C, Infante M, Milella M, Scarpa A, Milione M. Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications. Cancers (Basel) 2022; 14:4653. [PMID: 36230576 PMCID: PMC9562868 DOI: 10.3390/cancers14194653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/18/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. METHODS 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. RESULTS Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. CONCLUSIONS CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.
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Affiliation(s)
- Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Giovanni Centonze
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Luca Giudice
- Department of Computer Science, University of Verona, 37134 Verona, Italy
| | - Federica Grillo
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, 20132 Milan, Italy
| | - Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Chiara Ciaparrone
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Laura Cattaneo
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Giovanna Sabella
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Rosalba Giugno
- Department of Computer Science, University of Verona, 37134 Verona, Italy
| | - Paola Bossi
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, 20089 Milan, Italy
| | - Paola Spaggiari
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, 20089 Milan, Italy
| | - Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Luca Mastracci
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Alessandra Fabbri
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Martina Filugelli
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Giovanna Garzone
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Adele Testi
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Valentina Monti
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Luigi Rolli
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, 34137 Trieste, Italy
| | - Luisa Bercich
- Department of Pathology, ASST Spedali Civili of Brescia, 25123 Brescia, Italy
| | - Mauro Roberto Benvenuti
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, 25123 Brescia, Italy
| | - Emilio Bria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Sara Pilotto
- Department of Medicine, Section of Oncology, University of Verona, 37134 Verona, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, 25123 Brescia, Italy
| | - Ugo Pastorino
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Carlo Capella
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
| | - Maurizio Infante
- Thoracic Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Michele Milella
- Department of Medicine, Section of Oncology, University of Verona, 37134 Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
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Zhang J, Deng J, Feng X, Tan Y, Li X, Liu Y, Li M, Qi H, Tang L, Meng Q, Yan H, Qi L. Hierarchical identification of a transcriptional panel for the histological diagnosis of lung neuroendocrine tumors. Front Genet 2022; 13:944167. [PMID: 36105102 PMCID: PMC9465419 DOI: 10.3389/fgene.2022.944167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Lung cancer is a complex disease composed of neuroendocrine (NE) and non-NE tumors. Accurate diagnosis of lung cancer is essential in guiding therapeutic management. Several transcriptional signatures have been reported to distinguish between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) belonging to non-NE tumors. This study aims to identify a transcriptional panel that could distinguish the histological subtypes of NE tumors to complement the morphology-based classification of an individual.Methods: A public dataset with NE subtypes, including 21 small-cell lung cancer (SCLC), 56 large-cell NE carcinomas (LCNECs), and 24 carcinoids (CARCIs), and non-NE subtypes, including 85 ADC and 61 SCC, was used as a training set. In the training set, consensus clustering was first used to filter out the samples whose expression patterns disagreed with their histological subtypes. Then, a rank-based method was proposed to develop a panel of transcriptional signatures for determining the NE subtype for an individual, based on the within-sample relative gene expression orderings of gene pairs. Twenty-three public datasets with a total of 3,454 samples, which were derived from fresh-frozen, formalin-fixed paraffin-embedded, biopsies, and single cells, were used for validation. Clinical feasibility was tested in 10 SCLC biopsy specimens collected from cancer hospitals via bronchoscopy.Results: The NEsubtype-panel was composed of three signatures that could distinguish NE from non-NE, CARCI from non-CARCI, and SCLC from LCNEC step by step and ultimately determine the histological subtype for each NE sample. The three signatures achieved high average concordance rates with 97.31%, 98.11%, and 90.63%, respectively, in the 23 public validation datasets. It is worth noting that the 10 clinic-derived SCLC samples diagnosed via immunohistochemical staining were also accurately predicted by the NEsubtype-panel. Furthermore, the subtype-specific gene expression patterns and survival analyses provided evidence for the rationality of the reclassification by the NEsubtype-panel.Conclusion: The rank-based NEsubtype-panel could accurately distinguish lung NE from non-NE tumors and determine NE subtypes even in clinically challenging samples (such as biopsy). The panel together with our previously reported signature (KRT5-AGR2) for SCC and ADC would be an auxiliary test for the histological diagnosis of lung cancer.
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Affiliation(s)
- Juxuan Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jiaxing Deng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xiao Feng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yilong Tan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xin Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yixin Liu
- Basic Medicine College, Harbin Medical University, Harbin, China
| | - Mengyue Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Haitao Qi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Lefan Tang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Qingwei Meng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Haidan Yan
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- *Correspondence: Haidan Yan, ; Lishuang Qi,
| | - Lishuang Qi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- *Correspondence: Haidan Yan, ; Lishuang Qi,
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10
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Matsuoka S, Koizumi T, Otsuki K, Tanaka Y, Kanda S, Ide S, Mishima S, Takeda T, Miura K, Eguchi T, Hamanaka K, Shimizu K. Epidemiological analysis of lung and mediastinal neuroendocrine neoplasms in Japan based on the national database. Cancer Epidemiol 2022; 77:102116. [PMID: 35144127 DOI: 10.1016/j.canep.2022.102116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/20/2022] [Accepted: 01/22/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan. METHODS Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment. RESULTS We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%). CONCLUSIONS This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.
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Affiliation(s)
- Shunichiro Matsuoka
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Tomonobu Koizumi
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
| | - Kengo Otsuki
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Yuriko Tanaka
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Shintaro Kanda
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Shogo Ide
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Shuji Mishima
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Tetsu Takeda
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Kentaro Miura
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Takashi Eguchi
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Kazutoshi Hamanaka
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Kimihiro Shimizu
- Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
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11
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Subramaniyan V, Fuloria S, Gupta G, Kumar DH, Sekar M, Sathasivam KV, Sudhakar K, Alharbi KS, Al-Malki WH, Afzal O, Kazmi I, Al-Abbasi FA, Altamimi ASA, Fuloria NK. A review on epidermal growth factor receptor's role in breast and non-small cell lung cancer. Chem Biol Interact 2022; 351:109735. [PMID: 34742684 DOI: 10.1016/j.cbi.2021.109735] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
Epithelial growth factor receptor (EGFR) is a cell surface transmembrane receptor that mediates the tyrosine signaling pathway to carry the extracellular messages inside the cell and thereby alter the function of nucleus. This leads to the generation of various protein products to up or downregulate the cellular function. It is encoded by cell erythroblastosis virus oncogene B1, so called C-erb B1/ERBB2/HER-2 gene that acts as a proto-oncogene. It belongs to the HER-2 receptor-family in breast cancer and responds best with anti-Herceptin therapy (anti-tyrosine kinase monoclonal antibody). HER-2 positive breast cancer patient exhibits worse prognosis without Herceptin therapy. Similar incidence and prognosis are reported in other epithelial neoplasms like EGFR + lung non-small cell carcinoma and glioblastoma (grade IV brain glial tumor). Present study highlights the role and connectivity of EGF with various cancers via signaling pathways, cell surface receptors mechanism, macromolecules, mitochondrial genes and neoplasm. Present study describes the EGFR associated gene expression profiling (in breast cancer and NSCLC), relation between mitrochondrial genes and carcinoma, and several in vitro and in vivo models to screen the synergistic effect of various combination treatments. According to this study, although clinical studies including targeted treatments, immunotherapies, radiotherapy, TKi-EGFR combined targeted therapy have been carried out to investigate the synergism of combination therapy; however still there is a gap to apply the scenarios of experimental and clinical studies for further developments. This review will give an idea about the transition from experimental to most advanced clinical studies with different combination drug strategies to treat cancer.
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Affiliation(s)
- Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia
| | - Shivkanya Fuloria
- Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia
| | - Gaurav Gupta
- Department of Pharmacology, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India; Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical Sciences, Saveetha University, Chennai, India
| | - Darnal Hari Kumar
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selngor, 47500, Malaysia
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Malaysia
| | - Kathiresan V Sathasivam
- Faculty of Applied Science & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia
| | - Kalvatala Sudhakar
- School of Pharmaceutical Sciences (LIT-Pharmacy), Lovely Professional University, Jalandhar, 144411, India
| | - Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Waleed Hassan Al-Malki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam BinAbdulaziz University, AlKharj, 11942, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | | | - Neeraj Kumar Fuloria
- Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia.
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12
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Righi L, Volante M, Papotti M. Small-Cell Carcinoma of the Lung: What We Learned about It? Acta Cytol 2021; 66:257-268. [PMID: 34784591 DOI: 10.1159/000519688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022]
Abstract
Small-cell lung carcinoma (SCLC) is a high-grade aggressive disease that belongs to the neuroendocrine (NE) group of lung tumors that also includes typical carcinoid, atypical carcinoid, and large-cell NE carcinoma. SCLC has specific histological diagnostic criteria that are sometimes troublesome to be assessed in cytological samples that indeed represent the most frequent source of diagnostic material due to the typical advanced presentation at the onset of SCLC. However, cytological preparations could be in some instances more reliable than histology due to the better preservation of nuclear details. Cytological criteria for diagnosis of SCLC include high cellularity, small cell size, scant cytoplasm, coarsely granulated chromatin with "salt-and-pepper" appearance, inconspicuous or absent nucleoli, Azzopardi crush effect, and necrotic debris in the background. Despite being distinctive, these features could be incomplete to differentiate SCLC with other small-cell neoplasia. Therefore, immunocytochemical determination of diagnostic biomarkers is crucial to achieve a confident diagnosis. Furthermore, recent findings on molecular and transcriptomic studies of SCLC revealed the potential rise of new predictive and prognostic biomarkers that, whenever validated by immunocytochemistry, may potentially assist to tailor the best therapy, including immune checkpoint inhibition.
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Affiliation(s)
- Luisella Righi
- Pathology Unit, Department of Oncology, University of Torino at San Luigi Hospital, Orbassano (Torino), Italy
| | - Marco Volante
- Pathology Unit, Department of Oncology, University of Torino at San Luigi Hospital, Orbassano (Torino), Italy
| | - Mauro Papotti
- Pathology Unit, Department of Oncology, University of Torino at City of Health and Science, Torino, Italy,
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13
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Umakanthan S, Bukelo MM. Concise genetic profile of lung carcinoma. Postgrad Med J 2021; 99:postgradmedj-2021-139860. [PMID: 34083369 DOI: 10.1136/postgradmedj-2021-139860] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/21/2021] [Indexed: 12/15/2022]
Abstract
The WHO classification of lung cancer (2015) is based on immunohistochemistry and molecular evaluation. This also includes microscopic analysis of morphological patterns that aids in the pathological diagnosis and classification of lung cancers. Lung cancers are the leading cause of cancer deaths worldwide. Recent advancements in identifying the etiopathogenesis are majorly driven by gene mutation studies. This has been explained by The Cancer Genome Atlas, next-generation sequencer and TRAcking non-small cell lung cancer evolution through therapy [Rx]. This article reviews the genetic profile of adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell neuroendocrine carcinoma and pulmonary carcinoids. This includes the prolific genetic alterations and novel molecular changes seen in these tumours. In addition, target- specific drugs that have shown promising effects in clinical use and trials are also briefly discussed.
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Affiliation(s)
- Srikanth Umakanthan
- Paraclinical Sciences, The University of the West Indies at Saint Augustine Faculty of Medical Sciences, Saint Augustine, Trinidad and Tobago
| | - Maryann M Bukelo
- Department of Anatomical Pathology, Eric Williams Medical Sciences Complex, North Central Regional Health Authority, Mount Hope, Trinidad and Tobago.,Department of Anatomical Patholgy, Laboratory Services, Eric Williams Medical Sciences Complex, North Central Regional Health Authority, Mount Hope, Trinidad and Tobago
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14
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Pasala UJS, Hui M, Uppin SG, Kumar NN, Bhaskar K, Paramjyothi GK. Clinicopathological and immunohistochemical study of pulmonary neuroendocrine tumors - A single-institute experience. Lung India 2021; 38:134-138. [PMID: 33687006 PMCID: PMC8098896 DOI: 10.4103/lungindia.lungindia_482_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 09/09/2020] [Accepted: 11/24/2020] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Pulmonary neuroendocrine tumors (NETs) comprise a spectrum of tumors ranging from indolent to highly aggressive neoplasm. This study aims to study the clinicopathological and immunohistochemical features of NETs and assess the sensitivity of various IHC markers. MATERIALS AND METHODS All consecutive cases of pulmonary NETs diagnosed from January 2016 to June 2019 were analyzed retrospectively. The routine hematoxylin- and eosin-stained sections along with immunohistochemistry (IHC) slides were reviewed. IHC was done using a panel of markers which included synaptophysin, chromogranin, CD56, thyroid transcription factor-1 (TTF-1), p-40, napsin-A, and ki67. RESULTS Of total number of 53 patients, diagnosis was made on biopsy in 40 patients and resection specimen in 13 patients. Small cell lung carcinoma was the most common (31 cases), followed by 16 cases of typical carcinoid, 5 cases of atypical carcinoid, and 1 case of combined SCLC. Both synaptophysin and chromogranin were positive in all the cases of typical carcinoid. Synaptophysin had better sensitivity than chromogranin in atypical carcinoid and small cell carcinoma. CD56 was positive in 8 out of 9 cases done. TTF-1 was negative in all the cases of typical carcinoid. The sensitivity of TTF-1 in small cell carcinoma was 85.19%. The mean Ki67 labeling index was 1.4%, 6.6%, and 65.6% in typical, atypical carcinoid, and small cell carcinomas, respectively. CONCLUSION Synaptophysin was more sensitive than chromogranin, especially in atypical carcinoid and small cell carcinoma. TTF-1 along with high Ki67 differentiates small cell carcinoma from carcinoid.
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Affiliation(s)
| | - Monalisa Hui
- Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Shantveer G Uppin
- Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - N Narendra Kumar
- Department of Pulmonology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - K Bhaskar
- Department of Pulmonology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - GK Paramjyothi
- Department of Pulmonology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
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15
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Manem VS, Sazonova O, Gagné A, Orain M, Khoshkrood-Mansoori B, Gaudreault N, Bossé Y, Joubert P. Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors. Oncotarget 2021; 12:209-220. [PMID: 33613848 PMCID: PMC7869577 DOI: 10.18632/oncotarget.27874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 01/19/2021] [Indexed: 11/25/2022] Open
Abstract
Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.
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Affiliation(s)
- Venkata S.K. Manem
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
| | - Olga Sazonova
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
| | - Andréanne Gagné
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
| | - Michèle Orain
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
| | | | - Nathalie Gaudreault
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
| | - Yohan Bossé
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
- Department of Molecular Medicine, Laval University, Quebec City, QC G1V4G5, Canada
| | - Philippe Joubert
- Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada
- Department of Medical Biochemistry, Molecular Biology and Pathology, Laval University, Quebec City, QC G1V4G5, Canada
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16
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Milione M, Maisonneuve P, Grillo F, Mangogna A, Centonze G, Prinzi N, Pusceddu S, Garzone G, Cattaneo L, Busico A, Bossi P, Spaggiari P, Pellegrinelli A, Del Gobbo A, Ferrero S, Kankava K, Pruneri G, Rolli L, Roca E, Bercich L, Tironi A, Benvenuti MR, Gallazzi MS, Romano R, Berruti A, Pastorino U, Capella C. Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis. Neuroendocrinology 2021; 111:475-489. [PMID: 32365350 DOI: 10.1159/000508376] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/01/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.
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Affiliation(s)
- Massimo Milione
- First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy,
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Federica Grillo
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy
| | - Alessandro Mangogna
- Unit of Pathology, Clinical Department of Medical, Surgical and Health Science, University of Trieste, Ospedale di Cattinara, Trieste, Italy
| | - Giovanni Centonze
- First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Garzone
- First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Laura Cattaneo
- First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Adele Busico
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Paola Bossi
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy
| | - Paola Spaggiari
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy
| | - Alessio Pellegrinelli
- Department of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Brescia, Italy
| | - Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Biomedical Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Ketevani Kankava
- Teaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia
| | - Giancarlo Pruneri
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
- School of Medicine, University of Milan, Milan, Italy
| | - Luigi Rolli
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Elisa Roca
- Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy
| | - Luisa Bercich
- Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Andrea Tironi
- Department of Pathology, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Mauro Roberto Benvenuti
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Maria Sole Gallazzi
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Rosalia Romano
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy
| | - Ugo Pastorino
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Carlo Capella
- Unit of Pathology, Department of Medicine and Surgery and Research Center for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy
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17
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Moonen L, Derks JL, Hermans BCM, Bunnik IM, Hillen LM, van Suylen RJ, den Bakker MA, von der Thüsen JH, Damhuis RA, van den Broek EC, Buikhuisen WA, Dingemans AMC, Speel EJM. Preoperative Biopsy Diagnosis in Pulmonary Carcinoids, a Shot in the Dark. J Thorac Oncol 2020; 16:610-618. [PMID: 33333326 DOI: 10.1016/j.jtho.2020.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/25/2020] [Accepted: 12/07/2020] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The preferred treatment for pulmonary carcinoids (PCs) is lobectomy, and parenchyma-sparing approaches might be considered for typical carcinoids (TCs). Treatment decisions are based on a preoperative biopsy diagnosis. Following the WHO criteria (2015), definitive diagnosis is only feasible postoperatively, thereby hampering preoperative treatment decisions. Here, we determined whether the final carcinoid classification on a resection specimen can be predicted by a preoperative biopsy. METHODS We searched all stage I to III patients with a final carcinoid diagnosis who underwent a curative resection and of whom both a preoperative biopsy and paired resection specimen were available (2003-2012) using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry (IKNL). Pathology report conclusions of the biopsy-resection specimen were compared. RESULTS Paired biopsy-resection specimens in combination with clinical data were available from 330 patients. 57% (189 of 330) of the patients exhibited discordance between the preoperative biopsy and paired resection diagnosis, including 36% (44 of 121) preoperatively diagnosed TC, 40% (six of 15) atypical carcinoid (AC), and 65% (103 of 158) not-otherwise-specified (NOS) carcinoids. A quarter of preoperatively diagnosed TC and NOS was reclassified as AC on the resection specimen. Preoperatively diagnosed ACs exhibited the highest relapse rates (40%, 6 of 15). Preoperatively diagnosed TC and NOS patients who were reclassified as ACs exhibited higher relapse rates as compared to nonreclassified TCs and NOS (3% versus 1%, and 16% versus 6%). CONCLUSIONS We provide evidence that carcinoid classification on preoperative biopsies is imprecise, as is also stated by the current WHO classification. We advise clinicians to interpret the preoperative biopsy diagnosis with caution in deciding the extent of surgery (e.g., parenchyma-sparing versus non-parenchyma-sparing).
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Affiliation(s)
- Laura Moonen
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Jules L Derks
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Bregtje C M Hermans
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Iris M Bunnik
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Lisa M Hillen
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | | | | | | | - Ronald A Damhuis
- Department Research, Comprehensive Cancer Association, Utrecht, The Netherlands
| | | | - Wieneke A Buikhuisen
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Anne-Marie C Dingemans
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Pulmonary Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ernst Jan M Speel
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
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18
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Phospho-histone-H3 immunostaining for pulmonary carcinoids: impact on clinical appraisal, interobserver correlation, and diagnostic processing efficiency. Hum Pathol 2020; 106:74-81. [PMID: 33007357 DOI: 10.1016/j.humpath.2020.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/14/2020] [Accepted: 09/21/2020] [Indexed: 02/01/2023]
Abstract
Lung carcinoid tumors are classified as either typical or atypical based on the presence of necrosis and the maximum mitotic count per 2 mm2 area. Determining the mitotic count, which is manually conducted on slides stained with hematoxylin and eosin (HE), is time-consuming and subject to high interobserver variability. The objective of this study was to test the sensitivity and specificity of a surrogate mitosis marker, phospho-histone-H3 (PHH3) immunostaining, in the processing of pulmonary carcinoids as compared with the standard HE evaluation. Carcinoid tissue blocks that were available from lung resection specimens were analyzed using HE and PHH3 stains. Two thoracic pathologists and two residents determined the mitotic count on HE and PHH3 stains in accordance with the 2015 WHO guidelines and recorded the time required to complete this task. For both methods, the interobserver agreement among raters for the mitotic count/2 mm2 was assessed by conducting intraclass correlation analyses. We found that for both pathologists and residents, the time required to determine the mitotic count using the PHH3 method was reduced compared with the traditional HE method. Furthermore, residents detected more mitoses/2 mm2 using the PHH3 stain compared with the HE method. More importantly, the PHH3 method yielded better interobserver agreement than the HE method in terms of mitoses/mm2 detection. Overall, our data confirmed that histologic assessments of carcinoid tumors using PHH3 staining provides practical benefits in terms of scoring times, mitosis detection, and reproducibility of mitotic counts. In addition, we found that the benefit was even greater for less experienced pathologists.
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19
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Li Z, Hu J, Chen P, Zeng Z. Incidence, treatment, and survival analysis in esophageal neuroendocrine carcinoma population. Transl Cancer Res 2020; 9:4317-4329. [PMID: 35117798 PMCID: PMC8797452 DOI: 10.21037/tcr-19-2650] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 05/29/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND As a subtype of esophageal neuroendocrine neoplasms (ENENs), esophageal neuroendocrine carcinoma (ENEC) is rare. ENEC can be poorly differentiated and highly aggressive. This study aims to illustrate the incidence, treatment, and prognosis of ENEC by using a population-based database. METHODS We collected clinicopathological data [1975-2016] of ENEC, esophageal adenocarcinoma (EACA), and esophageal squamous cell carcinoma (ESqCC) from the Surveillance, Epidemiology and End Results (SEER) database, and analyzed their incidence, treatment, and prognosis. RESULTS A total of 60,238 cases were in our study cohort, including ENEC (n=686), EACA (n=26,575), and ESqCC (n=32,977). The incidence of ENEC in 2016 was 0.044 per 100,000 persons. The tumor grade of ENEC was significantly higher than that of EACA and ESqCC (P<0.001). Both cancer-specific survival (CSS) and overall survival (OS) of ENEC were significantly worse than those of EACA and ESqCC (P<0.001). Kaplan-Meier analysis showed significant improvement of CSS and OS by surgery, radiotherapy, and chemotherapy (all P<0.001). Besides, compared with monotherapies, combinational therapies brought more benefits to both CSS and OS of patients with ENEC. CONCLUSIONS Our population-based evidence revealed that ENEC, as a rare cancer, had a worse prognosis, compared with EACA and ESqCC. Surgery, chemotherapy, and radiotherapy can all improve the prognosis of ENEC patients. Combinational therapy can yield a better prognosis than monotherapy.
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Affiliation(s)
- Zhenhua Li
- Department of Cardiothoracic Surgery, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Jiali Hu
- Department of Pathology, Jiujiang University Clinic College/Hospital, Jiujiang, China
| | - Pifeng Chen
- Department of Pediatric Surgery, Jiujiang Maternal and Child Health Hospital, Jiujiang, China
| | - Zhi Zeng
- Department of Pathology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
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20
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Samaratunga H, Delahunt B, Srigley JR, Berney DM, Cheng L, Evans A, Furusato B, Leite KRM, MacLennan GT, Martignoni G, Moch H, Pan CC, Paner G, Ro J, Thunders M, Tsuzuki T, Wheeler T, van der Kwast T, Varma M, Williamson SR, Yaxley JW, Egevad L. Granular necrosis: a distinctive form of cell death in malignant tumours. Pathology 2020; 52:507-514. [PMID: 32561208 DOI: 10.1016/j.pathol.2020.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/11/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
Foci of necrosis are frequently seen in malignant tumours and may be due to a variety of causes. Different types of necrosis are given various names based upon their morphological features and presumed pathogenesis, such as coagulative, liquefactive and fibrinoid necrosis. Here, we propose the term 'granular necrosis' (GN) for a specific form of tumour necrosis characterised by the presence of well-defined necrotic foci being sharply demarcated from adjacent viable tumour. A constant feature is loss of architecture resulting in an amorphous necrotic mass containing granular nuclear and cytoplasmic debris, without an associated neutrophilic infiltrate. There is usually extensive karyorrhexis, which in larger tumours is more prominent at the periphery. These foci are often microscopic but may range up to several millimetres or larger in size. This distinctive form of necrosis has been erroneously given a variety of names in the literature including coagulative necrosis and microscopic necrosis, which on the basis of the aforementioned gross and microscopic findings is inappropriate. It is apparent that this is a specific form of necrosis, hence the descriptive term 'granular necrosis' that differentiates this form of necrosis from other types. The presence of GN is recognised as occurring in a variety of tumour types, being commonly seen in renal cell carcinoma, where it has been shown to have independent prognostic significance. In some epithelial and stromal tumours of the uterus, the presence of GN also has prognostic significance and is a defining feature for the differentiation of uterine leiomyoma and leiomyosarcoma. The pathogenesis of GN is unresolved. It does not show the features of apoptosis and in recent studies has been shown to have some of the molecular changes associated with necroptosis.
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Affiliation(s)
| | - Brett Delahunt
- Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
| | - John R Srigley
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Daniel M Berney
- Department of Molecular Oncology, Queen Mary University Hospital, London, United Kingdom
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrew Evans
- Department of Laboratory Information Support Systems, University Health Network, Toronto, ON, Canada
| | - Bungo Furusato
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences and Cancer Genomics Unit, Clinical Genomics Center, Nagasaki University Hospital, Sakamoto, Nagasaki, Japan
| | - Katia R M Leite
- Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Gregory T MacLennan
- Department of Pathology and Urology, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Guido Martignoni
- Department of Pathology and Diagnostics, School of Medicine and Surgery, University of Verona, Verona, Italy
| | - Holger Moch
- University and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
| | - Chin-Chen Pan
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Gladell Paner
- Departments of Pathology and Surgery (Section of Urology) University of Chicago, Chicago, IL, USA
| | - Jae Ro
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX, USA
| | - Michelle Thunders
- Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
| | - Toyonori Tsuzuki
- Department of Surgical Pathology, Aichi Medical University, School of Medicine, Nagakute, Japan
| | - Thomas Wheeler
- Department of Pathology and Laboratory Medicine, Baylor St Luke's Medical Center and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Theodorus van der Kwast
- Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Murali Varma
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
| | | | - John W Yaxley
- Department of Medicine, University of Queensland, Wesley Urology Clinic, Royal Brisbane and Womens Hospital, Brisbane, Qld, Australia
| | - Lars Egevad
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
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21
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Epithelial-Mesenchymal Transition Proteins in Neuroendocrine Neoplasms: Differential Immunohistochemical Expression in Different Sites and Correlation with Clinico-Pathological Features. Diagnostics (Basel) 2020; 10:diagnostics10060351. [PMID: 32481578 PMCID: PMC7345712 DOI: 10.3390/diagnostics10060351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 11/24/2022] Open
Abstract
The first step leading to metastasis, or for the acquisition of local invasiveness, involves changes in the phenotype of neoplastic cells in the primary tumor. The epithelial–mesenchymal transition (EMT) is a process that determines the acquisition of a form and a transcriptional program that are characteristic of mesenchymal cells, in epithelial cells. The factors involved in this process are E-cadherin and N-cadherin adhesion proteins and some transcription factors such as Slug and Twist. EMT is a site-specific mechanism that is also active in embryogenesis—embryonic cells are affected if invested in certain points, probably due to the signals emanating from the cells or groups of surrounding cells. It is known that neuroendocrine neoplasms have a biological behavior that differs in grading, staging, and site. The aim of our study was to investigate the immunohistochemical expression of EMT factors (Twist, Slug, and E-cadherin) in the neuroendocrine neoplasms of the gastrointestinal tract, the pancreas, and lungs, in 65 cases retrieved from the archives of the Department of Pathology, of three hospitals. The immunoscores were compared in each site and correlated with the clinico-pathological parameters. Statistical evaluation revealed an association between the higher Twist immunoscore and higher grading (p value < 0.0001) and staging (p value = 0.0055). Slug was detected only in pancreatic cases where its reduced expression was associated with a higher grading (p value = 0.0033). This data could be of diagnostic utility in the case of metastases from neuroendocrine neoplasm, to define the site of the primitive tumor when the traditional immunohistochemical panel is not sufficient. In summary, our results indicated, first that the EMT is also an active process in neuroendocrine neoplasms. To the best of our knowledge, this was the first study that evaluated the expression of EMT factors in neuroendocrine neoplasms of different districts.
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22
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Outcomes of Patients with Clinical Stage I-IIIA Large-Cell Neuroendocrine Lung Cancer Treated with Resection. J Clin Med 2020; 9:jcm9051370. [PMID: 32392725 PMCID: PMC7290504 DOI: 10.3390/jcm9051370] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/21/2020] [Accepted: 04/28/2020] [Indexed: 01/18/2023] Open
Abstract
Large-cell neuroendocrine carcinoma (LCNEC) is a rare malignancy with poor prognosis. The rationale of the study was to determine the survival of LCNEC patients in I–IIIA clinical stages who underwent resection. A total of 53 LCNEC (89%) and combined LCNEC (11%) patients in stages I–IIIA who underwent surgery with radical intent between 2002–2018 were included in the current study. Overall survival (OS) and time to recurrence (TTR) were estimated. Uni- and multivariable analyses were conducted using Cox-regression model. Patients were treated with surgery alone (51%), surgery with radiochemotherapy (4%), with radiotherapy (2%), with adjuvant chemotherapy (41%), or with neoadjuvant chemotherapy (2%). The median (95% Confidence Interval (CI)) OS and TTR was 52 months (20.1–102.1 months) and 20 months (7.0–75.6 months), respectively. Patients treated in clinical stage I showed better OS than patients in stages II–IIIA (p = 0.008). Patients with R0 resection margin (negative margin, no tumor at the margin) and without lymph node metastasis had significantly better TTR. In the multivariate analysis, age was an independent factor influencing OS. Recurrence within 1 year was noted in more than half cases of LCNEC. R0 resection margin and N0 status (no lymph node metastasis) were factors improving TTR. Age >64 years was observed as a main independent factor influencing OS.
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23
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Wang J, Ye L, Cai H, Jin M. Comparative study of large cell neuroendocrine carcinoma and small cell lung carcinoma in high-grade neuroendocrine tumors of the lung: a large population-based study. J Cancer 2019; 10:4226-4236. [PMID: 31413741 PMCID: PMC6691699 DOI: 10.7150/jca.33367] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/28/2019] [Indexed: 11/05/2022] Open
Abstract
Background: In 2015, large cell neuroendocrine carcinoma (LCNEC) was removed from the large cell carcinoma group and classified with small cell lung carcinoma (SCLC) constituting two members of the high-grade neuroendocrine tumors (NETs) of the lung. However, the difference between high-grade LCNEC and SCLC in terms of clinicopathological characteristics and prognosis has not been fully understood owing to the rarity of LCNEC. Patients and methods: Patients with high-grade LCNEC and SCLC at initial diagnosis between 2001 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) program database. Clinicopathological characteristics between high-grade LCNEC and SCLC were compared using the Pearson's chi-squared test or Fisher's exact test. Differences in overall survival (OS) and cancer-specific survival (CSS) were compared using the log-rank test, Cox models and propensity score matching (PSM) analysis. Results: A total of 1223 patients with high-grade LCNEC and 18182 patients with high-grade SCLC were enrolled. To the best of our knowledge, this study involved the largest number of high-grade LCNEC patients to date, with respect to a comparison between high-grade LCNEC and high-grade SCLC patients. There were significant differences in age, sex, race, laterality, SEER stage, nodal status, surgery, radiation and chemotherapy, but not marital status, between high-grade LCNEC and SCLC patients. High-grade LCNEC patients had a better OS and CSS than high-grade SCLC patients. Subgroup analysis also confirmed the better prognosis of the high-grade LCNEC patients in the regional stage, distant stage and surgery subgroups. However, no significant difference in prognosis was observed between the two non-surgery subgroups, which was confirmed using PSM analysis. Furthermore, high-grade LCNEC patients showed different metastatic patterns to high-grade SCLC patients. Conclusion: These results suggested that high-grade LCNEC and high-grade SCLC were different histological types, and that a detailed classification for high-grade NETs of the lung was needed.
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Affiliation(s)
- Jian Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200030, China
| | - Ling Ye
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200030, China
| | - Hui Cai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200030, China
| | - Meiling Jin
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200030, China
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24
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Yoxtheimer LM, Heymann JJ, Cohen C, Rao RA, Goyal A, Siddiqui MT. Immunohistochemical analysis of OTP and NKX6.1 in neuroendocrine tumors of the lung and pancreas. Diagn Cytopathol 2018; 46:1010-1014. [PMID: 30284410 DOI: 10.1002/dc.24088] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/16/2018] [Accepted: 09/11/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Homeobox transcription factors have demonstrated utility in diagnosing neuroendocrine tumors. Orthopedia homeobox protein (OTP) has a well-defined role in embryonic neurodevelopment and has also been described as a prognostic marker in lung neuroendocrine tumors (NET). Additionally, NK6 homeobox-1 (NKX6.1) has been described to be necessary for the development of neuroendocrine cells in the pancreas. We evaluated immunohistochemical (IHC) expression of OTP and NKX6.1 to determine their utility in the diagnosis of NETs from lung and pancreas fine-needle aspirations (FNA). METHODS Our study examined 50 FNA specimens, including 30 primary pulmonary NETs (8 carcinoid tumors (CT), 6 atypical carcinoids (AC), 11 small-cell neuroendocrine carcinomas (SCNEC), 5 large-cell neuroendocrine carcinomas (LCNEC)) and 20 primary pancreatic NETs (17 well-differentiated pancreatic neuroendocrine tumors (PanNET) and 3 poorly differentiated pancreatic neuroendocrine carcinomas (PanNEC)). IHC expression of OTP, NKX6.1, and Ki-67 was evaluated on FNA cell blocks. RESULTS Half of the pulmonary TC tumors expressed OTP, while only 17% of AC and 20% of LCNEC expressed OTP. Neither SCNECs nor any pancreatic NET expressed OTP. In contrast, intermediate and high-grade tumors expressed NKX6.1 (LCNEC-80%, SCNEC-82%, and AC-83%) more often than low-grade tumors (TC-63%, PanNET-71%). All three PanNECs expressed NKX6.1. CONCLUSIONS OTP may be useful in diagnosing well-differentiated NETs of pulmonary origin. NKX6.1 may have utility in segregating high from low-grade NETs of both pulmonary and pancreatic origin, although other methods will be required to determine site of origin.
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Affiliation(s)
- Lorene M Yoxtheimer
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Jonas J Heymann
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Cynthia Cohen
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia
| | - Rema A Rao
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Abha Goyal
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Momin T Siddiqui
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
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