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ES17.03 Updates in Squamous Cell Carcinoma and Neuroendocrine Tumors of the Lung

      Terminology for these tumours has been updated within the upcoming WHO classification (1), in order to become more consistent with neuroendocrine neoplasms arising at other sites. Neuroendocrine tumours (NETs) comprise low grade typical carcinoids (TCs) and intermediate grade atypical carcinoids (ACs), with neuroendocrine carcinomas (NECs) comprising large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) (2). However, although this overarching structure and terminology has changed, the specific criteria for all four of these tumour cell types essentially remain the same as those in the 2015 WHO classification, and are based primarily on morphology and supplemented by immunohistochemistry (IHC). Clinically, there has been little change in data , other than there is increased recognition of both SCLC and LCNEC arising in the setting of acquired resistance to tyrosine kinase inhibitor therapy for adenocarcinoma with EGFR mutations (3). Diagnostic IHC mainly comprises cytokeratins, neuroendocrine (NE) markers and TTF1. Use of Ki-67 still remains a topic of controversy, although its use for metastatic carcinoid tumours is recommended as medical oncologists use the level of proliferation to stratify patients for therapy. Also Ki-67 can be of particular value in biopsies where there is considerable crush artefact. Whilst these criteria and recommendations have not changed significantly, there has been increased data on molecular abnormalities in NENs since the last edition. Carcinoid tumours have low mutation rates, and recent publications have identification of 3 molecular cell subgroups. The first cluster is mainly TCs, showing over-expression of ASCL1 and DLL3. The second cluster was is mainly TCs and show down regulation of ROBO1 and SLIT1 genes, along with somatic EIF1AX mutations and expression of HNF1a and FOXA3. The third cluster contains more ACs and is characterised by somatic MEN1 mutations., again with expression of HNF1a and FOXA3 (4,5). For LCNEC, a high frequency of TP53 and RB1 inactivation has been identified (6,7) and they largely comprise two distinct genomic subsets. The first has a SCLC-like genomic profile and the second a profile similar to that found in adenocarcinoma (6,8,9). Whilst this raises the question of whether these should be better classified according to these data, transcriptomic analysis shows these subsets are distinct from SCLCs and NSCLCs, respectively. There have also been recent papers looking at whether there should be a third category of NET, equivalent to grade 3 at other sites, based on a carcinoid-like morphology but a mitotic rate of >10 per 2mm2. This is consistent with a small group of LCNEC showing molecular profile closest to carcinoids (6). At present, the recommendation is to still classify these as LCNEC but to note carcinoid-like morphology and the mitotic rate/proliferation index. DIPNECH remains as a precursor lesion for NETs, although not for NECs. It is found mainly in 50-60 year-old female never-smokers and is more common in peripheral than central carcinoids. Some patients have coexistent obliterative bronchiolitis and obstructive airways disease, although most patients remain stable. Histologically, there are multiple foci of neuroendocrine hyperplasia and/or tumourlets. Some cases are associated with type 1 multiple endocrine neoplasia (MEN) syndrome (10-12). Squamous cell carcinoma As for NENs, the overarching structure has been changed to reflect better the biology of primary epithelial lung cancers showing squamous differentiation, although criteria for specific tumours have not changed significantly. Squamous precursor lesions comprise dysplasia (mild, moderate (low-grade), severe (high-grade)) and squamous carcinoma in situ. The basaloid variant has been grouped within squamous cell carcinoma, although should still be reported as such when >50% of a resected tumour shows basaloid morphology. Lymphoepithelial carcinoma is also now included under squamous cell carcinoma as a poorly differentiated squamoid malignancy frequently associated with Epstein-Barr Virus . REFERENCES 1. WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. Lyon (France): International Agency for Research on Cancer; In press. 2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770-1786. 3. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. 4. Laddha SV, da Silva EM, Robzyk K, et al. Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids. Cancer Res. 2019;79(17):4339-4347. 5. Alcala N, Leblay N, Gabriel AAG, et al. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun. 2019;10(1):3407. 6. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res. 2016;22(14):3618-3629. 7. Miyoshi T, Umemura S, Matsumura Y, et al. Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung. Clin Cancer Res. 2017;23(3):757-765. 8. Derks JL, Leblay N, Lantuejoul S, Dingemans AC, Speel EM, Fernandez-Cuesta L. New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management. J Thorac Oncol. 2018;13(6):752-766. 9. George J, Walter V, Peifer M, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9(1):1048. 10. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248-252. 11. Mengoli MC, Rossi G, Cavazza A, et al. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Syndrome and Carcinoid Tumors With/Without NECH: A Clinicopathologic, Radiologic, and Immunomolecular Comparison Study. Am J Surg Pathol. 2018;42(5):646-655. 12. Rossi G, Cavazza A, Spagnolo P, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 2016;47(6):1829-1841.

      Keywords

      squamous cell carcinoma, neuroendocrine, classification