Contemporary Pathological Classification of Primary Lung Tumors: Integration of Morphology, Immunohistochemistry, and Molecular Pathology
DOI:
https://doi.org/10.5644/ama2006-124.521Keywords:
Lung Carcinoma, Morphology, Molecular Pathology, WHO Classification, BiomarkersAbstract
This review summarizes the current World Health Organization (WHO) classification of lung tumors, emphasizing key morphological, immunohistochemical, and molecular features relevant to diagnosis and management. Review. Primary pulmonary tumors comprise a heterogeneous spectrum of neoplasms with distinct morphological, immunophenotypic, molecular, and clinical characteristics. The current WHO classification integrates traditional histopathological assessment with immunohis- tochemical and molecular findings, reflecting advances in our understanding of tumor biology and the growing importance of precision medicine. This review summarizes the major categories of primary pulmonary tumors, including adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, sarcomatoid carcinomas, neuroendocrine neoplasms, salivary gland-type tumors, and mesenchymal tumors specific to the lung, as well as selected rare pulmonary neoplasms. Particular attention is given to the defining morphological characteristics and diagnostic criteria of individual tumor entities, relevant immunohistochemical profiles, and recurrent molecular alterations with diagnostic, prognostic, and therapeutic implications. The challenges of diagnosing pulmonary tumors in small biopsies and cytological specimens are also addressed, with an emphasis on the judicious use of immunohistochemistry and preservation of tissues for molecular testing. Conclusion. Accurate classification of primary pulmonary tumors requires the integration of morphological, immunohistochemical, and molecular findings within the framework of the current WHO Classification of Thoracic Tumors. Recognition of the characteristic morphological and immunophenotypic features, together with appropriate molecular characterization, is essential for precise diagnosis and optimal patient management. Continued advances in molecular pathology are expected to further refine pulmonary tumor classification and contribute to increasingly personalized therapeutic strategies.
References
International Agency for Research on Cancer. Global Cancer Observatory: Cancer Today. GLOBOCAN 2022 estimates of incidence and mortality worldwide for 36 cancers in 185 countries [Internet]. Version 1.1. Lyon (France): International Agency for Research on Cancer; 2024. [cited 2026 May 31]. Available from: https://gco.iarc.who.int.
WHO Classification of Tumours Editorial Board. Thoracic tumours. 5th ed. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series; vol. 5). [cited 2026 May 31]. Available from: https://publications.iarc.fr/595.
Sasaki T, Kuno H, Hiyama T, Oda S, Masuoka S, Miyasaka Y, et al. 2021 WHO Classification of Lung Cancer: Molecular Biology Research and Radiologic-Pathologic Correlation. Radiographics. 2024;44(3):e230136. doi: 10.1148/rg.230136.
Pan X, Yang X, Li J, Dong X, He J, Guan Y. Is a 5-mm diameter an appropriate cut-off value for the diagnosis of atypical adenomatous hyperplasia and adenocarcinoma in situ on chest computed tomography and pathological examination? J Thorac Dis. 2018;10(Suppl 7):S790-6. doi: 10.21037/jtd.2017.12.124.
Itami H, Taniguchi S, Yasukawa M, Fujii T, Ohbayashi C. A case of a rare non-invasive lung adenocarcinoma. Int J Surg Case Rep. 2020;76:386-9. doi: 10.1016/j.ijscr.2020.10.038.
Thunnissen E, Beasley MB, Borczuk AC, Brambilla E, Chirieac LR, Dacic S, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol. 2012;25(12):1574-83. doi: 10.1038/modpathol.2012.106.
Thunnissen E, Beasley MB, Borczuk A, Dacic S, Kerr KM, Lissenberg-Witte B, et al. Defining morphologic features of invasion in pulmonary nonmucinous adenocarcinoma with lepidic growth: a proposal by the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2023;18(4):447-62. doi: 10.1016/j.jtho.2022.11.026.
Filipello F, Blaauwgeers H, Lissenberg-Witte B, Schonau A, Doglioni C, Arrigoni G, et al. Stereologic consequences of iatrogenic collapse: the morphology of adenocarcinoma in situ overlaps with invasive patterns. Proposal for a necessary modified classification of pulmonary adenocarcinomas. Lung Cancer. 2024;197:107987. doi: 10.1016/j.lungcan.2024.107987.
Yotsukura M, Asamura H, Motoi N, Kashima J, Yoshida Y, Nakagawa K, et al. Long-term prognosis of patients with resected adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung. J Thorac Oncol. 2021;16(8):1312-20. doi: 10.1016/j.jtho.2021.04.007.
Tsuta K, Kawago M, Inoue E, Yoshida A, Takahashi F, Sakurai H, et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations. Lung Cancer. 2013;81(3):371-6. doi: 10.1016/j.lungcan.2013.06.012.
Abolfathi H, Maranda-Robitaille M, Lamaze FC, Kordahi M, Armero VS, Orain M, et al. Integrating histologic descriptors into the ninth edition TNM staging improves prognostic stratification of lung adenocarcinoma. J Thorac Oncol. 2026;21(9):103895. doi: 10.1016/j.jtho.2026.103895.
Möller K, Gulzar T, Lennartz M, Viehweger F, Kluth M, Hube-Magg C, et al. TTF-1 is a highly sensitive but not fully specific marker for pulmonary and thyroidal cancer: a tissue microarray study evaluating more than 17,000 tumors from 152 different tumor entities. Virchows Arch. 2024;485(5):815-28. doi: 10.1007/s00428-024-03926-1.
Rekhtman N, Ang DC, Riely GJ, Ladanyi M, Moreira AL. KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. Mod Pathol. 2013;26(10):1307-19. doi: 10.1038/modpathol.2013.74.
Mescam-Mancini L, Lantuéjoul S, Moro-Sibilot D, Rouquette I, Souquet PJ, Audigier-Valette C, et al. On the relevance of a testing algorithm for the detection of ROS1-rearranged lung adenocarcinomas. Lung Cancer. 2014;83(2):168-73. doi: 10.1016/j.lungcan.2013.11.019.
Lee SE, Lee B, Hong M, Song JY, Jung K, Lira ME, et al. Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma. Mod Pathol. 2015;28(4):468-79. doi: 10.1038/modpathol.2014.107.
Chang JC, Offin M, Falcon C, Brown D, Houck-Loomis BR, Meng F, et al. Comprehensive molecular and clinicopathologic analysis of 200 pulmonary invasive mucinous adenocarcinomas identifies distinct characteristics of molecular subtypes. Clin Cancer Res. 2021;27(14):4066-76. doi: 10.1158/1078-0432.CCR-21-0423.
Zuo Y, Zhong J, Bai H, Xu B, Wang Z, Li W, et al. Genomic and epigenomic profiles distinguish pulmonary enteric adenocarcinoma from lung metastatic colorectal cancer. EBioMedicine. 2022;82:104165. doi: 10.1016/j.ebiom.2022.104165.
Jurmeister P, Schöler A, Arnold A, Klauschen F, Lenze D, Hummel M, et al. DNA methylation profiling reliably distinguishes pulmonary enteric adenocarcinoma from metastatic colorectal cancer. Mod Pathol. 2019;32(6):855-65. doi: 10.1038/s41379-019-0207-y.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-80. doi: 10.1056/NEJMra0802714.
Tatsumori T, Tsuta K, Masai K, Kinno T, Taniyama T, Yoshida A, et al. p40 is the best marker for diagnosing pulmonary squamous cell carcinoma: comparison with p63, cytokeratin 5/6, desmocollin-3, and SOX2. Appl Immunohistochem Mol Morphol. 2014;22(5):377-82. doi: 10.1097/PAI.0b013e3182980544.
Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, et al. Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol. 2019;14(3):377-407. doi: 10.1016/j.
jtho.2018.12.005.
Joshi A, Mishra R, Desai S, Chandrani P, Kore H, Sunder R, et al. Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations. Oncotarget. 2021;12(6):578-88. doi: 10.18632/oncotarget.27905.
Meng Q, Dong Y, Tao H, Shi L, Tong L, Tang J, et al. ALK-rearranged squamous cell carcinoma of the lung. Thorac Cancer. 2021;12(7):1106-14. doi: 10.1111/1759-7714.13818.
Hanna NH, Schneider BJ, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2020;38(14):1608-32. doi: 10.1200/JCO.19.03022. Epub 2020 Jan 28.
Rekhtman N, Montecalvo J, Chang JC, Alex D, Ptashkin RN, Ai N, et al. SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas. J Thorac Oncol. 2020;15(2):231-47. doi: 10.1016/j.jtho.2019.10.023. Epub 2019 Nov 18.
Wang G, Zhou G, Han W, Jiang H. The role of SMARCA4 in lung cancer. Sci Rep. 2025;15:28605. doi: 10.1038/s41598-025-13913-4.
Olteanu GE, Brcic L. Pulmonary puzzles: salivary glandtype tumors of the lung and their metastatic equivalents. Memo. 2024;17:110-16. doi: 10.1007/s12254-023-00957-3.
Wang M, Gilani S, Xu H, Cai G. Salivary gland-type tumors of the lung: a distinct group of uncommon lung tumors. Arch Pathol Lab Med. 2021;145(11):1379-86. doi: 10.5858/arpa.2021-0093-RA.
Takamatsu M, Sato Y, Muto M, Nagano H, Ninomiya H, Sakakibara R, et al. Hyalinizing clear cell carcinoma of the bronchial glands: presentation of three cases and pathological comparisons with salivary gland counterparts and bronchial mucoepidermoid carcinomas. Mod Pathol. 2018;31(6):923-33. doi: 10.1038/s41379-018-0025-7. Epub 2018 Feb 12.
Li X, Ding K, Liu D, Wang Y, Xu Y. Histologic transformation after targeted therapy resistance in driver genepositive NSCLC: mechanisms and therapeutic challenges. Ther Adv Med Oncol. 2025;17:17588359251369038. doi: 10.1177/17588359251369038.
Tomic K, Krpina K, Baticic L, Samarzija M, Vranic S. Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report. J Drug Target. 2024;32(5):499-509. doi: 10.1080/1061186X.2024.2332733.
Liu S, Xu T, Cao X, Li H, Jin R. Histological transformation in lung cancer: mechanisms, clinical characteristics, and therapeutic approaches. BBA Rev Cancer. 2025;1880(5):189413. doi: 10.1016/j.bbcan.2025.189413.
Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other nonsmall cell carcinomas. Mod Pathol. 2012;25 Suppl 1:S18-30. doi: 10.1038/modpathol.2011.150.
Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol. 2019;32(1):100-9. doi: 10.1038/s41379-018-0122-7.
Baine MK, Hsieh MS, Lai WV, Egger JV, Jungbluth AA, Daneshbod Y, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. J Thorac Oncol. 2020;15(12):1823-35. doi: 10.1016/j.jtho.2020.09.009.
Yu Z, Zou J, Xu F. The molecular subtypes of small cell lung cancer defined by key transcription factors and their clinical significance. Lung Cancer. 2024;198:108033. doi: 10.1016/j.lungcan.2024.108033. Epub 2024 Nov 19.
Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO Classification of Lung Tumors: impact of advances since 2015. J Thorac Oncol. 2022;17(3):362-87. doi: 10.1016/j.jtho.2021.11.003.
Nassar AH, Kim C, Adeyelu T, Bou Farhat E, Abushukair H, Rakaee M, et al. Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma. Nat Commun. 2025;16(1):7717. doi: 10.1038/s41467-025-63091-0.
Hashimoto H, Tsugeno Y, Sugita K, Inamura K. Mesenchymal tumors of the lung: diagnostic pathology, molecular pathogenesis, and identified biomarkers. J Thorac Dis. 2019;11(Suppl 1):S9-24. doi: 10.21037/jtd.2018.12.04.
Thway K, Nicholson AG, Lawson K, Gonzalez D, Rice A, Balzer B, et al. Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a new tumor entity. Am J Surg Pathol. 2011;35(11):1722-32. doi: 10.1097/PAS.0b013e318227e4d2.
Smolarz B, Łukasiewicz H, Samulak D, Piekarska E, Kołaciński R, Romanowicz H. Lung cancer—epidemiology, pathogenesis, treatment and molecular aspect: review of literature. Int J Mol Sci. 2025;26(5):2049. doi: 10.3390/ijms26052049.
Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington J, Leighl NB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology clinical practice guideline update. J Clin Oncol. 2018;36(9):911-19. doi: 10.1200/JCO.2017.76.7293.
Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40(6):611-25. doi: 10.1200/JCO.21.01626.
Friedlaender A, Pérol M, Banna G, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res. 2024;12:24. doi: 10.1186/s40364-024-00566-0.
Sholl LM, Awad M, Basu Roy U, Beasley MB, Cartun RW, Hwang DM, et al. Programmed death ligand-1 and tumor mutation burden testing of patients with lung cancer for selection of immune checkpoint inhibitor therapies: guideline from the College of American Pathologists, Association for Molecular Pathology, International Association for the Study of Lung Cancer, Pulmonary Pathology Society, and LUNGevity Foundation. Arch Pathol Lab Med. 2024;148(7):757-74. doi: 10.5858/arpa.2023-0536-CP.
Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-62. doi: 10.1016/j.jtho.2021.06.017.
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