OBJECTIVES: Evaluating invasion in non-mucinous adenocarcinoma (NMA) of the lung is crucial for accurate pT-staging. This study compares the World Health Organization (WHO) with a recently modified NMA classification. MATERIALS AND METHODS: A retrospective case-control study was conducted on small NMA pT1N0M0 cases with a 5-year follow-up. Seventy cases were reviewed by 42 pulmonary pathologists first according to the WHO classification and after tutorial according to a modified classification. A third round was conducted based on feedback from 41 peers of previous rounds. Additionally, orthogonal biomarker analysis was performed. RESULTS: In the first two rounds, 42 pathologists from 13 countries assessed all 70 cases, while 36 pathologists evaluated 41 non-unanimous cases in the third round. Kappa values for invasiveness increased in rounds 1, 2, and 3 to 0.27, 0.45 and 0.62, respectively. In contrast to low variation in total tumor size measurements (6 %), a marked increase in invasive tumor size variation was observed (42 %), which was associated with high uncertainty. In the third round 10 cases were non-invasive, all without recurrence. The modified classification showed in the 3rd round marked reduction of the variation in pT staging compared to the current WHO classification. Proliferation rate, tumor mutational burden, and transcriptomic profiles supported the distinction between invasive cases and non-invasive cases of the modified classification. CONCLUSION: The modified classification demonstrates essentially higher reproducibility compared to the current WHO classification in NMA. The modified classification proves valuable in identifying low-risk lesions that are entirely non-invasive, and is supported by biomarker analysis.

Dept of Epidemiology and Data Science Amsterdam UMC VU University Amsterdam the Netherlands

Dept of Pathology Aarhus University Aarhus Denmark

Dept of Pathology Amsterdam UMC VU University Amsterdam the Netherlands

Dept of Pathology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Dept of Pathology Charles University ESP Hradec Kralove Czech Republic

Dept of Pathology Department of Oncology and Hemato Oncology University of Milan Milan Italy

Dept of Pathology Erasmus Medical Center Rotterdam the Netherlands

Dept of Pathology Fondazione Poliambulanza Hospital Institute Brescia Brescia Italy

Dept of Pathology Fox Chase Cancer Center Philadelphia PA USA

Dept of Pathology Hospital Universitari Vall d'Hebron Barcelona Spain

Dept of Pathology HUS Helsinki University Hospital Helsinki Finland

Dept of Pathology International University of Health and Welfare Mita Hospital Tokyo Japan

Dept of Pathology Jichi Medical University Tochigi Japan

Dept of Pathology LabPON Hengelo the Netherlands

Dept of Pathology Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Dept of Pathology Maggiore Hospital University of Bologna Bologna Italy

Dept of Pathology Meander Medisch Centrum Amersfoort the Netherlands

Dept of Pathology Medical University of Graz Graz Austria

Dept of Pathology Mount Sinai Medical Center New York NY USA

Dept of Pathology Naritatomisato Tokushukai Hospital Chiba Japan

Dept of Pathology National Hospital Organization Ibarakihigashi National Hospital Tokai Japan

Dept of Pathology National Institute of Pneumology M Nasta Bucharest Romania

Dept of Pathology OLVG LAB BV Amsterdam the Netherlands

Dept of Pathology Padova University Hospital Padova Italy

Dept of Pathology Rijnstate Ziekenhuis Arnhem the Netherlands

Dept of Pathology Saitama Cancer Center Saitama Japan

Dept of Pathology San Raffaele Scientific Institute Milan Italy

Dept of Pathology School of Cancer Sciences University of Glasgow Scotland UK; Dept of Pathology CRUK Beatson Cancer Research Institute Glasgow Scotland UK; Dept of Pathology Department of Histopathology Queen Elizabeth University Hospital Glasgow Scotland UK

Dept of Pathology St James's Hospital Dublin Ireland

Dept of Pathology St Olavs Hospital Trondheim University Hospital Trondheim Norway; Norwegian University of Science and Technology Trondheim Norway

Dept of Pathology Universitätsklinikum Schleswig Holstein Campus Lübeck Lübeck Germany

Dept of Pathology University Clinic Golnik Golnik Slovenia

Dept of Pathology University College London Cancer Institute London United Kingdom

Dept of Pathology University Medical Center Groningen Groningen the Netherlands

Dept of Pathology University of California San Francisco CA USA

Dept of Pathology University of Turin Turin Italy

Dept of Pathology UZ Leuven Leuven Belgium

Dept of Pathology Yale School of Medicine New Haven CT USA

Dept of Pathology Yokosuka Kyosai Hospital Yokosuka Japan

Dept Pathologie DNA St Antoniusziekenhuis Nieuwegein the Netherlands

IHU RespirERA FHU OncoAge Nice University Hospital Center Laboratory of Clinical and Experimental Pathology Nice France

Institute of Pathology Heidelberg University Hospital Heidelberg Germany; Center for Personalized Medicine Heidelberg Germany

PathoPulse Søborg Denmark

Lung Cancer. 2025 Jun;204:108488. doi: 10.1016/j.lungcan.2025.108488. PubMed

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