A reproducibility study on invasion in small pulmonary adenocarcinoma according to the WHO and a modified classification, supported by biomarkers

Erik Thunnissen ¹, Hans Blaauwgeers ², Federica Filipello ³

¹Dept. of Pathology, Amsterdam UMC, VU University, Amsterdam, the Netherlands.
²Dept. of Pathology, OLVG LAB BV, Amsterdam, the Netherlands.
³Dept. of Pathology, San Raffaele Scientific Institute, Milan, Italy.
⁴Dept. of Epidemiology and Data Science, Amsterdam UMC, VU University, Amsterdam, the Netherlands.
⁵Dept. of Pathology, National Hospital Organization Ibarakihigashi National Hospital, Tokai, Japan.
⁶Dept. of Pathology, Naritatomisato Tokushukai Hospital, Chiba, Japan.
⁷Dept. 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.
⁸Dept. of Pathology, University of Turin, Turin, Italy.
⁹Dept. of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁰Dept. of Pathology, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
¹¹Dept. of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹²Dept. of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹³Dept. of Pathology, Charles University, ESP, Hradec Kralove, Czech Republic.
¹⁴Dept. of Pathology, Medical University of Graz, Graz, Austria.
¹⁵Dept. of Pathology, Saitama Cancer Center, Saitama, Japan.
¹⁶Dept. of Pathology, Yokosuka Kyosai Hospital, Yokosuka, Japan.
¹⁷Dept. of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
¹⁸IHU RespirERA, FHU OncoAge, Nice University Hospital Center, Laboratory of Clinical and Experimental Pathology, Nice, France.
¹⁹Dept. of Pathology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Norwegian University of Science and Technology, Trondheim, Norway.
²⁰Dept. of Pathology, Fondazione Poliambulanza Hospital Institute, Brescia, Brescia, Italy.
²¹Dept. of Pathology, Maggiore Hospital, University of Bologna, Bologna, Italy.
²²Dept. of Pathology, Jichi Medical University, Tochigi, Japan.
²³Dept. of Pathology, International University of Health and Welfare, Mita Hospital, Tokyo, Japan.
²⁴Dept. of Pathology, UZ Leuven, Leuven, Belgium.
²⁵Dept. of Pathology, Padova University Hospital, Padova, Italy.
²⁶Dept. of Pathology, University Clinic Golnik, Golnik, Slovenia.
²⁷Dept. of Pathology, St. James's Hospital, Dublin, Ireland.
²⁸Dept. of Pathology, HUS Helsinki University Hospital, Helsinki, Finland.
²⁹Dept. of Pathology, Yale School of Medicine, New Haven, CT, USA.
³⁰Dept. of Pathology, Mount Sinai Medical Center, New York, NY, USA.
³¹Dept. of Pathology, University Medical Center Groningen, Groningen, the Netherlands.
³²Dept. of Pathology, Rijnstate Ziekenhuis, Arnhem, the Netherlands.
³³Dept. of Pathology, LabPON, Hengelo, the Netherlands.
³⁴Dept. Pathologie-DNA, St. Antoniusziekenhuis, Nieuwegein, the Netherlands.
³⁵Dept. of Pathology, Meander Medisch Centrum, Amersfoort, the Netherlands.
³⁶Dept. of Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.
³⁷Dept. of Pathology, University of California, San Francisco, CA, USA.
³⁸Dept. of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
³⁹Dept. of Pathology, Aarhus University, Aarhus, Denmark.
⁴⁰Dept. of Pathology, University College London Cancer Institute, London, United Kingdom.
⁴¹Dept. of Pathology, National Institute of Pneumology "M. Nasta", Bucharest, Romania.
⁴²PathoPulse, Søborg, Denmark.
⁴³Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; Center for Personalized Medicine (ZPM) Heidelberg, Heidelberg, Germany; Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

⁰Dept. of Pathology, Amsterdam UMC, VU University, Amsterdam, the Netherlands.

Lung +

|

January 10, 2025

View abstract on PubMed

Summary

A modified classification for non-mucinous lung adenocarcinoma (NMA) shows higher reproducibility than the WHO standard. This improved classification better identifies non-invasive, low-risk lesions, supported by biomarker analysis.

Area Of Science

Pulmonary Pathology
Oncology
Cancer Staging

Background

Accurate staging of lung adenocarcinoma is critical for patient treatment and prognosis.
Current World Health Organization (WHO) classification of non-mucinous adenocarcinoma (NMA) faces challenges in consistently evaluating tumor invasion.
Distinguishing invasive from non-invasive NMA is essential for precise pT-staging.

Purpose Of The Study

To compare the reproducibility of the current WHO classification with a modified NMA classification.
To assess the modified classification's effectiveness in identifying non-invasive, low-risk NMA lesions.
To evaluate the utility of orthogonal biomarker analysis in supporting the modified classification.

Main Methods

A retrospective case-control study of 70 small NMA pT1N0M0 cases with 5-year follow-up.
Review of cases by 42 pulmonary pathologists using both WHO and modified classifications across three rounds.
Orthogonal biomarker analysis including proliferation rate, tumor mutational burden, and transcriptomic profiles.

Main Results

Reproducibility (Kappa values) for invasiveness significantly improved with the modified classification across three rounds (0.27 to 0.62).
The modified classification reduced variation in pT staging compared to the WHO classification.
Biomarker analysis supported the distinction between invasive and non-invasive cases identified by the modified classification.

Conclusions

The modified NMA classification offers superior reproducibility over the current WHO classification.
This modified approach effectively identifies entirely non-invasive, low-risk NMA lesions.
Biomarker data corroborate the clinical utility of the modified classification for improved lung cancer staging.