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

Erik Thunnissen; Hans Blaauwgeers; Federica Filipello; Birgit Lissenberg-Witte; Yuko Minami; Masayuki Noguchi; John Le Quesne; Mauro Giulio Papotti; Douglas B. Flieder; Giuseppe Pelosi; Irene Sansano; Sabina Berezowska; Aleš Ryška; Luka Brcic; Noriko Motoi; Yukio Nakatani; Christiane Kuempers; Paul Hofman; Veronique Hofman; Vibeke Grotnes Dale; Giulio Rossi; Francesca Ambrosi; Daisuke Matsubara; Yuichi Ishikawa; Birgit Weynand; Fiorella Calabrese; Federica Pezzuto; Izidor Kern; Siobhan Nicholson; Aino Mutka; Sanja Dacic; Mary Beth Beasley; Gianluigi Arrigoni; Wim Timens; Marc Ooft; Mariel Brinkhuis; Nicole Bulkmans; Rieneke Britstra; Willem Vreuls; Kirk D. Jones; Jan H. von der Thüsen; Hendrik Hager; Sven Perner; David Moore; Diana Gabriela Leonte; Shaimaa Al-Janabi; Andreas Schønau; Olaf Neumann; Klaus Kluck; Iordanis Ourailidis; Markus Ball; Jan Budczies; Daniel Kazdal; Albrecht Stenzinger

doi:10.1016/j.lungcan.2024.108060

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

Erik Thunnissen
, Hans Blaauwgeers
, Federica Filipello
, Birgit Lissenberg-Witte
, Yuko Minami
, Masayuki Noguchi
, John Le Quesne
, Mauro Giulio Papotti
, Douglas B. Flieder
, Giuseppe Pelosi
, Irene Sansano
, Sabina Berezowska
, Aleš Ryška
, Luka Brcic
, Noriko Motoi
, Yukio Nakatani
, Christiane Kuempers
, Paul Hofman
, Veronique Hofman
, Vibeke Grotnes Dale

Giulio Rossi, Francesca Ambrosi, Daisuke Matsubara, Yuichi Ishikawa, Birgit Weynand, Fiorella Calabrese, Federica Pezzuto, Izidor Kern, Siobhan Nicholson, Aino Mutka, Sanja Dacic, Mary Beth Beasley, Gianluigi Arrigoni, Wim Timens, Marc Ooft, Mariel Brinkhuis, Nicole Bulkmans, Rieneke Britstra, Willem Vreuls, Kirk D. Jones, Jan H. von der Thüsen, Hendrik Hager, Sven Perner, David Moore, Diana Gabriela Leonte, Shaimaa Al-Janabi, Andreas Schønau, Olaf Neumann, Klaus Kluck, Iordanis Ourailidis, Markus Ball, Jan Budczies, Daniel Kazdal, Albrecht Stenzinger

Vrije Universiteit Amsterdam
Onze Lieve Vrouwe Gasthuis
IRCCS Ospedale San Raffaele
National Hospital Organization Ibarakihigashi National Hospital
Naritatomisato Tokushukai Hospital
University of Glasgow
Beatson Institute for Cancer Research
South Glasgow University Hospitals
University of Turin
University of Milan
University Hospital Vall d’Hebron
University of Lausanne
Charles University
Medical University of Graz
Saitama Cancer Center
Yokosuka Kyosai Hospital
University Hospital Schleswig-Holstein
Centre Hospitalier Universitaire de Nice
Norwegian University of Science and Technology
Fondazione Poliambulanza Hospital
University of Bologna
Jichi Medical University
International University of Health and Welfare
KU Leuven
Azienda Ospedaliera di Padova
University of Ljubljana
Trinity College Dublin
Helsinki University Hospital
Yale University
Icahn School of Medicine at Mount Sinai
University of Groningen
Rijnstate Hospital
LabPON
St. Antonius Ziekenhuis
Meander Medical Center
Canisius Wilhelmina Hospital
University of California at San Francisco
Erasmus University Rotterdam
Aarhus University
University College London
National Institute of Pneumology “M. Nasta”
PathoPulse
Heidelberg University
Center for Personalized Medicine (ZPM) Heidelberg
Member of the German Center for Lung Research (DZL)

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English
Article number	108060
Pages (from-to)	108060
Journal	Lung Cancer
Volume	199
DOIs	https://doi.org/10.1016/j.lungcan.2024.108060
State	Published - Jan 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adenocarcinoma of Lung/pathology
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor/metabolism
Case-Control Studies
Female
Follow-Up Studies
Humans
Lung Neoplasms/pathology
Male
Middle Aged
Neoplasm Invasiveness
Neoplasm Staging
Reproducibility of Results
Retrospective Studies
World Health Organization

Access to Document

10.1016/j.lungcan.2024.108060

Cite this

Thunnissen, E., Blaauwgeers, H., Filipello, F., Lissenberg-Witte, B., Minami, Y., Noguchi, M., Quesne, J. L., Papotti, M. G., Flieder, D. B., Pelosi, G., Sansano, I., Berezowska, S., Ryška, A., Brcic, L., Motoi, N., Nakatani, Y., Kuempers, C., Hofman, P., Hofman, V., ... Stenzinger, A. (2025). A reproducibility study on invasion in small pulmonary adenocarcinoma according to the WHO and a modified classification, supported by biomarkers. Lung Cancer, 199, 108060. Article 108060. https://doi.org/10.1016/j.lungcan.2024.108060

@article{705e0a1368d6464a9c4cbeb867181ebb,

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

abstract = "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.",

keywords = "Adenocarcinoma of Lung/pathology, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor/metabolism, Case-Control Studies, Female, Follow-Up Studies, Humans, Lung Neoplasms/pathology, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Reproducibility of Results, Retrospective Studies, World Health Organization",

author = "Erik Thunnissen and Hans Blaauwgeers and Federica Filipello and Birgit Lissenberg-Witte and Yuko Minami and Masayuki Noguchi and Quesne, \{John Le\} and Papotti, \{Mauro Giulio\} and Flieder, \{Douglas B.\} and Giuseppe Pelosi and Irene Sansano and Sabina Berezowska and Ale{\v s} Ry{\v s}ka and Luka Brcic and Noriko Motoi and Yukio Nakatani and Christiane Kuempers and Paul Hofman and Veronique Hofman and Dale, \{Vibeke Grotnes\} and Giulio Rossi and Francesca Ambrosi and Daisuke Matsubara and Yuichi Ishikawa and Birgit Weynand and Fiorella Calabrese and Federica Pezzuto and Izidor Kern and Siobhan Nicholson and Aino Mutka and Sanja Dacic and Beasley, \{Mary Beth\} and Gianluigi Arrigoni and Wim Timens and Marc Ooft and Mariel Brinkhuis and Nicole Bulkmans and Rieneke Britstra and Willem Vreuls and Jones, \{Kirk D.\} and \{von der Th{\"u}sen\}, \{Jan H.\} and Hendrik Hager and Sven Perner and David Moore and Leonte, \{Diana Gabriela\} and Shaimaa Al-Janabi and Andreas Sch{\o}nau and Olaf Neumann and Klaus Kluck and Iordanis Ourailidis and Markus Ball and Jan Budczies and Daniel Kazdal and Albrecht Stenzinger",

year = "2025",

month = jan,

doi = "10.1016/j.lungcan.2024.108060",

language = "English",

volume = "199",

pages = "108060",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Thunnissen, E, Blaauwgeers, H, Filipello, F, Lissenberg-Witte, B, Minami, Y, Noguchi, M, Quesne, JL, Papotti, MG, Flieder, DB, Pelosi, G, Sansano, I, Berezowska, S, Ryška, A, Brcic, L, Motoi, N, Nakatani, Y, Kuempers, C, Hofman, P, Hofman, V, Dale, VG, Rossi, G, Ambrosi, F, Matsubara, D, Ishikawa, Y, Weynand, B, Calabrese, F, Pezzuto, F, Kern, I, Nicholson, S, Mutka, A, Dacic, S, Beasley, MB, Arrigoni, G, Timens, W, Ooft, M, Brinkhuis, M, Bulkmans, N, Britstra, R, Vreuls, W, Jones, KD, von der Thüsen, JH, Hager, H, Perner, S, Moore, D, Leonte, DG, Al-Janabi, S, Schønau, A, Neumann, O, Kluck, K, Ourailidis, I, Ball, M, Budczies, J, Kazdal, D & Stenzinger, A 2025, 'A reproducibility study on invasion in small pulmonary adenocarcinoma according to the WHO and a modified classification, supported by biomarkers', Lung Cancer, vol. 199, 108060, pp. 108060. https://doi.org/10.1016/j.lungcan.2024.108060

TY - JOUR

T1 - A reproducibility study on invasion in small pulmonary adenocarcinoma according to the WHO and a modified classification, supported by biomarkers

AU - Thunnissen, Erik

AU - Blaauwgeers, Hans

AU - Filipello, Federica

AU - Lissenberg-Witte, Birgit

AU - Minami, Yuko

AU - Noguchi, Masayuki

AU - Quesne, John Le

AU - Papotti, Mauro Giulio

AU - Flieder, Douglas B.

AU - Pelosi, Giuseppe

AU - Sansano, Irene

AU - Berezowska, Sabina

AU - Ryška, Aleš

AU - Brcic, Luka

AU - Motoi, Noriko

AU - Nakatani, Yukio

AU - Kuempers, Christiane

AU - Hofman, Paul

AU - Hofman, Veronique

AU - Dale, Vibeke Grotnes

AU - Rossi, Giulio

AU - Ambrosi, Francesca

AU - Matsubara, Daisuke

AU - Ishikawa, Yuichi

AU - Weynand, Birgit

AU - Calabrese, Fiorella

AU - Pezzuto, Federica

AU - Kern, Izidor

AU - Nicholson, Siobhan

AU - Mutka, Aino

AU - Dacic, Sanja

AU - Beasley, Mary Beth

AU - Arrigoni, Gianluigi

AU - Timens, Wim

AU - Ooft, Marc

AU - Brinkhuis, Mariel

AU - Bulkmans, Nicole

AU - Britstra, Rieneke

AU - Vreuls, Willem

AU - Jones, Kirk D.

AU - von der Thüsen, Jan H.

AU - Hager, Hendrik

AU - Perner, Sven

AU - Moore, David

AU - Leonte, Diana Gabriela

AU - Al-Janabi, Shaimaa

AU - Schønau, Andreas

AU - Neumann, Olaf

AU - Kluck, Klaus

AU - Ourailidis, Iordanis

AU - Ball, Markus

AU - Budczies, Jan

AU - Kazdal, Daniel

AU - Stenzinger, Albrecht

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

KW - Adenocarcinoma of Lung/pathology

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biomarkers, Tumor/metabolism

KW - Case-Control Studies

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Lung Neoplasms/pathology

KW - Male

KW - Middle Aged

KW - Neoplasm Invasiveness

KW - Neoplasm Staging

KW - Reproducibility of Results

KW - Retrospective Studies

KW - World Health Organization

UR - https://www.scopus.com/pages/publications/85214332417

U2 - 10.1016/j.lungcan.2024.108060

DO - 10.1016/j.lungcan.2024.108060

M3 - Article

C2 - 39793325

AN - SCOPUS:85214332417

SN - 0169-5002

VL - 199

SP - 108060

JO - Lung Cancer

JF - Lung Cancer

M1 - 108060

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

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