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J Thorac Oncol. 2014 Sep;9(9):1354-62. doi: 10.1097/JTO.0000000000000264.

Reproducibility of histopathological diagnosis in poorly differentiated NSCLC: an international multiobserver study.

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Departments of *Pathology and ††††Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands; †Department of Pathology, Faculty of Medicine, Tsukuba, Japan; ‡Rutgers New Jersey Medical School, Newark, New Jersey; §Department of Pathology, Mount Sinai Medical Center, New York, New York; ‖Elisabeth Brambilla, CHU Albert Michallon, Institut de Biologie, Département d'Anatomie et Cytologie Pathologiques, Grenoble Cedex, France; ¶Brigham and Women's Hospital, Boston, Massachusetts; #Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; **Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; ††Piedmont Pathology Associates, Hickory, North Carolina, and University of North Carolina, Chapel Hill, North Carolina; ‡‡Department of Medicine and Pathology, University of Colorado Cancer Center, Aurora, Colorado; §§Division of Pathology, The Cancer Institute, Japanese Foundation Cancer Research, Tokyo, Japan; ‖Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; ¶¶Department of Pathology, CHU A Michallon, INSERM U 823-Institut A Bonniot-University J Fourier, Grenoble, France; ##Department of Pathology, Cancer Center Hospital, Tsukuba, Japan; ***Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan; †††Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; ‡‡‡Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, and Università degli Studi of Milan, Milan, Italy; §§§Institut für Pathologie, Jena, Germany; ‖‖‖Duke University Medical Center, Durham, North Carolina; ¶¶¶University of Texas MD Anderson Cancer Center, Houston, Texas; ###Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; ****Department of Oncology and Radiothe



The 2004 World Health Organization classification of lung cancer contained three major forms of non-small-cell lung cancer: squamous cell carcinoma (SqCC), adenocarcinoma (AdC), and large cell carcinoma. The goal of this study was first, to assess the reproducibility of a set of histopathological features for SqCC in relation to other poorly differentiated non-small-cell lung cancers and second, to assess the value of immunohistochemistry in improving the diagnosis.


Resection specimens (n = 37) with SqCC, large cell carcinoma, basaloid carcinoma, sarcomatoid carcinoma, lymphoepithelial-like carcinoma, and solid AdC, were contributed by the participating pathologists. Hematoxylin and eosin (H&E) stained slides were digitized. The diagnoses were evaluated in two ways. First, the histological criteria were evaluated and the (differential) diagnosis on H&E alone was scored. Second, the added value of additional stains to make an integrated diagnosis was examined.


The histologic criteria defining SqCC were consistently used, but in poorly differentiated cases they were infrequently present, rendering the diagnosis more difficult. Kappa scores on H&E alone were for SqCC 0.46, large cell carcinoma 0.25, basaloid carcinoma 0.27, sarcomatoid carcinoma 0.52, lymphoepithelial-like carcinoma 0.56, and solid AdC 0.21. The κ score improved with the use of additional stains for SqCC (combined with basaloid carcinoma) to 0.57, for solid AdC to 0.63.


The histologic criteria that may be used in the differential diagnosis of poorly differentiated lung cancer were more precisely refined. Furthermore, additional stains improved the reproducibility of histological diagnosis of SqCC and AdC, uncovering information that was not present in routine H&E stained slides.

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