title: The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases.
abstract: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise κ scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.
  
  
  
  Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).
  
  
  
  For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, κ scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.
  
  
  
  Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: e.thunnissen@vumc.nl.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.affiliation: Deptartment of Pathology, Weill Cornell Medicine, New York, New York.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Borczuk
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Flieder
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Birgit
authors.initials: B
authors.lastname: Witte
authors.affiliation: Department of Pathology, Mount Sinai Medical Center, New York, New York.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Beasley
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Republic of Korea.
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Chung
authors.affiliation: Department of Pathology University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sanja
authors.initials: S
authors.lastname: Dacic
authors.affiliation: Department of Biopathology, Centre Léon Bérard UNICANCER, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.affiliation: St. Vincent's Pathology and The University of Melbourne, Melbourne, Australia.
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Russell
authors.affiliation: Department of Pathology, Maasstad Ziekenhuis, Rotterdam, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: den Bakker
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.affiliation: CHU Albert Michallon-Institut de Biologie, Département d'Anatomie et Cytologie Pathologiques, Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erienne
authors.initials: E
authors.lastname: de Cuba
authors.affiliation: Department of Pathology, The University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Kim R
authors.initials: KR
authors.lastname: Geisinger
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Pathology, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Marchevsky
authors.affiliation: Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University, New York, New York.
authors.forename: Andre
authors.initials: A
authors.lastname: Moreira
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield Hospitals National Health Service Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, University Health Network-Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Institute of Pathology, Heidelberg University, Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Sullivan Nicolaides Pathology, The John Flynn Hospital, Tugun, Queensland, Australia.
authors.forename: Edwina
authors.initials: E
authors.lastname: Duhig
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.affiliation: Department of Pathology, University of Vermont, Burlington, Vermont.
authors.forename: Kelly
authors.initials: K
authors.lastname: Butnor
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Cooper
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Motoi
authors.affiliation: Laboratorio de Patología Torácica, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Poleri
authors.affiliation: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Kerr
authors.affiliation: Department of Pathology and Laboratory Medicine at Rutgers New Jersey Medical School, Rutgers University, Newark, New Jersey.
authors.forename: Seena C
authors.initials: SC
authors.lastname: Aisner
authors.affiliation: Division of Pathology, The Cancer Institute, Japan Foundation Cancer Research, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Cologne Institute for Pathology, Köln, Germany.
authors.forename: Reinhard H
authors.initials: RH
authors.lastname: Buettner
authors.affiliation: Tsukuba Clinical Research and Development Organization, University of Tsukuba, Tsukuba, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Keino
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Noguchi
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000175:diagnosis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000175:diagnosis / Q000378:metabolism; D003937:Diagnosis, Differential; D006801:Humans; D007124:Immunoenzyme Techniques; D007390:International Agencies; D008175:Lung Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D015203:Reproducibility of Results; D055752:Small Cell Lung Carcinoma / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor
keywords: Histopathology; Immunohistochemistry; Reproducibility; SCLC