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Semin Respir Crit Care Med 2011; 32(1): 022-031
DOI: 10.1055/s-0031-1272866
© Thieme Medical Publishers

Pathological Diagnosis and Classification of Lung Cancer in Small Biopsies and Cytology: Strategic Management of Tissue for Molecular Testing

William D. Travis1 , Natasha Rekhtman1
  • 1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
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Publication History

Publication Date:
15 April 2011 (online)

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ABSTRACT

Standardized lung cancer classifications by the World Health Organization have traditionally been based on the histological characteristics of resected tumors with little guidance about diagnosis based on small biopsies and cytology. The focus has mainly been on the separation of small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Until recently there have been no therapeutic implications to further classification of NSCLC, so little attention has historically been given to the distinction of adenocarcinoma and squamous cell carcinoma in these small tissue samples. This situation has changed dramatically in recent years with the discovery of several therapeutic options that are only available to patients with adenocarcinoma or NSCLC, not otherwise specified (NSCLC-NOS), rather than squamous cell carcinoma. Therefore this article reviews new criteria and terminology recently proposed by the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. This includes recommendation for use of special stains as an aid to diagnosis, particularly in the setting of poorly differentiated tumors that do not show clear differentiation by light microscopy. The need for every institution to develop a multidisciplinary strategy to obtain these small specimens and process them not only for diagnosis but also for molecular testing is emphasized.

KEYWORDS

Lung cancer - histology - adenocarcinoma - squamous cell carcinoma - EGFR mutation - KRAS mutation - non-small-cell carcinoma - immunohistochemistry - TTF-1 - p63 - mucin stain - molecular testing

REFERENCES

  • 1 World Health Organization .Histological Typing of Lung Tumours. Geneva, Switzerland: World Health Organization; 1967
    Google Scholar
  • 2 World Health Organization .Histological Typing of Lung Tumors. Geneva, Switzerland: World Health Organization; 1981
    Google Scholar
  • 3 Travis W D, Colby T V, Corrin B, Shimosato Y, Brambilla E in collaboration with LH Sobin and pathologists from 14 countries. Histological Typing of Lung and Pleural Tumors. Berlin, Germany: Springer; 1999
    CrossrefGoogle Scholar
  • 4 Travis W D, Brambilla E, Müller-Hermelink H K, Harris C C. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC; 2004
    Google Scholar
  • 5 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010.  CA Cancer J Clin. 2010;  60 (5) 277-300
    CrossrefPubMedGoogle Scholar
  • 6 Mok T S, Wu Y L, Thongprasert S et al.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.  N Engl J Med. 2009;  361 (10) 947-957
    CrossrefPubMedGoogle Scholar
  • 7 Mitsudomi T, Morita S, Yatabe Y et al.. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.  Lancet Oncol. 2010;  11 (1) 11-12
    CrossrefPubMedGoogle Scholar
  • 8 Maemondo M, Inoue A, Kobayashi K North-East Japan Study Group et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR .  N Engl J Med. 2010;  362 (25) 2380-2388
    CrossrefPubMedGoogle Scholar
  • 9 Zhou C, Wu Y-L, Chen G et al.. Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations.  Ann Oncol. 2010;  21 (suppl 8) LBA 13
    PubMedGoogle Scholar
  • 10 Johnson D H, Fehrenbacher L, Novotny W F et al.. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.  J Clin Oncol. 2004;  22 (11) 2184-2191
    CrossrefPubMedGoogle Scholar
  • 11 Ciuleanu T, Brodowicz T, Zielinski C et al.. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.  Lancet. 2009;  374 (9699) 1432-1440
    CrossrefPubMedGoogle Scholar
  • 12 Scagliotti G, Hanna N, Fossella F et al.. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies.  Oncologist. 2009;  14 (3) 253-263
    CrossrefPubMedGoogle Scholar
  • 13 Scagliotti G V, Parikh P, von Pawel J et al.. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.  J Clin Oncol. 2008;  26 (21) 3543-3551
    CrossrefPubMedGoogle Scholar
  • 14 Travis W D, Brambilla E, Noguchi M et al.. The New IASLC/ATS/ERS International Multidisciplinary Lung Adenocarcinoma Classification.  J Thorac Oncol. 2011;  6 244-285
    CrossrefPubMedGoogle Scholar
  • 15 Travis W D, Rekhtman N, Riley G J et al.. Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.  J Thorac Oncol. 2010;  5 (4) 411-414
    CrossrefPubMedGoogle Scholar
  • 16 Foot N C. The identification of types of pulmonary cancer in cytologic smears.  Am J Pathol. 1952;  28 (6) 963-983
    PubMedGoogle Scholar
  • 17 Ou S H, Zell J A. Carcinoma NOS is a common histologic diagnosis and is increasing in proportion among non-small cell lung cancer histologies.  J Thorac Oncol. 2009;  4 (10) 1202-1211
    CrossrefPubMedGoogle Scholar
  • 18 Rekhtman N, Brandt S M, Sigel C S et al.. Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.  Oncol. 2011;  In press
    PubMedGoogle Scholar
  • 19 Nicholson A G, Gonzalez D, Shah P et al.. Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis.  J Thorac Oncol. 2010;  5 (4) 436-441
    CrossrefPubMedGoogle Scholar
  • 20 Rossi G, Papotti M, Barbareschi M, Graziano P, Pelosi G. Morphology and a limited number of immunohistochemical markers may efficiently subtype non-small-cell lung cancer.  J Clin Oncol. 2009;  27 (28) e141-e142 author reply e143-e144
    CrossrefPubMedGoogle Scholar
  • 21 Ring B Z, Seitz R S, Beck R A et al.. A novel five-antibody immunohistochemical test for subclassification of lung carcinoma.  Mod Pathol. 2009;  22 (8) 1032-1043
    CrossrefPubMedGoogle Scholar
  • 22 Terry J, Leung S, Laskin J, Leslie K O, Gown A M, Ionescu D N. Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from squamous cell carcinomas in small tumor samples.  Am J Surg Pathol. 2010;  34 (12) 1805-1811
    CrossrefPubMedGoogle Scholar
  • 23 Lau S K, Luthringer D J, Eisen R N. Thyroid transcription factor-1: a review.  Appl Immunohistochem Mol Morphol. 2002;  10 (2) 97-102
    CrossrefPubMedGoogle Scholar
  • 24 Pelosi G, Fraggetta F, Pasini F et al.. Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung.  Am J Surg Pathol. 2001;  25 (3) 363-372
    CrossrefPubMedGoogle Scholar
  • 25 Bishop J A, Sharma R, Illei P B. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma.  Hum Pathol. 2010;  41 (1) 20-25
    CrossrefPubMedGoogle Scholar
  • 26 Siami K, McCluggage W G, Ordonez N G et al.. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas.  Am J Surg Pathol. 2007;  31 (11) 1759-1763
    CrossrefPubMedGoogle Scholar
  • 27 Penman D, Downie I, Roberts F. Positive immunostaining for thyroid transcription factor-1 in primary and metastatic colonic adenocarcinoma: a note of caution.  J Clin Pathol. 2006;  59 (6) 663-664
    CrossrefPubMedGoogle Scholar
  • 28 Klingen T A, Chen Y, Gundersen M D, Aas H, Westre B, Sauer T. Thyroid transcription factor-1 positive primary breast cancer: a case report with review of the literature.  Diagn Pathol. 2010;  5 37
    CrossrefPubMedGoogle Scholar
  • 29 Robens J, Goldstein L, Gown A M, Schnitt S J. Thyroid transcription factor-1 expression in breast carcinomas.  Am J Surg Pathol. 2010;  34 (12) 1881-1885
    CrossrefPubMedGoogle Scholar
  • 30 Wislez M, Antoine M, Baudrin L et al.. Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib.  Lung Cancer. 2010;  68 (2) 185-191
    CrossrefPubMedGoogle Scholar
  • 31 Garfield D H, Cadranel J, West H L. Bronchioloalveolar carcinoma: the case for two diseases.  Clin Lung Cancer. 2008;  9 (1) 24-29
    CrossrefPubMedGoogle Scholar
  • 32 Loo P S, Thomas S C, Nicolson M C, Fyfe M N, Kerr K M. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens.  J Thorac Oncol. 2010;  5 (4) 442-447
    CrossrefPubMedGoogle Scholar
  • 33 Kaufmann O, Fietze E, Mengs J, Dietel M. Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas.  Am J Clin Pathol. 2001;  116 (6) 823-830
    CrossrefPubMedGoogle Scholar
  • 34 Ang D C, Ghaffar H, Zakowski M F et al.. Expression of squamous markers in lung adenocarcinoma (AD): clinicopathologic and molecular correlates, and implications for differentiation from squamous cell carcinoma (SqCC).  Mod Pathol. 2010;  23 (suppl) 397A
    PubMedGoogle Scholar
  • 35 Savci-Heijink C D, Kosari F, Aubry M C et al.. The role of desmoglein-3 in the diagnosis of squamous cell carcinoma of the lung.  Am J Pathol. 2009;  174 (5) 1629-1637
    CrossrefPubMedGoogle Scholar
  • 36 Mukhopadhyay S, Katzenstein A L. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6.  Am J Surg Pathol. 2011;  35 (1) 15-25
    CrossrefPubMedGoogle Scholar
  • 37 Nonami Y, Ohtuki Y, Sasaguri S. Study of the diagnostic difference between the clinical diagnostic criteria and results of immunohistochemical staining of multiple primary lung cancers.  J Cardiovasc Surg (Torino). 2003;  44 (5) 661-665
    PubMedGoogle Scholar
  • 38 Bishop J A, Benjamin H, Cholakh H, Chajut A, Clark D P, Westra W H. Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach.  Clin Cancer Res. 2010;  16 (2) 610-619
    CrossrefPubMedGoogle Scholar
  • 39 Kwak E L, Bang Y J, Camidge D R et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.  N Engl J Med. 2010;  363 (18) 1693-1703
    CrossrefPubMedGoogle Scholar
  • 40 Arcila M E, Oxnard G R, Nafa K et al.. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.  Clin Cancer Res. 2010;  In press
    PubMedGoogle Scholar
  • 41 Solomon S B, Zakowski M F, Pao W et al.. Core Needle Lung Biopsy Specimens: Adequacy for EGFR and KRAS Mutational Analysis.  AJR Am J Roentgenol. 2010;  194 266-269
    CrossrefPubMedGoogle Scholar
  • 42 Boldrini L, Gisfredi S, Ursino S et al.. Mutational analysis in cytological specimens of advanced lung adenocarcinoma: a sensitive method for molecular diagnosis.  J Thorac Oncol. 2007;  2 (12) 1086-1090
    CrossrefPubMedGoogle Scholar
  • 43 Horiike A, Kimura H, Nishio K et al.. Detection of epidermal growth factor receptor mutation in transbronchial needle aspirates of non-small cell lung cancer.  Chest. 2007;  131 (6) 1628-1634
    CrossrefPubMedGoogle Scholar
  • 44 Travis W D. Advances in neuroendocrine lung tumors.  Ann Oncol. 2010;  21 (suppl 7) vii65-vii71
    CrossrefPubMedGoogle Scholar
  • 45 Smouse J H, Cibas E S, Jänne P A, Joshi V A, Zou K H, Lindeman N I. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer.  Cancer Cytopathol. 2009;  117 (1) 67-72
    CrossrefPubMedGoogle Scholar
  • 46 Rekhtman N, Brandt S M, Sigel C S et al.. Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.  J Thorac Oncol. 2011;  In press
    PubMedGoogle Scholar

William D TravisM.D. 

Department of Pathology, Memorial Sloan-Kettering Cancer Center

1275 York Ave., New York, NY 10065

Email: travisw@mskcc.org

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