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Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology

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Abstract

This study aimed at challenging pulmonary large cell carcinoma (LLC) as tumor entity and defining different subgroups according to immunohistochemical and molecular features. Expression of markers specific for glandular (TTF-1, napsin A, cytokeratin 7), squamous cell (p40, p63, cytokeratins 5/6, desmocollin-3), and neuroendocrine (chromogranin, synaptophysin, CD56) differentiation was studied in 121 LCC across their entire histological spectrum also using direct sequencing for epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and FISH analysis for ALK gene translocation. Survival was not investigated. All 47 large cell neuroendocrine carcinomas demonstrated a true neuroendocrine cell lineage, whereas all 24 basaloid and both 2 lymphoepithelioma-like carcinomas showed squamous cell markers. Eighteen out of 22 clear cell carcinomas had glandular differentiation, with KRAS mutations being present in 39 % of cases, whereas squamous cell differentiation was present in four cases. Eighteen out of 20 large cell carcinomas, not otherwise specified, had glandular differentiation upon immunohistochemistry, with an exon 21 L858R EGFR mutation in one (5 %) tumor, an exon 2 KRAS mutation in eight (40 %) tumors, and an ALK translocation in one (5 %) tumor, whereas two tumors positive for CK7 and CK5/6 and negative for all other markers were considered adenocarcinoma. All six LCC of rhabdoid type expressed TTF-1 and/or CK7, three of which also harbored KRAS mutations. When positive and negative immunohistochemical staining for these markers was combined, three subsets of LCC emerged exhibiting glandular, squamous, and neuroendocrine differentiation. Molecular alterations were restricted to tumors classified as adenocarcinoma. Stratifying LCC into specific categories using immunohistochemistry and molecular analysis may significantly impact on the choice of therapy.

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Abbreviations

KRAS :

v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

ALK :

Anaplastic lymphoma receptor tyrosine kinase

EGFR :

Epidermal growth factor receptor

LCC:

Large cell carcinoma

NSCLC:

Non-small cell lung carcinoma

SCLC:

Small cell lung cancer

LCNEC:

Large cell neuroendocrine carcinoma

BC:

Basaloid carcinoma

CCC:

Clear cell carcinoma

LELC:

Lymphoepithelioma-like carcinoma

LCC-R:

Large cell carcinoma with rhabdoid phenotype

LCC-U:

Large cell carcinoma, undifferentiated type

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Author information

Authors and Affiliations

  1. Department of Oncology and Advanced Technology, Operative Unit of Pathologic Anatomy, IRCCS Azienda Arcispedale S. Maria Nuova, Reggio Emilia, Italy

    G. Rossi, M. C. Mengoli & A. Cavazza

  2. Laboratory of Molecular Biology, IRCCS Azienda Arcispedale S. Maria Nuova, Reggio Emilia, Italy

    D. Nicoli

  3. Unit of Surgical Pathology, Laboratory of Molecular Pathology, S. Chiara Hospital, Trento, Italy

    M. Barbareschi & C. Cantaloni

  4. Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy

    M. Papotti

  5. Second Operative Unit of Pathologic Anatomy, Spedali Civili, Brescia, Italy

    A. Tironi

  6. Pathology Unit, San Camillo-Forlanini High Specialization Hospital, Malpighi Pavilion, Rome, Italy

    P. Graziano

  7. Operative Unit of Thoracic Surgery, IRCCS Azienda Arcispedale S. Maria Nuova, Reggio Emilia, Italy

    M. Paci

  8. Division of Thoracic Surgery, University Hospital Policlinico, University of Modena and Reggio Emilia, Modena, Italy

    A. Stefani

  9. Pathologic Anatomy, University Hospital Policlinico, University of Modena and Reggio Emilia, Modena, Italy

    M. Migaldi & G. Sartori

  10. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133, Milan, Italy

    G. Pelosi

  11. Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi, Milan, Italy

    G. Pelosi

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  1. G. Rossi
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  2. M. C. Mengoli
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  3. A. Cavazza
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  7. M. Papotti
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  8. A. Tironi
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  9. P. Graziano
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  10. M. Paci
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  11. A. Stefani
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  12. M. Migaldi
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  14. G. Pelosi
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Corresponding author

Correspondence to G. Pelosi.

Additional information

This work has been presented in part as oral communication at the 14th World Conference on Lung Cancer, Amsterdam, The Netherlands, 3–7 July 2011.

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Rossi, G., Mengoli, M.C., Cavazza, A. et al. Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology. Virchows Arch 464, 61–68 (2014). https://doi.org/10.1007/s00428-013-1501-6

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  • DOI: https://doi.org/10.1007/s00428-013-1501-6

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