Virchows Archiv

, Volume 464, Issue 1, pp 61–68

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

  • G. Rossi
  • M. C. Mengoli
  • A. Cavazza
  • D. Nicoli
  • M. Barbareschi
  • C. Cantaloni
  • M. Papotti
  • A. Tironi
  • P. Graziano
  • M. Paci
  • A. Stefani
  • M. Migaldi
  • G. Sartori
  • G. Pelosi
Original Article


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.


Lung Large cell carcinoma Immunohistochemistry p40 TTF-1 EGFR KRAS ALK Mutation Translocation Sequencing FISH 



v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog


Anaplastic lymphoma receptor tyrosine kinase


Epidermal growth factor receptor


Large cell carcinoma


Non-small cell lung carcinoma


Small cell lung cancer


Large cell neuroendocrine carcinoma


Basaloid carcinoma


Clear cell carcinoma


Lymphoepithelioma-like carcinoma


Large cell carcinoma with rhabdoid phenotype


Large cell carcinoma, undifferentiated type


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • G. Rossi
    • 1
  • M. C. Mengoli
    • 1
  • A. Cavazza
    • 1
  • D. Nicoli
    • 2
  • M. Barbareschi
    • 3
  • C. Cantaloni
    • 3
  • M. Papotti
    • 4
  • A. Tironi
    • 5
  • P. Graziano
    • 6
  • M. Paci
    • 7
  • A. Stefani
    • 8
  • M. Migaldi
    • 9
  • G. Sartori
    • 9
  • G. Pelosi
    • 10
    • 11
  1. 1.Department of Oncology and Advanced Technology, Operative Unit of Pathologic AnatomyIRCCS Azienda Arcispedale S. Maria NuovaReggio EmiliaItaly
  2. 2.Laboratory of Molecular BiologyIRCCS Azienda Arcispedale S. Maria NuovaReggio EmiliaItaly
  3. 3.Unit of Surgical Pathology, Laboratory of Molecular PathologyS. Chiara HospitalTrentoItaly
  4. 4.Department of Clinical and Biological SciencesUniversity of Turin at San Luigi HospitalTurinItaly
  5. 5.Second Operative Unit of Pathologic AnatomySpedali CiviliBresciaItaly
  6. 6.Pathology UnitSan Camillo-Forlanini High Specialization HospitalRomeItaly
  7. 7.Operative Unit of Thoracic SurgeryIRCCS Azienda Arcispedale S. Maria NuovaReggio EmiliaItaly
  8. 8.Division of Thoracic Surgery, University Hospital PoliclinicoUniversity of Modena and Reggio EmiliaModenaItaly
  9. 9.Pathologic Anatomy, University Hospital PoliclinicoUniversity of Modena and Reggio EmiliaModenaItaly
  10. 10.Department of Pathology and Laboratory MedicineFondazione IRCCS Istituto Nazionale TumoriMilanItaly
  11. 11.Department of Biomedical and Clinical Sciences “Luigi Sacco”Università degli StudiMilanItaly

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