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

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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.

Original languageEnglish
Pages (from-to)61-68
Number of pages8
JournalVirchows Archiv
Volume464
Issue number1
DOIs
Publication statusPublished - Jan 2014

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Large Cell Carcinoma
Molecular Biology
Immunohistochemistry
Lung
Mutation
Neoplasms
Epidermal Growth Factor Receptor
Exons
Adenocarcinoma
Desmocollins
Epithelial Cells
Keratin-6
Keratin-5
Keratin-7
Chromogranins
Neuroendocrine Carcinoma
Negative Staining
Neuroendocrine Cells
Synaptophysin
Cell Lineage

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Large cell carcinoma of the lung : Clinically oriented classification integrating immunohistochemistry and molecular biology. / Rossi, G.; Mengoli, M. C.; Cavazza, A.; Nicoli, D.; Barbareschi, M.; Cantaloni, C.; Papotti, M.; Tironi, A.; Graziano, P.; Paci, M.; Stefani, A.; Migaldi, M.; Sartori, G.; Pelosi, G.

In: Virchows Archiv, Vol. 464, No. 1, 01.2014, p. 61-68.

Research output: Contribution to journalArticle

Rossi, G. ; Mengoli, M. C. ; Cavazza, A. ; Nicoli, D. ; Barbareschi, M. ; Cantaloni, C. ; Papotti, M. ; Tironi, A. ; Graziano, P. ; Paci, M. ; Stefani, A. ; Migaldi, M. ; Sartori, G. ; Pelosi, G. / Large cell carcinoma of the lung : Clinically oriented classification integrating immunohistochemistry and molecular biology. In: Virchows Archiv. 2014 ; Vol. 464, No. 1. pp. 61-68.
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