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.