Abstract
Pulmonary large cell carcinoma (LCC) was re-defined under the 2015 WHO classification criteria. However, the clinicopathological features and genetic mutation statuses of Chinese LCC patients based on the new classification have rarely been investigated. Twenty-four Chinese surgically resected LCC patients previously diagnosed under the 2004 WHO criteria were re-classified under the 2015 WHO criteria. Genetic analysis was performed using next-generation sequencing of 46 cancer-related genes. The correlation of clinicopathological and genetic data was further analyzed. Eight patients were re-defined as LCCs, and 16 patients were defined as non-LCCs under the refined criteria. All LCC patients were male, and 7 patients were smokers. No significant differences in age, gender, smoking status, primary site, TNM staging and overall survival were observed between the LCC and non-LCC patients under the refined criteria. Four of the 8 LCC patients presented TP53 mutations, and no somatic mutations were detected in the other 4 LCCs under the refined criteria. For the 16 non-LCCs, not only TP53 and KRAS but also EGFR, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF mutations were also observed. In addition, LCCs without TP53 mutations did not present any gene mutations under the 2004 or 2015 WHO criteria. Importantly, the patients with TP53 mutation exhibited a trend with a worse survival outcome at the time of follow-up. The new WHO diagnosis criteria have superior performance in precise molecular classification for LCC patients.
Highlights
According to the current 2015 WHO classification, pulmonary large-cell carcinoma (LCC) is morphologically defined as an undifferentiated lung carcinoma lacking the features of adenocarcinoma, squamous, small-cell carcinoma and neuroendocrine carcinoma, which can only be diagnosed from surgically resected specimens [1]
NSCLC with negative immunomarkers that cannot be grouped as neuroendocrine carcinoma, adenocarcinoma or squamous cell carcinoma has been classified as large cell carcinoma (LCC) with null immunohistochemical features (LCC-N)
IHC staining for Thyroid transcription factor-1 (TTF-1), Napsin A, chromogranin A (CgA), Syn, p40, p63 and CK5/6 was performed in each specimen to reclassify the LCC in this cohort
Summary
According to the current 2015 WHO classification, pulmonary large-cell carcinoma (LCC) is morphologically defined as an undifferentiated lung carcinoma lacking the features of adenocarcinoma, squamous, small-cell carcinoma and neuroendocrine carcinoma, which can only be diagnosed from surgically resected specimens [1]. LCC with adenocarcinoma, squamous cell and neuroendocrine features is excluded according to the 2015 WHO criteria, LCC-N might still represent a clinicopathologically heterogeneous entity. This finding has emphasized the importance to further classify LCC into more specific pathologic subtypes based on histological and genetic characteristics, contributing to a more accurate prognosis that leads to more personalized cancer care. It is necessary to analyze the clinicopathological and genetic features in Chinese patients with LCC using the 2015 WHO classification, to explore the correlation of genotype and prognosis and to determine potential target therapeutic strategies
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