Small-cell carcinoma in the setting of pulmonary adenocarcinoma: New insights in the era of molecular pathology

Introduction: Transformation into small-cell lung carcinoma (SCLC) has been reported as an evolution of lung adenocarcinoma acquiring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). However, spontaneous association of SCLC and adenocarcinoma also exists. We sought to compare patients' clinical features and mutation status of EGFR in each tumor component in these conditions. Methods: Our study is based on nine consecutive cases of SCLC, occurring synchronously or after a previous diagnosis of pulmonary adenocarcinoma, with or without TKI-based therapy, diagnosed in Marie Lannelongue Surgical Center, France, between 2001 and 2013. Molecular analysis by DNA direct sequencing was performed to detect EGFR mutations on formalin-fixated tissue mostly from surgically resected tumors. Results: Six patients had a metachronous occurrence of SCLC after adenocarcinoma (2 after TKI); three had a synchronous form. There were four combined SCLCs/adenocarcinomas. Seven adenocarcinoma components were EGFR mutated: five exon 19 deletions and two mutations in exon 21 (L833-V834delinsFL and L858R). Four SCLC components were EGFR mutated. Two cases occurred in never-smoker women with adenocarcinoma treated with TKI: one with E872 mutation in exon 21 and one combined SCLC/adenocarcinoma with exon 19 deletion in both components. Two cases were spontaneous: a SCLC with exon 19 deletion occurring after a nonmutated adenocarcinoma and a combined SCLC/adenocarcinoma with exon 21 mutation (L833-V834delinsFL) in both components. Conclusion: SCLC developing in association with adenocarcinoma, either synchronously or metachronously, seem linked to EGFR mutation, regardless of TKI use. Our findings suggest that such associated cases should be tested for EGFR mutations.