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Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first line treatment for a subset of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Although transformation to small cell lung cancer (SCLC) is one of the known mechanisms of resistance to EGFR TKIs, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors. Methods: We identified six patients with primary lung adenocarcinoma that showed transformation to SCLC on second biopsy (n = 401) during a 6-year period. Clinicopathologic information was analyzed and EGFR mutation results were compared between initial and second biopsy samples. Results: Six patients showed transformation from adenocarcinoma to SCLC, of which four were pure SCLCs and two were combined adenocarcinoma and SCLCs. Clinically, four cases were EGFR-mutant tumors from non-smoking females who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The remaining two adenocarcinomas were EGFR wild-type, and one of these patients received EGFR TKI treatment. Conclusions: NSCLC can acquire a neuroendocrine phenotype with or without EGFR TKI treatment.
Key Words: Lung neoplasms; Receptor, epidermal growth factor; Tyrosine kinase inhibitor; Small cell lung carcinoma; Adenocarcinoma
Currently, lung cancer is classified into two broad histological subgroups: non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The distinction between these two categories is important because the treatment options differ substantially. There are different chemotherapeutic regimens for SCLC and NSCLC, and the initial response to chemotherapy is much greater for patients with SCLC than for those with NSCLC.1,2 Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for a subset of EGFR-mutated NSCLC patients.3 In many cases, however, acquired resistance emerges within a year.4 Although the secondary T790M mutation has been well-described and reported in up to 60% of resistant samples,5 there have been several studies proposing histological transformation from NSCLC to SCLC as another mechanism of EGFR TKI resistance.2,5-12 The possible explanation of this phenomenon can be the transformation of NSCLC, mostly adenocarcinoma (ADC), to high-grade neuroendocrine phenotype.2 The other possibility can be the presence of combined histology of NSCLC and SCLC in initial samples and acquisition of different histological areas in second biopsy samples.2 The reports...