Primary <i>de novo</i> Epidermal Growth Factor Receptor Mutant Small Cell Lung Carcinomas: Clinicopathological Study of a Rare Entity Presenting in Treatment-Naïve Setting with Review of Literature

<b>Introduction:</b> Small cell lung carcinomas (SCLC) are characterized by loss of function mutations in genes encoding for p53 (tumor protein p53-<i>TP53</i>) and retinoblastoma transcriptional corepressor 1 (<i>RB1</i>) proteins in the majority of tumors. They are aggressive, usually present with metastatic disease, and are treated with platinum-based chemotherapy with overall poor outcomes. Epidermal growth factor receptor (<i>EGFR)</i> mutations, classically associated with primary lung adenocarcinomas, have been reported in rare <i>de novo</i> SCLC outside the context of the relatively more common <i>transformed</i> SCLC that arise with emergence of tyrosine kinase inhibitor resistance in <i>EGFR</i>-mutant adenocarcinomas. <b>Aim:</b> To analyze the clinicopathological features of <i>EGFR</i>-mutant <i>de novo</i> SCLC. <b>Methods:</b> <i>EGFR</i>-mutant <i>de novo</i> SCLCs were retrieved over 5 years and reviewed for clinicopathological parameters. <b>Results:</b> Five patients were identified harboring either exon 19 deletion (n = 4) or exon 21 L858R mutation (n = 1) in <i>EGFR</i>. Median age at diagnosis was 48 years (30-58 years). Four patients were never-smokers of whom three were tobacco chewers. Three biopsies showed pure small cell carcinoma while others showed composite adenocarcinoma. Diffuse loss of RB1 (5/5) and mutant type p53 staining pattern (3/3) were noted in all tested samples. Among two patient samples subjected to sequencing, additional pathogenic mutations in <i>TP53</i> (2/2), <i>RB1</i> (1/2), <i>PTEN</i> (1/2), neurofibromatosis type 1 (1/2), and <i>CREBB1</i> (1/2) were identified. <b>Conclusion:</b> <i>EGFR-</i>mutant <i>de novo</i> SCLCs are extremely rare and show frequent inactivation of p53 and RB1, like the more common <i>transformed</i> SCLCs. Given the lack of tyrosine kinase inhibitor exposure, these tumors highlight the inherent lineage plasticity of <i>EGFR/TP53/RB1</i> triple mutant lung carcinomas.