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

Introduction: Small cell lung carcinomas (SCLC) are characterized by loss of function mutations in genes encoding for p53 (tumor protein p53-TP53) and retinoblastoma transcriptional corepressor 1 (RB1) 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 (EGFR) mutations, classically associated with primary lung adenocarcinomas, have been reported in rare de novo SCLC outside the context of the relatively more common transformed SCLC that arise with emergence of tyrosine kinase inhibitor resistance in EGFR-mutant adenocarcinomas. Aim: To analyze the clinicopathological features of EGFR-mutant de novo SCLC.

Methods: EGFR-mutant de novo SCLCs were retrieved over 5 years and reviewed for clinicopathological parameters.

Results: Five patients were identified harboring either exon 19 deletion (n = 4) or exon 21 L858R mutation (n = 1) in EGFR. 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 TP53 (2/2), RB1 (1/2), PTEN (1/2), neurofibromatosis type 1 (1/2), and CREBB1 (1/2) were identified.

Conclusion: EGFR-mutant de novo SCLCs are extremely rare and show frequent inactivation of p53 and RB1, like the more common transformed SCLCs. Given the lack of tyrosine kinase inhibitor exposure, these tumors highlight the inherent lineage plasticity of EGFR/TP53/RB1 triple mutant lung carcinomas.