Carcinoma of unknown primary with a lung cancer profile in mediastinal and/or hilar lymph nodes: EGFR-mutant cases and a literature review of actionable drivers

We report two cases of carcinoma of unknown primary (CUP) with a lung cancer profile harboring epidermal growth factor receptor (EGFR) mutations. Case 1 was node-limited and achieved a durable partial response for at least 15 months with osimertinib. Case 2 harbored an EGFR exon 20 insertion and showed disease progression despite therapy. While responses to first- and second-generation EGFR tyrosine kinase inhibitors have been reported in EGFR-mutant CUP, evidence for the third-generation EGFR-TKI osimertinib remains limited. These cases highlight that early molecular profiling can identify actionable targets and enable lung cancer-standard therapies even when the primary lesion remains undetected.