Unexpected Pericardial Cytology in a Patient With Primary Squamous Cell Carcinoma of the Lung: Emphasizing the Need for Advanced Molecular Characterization of Tumors

Non-small cell lung cancer (NSCLC) encompasses a diverse group of histologic subtypes, including adenocarcinoma, squamous cell carcinoma (SqCC), and the less common but clinically aggressive adenosquamous carcinoma. Intratumoral histologic heterogeneity is a recognized challenge in NSCLC and may result in diagnostic discordance when sampling is limited. Cytologic-pathologic discordance may raise concern for tumor heterogeneity, sampling error, or misidentified histologic subtype. In such scenarios, molecular profiling and re-biopsy are essential to refine diagnosis and guide therapy. Here, we present a case of a 70-year-old man with a known history of SqCC of the lung who presented with progressive shortness of breath and was found to have a large pericardial effusion. Cytologic analysis of the pericardial fluid revealed malignant adenocarcinoma cells, discordant with the prior SqCC diagnosis. Molecular profiling of the pericardial fluid identified a TP53 mutation, intermediate tumor mutational burden, and microsatellite stability, without actionable oncogenic drivers. Repeat tissue sampling reconfirmed SqCC histology with high PD-L1 expression. The patient was initially treated with pembrolizumab monotherapy but required escalation to carboplatin, pemetrexed, and pembrolizumab due to disease progression. The cytologic discordance raised suspicion for unrecognized adenosquamous carcinoma or tumor heterogeneity not captured on initial biopsy. No evidence of a second primary malignancy or histologic transformation was found. This case highlights the diagnostic challenges and therapeutic implications of cytologic-pathologic discordance in NSCLC. It underscores the importance of molecular profiling and repeat tissue sampling in guiding personalized treatment decisions when histologic uncertainty exists.