Dual onsets of small cell lung cancer with contrasting neuroendocrine features and immune microenvironments: A case report

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) offer modest survival benefits; however, their efficacy is inconsistent, and only a few reliable biomarkers are available for guiding treatment. The molecular subtypes of SCLC, defined by transcription factor expression (SCLC-A, SCLC-N, SCLC-P, and SCLC-Y), exhibit distinct therapeutic vulnerabilities. Among these, the SCLC-I subtype, characterized by low neuroendocrine differentiation and high immune activity, is associated with an improved response to ICIs. However, the implications of the subtype transitions during disease progression remain unclear. Here, we describe the case of a patient in their 60 s who developed SCLC twice, presenting with distinct neuroendocrine features and immune profiles. The initial tumor, classified as SCLC-I, exhibited significant CD8 + T-cell infiltration and negative ASCL1/NEUROD1 expression, which correlated with a prolonged atezolizumab response. Three years later, a newly developed tumor in the contralateral lung displayed SCLC-A features, with ASCL1/NEUROD1 positivity and an absence of CD8 + infiltration, resulting in limited durvalumab efficacy. This report highlights the dynamic nature of SCLC and the importance of histopathological evaluation for guiding treatment. Larger studies are needed to validate the generalizability of these findings and explore biomarkers for diagnostic strategies.