Phenotypic heterogeneity in primary tumors and brain metastases of small cell lung cancer: Insights into tumor microenvironment and metastatic behavior.

Abstract

8114 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with frequent brain metastases and pronounced phenotypic plasticity. How the tumor microenvironment and phenotypic heterogeneity relate to brain metastases remains poorly understood. Methods: We conducted a retrospective study of 124 patients with pathologically confirmed SCLC treated at a tertiary cancer center. In primary tumors, pathological features—including tumor-infiltrating lymphocytes (TILs), morphological patterns (necrosis, hyalinization, desmoplasia), and immunohistochemical characterization of lineage-associated SCLC markers—were assessed on H&E-stained sections. Immune-desert tumors were defined as having no detectable lymphocytic infiltration. Associations between these pathological features and baseline brain metastases were evaluated using appropriate statistical tests for categorical and continuous variables, with available brain metastasis samples also analyzed histopathologically and immunohistochemically to assess spatial heterogeneity and microenvironmental plasticity. Results: Among 124 patients, TIL levels were lower in those with baseline brain metastases than without (1.46% ± 4.54 vs 3.04% ± 5.29; p = 0.049), and the immune-desert phenotype was more frequent (88% vs 65%; p = 0.041), indicating a cold tumor microenvironment in patients with brain metastases. Immunohistochemical and morphological patterns were similar regardless of baseline brain metastases. Histopathological evaluation of the two available brain metastases showed marked intralesional heterogeneity. Regions had inflammatory infiltrates, coagulative necrosis, or stromal hyalinization. Tumor cells showed a spiculated growth pattern along the GFAP-positive astrocytic network, suggesting interaction with astrocytes. Synaptophysin expression was higher adjacent to lymphocytes, NEUROD1 predominant near necrotic zones, and POU2F3 higher in hyalinized regions. These findings indicate regional activation of different SCLC transcriptional programs, reflecting microenvironmental plasticity. Conclusions: An immune-desert phenotype in primary SCLC tumors is associated with baseline brain metastases, which exhibit pronounced spatial heterogeneity and region-specific tumor programs. These findings suggest that the immune context of the primary tumor may influence microenvironmental plasticity and contribute to brain metastasis development, warranting validation in larger cohorts.