Genomic-immunophenotypic landscape of early-stage pulmonary carcinoid tumors and their prognostic implications

Background: Pulmonary carcinoids (PCs), encompassing atypical carcinoids (ACs) and typical carcinoids (TCs), represent a rare category of lung cancer characterized by low to moderate malignancy. However, there is a limited understanding of the genomic and immune characteristics associated with PCs on a global scale. Methods: This study enrolled 126 surgically resectable PC patients, comprising 44 ACs and 82 TCs. Next-generation sequencing utilizing a 578-gene panel was conducted and immunohistochemical staining for PD-L1 and CD8 was also carried out. Findings: The most frequently altered genes in PCs were identified as EGFR (n=16, 18%), KMT2C (n=11, 12%), LRP1B (n=10, 11%), MEN1 (n=10, 11%), and NOTCH2 (n=9, 10%). Dysregulation of the RTK/RAS, NOTCH, and PI3K pathways was commonly observed in these PCs. Our study unveiled that only 4.6% of the PC patients were identified as PD-L1 positivity, and TMB and CD8+ T cell infiltration were found to be low in early-stage PCs, as manifested by the “immune-excluded” or “immune-desert” microenvironment. We identified age, gender, TNM stage, tumor type, smoking status, TMB, and LRP1B mutation as indicators of poor prognosis. We found that for those surgically resectable early-stage PC patients with LRP1B mutation, patients exhibit an increased risk for tumor-related mortality and recurrence, and subsequently further proposed a molecular classification based on the status of LRP1B mutation. Interpretation: We depicted the genetic and immune landscape of PCs and proposed a LRP1B mutation based molecular classification. Our research offers novel insights into the biological mechanisms of PCs which contributes to the individualized treatment for PC patients.