Occult primary non-small cell lung cancer (OP-NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation, with little known about how outcomes compare to typical Stage III NSCLC. We reviewed our experience treating OP-NSCLC with definitive radiotherapy and compared outcomes to a contemporary cohort of stage III NSCLC patients.

We reviewed 605 patients with stage III NSCLC staged with PET-CT and treated with definitive radiotherapy between 1998 and 2013. Overall survival, intrathoracic control, and freedom from distant metastasis were computed using Kaplan-Meier method and logrank comparison. Cox hazard ratios were used to perform univariate and multivariate analyses.

Twenty-one patients were identified with OP-NSCLC (3.5%). Patients with OP-NSCLC, as compared to known primary NSCLC, had significantly better 5-year rates of intrathoracic control (83.5% vs. 24.2%, P < 0.001), freedom from distant metastasis (59.0% vs. 26.3%, P = 0.003), and overall survival (61.6% vs. 15.2%, P < 0.001). Multivariate analyses confirmed occult primary as an independent prognostic factor associated with a 70% reduction in risk of intrathoracic failure, a 55% reduction in risk of distant metastasis, and a 70% reduction in risk of death.

To our knowledge, this is the largest reported series of OP-NSCLC and the first to compare it to a contemporary cohort of Stage III NSCLC with known primary lesion. Definitive radiation therapy was associated with favorable locoregional control and survival, particularly compared with typical stage III NSCLC. This difference suggests that occult primary NSCLC may be a distinct entity with different biology than typical NSCLC.