Histopathological and Molecular Predictors of the First Site of Dissemination in Non-Small Cell Lung Cancer.

[BACKGROUND] Non-small-cell lung cancer (NSCLC) is often diagnosed at stage IV, when prognosis depends on metastatic spread. The impact of histopathology on the first metastatic site remains underexplored.

[METHODS] We retrospectively analyzed 364 patients with stage IV NSCLC diagnosed at OncoHelp Medical Center, Timișoara, Romania (2020-2024). All underwent baseline CT chest-abdomen-pelvis, whole-body FDG PET-CT, and brain MRI within seven days of histological confirmation. Patients were stratified into adenocarcinoma ( = 164), squamous cell carcinoma ( = 112), and large-cell carcinoma ( = 88). The first metastatic site was defined as the earliest confirmed location. Associations were evaluated using Fisher's exact test and multinomial logistic regression.

[RESULTS] Histology was associated with the first metastatic site (global = 0.013). Adenocarcinoma was more likely than squamous carcinoma to present with brain metastases (RRR 3.74, 95% CI 1.48-9.45; = 0.005; = 0.053) and showed directional signals toward bone and adrenal involvement. Squamous carcinoma more frequently spread to the pleura as the first site (adjusted = 0.008). Large-cell carcinoma showed no consistent differences compared to squamous carcinoma. In adenocarcinoma subgroups, EGFR-mutant tumors most often metastasized to the brain (55.6%), KRAS-mutant tumors to the liver (44.4%), and ALK-rearranged tumors to bone (100%).

[CONCLUSIONS] The first metastatic site in NSCLC follows histology-specific patterns, with adenocarcinoma favoring hematogenous spread and squamous carcinoma showing locoregional involvement. Molecular status further refines these patterns in adenocarcinoma. Incorporating histology into baseline staging may improve diagnostic efficiency and prognostic accuracy.