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

## TL;DR

This study finds that the type of lung cancer and its genetic features predict where it first spreads, helping doctors choose better imaging tests.

## Contribution

The study identifies histology- and mutation-specific patterns of first metastasis in non-small cell lung cancer.

## Key findings

- Adenocarcinoma is more likely to spread first to the brain, bones, or adrenal glands.
- Squamous cell carcinoma more often spreads first to the pleura.
- EGFR, KRAS, and ALK mutations in adenocarcinoma are linked to specific first metastatic sites.

## Abstract

Lung cancer is often discovered after it has already spread, and the location of the first metastasis can strongly influence treatment decisions. In this study, we analyzed patients with advanced non-small-cell lung cancer to see if the tumor’s histological type could predict the first site of spread. We found that adenocarcinoma was more likely to involve the brain, bones, or adrenal glands, while squamous cell carcinoma more often affected the pleura. Certain genetic changes in adenocarcinoma also showed specific patterns. These results may help doctors select the most useful imaging tests at diagnosis and personalize patient care.

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 (n = 164), squamous cell carcinoma (n = 112), and large-cell carcinoma (n = 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 p = 0.013). Adenocarcinoma was more likely than squamous carcinoma to present with brain metastases (RRR 3.74, 95% CI 1.48–9.45; p = 0.005; pFDR = 0.053) and showed directional signals toward bone and adrenal involvement. Squamous carcinoma more frequently spread to the pleura as the first site (adjusted p = 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.