The impact of spread through air spaces on intrapulmonary metastasis in lung cancer: a retrospective study of multiple primary lung adenocarcinomas with confirmed common origin based on histological classification alone and combined histological-molecular classification.

BACKGROUND

Distinguishing multiple primary lung adenocarcinomas (MPLAs) from intrapulmonary metastases (IPMs) is essential for accurate staging and treatment planning. However, existing histologic and molecular criteria remain limited in diagnostic accuracy. Spread through air spaces (STAS) has been recognized as a marker of tumor aggressiveness, but its role in differentiating MPLA from IPM remains unclear. This study aimed to assess whether STAS can serve as a supportive marker to differentiate IPM from MPLA under both histologic and molecular frameworks.

METHODS

We retrospectively enrolled 170 patients who were preoperatively diagnosed with MPLA and underwent surgical resection of multiple lung lesions. Clinical, histopathologic, and molecular data-including broad-panel next-generation sequencing (NGS) results [e.g., epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein p53 (TP53), among others]-were collected. Tumors were classified as MPLA or IPM using histologic criteria alone and a combined histologic-molecular algorithm. The presence and quantity of STAS were evaluated and analyzed as potential predictors of IPM.

RESULTS

STAS was more frequent in the IPM group across both classification methods and was an independent predictor of IPM. Driver gene mutations (e.g., EGFR, KRAS) differed significantly between MPLA and IPM. The 83.5% concordance between histologic and combined classifications suggests potential bias in histology alone. In resource-limited settings, STAS may offer a cost-effective adjunct to support IPM diagnosis when molecular data are unavailable.

CONCLUSIONS

STAS is associated with IPM and may serve as a supportive diagnostic marker when distinguishing IPM from MPLA. In resource-limited settings where molecular testing is not always available, STAS may offer a practical, cost-effective histologic adjunct to guide clinical decision-making.