Distinct Clinical and Biological Features of Diffusely Metastatic Versus Bulky Localized Lung Cancer: Real-World Outcomes from a University Cancer Center in Germany

<b>Background:</b> Lung cancer metastasis results from local invasion, loss of adhesion, migration, and distant implantation. Some small tumors metastasize diffusely other tumors progress to local bulky disease without metastasis. Here we compare these biologically divergent courses of progression and present an analysis of clinical features related to early diffuse metastasis vs. bulky disease. <b>Methods</b>: We retrospectively collected data from pathologically confirmed not-metastatic "bulky" (cT3-T4cN0cM0) or "diffusely metastatic" (cT1-T2cN1-3cM1) patients with lung cancer treated at our center from 2013 to 2023. Clinical data including sex, age, histology, ECOG-PS, tumor stage, smoking status, presence, and site of metastases, LDH, CRP, NLR ratio were collected. <b>Results</b>: A total of 375 patents with "bulky" (<i>n</i> = 95) or diffusely metastatic lung cancer (<i>n</i> = 280) were included in the analysis. In the univariate analysis, the diffusely metastatic population was younger (<i>p</i> = 0.001), had a higher proportion of never smokers (<i>p</i> = 0.02), histologically adenocarcinoma (<i>p</i> < 0.0001), TTF1 positive (<i>p</i> < 0.00001) and elevated baseline LDH in serum (LDH > 250U/l, <i>p</i> < 0.0001) compared to "bulky" population. Patients with diffuse metastatic disease presented worse OS (HR = 2.34, <i>p</i> = 0.0001) and PFS (HR = 6.89, <i>p</i> < 0.0001) compared to patients with bulky disease. <b>Conclusions</b>: Younger age, never smokers, TTF1 positivity, poorly differentiated tumors, adenocarcinoma histology were independently associated with risk of distant metastasis.