PROX1 Expression in Resected Non-Small Cell Lung Cancer: Immunohistochemical Profile and Clinicopathological Correlates

<b>Background/Objectives:</b> PROX1 (prospero homeobox 1) is a transcription factor involved in lymphangiogenesis and cellular differentiation. Its role in cancer biology appears to be highly context-dependent, with it exhibiting both tumor-promoting and -suppressive functions across various malignancies. Nonetheless, the clinical significance of PROX1 expression in non-small cell lung cancer (NSCLC) remains poorly elucidated. The objective of this study is to evaluate the immunohistochemical expression of PROX1 in NSCLC, specifically in the adenocarcinoma and squamous cell carcinoma subtypes, and to assess its correlation with clinicopathologic features and overall survival (OS). <b>Methods:</b> This retrospective study included surgically resected specimens from 121 patients with histologically confirmed NSCLC. PROX1 expression was assessed via immunohistochemistry on formalin-fixed, paraffin-embedded specimens. Staining intensity (graded 0- National and Kapodistrian University of Athens 3) and the percentage of positive tumor cells were recorded. Correlations with histological subtype, tumor characteristics, and OS were analyzed using chi-square tests, one-way ANOVA, and Kaplan-Meier survival analysis with log-rank testing. <b>Results:</b> Low PROX1 intensity (level 1) was significantly associated with P63 positivity (<i>p</i> = 0.028), while high PROX1 intensity (level 3) correlated with nodal metastasis to station 3 (S3+) (<i>p</i> = 0.025). Additionally, alveolar-pattern adenocarcinomas exhibited intermediate PROX1 expression (26-50%) (<i>p</i> = 0.010). Although PROX1 positivity did not differ among mucinous and non-mucinous adenocarcinomas (<i>p</i> = 0.152), its distribution across defined expression subgroups was statistically significant (<i>p</i> = 0.002). Tumors with low PROX1 expression (0-24%) were associated with a larger maximum tumor diameter (<i>p</i> = 0.026). PROX1 expression was not independently associated with OS (<i>p</i> > 0.05). Factors significantly associated with improved survival included an age < 50 years, female sex, the absence of necrosis, fewer than 10 positive lymph nodes, a lymph node ratio < 0.5, and the absence of extensive nodal involvement in stations 5, 10, 11, and 12. <b>Conclusions:</b> Although PROX1 expression is variably associated with specific histologic subtypes and nodal metastases in NSCLC, it does not independently predict overall survival. Its expression patterns suggest a potential role in tumor differentiation and lymphatic spread. Further mechanistic and immunologic studies are warranted to elucidate the functional significance of PROX1 in lung cancer biology.