SHOX2-Driven Lymphatic Metastasis in pT1 Non-Clear Cell Renal Cell Carcinoma: A Biomarker-Guided Risk Stratification and Therapeutic Strategy

Background Non-clear cell renal cell carcinoma (nccRCC), representing 25–30% of RCC cases, exhibits higher lymph node metastasis (LNM) risk than clear cell RCC (ccRCC). Despite favorable outcomes in early-stage pT1 nccRCC, metastatic potential persists, necessitating improved risk stratification. Methods A single-center retrospective cohort of 528 pT1 RCC patients (96 nccRCC; 432 ccRCC) and TCGA data (n = 355) were analyzed. Differential gene expression (DESeq2, log2FC > 1, FDR < 0.05, p < 0.05 ), survival analyses (Kaplan-Meier/Cox regression), and immunohistochemistry (IHC) validated SHOX2 as a biomarker. Results The LNM rate in pT1 nccRCC was significantly higher than in ccRCC (4.1% vs. 0.4%, p < 0.001 ). SHOX2 was markedly overexpressed in LNM + tumors (log2FC = 6.01, p < 0.01 ) and independently predicted adverse prognosis (HR = 2.896, 95% CI 1.329–6.31, p < 0.01 ). Functional enrichment linked SHOX2 to ECM remodeling (r = 0.401, p < 0.001 ) and EMT activation (r = 0.381, p < 0.001 ). IHC validation demonstrated SHOX2’s predictive value for LNM (AUC = 0.77, 95% CI 0.61–0.93), with optimal cutoff ≥ 3.5 (70% sensitivity, 90% specificity). SHOX2 positivity was enriched in LNM + specimens (70% vs. 10%, p < 0.001 ). Conclusions SHOX2 drives lymphatic dissemination in pT1 nccRCC via ECM-EMT crosstalk, serving as a robust biomarker. A tripartite strategy integrating preoperative mSHOX2 liquid biopsy, image-guided lymph node dissection, and postoperative targeted-immunotherapy (e.g., toripalimab-axitinib) is proposed to optimize outcomes. Multicenter validation is warranted for clinical translation.