To investigate the role of SHOX2 in lymph node metastasis (LNM) and poor prognosis of pT1 non-clear cell renal cell carcinoma (nccRCC), and to evaluate its potential as a risk stratification biomarker.

Clinical data of 528 pT₁ renal cell carcinoma (RCC) patients who underwent robot-assisted partial nephrectomy at a single center were retrospectively analyzed, including 96 patients of nccRCC and 432 patients of clear cell renal cell carcinoma (ccRCC). LNM rates and prognosis were compared between the two groups. Transcriptomic data of nccRCC (n=355) were obtained from the TCGA database to screen differentially expressed genes between positive lymph nodes (LN+) and negative lymph nodes (LN-) groups, followed by survival analysis and pathway enrichment analysis. SHOX2 immunohistochemistry (IHC) was performed on paraffin-embedded specimens from 20 pT₁ nccRCC patients, and protein expression levels were compared between the two groups.

In the clinical cohort, the LNM rate was higher in nccRCC than in ccRCC (5.21% vs 0.46%, P=0.001), and LNM independently predicted poor prognosis (HR=36.44, 95%CI: 4.67-284.47, P<0.001). In the TCGA cohort, SHOX2 was the most upregulated gene in LN+ tumors (log₂FC=6.01, P<0.001), and high SHOX2 mRNA expression was associated with shorter disease-free survival (HR=2.896, 95%CI: 1.329-6.310, P=0.007). Functional enrichment linked SHOX2 to extracellular matrix (ECM) remodeling (r=0.401) and epithelial-mesenchymal transition (EMT) activation (r=0.381) (both P<0.001). Preliminary IHC analysis showed higher SHOX2 protein expression in LN+ than in LN- specimens (Mann-Whitney U=9.500, P=0.002).

SHOX2 may drive lymphatic metastasis in pT₁ nccRCC through the ECM-EMT axis and serve as a potential prognostic biomarker. Future studies could explore the value of combining SHOX2 expression with its methylation detection for risk stratification in high-risk nccRCC, though multicenter prospective validation is required.