SOX2‑positive upper tract urothelial carcinoma: Clinicopathological characteristics and therapeutic implications

Upper tract urothelial carcinoma (UTUC) is a rare subtype of urothelial malignancy associated with poor prognosis, particularly in advanced stages. Sex determining region‑Y‑related high mobility group box 2 (SOX2), a key transcription factor involved in the maintenance of cellular stemness, has been identified as a potential biomarker in multiple cancer types; however, its prognostic significance in UTUC remains unclear. The present study aimed to investigate the expression pattern of SOX2 in UTUC and examine its association with clinicopathological characteristics. Moreover, the present study aimed to evaluate the association of SOX2 with programmed cell death ligand 1 (PD‑L1) and antibody‑drug conjugate (ADC) targets, including Nectin‑4 and trophoblast cell surface antigen 2, to explore potential therapeutic implications. A total of 87 patients with UTUC who underwent radical nephroureterectomy were retrospectively analyzed. SOX2 expression was assessed using immunohistochemistry with a 10% cut‑off value. Notably, SOX2 expression was detected in 24% (21/87) of cases. No significant associations were observed between SOX2 expression and clinicopathological parameters, molecular subtypes, or the expression of PD‑L1 and ADC targets, except for hydronephrosis grade. Patients with SOX2‑positive tumors exhibited significantly worse overall survival (OS), cancer‑specific survival (CSS) and recurrence‑free survival (RFS; P=0.004, P=0.005 and P=0.011, respectively) during a median follow‑up period of 39.3 months. The 5‑year CSS rates were 69% in the SOX2‑negative group and 43% in the SOX2‑positive group. Multivariate analysis identified SOX2 expression as an independent prognostic factor for CSS (P=0.001). Among patients who did not receive perioperative chemotherapy, those with SOX2‑positive tumors demonstrated significantly poorer OS, CSS and RFS, compared with SOX2‑negative patients. These findings indicated that SOX2 expression represents an independent and robust prognostic biomarker in UTUC, identifying a biologically distinct high‑risk subgroup with unfavorable clinical outcomes. The preserved expression of PD‑L1 and ADC targets in this subgroup may suggest potential responsiveness to immune checkpoint inhibitors and ADC‑based therapies, supporting the consideration of intensified perioperative or systemic treatment strategies in SOX2‑positive patients.