Immunohistochemistry-based risk stratification of upper tract urothelial carcinoma

Upper tract urothelial carcinoma (UTUC) is characterized by significant biological heterogeneity. Although high-throughput sequencing has unveiled the genomic landscape of UTUC, its routine clinical application is hindered by high costs and technical complexity. This study aimed to develop a cost-effective molecular subtyping strategy using immunohistochemistry (IHC) as surrogate markers and to construct a novel risk stratification model integrating driver genes (TP53/FGFR3) for predicting postoperative recurrence-free survival (RFS).

We retrospectively analyzed 215 patients with UTUC who underwent radical nephroureterectomy between 2021 and 2024. IHC staining was performed for GATA3, CK20, CK5/6, CD44, P53, and FGFR3. Tumors were initially stratified into Luminal-like or Basal-like subtypes. Subsequently, a three-tier "RiskGroup" stratification was constructed: Low Risk (Luminal-like with wild-type P53), Intermediate Risk (Luminal-like with aberrant P53), and High Risk (Basal-like). A prognostic nomogram was developed based on multivariate Cox regression analysis and validated using the Concordance Index (C-index) and Decision Curve Analysis (DCA).

Luminal-like and basal-like subtypes showed distinct clinicopathologic profiles. RiskGroup further captured heterogeneity, with increasing Ki-67 across low-, intermediate-, and high-risk groups (median 30%, 60%, 60%; P<0.001). The intermediate-risk group, despite luminal immunophenotype, was enriched for high-grade disease (94.2%) and had worse RFS than the low-risk group. RFS differed across RiskGroup (P<0.001); the high-risk group had the poorest outcomes and remained independently associated with RFS (HR 2.60, 95% CI 1.27-5.33; P = 0.009), whereas intermediate risk was not significant after adjustment (HR 1.63; P = 0.227). RiskGroup, pathological T stage, and lymphovascular invasion were independent prognostic factors. The nomogram showed good discrimination (C-index 0.769) and 1-year RFS AUC 0.823 with net clinical benefit.

This IHC-based, biologically informed stratification identifies an occult aggressive subset within luminal tumors and complements routine pathology. The internally validated nomogram is exploratory given cohort composition and lack of external validation; multicenter validation is warranted.