Immunohistochemistry-based Subtyping of Urothelial Carcinoma

Molecular subtyping of urothelial carcinoma (UC) based on RNA expression profiling provides additional prognostic insights beyond traditional staging and grading systems. A recent study developed an immunohistochemistry (IHC)-based alternative using four accessible antibodies to stratify UC patients in resource-constrained settings.

The investigators examined 100 chemotherapy-naïve UC patients (both muscle-invasive and non-muscle-invasive), including both transurethral resection and radical cystectomy specimens. Tissue microarrays were stained for GATA3, KRT5, KRT14, and KRT20 markers. Positive staining was defined as >20% tumor cell positivity. Subtypes were classified as: IHC luminal (GATA3+/KRT20+ but KRT5-/KRT14-), IHC basal (KRT5+/KRT14+ but GATA3-/KRT20-), IHC dual-positive (markers from both groups), and IHC dual-negative (all markers negative). The mean age of the cohort was 64 years. The cohort included 60% NMIBC versus 40% MIBC tumors. Molecular subtypes included IHC luminal (55%), IHC dual-positive (22%), IHC basal (19%), and IHC dual-negative (4%). Overall survival rates were highest for IHC luminal subtype (80%), followed by IHC dual-positive (72.72%), IHC basal (63.15%), and IHC dual-negative (25%) (p=0.012). Squamous differentiation occurred predominantly in IHC basal subtype (75% of cases, p<0.001). IHC basal tumors were significantly larger (57.9% ≥3.0 cm) and more frequently lacked papillary morphology (45.4%). Most NMIBC (65%) were IHC luminal subtype, while 60% of MIBC were non-luminal subtypes. Lymphovascular invasion was a poor prognostic factor in both univariate (crude HR=8.80, 95% CI 3.31-23.37, p<0.001) and multivariate analyses (adjusted HR=5.26, 95% CI 2.01-18.11, p<0.001). IHC dual-negative subtype had a significantly higher risk versus IHC luminal reference (adjusted HR=6.39, 95% CI 1.73-6.55, p<0.01).

The study examined IHC-based molecular subtyping using four accessible markers to stratify UC patients with significant prognostic implications. While the cost of transcriptomic and genomic approaches continues to decrease and their applicability to generate clinical biomarkers improves, this study shows the feasibility of supporting molecular stratification in resource-limited settings.

Written by: Bishoy M. Faltas, MD, Chief Research Officer, Englander Institute for Precision Medicine, Gellert Family - John P. Leonard, MD, Research Scholar, Associate Professor of Medicine, Cell and Developmental Biology, Weill Cornell Medicine, New York- Presbyterian Hospital, NY

References:

Indulkar S, Rao BV, Das D, Pasam MK, Kodandapani S, Sharma RM, Thammineedi SRT. Deciphering the molecular landscape of urothelial carcinoma: immunohistochemistry-based subtyping using 4 easily available antibodies for cost-effective stratification. Appl Immunohistochem Mol Morphol. 2025;00:000-000. doi:10.1097/PAI.0000000000001272.

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