Tissue Prognostic Markers for Clear Cell Renal Cell Carcinoma Tumor-stroma Interaction: Impact on TNM Staging Parameters

Background/Aim: Clear cell renal cell carcinoma (cc-RCC) is known for its rapid development of therapy resistance, highlighting the need for new prognostic biomarkers. This study aimed to evaluate the impact of Chloride Intracellular Channel Protein 1 (CLIC1) expression in both tumor and stromal compartments on TNM staging parameters, with a focus on cases that are positive or negative for tertiary lymphoid structures (TLSs).

Materials and Methods: CLIC1 immunohistochemistry (IHC) was performed on 60 cc-RCC tissue samples. Expression was assessed in tumor and stromal compartments, with particular attention to expression patterns in tumor cells – nuclear (N), cytoplasmic (C), membranous (M), or combined. TLSs were quantified for each case. Digital analysis using QuPath software enabled evaluation of CLIC1 expression and its correlation with TNM staging parameters in TLS-positive versus TLS-negative cc-RCC cases.

Results: TLS presence was predominantly associated with a cytoplasmic and membranous (CM) pattern of CLIC1 expression in tumor cells. The CM pattern significantly correlated with CLIC1-positive stromal microvessel density (CLIC1-MVD, p=0.026), and with TNM parameters T (p=0.028) and M (p=0.031). Tumors with a nuclear-cytoplasmic (NC) expression pattern and TLSs showed significant correlations with grade (G, p=0.026) and M (p=0.025) but not with CLIC1-MVD. In TLS-negative cases, CLIC1 expression was primarily nuclear in tumor cells. The only significant correlation in TLS-negative cases was between the N and M parameters (p=0.028).

Conclusion: The interplay between TLSs, CLIC1 expression in tumor cells, and stromal vasculature significantly influences TNM staging parameters. Preliminary data suggest that CLIC1 CM and M patterns may promote metastasis and stromal vascularization, whereas TLS presence, particularly with certain CLIC1 patterns, may serve as a negative prognostic marker.