Background: Overexpression of chloride intracellular channel protein 1 (CLIC1) in tumor cells has been confirmed, but it has received less attention in the tumor blood vessel endothelium. Aim: The assessment of CLIC1 expression in ccRCC tumor blood vessels and its relationship with TNM parameters and tumor cell CLIC1 expression. Methods: CLIC1 immunostaining in ccRCC was evaluated in 50 cases in both malignant cells and tumor blood vessels (CLIC1 microvessel density-CLIC1-MVD) and was correlated with TNM staging parameters. Results: CLIC1-MVD was observed in approximately 65% of cases, and CLIC1 co-localization in both tumor and endothelial cells was observed in 59% of cases. ccRCC was classified into four groups (Classes 0–3) based on the percentage of positive tumor cells, with each group including sub-groups defined by CLIC1 expression in the endothelium. Class 3 (60–100% positive tumor cells) had the highest CLIC1-MVD, with an impact on T and M parameters (p value = 0.007 for T, and p value = 0.006 for M). For cases with CLIC1 intracellular translocation, there was a strong correlation between CLIC1-MVD and M (p value < 0.001). Conclusions: Co-expression of ccRCC tumor and endothelial cells promotes tumor progression and metastasis and should be investigated further as a potential therapeutic target for ccRCC and other human malignancies.

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.

Background/Aim: Multiple metastases of clear-cell renal cell carcinoma (cc-RCC) worsen therapeutic response and survival. There are few predictive markers for assessment of metastases upon diagnosis, most of which relate to therapeutic response, recurrences, and survival. Our goal was to determine if there is a relationship of leucocyte and platelet counts with the number and location of metastases at initial diagnosis. Stratifying patients by age, we aimed to correlate leucocyte and platelet counts with the number of metastases and their location at first diagnosis. Materials and Methods: After accurate inclusion and exclusion criteria, three age groups of patients with cc-RCC were defined: 35-50, 51-65 and 66-85 years old. Metastases mapping was applied for each patient by recording their location and number (unique versus multiple sites) and this was correlated to the clinicopathologic factors age, sex, white blood cells and platelets count. Results: For the group aged 35-50 years, preferred sites of metastasis of cc-RCC were the brain, bone, and liver. Neutrophil count was significantly correlated to brain (p=0.003) and bone (p=0.039) metastases. A predominance of liver metastases in women was observed. Skin metastases were significantly correlated with lymph node metastases (p=0.02). The lowest metastatic rate was found in patients aged 51-65 years. Lung and pleural metastases were predominantly reported in men for this subgroup (p=0.017) and weak positive correlation of these with the neutrophil count was found (p=0.026 and p=0.037, respectively). Negative correlation was identified for brain metastases with leucocyte count (p=0.049) and neutrophil count (p=0.044). Elderly patients (66-85 years old) had the highest metastasis rates, and neutrophil counts were significantly positively correlated with platelet counts (p=0.035). Conclusion: The metastatic potential of cc-RCC is highly heterogeneous amongst different age subgroups, with a potential for strong clinical impact related to therapy response and development of therapy resistance.