CD163 Outperforms CD68 in Clear Cell Renal Cell Carcinoma: Clinicopathological and Prognostic Correlations

Tumor-associated macrophages (TAMs) shape the immune microenvironment of renal cell carcinoma (RCC). We quantified TAM burden and polarization using CD68 (pan-macrophage) and CD163 (M2-skewed) and examined their clinicopathological and prognostic correlates.

In a single-center study, 60 histopathologically confirmed RCC cases were evaluated. Immunohistochemistry for CD68 and CD163 was scored by two blinded pathologists using (i) an intensity with proportion composite score (0-9; mean of five hotspot HPFs) and (ii) TAM density (positive cells/HPF). Associations with clinicopathological features were tested.

Mean age was 53.7 ± 11.5 years; 78.3% were male. Necrosis was present in 78.3%; lymphovascular invasion in 1.7%. CD68 intensity was weak/moderate/strong in 33.3%/36.7%/30.0%; CD163 was 51.7%/30.0%/11.7%, with 6.7% negative. Mean composite scores were 1.22 ± 0.45 (CD68) and 2.20 ± 0.75 (CD163); densities were 9.59 ± 4.33 and 7.17 ± 3.82 cells/HPF, respectively. Grade correlated strongly with CD68 composite (ρ = 0.60, P < 0.0001) and moderately with CD163 metrics (ρ ≈0.39-0.45, P ≤ 0.002); CD68 density showed a small inverse correlation (ρ = -0.27, P = 0.037). Necrosis was associated with higher CD68 and CD163 intensity ( P = 0.0178 and 0.0164); CD68 intensity varied across TIL strata ( P < 0.0001). In multivariable analysis, CD163 overall (β = 0.67, P = 0.03) and CD163 percentage (β = -0.86, P = 0.04) remained independent, alongside tumour size (β = 0.00059/cm, P = 0.004); CD68 parameters were not.

TAM polarization carries greater pathological signal than bulk macrophage burden in RCC. CD163-based metrics associate with necrosis and retain independence alongside tumor size, supporting their incorporation into risk assessment and motivating TAM-directed therapeutic strategies. Prospective validation with survival endpoints is warranted.