Cytoplasmic Morphology Predicts the Tumor Immune Microenvironment and Recurrence in Localized Clear Cell Renal Cell Carcinoma.

Abstract

It has been suggested that cytoplasmic pattern (CPP) reflects the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC). This study investigated the associations between CPP and clinicopathological features, including tumor-associated immune cell status (TAICs) and immunosuppressive immune cell infiltration, in localized ccRCC. This retrospective analysis included 112 patients with pT1b ccRCC. CPP (clear, mixed, eosinophilic) and TAICs were evaluated on hematoxylin-eosin (HE)-stained sections. Immunohistochemistry for cluster of differentiation 8 (CD8), programmed cell death protein 1 (PD-1), programmed cell death ligand-1 (PD-L1), and FOXP3 was performed. Immune cell infiltration was compared across CPP subtypes. Cox proportional hazards models were used to identify predictors of recurrence and cancer-specific survival. CPP distribution was clear in 36 patients (32%), mixed in 54 (48%), and eosinophilic in 22 (20%). CPP was significantly associated with nuclear grade, tumor necrosis, and lymphovascular invasion. CPP correlated with TAICs, with eosinophilic tumors showing the highest proportion of the hot phenotype. Infiltration of PD-1-, PD-L1-, CD8-, and FOXP3-positive immune cells increased stepwise from clear to eosinophilic types. Time to recurrence differed significantly among CPP groups (p < 0.0001). The 3-year recurrence-free probability was 63% in the eosinophilic type and 94.8% in the non-eosinophilic type. In multivariate analysis, eosinophilic type was the only independent predictor of recurrence. For cancer-specific survival, eosinophilic type was a significant predictor in univariate analysis. CPP is associated with adverse pathological features and immunosuppressive immune cell infiltration in localized ccRCC. Eosinophilic CPP independently predicted time to recurrence, indicating that CPP may serve as a practical pathological marker for stratifying recurrence risk and guiding postoperative surveillance strategies.