Deciphering intratumor heterogeneity in clear cell renal cell carcinoma utilizing clinicopathologic and molecular platforms.

Clear cell renal cell carcinoma (CCRCC) is a common renal malignancy known for its lethality and chromosome 3p aberrancies associated with loss of VHL. It has been shown that additional prognostic molecular markers exist in other transcriptional modifiers such as BAP1 and SETD2. Molecular heterogeneity has been described between primary and metastatic sites as well as genetic diversity in spatial tumor analysis; however, morphologic and proteogenomic heterogeneity information is lacking. We assessed 77 nephrectomy specimens with a diagnosis of CCRCC for morphologic architectural patterns including nodular growth patterns and variations in WHO/ISUP grade. Evaluation of highly heterogeneous areas with immunohistochemical (IHC) staining for BAP1, UCHL1, SETD2, and CAIX was performed and correlated with morphologic and histology data. Ultimately, high variability in the morphologic and histological findings matched the complexity of the IHC findings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional regulators BAP1 and SETD2 within the tumor. High-grade morphology, such as eosinophilia, were areas enriched for alteration of biomarker expression. This highly complex data set of morphologic and biomarker characteristics highlights the heterogeneity of morphology amongst high-grade CCRCC tumors.