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 addi-tional 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 informa-tion 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. Evalua-tion 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 find-ings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional reg-ulators 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 tu-mors. (c) 2022 Elsevier Inc. All rights reserved.