(1) Background: There are limited data concerning inter-tumoral and inter-metastatic heterogeneity in clear cell renal cell carcinoma (CCRCC). The aim of our study was to review published data and to examine mutation profile variability in primary and multiple pulmonary metastases (PMs) in our cohort of four patients with metastatic CCRCC. (2) Methods: Four patients were enrolled in this study. The clinical characteristics, types of surgeries, histopathologic results, immunohistochemical and genetic evaluations of corresponding primary tumor and PMs, and follow-up data were recorded. (3) Results: In our series, the most commonly mutated genes were those in the canonically dysregulated VHL pathway, which were detected in both primary tumors and corresponding metastasis. There were genetic profile differences between primary and metastatic tumors, as well as among particular metastases in one patient. (4) Conclusions: CCRCC shows heterogeneity between the primary tumor and its metastasis. Such mutational changes may be responsible for suboptimal treatment outcomes in targeted therapy settings.

2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Pathology Faculty of Medicine in Pilsen and University Hospital Pilsen Charles University 305 99 Pilsen Czech Republic

Department of Pathology University of British Columbia Vancouver BC 2329 Canada

Department of Surgery Faculty of Medicine in Pilsen and University Hospital Pilsen Charles University 304 60 Pilsen Czech Republic

Department of Urology Faculty of Medicine in Pilsen and University Hospital Pilsen Charles University 305 99 Pilsen Czech Republic

Robert J Tomsich Pathology and Laboratory Medicine Institute and Glickman Urological Institute Cleveland Clinic Cleveland OH 44195 USA

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