Mutation Profile Variability in the Primary Tumor and Multiple Pulmonary Metastases of Clear Cell Renal Cell Carcinoma. A Review of the Literature and Analysis of Four Metastatic Cases.

Abstract

Simple SummaryClear cell renal cell carcinoma (CCRCC) is well known for intra-tumoral heterogeneity. However, there are limited data focusing on the inter-tumoral and inter-metastatic heterogeneity of CCRCC. In one study, primary and metastatic tumors were classified as clear cell type A or B subtypes, using nanostring expression technology. It was found that primary and metastatic tumors of CCRCC differed in nearly one half of patients. Approximately one quarter of metastatic tumors display inter-metastatic heterogeneity. Another study, using an immunohistochemical assay, found inter-metastatic tumor heterogeneity of BAP1 in only 1 of 32 patients (3%). Comparing gene expression across patient-matched primary-metastatic tumor pairs, 98% had concordant BAP1 status. We aimed 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.(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.