Clinicopathologic and Genomic Factors Associated With Oncologic Outcome in Patients With Stage III to IV Chromophobe Renal Cell Carcinoma

In the modern era, the majority of kidney tumors are diagnosed as organ confined disease. cT1-2 masses are manageable with extirpative surgery and treatment outcome remains excellent. However, disease-specific outcome is far less favorable for cT3 and cT4 renal tumors. Although tumor stage is a very important predicting factor from an outcome standpoint, tumor histology plays a significant role as well. Approximately 80% of renal cell carcinoma have clear cell histology. Therefore, the majority of studies in locally advanced and metastatic renal cell carcinoma (RCC) are focused on this subtype. However, there is limited evidence in the literature regarding the outcome of other subtypes of RCC.

In our study, we wanted to focus on chromophobe renal cell carcinoma (chRCC). chRCC makes up approximately 5% of RCC and it is known to be a more indolent type of RCC. It has morphological characteristics very similar to oncocytoma, which is a benign tumor. However, we see chRCC as cT3 or cT4 disease in our practice and there is a reported 6% mortality rate from this disease. Therefore, all chRCC do not demonstrate indolent behavior. Because chRCC is a rare subtype, we decided to analyze the American College of Surgeons’ National Cancer Database (NCDB) to achieve an adequate sample size (n=1,693).

In our multivariable analysis of the NCDB data, older age (HR=1.04; 95% CI=1.03, 1.05; p<0.001), TNM stage IV vs. III (HR=3.86; 95% CI=2.98, 5.00; p<0.001), and positive surgical margins (HR=1.68; 95% CI=1.45, 1.96, p<0.001) were associated with worse OS at a median follow-up of 41.4 months. 5-year overall survival (OS) was significantly lower for stage IV patients compared to stage III. (80.0% vs. 29.9%, p<0.001). Despite the statistical significance, this information does not help greatly in a clinical setting with regards to adjuvant/salvage treatment options. Therefore, we wanted to identify the genomic factors associated with recurrence following radical nephrectomy.

For genomic analysis we used the Cancer Genome Atlas (TCGA) Database, which is a multi-institutional collaborative. RNA expression analysis of 18,745 genes was conducted between the recurrent (n=5, 27.8%) and non-recurrent patients (n=13, 72.2%). Biological significance was identified via pathway enrichment and gene function analyses. Most commonly overexpressed pathways were neuroactive ligand-receptor interactions and cytokine-cytokine receptor interaction. In a previous study, Liu et al. reported the same two pathways as the most significantly activated pathways in RCC ¹. Mitochondrial pathway analysis showed differential expression of 33 genes related to mitochondria function. These genes were involved in amino acid transport and metabolism, fatty acid metabolism, and oxidative phosphorylation.

Identifying these genomic alterations could help predict outcome and identify potential targeted therapy options in the future, as well as predicting treatment outcome. However, even in a comprehensive database like TCGA, we have been able to identify only 18 patients to analyze. Therefore, these expression profiles and clinical characteristics will require further validation.

Written by: Alp Tuna Beksac, MD and Ketan K Badani, MD, Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York

References
1. Liu X, Wang J, Sun G. Identification of key genes and pathways in renal cell carcinoma through expression profiling data. Kidney Blood Press Res. 2015;40(3):288-97.

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