A prognostic biomarker panel for chromophobe renal cell carcinoma using immunohistochemistry.
Authors: Ellis Elizabeth , Li Ashley , Rappold Phillip , Hensley Patrick J. , Wu Guan , Messing Edward M. , Yang Qi , Miyamoto Hiroshi , Tabayoyong William 
Published: February 2025

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Background:
The American Cancer Society estimates 14,390 deaths from kidney cancer in 2024 Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of kidney cancer, and 5-10% of patients with chRCC develop metastatic disease. Being able to prognosticate which tumors are aggressive vs. indolent is a significant unmet need.
Methods:
All partial and radical nephrectomies performed at our institution between 2012-2018 were queried. Cases stage pT1a-pT3a N0M0 at the time of surgery with a minimum of three-year follow up were included. Cases were evaluated for recurrence after surgery. chRCC tissue microarrays (TMA) were constructed from formalin-fixed paraffin-embedded surgical specimens with five 2 mm cores obtained from each tumor. Biomarker choice was hypothesis driven based on publicly available TCGA data. Immunohistochemistry (IHC) was performed for each antibody (Ab) of interest per protocol, with appropriate positive and negative controls. A blinded genitourinary pathologist reviewed the slides and designated an average Immunoreactive Score for all 5 punches for each Ab. Log rank test was used to compare expression levels of recurrent disease to non-recurrent disease based on high and low biomarker expression. Survival analysis for 0-3 positive markers was performed using Log-rank test.
Results:
Forty-six patients were included in the TMA. Six had recurrent disease: two developed metastasis and four had local recurrences. Two recurrences were from pT1a primaries, two were from pT1b primaries, and two were from pT3a primaries. One metastasis developed from a pT1b primary and one from a pT3a primary. Median length of follow up was 70.5 months, median age at surgery was 54.5 years, median time to recurrence was 32 months, and median mass size was 4.1 cm. High expression of glucose transporter 1 (GLUT1; hazard ratio (HR) = 33.6, p = 0.02) and Claudin-7 (HR = 6.1, p = 0.02) and low expression of platelet derived growth factor receptor (PDGFR; HR = 7.9, p = 0.005) relative to the median was associated with metastatic disease. Recurrences also tended to have high expression of cluster of differentiation 10 (CD10). When markers were combined as a panel, having two to three positive markers was associated with decreased recurrence free survival (RFS) on univariate analysis. Median RFS was 23 months vs. 92 months for three vs. two positive markers, respectively (p < 0.0001).
Conclusions:
High expression of GLUT1, important in glycolysis, and the epithelial mesenchymal transitional markers CD10 and Claudin-7 and low PDGFR is a protein expression signature that may signal chRCC capable of recurrent or metastatic disease. This provides post-translational insight to proteins that may be important for chRCC invasion and metastasis. Biomarker analysis using IHC is readily and widely available for use. External validation in a larger cohort is currently underway.