# Biomarkers in Renal Cell Carcinoma: A Systematic Review and Immunohistochemical Validation Study

## TL;DR

This study identifies neuron-specific enolase (NSE) as a potential biomarker for clear cell kidney cancer, especially in older patients.

## Contribution

The study validates NSE as a potential biomarker for clear cell renal cell carcinoma through immunohistochemical analysis.

## Key findings

- NSE showed increased expression in tumors compared to normal tissue (p < 0.001).
- NSE expression was more pronounced in patients over 60 years old (p = 0.038).
- APA, APN, and GGT had reduced staining intensity in tumors but limited diagnostic utility.

## Abstract

The incidence of kidney cancer is rising. The development of better and more targeted diagnostic and therapeutic techniques may help to improve the management of kidney cancer. This study aimed to identify potential biomarkers that could assist with this goal. Of four potential biomarkers, only one was found to have a potential role in diagnosis and management of the most common form of kidney cancer, clear cell renal cell carcinoma.

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in diagnosis and management. Methods: A systematic review of immunohistochemical markers of RCC studies published between 1990 and 2019 was undertaken to select candidate biomarkers of RCC. Immunohistochemical staining of 73 clear cell RCC tumors and paired normal tissue was undertaken using selected markers. Semi-quantitative and quantitative analysis of staining intensity between paired samples was undertaken to evaluate utility as potential biomarkers, using Chi-square tests and paired t-tests for analysis. As an exploratory analysis, staining intensity was also compared on clinical/demographic variables using linear and logistic regression. Results: There were 123 candidate biomarkers identified in 91 studies. Four candidate markers were selected for further investigation: aminopeptidase A (APA)/cluster of differentiation (CD)249, aminopeptidase N (APN)/CD13, gamma-glutamyl transferase (GGT), and neuron-specific enolase (NSE). APA, GGT, and APN all demonstrated reduced staining intensity in the tumor compared with normal tissue (p < 0.001 for all). NSE demonstrated a statistically significant increase in expression in tumor compared with normal tissue (p < 0.001), and this was more pronounced in patients aged >60 years (p = 0.038). Conclusions: The utility of APA, APN, and GGT as diagnostic biomarkers in clear cell RCC is limited. NSE may have some role as a biomarker for clear cell RCC, particularly among older patients; however, further investigation is required.