Aqueous Humor Markers in Retinoblastoma, a Review

PURPOSE: Retinoblastoma (Rb) is the most common primary intraocular cancer in children. Unlike with most solid tumors, direct biopsy is contraindicated due to risk of tumor dissemination. However, recent therapeutic techniques have allowed for the safe extraction of aqueous humor (AH) from eyes undergoing therapy, providing the unique opportunity to use AH as a liquid biopsy for Rb. Although the extraction of AH in Rb eyes undergoing therapy is new, the consideration of whether there are tumor biomarkers in the AH is not. The current manuscript is a systematic review of all studies that have examined biomarkers in the AH of Rb eyes. The authors hypothesized that AH sampling and analysis of tumor biomarkers may have new clinical relevance for the diagnosis, prognosis, and/or management of Rb. METHODS: A comprehensive database search (PubMed, Web of Science, Embase, and Cochrane Databases) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to identify articles on AH markers in Rb eyes. Inclusion criteria included English language articles with original reports on AH markers in the eyes of patients with confirmed Rb. Data on marker type, number of eyes, marker means and ranges, and when available, control values and clinicopathological correlations were collected. Articles were stratified based on marker type, and assessed quantitatively and qualitatively. RESULTS: An initial database search produced 325 articles, and an additional 11 articles were identified through searching citations. After removing duplicates and applying the eligibility criteria, we selected 27 articles to be included in the current review. A total of 463 eyes with histologically confirmed Rb were included in this review. The various markers and their values, with comparison to controls and clinicopathological correlations, are discussed. CONCLUSIONS: AH sampling and tumor biomarker analysis in eyes without undergoing enucleation have the potential to revolutionize the management of Rb. TRANSLATIONAL RELEVANCE: Although previous studies evaluated markers in the AH only after enucleation and not at diagnosis or during therapy, the clinical relevance of these markers was limited. However, recent changes in the management of Rb have allowed for safe sampling of the aqueous during therapy and, thus, correlation of tumor biomarkers with disease course. Thus, the authors felt it important to revisit previous research to evaluate whether these markers may now be applicable for the diagnosis, prognosis, or management of Rb