Liquid Biopsy Biomarkers in Thyroid Cancer: Current Evidence and Future Directions

Abstract

Background: Thyroid cancer (TC) incidence has risen globally, yet the diagnostic and management paradigms remain heavily reliant on invasive tissue biopsies and ultrasonography, plagued by high rates of indeterminate cytology and overtreatment. Liquid biopsy, the analysis of tumor-derived material from bodily fluids, has emerged as a transformative tool in oncology, offering a minimally invasive window into tumor biology. This systematic review synthesizes the evidence from 2020 to 2026 on liquid biopsy biomarkers in TC, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), and extracellular vesicles (EVs).

Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted for articles published between January 1, 2020, and January 1, 2026, using PRISMA guidelines. Studies investigating the diagnostic, prognostic, or predictive utility of blood-based liquid biopsy biomarkers in differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC) were included. A total of 50 studies were selected for final synthesis after critical appraisal.

Results: The evidence demonstrates a paradigm shift from single-analyte assays to multi-analyte and multi-omics platforms. ctDNA analysis, particularly for BRAF V600E and TERT promoter mutations, shows high specificity but variable sensitivity for DTC, proving most valuable in advanced and metastatic settings. For MTC, ctDNA-based RET mutational profiling and minimal residual disease (MRD) monitoring have become clinically actionable. The landscape for miRNAs and EVs has matured, with panels like miR-221, miR-222, and miR-146b showing robust diagnostic performance in discriminating benign from malignant indeterminate thyroid nodules, with some achieving validation in large, prospective multi-center cohorts. Strikingly, the integration of long-read sequencing and methylation-based cfDNA fragmentomics has opened new frontiers for early-stage detection.

Conclusion: Liquid biopsy is poised to transition from a research tool to an integral component of precision thyroid cancer care. The most impactful advances between 2020 and 2026 are in three areas: (1) the clinical validation of miRNA panels for indeterminate nodule triage, (2) the establishment of ctDNA for real-time therapeutic monitoring and resistance detection in advanced TC, and (3) the emergence of fragmentomics and AI-driven multi-analyte signatures. While challenges in standardization and early-stage sensitivity persist, the trajectory points toward integrating liquid biopsy into diagnostic algorithms, active surveillance protocols, and dynamic therapeutic strategies.

Keywords:

hyroid Cancer, Liquid Biopsy, Circulating Tumor DNA (ctDNA), MicroRNAs, Extracellular Vesicles, Molecular Biomarkers, Precision Oncology, Fragmentomics

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