Liquid/Fluid Biopsy and Its Role in Lymphomas

Circulating tumor DNA (ctDNA) has emerged as a powerful biomarker for the detection, monitoring, and genotyping of hematopoietic malignancies, particularly lymphoid cancers. This chapter explores the characterization of ctDNA in lymphoid malignancies, highlighting its applications in diagnosis, treatment response assessment, and minimal residual disease (MRD) detection. Early studies focused on immunoglobulin heavy chain (IgH) rearrangements, while advancements in next-generation sequencing (NGS) techniques, such as Immunoglobulin High-Throughput Sequencing (IgHTS) and Cancer Personalized Profiling by Deep Sequencing (CAPP-seq), have significantly improved sensitivity and accuracy. We discuss large-scale studies that validate the clinical utility of ctDNA, including comparisons with traditional imaging methods like PET-CT. While extensive research has been conducted on B-cell lymphomas, there remains a gap in T-cell lymphoma ctDNA profiling, necessitating further investigations. Additionally, we examine the role of ctDNA genotyping in detecting single-nucleotide variations (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and fusion events, with an emphasis on its integration into clinical decision-making. Emerging evidence underscores the significance of DNA methylation analysis as a biomarker for tumor suppressor gene silencing in lymphomas. Furthermore, ctDNA quantification has been linked to risk stratification, with studies demonstrating its predictive value in treatment outcomes. However, challenges persist, including the lower sensitivity of plasma ctDNA detection in central nervous system (CNS) lymphomas and the potential for false positives due to clonal hematopoiesis. Finally, the chapter explores the role of liquid biopsies in MRD detection, emphasizing their advantages over invasive tissue biopsies. Despite the absence of standardized protocols, liquid biopsies show promise in guiding therapeutic decisions, reducing reliance on invasive procedures, and improving patient outcomes. Future advancements in ultra-deep sequencing, tumor-informed approaches, and optimized sample processing will be critical in refining ctDNA-based diagnostics for lymphoid malignancies.