Circulating tumor DNA in appendiceal malignancies: a comprehensive review of clinical applications and limitations.

Appendiceal cancer is a rare and biologically distinct gastrointestinal malignancy characterized by marked molecular heterogeneity and a strong propensity for peritoneal dissemination. Traditional surveillance modalities, including cross-sectional imaging and serum tumor markers, often demonstrate limited sensitivity for detecting residual or recurrent peritoneal disease, creating a need for more effective biomarkers. Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive tool for genomic profiling, prognostication, and disease monitoring across gastrointestinal (GI) cancers. In this review, we synthesize current evidence regarding the application of ctDNA in appendiceal malignancies. Available studies demonstrate high concordance between plasma ctDNA and tissue-based genomic profiling, while longitudinal ctDNA monitoring shows its potential for risk stratification, recurrence detection, and postoperative surveillance, with some studies suggesting improved performance compared with conventional biomarkers. However, the clinical utility of plasma ctDNA is limited by the unique biology of appendiceal cancer, particularly its tendency toward isolated peritoneal spread and pseudomyxoma peritonei (PMP), both of which are associated with reduced systemic tumor DNA shedding and frequent false negative results. We discuss the biological mechanisms underlying these limitations and highlight peritoneal tumor DNA (ptDNA) as a promising complementary biomarker capable of overcoming the peritoneal-vascular barrier through direct sampling of the local tumor microenvironment. Emerging evidence suggests that ptDNA may improve detection of occult peritoneal disease, enhance molecular characterization, and provide prognostic information beyond that obtainable from plasma-based assays alone. While liquid biopsy technologies hold substantial promise for advancing personalized management of appendiceal cancer, prospective validation studies and standardized assay approaches are needed before widespread clinical implementation.