Liquid Biopsy and Molecular Biomarkers in Mucinous Appendiceal and Colorectal Tumors: Current Evidence and Unmet Challenges in Precision Oncology

Mucinous appendiceal and colorectal tumors represent a biologically and clinically distinct subset of gastrointestinal malignancies, defined by abundant extracellular mucin, characteristic molecular alterations, and a strong predilection for peritoneal dissemination. Despite these distinctive features, they remain relatively underrepresented in biomarker-driven clinical frameworks, and evidence specific to liquid biopsy performance in this subgroup is fragmented. These features complicate clinical assessment and limit the applicability of tissue-based and circulating biomarkers that perform well in non-mucinous colorectal cancer. Although liquid biopsy is now integral to precision oncology across multiple solid tumors, its role in mucinous disease remains incompletely defined. This review synthesizes evidence on liquid biopsy and molecular biomarkers in mucinous appendiceal and colorectal tumors, with emphasis on circulating tumor DNA (ctDNA) and emerging multi-analyte approaches. Rather than extrapolating from non-mucinous colorectal cancer paradigms, we examine liquid biopsy performance through the lens of mucinous tumor biology and peritoneal compartmentalization. We summarize how peritoneal-dominant spread, limited vascular access, low tumor cellularity, and sequestration of malignant cells within mucin pools constrain biomarker shedding into peripheral blood and contribute to low ctDNA detectability. We discuss the clinical implications for postoperative surveillance after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, molecular profiling when tissue is limited, and longitudinal monitoring in selected patient subsets. A central focus is the context-dependent interpretation of positive versus negative plasma findings, particularly in low-shedding disease, where false reassurance may occur. We also review strategies beyond plasma ctDNA, including compartment-specific sampling and non-mutational platforms that may improve sensitivity in low-shedding settings. By integrating biological rationale with comparative findings across studies, we identify key evidence gaps and priorities for prospective, biologically stratified validation. We further outline practical considerations for integrating liquid biopsy results into multidisciplinary decision-making in mucinous malignancies. Aligning biomarker class and sampling compartment with mucinous tumor biology may improve interpretability and support more precise clinical management.