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Review
. 2025 Jun;47(6):1779-1787.
doi: 10.1002/hed.28138. Epub 2025 Mar 21.

Emerging Proximal Liquid Biopsy Approaches for Detecting Residual Disease and Predicting Recurrence in Head and Neck Cancer: A Review and Proposal of Novel Liquid Staging

Vanessa Helou  1 , Joshua D Smith  1 , Micah Harris  1 , Noah Earland  2   3 , Kevin J Contrera  1   4 , Aadel A Chaudhuri  5   6 , Jose P Zevallos  1   4
Affiliations
Review

Emerging Proximal Liquid Biopsy Approaches for Detecting Residual Disease and Predicting Recurrence in Head and Neck Cancer: A Review and Proposal of Novel Liquid Staging

Vanessa Helou et al. Head Neck. 2025 Jun.

Abstract

Background: Head and neck squamous cell carcinoma remains challenging due to high recurrence rates and poor survival outcomes. Developing precise technologies for disease burden assessment, treatment response, and minimal residual disease (MRD) surveillance is crucial for improving prognosis.

Methods: This review explores the potential of liquid biopsy for MRD and recurrence detection. A novel liquid TNM (LiTNM) staging system is introduced, integrating biomarkers from saliva, surgical drain lymphatic fluid (SLF), and peripheral blood.

Results: Proximal liquid biopsies, particularly saliva and SLF, offer advantages due to their proximity to the tumor microenvironment. Saliva demonstrates high sensitivity in HPV-associated oropharyngeal cancers, while SLF holds potential in identifying early postoperative recurrence. Despite these advancements, standardization and validation remain challenges.

Conclusions: Liquid biopsy approaches show promise for postoperative disease monitoring, yet their clinical implementation remains in the early stages. The proposed LiTNM staging system could complement TNM staging by providing a molecular framework for risk stratification. However, rigorous prospective studies are necessary to validate its clinical utility and facilitate adoption.

Keywords: head and neck squamous cell carcinoma; liquid biopsy; minimal residual disease; saliva liquid biopsy; surgical drain fluid liquid biopsy.

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Conflict of interest statement

Jose P. Zevallos is a founder and equity shareholder in Droplet Biosciences. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
A novel liquid TNM (LiTNM) staging system for HNSCC integrating biomarker analysis from saliva, surgical drain fluid, and peripheral blood for detecting minimal residual disease, predicting recurrence, and guiding postoperative treatment. CtDNA, circulating tumor DNA; ctHPV DNA, circulating tumor human papillomavirus DNA; LiTNM, Liquid tumor (T), node (N), and distant metastasis (M) staging. [Color figure can be viewed at wileyonlinelibrary.com]
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