Postoperative Lymph ctDNA Outperforms Plasma in Predicting Early Recurrence of HPV-Independent Head and Neck Cancer

Introduction: The Challenge of HPV-Independent HNSCC

Human papillomavirus (HPV)-independent head and neck squamous cell carcinoma (HNSCC) remains one of the most challenging malignancies in oncology. Unlike its HPV-associated counterparts, which often respond well to treatment, HPV-independent HNSCC is characterized by genomic instability, a higher propensity for recurrence, and a generally poorer prognosis. Currently, the decision to administer adjuvant therapy—such as radiotherapy or chemoradiotherapy—relies on clinicopathologic criteria that have remained largely unchanged for decades. These include surgical margin status, extracapsular nodal extension (ENE), and the number of involved lymph nodes.

However, these traditional markers are often imprecise. Many patients classified as “intermediate-risk” undergo intensive adjuvant treatments that carry significant morbidity, yet still experience relapse. Conversely, some patients deemed low-risk suffer early recurrences. There is a desperate clinical need for a more precise, molecular-based method to identify molecular residual disease (MRD) immediately following surgery to better stratify patients and personalize postoperative care.