Management of unknown primary head and neck cancer with radiation therapy in the era of human papillomavirus (HPV): No longer cutting down the tree to get an apple

Purpose: Given the central role that radiation has in the management of head and neck squamous cell carcinoma of unknown primary origin, it is imperative to review how treatment paradigms have been refined and continue to evolve in the modern era. Methods and Materials: This study was designed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. A literature search of peer-reviewed publications was undertaken to identify works pertaining to the use of radiation for squamous cell carcinoma of unknown primary origin presenting as cervical lymph node metastases. Articles published from January 2002 to January 2023 with full text available on PubMed and restricted to the English language and human subjects were included. The full bibliographies of identified articles were reviewed and irrelevant studies were removed. Results: While such breakthroughs as intensity-modulated radiotherapy, positron emission tomography, biomarker testing with immune-histochemistry, and minimally invasive surgical techniques such as transoral robotic surgery have fundamentally changed the approach to this disease in recent decades, controversies still exist with respect to the manner in which radiation is delivered. Although the incidence of head and neck unknown primary cancer is relatively low, questions regarding the necessity of comprehensive radiation using the age-old standard method of targeting the bilateral necks and entire pharyngeal axis to encompass all putative sites of mucosal disease persist. Conclusions: Prospective evidence is lacking, and the available studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in work-up, treatment, inclusion criteria, and followup. Regardless, advances in science and technology have ushered in more precise approaches with a high degree of customization, particularly given the increased proportion of patients presenting with human papillomavirusrelated disease.