Atypical metastases highlight the true potential of ctDNA liquid biopsies for cancer monitoring

•Human papillomavirus associated oropharyngeal cancer (HPV + OPSCC) has a more atypical pattern of metastasis and longer average time to metastasis development, presenting a challenge to current monitoring strategies.•This case highlights the potential of circulating tumor HPV DNA (ctHPVDNA) in HPV + OPSCC disease monitoring and raises important questions within the field of liquid biopsy.•We discuss a changing understanding of persistent vs recurrent disease in the context of blood-based molecular monitoring and the implications of ctHPVDNA-based strategies for surveillance and treatment paradigms.