For HPV-negative head and neck cancer of unknown primary after proper work up and biopsies, what mucosal surface(s) do you cover?

The treatment for CUP has evolved quite a bit, and frankly, I don't think there is a true standard. Even in our group, we often don't have consensus with regards to whether to even treat mucosa and if treating, which sites.

Very weak data suggests that whether you just treat the involved neck or chase elective mucosal sites and the contralateral neck the survival outcomes are similar. Thus, over the years, with improvements in my ability to find the primary, and therefore, believing the old 30% emergence rate from papers in the 1980s is likely at best 15-20%, I have leaned more towards not treating large volumes, and considering a more disease focused approach (i.e., treat the neck only).

Assuming viral negative, the location, extent of disea...

Assuming the patient is a heavy smoker, EBV- and Caucasian, I would cover the nasopharynx bilaterally (EBV- NPC in an Asian patient is less likely), ipsilateral oropharynx, whole supraglottic larynx, and ipsilateral hypopharynx. While the oral tongue and buccal mucosa are theoretically at risk, I would avoid them unless level Ib is involved. Being usually well-differentiated, a very small oral Sq. c. ca that is not detected clinically has a low risk of LN mets compared to the poorly diff cancers in the other sites. Taking into account the morbidity of oral cavity irradiation, it has a low therapeutic ratio in this patient.

In cases of unknown primary HPV+, I would irradiate the ipsilateral oropharynx and include the nasopharynx (HPV+ NPC ha...

Oropharynx and nasopharynx