HPV-associated oropharyngeal cancer — discussion points

In their recent Review (Lechner, M. et al. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat. Rev. Clin. Oncol., https://doi.org/10.1038/s41571-022-00603-7; 2022)¹, Lechner et al. provide a useful addition to the medical literature. Nonetheless, we would like to raise a few important discussion points. Several reviews (including that of Lechner et al.¹) have now mentioned that HPV⁺ oropharyngeal cancers do not have a neoplastic–dysplastic phase, and that hence it follows that screening for premalignant lesions and prevention of invasion is not possible^2,3.

For example, in the legend of figure 2 of their Review, the authors mention “ … the development of neoplasia (in the cervix this is evident as lesions detectable by screening but no such lesions have been identified in the oropharynx)”. This is incorrect. L. Masterson himself (as first author, with M. Lechner and ourselves among the coauthors) demonstrated in 2015 (ref.⁴), using laser capture and microdissection, that it is possible to find, isolate and detect cells of a premalignant dysplastic, or carcinoma in situ, phenotype adjacent to many HPV⁺ oropharyngeal cancers and then perform transcriptomic studies using the mRNA isolated from them. This study⁴ showed that a novel biomarker, SYCP2, had consistently increased levels of expression, in addition to SFRP1, CRCT1, DLG2 and CRNN, which also had altered levels of expression compared to the nonmalignant epithelium. This study was the first, to our knowledge, to demonstrate that: (1) population or targeted screening for HPV⁺ oropharyngeal cancer is possible, analogous to the cervical screening model; (2) that novel biomarkers such as those described above could potentially be used for molecular screening; and (3) that the pathogenesis and oncogene addiction profile of HPV-associated oropharyngeal cancer is highly likely to be similar to that of both cervical cancer and HPV⁺ anogenital cancers.

Furthermore, sequencing studies involving samples from patients with head and neck cancers have revealed interesting subgroups, such as patients with HPV⁺ head and neck squamous cell carcinoma (HNSCC), who also have a history of heavy smoking (>10 pack years), and/or betel quid (comprising betel leaf, areca nut, slaked lime and/or tobacco) consumption. A subgroup of these patients have tumours of a mixed pathogenesis, driven by a combination of oncogenic driver alterations and exposure to carcinogens. A whole-exome sequencing analysis from India demonstrates that the mutational burden of HPV⁺ HNSCC (mostly oral squamous cell carcinomas, although the same principle applies to all subgroups) is not significantly different compared to the larger group of patients with HPV^– HNSCC; the majority in both groups have exposure to the carcinogens present in betel quid, thus demonstrating the effects of these additional oncogenic drivers⁵. Discussions of some of these newer HPV⁺ HNSCC subgroups, and the relative importance of some of the known risk factors and carcinogen exposures (such as tobacco smoking)⁶, within the group of HPV⁺ oropharyngeal cancers would have been a useful addition to Lechner et al.’ s Review¹.

In conclusion, we reiterate that Lechner et al.¹ have written an excellent review, apart from the omission of a couple of interesting and important discussion points. No doubt these will be covered in detail in the future. We hope that this Correspondence will help to stimulate debate, discussion and further research for the benefit of all patients with head and neck cancer, both currently and in the future.

There is a reply to this letter by Lechner, M., Liu, J., Masterson L. & Fenton, T. R. Nat. Rev. Clin. Oncol., https://doi.org/10.1038/s41571-022-00627-z (2022).