HPV-Related Cervical and Oropharyngeal Cancers: Why They Differ –⁠ and What It Means for Clinical Practice

Same Virus, Different Diseases

HPV contributes to about 5% of all cancer cases worldwide. Among more than 200 HPV genotypes, only a few (especially HPV 16 and 18) are highly carcinogenic and sexually transmitted. HPV causes nearly all CSCC cases and about 70% of OPSCC cases. OPSCC is more common in men, particularly between ages 20 and 44.

Although HPV infection is assumed to act similarly in the oropharynx and cervix, this has not been fully confirmed by studies. The viral genome does not encode all proteins needed for DNA replication and therefore depends on the host cell machinery.

Researchers compared molecular mechanisms underlying both cancer types to understand why their radiosensitivity and treatment outcomes diverge.

Oncoproteins E6 and E7 in the Spotlight

HPV induces genetic, epigenetic, and metabolic alterations that reprogram cellular processes and dysregulate key signalling pathways. These changes allow infected cells to bypass checkpoints, avoid apoptosis, and evade immune surveillance.

The viral oncoproteins E6 and E7 are major drivers of carcinogenesis. They inactivate two crucial tumor-suppressor proteins: p53 and RB, leading to uncontrolled proliferation. While HPV infection is common, malignant transformation is rare and typically takes more than 10 years. Risk factors include immunosuppression, smoking, alcohol use, poor hygiene, and disruption of the local microbiome.

Integration of viral DNA into the host genome is a pivotal step transforming infection into malignancy in both CSCC and OPSCC.

Where Do the Divergences Arise?

It appears that HPV “speaks a different language” in each tissue. It exploits distinct mechanisms to drive tumorigenesis, influenced by multiple factors —⁠ hormones, growth factors, tissue-specific cytokines, immune-cell composition, viral variants, mutations within oncogene E6, and differences in infected target cells. In the cervix, these are reserve cells of the transformation zone; in the oropharynx, epithelial progenitor cells of tonsillar crypts.

The two cancers also differ in their mutational landscapes: some genes are commonly altered in both, others are distinct. Structural DNA alterations induced by HPV also vary between OPSCC and CSCC.

In addition, HPV-positive OPSCCs rely heavily on PD-L1/PD-L2 signalling to escape immune recognition. This creates a clear therapeutic opportunity for anti-PD-1/PD-L1 immunotherapy.

Clinical Implications and Challenges

Understanding the biological differences is essential for optimizing treatment and reducing toxicity. The 2024 ASTRO guidelines recommend lower radiation doses for HPV-positive OPSCC, which reduces treatment burden, lowers the risk of severe dysphagia, mucositis and xerostomia, and improves quality of life.

However, due to caution in translating biological insights into clinical practice, de-escalation is currently recommended only for carefully selected patient subgroups. Continued research is essential.

What else could improve outcomes in CSCC and HPV-positive OPSCC? Besides immunotherapy opportunities in OPSCC, researchers highlight the potential of tailoring treatment based on molecular markers of HPV integration, immune-response profiles, or amplifications of genes such as MYC and HMGA2. These directions may pave the way for next-generation combination therapies.

Editorial Team, Medscope.pro

Source:

Martinelli C., Ercoli A., Parisi S. et al. *Molecular mechanisms and clinical divergences in HPV-positive cervical vs. oropharyngeal cancers: a critical narrative review.* BMC Med 2025; 23 : 405. doi: 10.1186/s12916-025-04247-z.