Key differences between HPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC)

Head and neck squamous cell carcinomas (HNSCC) develop from the mucosal epithelium in the oral cavity, pharynx, and larynx and are the most common malignancies that arise in the head and neck.1 Increasingly, tumors in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus (HPV), primarily HPV-16 and, to a lesser extent HPV-18 and others.2,3 HNSCCs of the oral cavity and larynx are primarily associated with tobacco-derived carcinogens, excessive alcohol consumption, or both, and are collectively referred to as HPV-negative HNSCC.4 The median age of diagnosis for non-virally associated HNSCC is 66 years, whereas the median age of diagnosis for HPV-associated oropharyngeal cancer is about 53 years.5

HPV-positive and HPV-negative HNSCC are two distinct diseases with different sites of origin, etiological agents, risk factors, and contributions to the development of oropharyngeal squamous cell carcinoma (OPSCC). The demographics, cause, and prevalence of HPV-positive and NPV-negative cancers are summarized in Table 1.

Table 1: Demographics, Cause, and Prevalence of HNSCC.

Whereas the incidence of smoking-related HNSCC continues to decline worldwide, that of HPV-positive HNSCC is on the rise.6 During 2007-2016, HPV-associated cancers increased by 2.1% per year on average, whereas cancers not associated with HPV decreased by 0.4% per year on average.6

HPV-positive and HPV-negative HNSCCs present with different molecular characteristics, immune landscapes, and clinical prognosis (Table 2) and lead to two fundamentally different diseases with distinct pathogenesis in terms of gene expression, tumor microenvironment (TME), and mutational burden.

Table 2. Pathology and Disease Signature in HNSCC.

Genomic and epigenetic analyses reveal extremely high heterogeneity in HNSCC in terms of characteristic mutations, molecular signature, cellular phenotype, composition of TME, and immune landscape (Table 3).

Table 3. Characteristic mutations in HPV-positive and HPV-negative HNSCC.

Various promising vaccine targets have been identified and treatment options employed for the treatment of HPV-positive and HPV-negative cancers with varying degrees of success (Table 4).

Table 4. Treatment options and targets.
Treatment personalization and de-escalation

According to Dr. Nishant Agrawal, Chief of Otolaryngology-Head & Neck Surgery UChicago Medicine, “We have seen a significant increase in the incidence of HPV-associated oropharyngeal cancer in relatively younger patients, with the median age of diagnosis in the 50s, even patients in their 30s.”32 He added that “Even at 2 years after radiation therapy, 15% of patients had grade 2 swallowing dysfunction and 8% had progressive dysphagia, so their swallowing is going to continue to get worse. Patients may also have chronic xerostomia. The dry mouth improves but it never gets back to 100%.”33 In contrast to patients with HPV-negative HNSCC, who have a five-year survival rate of about 25%-40%, patients with HPV-positive HNSCC fare much better with a disease-free survival rate of 85%-90% over five years. According to Dr. Agrawal, the better prognosis for HPV-positive patients suggests a need to de-escalate treatment while preserving survival.


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  33. https:\\\\issues\\april-25-2017\\deintensifiying-treatment-of-hpv-positive-oropharyngeal-cancer-could-reduce-toxicity-while-maintaining-function-and-survival

New ASCO 2021 poster highlights HPV-SEQ test’s ultra-sensitive detection of HPV 16/18 in plasma

Download our new poster, presented at the recent ASCO 2021 Annual Meeting: “Ultra-sensitive detection and quantification of human papillomavirus (HPV) DNA in the plasma of patients with oropharyngeal squamous cell carcinoma (OPSCC) enrolled in the OPTIMA 2 treatment de-escalation trial”.


As patients with HPV-driven tumors often have a good prognosis, clinical investigators have recently explored new strategies for treatment de-escalation to avoid unnecessary side-effects caused by overtreatment.  Important clinical data for HPV-SEQ was generated while investigating induction chemoimmunotherapy followed by risk/response stratified de-escalated locoregional therapy for patients with HPV+ OPSCC. During the trial, HPV-SEQ was employed to evaluate levels of cfHPV-DNA alongside patients’ radiographic response to therapy to assess the future utility in guiding treatment de-escalation strategies. HPV-SEQ showed robust quantitative detection of HPV 16/18 across a broad dynamic range over five orders of magnitude with low quantitative variability. Importantly, a high correlation was observed between dynamic changes in patients’ cfHPV DNA levels and radiographic responses following induction therapy.