Head and Neck Cancers and Their Relationship with HPV

Human papillomavirus (HPV) causes excessive proliferation by suppressing factors that prevent uncontrolled cell division. Among the virus’s 179 known subtypes, strains 16, 18, 31 and 33 carry high cancer risk in humans. Different subtypes can produce different clinical effects, from warts to cancer. HPV is associated with genital warts and head and neck, vaginal-vulvar, penile, anal, cervical and rectal cancers.

- Related Topic: What is HPV – human papillomavirus, and how does it cause cancer?

The proportion of HPV-related head and neck cancers is increasing. Previously, smoking and alcohol consumption caused most head and neck cancers (as remains the case in our country). Today, however, more than half of head and neck cancers in Western populations are HPV-positive. Recent studies have shown that 25% of head and neck cancers and 60% of oropharyngeal (oral cavity and pharynx) cancers are caused by HPV.

The oral cavity, tonsils, nasopharynx (upper throat behind the nose), pharynx (throat) and larynx (voice box) are the sites where head and neck cancers develop.

Squamous (flat) cell cancer is the most common cancer type in the head and neck region and is also the world’s 6th most common cancer. Although alcohol and tobacco use are the greatest risk factors for squamous cell head and neck cancer, the link between HPV and cervical cancer was demonstrated by Dr. Harald zur Hausen , who won the Nobel Prize for this discovery in 1970. Subsequent studies in 1983 identified the relationship between HPV and oropharyngeal cancer, a type of head and neck cancer.

Among people with HPV-related squamous cell head and neck cancer (SCHNC), 80% had HPV subtype 16. A study examining 515 SCHNC cases found HPV positivity in 14%; of these, 84% were HPV16, 16% HPV12, and the remainder other subtypes.

A study of oropharyngeal cancer examined 529 cases, finding 61% associated with HPV16 and 11% with other subtypes.

In HPV-related tumors, 3 proteins (E5, E6 and E7) are responsible for uncontrolled cell proliferation. E6 and E7 act by suppressing p53 and retinoblastoma (Rb) genes, which enable controlled death of damaged cells.

What is the disease course of HPV-related head and neck cancers?

HPV-related and non-HPV-related head and neck cancers show different clinical features.

HPV-related cancers occur at younger ages and are less associated with heavy alcohol and tobacco use. Tumors are smaller, have fewer cellular changes and more frequently show lymph node metastases .

A retrospective study covering 1973-2003 found that smoking-related head and neck cancer decreased by 1,85% compared with previous years, while HPV-related head and neck cancer increased by 0.8%. Among HPV-related cancers, oropharyngeal cancer particularly increased, while smoking-related cancers showed increases in oral, laryngeal and hypopharyngeal (lower pharynx) cancers.

Although HPV-related tumors have a faster clinical course, their lymph node metastases are controlled and regress more quickly with treatment. In oropharyngeal cancer, HPV-related tumors have 58% greater survival than others; HPV-related patients who do not smoke also have higher survival than smokers.

Comparing HPV-related and non-HPV-related oropharyngeal cancer, distant organ metastasis rates are the same. However, despite more rapid development and a worse clinical presentation, HPV-related cancers show a better response to treatment .

What molecular changes occur in HPV-related head and neck cancers?

In HPV-related and non-HPV-related head and neck cancers, p53 and Rb genes are affected through different mechanisms. In the HPV-related group, these tumor-suppressing genes, by the viral E6 and E7 proteins, are suppressed. In the non-HPV-related group, genetic susceptibility or other carcinogenic factors (particularly smoking and alcohol) cause mutations in these genes, affecting their function. Both groups show activation of TP63, SOX2 and PIK3CA oncogenes (genes causing excessive cell proliferation). Other genes are affected differently in the two types. For example, the HPV-related group shows TRAF3 suppression, PIK3CA activation and increased CASP8 activation; the non-HPV-related group shows CASP8 and HRAS mutations and increased activity on chromosome 1’s q arm.

Micro-RNA as a biological marker in HPV-related cancers

MicroRNAs (miRNA) affect gene function, influencing activation of both cancer-causing genes (oncogenes) and tumor suppressor genes. Studies suggest measured miRNA levels may be associated with prognosis (disease outlook), life expectancy and distant organ spread in head and neck cancers. They may also be used to observe treatment response. Although miRNA measurements are not routinely used in current practice, studies are ongoing to bring them into routine use.

- What is RNA and what does it do? Its use in cancer diagnosis and treatment

Treatment approach in HPV-related head and neck cancers

Because clinical features differ between HPV-related and non-HPV-related groups, HPV status is a decisive prognostic factor (affecting disease course) in these diseases.

The HPV-related group is more sensitive to radiotherapy and has a distinctive treatment approach. Here, radiation reduces E6-mediated suppression of p53, increasing apoptosis (programmed cell death), meaning cancer cell death. The non-HPV-related group is also more hypoxic (has less tissue oxygen) and therefore responds less to radiotherapy.

Smoking is an important risk factor, particularly in the non-HPV-related group, and heavy smoking is associated with poor prognosis. It is also an important risk factor in the HPV-related group. A study of stage 3 and stage 4 squamous cell head and neck cancer in 96 patients found that HPV-negative individuals with 20 pack-years of smoking had 5-year survival of 63%. In HPV-positive individuals with more than 20 pack-years, 5-year survival was 80%, whereas those with less than 20 pack-years had 5-year survival of 95%.

HPV-positive head and neck cancers have also been found to stimulate the immune system more and respond better to immunotherapies . In HPV-positive cases, E7 protein-mediated increases in T-cell levels occur. This increase is also considered a potential biomarker .

An aggressive treatment approach is used to achieve cure (complete recovery) in head and neck cancers. Surgery, radiotherapy and chemotherapy may cause mucositis (mouth sores), pain, nausea, changes in blood parameters, edema, painful swallowing and dry eyes as treatment side effects . Identifying risk and prognostic factors is therefore important. The aim is to determine the best treatment regimen and minimize treatment side effects.

As noted, HPV 16 is the most common subtype in the HPV-related group. Clinical course and treatment response also differ between subtypes. Interestingly, HPV16-positive head and neck cancers occur at younger ages than others (median age at diagnosis 56-57). One study found that in HPV16-related oropharyngeal cancer, 5-year survival was 65%, compared with 46% in other high-risk HPV-related cancers and 28% in non-HPV-related cancers. Thus, HPV association and subtype are important in determining treatment, and treatment approach and intensity may vary according to these relationships.

In conclusion, The relationship between HPV and head and neck cancer continues to be clarified. Studies have identified differences between HPV-related and non-HPV-related groups in disease mechanisms, treatment response and survival rates, aiming for maximum effectiveness with minimum side effects through the most appropriate treatment at the optimal dose. Let us also remember that HPV-related cancers can be prevented with the HPV vaccine .

*

The following infographic poster provides comprehensive information about head and neck cancers at a glance.