Introduction

Tonsil cancer is the most common form of oropharyngeal malignancy, with it contributing to nearly a quarter of all malignancies within this anatomical area. Due to the growing number of malignancies caused by the human papillomavirus (HPV), its incidence is rapidly increasing. Up to 93% of new oropharyngeal cancers have shown HPV positivity in Western Europe, emphasising the importance of vaccination and early detection strategies. Patients may experience weight loss, a sensation of mass in the throat, dysphagia, hoarseness, or be entirely asymptomatic. HPV can induce genetic mutations in the host, which causes abnormal cell behaviour and potentially leads to cancer. This article will be exploring the genetic mutations linked to tonsil cancer, their implications, and current therapeutic strategies to mitigate them.¹

Understanding Tonsil Cancer

Tonsil cancer is a type of head and neck cancer, with the majority being squamous cell carcinomas, which develop from the squamous cells within the mucous layer of the tonsil. The most common location for tonsil cancer is the palatine tonsils, but it can also develop in the lingual tonsils or the pharyngeal tonsils. Since there is lymphatic tissue at the back of the throat, tonsillar lymphoma can also develop, although this is less common.¹

What are the risk factors for tonsil cancer?

• Smoking
• Alcohol use
• HPV infection through sex, oral sex, or open-mouthed kissing
• Poor nutrition
• Obesity
• Age¹

Genetic mutations associated with tonsil cancer

HPV invades squamous cells upon infection, which can occur through small cuts or tears in the skin, and over time, its DNA is incorporated into the host’s genome. This insertion is the key driver mutation. As a result, the oncogenes E6 and E7 are produced within the host and are able to promote HPV-associated malignancies.²

E6 associates with the host’s E6AP, which forms a complex to target p53 - the guardian of the genome. As a result, p53 is degraded in host cells, meaning its tumour suppressor function is effectively lost. This means that p53 cannot control the cell cycle, cell metabolism, or induce cell death. This allows the infected cell to proliferate rapidly so DNA synthesis goes unchecked, and can also depend on glycolysis for quickly generating energy and other cellular components to meet the proliferative demands of the cell. This, in combination, with the inhibition of apoptosis, allows HPV-infected cells to accumulate and drive further genetic mutations that provide them with advantages to survive.²

E7, on the other hand, associates with the tumour suppressor gene pRb, which in turn causes the release of E2F from it. E2F is a protein that is then able to increase the gene expression of genes that promote the infected cell’s cell cycle progression and self-renewal, which results in rapid tumour growth. If a cell unlocks self-renewal, it allows the tumour to thrive because these are effectively cancer stem cells, which can expand rapidly but also have resistance to chemotherapy.²

A study found that epidermal growth factor receptor (EGFR) signalling was involved in over half of tonsillar cancer cases, but was correlated with the absence of HPV. Its overexpression means that it is activated more frequently, so the cells it is expressed on undergo constitutive activation of signalling pathways that drive the infected cell to obtain a cancerous phenotype. While this can drive cancer development, EGFR mutations provide clinicians with an opportunity for targeted therapies which can reduce EGFR activity and consequently inhibit the further growth of cancer.³

Diagnosis and Genetic Testing

Patients with tonsil cancer have a varied clinical history. Some may be asymptomatic, while others may have a sore throat, weight loss, dysphagia or persistent hoarseness. This means the patient would require extensive examinations of their ears, nose, neck, and throat. The presence of HPV is usually confirmed by a polymerase chain reaction test, which can detect the DNA of HPV within a patient’s sample. For a more precise diagnosis, the following techniques could be used:⁴

Imaging

MRI scans provide the best quality of soft tissue to analyse the primary tumour and whether or not it has spread to local sites. CT scans, however, are the most common choice for staging head and neck cancers. The use of CT scans can also help decide whether a surgical removal of the tumour is appropriate.

Next Generation Sequencing

This is a powerful tool that can detect common mutations linked to tonsil cancer, such as those in the TP53 and EGFR genes. Typically conducted after imaging, this approach helps to create a personalized treatment plan tailored to the patient's specific genetic profile.

Tonsil cancer treatments

• Cetuximab → This is a monoclonal antibody that can target EGFR. As a result, the receptor is not activated and the cell it is expressed on cannot activate signalling pathways that enhance tumour growth⁵
• Pembrolizumab → This is an immune checkpoint inhibitor. It binds to a specific receptor on the cancer cell which means it can no longer evade the immune system, leading to an enhanced anti-tumour response⁶
• Surgical management → This is preferred for patients who have  lower tumour stage
• Radiotherapy → This is associated with good overall survival, and can be combined with chemotherapies.¹

The future of tonsil cancer research

With advancements in technology and a deeper understanding of the disease, the future of tonsil cancer research holds great promise for better outcomes and improved quality of life for patients. An example of this is a recent study that discovered 10% of tonsil cancer patients had spread to the other side of the neck without realising it. The study found that the larger the tumour, the more likely that this could happen. This is important for the future of tonsil cancer patients because it could lead to changes in the current diagnostic protocols, as well as more personalised treatment. This is because a larger tumour may require a more aggressive treatment strategy such as surgery, while smaller ones may have different approaches.⁷

A case study of a woman with head and neck cancer who participated in a phase II clinical trial experienced her tumours reduced by more than half after taking an immunotherapy drug. This has ignited hope that this drug could become a standard treatment for head and neck cancer in the future, since this patient did not experience any side effects too.⁸

Summary

HPV is responsible for the majority of tonsil cancers, so it is important that the public is aware of its mode of transmission, and the fact that a HPV vaccine is available. The insertion of HPV DNA into the host genome is a detrimental mutation that inactivates tumour suppressor proteins p53 and pRB. Their inactivity means that cell behaviour is no longer controlled, which can drive further mutations. EGFR mutations can occur independently of HPV infections, which enhance cell proliferation and survival, driving carcinogenesis. The symptoms of tonsil cancer include dysphagia, a sore throat, persistent hoarseness, and weight loss. A diagnosis is typically reached during a CT scan, but genetic analyses must also be performed to allow for a targeted therapy to be administered.

Tonsil cancer is the most common form of oropharyngeal malignancy, with it contributing to nearly a quarter of all malignancies within this anatomical area. Due to the growing number of malignancies caused by the human papillomavirus (HPV), its incidence is rapidly increasing. Up to 93% of new oropharyngeal cancers have shown HPV positivity in Western Europe, emphasising the importance of vaccination and early detection strategies. Patients may experience weight loss, a sensation of mass in the throat, dysphagia, hoarseness, or be entirely asymptomatic. HPV can induce genetic mutations in the host, which causes abnormal cell behaviour and potentially resulting in cancer. This article will be exploring the genetic mutations linked to tonsil cancer, their implications, and current therapeutic strategies to mitigate them.