What causes Human Papillomavirus (HPV) throat cancer to metastasize?

From the Guidelines

Human Papillomavirus (HPV) throat cancer metastasizes primarily through the lymphatic system when cancer cells break away from the primary tumor and enter nearby lymph nodes, with the most recent evidence suggesting that HPV status is a significant prognostic factor in head and neck cancers 1. The metastatic process begins when HPV, particularly high-risk types like HPV-16, causes genetic changes in infected cells by producing oncoproteins E6 and E7, which disrupt normal cell cycle regulation by inactivating tumor suppressor proteins p53 and retinoblastoma protein (pRb) 1. As the cancer progresses, these genetically altered cells develop the ability to invade surrounding tissues by producing enzymes that break down the extracellular matrix. They can then enter lymphatic vessels, with cervical lymph nodes being the most common site of metastasis. From there, cancer cells may spread to distant organs like the lungs, liver, or bones through the bloodstream. Risk factors that may accelerate metastasis include delayed diagnosis, advanced stage at detection, continued tobacco and alcohol use, and certain genetic factors. HPV-positive throat cancers generally have better prognosis than HPV-negative ones, even when metastasized, due to their better response to treatment, as shown in recent studies 1. Early detection through screening for persistent symptoms like sore throat, difficulty swallowing, or neck lumps is crucial for preventing metastasis. Some key points to consider in the management of HPV-related throat cancer include:

• The optimal treatment strategy must be discussed in a multidisciplinary team (MDT) including not only the treating physicians but all the supportive specialties 1.
• Patients should be treated at high-volume facilities 1.
• The treatment strategy for HPV-positive SCCHN should be the same as HPV-negative SCCHN 1.
• Pembrolizumab in combination with platinum/5-FU and pembrolizumab monotherapy are two approved regimens for patients with recurrent/metastatic SCCHN expressing PD-L1 (CPS 1) 1. It is essential to note that the current evidence does not support deintensification of treatment for HPV-positive oropharyngeal cancers, and more research is needed to determine the best approach for these patients 1.

From the Research

Causes of HPV Throat Cancer Metastasis

• The exact causes of Human Papillomavirus (HPV) throat cancer metastasis are not fully understood, but several studies have investigated the factors that contribute to the spread of this disease 2, 3, 4, 5, 6.
• HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) has been found to have a distinct pattern of metastasis, with a higher incidence of distant metastases, including bone metastases 4.
• The expression of p16 and HPV in the primary tumor and metastatic lesions has been found to be a reliable predictor of the site of the occult head and neck primary carcinoma 6.
• A mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV-related head and neck cancer has been developed, which may help to elucidate the mechanisms of metastasis in this disease 5.
• The use of cetuximab combined with radiotherapy instead of cisplatin combined with radiotherapy has been found to result in shorter overall survival and progression-free survival, and increased local regional failure rate and distant metastasis rate in patients with HPV-positive OPSCC 3.

Factors Contributing to Metastasis

• The presence of extracapsular spread (ECS) and positive surgical margins have been found to be high-risk features for postsurgical recurrence and metastasis in HPV-related head and neck cancer 5.
• The histologic identification of HPV-related squamous cell carcinoma in cervical lymph nodes has been found to be a reliable predictor of the site of an occult head and neck primary carcinoma 6.
• The nonkeratinizing basaloid morphology and strong reactivity to p16 immunostain have been found to be characteristic of HPV-related SCC, and may be useful in identifying the primary tumor site in cases of metastatic disease 6.

Future Directions

• Further studies are needed to fully understand the causes of HPV throat cancer metastasis and to develop effective treatments for this disease 2, 3, 4, 5, 6.
• The development of preclinical models, such as the mouse model described in 5, may help to elucidate the mechanisms of metastasis and to identify potential therapeutic targets.
• The use of biomarkers, such as p16 and HPV, may help to identify patients at high risk of metastasis and to develop personalized treatment plans 6.