HPV-related oropharynx cancer: The new staging system

Patients with HPV-positive oropharyngeal cancer now have a better prognosis and may not need as aggressive therapy as patients with HPV-negative head and neck cancers. In this blog, Dr Shrujal Baxi discusses a staging system for oropharyngeal cancers that are HPV-related and those that are not which reflects this improved prognosis.

In the American Joint Committee on Cancer  (AJCC) 8th edition, human papillomavirus (HPV)-related oropharyngeal tumors will be staged using a unique staging system to reflect the better  prognosis associated in this subset of oropharyngeal tumors.

The AJCC uses the Tumor-Node-Metastases (TNM) system to describe the anatomical extent of disease and include additional prognostic factors. The AJCC staging system is used to categorize patients into groups that share a similar risk of survival.  In general, the stages range from 0-IV.  As a general principal, carcinoma in situ is categorized as stage 0; most often tumors localized to the organ of origin (without nodal involvement) are staged as I or II, depending on the size or extent of disease. Tumors with local spread to the regional lymph nodes are staged as III, and those with distant metastasis are staged as stage IV.

However, in some tumors, such as head and neck squamous cell carcinoma, the staging is slightly different. In head and neck cancer, stage IV is divided into three stages IVA, IVB and IVC. Stage IVA includes larger primary tumors and those with more than 1 lymph node (<6cm in size) involved. Stage IVB are tumors that are large and unresectable or have lymph nodes that are >6cm in size. Stage IVC is distant metastatic disease, which in most other cancers is simply stated as Stage IV.

Recent analysis of large databases and retrospective experiences found that while the old AJCC staging system worked well at prognosticating for head and neck squamous cell carcinoma not related to HPV,  it  did not work for patients with HPV-related oropharyngeal cancers. In response to these observations, the 8th version of the AJCC staging system has been modified to account for the difference between HPV-related oropharyngeal tumors and other head and neck squamous cell carcinoma. The new system has only three stages for non-metastatic HPV-related oropharyngeal cancer as demonstrated in the table below.

AJCC Comprehensive Stage

T and N staging

HPV-related ( p16+) Non HPV-related
Stage I T0-T2N0-N1 T1N0
Stage II T0-T2N2 or T3N0-N2 T2N0
Stage III T4 or N3 T1-3N1 or T3N0
Stage IVA M1 T1-T3N2a-N2b or T4aN0-N2b
Stage IVB NA Either T4b or N2c
Stage IVC NA M1

Additionally, cancers that present as squamous cell carcinoma in the lymph nodes in the neck but whose primary tumors cannot be identified within the mouth or throat (also called unknown primary cancer) that are HPV+, may now be regarded as oropharyngeal cancers.

Cure is paramount. The take home message is that patients with HPV-positive disease have a better prognosis and may not need as aggressive therapy as patients with HPV-negative head and neck cancers. Proper staging allows us to identify the appropriate intensity of treatment. More intense treatment will come with more significant acute and long-term toxicities. The goal of staging is to allow us to prognosticate more accurately and select the appropriate intensity of treatment to achieve cure but minimize toxicity, if possible.

This new staging system for HPV-related oropharyngeal cancers can hopefully provide the guidance needed. The next challenge will be interpreting the published data in light of the new staging system. This change in the staging system will impact clinical practice, clinical trials and subsequent research on the outcomes in patients with HPV-related oropharyngeal cancer.

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