What are the stages of Human Papillomavirus (HPV) related oropharyngeal cancer?

Stages of HPV-Related Oropharyngeal Cancer

HPV-related oropharyngeal cancer is staged according to the UICC/AJCC TNM 8th edition staging system, which specifically separates HPV-positive from HPV-negative oropharyngeal cancers due to their distinct biological behavior and improved prognosis. 1

The Four Stages of HPV-Related Oropharyngeal Cancer

Stage I

• T1-T2, N0-N1, M0
• Primary tumor size ≤4 cm (T1-T2)
• No lymph node involvement (N0) or single ipsilateral node ≤6 cm (N1)
• No distant metastasis (M0)
• Treatment typically involves single-modality approach: either radiotherapy or transoral surgery 1

Stage II

• T1-T2, N2, M0 or T3, N0-N2, M0
• Primary tumor ≤4 cm (T1-T2) with multiple or bilateral nodes ≤6 cm (N2), OR
• Primary tumor >4 cm or extension to lingual surface of epiglottis (T3) with nodes ≤6 cm (N0-N2)
• No distant metastasis (M0)
• Treatment typically involves concomitant chemoradiotherapy 1

Stage III

• T4 or N3, M0
• Tumor invades adjacent structures (T4) OR
• Lymph node(s) >6 cm (N3)
• No distant metastasis (M0)
• Treatment typically involves concomitant chemoradiotherapy 1

Stage IV

• Any T, Any N, M1
• Distant metastasis present (M1)
• Common metastatic sites include bone, lungs, liver, and pancreas 2
• Treatment typically involves systemic therapy with palliative intent 1

Important Clinical Considerations

HPV Testing and Diagnosis

• p16 immunohistochemistry is strongly recommended for all oropharyngeal cancers [I, A] 1
• If p16 staining is positive, another specific HPV test should be performed to confirm HPV status [III, A] 1
• HPV-16 is the most common type associated with oropharyngeal cancer 3

Prognostic Factors

• HPV-positive status is associated with significantly better prognosis (82.4% 3-year survival vs. 57.1% for HPV-negative) 4
• Tobacco exposure significantly impacts prognosis even in HPV-positive disease, with risk of death increasing with each additional pack-year 4
• Recursive-partitioning analysis classifies patients into low, intermediate, or high risk of death based on: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage 4

Metastatic Patterns

• HPV-positive oropharyngeal cancer can occasionally present with unusual metastatic patterns, including bone-only metastases to sternum, humerus, clavicle, and vertebrae 2
• Metastatic lesions typically retain the nonkeratinizing morphology of the primary tumor and remain p16/HPV positive 2

Treatment Approach

• Early stage disease (Stage I) can be treated with single-modality therapy (surgery or radiotherapy) 1
• Advanced disease (Stages II-III) typically requires multimodal therapy including surgery, radiotherapy, and chemotherapy 1
• Stage IV disease may be treated with systemic chemotherapy/immunotherapy and/or palliative radiotherapy 1
• Current research focuses on treatment de-escalation for HPV-positive disease to reduce long-term morbidity while maintaining survival outcomes 5, 3

Clinical Pitfalls and Caveats

• Despite the generally better prognosis of HPV-positive oropharyngeal cancer, some patients can experience unexpected clinical outcomes including distant metastases 2
• Metastatic disease can occur even after complete response to initial therapy, with disease-free survival ranging from 7-15 months in some cases 2
• Tumor heterogeneity exists even within HPV-positive oropharyngeal cancers, which may explain variations in treatment response and metastatic potential 6
• The staging system for HPV-positive oropharyngeal cancer is distinct from HPV-negative disease, and using the wrong staging system could lead to inappropriate treatment decisions 1