AJCC 8 and HPV-mediated (p16+) oropharyngeal cancer: what changed in staging?

Key points

• The AJCC 8th edition introduced a staging algorithm for high-risk HPV-associated oropharyngeal cancer that is separate from oropharyngeal cancer of other causes; this is described as the most significant change in the head and neck section.
• The new system is based on the ICON-S study (O'Sullivan et al., Lancet Oncol 2016), which included 1,907 HPV-positive patients from seven centres.
• In AJCC 8, T4 is not subdivided for p16+ disease, clinical N is based on laterality and a 6 cm threshold, and pathological N on the number of metastatic nodes; extranodal extension (ENE) is not used for staging in this group.
• In non-HPV head and neck cancers, ENE was added to the N category, and depth of invasion (DOI) became part of the oral cavity T category.
• The AJCC Version 9 protocol for HPV-associated oropharyngeal cancer has replaced the 8th edition content from 1 January 2026; its most notable difference is the inclusion of ENE in N classification.
• Staging is a prognostic tool; a lower stage alone is not a justification for de-intensifying treatment (de-escalation).

Why a separate system?

AJCC 7 discriminated survival poorly in HPV-positive oropharyngeal cancer. In the ICON-S data, 5-year overall survival was similar for 7th edition stage I, II, III and IVA patients (about 81–88%), and only stage IVB was clearly lower. Likewise, there was no difference between the N0, N1–N2a and N2b subsets; separation appeared only in N3 disease. In other words, many patients with a good prognosis were labelled as "advanced stage".

ICON-S derived a new classification using adjusted hazard ratio (AHR) models in training and validation cohorts, and this proposal became the basis of the AJCC/UICC 8th edition.

p16 immunohistochemistry and HPV testing

In AJCC 8, p16 immunohistochemistry (IHC) is accepted as a surrogate marker for high-risk HPV. Positivity is generally defined as diffuse nuclear and cytoplasmic staining of at least moderate intensity in at least 75% of tumour cells, whereas the 2018 CAP guideline recommended a 70% cutoff. It is important to know which threshold your laboratory reports.

The 2025 CAP update keeps p16 IHC as the primary test for oropharyngeal squamous cell carcinoma with classic features, but recommends HPV-specific testing (RNA ISH or DNA PCR) in situations such as equivocal p16 results, regions with a low proportion of HPV-attributable cases, discordance between p16 and morphology, subsites other than the tonsil and base of tongue, and clinical trial requirements. HPV-specific testing is also emphasised for neck metastases of unknown primary and for fine-needle aspiration samples.

p16+ oropharynx in AJCC 8: T, N and stage groups

As a result, many patients who were stage IV under AJCC 7 move to stage I or II under AJCC 8. When explaining this to patients, it is helpful to point out that a lower stage does not mean the disease will be taken less seriously.

Other key head and neck changes

• Oral cavity: depth of invasion (DOI) was added to the T category; the 5 mm and 10 mm thresholds are used together with tumour size to separate T1–T3. DOI differs from tumour thickness and is measured from the basement membrane of the adjacent normal mucosa; invasion of the extrinsic tongue muscles is no longer a T4 criterion.
• N category in non-HPV tumours: ENE was added to N classification in all head and neck cancers except viral-related cancers and mucosal melanoma. Unequivocal clinical ENE is classified as cN3b; on pathology, ENE positivity results in pN2a or pN3b depending on node number and size.
• Pharyngeal cancers were divided into three separate chapters (nasopharynx, HPV-mediated oropharynx, and non-HPV oropharynx and hypopharynx), and a separate chapter was created for head and neck cutaneous carcinomas.

AJCC Version 9: what is known

Rather than renewing the 8th edition as a single book, AJCC is publishing Version 9 protocols site by site. Version 9 for the nasopharynx took effect in 2025 (Pan et al., JAMA Oncol 2024); advanced radiological ENE was added as an N3 criterion and non-metastatic disease was regrouped into stages I–III.

The Version 9 protocol for HPV-associated oropharynx applies from 1 January 2026. According to published summaries, T and M definitions are retained, the anatomical definitions for clinical T4 are clarified, unequivocal clinically or imaging-detected ENE is incorporated into clinical N, and definitive pathological ENE into pathological N. Interobserver variability in imaging assessment of ENE is high, so attention to the "unequivocal" ENE criterion is advised.

Implications for clinical practice

• Make sure the pathology report clearly states the p16 result, the threshold used and, where needed, the HPV-specific test result; the staging system is chosen on that basis.
• State in records and tumour board notes which edition (AJCC 8 or Version 9) was used; the same patient may be staged differently in the two systems.
• Treatment de-intensification (de-escalation) is not recommended outside clinical trials. In the RTOG 1016 and De-ESCALaTE HPV trials, cetuximab added to radiotherapy gave worse outcomes than cisplatin, and Huang et al. (JAMA Otolaryngol Head Neck Surg 2025) have highlighted a subgroup with poor outcomes within AJCC 8 stage I–II.
• Factors such as smoking history, nodal burden and ENE may not be reflected in the AJCC 8 stage; they are assessed separately in treatment planning.

Limitations and currency note

This summary reflects the outline of the AJCC 8th edition and published information about Version 9; it does not replace the official tables and explanatory notes. For the detailed criteria and transition dates of Version 9, check the current AJCC protocol and your institution's pathology reporting standard. Because staging and HPV testing guidelines are updated regularly, readers should consult the latest version. This text is not a treatment recommendation for an individual patient; the final decision is made through multidisciplinary assessment.