AJCC 8th Edition TNM Staging — Oropharyngeal Squamous Cell Carcinoma

PART A. HPV-MEDIATED (p16-POSITIVE) OROPHARYNGEAL CANCER — AJCC 8th ed., 2017 (ST-7)
– Note: Tis and T4b categories do not exist in this system
PRIMARY TUMOR (T)
- T0: No primary identified
- T1: Tumor 2 cm or smaller in greatest dimension
- T2: Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
- T3: Tumor larger than 4 cm in greatest dimension, or extension to lingual surface of epiglottis
- T4: Moderately advanced local disease — tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible, or beyond:
  - Mucosal extension to the lingual surface of the epiglottis from primary tumors of the base of tongue and vallecula does not constitute invasion of the larynx
CLINICAL REGIONAL LYMPH NODES (cN)
- NX: Regional lymph nodes cannot be assessed
- N0: No regional lymph node metastasis
- N1: One or more ipsilateral lymph nodes, none larger than 6 cm
- N2: Contralateral or bilateral lymph nodes, none larger than 6 cm
- N3: Lymph node(s) larger than 6 cm
PATHOLOGICAL REGIONAL LYMPH NODES (pN)
- NX: Regional lymph nodes cannot be assessed
- pN0: No regional lymph node metastasis
- pN1: Metastasis in 4 or fewer lymph nodes
- pN2: Metastasis in more than 4 lymph nodes
DISTANT METASTASIS (M)
- M0: No distant metastasis
- M1: Distant metastasis
HISTOLOGIC GRADE (G)
- No grading system exists for HPV-mediated oropharyngeal tumors
CLINICAL PROGNOSTIC STAGE GROUPS (p16+)
- Stage I:
  - T0, T1, T2 — N0, N1 — M0
- Stage II:
  - T0, T1, T2 — N2 — M0; or T3 — N0, N1, N2 — M0
- Stage III:
  - T0, T1, T2, T3 — N3 — M0; or T4 — N0, N1, N2, N3 — M0
- Stage IV:
  - Any T — Any N — M1
PATHOLOGICAL PROGNOSTIC STAGE GROUPS (p16+)
- Stage I:
  - T0, T1, T2 — N0, N1 — M0
- Stage II:
  - T0, T1, T2 — N2 — M0; or T3, T4 — N0, N1 — M0
- Stage III:
  - T3, T4 — N2 — M0
- Stage IV:
  - Any T — Any N — M1
PART B. p16-NEGATIVE OROPHARYNGEAL CANCER — AJCC 8th ed., 2017 (ST-4, ST-5, ST-6):
- Same system as hypopharynx; excludes p16+ oropharyngeal and nasopharyngeal cancers
PRIMARY TUMOR (T)
- TX: Primary tumor cannot be assessed
- Tis: Carcinoma in situ
- T1: Tumor 2 cm or smaller in greatest dimension
- T2: Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
- T3: Tumor larger than 4 cm in greatest dimension, or extension to lingual surface of epiglottis
- T4a: Moderately advanced local disease — tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
- T4b: Very advanced local disease — tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid artery:
- Mucosal extension to the lingual surface of the epiglottis from primary tumors of the base of tongue and vallecula does not constitute invasion of the larynx
CLINICAL REGIONAL LYMPH NODES (cN)
- NX: Regional lymph nodes cannot be assessed
- N0: No regional lymph node metastasis
- N1: Metastasis in a single ipsilateral lymph node, 3 cm or smaller, ENE(−)
- N2a: Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm, ENE(−)
- N2b: Metastases in multiple ipsilateral nodes, none larger than 6 cm, ENE(−)
- N2c: Metastases in bilateral or contralateral nodes, none larger than 6 cm, ENE(−)
- N3a: Metastasis in a lymph node larger than 6 cm, ENE(−)
- N3b: Metastasis in any node(s) with clinically overt ENE(+)
PATHOLOGICAL REGIONAL LYMPH NODES (pN)
- NX: Regional lymph nodes cannot be assessed
- N0: No regional lymph node metastasis
- N1: Metastasis in a single ipsilateral lymph node, 3 cm or smaller, ENE(−)
- N2a: Metastasis in a single ipsilateral node 3 cm or smaller with ENE(+); or a single ipsilateral node larger than 3 cm but not larger than 6 cm, ENE(−)
- N2b: Metastases in multiple ipsilateral nodes, none larger than 6 cm, ENE(−)
- N2c: Metastases in bilateral or contralateral nodes, none larger than 6 cm, ENE(−)
- N3a: Metastasis in a lymph node larger than 6 cm, ENE(−)
- N3b: Metastasis in a single ipsilateral node larger than 3 cm with ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes any with ENE(+); or a single contralateral node of any size with ENE(+)
  - Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above (U) or below (L) the lower border of the cricoid
  - Clinical and pathological ENE should be recorded as ENE(−) or ENE(+)
DISTANT METASTASIS (M)
- M0: No distant metastasis
- M1: Distant metastasis
HISTOLOGIC GRADE (G)
- GX: Grade cannot be assessed
- G1: Well differentiated
- G2: Moderately differentiated
- G3: Poorly differentiated
- G4: Undifferentiated
PROGNOSTIC STAGE GROUPS (p16-negative)
- Stage 0:
  - Tis — N0 — M0
- Stage I:
  - T1 — N0 — M0
- Stage II:
  - T2 — N0 — M0
- Stage III:
  - T3 — N0 — M0; or T1, T2, T3 — N1 — M0
- Stage IVA:
  - T1, T2, T3 — N2 — M0; or T4a — N0, N1, N2 — M0
- Stage IVB:
  - T4b — Any N — M0; or Any T — N3 — M0
- Stage IVC:
  - Any T — Any N — M1
KEY DIFFERENCES BETWEEN THE TWO SYSTEMS
- p16+ system has no Tis, no T4a/T4b split (single T4 category), and no N2a/b/c or N3a/b subcategories
- p16+ cN is based on laterality and size only; extranodal extension is not a cN determinant
- p16+ pN is based solely on the number of positive nodes (≤ 4 vs > 4)
- p16+ Stage IV is reserved exclusively for M1 disease; there is no Stage IVA/IVB/IVC
- p16+ clinical and pathological stage groupings differ from each other and must not be used interchangeably
p16 IHC is required for all oropharyngeal cancers; positivity threshold is ≥ 70% of tumor cells with moderate-to-strong nuclear and cytoplasmic staining
Confirmatory direct HPV testing (PCR or RNA in situ hybridization) is recommended, especially for clinical trials; PCR adds sensitivity, ISH adds specificity:
- Patients with p16+/HPV+ tumors have better prognosis than p16+/HPV-negative tumors
Routine HPV/p16 testing of non-oropharyngeal, non-sinonasal head and neck sites is not recommended
AJCC 9th Edition (Version 9) Changes — HPV-Positive Oropharyngeal Carcinoma – NCCN Guidelines, Head and Neck Cancers (v2.2026):
- Still base clinical staging definitions on AJCC 8th edition (ST-4 for p16-negative, ST-7 for p16-positive):
  - Version 9 is not yet incorporated
Version 9 changes apply only to HPV-positive (p16+) oropharyngeal carcinoma:
- The p16-negative oropharynx / hypopharynx system is unchanged in the current NCCN tables
PART A. VERSION 9 PATHOLOGICAL CLASSIFICATION (AJCC9V) — HPV-POSITIVE
- Rationale for revision:
- In AJCC 8th edition, > 85% of cases were pN1 and > 80% were Stage I, producing wide hazard variance within dominant groupings and a disconnect between stage and treatment
- Pathological extranodal extension (pENE), widely used in trials and clinical decision making, was absent from the 8th edition system:
  - Derivation: 14,447 surgically treated patients across 984 US facilities (derivation n = 7,768; validation n = 6,679), treated 2010–2019; median follow-up 52.4 months; 31.5% pENE-positive
Key prognostic findings:
- Mortality risk rose with each additional metastatic lymph node (HR 1.20, 95% CI 1.11–1.29, p < 0.0001), with an optimal cutoff at 4.3 nodes
- pENE independently associated with mortality (HR 1.47, 95% CI 1.30–1.65, p < 0.0001)
- Extent of pENE (minor vs major) showed no significant prognostic difference
VERSION 9 pN CLASSIFICATION (HPV-positive)
- pN0: 0 positive lymph nodes
  - pN1a: 1 positive lymph node, ENE-negative
- pN1b:
  - 2 to 4 positive lymph nodes, ENE-negative
- pN2:
  - > 4 positive lymph nodes and ENE-negative; OR 1 to 4 positive lymph nodes and ENE-positive
- pN3:
  - > 4 positive lymph nodes and ENE-positive
- Compare AJCC 8th edition: pN1 = 1 to 4 positive nodes; pN2 = > 4 positive nodes; ENE not incorporated
VERSION 9 PATHOLOGICAL STAGE GROUPS (HPV-positive)
- Stage I:
  - T0 to T2, N0 to N1, M0
- Stage II:
  - T0 to T2, N2 to N3, M0; or T3, N0 to N2, M0
- Stage III:
  - T3, N3, M0; or T4, N0 to N3, M0
- Stage IV:
  - Any T, Any N, M1
- Compare AJCC 8th edition pathological: Stage I = T0 to 2 N0–1; Stage II = T0 to 2 N2 or T3 to 4 N0 to 1; Stage III = T3 to 4 N2; Stage IV = M1
PERFORMANCE
- Stage distribution rebalanced:
  - AJCC8E 81.4% Stage I / 15.0% Stage II / 3.6% Stage III versus AJCC9V 54.9% Stage I / 41.3% Stage II / 3.8% Stage III
- Curve separation preserved:
  - 5-year overall survival 92.3% (Stage I), 85.2% (Stage II), 71.3% (Stage III); p < 0.001
- AJCC9V showed superior hazard consistency, outcome prediction, and balance, but NOT superior hazard discrimination, versus AJCC8E
- Endorsed by the AJCC Expert Panel on HPV-positive oropharyngeal carcinoma by Delphi consensus
- Caveat:
  - T4N1 cases fit imperfectly within their assigned Stage III grouping, likely reflecting small numbers, as few T4 cases undergo surgery; these were retained in Stage III for clinical consistency
PART B. VERSION 9 CLINICAL CLASSIFICATION — HPV-POSITIVE
- Principal change:
  - Incorporation of imaging-detected extranodal extension (iENE)
    - Rule:
      - Each N category is reclassified one stratum higher when iENE is present; iENE-negative cases are unchanged
  - Derivation: ICON-N dataset, 2,053 patients from 4 institutions, with validation in an independent CHUM cohort (n = 451); median follow-up 5.1 years:
    - iENE was present in 37.4% of cN-positive patients and was the strongest prognostic nodal feature: adjusted HR 2.43 (95% CI 1.96–3.03) in ICON-N and 2.04 (95% CI 1.28–3.23) in CHUM
    - The iENE-adjusted schema outperformed AJCC 8th edition for disease-free and overall survival (overall normalized score 2 vs 3)
  - External validation:
    - In a retrospective series of 26 node-positive HPV-associated oropharyngeal carcinoma patients treated with definitive chemoradiotherapy, iENE was present in 61.5% and associated with lower 2-year disease-free survival (68.8% vs 100%, p = 0.048)
    - Reclassification by version 9 improved prognostic discrimination over the 8th edition (p = 0.043)
PART C. PRACTICAL IMPLICATIONS
- Report the number of metastatic lymph nodes and ENE status explicitly on pathology, and iENE status on pretreatment CT / MRI, since both now drive N classification under version 9
- Version 9 does not alter T categories or M categories for HPV-positive disease
- Stage IV remains reserved for M1 disease
References:
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Head and Neck Cancers. Version 2.2026. Staging tables ST-4, ST-5, ST-6 (oropharynx p16-negative and hypopharynx) and ST-7 (HPV-mediated p16-positive oropharynx); ORPH-1, ORPH-B.
- Ho AS, Huang SH, O’Sullivan B, et al. Derivation and validation of the AJCC9V pathological stage classification for HPV-positive oropharyngeal carcinoma: a multicentre registry analysis. Lancet Oncol. 2025.
- Cramer JD, Hicks KE, Rademaker AW, Patel UA, Samant S. Validation of the eighth edition American Joint Committee on Cancer staging system for human papillomavirus-associated oropharyngeal cancer. Head Neck. 2018.
- Hall SR, Neel GS, Chang BA, et al. American Joint Committee on Cancer eighth edition human papilloma virus positive