Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Lymph node metastases:
  • At presentation are common in OPSCC:
    • With over half of patients:
      • Having clinical or radiological evidence of cervical metastasis
    • Around a third of patients diagnosed as cN0:
      • Having pathologic evidence of lymph node metastasis
  • The lymphatic drainage from the oropharynx:
    • Is mainly to:
      • Levels II, III and IV
    • It also drains into:
      • The retropharyngeal (RP) nodes:
        • Which need to be considered in the assessment of disease in this area
        • The risk of metastasis to RP lymph nodes depends on subsite:
          • A meta-analysis of papers suggests risk of RP lymphadenopathy being:
            • 19% for soft palate
            • 12% for tonsil
            • 6% for base of tongue and
            • 21% to 57% for posterior pharyngeal wall tumors:
              • Including hypopharynx
      • The prognostic impact of positive RP lymph node metastasis is disputed:
        • Some authors showing an adverse impact:
          • And others not
  • A particular feature of OPSCC:
    • Is the propensity to metastasis to the contralateral neck:
      • This occurring in up to 30% of patients overall in one series:
        • The subsites in which this is mostly likely to occur are the:
          • Soft palate
          • Base of tongue
          • Posterior pharyngeal wall:
            • However:
              • Even tonsil cancers have an approximate rate:
                • Of contralateral nodal spread of 10%

• Oropharyngeal tumor histological types:
  • Squamous cell carcinoma (SCC):
    • Is the most common malignancy of the oropharynx:
      • Making up 90% of the tumors in this region
  • Non-Hodgkin’s lymphomas:
    • Accounts for 8% of tumors in these region
  • Minor salivary gland tumors:
    • Account for 2% of tumors in these region
• With regard to squamous cell carcinoma:
  • The most frequent locations of affected sites is:
    • Tonsil / lateral wall:
      • 60% of the cases
    • Tongue base:
      • 25% of the cases
    • Soft palate:
      • 10% of the cases
    • Posterior pharyngeal wall:
      • 5% of the cases

• The pterygopalatine fossa:
  • Is a small, cone- or inverted pyramid-shaped depression located deep within the upper face
  • It sits beneath the apex of the orbit, posterior to the maxilla, and medial to the infratemporal fossa
  • It acts as a major neurovascular crossroad connecting multiple regions of the skull
• Borders / Boundaries – The borders of the pterygopalatine fossa are formed by the palatine, maxilla and sphenoid bones:
  • Anterior: 
    • Maxillary tuberosity and posterior surface of the maxilla
  • Posterior: 
    • Pterygoid process of the sphenoid bone (lateral pterygoid plate)
  • Medial: 
    • Perpendicular plate of the palatine bone
  • Lateral: 
    • Pterygomaxillary fissure opening into the infratemporal fossa
  • Superior: 
    • Inferior surface of the greater wing of the sphenoid bone
    • Inferior orbital fissure of the eye
  • Inferior:
    • Pyramidal process of the palatine bone
• Major Contents:
  • Maxillary nerve (V2): 
    • The second division of the trigeminal nerve (cranial nerve V):
      • Passing through via the foramen rotundum (middle cranial fossa)
  • Pterygopalatine ganglion (Sphenopalatine ganglion): 
    • A parasympathetic ganglion:
      • Associated with cranial nerve VII
  • Maxillary artery: 
    • The third (terminal) part of the maxillary artery and its accompanying branches
  • Nerve of the pterygoid canal (Vidian nerve): 
    • Carrying sympathetic (via the deep petrosal nerve) and parasympathetic fibers (via the greater petrosal nerve) into the fossa
• Communications and Openings:
  • The fossa communicates with surrounding anatomic regions via several key foramina and fissures:
    • Middle cranial fossa: 
      • Via the foramen rotundum
    • Orbit: 
      • Via the inferior orbital fissure
    • Nasal cavity: 
      • Via the sphenopalatine foramen
    • Oral cavity / Palate: 
      • Via the greater and lesser palatine canals
    • Infratemporal fossa: 
      • Via the pterygomaxillary fissure
    • Pharynx / Nasopharynx: 
      • Via the pharyngeal / palatovaginal canal
• Clinical Significance:
  • Because of its numerous pathways and high density of nerves and blood vessels:
    • The pterygopalatine fossa can act as a conduit for the spread of infections and malignant tumors from the face or nasal cavity into the cranial vault
  • Surgeons also target this area for nerve blocks or approaches to control severe bleeding (epistaxis)

• Surgical margin status:
  • Remains one of the most powerful and actionable prognostic factors in oral tongue / oral cavity SCC
• Classically, Scholl and colleagues:
  • Reviewed 268 patients with squamous carcinoma of the oral tongue:
    • They found that 54 (20.1%) had microscopic “cut-through” at the intraoperative frozen section margin:
      • An initially positive margin
  • Even when additional resection converted these to final negative margins:
    • Local control remained significantly worse:
      • Than in patients whose margins were clear on the first pass
  • They also reported that margin involvement patterns differed by T stage:
    • T1 to T2 tumors:
      • More often had positive mucosal margins
    • T3 to T4 tumors:
      • Commonly failed at the deep / soft-tissue margins
• Similar observations were made in classic series evaluating “positive” epidermoid carcinoma margins in the head and neck:
  • Looser, Shah, and Strong:
    • Demonstrated that patients with involved margins:
      • Had substantially higher local recurrence than those with negative margins:
        • With early reports quoting local recurrence in roughly two-thirds to three-quarters of patients with positive margins versus about one-third with negative margins
  • Loree and Strong:
    • Subsequently examined 398 oral cavity SCCs:
      • Showing that positive or “close” margins (tumor at or within 0.5 mm of the inked edge, or significant premalignant change / in situ carcinoma at the margin):
        • Were associated with a doubling of local recurrence (36% vs 18%) and inferior 5-year survival compared with negative margins (52% vs 60%)
• The reliability and utility of intraoperative frozen section (FS) margin assessment have also been extensively studied:
  • Spiro et al:
    • Reported an overall intraoperative FS diagnostic accuracy of:
      • Roughly 89% for oral tongue cancer:
        • Importantly found that accuracy was similar whether sections were taken directly from the patient’s tumor bed or from the oriented surgical specimen
    • Positive or “close” margins:
      • Defined in their series as tumor present at the ink or within roughly one high-power field of the resection edge:
        • Were associated with a significantly increased risk of local recurrence (p < 0.003)
  • Subsequent work by Byers and others:
    • Confirmed the prognostic and therapeutic value of frozen section (FS):
      • Guided re-resection in HNSCC:
        • But also highlighted that FS cannot fully compensate for suboptimal initial resection planes
• Definitions of margin status and distance:
  • There is now better consensus on margin nomenclature
  • Most contemporary series and guidelines define:
    • Positive margin:
      • Invasive carcinoma or severe / high-grade dysplasia:
        • At the inked edge, or < 1 mm from the inked edge
    • Close margin:
      • Invasive carcinoma typically 1 to 4 or 1 to 5 mm from the inked edge:
        • Cut-off values vary:
        • But a 5 mm microscopic threshold is most commonly used in oral cavity SCC
    • Clear margin:
      • ≥ / > 5 mm from invasive tumor to the inked edge after formalin fixation
• Tasche et al., in a large JAMA Otolaryngology analysis:
  • Proposed that a distance < 1 mm behaves biologically like an involved margin:
    • With similarly high local recurrence risk
  • Whereas 1 to 5 mm margins had intermediate risk and ≥ 5 mm margins were associated with the lowest recurrence
• More recent multicenter work emphasizes the importance of deep margin distance in particular:
  • With data suggesting that deep margins ≤ 3 mm carry a significantly higher risk of local failure compared with > 3 mm:
    • Even when the mucosal margin is wide
• Impact of positive and close margins on outcomes:
  • Multiple retrospective series and meta-analyses now support and refine the early observations of Scholl, Looser, Loree, and Strong:
    • Positive final margins are consistently associated with:
      • ~ 2-fold higher risk of local recurrence,
        increased regional / distant failure in some series, and significantly worse disease-specific and overall survival
  • Binahmed et al. and McMahon et al:
    • Both showed that patients with involved margins:
      • Had roughly double the local recurrence and significantly poorer survival compared with those with clear margins, and that close margins behaved intermediately between clearly negative and frankly positive margins
  • Liao et al:
    • Identified margin status, together with T stage, DOI, and perineural invasion:
      • As major predictors of local tumor control in oral cavity SCC
  • A 2019 systematic review and meta-analysis by Gorphe:
    • Concluded that positive margins carry an approximately two-fold increased risk of death and local failure across head and neck sites, independent of other factors
  • More granular contemporary analyses, including Buchakjian et al. and Szewczyk et al., have shown that:
    • Positive margins (< 1 mm) remain the strongest margin-related predictor of:
      • Local, regional, and distant recurrence
    • Close margins (1 to 4.9 mm) often do not independently worsen outcomes if other adverse factors (lymphovascular invasion, perineural invasion, ENE, nodal disease, advanced T stage):
      • Are absent and if appropriate adjuvant therapy is given when indicated
  • The prognostic effect of close margins is modulated by:
    • Depth of invasion (DOI), pattern of invasion, and composite histologic risk models (e.g., Brandwein-Gensler)
  • Subsite-specific studies have further refined this:
    • Tongue and floor-of-mouth tumors are particularly prone to failure at the deep margin:
      • In several series, deep margin positivity or ≤ 2 to 3 mm clearance:
        • Has been more predictive of local recurrence than mucosal margin distance
• Microscopic cut-through and “revised” margins:
  • Building on Scholl’s original work, the concept of microscopic tumor cut-through (MTCT):
    • A positive FS margin that is revised to negative on final pathology, has been extensively studied
    • Patel et al. (Head & Neck 2010) showed that MTCT:
      • Was associated with significantly worse local control and disease-specific survival compared with margins that were negative from the outset:
        • Particularly in patients with nodal disease
    • Guillemaud et al. similarly reported that intraoperative cut-through, even if revised to R0:
      • Predicted higher local recurrence and worse outcomes in oral cavity SCC
    • A meta-analysis by Bulbul et al. concluded that clearance of a positive margin improves outcomes relative to leaving it unrevised:
      • But patients with MTCT still fare worse than those whose margins were always negative:
        • Suggesting MTCT is a marker of more aggressive biology and / or challenging local anatomy
    • More recently, Agne et al. evaluated T3 to T4 OCSCC and confirmed that MTCT:
    • Remained an independent predictor of local recurrence on multivariable analysis (HR ~1.8–2.2 for local failure):
      • Although its effect on disease-specific survival attenuated when controlling for nodal stage and other high-risk features
• These data support considering MTCT as a high-risk feature warranting discussion of treatment intensification:
  • For example (e.g., adjuvant chemoradiotherapy) in a multidisciplinary tumor board, even when final margins are technically negative
• Kwok et al. addressed the related question of “clear versus revised margins” in 417 patients with oral and pharyngeal carcinoma:
  • Patients who required immediate re-resection for a positive FS margin but ended with R0 status:
    • Had survival similar to those with primary R0 resection, and both groups did substantially better than patients left with residual microscopic or macroscopic disease
  • This suggests that while MTCT carries biologic risk:
    • An aggressive intraoperative strategy to convert to R0 is still beneficial and should remain standard practice
• Intraoperative margin assessment:
  • Specimen vs tumor bed:
    • There is growing recognition that how margins are sampled:
      • Is almost as important as the final measurement
    • Meier et al.’s AHNS survey and several subsequent series have documented wide variation in intraoperative margin practices (tumor bed vs specimen mapping, number of samples, definition of “adequate” clearance), and a substantial rate of FS–permanent section discrepancy
  • Key contemporary points include:
    • Specimen-based mapping (oriented and inked, with communication between surgeon and pathologist):
      • Tends to provide more reliable correlation between FS and final margins than random tumor-bed biopsies
    • FS accuracy remains high (often ~ 85% to 95%):
      • But false-negatives and false-positives still occur:
        • Particularly at the deep margin, in previously irradiated fields, and in specimens with significant shrinkage
    • In some series, “complete FS margins” with a measurable 1 to 5 mm histologic buffer were associated with improved local control compared with conventional limited sampling
  • Recent reviews and consensus statements (e.g., Kubik et al., Kain et al., Chen et al. 2024) now recommend:
    • A planned 1 to 1.5 cm gross resection margin in vivo for oral tongue SCC, anticipating ~30% to 50% shrinkage with formalin fixation and tissue relaxation
    • Routine use of oriented, inked specimens with targeted FS from high-risk areas (deep margin, close relationship to muscle bundles or neurovascular structures)
    • Consideration of advanced adjuncts—near-infrared fluorescence mapping, specimen 3D-mapping, and emerging augmented-reality registration—for difficult tongue and floor-of-mouth resections
• Integration with histologic risk models:
  • Finally, margin status must be interpreted in the context of overall histologic risk
  • The Brandwein-Gensler model:
    • Worst pattern of invasion, perineural invasion, lymphocytic host response and later refinements:
      • Have shown that high-risk tumors have markedly increased recurrence and disease-specific mortality even when margins are clear
  • Conversely, some low-risk early-stage tumors with close (but not involved) margins may do well without aggressive adjuvant therapy
  • This supports a nuanced, risk-adapted approach in which:
    • Positive margins or MTCT → strong indication for adjuvant chemoradiotherapy in most patients
    • Close margins (1 to 4 mm) → individualized decision based on DOI, nodal status, PNI/LVI, pattern of invasion, and patient-specific factors
    • Clear margins (≥ 5 mm) → lowest risk group, managed according to other adverse features
• Reviewed:
  • Scholl P, Byers RM, Batsakis JG, Wolf P, Santini H. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue: prognostic and therapeutic implications. Am J Surg. 1986;152:354-360. 
  • Looser KG, Shah JP, Strong EW. The significance of “positive” margins in surgically resected epidermoid carcinomas. Head Neck Surg. 1978;1:107-111. 
  • Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg. 1990;160:410-414. 
  • Spiro RH, Guillamondegui O, Paulino AF, et al. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck. 1999;21:408-413. 
  • Chen TY, Emrich LJ, Driscoll DL. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys. 1987;13:833-837. 
  • McMahon J, O’Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg. 2003;41:224-231. 
  • Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol. 2007;43:780-784. 
  • Liao CT, Chang JTC, Wang HM, et al. Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol. 2008;15:915-922. 
  • Patel RS, Goldstein DP, Guillemaud J, et al. Impact of positive frozen section microscopic tumor cut-through revised to negative on oral carcinoma control and survival rates. Head Neck. 2010;32:1444-1451. 
  • Guillemaud J, Patel RS, Goldstein DP, et al. Prognostic impact of intraoperative microscopic cut-through on frozen section in oral cavity squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2010;39:370-377. 
  • Kwok P, Gleich O, Hübner G, Strutz J. Prognostic importance of “clear versus revised margins” in oral and pharyngeal cancer. Head Neck. 2010;32:1479-1484. 
  • Gorphe P. A systematic review and meta-analysis of margins in head and neck cancer. Oral Oncol. 2019;95:93-101. 
  • Tasche KK, Buchakjian MR, Pagedar NA, Sperry SM. Definition of “close margin” in oral cancer surgery and association of margin distance with local recurrence rate. JAMA Otolaryngol Head Neck Surg. 2017;143:1166-1172. 
  • Buchakjian MR, Tasche KK, Robinson RA, et al. Association of main specimen and tumor bed margin status with local recurrence and survival in oral cancer surgery. JAMA Otolaryngol Head Neck Surg. 2016;142:1191-1198. 
  • Kain JJ, Birkeland AC, Udayakumar N, et al. Surgical margins in oral cavity squamous cell carcinoma: current practices and future directions. Laryngoscope. 2020;130:128-138. 
    Szewczyk M, et al. A matter of margins in oral cancer—how close is enough? Cancers (Basel). 2024;16(8):1488. 
  • Agne GR, et al. Oncologic outcomes of microscopic tumor cut-through in locally advanced oral squamous cell carcinoma. Arch Head Neck Surg. 2022;51:e20220013. 
    Chen Y, et al. Surgical margins in head and neck squamous cell carcinoma. Int J Surg. 2024;109:54-66. 
  • Brandwein-Gensler M, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29:167-178.  

• What it asked?
  • Does adding concurrent chemotherapy to definitive RT improve outcomes vs RT alone in stage III to IV oropharyngeal cancer? PubMed
• Who was enrolled?
  • n=226 adults with stage III to IV oropharynx SCC:
    • No planned primary surgery
  • Arms well balanced by age, sex, stage, PS, site  PubMed
• Treatment and dosing (the “GORTEC” CRT)
  • RT (both arms): 
    • 70 Gy in 35 fractions
  • CRT arm chemotherapy: 
    • Carboplatin 70 mg/m²/day (IV bolus) + 5-FU 600 mg/m²/day (continuous infusion), days 1 to 4, given during weeks 1, 4, and 7 of RT (total 3 cycles) PubMed+1
• Endpoints:
  • Primary intent:
    • Improve DFS:
      • Reported OS, DFS, and locoregional control (LRC) at 3 and 5 years; plus acute and late toxicity PubMed+1
• Key efficacy results
  • 3-year (initial JNCI report, 1999):
    • OS: 51% CRT vs 31% RT (P=.02)
    • DFS: 42% vs 20% (P=.04)
    • LRC: 66% vs 42% (favored CRT) PubMed
  • 5-year (final JCO report, 2004):
    • OS: 22% CRT vs 16% RT (P=.05)
    • DFS: 27% vs 15% (P=.01)
    • LRC: 48% vs 25% (P=.002)
  • Independent adverse prognostic factors: 
    • Stage IV, Hgb < 12.5 g/dL, and RT alone PubMed
  • Toxicity (what to remember)
    • Acute (during treatment):
      • Grade 3 to 4 mucositis: ~ 71% CRT vs 39% RT
    • Higher hematologic toxicity with CRT PubMed
  • Late (5-year assessments):
    • Any late effect common in both arms; organs most affected with CRT:
      • Salivary glands, skin, teeth, mandible
    • In a dedicated late-toxicity paper using LENT/SOMA, RTOG/EORTC, and NCI-CTC scales:
      • Severe late effects differed significantly only for dental complications (higher with CRT)
      • Spinal cord not adversely affected
      • No late-toxicity deaths
      • Scale choice influenced perceived rates PubMed
    • In the JCO final report, “≥ G3 to G4 late complications” were:
      • 56% CRT vs 30% RT (not statistically significant) PubMed
• Why it still matters:
  • One of the pivotal pre-HPV-era trials establishing concurrent CRT as superior to RT alone for oropharynx SCC:
    • Supporting today’s practice where cisplatin-based CRT is standard for eligible patients:
      • Carboplatin / 5-FU remains a reasonable alternative when cisplatin is contraindicated PubMed+1
• Fast facts to quote:
  • Site: 
    • Oropharynx only
  • Regimen: 
    • Carboplatin 70 mg / m² day 1 + 5-FU 600 mg/m²/d CI day 1 to 4, weeks 1/4/7 with 70 Gy/35 fx
  • 3-yr OS: 
    • 51% vs 31%
  • 5-yr LRC: 
    • 48% vs 25% (all favor CRT) PubMed+1

1. Perioperative Immunotherapy – KEYNOTE-689 Continues to Shape Practice:
   • The KEYNOTE-689 phase 3 trial:
     • Which led to the FDA approval of perioperative pembrolizumab (June 2025):
       • For resectable locally advanced HNSCC with PD-L1 CPS ≥ 1:
         • Remains a central focus
     • New ASCO 2026 exploratory analyses demonstrate that the EFS benefit of neoadjuvant / adjuvant pembrolizumab:
       • Persists across surgical outcome subgroups, including:
         • Patients with and without extranodal extension or positive margins
       • Notably, fewer patients in the pembrolizumab arm had ENE or positive margins post-surgery:
         • Suggesting neoadjuvant pembrolizumab contributes to pathologic downstaging
   • A pooled meta-analysis of three phase 3 trials (KEYNOTE-689, NIVOPOSTOP, and IMvoke010; n=1,786) presented at ASCO 2026:
     • Confirmed a significant improvement in event-free / disease-free survival with perioperative or adjuvant PD-1 / PD-L1 blockade (pooled HR 0.79, 95% CI 0.68–0.91):
       • With no meaningful increase in treatment-related deaths

The following figure from the KEYNOTE-689 trial illustrates the event-free survival benefit across PD-L1 subgroups:

2. Neoadjuvant Bispecific Antibody Combinations: Ivonescimab Leads the Way:
   • Several ASCO 2026 abstracts highlight the emerging role of bispecific antibodies in the neoadjuvant setting:
     • Ivonescimab (PD-1 / VEGF bispecific) + nab-paclitaxel / cisplatin:
       • Achieved a remarkable 100% ORR:
         • 50% CR, 50% PR
       • Achieved a 50% pCR rate:
         • In 30 surgical patients with resectable LA-HNSCC
       • All patients with CPS >30 achieved pCR, and 100% laryngeal / pharyngeal preservation was achieved
   • A randomized phase II trial comparing ivonescimab (PD-1 / VEGF), cadonilimab (PD-1 /CTLA-4), and penpulimab (PD-1 alone), each combined with chemotherapy:
     • Showed the highest pCR rate with ivonescimab at 60%, compared to 42.1% with cadonilimab and 40% with single-agent PD-1
   • Adebrelimab (PD-L1 inhibitor) + chemotherapy demonstrated:
     • An 87.5% ORR and a 95.8% larynx preservation rate in resectable LA-HNSCC:
       • With all p16-positive and CPS ≥ 20 patients responding

3. Novel Agents in Recurrent / Metastatic HNSCC:
   • Bispecific antibodies are generating significant excitement in the recurrent / metastatic setting:
     • Ficerafusp alfa (EGFR × TGF-β) + pembrolizumab:
       • Two-year follow-up data showed a confirmed ORR of 54% in HPV-negative R/M HNSCC (21% CR), with a median DOR of 21.7 months and median OS of 21.3 months
         • The phase 2 / 3 FORTIFI-HN01 trial is now actively enrolling
     • Petosemtamab (EGFR × LGR5) + pembrolizumab:
       • Updated phase 2 data showed a 60% ORR (including 5 CRs) in first-line PD-L1+ R/M HNSCC, with median DOR of 11 months
         • Two phase 3 trials (LiGeR-HN1 and LiGeR-HN2) are recruiting
     • CRB-701 (Nectin-4 ADC):
       • A phase 1 / 2 study in heavily pretreated R/M HNSCC (85% refractory to immunotherapy and platinum):
         • Showed a confirmed ORR of 33.3% at both 2.7 and 3.6 mg/kg doses, regardless of HPV status
     • Becotatug vedotin (EGFR ADC):
       • A new randomized phase II trial is evaluating neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors in resectable LA-HNSCC

4. HPV-Directed Immunotherapy and De-escalation:
   • The TARGET-HPV trial presented at ASCO 2026:
     • Evaluated neoadjuvant HB200 (HPV16-specific viral immunotherapy) + carboplatin / paclitaxel in HPV16+ oropharyngeal SCC:
       • The deep response rate was 87.9%, with 86% of patients receiving de-escalated definitive therapy
       • At 23 months median follow-up, 2-year PFS was 86% and OS was 100%
       • Circulating tumor HPV-DNA was significantly associated with recurrence

5. Evolving First-Line R / M HNSCC Pipeline:
   • A landscape analysis presented at ASCO 2026 identified 145 active regimens (111 unique assets) in the first-line R / M HNSCC pipeline
   • Key trends include a shift toward chemotherapy-free combinations alongside PD-1 blockade:
     • With bispecific antibodies (10.8%), ADCs (10.8%), and cancer vaccines (9.0%) representing the most common novel modalities
   • Eight key phase 3 trials are underway:
     • All incorporating PD-1 as a target, with pembrolizumab as the backbone in 7 of 8

• Overall, ASCO 2026 highlights a transformative period in head and neck oncology:
  • With perioperative immunotherapy now established as a new standard, bispecific antibodies and ADCs showing compelling early efficacy, and biomarker-driven strategies (PD-L1 CPS, HPV status, ctHPV-DNA, MRD) increasingly guiding treatment selection

References

1. Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer. Uppaluri R, Haddad RI, Tao Y, et al. The New England Journal of Medicine. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434.
2. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma | FDA. Food and Drug Administration. 2025-06-13.
3. Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.. Adkins D, Haddad R, Tao Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6057. doi:10.1200/JCO.2026.44.16_suppl.6057.
4. Perioperative or adjuvant PD-1/PD-L1 blockade with curative-intent multimodality therapy for locally advanced head and neck squamous cell carcinoma: A systematic review and meta-analysis of randomized trials.. Daher S, Daher H, Altal H, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18074. doi:10.1200/JCO.2026.44.16_suppl.e18074.
5. Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.. Kunyu Yang, Xiaomeng Zhang and Lu Wen. Journal of Clinical Oncology. 2026;44(Suppl 16):6014. doi:10.1200/JCO.2026.44.16_suppl.6014.
6. Neoadjuvant immunotherapy in combination with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma: Updated efficacy and safety data from a randomized phase II trial.. Liu L, Chen F, Li Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6091. doi:10.1200/JCO.2026.44.16_suppl.6091.
7. Neoadjuvant adebrelimab plus chemotherapy in untreated locally advanced head and neck squamous cell carcinoma: Efficacy and biomarker insights from a single-arm phase 2 trial.. Fang R, Lei W, Huang B, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6106. doi:10.1200/JCO.2026.44.16_suppl.6106.
8. Ficerafusp Alfa (BCA101) With Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Two-Year Results of an Expansion Cohort of a Phase I/Ib Trial. Hanna GJ, Zandberg DP, Wong DJ, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2026;:JCO2502027. doi:10.1200/JCO-25-02027.
9. A multicenter, randomized, double-blind, phase 2/3 study of ficerafusp alfa (BCA101) or placebo in combination with pembrolizumab for first-line treatment of HPV-negative, PD-L1–positive, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): FORTIFI-HN01.. Ferrarotto R, Kaczmar J, Spigel D, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6129. doi:10.1200/JCO.2026.44.16_suppl.TPS6129.
10. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of PD-L1+ recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 trial. Herpen C, Daste A, Arrazubi V, et al. Journal of Clinical Oncology. 2025;43(Suppl 16):6024. doi:10.1200/JCO.2025.43.16_suppl.6024.
11. LiGeR-HN Phase III Trials of Petosemtamab + Pembrolizumab and Petosemtamab Monotherapy in Recurrent or Metastatic HNSCC. Machiels JP, Fayette J, Haddad R, et al. Future Oncology (London, England). 2025;21(16):2007-2016. doi:10.1080/14796694.2025.2511470.
12. A phase 1/2 study of the next-generation nectin-4–targeting antibody-drug conjugate CRB-701 (SYS6002) in patients with recurrent or metastatic head and neck squamous cell carcinoma.. Mantia C, Hanna G, Loriot Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6062. doi:10.1200/JCO.2026.44.16_suppl.6062.
13. A randomized, non-comparative, multicenter phase II trial of neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors (penpulimab/ivonescimab) in resectable locally advanced head and neck squamous cell carcinoma.. Wei X, Xiang Z, Zeng Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6135. doi:10.1200/JCO.2026.44.16_suppl.TPS6135.
14. Neoadjuvant HPV16-specific viral immunotherapy (HB200) plus chemotherapy with response-adapted de-escalation in HPV16+ oropharyngeal squamous cell carcinoma: TARGET-HPV trial.. Rosenberg A, Juloori A, Cursio J, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6097. doi:10.1200/JCO.2026.44.16_suppl.6097.
15. Emerging trends in research strategies in the first-line recurrent or metastatic head and neck cancer (R/M SCCHN) landscape: A top-level analysis by Oncofocus.. Shukla A, Keeshara V, Chamaria M, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18029. doi:10.1200/JCO.2026.44.16_suppl.e18029.
16. Recent Highlights and Breakthroughs in Immunotherapy for Head and Neck Cancers. Vuille JA, Szturz P. Current Opinion in Oncology. 2026;38(3):201-211. doi:10.1097/CCO.0000000000001211.
17. Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: The Current Status and Future Outlook. Köylü B, Selçukbiricik F, Aksoy S, Güven DC. Critical Reviews in Oncology/Hematology. 2026;:105145. doi:10.1016/j.critrevonc.2026.105145.

• The Groupe d’Oncologie Radiotherapie Tete et Cou trial evaluated the concomitant approach in patients with oropharynx cancer only
• A total of 226 patients were randomly assigned to either:
  • Radiation therapy alone (70 Gy) or
  • Radiation therapy (70 Gy) with concurrent carboplatin and infusion 5-FU
• Significant benefits in 5-year overall survival (22% versus 16%, p = .05) and locoregional control (48% versus 25%, p = .002) were noted in the combined treatment arm
• Complete responses were observed in a significant number of patients:
  • Thus avoiding the sequelae and short-term morbidity of surgical resection

• Other Phase II trials also support the feasibility of administering other chemotherapy regimens concurrently with radiation therapy for patients with locoregionally advanced head and neck cancer, including but not limited to:
  • Cisplatin plus paclitaxel
  • Cisplatin plus infusional 5-FU
  • 5-FU plus hydroxyurea
  • Carboplatin plus paclitaxel
  • Paclitaxel, 5-FU, and hydroxyurea

• Definition:
  • A benign, midline nasopharyngeal cyst:
    • Arising from remnants of the embryonic notochord at the pharyngeal bursa
  • It is superficial to the superior pharyngeal constrictor muscle and covered by nasopharyngeal mucosa
  • The pharyngeal bursa forms from a communication between the notochord and nasopharyngeal endoderm:
    • Obstruction of the bursa orifice by inflammation, infection, or mechanical causes leads to cyst formation
  • Histopathologically:
    • The cyst wall is lined by respiratory epithelium and infiltrated diffusely by lymphocytes without lymphoid follicles
• Epidemiology:
  • The pharyngeal bursa is present in approximately 3% of healthy adults
  • In an MRI series of 3,000 patients:
    • Tornwaldt cysts were found in 6%:
      • With peak prevalence at age 51 to 60
  • An earlier MRI series of 1,208 subjects:
    • Found a prevalence of 1.9%:
      • With a mean age of 57 years
  • No significant gender predilection
• Clinical Presentation:
  • Most cases are asymptomatic and discovered incidentally on imaging
  • When symptomatic (typically from infection or inflammation), presentations include:
    • Nasal obstruction and postnasal drip
    • Halitosis and unpleasant taste
    • Occipital headache
    • Eustachian tube dysfunction with hearing loss or middle ear effusion
    • Foreign body sensation in the nasopharynx
• Diagnosis — Imaging:
  • MRI is superior to CT for detection and characterization
  • MRI features:
    • High signal on T1-weighted images (proteinaceous content)
    • High signal on T2-weighted images (isointense to CSF)
    • Hyperintense on FLAIR
    • Round or oval, mean size approximately 6 mm
    • No enhancement of cyst contents; thin rim enhancement may be seen with infection
  • CT features:
    • Well-defined, hypodense midline nasopharyngeal lesion
    • Less sensitive than MRI
• Key distinguishing feature from mucous retention cysts:
  • Tornwaldt cysts are midline:
    • They are located in the posterior nasopharyngeal wall:
  • Mucous retention cysts:
    • Are more commonly lateral or off-midline
  • On nasopharyngoscopy:
    • Smooth, submucosal midline mass in the posterior nasopharynx
• Differential Diagnosis:
  • Mucous retention cyst (most common mimic)
  • Nasopharyngeal carcinoma
  • Minor salivary gland tumor
  • Branchial cleft cyst
  • Dermoid / epidermoid cyst
  • Nasopharyngeal abscess
• Treatment:
  • Asymptomatic cysts:
    • Observation only:
      • No treatment required
  • Symptomatic cysts:
    • Surgical intervention via transnasal endoscopic or transoral approach
  • Marsupialization is the procedure of choice:
    • Preferred over complete excision to minimize recurrence
    • In a series of 21 patients treated with transnasal endoscopic marsupialization:
      • All had symptom resolution with no recurrence at 4-year follow-up and no intraoperative or postoperative complications
    • Antibiotics may be used as adjunct therapy for infected cysts prior to definitive surgical management
• References:
  • Cetinkaya EA. Thornwaldt Cyst. J Craniofac Surg. 2018.
  • Righi S, Boffano P, Pateras D, et al. Thornwaldt Cysts. J Craniofac Surg. 2014.
  • Chang SL, Wu TC, Yiu CY. Tornwaldt’s Cyst Formation After Concurrent Chemoradiotherapy for Nasopharyngeal Carcinoma. J Laryngol Otol. 2006.
  • Sekiya K, Watanabe M, Nadgir RN, et al. Nasopharyngeal Cystic Lesions: Tornwaldt and Mucous Retention Cysts of the Nasopharynx: Findings on MR Imaging. J Comput Assist Tomogr. 2014.
  • Ikushima I, Korogi Y, Makita O, et al. MR Imaging of Tornwaldt’s Cysts. AJR Am J Roentgenol. 1999.
  • Turan S, Gürbüz MK, Kaya E, et al. Is Transnasal Endoscopic Marsupialization Sufficient in Thornwaldt Cysts? J Craniofac Surg. 2020.
    
    

1. Perioperative Immunotherapy – KEYNOTE-689 Continues to Shape Practice:
   • The KEYNOTE-689 phase 3 trial:
     • Which led to the FDA approval of perioperative pembrolizumab (June 2025):
       • For resectable locally advanced HNSCC with PD-L1 CPS ≥ 1:
         • Remains a central focus
     • New ASCO 2026 exploratory analyses demonstrate that the EFS benefit of neoadjuvant / adjuvant pembrolizumab:
       • Persists across surgical outcome subgroups, including:
         • Patients with and without extranodal extension or positive margins
       • Notably, fewer patients in the pembrolizumab arm had ENE or positive margins post-surgery:
         • Suggesting neoadjuvant pembrolizumab contributes to pathologic downstaging
   • A pooled meta-analysis of three phase 3 trials (KEYNOTE-689, NIVOPOSTOP, and IMvoke010; n=1,786) presented at ASCO 2026:
     • Confirmed a significant improvement in event-free / disease-free survival with perioperative or adjuvant PD-1 / PD-L1 blockade (pooled HR 0.79, 95% CI 0.68–0.91):
       • With no meaningful increase in treatment-related deaths

The following figure from the KEYNOTE-689 trial illustrates the event-free survival benefit across PD-L1 subgroups:

2. Neoadjuvant Bispecific Antibody Combinations: Ivonescimab Leads the Way:
   • Several ASCO 2026 abstracts highlight the emerging role of bispecific antibodies in the neoadjuvant setting:
     • Ivonescimab (PD-1 / VEGF bispecific) + nab-paclitaxel / cisplatin:
       • Achieved a remarkable 100% ORR:
         • 50% CR, 50% PR
       • Achieved a 50% pCR rate:
         • In 30 surgical patients with resectable LA-HNSCC
       • All patients with CPS >30 achieved pCR, and 100% laryngeal / pharyngeal preservation was achieved
   • A randomized phase II trial comparing ivonescimab (PD-1 / VEGF), cadonilimab (PD-1 /CTLA-4), and penpulimab (PD-1 alone), each combined with chemotherapy:
     • Showed the highest pCR rate with ivonescimab at 60%, compared to 42.1% with cadonilimab and 40% with single-agent PD-1
   • Adebrelimab (PD-L1 inhibitor) + chemotherapy demonstrated:
     • An 87.5% ORR and a 95.8% larynx preservation rate in resectable LA-HNSCC:
       • With all p16-positive and CPS ≥ 20 patients responding

3. Novel Agents in Recurrent / Metastatic HNSCC:
   • Bispecific antibodies are generating significant excitement in the recurrent / metastatic setting:
     • Ficerafusp alfa (EGFR × TGF-β) + pembrolizumab:
       • Two-year follow-up data showed a confirmed ORR of 54% in HPV-negative R/M HNSCC (21% CR), with a median DOR of 21.7 months and median OS of 21.3 months
         • The phase 2 / 3 FORTIFI-HN01 trial is now actively enrolling
     • Petosemtamab (EGFR × LGR5) + pembrolizumab:
       • Updated phase 2 data showed a 60% ORR (including 5 CRs) in first-line PD-L1+ R/M HNSCC, with median DOR of 11 months
         • Two phase 3 trials (LiGeR-HN1 and LiGeR-HN2) are recruiting
     • CRB-701 (Nectin-4 ADC):
       • A phase 1 / 2 study in heavily pretreated R/M HNSCC (85% refractory to immunotherapy and platinum):
         • Showed a confirmed ORR of 33.3% at both 2.7 and 3.6 mg/kg doses, regardless of HPV status
     • Becotatug vedotin (EGFR ADC):
       • A new randomized phase II trial is evaluating neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors in resectable LA-HNSCC

4. HPV-Directed Immunotherapy and De-escalation:
   • The TARGET-HPV trial presented at ASCO 2026:
     • Evaluated neoadjuvant HB200 (HPV16-specific viral immunotherapy) + carboplatin / paclitaxel in HPV16+ oropharyngeal SCC:
       • The deep response rate was 87.9%, with 86% of patients receiving de-escalated definitive therapy
       • At 23 months median follow-up, 2-year PFS was 86% and OS was 100%
       • Circulating tumor HPV-DNA was significantly associated with recurrence

5. Evolving First-Line R / M HNSCC Pipeline:
   • A landscape analysis presented at ASCO 2026 identified 145 active regimens (111 unique assets) in the first-line R / M HNSCC pipeline
   • Key trends include a shift toward chemotherapy-free combinations alongside PD-1 blockade:
     • With bispecific antibodies (10.8%), ADCs (10.8%), and cancer vaccines (9.0%) representing the most common novel modalities
   • Eight key phase 3 trials are underway:
     • All incorporating PD-1 as a target, with pembrolizumab as the backbone in 7 of 8

• Overall, ASCO 2026 highlights a transformative period in head and neck oncology:
  • With perioperative immunotherapy now established as a new standard, bispecific antibodies and ADCs showing compelling early efficacy, and biomarker-driven strategies (PD-L1 CPS, HPV status, ctHPV-DNA, MRD) increasingly guiding treatment selection

References

1. Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer. Uppaluri R, Haddad RI, Tao Y, et al. The New England Journal of Medicine. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434.
2. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma | FDA. Food and Drug Administration. 2025-06-13.
3. Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.. Adkins D, Haddad R, Tao Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6057. doi:10.1200/JCO.2026.44.16_suppl.6057.
4. Perioperative or adjuvant PD-1/PD-L1 blockade with curative-intent multimodality therapy for locally advanced head and neck squamous cell carcinoma: A systematic review and meta-analysis of randomized trials.. Daher S, Daher H, Altal H, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18074. doi:10.1200/JCO.2026.44.16_suppl.e18074.
5. Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.. Kunyu Yang, Xiaomeng Zhang and Lu Wen. Journal of Clinical Oncology. 2026;44(Suppl 16):6014. doi:10.1200/JCO.2026.44.16_suppl.6014.
6. Neoadjuvant immunotherapy in combination with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma: Updated efficacy and safety data from a randomized phase II trial.. Liu L, Chen F, Li Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6091. doi:10.1200/JCO.2026.44.16_suppl.6091.
7. Neoadjuvant adebrelimab plus chemotherapy in untreated locally advanced head and neck squamous cell carcinoma: Efficacy and biomarker insights from a single-arm phase 2 trial.. Fang R, Lei W, Huang B, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6106. doi:10.1200/JCO.2026.44.16_suppl.6106.
8. Ficerafusp Alfa (BCA101) With Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Two-Year Results of an Expansion Cohort of a Phase I/Ib Trial. Hanna GJ, Zandberg DP, Wong DJ, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2026;:JCO2502027. doi:10.1200/JCO-25-02027.
9. A multicenter, randomized, double-blind, phase 2/3 study of ficerafusp alfa (BCA101) or placebo in combination with pembrolizumab for first-line treatment of HPV-negative, PD-L1–positive, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): FORTIFI-HN01.. Ferrarotto R, Kaczmar J, Spigel D, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6129. doi:10.1200/JCO.2026.44.16_suppl.TPS6129.
10. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of PD-L1+ recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 trial. Herpen C, Daste A, Arrazubi V, et al. Journal of Clinical Oncology. 2025;43(Suppl 16):6024. doi:10.1200/JCO.2025.43.16_suppl.6024.
11. LiGeR-HN Phase III Trials of Petosemtamab + Pembrolizumab and Petosemtamab Monotherapy in Recurrent or Metastatic HNSCC. Machiels JP, Fayette J, Haddad R, et al. Future Oncology (London, England). 2025;21(16):2007-2016. doi:10.1080/14796694.2025.2511470.
12. A phase 1/2 study of the next-generation nectin-4–targeting antibody-drug conjugate CRB-701 (SYS6002) in patients with recurrent or metastatic head and neck squamous cell carcinoma.. Mantia C, Hanna G, Loriot Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6062. doi:10.1200/JCO.2026.44.16_suppl.6062.
13. A randomized, non-comparative, multicenter phase II trial of neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors (penpulimab/ivonescimab) in resectable locally advanced head and neck squamous cell carcinoma.. Wei X, Xiang Z, Zeng Y, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):TPS6135. doi:10.1200/JCO.2026.44.16_suppl.TPS6135.
14. Neoadjuvant HPV16-specific viral immunotherapy (HB200) plus chemotherapy with response-adapted de-escalation in HPV16+ oropharyngeal squamous cell carcinoma: TARGET-HPV trial.. Rosenberg A, Juloori A, Cursio J, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):6097. doi:10.1200/JCO.2026.44.16_suppl.6097.
15. Emerging trends in research strategies in the first-line recurrent or metastatic head and neck cancer (R/M SCCHN) landscape: A top-level analysis by Oncofocus.. Shukla A, Keeshara V, Chamaria M, et al. Journal of Clinical Oncology. 2026;44(Suppl 16):e18029. doi:10.1200/JCO.2026.44.16_suppl.e18029.
16. Recent Highlights and Breakthroughs in Immunotherapy for Head and Neck Cancers. Vuille JA, Szturz P. Current Opinion in Oncology. 2026;38(3):201-211. doi:10.1097/CCO.0000000000001211.
17. Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: The Current Status and Future Outlook. Köylü B, Selçukbiricik F, Aksoy S, Güven DC. Critical Reviews in Oncology/Hematology. 2026;:105145. doi:10.1016/j.critrevonc.2026.105145.

• 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