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The Phase III LEAP-10 trial represents a major collaborative effort between Merck & Co. and Eisai, addressing a persistent unmet need in recurrent /metastatic head and neck squamous cell carcinoma (R/M HNSCC).

In patients with PD-L1 CPS ≥1 disease, the combination of lenvatinib + pembrolizumab demonstrated:

• Improved objective response rate (ORR)
• Prolonged progression-free survival (PFS)

However, these gains did not translate into an overall survival (OS) benefit compared with pembrolizumab monotherapy, which remains the backbone of first-line treatment.

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Clinical Context: Why OS Remains Elusive

Despite encouraging activity, the absence of OS improvement reinforces the durability of the current standard established by KEYNOTE-048 trial, where:

• Pembrolizumab ± chemotherapy continues as standard of care
• Survival benefit is tightly linked to PD-L1 expression and patient selection

The LEAP-10 findings highlight a recurring challenge in HNSCC:

Early efficacy signals (ORR, PFS) do not reliably predict survival benefit, particularly in an immunotherapy-sensitive disease where post-progression treatments and tumor biology heavily influence OS.

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Biologic Interpretation

The addition of lenvatinib, a multi-kinase inhibitor targeting VEGFR, FGFR, and others, likely:

• Enhances tumor microenvironment modulation
• Improves initial tumor shrinkage and disease control

However, potential limitations include:

• Lack of deep, durable immune reprogramming
• Emergence of resistance mechanisms
• Possible toxicity-related treatment discontinuation

These factors may blunt long-term survival impact despite improved early endpoints.

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Where the Field Is Heading: EGFR and Beyond

Attention is now shifting toward next-generation EGFR-targeted strategies, with the hypothesis that:

• More precise targeting of EGFR-driven signaling
• Coupled with immune engagement mechanisms

may yield more durable survival benefits.

Key players advancing this space include:

• Dana-Farber Cancer Institute
• Genmab
• Bicara Therapeutics
• Johnson & Johnson
• Merus N.V.
• Harvard Medical School

Emerging modalities include:

• Bispecific antibodies (EGFR × immune targets)
• Antibody-drug conjugates (ADCs)
• Combination immunotherapy strategies

These approaches aim to:

• Overcome primary and acquired resistance
• Deliver more sustained immune activation
• Ultimately shift the OS curve, not just early endpoints

---

Key Takeaway for Clinical Practice

While lenvatinib + pembrolizumab shows meaningful biologic and clinical activity, it does not currently challenge pembrolizumab-based regimens as standard of care in PD-L1–positive R/M HNSCC.

The central question remains:

What therapeutic strategy will meaningfully and reproducibly improve overall survival in first-line HNSCC?

The next wave of EGFR-targeted and immune-engaging therapies may be the most promising path forward.

Maxillary Artery

• The maxillary artery supplies deep structures of the face.

• It branches from the external carotid artery just deep to the neck of the mandible.

• Structure:

  • The maxillary artery, the larger of the two terminal branches of the external carotid artery:

    • Arises behind the neck of the mandible, and is at first imbedded in the substance of the parotid gland.

  • It passes forward between the ramus of the mandible and the sphenomandibular ligament, and then runs, either superficial or deep to the lateral pterygoid muscle, to the pterygopalatine fossa.

  • It supplies the deep structures of the face.

• May be divided into:

  • Mandibular portion (first part / bony part)

  • Pterygoid portion (second part / muscular part)

  • Pterygopalatine portions (third part).

• Mandibular portion (first part / bony part):

  • The first or mandibular portion (or bony portion) passes horizontally forward, between the neck of the mandible and the sphenomandibular ligament:

    • Where it lies parallel to and a little below the auriculotemporal nerve.

    • It crosses the inferior alveolar nerve, and runs along the lower border of the lateral pterygoid muscle.

    • Branches include:

      • Deep auricular artery

      • Anterior tympanic artery

      • Middle meningeal artery

      • Inferior alveolar artery:

        • Which gives off its mylohyoid branch just prior to entering the mandibular foramen

      • Accessory meningeal artery

• Pterygoid portion (second part / muscular part):

  • The second or pterygoid portion (or muscular portion) runs obliquely forward and upward under cover of the ramus of the mandible and insertion of the temporalis muscle:

    • On the superficial (very infrequently on the deep) surface of the lateral pterygoid muscle.

    • It then passes between the two heads of origin of this muscle and enters the fossa.

  • Branches include:

    • Masseteric artery

    • Pterygoid branches

    • Deep temporal arteries:

      • Anterior and posterior

    • Buccal (buccinator) artery

• Pterygopalatine portions (third part):

  • The third or pterygopalatine portion lies in the pterygopalatine fossa in relation with the pterygopalatine ganglion.

  • This is considered the terminal branch of the maxillary artery.

  • Branches include:

    • Sphenopalatine artery:

      • Nasopalatine artery is the terminal branch of the maxillary artery

    • Descending palatine artery:

      • Greater palatine artery

      • Lesser palatine artery

    • Infraorbital artery

    • Posterior superior alveolar artery

    • Artery of pterygoid canal

    • Pharyngeal artery

    • Middle superior alveolar artery (could be a branch of the infraorbital artery)

    • Anterior superior alveolar arteries (could be a branch of the infraorbital artery)

 

 

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon at the Braman Comprehensive Cancer Center at Mount Sinai Medical Center in Miami, Florida.

He is first author on some publications on oral cavity cancer:

• Oral Tongue Cancer: Literature Review and Current Management 

  • https://www.oatext.com/pdf/CRR-2-153.pdf

• Understand Cancer: Research and Treatment Oral Cavity Cancer: Literature Review and Current Management. 

  • https://www.researchgate.net/publication/303366031_Understand_Cancer_Research_and_Treatment_Oral_Cavity_Cancer_Literature_Review_and_Current_Management

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

• The main trunk of the maxillary artery:
  • Is divided into three parts:
    • Which are named according to related structures along the artery’s course
  • These three parts are:
    • The mandibular division (1st part / bony part):
      • Named as such because it winds around deep to the neck of the mandible
    • The pterygoid division (2nd part / muscular part):
      • It has this name because it travels between the two heads of the lateral pterygoid muscle
    • The pterygopalatine division (3rd part):
      • This part derived its name from the pterygopalatine fossa, into which it enters
  • Conventionally, these three parts are described as the:
    • Part before-, part on-, and part beyond the lateral pterygoid muscle
    • This is also useful since out of the 15 branches of the maxillary artery:
      • The five branches from the second part (part on the lateral pterygoid muscle):
        • Are regarded as branches to soft tissues:
          • That do not course through foramina in bones
      • However, the remaining 10 branches:
        • From the first and third parts:
          • Go through foramina in bones
• Course:
  • The maxillary artery:
    • Continues as one of the terminal divisions of the external carotid artery:
      • At the level of the neck of the mandible:
        • Passing forward between the neck of the mandible and the sphenomandibular ligament
      • It continues its path by running deeply to the lower head and passes forward between the two heads of the lateral pterygoid muscle:
        • To break into its terminal branches at the pterygopalatine fossa

• Maxillary artery branches:
  • Branches of the first (mandibular) division:
    • The deep auricular artery:
      • Is the first branch of the mandibular part:
        • This branch runs upwards to enter the ear and courses superficially to the tympanic membrane, passing between the cartilage and bone
      • It supplies the external acoustic meatus of the ear and the deep surface of the tympanic membrane
      • The anterior tympanic artery:
        • Is the second branch that courses near the tympanic membrane
        • It passes deep to the membrane:
          • Through the petrotympanic fissure to the middle ear:
            • To join the circular anastomosis around the tympanic membrane
      • The middle meningeal artery:
        • Passes straight upwards through the foramen spinosum:
          • To join the two roots of the auriculotemporal nerve
        • It supplies bones of the skull (calvaria) and the dura mater
      • The inferior alveolar artery:
        • Runs inferiorly and anteriorly towards the inferior alveolar nerve:
          • To meet the nerve at the inferior alveolar (a.k.a. mandibular) foramen
        • The artery runs further anteriorly in the mandible:
          • Supplying the pulps of the mandibular teeth (with its dental branches) and the body of the mandible
        • Its other branch, the mental branch:
          • Emerges from the mental foramen and supplies the lower lip and skin of the chin 
      • The accessory meningeal artery:
        • Is the main source of blood supply to the trigeminal ganglion
        • It passes upwards through the foramen ovale to supply the dura mater of the floor of the middle fossa and of the trigeminal cave (Meckel’s cave)
  • Branches from the 2nd (pterygoid / muscular) segment:
    • All branches from the pterygoid part supply only soft tissues
    • The masseteric artery:
      • Accompanies the lingual nerve
      • It is small, and passes laterally through the mandibular notch to the deep surface of the masseter muscle
    • The pterygoid arteries:
      • Are small branches that vary in number
      • They supply the lateral pterygoid muscle and medial pterygoid muscle
    • The deep temporal arteries:
      • Course between the temporalis muscle and the pericranium
      • The main function of this branch is to:
        • Provide arterial supply to the temporalis muscle
    • The buccal (buccinator) artery:
      • Runs obliquely forward, between the medial pterygoid muscle and the insertion of the temporalis muscle, to the outer surface of the buccinator muscle
      • It mainly supplies the:
        • Buccinator muscle
      • Along its course, it forms anastomoses with branches of the facial and infraorbital arteries
  • Branches from the 3rd (pterygopalatine) segment:
    • The sphenopalatine artery:
      • Mainly supplies the nasal cavity:
        • Which is why it is also referred to as the nasopalatine artery
      • It passes through the sphenopalatine foramen and enters the nasal cavity
      • Here it gives off its posterior lateral nasal branches
      • Crossing the inferior surface of the sphenoid:
        • The sphenopalatine artery ends on the nasal septum giving off the posterior septal branches
    • The descending palatine artery:
      • Descends through the greater palatine canal:
        • With the greater and lesser palatine branches:
          • Of the pterygopalatine ganglion
        • It terminates by dividing into the greater and lesser palatine arteries:
          • That provide blood supply for the hard palate and soft palate, respectively
    • The infraorbital artery:
      • Passes forwards through the inferior orbital fissure:
        • Along the floor of the orbit and infraorbital canal:
          • To emerge with the infraorbital nerve on the face.
    • The posterior superior alveolar artery:
      • Supplies the maxillary teeth
      • It gives branches that accompany the corresponding nerves through foramina in the posterior wall of the maxilla
    • The middle superior alveolar artery:
      • Is most often a branch of the infraorbital artery
      • It arises within the infraorbital canal:
        • Where it descends to supply the maxillary sinus and plexus at the level of the canine tooth
    • The pharyngeal artery:
      • Supplies structures such as the pharynx and roof of the nose
    • The anterior superior alveolar artery:
      • Is branch of the infraorbital artery. 
    • The artery of the pterygoid canal:
      • Runs into the pterygoid canal:
        • It passes backwards along the pterygoid canal with the corresponding nerve
      • It supplies the upper part of the pharynx, and sends a small division into the tympanic cavity to anastomose with the tympanic arteries
        
        
        
        

The proximity or direct extension of a primary tumor of the oral cavity to the mandible requires appropriate radiological studies to establish the presence and extent of bone involvement:

• Although the absence of radiographic findings does not rule out bone invasion:

  • Bone destruction as seen on the radiograph confirms tumor invasion

• Radionuclide bone scans:
  • Often are positive before the radiographic appearance of bone destruction:
    • But they seldom provide accurate information regarding the extent of bone invasion
  • Bone scans also may be positive in non-neoplastic conditions:
    • Such as inflammatory lesions
• Plain radiographs of the mandible in the antero-posterior and oblique views:
  • Are not satisfactory as a routine screening test to establish or rule out bone destruction
• A panoramic view of the mandible (an orthopantomogram):
  • Is helpful to assess the general architecture of the mandible in relation to the dento-alveolar structures and invasion by the tumor (Figure)

• However, for technical reasons:

  • The midline of the mandible near the symphysis is not adequately evaluated by a panoramic view

  • In addition, early invasion of the lingual cortex of the mandible is not seen on a panoramic view

  • Occlusal films of the body of the mandible and intraoral dental films:

    • Often are most accurate in demonstrating early invasion by a tumor

      
      
• CT scans of the mandible:
  • Generally are not optimal for routine screening:
    • But may be considered in certain circumstances:
      • Such as primary tumors of the mandible and lesions where soft tissue extension from tumors involving the ascending ramus of the mandible is suspected (Figure)

Three-dimensional reconstructions of CT images provide an excellent overview of the mandible or maxilla from any desired angle

• A computerized tomogram of the oral cavity and neck:
  • Is the standard initial radiographic study for assessment of locoregional extent of the tumor
  • It allows comprehensive evaluation of neck nodes and also the relationship of the primary tumor to adjoining bone:
    • Especially in situations such as primary tumors of the mandible and lesions where soft-tissue extension from tumors involving the ascending ramus of the mandible is suspected

• Three-dimensional reconstructions of the mandible of a patient with an ossifying fibroma of the body of the mandible on the left-hand side causing expansion and involving the lingual cortex are shown in the Figures

  
  

 

 

• A three-dimensional CT scan and a one-to-one reproduction of the CT scan:

  • Are of great value to the surgeon for mandible reconstruction with a microvascular free flap

• The decision to extend a supraomohyoid neck dissection (levels I to III) to include level IV (extended supraomohyoid neck dissection):
  • Hinges on whether pN+ disease is discovered in levels I to III, the number of positive nodes, and the pN classification
    • Below is a comprehensive review of the specific scenarios and supporting data
• Scenario 1 – cN0 Neck → Intraoperative Discovery of pN+ Disease in Levels I to III:
  • This is the most clinically relevant scenario
  • When a patient undergoes END for a cN0 neck and positive nodes are found on frozen section or final pathology:
    • The risk of concurrent level IV to V disease rises substantially compared to the overall cN0 population
  • The Haas et al. (2025) study directly addressed this question in 61 cN0 patients who were found to be pN+ in levels I to III [1]:
    • 9.8% (6/61) had metastases in levels IV to V:
      • Well above the 5% threshold generally used to justify elective dissection
      • > 1 positive node in levels I to III was the strongest predictor of level IV to V involvement (p = 0.027)
      • pN classification > pN2b significantly increased the prevalence of level IV to V metastases (p = 0.002)
      • Extracapsular spread (ECS) showed a trend toward increased IV to V involvement (p = 0.078), though not statistically significant in this cohort
      • This 9.8% rate stands in stark contrast to the 0.50% true skip metastasis rate in the overall cN0 population, underscoring that the discovery of pN+ disease in levels I to III fundamentally changes the risk calculus
• Scenario 2 – cN+ Neck (Preoperatively Known Nodal Disease):
  • For the clinically node-positive neck, both ASCO and NCCN guidelines explicitly recommend including level IV in the dissection [2][3]
  • The ASCO guideline states:
    • An ipsilateral therapeutic selective neck dissection for a cN+ neck should include:
      • Nodal levels Ia, Ib, IIa, IIb, III, and IV with ≥ 18 lymph nodes (evidence-based, intermediate quality, moderate strength) [2]
    • The NCCN guidelines specify:
      • cN1 to cN2a–c disease warrants selective or comprehensive neck dissection [3]
  • The American Head and Neck Society review provides the supporting data:
    • Occult level IV nodal metastatic disease is reported in 11.1% to 23.7% of cN+ oral tongue cancers, and 15% of all patients undergoing therapeutic neck dissection had level IV metastases [4]:
      • This rate is high enough that level IV dissection should be considered even in the absence of overt metastatic lymph node involvement at that level [4]
• Scenario 3 – When to Add Level V:
  • Level V dissection carries significant risk to the spinal accessory nerve and is not routinely recommended
  • However, the data support its inclusion in specific circumstances [4]:
    • Clinical involvement of levels I to IV:
      • Was associated with occult metastases in level V in 27% of oral cavity SCCs in one study
    • Level V should be considered in patients with bulky, multilevel nodal disease
  • The overall rate of level V metastasis:
    • In therapeutic neck dissections is only ~4%
• Practical Decision Framework – When to Extend to Level IV:
  • Prognostic Implications of Level IV Disease:
    • Importantly, the discovery of level IV or V disease is not merely an anatomic finding:
      • It carries significant prognostic weight
    • The NCCN guidelines list nodal disease in levels IV or V as an adverse pathologic feature:
      • Which triggers consideration of adjuvant systemic therapy / RT [3]
    • A SEER-based study of 8,281 patients:
      • Found that 5-year disease-specific survival dropped from 42.0% for level I to III disease to 30.6% for level IV [5]
    • Furthermore, level IV to V metastasis:
      • Is an independent risk factor for distant metastasis on multivariate analysis [6]
• Morbidity Considerations:
  • Extension to level IV is not without cost
  • The American Head and Neck Society review notes that dissection of level IV:
    • Is associated with a low but possible risk of injury to the phrenic nerve or brachial plexus and increases the risk of chylous fistula [4]:
      • These risks must be weighed against the oncologic benefit, particularly in the cN0 setting where the absolute risk of level IV disease is low
• Summary:
  • For the cN0 neck with no intraoperative evidence of nodal disease:
    • Levels I to III remain the standard
  • However, when intraoperative frozen section or final pathology reveals pN+ disease:
    • Particularly > 1 positive node or pN > pN2b:
      • The risk of level IV to V involvement rises to ~10%:
        • Justifying extension to level IV [1]
  • For any preoperatively cN+ neck:
    • Level IV should be included as standard practice per ASCO and NCCN guidelines [2][3]
  • Level V should be reserved for:
    • Multilevel, bulky nodal disease
• References:
  • 1. In Vivo Probability of Metastases in Levels IV-V in Oral Squamous Cell Carcinoma With a cN0/pN+ Situation in Levels I-Iii. Haas L, Mischkowski RA, Knape U, Król KM, Sakkas A. In Vivo (Athens, Greece). 2025 Nov-Dec;39(6):3437-3444. doi:10.21873/invivo.14141.
  • 2. Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline. Koyfman SA, Ismaila N, Crook D, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2019;37(20):1753-1774. doi:10.1200/JCO.18.01921.
  • 3. Head and Neck Cancers. National Comprehensive Cancer Network. Updated 2025-12-08.
  • 4. Oral Cavity Cancer Surgical and Nodal Management: A Review From the American Head and Neck Society. Eskander A, Dziegielewski PT, Patel MR, et al. JAMA Otolaryngology– Head & Neck Surgery. 2024;150(2):172-178. doi:10.1001/jamaoto.2023.4049.
  • 5. Impact of Nodal Level Distribution on Survival in Oral Cavity Squamous Cell Carcinoma: A Population-Based Study. Marchiano E, Patel TD, Eloy JA, Baredes S, Park RC. Otolaryngology–Head and Neck Surgery : Official Journal of American Academy of Otolaryngology-Head and Neck Surgery. 2016;155(1):99-105. doi:10.1177/0194599816636356.
  • 6. Risk Factors for Distant Metastasis in Locoregionally Controlled Oral Squamous Cell Carcinoma: A Retrospective Study. Tomioka H, Yamagata Y, Oikawa Y, et al. Scientific Reports. 2021;11(1):5213. doi:10.1038/s41598-021-84704-w.

• 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 approximately 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, 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.  

• The 15.8% skip metastasis rate reported by Byers et al. (1997):
  • Is widely considered an overestimate due to several important methodological issues that have been carefully dissected in subsequent literature:
    • Most notably by Warshavsky et al. in their 2019 JAMA Otolaryngology meta-analysis [1][2]
• What Byers Reported:
  • Byers et al. reviewed 277 previously untreated patients with oral tongue SCC (1970 to 1990):
    • Who underwent glossectomy and neck dissection
  • They reported that 15.8% of all patients had either:
    • Level IV metastasis as the only manifestation of neck disease
    • Level III as the only positive node without disease in levels I to II
    • Subsequent level IV recurrence after initial dissection that did not include level IV
  • Based on this, they recommended routine dissection of levels I to IV for all oral tongue SCC [2]
• Why the 15.8% Figure Is Misleading:
  • Warshavsky et al. performed a careful reanalysis of the Byers data and identified several critical flaws that inflated the rate [1]:
    • Conflation of skip metastasis definitions:
      • Byers combined true level IV skip metastasis with level III skip metastasis (level III positive without levels I to II involvement):
        • These are fundamentally different clinical scenarios — level III disease is already captured by a standard supraomohyoid neck dissection (levels I to III)
        • By lumping both together, the rate was artificially elevated
    • Inclusion of neck recurrences as “skip metastases”:
      • Nine patients (9.9%) who developed level IV recurrences after an initial dissection that did not include level IV were counted toward the 15.8% figure:
        • As Warshavsky et al. noted, counting neck recurrence as a missed pathological lymph node is problematic because the neck has lost its normal anatomical lymphatic drainage and, in many cases, has been irradiated
        • This makes it impossible to determine whether these were true skip metastases or recurrences from altered lymphatic flow [1]
    • True level IV skip metastasis rate was only 5.5%:
      • When the data are restricted to patients with cN0 disease who had level IV metastasis found in the initial neck dissection specimen (i.e., true pathologic skip metastasis):
        • The rate drops to 5.5% — roughly one-third of the reported figure [1]
      • Even the most generous calculation yields only 4.8%:
        • When accounting for all cases mentioned in the study (both initial pathologic findings and subsequent recurrences), the combined incidence of skip metastasis or subsequent recurrence in level IV was only 4.8% (13 of 270), not 15.8% [1]
  • Mixed cN0 and cN+ populations:
    • The study included patients across all clinical N stages, and the data were not clearly stratified by preoperative nodal status, making it difficult to isolate the true elective (cN0) skip metastasis rate
  • Era of the study (1970 to 1990):
    • Preoperative imaging was far less sophisticated, meaning some patients classified as cN0 may have had undetected nodal disease, further confounding the results
• What Modern Data Shows:
  • The Warshavsky et al. meta-analysis of 13 studies (1,359 cN0 patients):
    • Found the true skip metastasis rate to level IV is only 0.50% (95% CI, 0.09%–1.11%):
      • With an overall level IV involvement rate of 2.53% [1]
    • Even for oral tongue specifically — the highest-risk subsite:
      • The level IV involvement rate was 3.60% [1]
  • A large Tata Memorial audit of 761 early-stage cN0 patients:
    • Found skip metastasis to level IV in only 0.3% [3]
• In summary, the Byers 15.8% figure resulted from a broad definition of “skip” that included level III skips (already addressed by SOHND), conflation of initial pathologic findings with subsequent recurrences, and lack of stratification by preoperative nodal status:
• Modern evidence overwhelmingly supports that true skip metastasis to level IV in cN0 oral tongue SCC is a rare event (~0.5%), and supraomohyoid neck dissection (levels I to III) remains adequate for the elective setting
• References:
  • 1. Assessment of the Rate of Skip Metastasis to Neck Level IV in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma: A Systematic Review and Meta-analysis. Warshavsky A, Rosen R, Nard-Carmel N, et al. JAMA Otolaryngology– Head & Neck Surgery. 2019;145(6):542-548. doi:10.1001/jamaoto.2019.0784.
  • 2. Frequency and Therapeutic Implications of “Skip Metastases” in the Neck From Squamous Carcinoma of the Oral Tongue. Byers RM, Weber RS, Andrews T, et al. Head & Neck. 1997;19(1):14-9. doi:10.1002/(sici)1097-0347(199701)19:13.0.co;2-y.
  • 3. Incidence and Impact of Skip Metastasis in the Neck in Early Oral Cancer: Reality or a Myth?. Gurmeet Singh A, Sathe P, Roy S, et al. Oral Oncology. 2022;135:106201. doi:10.1016/j.oraloncology.2022.106201.

• The basis and need for elective nodal treatment in head and neck cancer:
  • Have been based largely on surgical series evaluating pathologic nodal involvement found on elective neck dissection in patients with clinically negative necks
• In a consecutive series of 1,081 head and neck cancer patients undergoing radical neck dissection:
  • The incidence of pathologic node involvement:
    • Was 33% among those undergoing elective neck surgery
  • The pathologic findings identified the nodal stations at risk by tumor site:
    • To establish the rationale for selective neck dissection (SND) as the elective surgical procedure
• Several reports have summarized the risk for metastases and nodal stations at risk
• Some general observations from such data can be made:
  • Regarding larynx cancers:
    • Candela reported the Memorial Sloan Kettering Cancer Center (MSKCC) experience in determining the patterns of cervical nodal metastases in 247 larynx cancer patients undergoing radical neck dissections:
      • Seventy-eight underwent elective radical neck dissection whereas 118 underwent immediate radical dissection for clinically node-positive disease
      • The majority of patients (n = 189) were supraglottic larynx and 58 were glottic
      • Pathologic nodal involvement:
        • Was found in 37% undergoing elective neck dissection
      • It is noted that cervical nodes spread in a similar fashion whether the patients are clinically node negative or positive:
        • With predominant involvement of:
          • Level II and III jugular nodes
      • In clinically node-negative patients:
        • The incidence of involvement of level I and V:
          • Is less than 5% with less than 10% involvement of level IV
      • In node-positive patients:
        • The incidence of level IV node increases from 15% to 31% with greater involvement of levels II and III
      • In clinically node-positive patients:
        • Very rarely did patients present with isolated level I nodal metastases without involvement of the jugular nodes
• Shah and Candela reported that among oropharynx or hypopharynx cancers:
  • Treated with elective radical neck dissection:
    • Occult metastases are found in 26%
  • Level I and V were involved in only 1.4%:
    • Always in association with nodal disease at level II to IV
  • No skip metastases were reported
  • Among oropharynx patients:
    • Levels II to IV were predominantly involved
  • Among hypopharynx lesions:
    • The primary levels involved were levels II and III
  • In patients clinically node positive undergoing therapeutic neck dissection:
    • The incidence of level I and V involvement increased to about 10% to 15%:
      • However, levels II to IV were predominantly involved
    • Level V involvement:
      • Only occurred in association with nodal involvement at levels II to IV
    • Whereas the incidence isolated level I involvement without levels II to IV involvement (“skip metastasis”):
      • Occurred in 0.4%:
        • Thus, based on these studies, elective treatment of the neck in oropharynx or hypopharynx can be directed at levels II to IV
• Among oral cavity patients:
  • The incidence of nodal disease was 34% on elective evaluation
  • The majority of metastatic nodes involved:
    • Levels I to III:
      • With only 1.5% incidence of skip metastasis to level IV
  • Level V involvement:
    • Is found in only 0.5% with occult disease simultaneously involving other levels
  • Among those undergoing therapeutic neck dissections:
    • The incidence of level IV involvement increased to 20%
    • Level V was 4% always restricted to lower gum or floor of mouth primary sites
• The need for elective treatment not only relates to the estimated probability of nodal involvement and usually is implemented when the risk is 20% or greater but also relates to the morbidity of such treatment as well as the adequacy of coverage

• Indications for END:
  • Depth of Invasion (DOI) Thresholds:
    • DOI is the single most important predictor:
      • Guiding the decision to perform END in cN0 oral cavity SCC
    • The NCCN Guidelines stratify the decision as follows [1]:
      • DOI 3 mm:
        • END should be strongly considered if RT is not already planned (supported by level 1 evidence from the D’Cruz / Tata Memorial trial)
      • The landmark D’Cruz et al. (2015) randomized trial of 500 patients with cT1 to T2 cN0 oral cavity SCC:
        • Demonstrated that upfront END significantly improved 3-year overall survival (80.0% vs. 67.5%) and disease-specific survival (69.5% vs. 45.9%) compared to therapeutic neck dissection [2]
        • Post hoc analysis showed no benefit for tumors with DOI ≤ 3 mm, while 28% of cN0 necks with DOI >3 mm harbored occult metastases [3]
      • A 2025 meta-analysis of 17 studies (2,263 patients):
        • Confirmed END reduces regional recurrence (RR 0.47) and improves OS (RR 0.75) and DSS (RR 1.32) [4]
    • A validation study of 300 patients:
      • Confirmed that DOI ≥ 4 mm is the optimal ROC-derived threshold (95.1% sensitivity, 52.9% specificity) for predicting occult nodal metastasis:
        • With regional recurrence-free survival significantly higher in the END group for DOI ≥ 4 mm (p = 0.002) [5]
    • A recent systematic review found:
      • Diagnostic thresholds converging around 4 mm for mixed oral cavity sites and 3 mm for high-risk subsites (floor of the mouth) [6]
• The ASCO Clinical Practice Guideline (2019) recommends [2]:
  • cT2 to cT4, cN0:
    • Ipsilateral END should be performed (strong recommendation, high-quality evidence)
  • cT1, cN0:
    • Ipsilateral END should be performed:
      • Alternatively, close surveillance with specialized ultrasound may be offered for selected highly reliable patients
• Tumor Size Considerations:
  • Under AJCC 8th edition staging, both surface size and DOI determine T classification [1]:
    • T1:
      • ≤ 2 cm with DOI ≤ 5 mm
    • T2:
      • ≤ 2 cm with DOI > 5 mm
      • > 2 cm and ≤ 4 cm with DOI ≤ 10 mm
    • T3 to T4:
      • T3:
        • > 4 cm
        • DOI > 10 mm
      • Locally advanced tumors carry ~40% to 50% risk of occult nodal metastases, making END essentially mandatory [2]
  • DOI cutoffs are more predictive of overall survival than T category based on tumor surface size alone [3]:
    • For T1 tumors, those with DOI ≤ 2 mm rarely demonstrate occult neck disease:
      • While DOI ≥ 2 mm confers at least a 20% risk of pN+ disease [3]
• Subsite-Specific Considerations:
  • Oral Tongue:
    • The most extensively studied subsite
    • DOI ≥ 3 mm to 4 mm:
      • Is the standard threshold for END [3]
    • Higher propensity for skip metastases:
      • To level III (17.5% of specimens) compared to other subsites
    • Anterior tongue tumors at / near midline:
      • Warrant consideration for bilateral neck dissection [1]
  • Floor of Mouth (FOM):
    • FOM tumors cross the critical 20% threshold for nodal metastasis at a lower DOI (≥ 2 mm) compared to oral tongue (≥ 4 mm):
      • Based on a study of 343 patients:
        • 41.7% nodal metastasis rate for FOM tumors 2.1 mm to 4 mm thick vs. 11.2% for tongue tumors of similar thickness [7]
    • FOM primaries have a predisposition for contralateral metastases even at earlier T stages:
      • With a 50% higher risk of contralateral metastasis and 2.6-times higher risk when FOM invasion / extension is present [3][2]
    • However, a more recent study of 825 patients:
      • Found no significant difference in the incidence of or correlation between DOI and nodal metastases when FOM was compared to other subsites [8]
    • SLN biopsy accuracy:
      • Is lower for FOM than for tongue primaries [1]
  • Buccal Mucosa:
    • Behaves more aggressively:
      • With occult metastasis rates as high as 32% and up to 43% presenting with clinical / radiographic nodal disease [3]
    • END is recommended for all buccal cases:
      • Irrespective of DOI given higher rates of nodal metastases even in early T-category disease [3]
    • A multicenter study of 101 patients confirmed END improved survival in pT2, cN0 buccal SCC:
      • 123 months vs. 26 months, p = 0.009) [9]
    • END demonstrated improved:
      • Locoregional recurrence-free rates (61% vs. 38%, p = 0.042)
      • 5-year DFS (75% vs. 63%, p = 0.019) [10]
  • Other Subsites (Alveolar Ridge, Retromolar Trigone, Hard Palate):
    • Generally follow the same DOI-based principles
    • Hard palate and upper gingiva:
      • May not lend themselves well to SLN biopsy [1]
• Levels of Dissection: I to III vs. I to IV:
  • This is the NCCN treatment algorithm for cT1 to cT2, N0 oral cavity SCC:
    • For the cN0 neck:
      • The standard END is a supraomohyoid neck dissection (SOHND) encompassing levels I to III
    • Both the NCCN and ASCO guidelines recommend at minimum:
      • Levels Ia, Ib, II, and III, with an adequate yield of ≥ 18 lymph nodes [1][2]
    • Two randomized trials comparing SOHND (levels I to III) versus modified radical neck dissection (levels I to V):
      • Showed the adequacy of SOHND, with more extensive dissection increasing morbidity (particularly shoulder dysfunction) without survival or recurrence benefit:
        • Only 3.7% of occult metastases were detected in levels IV and V [2]
    • The American Head and Neck Society review consolidates the recommendation:
      • Level I to III dissection in the cN0 setting, with consideration of level IV inclusion in higher-risk tumors [3]
• Skip Metastasis to Level IV:
  • The Key Data:
    • The Warshavsky et al. (2019) systematic review and meta-analysis in JAMA Otolaryngology (13 studies, 1,359 patients) provides the most comprehensive data [11]:
      • Overall rate of level IV involvement in cN0 patients:
        • 2.53% (95% CI, 1.64%–3.55%)
      • True skip metastasis rate:
        • Level IV positive without levels I to III involvement): 0.50% (95% CI, 0.09%–1.11%)
  • Subgroup by T stage:
    • Level IV involvement was 0% for stages I to II and 0% for stages III to IV in the skip metastasis analysis
  • Oral tongue subsite:
    • Level IV involvement was notably higher at 3.60% (95% CI, 2.09%–5.42%):
      • The only subsite with significant findings
    • A large audit of 1,004 cases:
      • Confirmed skip metastases to level IV were 2.2% for tongue and 1.2% for gingivobuccal primaries [12]
    • A 2024 study of 544 early-stage oral tongue SCC patients:
      • Found only 1.3% had nodal involvement of level IV or V, concluding that END of levels I to III is sufficient [13]
    • A recent 2026 study directly comparing outcomes of END levels I to III vs. I to IV in 120 oral tongue SCC patients found [14]:
      • Only 1 of 33 patients (3%) undergoing level I to IV dissection had level IV metastasis
      • No significant difference in regional recurrence (21.8% vs. 18.2%, p = 0.66), level IV recurrence (3.5% vs. 3%, p = 0.91), or 5-year OS (69.3% vs. 61.1%, p = 0.7)
    • However, one study of 111 T1 / T2 N0 oral tongue SCC patients:
      • Found a 6.3% occult metastasis rate to level IV:
        • Arguing that extended SOHND covers this risk [15]
    • Additionally, when levels I to III are already pN+:
      • The risk of level IV to V metastases rises to 9.8%:
        • Particularly with > 1 positive node or pN classification > pN2b [16]
• Summary of Frequency of Nodal Metastasis by Level:
  • A meta-analysis of 17 studies found the following frequencies of lymph node metastasis across all OSCC [17] – Figure
• Clinical Synthesis:
  • For the cN0 neck, levels I to III dissection is the standard of care across all oral cavity subsites
  • The evidence does not support routine inclusion of level IV given the extremely low rate of true skip metastasis (0.50% overall)
  • For oral tongue SCC specifically:
    • The slightly higher rate of level IV involvement (3.60%) has prompted some authors to advocate for level IV inclusion:
      • But direct comparative studies show no survival or recurrence benefit from extending to level IV [14]
  • Level IV should be considered in higher-risk scenarios:
    • pN+ disease in levels I to III (especially multistation), greater DOI, or adverse pathologic features
  • For the cN+ neck:
    • Therapeutic dissection should include levels I to IV:
      • With level V considered in multistation disease [2]
• References:
  • 1. Head and Neck Cancers. National Comprehensive Cancer Network. Updated 2025-12-08.
  • 2. Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline. Koyfman SA, Ismaila N, Crook D, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2019;37(20):1753-1774. doi:10.1200/JCO.18.01921.
    
  • 3. Oral Cavity Cancer Surgical and Nodal Management: A Review From the American Head and Neck Society. Eskander A, Dziegielewski PT, Patel MR, et al. JAMA Otolaryngology– Head & Neck Surgery. 2024;150(2):172-178. doi:10.1001/jamaoto.2023.4049.
  • 4. Impact of Elective Cervical Dissection on the Prognosis of Patients With Oral Squamous Cell Carcinoma cT1/T2N0: A Systematic Review and Meta-Analysis. Binda NC, Lavareze L, de Souza Vieira G, et al. Critical Reviews in Oncology/Hematology. 2025;:104982. doi:10.1016/j.critrevonc.2025.104982.
  • 5. Depth of Invasion in Early Stage Oral Cavity Squamous Cell Carcinoma: The Optimal Cut-Off Value for Elective Neck Dissection. van Lanschot CGF, Klazen YP, de Ridder MAJ, et al. Oral Oncology. 2020;111:104940. doi:10.1016/j.oraloncology.2020.104940.
  • 6. Elective Neck Dissection Strategies Guided by AJCC-8 Depth-of-Invasion (DOI) in cT1-T2N0 Oral Cavity Cancer-a Systematic Review. Abdul NS, Shivakumar S, Alreshaid L, et al. Cancers. 2026;18(4):697. doi:10.3390/cancers18040697.
  • 7. Tumour Thickness as a Predictor of Nodal Metastases in Oral Cancer: Comparison Between Tongue and Floor of Mouth Subsites. Balasubramanian D, Ebrahimi A, Gupta R, et al. Oral Oncology. 2014;50(12):1165-8. doi:10.1016/j.oraloncology.2014.09.012.
  • 8. The Relative Propensity for Regional Metastasis in Floor of Mouth Squamous Cell Carcinoma Versus Other Oral Cavity Subsites. Wicks C, Zubair F, Ogunbowale A, McMahon J. The British Journal of Oral & Maxillofacial Surgery. 2022;60(9):1276-1278. doi:10.1016/j.bjoms.2022.07.012.
  • 9. Management of the Neck in T1 and T2 Buccal Squamous Cell Carcinoma. Nicholson OA, Van Lanschot CGF, van den Besselaar BN, et al. International Journal of Oral and Maxillofacial Surgery. 2024;53(4):259-267. doi:10.1016/j.ijom.2023.07.004.
  • 10. What Is the Role of Elective Neck Dissection in the Management of Patients With Buccal Squamous Cell Carcinoma and Clinically Negative Neck?. Dillon JK, Villing AS, Jones RS, et al. Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2019;77(3):641-647. doi:10.1016/j.joms.2018.10.021.
  • 11. Assessment of the Rate of Skip Metastasis to Neck Level IV in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma: A Systematic Review and Meta-analysis. Warshavsky A, Rosen R, Nard-Carmel N, et al. JAMA Otolaryngology– Head & Neck Surgery. 2019;145(6):542-548. doi:10.1001/jamaoto.2019.0784.
  • 12. Nodal Yield and Topography of Nodal Metastases From Oral Cavity Squamous Cell Carcinoma – An Audit of 1004 Cases Undergoing Primary Surgical Resection. Roy P, Mallick I, Arun I, et al. Oral Oncology. 2021;113:105115. doi:10.1016/j.oraloncology.2020.105115.
  • 13. Risk Factors and Impact of Occult and Skip Metastasis in Early-Stage Oral Tongue Squamous Cell Carcinoma. Yang X, Xiang W, Sun Y, et al. Clinical Oral Investigations. 2024;28(9):510. doi:10.1007/s00784-024-05897-8.
  • 14. The Prognostic Significance of Elective Level 4 Neck Dissection in Oral Tongue Cancer. Yosefof E, Edri N, Ritter A, et al. Journal of Surgical Oncology. 2026;133(4):459-464. doi:10.1002/jso.70191.
  • 15. How Adequate Is Supraomohyoid Neck Dissection for Node-Negative Oral Tongue Squamous Cell Carcinoma?. Sharma R, Singh N, Joshi KD, Sr A, Patrikar S. Journal of Cranio-Maxillo-Facial Surgery : Official Publication of the European Association for Cranio-Maxillo-Facial Surgery. 2025;:S1010-5182(25)00102-7. doi:10.1016/j.jcms.2025.03.006.
  • 16. In Vivo Probability of Metastases in Levels IV-V in Oral Squamous Cell Carcinoma With a cN0/pN+ Situation in Levels I-Iii. Haas L, Mischkowski RA, Knape U, Król KM, Sakkas A. In Vivo (Athens, Greece). 2025 Nov-Dec;39(6):3437-3444. doi:10.21873/invivo.14141.
  • 17. Frequency of Lymph Node Metastases at Different Neck Levels in Patients With Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Yu YF, Cao LM, Li ZZ, et al. International Journal of Surgery (London, England). 2025;111(1):1285-1300. doi:10.1097/JS9.0000000000001953.

• Big Picture:
  • AJCC 8th Edition (2017):
    • Introduced Depth of Invasion (DOI) as a major determinant of T stage in oral cavity squamous cell carcinoma (OCSCC)
  • AJCC 9th Edition (2024 / 2025 update):
    • Retains DOI as a core component of T staging, with refinements and clarifications, not a paradigm shift

• Key Concepts Introduced:
  • DOI ≠ tumor thickness
  • DOI measured from basement membrane of adjacent normal mucosa
  • DOI strongly correlates with:
    • Nodal metastasis
    • Survival
• AJCC 9th Edition (What Changed?):
  • DOI Thresholds: UNCHANGED
    • The 5 mm and 10 mm cutoffs remain identical
    • DOI continues to upstage tumors independent of surface dimensions
    • This is critical:
      • No numeric change in DOI staging thresholds
  • Clarification of Measurement Technique:
    • The 9th edition places stronger emphasis on standardization and reproducibility:
      • Clearer distinction between:
        • Exophytic tumors (avoid overestimation)
        • Ulcerated lesions (reconstruct mucosal surface)
      • Addresses interobserver variability among pathologists
      • Reinforces:
        • Measurement from reconstructed basement membrane line
  • Integration With Other Risk Factors:
    • While DOI remains central, AJCC 9 emphasizes its interpretation within a broader biologic context:
      • DOI alone is not sufficient for prognosis
      • Must be integrated with:
        • Perineural invasion (PNI)
        • Lymphovascular invasion (LVI)
        • Worst pattern of invasion (WPOI) (not formally in AJCC but increasingly relevant)
        • Nodal disease / ENE
• This reflects modern understanding:
  • Tumor biology > single metric
• Clinical vs Pathologic DOI:
  • Reinforces distinction:
    • cDOI (imaging / clinical) vs pDOI (pathologic gold standard)
  • Encourages better use of:
    • MRI / ultrasound for preoperative planning
• What Did NOT Change
  • DOI is still:
    • A T-category modifier, not a standalone staging variable
    • Only used in oral cavity cancers (not oropharynx, etc)
    • No change to:
      • T1 / T2 / T3 definitions based on DOI
      • Surgical decision-making thresholds (though clinical use continues evolving)
• Practical Clinical Impact (2025 Reality):
  • Surgical Oncology Perspective:
    • DOI continues to guide:
      • Elective neck dissection:
        • DOI ≥ 3 mm to 4 mm → strong consideration
      • Margin planning
      • Adjuvant therapy discussions
  • Research / Modern Trends:
    • DOI is increasingly being:
      • Combined with molecular markers
      • Supplemented by AI-based histologic risk models
      • Some argue DOI may eventually be:
        • Refined or replaced by composite risk scores