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 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:
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
Byers RM, Weber RS, Andrews T, McGill D, Kare R, Wolf P. Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997 Jan;19(1):14-9. doi: 10.1002/(sici)1097-0347(199701)19:1<14::aid-hed3>3.0.co;2-y. PMID: 9030939.
Background:
Supraomohyoid neck dissection (Levels I, II, III):
Is an adequate operation for the elective treatment of the neck for patients with oral cavity cancer
Squamous cell carcinoma of the oral tongue:
Metastasize to clinically negative nodes:
In 20% to 30% of patients:
These nodes usually are located in:
Levels I to III
Methods:
The medical records of 277 previously untreated patients with squamous cell carcinoma of the oral tongue were reviewed between the years 1970 and 1990
All patients had a glossectomy and neck dissection as part of their initial treatment
Patients were evaluated as to the findings in their neck
The following group of patients were included:
Patients who had level III nodes positive, without disease in levels I and II
Patients with disease in level IV
Patients with disease in level IIB or IIIB
Patients who were electively dissected and whose neck did not demonstrate any pathologically involved nodes:
But level IV was not included in the dissection and the patient subsequently developed pathologically positive nodes in level IV
Results:
Of all patients:
15.8% had either level IV metastasis as the only manifestation of disease in the neck or the level III node was the only node present without disease in level I to II
Conclusion:
The usual supraomohyoid neck dissection is inadequate for a complete pathologic evaluation of all the nodes at risk for patients with squamous carcinoma of the oral tongue
This may create a dilemma in determining whether postoperative radiotherapy is necessary
Consequently, all patients with squamous cell carcinoma of the oral tongue should have levels I to IV nodes (Extended Supraomohyoid Neck Dissection) removed:
If an elective neck dissection is part of their initial therapy
Here is an expanded summary of Baratz et al., “Neoadjuvant Immunotherapy and Chemoimmunotherapy Regimens in Head and Neck Cancer: A Systematic Review and Meta-Analysis,” published online in JAMA Otolaryngology–Head & Neck Surgery on March 12, 2026
Why this paper matters:
Neoadjuvant immunotherapy in resectable HNSCC:
Has been attractive because:
It may treat micrometastatic disease early
Exploit the intact tumor-immune microenvironment before surgery
It may potentially improve pathologic response without delaying definitive treatment
What has been unclear is whether immunotherapy alone or chemoimmunotherapy is more effective
This meta-analysis addresses that question by pooling the available prospective data in resectable, treatment-naive HNSCC
Objective:
The investigators aimed to:
Summarize the efficacy of neoadjuvant chemoimmunotherapy in HNSCC
Compare outcomes of chemoimmunotherapy vs immunotherapy alone:
Before definitive surgery in locoregionally advanced resectable HNSCC
Methods:
This was a librarian-led systematic review and meta-analysis performed according to PRISMA methodology
The authors searched MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus from database inception through October 2024
They included prospective interventional trials in resectable, treatment-naive HNSCC that had completed accrual and reported pathologic response and / or RECIST response data
Two investigators independently performed study screening and extraction
The main outcomes were:
Major pathologic response (MPR)
Complete pathologic response (CPR)
Complete radiographic response (CR):
By RECIST 1.1
Secondary outcomes included:
1-year overall survival
Toxicity
The pooled analysis used a binary random-effects model, with heterogeneity reported as I²
Study population:
The meta-analysis included 23 studies with a total of 751 patients. Of these:
357 patients (47%) received chemoimmunotherapy
102 patients (14%) received dual-agent immunotherapy
292 patients (39%) received single-agent immunotherapy
The pooled cohort was predominantly male (77%) with an age range of 27 to 87 years
Main findings:
Pathologic response:
Strongly favored chemoimmunotherapy
The most important finding was:
The marked gradient in pathologic response across regimens:
Pooled MPR + CPR rates were:
66% for chemoimmunotherapy 95% CI 58%-73%
18% for dual-agent immunotherapy 95% CI 6%–29%
6% for single-agent immunotherapy 95% CI 3%–9%
This is the key take-home point:
Adding chemotherapy to immunotherapy:
Was associated with substantially higher pathologic response rates than immunotherapy alone
Clinically, this matters because in head and neck cancer:
Pathologic response has increasingly been explored as an early signal of antitumor activity and a possible surrogate for longer-term benefit:
Although it is not yet a fully validated surrogate for survival in this setting
That distinction is important when interpreting these results
The paper shows better tumor kill in the surgical specimen:
But it does not yet prove that patients live longer because of the neoadjuvant regimen:
That is why the authors call for phase 3 trials
Short-term survival looked promising across groups, but differences were not definitive:
Across the included studies, 1-year overall survival ranged:
88% to 96% with single-agent immunotherapy
88% to 96% with dual-agent immunotherapy
88% to 100% with chemoimmunotherapy
These ranges suggest that all three strategies can be delivered with good short-term outcomes in selected patients:
However, because these were mainly early-phase, non-comparative studies with heterogeneous populations and follow-up:
The survival data should be viewed as hypothesis-generating, not practice-defining
Toxicity was higher than dual immunotherapy, but not prohibitive:
Among studies reporting adverse events, grade 3 to 5 adverse events occurred in:
29% of patients receiving single-agent immunotherapy
3% with dual-agent immunotherapy
17% with chemoimmunotherapy
These numbers need cautious interpretation because toxicity reporting was not uniform across studies, and the denominators were limited to reporting studies rather than all pooled patients:
Still, the overall message is that chemoimmunotherapy increased efficacy while maintaining an acceptable:
Though not trivial, toxicity burden in selected surgical candidates.
Authors’ conclusion:
The authors concluded that neoadjuvant chemoimmunotherapy:
Was associated with higher pathologic and radiographic response rates than immunotherapy alone in locoregionally advanced resectable HNSCC, and that these findings support the need for head-to-head phase 3 trials
How to interpret this as a head and neck oncologic surgeon:
Strengths:
This study has several strengths:
It focuses specifically on resectable, treatment-naive HNSCC:
Which is the clinically relevant population for neoadjuvant decision-making
It includes only prospective interventional studies
It separates single-agent, dual-agent, and chemoimmunotherapy approaches rather than lumping all neoadjuvant immunotherapy together
It uses outcomes surgeons and multidisciplinary teams care about:
Pathologic response, radiographic response, survival, and toxicity
Important limitations:
The paper is very useful, but it does not settle the question of standard of care
The biggest limitations are:
Most included studies were phase 1 / 2, small, and often single-arm
There was likely substantial clinical heterogeneity:
Primary site, stage, PD-L1 status, regimen, number of cycles, and adjuvant treatment strategies
The outcome driving the signal is primarily pathologic response:
Not mature event-free survival or overall survival
Cross-trial comparisons may exaggerate differences:
Because these were not randomized head-to-head comparisons
Toxicity and imaging response reporting were not fully standardized
So the paper supports promise:
Not final proof
Practical clinical implications:
For a practicing surgeon:
This meta-analysis suggests that chemoimmunotherapy is currently the most active neoadjuvant immune-based strategy in resectable HNSCC:
At least if the endpoint is pathologic response
If a center is considering neoadjuvant treatment within a trial or highly selected multidisciplinary framework:
The data support prioritizing chemoimmunotherapy over immunotherapy alone when the goal is maximizing preoperative tumor regression
At the same time, these data do not mean every resectable oral cavity, larynx, or oropharynx patient:
Should routinely receive neoadjuvant chemoimmunotherapy outside a protocol
The field is moving quickly, and the editorial accompanying this paper emphasizes that these results arrive in the context of KEYNOTE-689:
The first phase 3 randomized study to establish perioperative immunotherapy as a standard-of-care option in locally advanced resectable HNSCC:
While also warning that enthusiasm should be balanced with caution as these strategies enter broader practice
Bottom line:
This meta-analysis is one of the clearest pooled signals so far that in resectable locoregionally advanced HNSCC, neoadjuvant chemoimmunotherapy produces substantially higher pathologic response rates than immunotherapy alone
The benefit signal is strong for tumor response, short-term survival appears encouraging, and toxicity seems manageable in selected patients:
But the evidence base is still dominated by early-phase studies, so phase 3 randomized data remain essential before universal adoption
As published by the AJCC and UICC is widely accepted
In its most recent revision (eighth edition of the AJCC Staging Manual):
Depth of invasion (DOI):
Is added to the surface dimensions and local extent of the tumor:
As the required parameters for primary tumor staging in the oral cavity
Depth of invasion and surface dimensions are the parameters required for T staging of oral cancer
Accurate assessment of DOI by clinical examination is not possible:
However, the staging system stratifies DOI by 5 mm increments, and thus clinical estimates of DOI can be categorized into:
Thin (less than 5 mm)
Thick (5 to 10 mm)
Very thick (greater than 10 mm)
By palpation to assign clinical T stage
Primary tumors of the oral cavity are categorized as thin, thick, and very thick by palpation
The stage distribution of patients with squamous cell carcinoma of the oral cavity at the Memorial Sloan Kettering Cancer Center in New York is shown in the graph:
Stage distribution for squamous cell carcinoma of the oralcavity (MSKCC data 1985 to 2015)
The most important histologic feature of the primary tumor:
That affects selection of treatment and eventual prognosis:
Is its depth of invasion (DOI)
Thin and superficially invasive lesions:
Have a lower risk of regional lymph node metastasis
Are highly curable
Offer an excellent prognosis
Thicker lesions that deeply infiltrate the underlying soft tissues:
Have a significantly increased incidence of regional lymph node metastasis and an adverse impact on prognosis
The risk of lymph node metastasis and survival rates in relation to the DOI of the primary lesion for T1 and T2 squamous carcinomas of the oral tongue and floor of mouth are shown in Figure:
Although it would be ideal to know the exact DOI of the lesion before surgical intervention, having that information before surgical excision and histopathologic examination of the primary tumor is not possible
In general, however, estimate of DOI by assessing thickness of the lesion as appreciated by palpation:
Is a reasonably good indicator of deeply invasive lesions versus superficial lesions:
To estimate the extent of soft tissue and / or bone resection for the primary lesion and to decide on the need for elective dissection of the regional lymph nodes at risk in a clinically negative neck
Primary tumors of the oral cavity are categorized as thin,thick, and very thick by palpation
Several retrospective studies have identified DOI of the primary tumor:
As an important determinant of prognosis:
Thus DOI is now included in T staging of primary tumors of the oral cavity
The incidence of occult nodal metastasis in the clinicallynegative neck for patients and disease-specific survival for patients withT1 and T2 oral carcinoma in relation to depth of invasion (DOI). (Memorial Sloan Kettering Cancer Center data, 1985 to 2015).
Depth of invasion (DOI) is the vertical depth of tumor invasion:
Measured from the basement membrane of the adjacent normal mucosa to the deepest point of invasion:
It is not the same as “tumor thickness”
DOI is now a core determinant of T category in AJCC 8th and 9th oral cavity SCC:
AJCC 8 DOI cut points (oral cavity):
T1:
≤ 2 cm and DOI ≤ 5 mm
T2:
≤ 2 cm with DOI > 5 to 10 mm OR > 2 to 4 cm with DOI ≤ 10 mm
T3:
DOI >10 mm (or tumor > 4 cm)
Clinical implication:
A small “T1 by size” lesion can become T2 / T3 purely based on DOI:
Changing risk counseling and neck strategy
Risk of occult nodal metastasis vs DOI (tongue and floor of mouth):
Big picture (consistent across studies):
DOI is one of the strongest predictors of occult cervical lymph node metastasis (CLNM) in cN0 oral cavity SCC
A commonly used operative decision threshold is:
DOI ~ 3 to 4 mm:
But subsite matters, and FOM often carries higher nodal risk at the same DOI
Practical DOI “risk bands” used in tumor boards
Evidence supporting ≥ 4 mm as an elective neck dissection (END) trigger (early OCSCC):
Multiple analyses suggest DOI ≥ 4 mm is an effective cutoff where END improves regional control / survival compared with observation in early-stage OCSCC
Recent work continues to evaluate / validate a 4 mm threshold, acknowledging imperfect sensitivity / specificity
Meta-analytic evidence shows higher lymph node metastasis (LNM) risk when DOI > 4 mm (RR ~2.18 in one large study, alongside other adverse pathologic factors)
Floor of mouth nuance:
At the same DOI:
FOM cancers may metastasize more frequently than tongue cancers in some datasets:
Implying that a single universal DOI cutoff across all subsites can be overly simplistic
Prognosis vs DOI (local control, survival, and upstaging):
DOI correlates with:
Higher probability of nodal metastasis:
Including occult disease
Worse disease-specific outcomes:
It is sufficiently prognostic that it was incorporated into AJCC 8 edition T staging
DOI > 10 mm is particularly important because it upstages to pT3 (even if tumor is small in surface dimension):
Reflecting its association with advanced / aggressive behavior
Key point for counseling:
DOI is not just a “neck decision tool”:
It is a global biologic aggressiveness marker and a staging variable
Elective neck management in cN0 tongue / FOM SCC:
Guideline-consistent approach:
NCCN guidance (summarized in literature):
Consider elective neck dissection (END) in early oral cavity SCC when DOI exceeds ~3 mm (often framed as “consider END”)
Many institutions operationalize:
Tongue:
END commonly at ≥ 4 mm
FOM:
Lower threshold and / or stronger lean toward END due to higher nodal propensity in several series
END vs sentinel lymph node biopsy (SLNB) vs observation:
Elective Neck Dissection (END):
Typical for cN0 early tongue / FOM:
Selective neck dissection levels I to III ± IV based on institutional practice, DOI, and risk factors:
Benefit is maximizing regional control and avoiding “salvage neck failure” biology
Sentinel Lymph Node Biopsy (SLNB):
Valid alternative to END for T1 to T2 cN0 oral cavity SCC in experienced centers:
Especially when trying to reduce morbidity
Practical pearl:
SLNB is most attractive when DOI is low / intermediate and imaging is negative:
But your workflow must support reliable mapping / pathology
Observation:
Reasonable primarily for very thin lesions (e.g., ≤ 2 mm) without other high-risk features and with reliable follow-up
Remember:
DOI cutoffs have imperfect test characteristics:
A “thin” tumor can still metastasize
A pragmatic surgeon algorithm (tongue + floor of mouth, cN0):
Pre-op:
High-quality exam + imaging
Estimate DOI if possible:
US / MRI can help in some settings
If DOI likely > 10 mm (or bulky lesion):
Treat the neck (END)
If DOI 4 to 10 mm:
Strong default to END (levels I to III) or SLNB if program is robust
