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.
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 patternsdiffered 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:
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:
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
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.
A meta-analysis of 17 studies found the following frequencies of lymph node metastasis across all OSCC [17]#Arrangoiz #Doctor #Surgeon #SurgicalOncologist #HeadandNeckSurgeon #CancerSurgeon #Miami #MSMC #MountSinaiMedicalCenter #Mexico
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).
Rodrigo Arrangoiz MS, MD, FACS, FSSO 