The incorporation of extranodal extension (ENE) into the AJCC 8th edition TNM staging system has led to a significant shift in the staging of head and neck cancers, with the presence of macroscopic ENE resulting in upstaging to stage IV. ENE has consistently been associated with poor prognosis, particularly when coexisting with other high-risk features such as T4 disease, lymphovascular invasion (LVI), and perineural invasion (PNI), with a clear impact on both overall survival (OS) and disease-free survival (DFS) (Mamic et al. 2020; Majercakova et al. 2018; Woolgar et al. 2003).

In a study by Mamic et al. (Mamic et al. 2020), 174 patients with oral cavity squamous cell carcinoma (OC-SCC) were evaluated postoperatively, and ENE was identified in approximately 30% of nodal specimens. Through receiver operating characteristic (ROC) curve analysis, a 1.9 mm cutoff was established to distinguish minor versus major ENE. Patients with major ENE (> 1.9 mm) demonstrated significantly worse OS and DFS compared to those with minor ENE, suggesting that ENE extent is a critical prognostic stratifier.

Our study focused on a cohort of 85 patients with pathologically confirmed ENE, most of whom had major ENE. By directly comparing this cohort with ENE-negative counterparts, we aimed to quantify the prognostic impact of ENE as an independent variable. While prior studies have explored ENE in broader contexts, few have specifically examined the subset of major ENE-positive OC-SCC patients. Our findings support the growing evidence that standard postoperative chemoradiotherapy, though beneficial, may not be sufficient to match the survival outcomes of patients without ENE.

Historically, the landmark meta-analyses by Bernier and Cooper (Bernier and Cooper 2005) provided the rationale for adjuvant chemoradiotherapy in ENE-positive patients, demonstrating improvements in locoregional control and survival. These findings led to widespread adoption of platinum-based concurrent chemoradiotherapy. However, our data suggest that this approach, although practice-changing, does not adequately mitigate the adverse impact of ENE. Real-world outcomes in our cohort reinforce the need for further treatment intensification in this high-risk group.

One potential avenue lies in preoperative identification of ENE. In our study, radiological ENE—assessed using CT and MRI—showed strong correlation with pathological ENE, with high diagnostic accuracy (sensitivity 85.9%, specificity 92.9%). This reinforces the utility of radiological ENE as a preoperative prognostic marker and a tool for treatment planning. Radiologic features such as fat stranding, vascular or muscular invasion, and fat suppression were consistently used in our institution for this purpose, in alignment with the grading system proposed by a randomized trial at Tata Memorial Hospital (TMH), Mumbai (Mahajan et al. 2022). Their findings, derived from oropharyngeal cancer patients treated with definitive chemoradiation, emphasized that radiologic ENE (iENE) independently predicted worse outcomes and should be routinely reported with standardized criteria.

Further supporting evidence comes from a retrospective Japanese study which suggested that iENE may also confer resistance to doublet induction chemotherapy in oropharyngeal cancers. Though not directly transferable to oral cancers, these findings raise the hypothesis that patients with iENE may benefit from alternative or intensified neoadjuvant strategies, including the incorporation of immunotherapy or altered radiotherapy fractionation (Onaga et al. 2024).

At our institution, prospective trials are planned to compare doublet versus triplet neoadjuvant chemotherapy (NACT) in OC-SCC, with iENE included as a stratification factor. We also intend to evaluate the feasibility and efficacy of delayed concomitant boost schedules in the adjuvant setting for ENE-positive patients. This is supported by the RTOG 99–14 trial (Garden et al. 2008), which demonstrated promising outcomes using high-dose cisplatin and concomitant boost radiotherapy, albeit with increased acute toxicity attributable to 2D planning techniques. With modern IMRT-based techniques, the toxicity profile may improve while preserving the therapeutic benefit.

In a more recent attempt to intensify adjuvant therapy, the OCAT trial at TMH (Laskar et al. 2023) tested the addition of a sixth fraction of radiotherapy per week. Although the overall results did not reach statistical significance, a trend toward improved DFS was observed in patients with multiple high-risk features—including T3–T4 primaries, N2–N3 nodes, and ENE. These findings warrant further exploration of altered fractionation in combination with concurrent chemotherapy for ENE-positive OC-SCC.

While our study is retrospective in nature and limited by sample size, it provides valuable real-world evidence from a high-incidence region. Our results reaffirm the poor prognosis associated with ENE and support the need for enhanced treatment strategies. The strong correlation between radiological and pathological ENE highlights the importance of integrating imaging findings into multidisciplinary decision-making and treatment planning.

Future prospective studies should focus on the stratification of ENE by extent, the role of radiological ENE as a biomarker, and the development of intensified adjuvant or neoadjuvant treatment protocols to improve outcomes in this high-risk group.