Predicting extra nodal extension in oral squamous cell carcinoma: Attaining the holy grail

Extra nodal extension (ENE) has long been a critical challenge for oncologists treating oral squamous cell carcinoma (OSCC). The prognostic significance of ENE was established by EORTC 22931 and RTOG 9501 trials, which emphasized the addition of chemotherapy to adjuvant radiotherapy to improve survival outcomes.[1] Incorporating this, the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual designates ENE as a significant prognostic factor. In their article, Majumdar et al.[2] entitled “Predictors of extra-nodal extension in oral squamous cell carcinoma: A retrospective analysis,” highlighted key histological and radiological predictors of ENE, such as pathological bone invasion, perineural invasion (PNI), the total number of positive lymph nodes, and lymph node ratio (LNR). The authors must be congratulated for their meticulous data analysis, underscoring the importance of detailed histopathological evaluation. However, we would like to elaborate on certain points that could enhance our understanding of ENE predictors. For instance, a depth of invasion (DOI) >10 mm has been described as an independent risk factor for ENE,[3] with a significant association between tumor deposit size and ENE. Interestingly, Majumdar et al. found no correlation between DOI and ENE, despite 31 of 45 (68.8%) ENE-positive patients having a DOI >10 mm. The authors speculate that this discrepancy may be due to the inclusion of a large proportion of clinically node-negative (N0) patients. Conducting a subgroup analysis stratified by nodal status could provide further clarity. Woolgar et al.[4] demonstrated that positive surgical margins often correlate with ENE due to aggressive tumor biology.[4] While Majumdar et al. report a 3.7% (11 patients) margin positivity rate, they did not correlate this with ENE. Exploring this relationship in future studies could reveal additional histological predictors. Trifiletti et al.[5] suggested that an increased number of positive lymph nodes inversely correlates with survival. However, this parameter is notably absent from the latest AJCC staging system. The literature shows variable thresholds for the number of positive nodes (ranging from >2 to >6) and their correlation with ENE. Majumdar et al. identified >5 nodes as a potential predictor, and prospective studies could help establish a definitive correlation. In addition, metastatic node size (>15 mm) has been significantly associated with ENE, as noted in prior research.[6] In terms of histological parameters, the study identifies bone invasion and PNI as significant predictors of ENE, consistent with the existing literature.[7] However, other factors, such as desmoplastic reaction, tumor-infiltrating lymphocytes, and tumor budding, when combined with DOI >10 mm, have shown high sensitivity and specificity for predicting ENE in earlier studies.[3] A comprehensive approach integrating these parameters could enhance prediction accuracy. One of the study’s secondary objectives was to correlate clinical ENE with pathological ENE (pENE). As anticipated, clinical ENE exhibited high specificity (92%) for pENE, but with poor sensitivity. The literature suggests that imaging can predict approximately 50-60% of pathological ENE cases.[8] Emerging imaging criteria, such as the four-tier system recommended by the 2024 head-and-neck Cancer International Group, could help standardize ENE assessment on imaging.[9] In conclusion, integrating imaging data with histopathological parameters - such as node size, DOI, PNI, bone invasion, and lymphovascular invasion (LVI) - could significantly enhance predictive models for ENE in OSCC. Such models would ultimately improve risk stratification and treatment planning.[10] Future studies exploring these relationships and developing comprehensive predictive models are essential for improving patient outcomes. Moreover, advancements in radiomics may bring us closer to achieving the “holy grail” of ENE prediction in the years to come. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.