Extranodal spread of primary and secondary metastatic nodes: The dominant risk factor of survival in patients with head and neck squamous cell carcinoma

Extranodal spread (ENS) in patients with head and neck squamous cell carcinoma (HNSCC) can greatly influence the prognostic outcomes. However, the relative risks of ENS in the primary (1st) and secondary (2nd) metastatic nodes (mets) are not well documented. We retrospectively analyzed the hazard ratios (HRs) of ENS in the 1st and 2nd mets from 516 HNSCC patients who had undergone primary tumor excision. The impact of clinically and/or histologically confirmed ENS-positive mets on prognosis in terms of cancer-specific survival was analyzed. Cox proportional hazard regression analysis indicated that ENS-positive 1st met (adjusted HR = 3.15; 95% CI, 1.40-7.56; p = 0.006) and ENS-positive 2nd met (adjusted HR = 4.03; 95% CI, 1.41-16.96; p = 0.007) significantly and independently predicted poor prognosis; however, other variables including primary site, met size or numbers, and met location in the contralateral side of the primary lesion, did not. Cumulative incidence function and Cox analyses indicated that differences in ENS profiles of 1st and 2nd mets stratified HNSCC patients with varying risks of poor outcome; HRs relative to patients with ENS-positive 1st met (-)/ENS-positive 2nd met (-) were 4.02 (95% CI, 1.78-8.24; p = 0.002), 8.29 (95% CI, 4.58-14.76; p <0.001), and 25.80 (95% CI, 10.15-57.69; p <0.001) for patients with ENS-positive 1st met (+)/ENS-positive 2nd met (-), ENS-positive 1st met (-)/ENS-positive 2nd met (+), and ENS-positive 1st met (+)/ENS-positive 2nd met (+) patients, respectively. Kaplan-Meier analysis indicated that the 2nd met that appeared in the neck side with a history of 1st met and neck dissection had a higher risk of ENS than the 2nd met in the neck side without the history (p = 0.003). These results suggested that ENS is a dominant prognostic predictor of HNSCC patients, with double-positive ENS in the 1st and 2nd mets predicting the most devastating outcome.