Extranodal extension predicts poor survival in HNSCC independent of nutritional status

Extranodal extension (ENE) of lymph node metastases is a robust predictor of survival in head and neck squamous cell cancers (HNSCC) and appears to be independent of nutritional status, reports a study.

“ENE is one of the most powerful prognostic factors in HNSCC, exerting a survival impact that is independent of tumour stage and increasingly central to diagnostic and therapeutic decision-making,” the researchers said.

ENE was seen in more than half (54.1 percent) of the 109 treatment-naïve HNSCC patients with pathologically confirmed nodal metastases who underwent primary tumour resection and neck dissection between 2014 and 2025 at a national tertiary centre. Its presence reduced overall survival (OS; Kaplan‒Meier: p=0.006; Cox regression risk ratio [RR], 1.927; p=0.008). [Nutrients 2026;18:706]

The researchers determined ENE status histologically and evaluated nutritional status using BMI, Prognostic Nutritional Index (PNI), serum albumin, and percentage of weight loss at diagnosis. They also performed statistical analyses including t-tests, Chi-square tests, ANOVA, Cox regression, Kaplan‒Meier survival analysis, and Full Factorial General Linear Models.

ENE-positive and ENE-negative patients showed no significant differences in BMI, PNI, weight loss, or serum albumin.

Moreover, the prevalence of ENE varied significantly by tumour origin (p=0.018), with the highest prevalence observed in patients with hypopharyngeal cancers (75.8 percent) and the lowest in those with oral cavity tumours (25.0 percent). Notably, ENE status was independent of tobacco use, alcohol abuse, and all nutritional markers across TNM 8/9 subgroups.

“Given that nutritional status itself carries prognostic significance, it should remain an integral component of routine patient evaluation and treatment planning, complementing TNM-based risk stratification rather than interacting with ENE,” the researchers said.

Nutritional status

The importance of nutritional assessment in patient workup cannot be ignored or underestimated because it influences ECOG performance status, fitness for curative (chemo)radiotherapy or surgery, and wound healing. Adequate nutrition is also essential in prolonging the OS of patients with recurrent/metastatic HNSCC. [Front Oncol 2024;14:1430845; Front Oncol 2025;15:1667150]

“In our cohort, ENE-positive patients had significantly shorter OS (log-rank p=0.006; Cox p=0.008; RR, 1.927), consistent with the literature,” the researchers said.

“As nutritional status affects several protecting mechanisms (eg, the immune system), we hypothesized that … ENE-positivity is more common among patients with poor nutritional status,” they added.

ENE criteria

ENE evaluation has been expanded in the UICC TNM classification. It was absent from the 7th Edition, but the 8th Edition introduced ENE as a prognostic factor, upstaging clinical and pathological nodal disease to N3b, except in p16-positive-oropharyngeal cancers. [Indian J Surg Oncol 2018;9:116-120]

The 9th Edition has extended ENE staging to this subgroup and improved imaging-detected ENE criteria for clinical and pathological nodal staging. [Turk Arch Otorhinolaryngol 2025;63:166-168]

“The urge to emphasize ENE staging was supported by a study of 2,053 patients, which found that multivariable analysis identified ENE as the strongest prognostic nodal feature in p16-positive oropharyngeal cancer (adjusted hazard ratio for imaging-detected ENE, 2.43),” the researchers said. [JAMA Otolaryngol Head Neck Surg 2025;151:655-664]