Impact of Tumor Budding in Head and Neck Cancers on Neck Lymph Node Metastasis and Prognosis

Abstract

Background/Objectives: Tumor budding (TB)-clusters of one to five tumor cells at the invasive front-has emerged as a prognostic marker in various cancers. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: We retrospectively analyzed 98 HNSCC patients. The tumor buds were counted on hematoxylin-eosin-stained sections as per the 2016 International Tumor Budding Consensus Conference (ITBCC) guidelines. An optimal cutoff was determined by ROC analysis using excisional lymph nodes and five-year overall survival (OS) as the endpoint, stratifying patients into low- (≤4 buds) and high-risk (>4 buds) groups. The associations with clinicopathological features, OS, and disease-free survival (DFS) were assessed using Kaplan-Meier curves and Cox regression. Results: Among the 98 patients (median follow-up 58 months, range 18-108), 32 (32.7%) died. The optimal TB cutoff was 4.5 (AUC 0.85, 95% CI 0.76-0.93). High TB was associated with poorer five-year OS (26.4% vs. 85.3%). Multivariate Cox regression identified TB and extranodal extension as independent predictors of OS (TB HR: 3.4, 95% CI 1.3-9.2, p = 0.013). In the laryngeal cancer subgroup, TB was associated with worse survival in the univariate analysis (HR 7.5, 95% CI 1.6-35.6, p = 0.011), though this was not significant in the multivariate modeling. High TB independently predicted neck lymph node metastasis (multivariate OR 4.9, 95% CI 1.2-20.5, p = 0.029), which was present in 65.8% of the high-TB vs. 31.7% of the low-TB patients. High TB correlated with advanced AJCC stage and lymphovascular invasion. No clinicopathological factors, including TB, independently predicted DFS, in either the full cohort or the laryngeal subgroup. Conclusions: High tumor budding denotes an aggressive HNSCC phenotype and may guide decisions on elective neck dissection. Its assessment is simple, cost-effective, and potentially valuable for routine pathology, pending external validation.

Keywords: head and neck cancer; head and neck squamous cell carcinoma; neck lymph node metastasis; overall survival; prognosis; tumor budding.

Figure 1

(A): High-magnification view of a head and neck squamous cell carcinoma with high tumor budding (H&E×200); (B): Head and neck squamous cell carcinoma with low tumor budding (H&E×200). Black circles indicate tumor buds, defined as isolated single tumor cells or small clusters at the invasive front.

Figure 2

Receiver operating characteristic curve demonstrating the diagnostic performance of tumor budding in predicting overall survival in HNSCC patients. The analysis yielded an area under the curve of 0.847 (95% CI: 0.763–0.931) with an optimal cutoff value of 4.5, achieving a sensitivity of 77.4% and a specificity of 79.1% (p < 0.001).

Figure 3

Kaplan–Meier survival curves comparing overall survival between patients with low tumor budding (≤4) and high tumor budding (>4). The high-risk group demonstrated significantly reduced overall survival (log-rank p < 0.05). Please note that the abrupt drop in the low tumor budding group after 75 months reflects a late event, with only three low-TB and two high-TB patients remaining at risk, as shown in the risk table.

Figure 4

Kaplan–Meier curves illustrating the disease-free survival (DFS) in HNSCC patients grouped by tumor budding status (low: ≤4; high: >4). No statistically significant difference in the DFS was observed between the groups (log-rank p > 0.05). Please note that the number at risk fell to three or fewer after 75 months, so estimates beyond this timepoint should be interpreted with caution.

Figure 5

Overall survival in the larynx  +  oral cavity sensitivity cohort (n = 76), stratified by tumor budding status. Kaplan–Meier curve for overall survival by tumor budding group using the Youden-derived cut-point of 3.5 buds (low: ≤3 buds, n = 37; high: ≥4 buds, n = 39). High tumor budding was associated with significantly poorer OS (log-rank p < 0.001). Tick marks indicate censored observations. Number at risk is shown below the x-axis; after ~2000 days (~66 months), fewer than 10 patients remained at risk, so estimates beyond this time should be interpreted with caution.

Figure 6

Disease-free survival in the larynx  +  oral cavity sensitivity cohort (n = 76), stratified by tumor budding status. Kaplan–Meier curve for disease-free survival by tumor budding group using the same 3.5-bud threshold (low: ≤3 buds, n = 37; high: ≥4 buds, n = 39). High tumor budding correlated with significantly reduced DFS (log-rank p < 0.001). Tick marks denote censored observations. Number at risk is shown below; because fewer than 10 patients were at risk after ~2000 days, DFS estimates beyond that time should be interpreted with caution.