Metastatic Lymph Node Burden and Survival in Oral Cavity Cancer

Abstract

Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions.

Fig 1.

Kaplan-Meier estimates of overall survival in oral cavity cancer, stratified by number of positive metastatic lymph nodes in (A) all patients, (B) patients with N2b disease, and (C) patients with N2c disease. LN+, lymph node–positive;

Fig 2.

Adjusted hazard ratio (HR) with increasing number of positive metastatic lymph nodes (LNs) and LNs examined in oral cavity cancer. Blue dashed lines represent estimated 95% CIs of the predicted HRs. (A) Gold solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus the number of positive metastatic LNs, with a reference value of 0. Gray vertical line represents the estimated change point at four positive LNs. (B). Gold solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus the number of LNs examined, with a reference value of 10. Gray vertical line represents the estimated change point at 35 examined LNs.

Fig 3.

Novel proposed nodal staging system developed by recursive partitioning analysis in patients with oral cavity cancer with determinable American Joint Committee on Cancer (8th edition) stage. Bonferroni-adjusted P values are given in the inner nodes, and Kaplan-Meier estimates for 3-year overall survival (OS) are displayed in the terminal nodes. Given similar OS rates, one LN+/ENE+ and two LN+ categories were merged to N2 status. ENE–, extranodal extension–negative; ENE+, extranodal extension–positive; LN+, lymph node–positive; OS, overall survival.

Fig 4.

Kaplan-Meier estimates for (A) proposed and (B) AJCC (8th edition) N classification systems in oral cavity cancer. AJCC, American Joint Committee on Cancer; ENE–, extranodal extension–negative; ENE+, extranodal extension–positive; LN+, lymph node–positive.

Fig A1.

CONSORT diagram. LN, lymph node.

Fig A2.

Adjusted hazard ratio (HR) with increasing number of lymph nodes (LNs) examined in (A) stage I to II (T1-2N0) compared with (B) stage III to IV (T1-2N1-3/T3-4N0-3) oral cavity cancer. Gold solid lines represent smoothed restricted cubic spline plots of the natural logarithm of predicted adjusted HR versus the number of LNs examined, with a reference value of 10. Gray vertical lines represent the estimated change point of (A) 31 LNs examined and (B) 37 LNs examined. Three knots for the number of LNs examined were placed at (A) 13, 25, and 49 and (B) 14, 30, and 60, each corresponding to 10th, 50th, and 90th percentiles, respectively. Blue dashed lines represent estimated 95% CIs of the predicted HRs.