Refining nodal category in TNM staging with extent of extranodal extension for oral cavity squamous cell carcinoma.
Authors: de Almeida John R , Su Jie , Manojlovic Kolarski Mirko , Weinreb Ilan , Perez-Ordonez Bayardo , Smith Stephen , Patel Snehal G. , Valero Cristina , Xu Bin , Ghossein Ronald A , Clark Jonathan , Low Hubert , Gupta Ruta , Graboyes Evan Michael , Davies Joel C , Richardson Mary , Goldstein David Paul , Huang Shao Hui , Xu Wei , O'Sullivan Brian 
Published: October 2024

6015

Background:
The TNM 8th edition N classification (TNM-8-N) has limitations based on evidence that: (1) extent of extranodal extension (ENE), classified as minor(
min
) (≤ 2mm) or major (
maj
)(> 2mm), is prognostic, and (2) N3a category (i.e. lymph node (LN)s > 6 cm, no ENE) is rare and redundant. Refining N classification may improve staging performance.
Methods:
Patients with surgically resected T1-4,N0-3 OCSCC at four centers between 2005 - 2018 were included. Pathologists were asked to measure extent of ENE on archived slides for all cases. Thresholds for stratification of adverse LN features were determined using the Contal O’Quigley method. Multivariable analyses for overall survival (OS) were performed using Cox proportional hazard models. Two new N classification proposals were created based on LN features using (1) adjusted hazard ratios (aHR) and (2) recursive partitioning analysis (RPA). These were ranked against two published proposals and TNM-8-N with the following criteria: hazard consistency, hazard discrimination, explained variance, likelihood difference, sample size balance.
Results:
In total, 1460 patients were included, 764 (52%) were LN positive, and 135 (18%) had contralateral LNs. The following TNM-8-N subgroups were rare and had poor prognosis: LN between 3-6 cm without ENE (N2a) [n=4] and LN(s) > 6 cm without ENE (N3a) [n=1]. All 5 either recurred or died. TNM-8-N N2b and N2c categories had disordered 5-year OS (45% vs. 67%). Thresholds for stratification of LN features, rounded to the nearest whole number, were <=1 vs >1 for number of LNs; ≤ 3 vs. > 3 cm for size of largest LN, and ≤ 2 mm vs. > 2 mm for extent of ENE. Significant predictors of OS included (1) the presence of ENE
maj
and no ENE vs. ENE
min
(HR 1.37; 95% CI 1.03-1.82 and HR=0.66, 95%CI 0.49-0.88), (2) multiple LNs vs. 1 LN (HR 1.72; 95% CI, 1.33-2.22), and (3) size of largest LN > 3 cm vs. <=3 (HR 1.86; 95% CI 1.42-2.43), but contralateral LN(s) vs. ipsilateral LN(s) was not (HR 1.08; 0.83-1.40). The aHR proposal ranked highest (table).
Conclusions:
A new N-classification proposal based on aHR provides improved staging information. Major changes include: (1) stratification by ENE extent (2) elimination of N2c (3) stratification of multiple LNs without ENE by size, and (4) elimination of the 6 cm threshold. New TNM iterations may incorporate these changes.

TNM-8-N
aHR
RPA
Liao et al.
Ho et al.

N1
1 LN, ≤ 3cm, no ENE

same

Same
same
1 LN, no ENE

N2a
1 LN, ≤ 3 cm, with ENEOR1 LN, 3-6 cm, no ENE
1 LN, ≤ 3 cm, with ENE
1 LN, any size, with ENE
same
1 LN, with ENEOR2 LNs

N2b
>1 LN, ≤ 6 cm, no ENE
> 1 LNs,≤ 3 cm, no ENE
>1 LN, ≤ 3 cm, no ENE
same

N2c
Contralateral LN(s), ≤ 6 cm, no ENE
*
*
same

N3a
LN(s) > 6 cm, no ENE

LN(s) > 3 cm, no ENEOR1 LN, > 3 cm, ENE
min
OR> 1 LNs, ENE
min

LN (s) > 3 cm, no ENEOR>1 LN, ENE
min

≤ 7 LNs,OR≤ 4 LNs with ENE
3-7 LNs

N3b
1 LN, > 3 cm, any ENEOR>1 LN(s), any ENE

1 LN > 3 cm, ENE
maj
OR>1 LNs, ENE
maj

> 1 LN, ENE
maj

≥
8 LNsOR
≥
5 LNs with ENE

≥
8 LNs

Ranking
5
1
2
4
3

*eliminated