The UICC/AJCC TMN staging system is the authoritative method of assessing the extent of local invasion, regional lymphatic spread and distant metastasis, and is considered the most valuable prognostic factor in NPC. Although the 8
thedition was only published one year ago, several studies have attempted to validate its clinical applicability. Pan et al. reported clear separation was not observed between stage I and II (
P = 0.07 and
P = 0.10, respectively) of the 7th and 8th editions. Tang et al. [
18] and Xu et al. [
19] found no significant differences between stage II and III (all
P > 0.05) of either edition. However, overlapping between these cohorts was inevitable, as the patients were from the same center and treated during the same period [
21,
22]. OuYang et al. [
20] compared the proposed Guangzhou, Hong Kong, Guangxi staging system with the 7th and 8th editions of the AJCC/UICC staging system using a cohort of 899 patients. They found the N classification of the 8th edition had better prognostic performance than the 7th, while the T category classification still required further optimization. In this study, a total of 1317 patients treated with IMRT at two different hospitals were assessed to compare the prognostic value of the 7th and 8th editions of the UICC/AJCC staging system.
T classification
In a study which compared different staging systems including the 7th, 8th edition of AJCC/UICC staging system and Guangzhou, Hongkong, Guangxi staging system, Guangzhou staging system led to the highest c-index in T classification and the 8th edition ranked the second [
20]. Minor difference was found between these two systems, which was extension of Oropharynx or nasal cavity was staged as T1 disease in the 8th edition but T2 in Guangzhou system. Nevertheless, validation between 7th and 8th edition of AJCC/UICC staging system from the same center showed c-index in the previous edition was slightly higher than the latest one [
18].
In this study, the 8th edition failed to solve the problem of similar survival between adjacent T-classification, which has been exited since 7th edition; indeed, the lack of significance between T categories was more obvious for the 8th edition, which mainly own to the alteration of ITF/MS. In fact, IFT/MS involvement has long been included in the UICC/AJCC staging system as a T4 criterion, though the exact anatomical boundaries for these structures have varied between editions [
23,
24]. In the 5th and 6th editions, the ITF/MS did not involve the medial pterygoid (MP) or lateral pterygoid (LP) [
25], while the 7th edition definition of the MS included all four masticatory muscles: MP, LP, temporalis and masseter [
14]. It was laudable that descriptions in the latest edition were more specific. However, the best classification of IFT /MS had not reach a consensus. Pan et al. found patients without T3 or T4 criteria but MP/LP involvement achieved much better 5-year OS than patients with T4 disease with other criteria except for MP/LP involvement (93% vs. 71%, respectively,
P = 0.003) [
15]. A similar result was reported by Tang et al. [
26], though different degrees of MS invasion did not significantly affect LRFS or OS (
P = 0.34 and
P = 0.54, respectively). In another study of 816 patients, including 283 (36.4%) patients with MS invasion, MS involvement was an independent prognostic factor for local control (
P = 0.007) and OS (
P = 0.024) in multivariate analyses, and patients with MP involvement had similar survival rates as T2 or T3 disease (all
P > 0.1), though the outcomes for patients with LP involvement were similar to T4 disease (
P > 0.1) [
27]. In this study, limited number of patients in the subgroup showed that MS involvement with T3 criteria had similar survival outcomes to T4 disease in this study (
P = 0.134 for LRFS,
P = 0.292 for OS). Such discrepancies may be due to the varied demographics, inclusion criteria, treatment strategies and follow-up times in each study, and the a larger-scale, multicenter study is wanted to figure the staging of MS.
Involvement of the prevertebral muscles, mentioned for the first time in the 8th edition as a T2 criterion, has been shown to increase the risk of local and distance failure. In a study of 506 patients, prevertebral space invasion (PSI) was associated with similar survival to T4 disease, but not T3 [
28]. However, due to the lack of a significant difference in OS between PSI and MS invasion reported by Pan et al. [
15], single PSI was classified as T2 in the 8th edition. Unfortunately, only eight patients had PSI without T2, T3 or T4 criteria in this study; this sample size was too small conduct subgroup analysis. However, multivariate analysis showed PSI was independent prognostic factor for LRFS, DFS and OS. More detailed studies of a lager cohort are required.
The marginal differences in prognosis between adjacent T categories of the 7th and 8th editions (Fig.
1) reflect developments in diagnosis and treatment. On the one hand, the widespread use of MRI makes skull base erosion easier to detect [
3,
29]. Although MRI can more precisely detect deep tumor infiltration and has improved LRFS by around 20% [
30], some early micro-migration—which can only be detected by MRI—may have a better prognosis than the obvious invasion easily observed on CT scans in other patients with the same T category. Compared to the erosion easily detected on CT, skull-base erosion detectable on MRI but undetectable on CT may have a more favorable prognosis [
30,
31]. On the other hand, the popularity of IMRT and addition of chemotherapy have also reduced local failure [
32]. Distant metastasis remains the main failure pattern in NPC, further emphasizing the importance of accurate N category classification.
N classification
In Ouyang’s study, which compared five staging systems, N-classification in the 8th edition of AJCC/UICC staging system owned higher C-index for OS, DMFS and RRFS than the previous edition [
20]. Another validation of the 8th edition also supported that the new prognostic model of N-classification predicted outcomes fairly well [
18].
Compared to the N category classification of the 7th edition, the 8th edition became consistent with the consensus guidelines used for other head-and-neck cancers [
33], making the staging system more convenient in clinical practice, and also resulting in better segregation of both DMFS and OS (Fig.
2).
The 8th edition uses the caudal border of the cricoid cartilage to differentiate N1–2 and N3 [
15], in other words, the LL is a demarcating criterion for N3. The data supporting the proposal of the 8th edition did not show this replacement improved prognostic value, though there was little controversy about the alternation. SCF, defined by the superior margin of the sternal end of the clavicle, the superior margin of the lateral end of the clavicle and the point where the neck meets the shoulder [
34], is not a reliable radiological landmark in this IMRT era when MRI is widely used for diagnosis while the new boundary - lower level (LL), defined as the area below the caudal border of the cricoid cartilage -is an anatomical landmark that can be reliably defined on physical examination and also accurately located in cross-sectional images. Replacing the SCF with the LL is sensible and practicable as the LL corresponds to the entire area of levels IVa, IVb, Vb and Vc as defined by the 2013 International Consensus Guidelines [
33]. Yue et al. found that, compared to Ho’s SCF, the LL provided more distinct separation of DMFS, DFS and OS between adjacent N categories [
11]. A similar result was obtained in this study. Moreover, 38 patients (about 3%) in our cohort were upstaged from 7th edition N1 or N2 to 8th edition N3 because of this change, and these patients achieved closer survival outcomes to N3 than N1 or N2 (Fig.
4). Therefore, it is reasonable to assign lymph node(s) metastasis in the LL as a new N3 criterion.
Although Lee et al. [
35] found maximal axial diameter (MAD) was a significant independent predictor of survival, other relevant studies such as Teo et al. [
36] and Heng et al. [
37] deemed the prognostic value of MAD was mainly due to the fact large lymph nodes are more frequent at lower nodal levels. Only 25 (1.9%) patients had lymph node(s) with a MAD larger than 6 cm, of whom eight had lymph node involvement extending to the SCF (7th edition N3b). Similar overlaps have also been reported in other studies [
10,
15]. Furthermore, the similar DMFS and DFS rates for N3a and N3b indicate that this sub-category separation is unnecessary.
Clinical stage
Stages IVA and IVB of the 7th edition were merged into stage IVA in the 8th edition, and naturally, previous stage IVC was upgraded to IVB. The differences in DFS and OS between IVA and IVB of the 7th edition were insignificant, whereas the overall stages of the 8th edition resulted in better separation of the DFS and OS curves. Although no significant difference in OS was observed between stage I and II in either the 7th and 8th editions (P = 0.157 and P = 0.171, respectively), the distinction between stage I and II is necessary as chemotherapy may benefit patients with stage II.