Staging of T2 and T3 nasopharyngeal carcinoma: Proposed modifications for improving the current AJCC staging system

Abstract Objectives We aimed to reconstitute T2 and T3 stage classification in nasopharyngeal carcinoma (NPC) cases and verify its utility in clinical settings. Materials and Methods We enrolled 792 NPC patients. Cox proportional hazards model was used to compare the effect sizes (hazard ratio [HR]) of the cranial structure invasion on survival and select the structures for up‐staging or downstaging T2 and T3 NPC. The samples were reclassified and the survival curves for T2 and T3 stages were analyzed. The proposed new staging system was validated on an external sample (n = 433). Results Thirteen cranial structures were examined. American Joint Committee on Cancer (AJCC) T3 stage patients with the invasion of the base of the sphenoid (HR = 2.58, 95% CI = 1.16‐5.77) or base of the pterygoid (HR = 2.00, 95% CI = 0.84‐4.77) had significantly lower hazard ratios than T2 stage patients with the invasion of soft tissues in the bilateral parapharyngeal space (HR = 5.26, 95% CI = 2.02‐13.68) and single/bilateral carotid sheath (HR = 7.78, 95% CI = 3.06‐19.76). T3 stage with the invasion of the above‐mentioned bones was reclassified as T2, and T2 stage with the invasion of the above‐mentioned soft‐tissue structures was reclassified as T3. Survival analysis showed a significant difference between the reclassified T2 and T3 stages (P < 0.001). The results were replicated in the validation samples. Conclusion The proposed staging system for defining T2 and T3 stage NPC appears to be superior to the AJCC 8th edition. It could improve prognosis and optimize the treatment selection.


| INTRODUCTION
Nasopharyngeal carcinoma (NPC) is one of the commonest malignant diseases in southern China, with an annual incidence of approximately 30/100 000 persons. 1 The choice of appropriate treatment for NPC depends on accurate T staging of cancer. A major problem with the 7th and the current 8th version of the American Joint Committee on Cancer (AJCC) staging systems is that T2 and T3 stage NPC patients show comparable survival. 2,3 The overlapping of the survival curves for AJCC T2 and T3 stage NPC could possibly be due to the following reasons. First, the current 8th version of the AJCC staging system distinguishes T2 and T3 stage NPC cases according to whether or not a tumor invades the cranial bony structure. Specifically, NPC with the invasion of only the parapharyngeal space or nearby soft tissues (ie, medial pterygoid, lateral pterygoid, or prevertebral muscles) is classified as T2 stage, while a tumor invading any of the bony structures of the skull base or cervical vertebrae and/or paranasal sinuses is classified as T3 stage. 4,5 However, studies have consistently shown that invasion of different bony skull-base structures had widely differing effects on the long-term survival of NPC patients. [4][5][6][7][8][9][10][11] It is possible that NPC patients with the invasion of some specific bony structures may actually have better survival than patients with the invasion of parapharyngeal space or nearby soft tissues. If that is the case, patients with the invasion of these bony structures should be classified as T2 stage patients and those with parapharyngeal space invasion as T3 stage patients. Second, all the structures used for defining T2 and T3 stages in the AJCC 8th version staging system are derived from the reviews of the literature [12][13][14] and it is highly likely that some structures (eg, the carotid sheath) that are important in distinguishing between T2 and T3 stage NPC cases were missed.
The aim of this study was to develop and validate a more efficient system for staging T2 and T3 NPC, by moving some of the T3 stage NPC cases with a minor invasion of certain specific bony structures into T2 stage and some T2 stage cases with the invasion of soft tissues into T3 stage. In addition, we aimed to find new anatomic structures that were not included in the 8th version of the AJCC staging system but that may add an important prognostic value to the recommended new staging system. We expect that this modified staging system for T2 and T3 NPC will help in a more accurate prognosis and the selection of appropriate treatments.

| Training and validation samples
The training sample comprised 792 NPC patients treated at the Sun Yat-sen University Cancer Center between January 2010 and January 2013. Only patients with pathologically confirmed squamous-cell carcinoma, without distant metastasis, were included. Those without complete magnetic resonance imaging (MRI) data or information on hepatitis B virus (HBV) or Epstein-Barr virus (EBV) loads were excluded. Figure S1 shows the training sample selection process. The validation sample comprised 433 NPC patients treated at the First People's Hospital of Foshan between April 2010 and March 2014. The inclusion and exclusion criteria were the same as for the training sample.
This study was approved by the Institutional Review Boards at Sun Yat-sen University Cancer Center and the First People's Hospital of Foshan. All participants provided written informed consent for participation in the study.

| MRI examination
MRI scans of the head and neck regions (ie, from the saddle pool to the lower edge of the sternal end of the clavicle) were performed on 1.5T or 3.0T MR imaging systems, using dedicated head and neck combined coils. Patients first underwent non-contrast-enhanced T1-weighted image (T1WI) and T2weighted image (T2WI) scans in the axial, coronal, and the sagittal planes. Subsequently, the contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA; 0.1 mmol/kg) was injected intravenously using an automatic high-pressure injector and contrast-enhanced T1-weighted images were acquired. The scanning parameters for T1WI scans were fast spin-echo (FSE), repetition time (TR) = 540 ms, and echo time (TE) = 11.8 ms. For the T2WI scan, the parameters were FSE, TR = 4000 ms, and TE = 99 ms. The section thickness was 5 mm and the intersection gap was 1 mm.

| MRI assessment
All MR images were independently analyzed by two experienced radiologists. Disagreements were resolved by discussion and, if necessary, a third radiologist was consulted to help reach a consensus. As explained above, the 8th AJCC staging system differentiates between T2 and T3 stage NPC based on the presence or absence of invasion into the bony structures of the skull base or cervical vertebra and/or paranasal sinuses. In this study, however, instead of evaluating the invasion of the skull base as a whole, the radiologists assessed the invasion of each of the structures in the skull base. Table 1 lists the structures examined by the radiologists for signs of tumor invasion; the additional structures specifically examined in this study are in bold font. Invasion of the parapharyngeal space was defined as tumor extension beyond the pharyngobasilar fascia 15 and invasion of the carotid sheath was defined as tumor extension into the post-styloid space, as the carotid sheath region is medial to the styloid. 16 Since invasion of other structures are obvious and easy to read on MRI images, they are not listed here.

| Treatment and follow-up
All patients received intensity-modulated radiation therapy (IMRT). Briefly, the prescribed dose to nasopharyngeal gross tumor volume (GTVnx), that is, the primary tumor seen on clinical examination and in radiographs, was 66-72 Gy, and the dose to the metastatic lymph node area (GTVnd), that is, the clinically and/or radiologically observed enlarged lymph node area, was 64-70 Gy. In addition to IMRT, patients (stage II-IV) also received cisplatin-based concomitant or induction chemotherapy. Details of IMRT planning and dose prescription have been described previously. 4,17,18 Patients were followed up every 3 months in the first 2 years, and every 6 months thereafter, with a total follow-up duration T A B L E 1 Structures examined for T staging in the AJCC 8th staging system and our staging system of 5 years. The endpoints were overall survival (OS), defined as the period from the date of initial diagnosis to the date of death due to any cause; local recurrence-free survival (LRFS), calculated as the period from the date of initial diagnosis to the date of relapse; and progression-free survival (PFS), defined as the period from the date of initial diagnosis to the date of relapse or death from any cause, whichever occurred first.   Figure S2 shows the results of network analysis for selecting potential up-staging or downstaging factors. Invasion of the base of the sphenoid and the base of the pterygoid was very close to the survival node ( Figure  S2A), while the invasion of the bilateral parapharyngeal space or single/bilateral carotid sheath was close to the death node ( Figure S2B). On multivariate Cox regression  Table 3). Thus, it is reasonable to suggest that AJCC T3 stage NPC, with the invasion of the base of the sphenoid or base of the pterygoid, be reclassified as T2 stage, and that AJCC T2 stage NPC, with the invasion of bilateral parapharyngeal space or single/bilateral carotid sheath, be reclassified as T3 stage (Table 4).  Figure 1 shows the survival curves (OS, LRFS, and PFS) of T1 to T4 stage NPC patients classified by the AJCC 8th version and by our modified staging system. The survival curves for OS of AJCC T2 and T3 stage NPC are close together (log-rank test P = 0.531), whereas the survival curves for OS of reclassified T2 and T3 stage NPC are well separated from each other (log-rank test P = 0.020). We found a similar trend in PFS analysis. However, the survival curves for LRFS were close together for AJCC T2 and T3 stage NPC and reclassified T2 and T3 stage NPC. Figure S3 shows the N stage survival curves (OS, LRFS, and PFS) of T1 to T4 stage NPC patients classified by the AJCC 8th version. Figure 2 shows the survival curves for OS and PFS of T2 and T3 stage NPC patients in the validation dataset F I G U R E 1 Survival curves of T1 to T4 stage NPC patients classified by the AJCC 8th version and our recommended new staging systems. The survival curves for OS of AJCC T2 and T3 stage NPC are close together ( Figure 1A), whereas the survival curves for OS of reclassified T2 and T3 stage NPC are well separated from each other ( Figure 1B). OS, overall survival; LRFS, local recurrence-free survival; PFS, progression-free survival F I G U R E 2 Survival curves of T2 and T3 stage NPC patients in the validation dataset classified by our recommended new staging system. The survival curves for OS and PFS were clearly separated by our new staging system. Abbreviations: OS, overall survival; PFS, progression-free survival classified by our recommended new staging system. As in the training dataset, the survival curves for OS and PFS were clearly separated by our recommended new staging system. The 5-year OS and PFS were 87.2% and 75.7% for T2, and 75.7% and 68.1% for T3 stage NPC patients, respectively.

| Validation of our recommended new T2 and T3 staging systems
It should be mentioned that after reclassifying patients with the new criteria, the survival curves (especially for PFS) of T1 and T2 stages showed some overlap in the training dataset (P = .368).

| DISCUSSION
Our study confirmed that the 8th AJCC staging system does not separate the survival curves of T2 and T3 stage NPC cases. However, when AJCC T3 stage patients with the invasion of the base of the sphenoid bone or base of the pterygoid bone were downstaged to T2, and AJCC T2 stage patients with the invasion of bilateral parapharyngeal space or single/bilateral carotid sheath were upstaged to T3, the survival curves of the recommended new T2 and T3 stages showed clear separation. The recommended new staging system was also validated on an external sample.
Consistent with our hypothesis, we found that the invasion of different bony skull-base structures had a widely differing effect on the long-term survival of NPC patients. The best prognosis was seen with the invasion of the base of the sphenoid bone and the base of the pterygoid bone. This may be because these two bony structures are relatively close to the nasopharynx and therefore more likely to be invaded in the early stages when the tumor is small and the prognosis better. Furthermore, these two bony structures are located within the pharyngobasilar fascia, which acts as a barrier to remote metastasis. 19,20 Once the tumor extends to the bony structures located outside the pharyngobasilar fascia, the risk of remote metastasis and death increases substantially. These findings are very similar to those of Chen et al, 9 who observed that patients with the invasion of the base of the sphenoid or the base of the pterygoid had a better prognosis than those with the invasion of other bony structures, especially those with neural foramina. They suggested that instead of grouping all patients with skull base involvement together as one risk group, NPC patients should be classified into low-risk and high-risk groups according to the involvement of specific bony structures.
Consistent with previous reports, 15,21 we found that the invasion of the parapharyngeal space or single/bilateral carotid sheath was associated with poor prognosis. Parapharyngeal space involvement is known to be closely associated with distant metastasis, 16,22,23 which would explain the poorer prognosis of these patients. An interesting finding was that PFS and OS were shorter with the invasion of bilateral parapharyngeal spaces than with the invasion of a single parapharyngeal space. This phenomenon indicated that the identification of bilateral parapharyngeal invasion would be useful for prognostication. We also found that patients with the invasion of single/bilateral carotid sheath (which is also called the post-styloid parapharyngeal space) had poorer long-term survival than those with the invasion of some of the bony structures. This is not surprising as carotid sheath invasion by the tumor is very likely to also involve the blood vessels within the carotid sheath, 8 which would inevitably increase the risk of metastasis.
In this study, we attempt to create a recommended new staging system to separate T2 and T3 stage NPC cases. If this staging system is applied, about 30% of AJCC T2 or T3 stage NPC will be either upstaged or downstaged. The treatments for AJCC T2 and T3 stage NPCs differ, and this reclassification will help further optimize the treatment of NPC patients. Specifically, it will help avoid the overtreatment of some tumors that are misclassified as T3 stage NPC using the AJCC 8th edition. Moreover, it will also allow the timely intervention of other cases that are misclassified as T2 stage NPC.
The recommended new staging system described here has some limitations. First, it requires a thorough examination of MR images for evidence of invasion into each part, making the staging procedure more time-consuming. Second, with this recommended new staging system, the survival curves for T1 and T2 stages show some overlap. More studies are needed to establish a system that can clearly separate the different T stages. Finally, it should be mentioned that our study sample was relatively small; therefore, studies on larger samples are needed to confirm our findings.
In summary, we propose a new T2 and T3 staging system for NPC based on the absolute effect sizes of invasion of each skull anatomical structure. The recommended new staging system clearly separates the survival curves of T2 and T3 stage NPC and could help improve the prognosis accuracy and treatment selection in NPC.