Our study provided several notable findings: (1) among 505 NPC patients with synchronous metastasis, the most frequently involved organs or sites at diagnosis were the bones (65.9%), the liver (30.7%), distant lymph nodes (28.5%), and the lungs (26.9%), respectively; (2) UICC N category, number of metastatic lesions, liver involvement, cycles of chemotherapy, and radiotherapy to primary tumors were independently associated with the OS of patients with synchronous metastatic NPC; and (3) based on liver involvement and number of metastatic lesions, we proposed a new M categorization system to further subdivide the population into three M1 subcategories, which showed a high degree of difference regarding OS and have important implications in the management of the metastatic disease.
There has been only one report that has specifically evaluated the data related to synchronous metastatic NPC. Pan et al.  retrospectively analyzed the data of 376 NPC patients with synchronous metastasis, and the results in univariate analysis suggested that both liver involvement and the presence of multiple lesions were unfavorable factors for OS. However, these two factors failed to reach significance in multivariate analysis, which may possibly be explained by the relatively small sample size and the heterogeneity of the involved population, with the admission time ranging from 1995 to 2007 . Therefore, in this study, we conducted a detailed analysis based on a large cohort of NPC patients with synchronous metastases admitted to our center between 2000 and 2009.
The current study introduced the clinical course of synchronous metastasis in a large cohort of NPC patients treated in the contemporary era. The OS time after metastasis ranged from 1 to 120 months, indicating that long-term survival is possible in certain proportions of patients with metastases. The median OS time in our study was 24.9 months, which was close to the estimated 25 months reported by Lin et al.  and 22 months reported by Li et al. .
Liver involvement was reported to associate with an unfavorable prognosis [21, 22], and lung metastasis alone was a favorable prognostic factor among patients with metachronous metastatic NPC . By contrast, few studies addressed the issue of the prognostic values of metastatic locations among patients with synchronous metastatic NPC. In our study, a significant difference in OS time was found between patients with metastatic NPC with and without liver involvement (21.7 vs. 41.1 months, P < 0.001), whereas no significant difference was found between patients with lung metastasis alone and those with bone metastasis alone or distant lymph nodal metastasis alone. As liver metastasis has been conventionally regarded as an indicator of poor prognosis among NPC patients, the treatment has largely been palliative [8, 23]. In recent years, several studies showed that CT-guided radiofrequency ablation (RFA) can be performed with a high degree of technical effectiveness and offer the promise of prolonged survival time in selected NPC patients with liver metastases [17, 18]. However, these results must be interpreted with caution and future prospective studies with a large cohort are needed to validate these findings.
The association between the number of metastatic lesions (single/multiple) and OS has been extensively studied and demonstrated to be significant in NPC patients with synchronous and metachronous metastases by a series of studies [14, 15], whereas its prognostic value as compared with the number of metastatic locations remains unknown. It is intriguing that in our study, both the number of metastatic lesions (single/multiple) and the number of metastatic locations (isolated/multiple) were significant associated with OS in univariate analysis. A multivariate analysis that included all of the significant covariates suggested that the number of metastatic lesions, but not the number of metastatic locations, was an independent prognostic factor for OS. These results indicated that patients with single metastatic lesion need special attention. As there is enormous evidence that NPC patients with single metastatic lesion in isolated organ, such as the lung [17, 24], the liver , and the bone , can benefit from combined local and systemic therapies , an accurate imaging diagnosis for NPC patients with limited metastatic lesions will be of vital importance in identifying this group of patients and providing individualized treatment.
A major challenge we face with the TNM staging system is how to modify the M categorization system for a more precise prognostic prediction and treatment planning. Many studies have reported that the greater the tumor load, the worse the prognosis in NPC [28, 29]. We have proposed a theoretical formula for the assessment of metastatic NPC, V
t = V
1 + V
2 + V
3 +, …, + V
n + V
x, where V
3, …, and V
n are defined as the tumor volume of each visible lesion under the current best diagnostic imaging system, and V
x is defined as the total tumor volume of invisible lesions . The ideal strategy in the management of metastatic NPC is to eliminate all the visible lesions to achieve complete remission (CR) by combined local and systemic therapies and then to eradicate invisible lesions (V
x) by using chemotherapy, immunotherapy, or targeted therapy. However, this sophisticated system that localizes and targets every visible metastatic lesion is difficult to practice due to the restrictions in current diagnostic and treatment techniques. Hence, an M categorization system with a delicate balance of accuracy and practicality should be considered. Practicality requires that a new category strategy shall be relevant to current clinical practice, be evidence-based, and reflect the dominant prognostic factors consistently identified in Cox multivariate regression analyses. Based on our results and a review of the published literature, we propose to subdivide the status of synchronous metastasis of NPC into three M1 subcategories. The advantage of this proposed M categorization system is that it can differentiate patients with drastically different prognoses and emphasize a more active way to manage patients with single metastatic lesion. This system may also be useful in the design of clinical trials and help standardize the reported results of any therapeutic interventions.
A major controversy exists concerning the necessity of treating the primary NPC with an optimal treatment, especially for patients with distant metastases involving the liver or multiple organs or sites [20, 31]. Since 2011, concurrent chemoradiotherapy was suggested as a choice for selected patients (patients with distant metastases in limited sites or with a small tumor burden, or patients with symptoms in the primary or any nodal site) in the National Comprehensive Cancer Network (NCCN) guidelines. In more recent years, Tian et al.  retrospectively analyzed the prognosis of 85 NPC patients initially presenting with liver metastasis and found that radiotherapy for the primary tumor could significantly prolong survival time (no/yes: HR = 2.87, 95% CI = 1.61–5.10, P < 0.001), and 5 patients achieved long-term disease-free survival after undergoing radiotherapy for the primary lesion. Consistent with their study, our study showed that primary radiotherapy was independently associated with prolonged OS for patients with M1b and M1c NPC. These findings revealed that a considerable proportion of patients with extensive distant metastases could benefit from radiotherapy for primary NPC, and further studies are needed to identify the targeted patients.
Our study has several limitations. First, it is a retrospective study and the cohort was obtained from a specific, regionally based population that may be not representative of the general population of NPC patients with synchronous metastases. Second, the modes of chemotherapy and radiotherapy applied varied, which might have a confounding effect. Third, the serum Epstein-Barr virus (EBV) DNA level has been demonstrated to be an important prognostic factor among patients with recurrent/metastatic NPC ; however, we failed to include it in our analysis due to the lack of data at diagnosis in our cancer center (116 patients, 23.0%). The prognostic value of serum EBV DNA level and its association with the anatomical extent of the metastasis of NPC should be further assessed. Finally, the metastases of NPC in most patients involved in our study were clinically diagnosed, and only a small proportion (44 patients, 8.7%) had pathologic confirmation, which could be a potential source of bias. For these reasons, we must validate our findings in a multi-institutional prospective study in the future.