Nasopharynx carcinoma (NPC) is the most common malignant tumor of the nasopharynx, and this cancer is especially endemic in southeast Asian and Mediterranean populations (1). Other risk factors also include Epstein-Barr virus (EBV) exposure (2–4), environment (5, 6) and heavy alcohol intake (7, 8). This disease is often initially asymptomatic, and the first symptoms (nasal obstruction, sore throat, headache, epistaxis, and seromucous otitis) are non-specific. NPC is unfortunately commonly diagnosed once it is locally evolved, and greater than 80% of patients present with lymph node metastases at the time of the diagnosis. Based on the World Health Organization (WHO) histopathological grading system (9), there are three types of NPC including keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, and undifferentiated carcinoma.

Diagnosis is based on biopsy of the resected nasopharyngeal mass. Prior to biopsy, careful physical examination and fiberoptic endoscopic examination, evaluation of cranial nerve function, computed tomographic (CT) scan, magnetic resonance imaging (MRI) and EBV titers test should be performed (10). Detailed stage information for NPC is defined by the TNM system (11).

Given the proximity between nasopharyngeal cancer and essential risk organs, such as the brainstem and visual apparatus, treatment is complicated (10). Standard treatments for nasopharyngeal cancer patients include radiation therapy, concurrent chemoradiation followed by adjuvant chemotherapy, and surgery. Among these treatments, high-dose radiation therapy with chemotherapy is the primary treatment (12). Some new types of treatment for NPC are currently being tested in clinical trials. For example, monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread (13). For patients with EBV infection, a trial focused on EBV DNA-based individualized treatment is ongoing (14, 15). NPC treatments may cause side effects, such as anemia, appetite loss, alopecia, and lymphedema, which are also commonly reported in other cancer treatments.

According to our literature review, major factors affecting the prognosis of NPC include tumor size, and neck node involvement (16). Other factors potentially associated with the outcome of treatment include age, pregnancy, immunodeficiency, incomplete excision of involved neck nodes, and locoregional relapse, are still under study. The purpose of this article is to assess the prognosis differences between patients of initial and second primary NPC.

In our study, we used SEER data to assess the interaction between TNM stage, AJCC stage, primary site, histology type, marital status, race, age at diagnosis, and survival in patients with NPC. Patients with second primary NPC suffered worse prognosis in comparison with the initial primary NPC group. Our study showed a significant survival benefit for patients younger than 45 years of age as well, regardless of the primary tumor site. As age increased, the prognosis tended to become worse. Moreover, in each age group, the initial NPC subgroup exhibited a better prognosis compared with the second NPC group. A study showed the negative effect of second primary malignancies, including the occurrence of NPC, on the survival rate of 93,891 patients who suffered from head and neck cancer (17). In addition, it is thought-provoking that in other tumors, such as lung and colorectal cancer, the mortality of the second primary cancer was higher than that of the initial (18, 19). These survival patterns are fundamentally consistent with our literature review. The existence of this situation is complex and multifactorial. Chen et al. found that the longer the interval between the second and initial primary cancer, the higher the morbidity and mortality of the second primary cancer occurred in a 25-year study in Taiwan (20). Kong et al. reported that the morbidity of second primary tumors tended to increase after definitive radiation therapy. Older patients with NPC (age ≥ 50 years) may be at increased risk (21). Chemotherapy and radiation therapy as well as some other types of cancer treatment may increase the risk of a second primary cancer. The presence of an initial primary cancer may also indicate some inherited gene mutations or existing exposure to cancer-causing factors, such as alcohol and tobacco, thus, the risk of second primary cancer increases. Overall, advanced age is the most important risk factor for most cancers (22). In addition to increased susceptibility to cancers, aging patients also commonly exhibit other diseases, leading to a weak physical condition that confers fragility when facing extra health problems and poorer long-term survival. A small discrepancy was noted in the groups of patients >45 years of age. Specifically, differences in CSS rates between initial and second primary NPC were not markable. This finding may be attributed to the fact that as patients age, more patients die as a result of factors other than NPC, especially in consideration of the aforementioned physical characteristics of aging people.

Female was observed as a weak protective factor for NPC via multivariate analysis. Compared with cases with unknown race information, a notable survival benefit was observed in African and Caucasian patients. Similar results were found both in our study and a previous study, which indicated that survival of initial NPC exhibited no preference for any gender or race (23). However, the concentration on race- or gender-related survival benefits of previous research in second NPC is lacking. NPCs most commonly start in the squamous cells lining the nasopharynx (24). The squamous cell subtype of NPC, which was reported as the major type in both initial and second primary NPC cases, was associated with a less favorable prognosis in our study. Baxi SS et al. reported that many survivors afflicted with head and neck squamous cell carcinomas ultimately died from cancers other than these malignancies and/or noncancer causes (25). The primary site may not significantly affect the prognosis of squamous cell NPCs.

The risk of death was steadily augmented based on elevated tumor T-stage except for T0, and the lethal risk of M1 stage cases dramatically exceeded that of M0. In contrast, such a clear trend was not noted in patients of different N-stage subgroups. Risk of N3 stage noticeably outweighed N0, N1, and N2, but the risks in the three latter stages were not distinguishable. Primary NPC is known for its high metastatic potential, primarily to lymph nodes, via TGF-β/SMAD signaling and Snail/TEL2 pathways (26, 27). Malignancy of tumors exclusively involving adjacent lymph nodes may not conspicuously influence the differences in NPC prognosis. Initial NPC exhibited an incidence roughly equivalent to that of second NPC for each grade of T, N, or M stage. With respect to the composition of T0 group in our dataset (only 16 cases in total and 9 out of them were M1, which meant grouping by one dimension perhaps interrelated with others) and based on clinical experience, we analyzed the AJCC stage of cases. As the stage changed from I to IV, the risk of death significantly increased, ideally displaying the consistency between clinic prognosis and AJCC staging. In each AJCC stage group, the initial NPC subgroup exhibited a more favorable prognosis compared with the second NPC subgroup, indicating that primary site may be an independent risk factor beyond AJCC staging, and second primary malignancies might be a complex condition for current staging systems.

Prominent benefits were also noted for patients receiving standardized treatments compared with untreated. Any type of surgery, radiation, or chemotherapy that was appropriately performed significantly reduced mortality regardless of the primary site. Given that radiation therapy in localized head and neck cancers decreased the incidence of second head and neck cancer cancers, the reason for the better prognosis may be complicated (28). This finding indicates that once NPC is diagnosed, the patient should initiate available treatments as recommended as soon as possible.

The survival trends in SEER datasets in this study are generally consistent with the published literature, and statistical analysis of different aspects revealed compatible results. These results demonstrated that our findings were robust. Although SEER has collected information for cancer statistics on a large number of patients in the United States, NPC is still a rare tumor in this database considering the significant difference in prevalence among races and districts. Given that certain information is limited in SEER datasets, grouping criteria may not be definite and may require more deliberated discussion. For example, subgroups of the histological type “non-squamous cell carcinoma” and age could be stratified using a more detailed method, which may help adjust the accuracy of our conclusions. Additionally, the factor of interval between the index cancer and the second primary cancer was not included in this study. Patients with metachronous second primary head and neck cancers exhibit a better prognosis compared with those who present with synchronous lesions, implying the possibility of survival variance between early and late second NPCs (29–31). Tobacco and alcohol use in NPC survivors was not discussed here but has been highlighted as a threat to survival rates of cancer patients (32–34). Given these limitations, future studies are warranted to confirm the observations reported here.

In conclusion, our study indicated that patients with second primary NPC exhibited a worse prognosis compared with those with initial NPC in all AJCC stage and age at diagnosis subgroups. Despite the primary site, NPC patients could benefit from standardized treatments, including surgery, radiation and chemotherapy.