Paranasal sinus (PNS) malignant neoplasms are a rare form of head and neck malignancy, accounting for <3% of upper aerodigestive tract malignancies [1], with approximately 0.6 cases per 100,000 people in the United States [2]. PNS cancers usually present as locally advanced disease due to the late onset of symptoms or the fact that early symptoms resemble common sinusitis or rhinitis. As a result, the treatment strategy is focused on achieving adequate local control while preserving critical nearby anatomic structures [3]. To our knowledge, although there are no randomized trials comparing different treatment strategies, surgery followed by adjuvant radiation is generally accepted as the mainstay of treatment, when resectable [3-5].

PNS malignancies have a relatively low incidence of regional nodal metastases at initial diagnosis, ranging from 8.3% to 21.9% [6-8]. This low incidence could be explained by a relatively sparse network of lymphatic drainage in the maxillary sinus, which consists most of the PNS malignancies. This low incidence has led to controversies regarding treatment of the neck in patients with clinically node-negative (cN0) PNS cancer. Some researchers argue that elective neck treatment (ENT) in these patients is unnecessary as no factors predictive of regional nodal metastasis are found, making the patient selection for ENT difficult [9]. In addition, the absolute regional nodal metastasis rate remains relatively low and is usually accompanied by local failure, which remains a major problem that results in poor prognosis [10]. On the other hand, several other retrospective reports insist that ENT is beneficial, especially when some adverse features exist [11,12]. Recently, a retrospective review of regional failure (RF) in cN0 patients with squamous cell carcinoma of the maxillary sinus with treatment of primary site only, showed that the rate of occult neck metastases was not negligible (14.3%) [13]. As there have been no randomized trials regarding this issue, the controversy over ENT is ongoing.

Despite considerable debate surrounding this issue, little is known about the need for ENT or pattern of failure in PNS cancers other than cancer of the maxillary sinus. In light of these issues and the ongoing controversy, we conducted a retrospective study to investigate different treatment outcomes between patients with and without ENT in cN0 PNS carcinoma, including sites other than the maxillary sinus and pathology other than squamous cell carcinoma. In this study, we aimed to propose optimal indications regarding ENT in patients with cN0 PNS cancers and investigate the prognosis of patients with RF.

In the present study, we showed that ENT has no benefit regarding survival rates or failure patterns, including RF rates, in patients with cN0 PNS cancer. RM was the only significant factor for survival rate; however, the addition of ENT did not have a significant impact on OS, PFS, or pattern of failure. This result was consistent in the subgroup analysis by tumor site, histologic type, and T stage. However, the RF (+) group showed dismal prognosis, similar to that of the DF (+) group, mainly due to sequential distant metastasis or combined local progression, suggesting the need for further investigation of proper regional management.

The efficacy of ENT in PNS cancer has been a controversial issue for many years. As a result, there has been no ‘gold standard’ regarding ENT in patients with cN0 PNS cancer. Our results, showing no significant benefits of ENT, are consistent with those of several studies stating that ENT is unnecessary in patients with cN0 PNS cancer. The clinical significance of ENT has been questioned by several researchers owing to the relatively low incidence of RF compared with local failure. Kim et al. [10] analyzed 116 patients with maxillary sinus squamous cell carcinoma. During follow-up, the RF rate (19%) was far lower than the local failure rate (68%). Park et al. [15] also recently reported that the rate of occult cervical metastasis in maxillary squamous cell carcinoma was not sufficiently high (15%) to routinely recommend elective neck dissection. The RF rates in previous studies are fairly consistent with the RF rate in our study (17%). Moreover, previous researchers have pointed out that no subgroup of patients at higher risk of RF has been identified [9]. Our findings, showing no benefit of ENT in the subgroup analysis by tumor site, histologic type and T stage, support this idea. In addition to these findings, our study showed that ENT had no benefit with respect to OS, PFS, or RF rates. Also, pattern of failure revealed that RF mostly occurred in maxillary sinus cancer or squamous cell carcinoma when ENT was not performed. The most common RF site was ipsilateral neck level I or II. We believe that these findings could provide useful information to radiation oncologists when they need to decide whether to perform elective neck irradiation or not in cN0 PNS cancer patients. In addition, to our knowledge, this study is one of the few studies including a considerable number of patients that directly compares the efficacy of ENT with respect to survival and pattern of failure in patients with cN0 PNS cancer.

However, our results contradict some previous arguments made in former studies. Jiang et al. [12] and Joosten et al. [13] claimed that elective neck irradiation should be considered in patients with squamous cell and undifferentiated carcinoma or advanced T stage because the RF rate was high (19%–38%) in these patients. Recently, Jeon et al. [16] reported that ENT was effective in preventing RF in squamous cell and undifferentiated carcinoma of the maxillary sinus with posterior wall invasion. Among 8 patients who received ENT in their study, only 1 patient had RF, whereas 9 of 47 patients who received ENT and were initially cN0 experienced RF in our study, showing that ENT might have a considerable effect on survival.

The reason that the results of our study conflict with those of other studies could be explained in several ways. First, the patient subset in our study differs considerably from that of other studies [11-13,16,17]. We enrolled all patients with PNS cancer, including those with ethmoid sinus and sphenoid sinus cancers. We also included histologic subtypes other than squamous cell carcinoma, to determine the efficacy of ENT in all PNS cancers. Although our subgroup analysis by tumor site, histologic type, and T stage did not show positive impact of ENT on OS and PFS, the number of patients in each subgroup might have been insufficient to achieve statistically significant difference since other studies showed clinical benefit in specific patient subsets as aforementioned. Also, the possibility that other factors such as surgical pathology characteristics (e.g., RM, LVI, PNI) could affect survival outcomes cannot be excluded [13,18]. Second, previous studies [12,17] might have included patients that would currently be diagnosed as clinically node positive due to advancements in imaging techniques. Studies conducted before the widespread use of CT or MRI relied on clinical nodal staging based on physical examination or plain radiography, which likely missed some patients that would have been diagnosed as node positive using modern imaging. On the other hand, at our institution, CT has routinely been used for initial staging in head and neck cancer patients, and MRI was added to the routine staging process after the mid-2000s. In other words, our results should be accepted on the basis of precise radiologic evaluation. Lastly, the proportion of patients who underwent chemotherapy differed from that of other groups. In our study, 35% of the total patients had chemotherapy. This differs substantially from other studies specifying the proportion of patients that received chemotherapy (58%–81%) [16,19]. Although our study did not show a significant effect of chemotherapy on survival, we should nevertheless consider the impact of chemotherapy, as some reports insist that survival or RF rates could be affected by chemotherapy [16,19,20].

In our study, univariate analysis of PFS showed that primary site and RM were significant factors whereas chemotherapy showed marginal significance. After multivariate analysis with ENT and the above factors, RM was the only significant factor (p = 0.02). Regarding OS, although RM did show prognostic marginal significance in univariate analysis (p = 0.12), no factors showed significant prognostic values in multivariate analysis. These findings are in line with previous findings that complete surgical resection of the primary tumor is essential for long-term survival in this type of cancer [3,10,19,21]. Local control is the key treatment factor in patients with PNS cancer because of the critical organs located nearby, such as the brain, brainstem, optic nerve, inner ear, and so forth. Repetitive local failures may unfavorably affect patient quality of life and may make local control very difficult. Furthermore, according to a report by Kim et al. [10], local recurrence precedes most nodal failures, again highlighting the importance of local control. Similarly, in our study, 13 of 21 (62%) patients with RF had local failure preceding RF. Especially in the ENT (+) group, all in-field failures had local failure preceding RF, or simultaneously with RF. These local failures might have contributed to the relatively high in-field failure rate despite that adequate elective irradiation dose of 44-51 Gy was given. Moreover, patients who underwent chemotherapy had worse prognosis in univariate analysis than patients who did not receive chemotherapy. This indicates that this patient subset featured various risk factors at initial diagnosis or after surgery, which led physicians to add chemotherapy. After multivariate analysis, chemotherapy showed no prognostic significance.

In subgroup analysis, no subgroups were identified to have benefit from ENT in terms of survival outcomes or regional failure rates. All tumor sites showed no statistically significant differences according to addition of ENT in OS and PFS. All histologic subtypes (squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma) and T stages (T2-3, T4 stage) also mostly showed similar results in OS and PFS. However, this result should be carefully interpreted. It is highly likely that patients with known risk factors of locoregional recurrences would have received ENT (+), which could have resulted in bias in this retrospective study. The finding of worse PFS even with ENT in subgroup of adenoid cystic carcinoma and T2-3 stage might be explained by this bias. Although statistically significant difference of patient and tumor characteristics between the ENT (+) and the ENT (−) group in each subgroup was not found due to small number of patients, it is possible that the effect of ENT on survival outcomes and RF rates was masked by this bias.

On the other hand, despite the inefficacy of ENT on survival outcomes and pattern of failure shown in our study, patients with RF clearly had dismal prognosis compared with patients who did not have RF. The 5-year OS and PFS rates were 41% and 14%, respectively, in the RF (+) group, which were significantly worse than those of the RF (−) group (p < 0.01). A notable point was that the survival outcomes in the RF (+) group were similar to those in the DF (+) group. The worse prognosis of patients with RF than that of patients without RF has been previously reported in several studies. Paulino et al. [17] found a statistically significant difference in OS rates between the RF (+) and RF (−) groups. A similar pattern was also discovered in a retrospective review of maxillary sinus cancer, showing 5-year survival of 37% in patients with neck control, and 0% in patients with neck relapse [11]. Another study also pointed out that the prognosis of RF patients was similar to that of patients with T4N0 disease [10]. According to our study, patients who experienced RF mostly died of organ failure caused by subsequent distant metastasis or combined local disease progression. The dismal prognosis of patients with RF and possible bias in our study emphasizes that efforts should continue to find a specific patient subgroup in this disease that would benefit from ENT, to improve survival in this disease, yet it has not been found in present study.

Our study is a retrospective review, and thus has innate limitations. First, some specific surgical pathology characteristics (e.g., RM, PNI, LVI status) were missing. Among patients who underwent surgery, many previous pathology reports have lacked information on those characteristics. As a result, analysis based on specific pathology characteristics was limited. In addition, PNS cancers other than maxillary sinus (ethmoid sinus, n = 13; sphenoid sinus, n = 2) or pathology other than squamous cell carcinoma (adenocarcinoma, n = 5; adenoid cystic carcinoma, n = 23) might have been insufficient in number to show any statistically significant difference in subgroup analysis. However, although the number of patients was small, subgroup analysis with specific tumor site or pathology, including analysis excluding adenoid cystic carcinoma, did not show different outcomes. Also, the strength of the present study is quite clear in that it is the one of the few studies directly comparing the efficacy of ENT in patients with PNS cancer whose initial clinical diagnosis was N0, with respect to survival and pattern of failure.

In conclusion, our retrospective review indicated that ENT might have no apparent benefit regarding OS, PFS, pattern of failure, as well as RF rates, in patients with cN0 PNS cancer. ENT should not be generalized to all patients with cN0 PNS cancer. This treatment should only be considered carefully in patients with many adverse features after multidisciplinary discussion. Instead, local control should be considered first; our result showing that RM status is a statistically significant prognostic factor for survival supports this idea. However, the dismal prognosis of patients after RF and the limitations of this retrospective study emphasize the need for further research with larger cohorts, to identify the specific patient subset that would benefit from ENT.