This is a large single-center retrospective cohort study with consistent treatment modality including surgery and radiotherapy, which has achieved good survival results. The majority of frontal sinus malignancies present with peripherally invasive progression lesions without regional lymph node metastasis. And most of them fail to achieve complete resection with negative margins, suggesting the importance of postoperative radiotherapy and the potential role of neoadjuvant therapy. Local recurrence is still the predominant failure pattern, and no regional lymph node failure has been found. In addition, this is also the first study to identify the tumor invasion pathways of primary frontal sinus malignancies.
Regarding the characteristics of entire cohort, our series included only six males, aging from 30 to 53 years, which was similar to the male predominance of sinonasal tumors, but different from the peak incidence in the 5th and 6th decades of life [2, 18]. The most possible reason was the selection bias because of small sample sizes. Basically consistent with the incidence of 90% reported in the previous literatures , SCC occupied an absolute superiority (83.3%) in our series, which was higher than the proportion of SCC ranging 42–54% in sinonasal tumors [2, 20]. However, the contradictory results were that two large population-based studies showed that SCC accounted for 40% -48% of frontal sinus tumors [1, 2]. On one hand, it might be due to the bias caused by small sample size in our study. On the other hand, it should not be ignored that the population-based study was difficult to ensure the correct diagnosis and lymphoma was usually included for analysis. Considering tumor characteristics, both six cases from our cohort and 13 cases summarized in Table 1 were stage II or III at diagnosis. Consistent with this, the population-based analysis including 171 FSMs showed localized diseases (no tumor invasion) represented only 11% . In comparison to FSMs, many studies reported that locally advanced lesions (T3 or T4) accounted for 60% -75% of overall sinonasal tumors [2, 20, 21], demonstrating FSMs were more prone to present with extensive invasion of adjacent sites than other paranasal sinus tumors. Although many studies reported that overall lymphatic metastasis of sinonasal tumors at diagnosis usually occured in 10–20% of patients [20, 22], which could be as high as 30% in squamous cell or poorly differentiated carcinoma of maxillary sinus , the incidence of lymphatic metastasis for FSMs was seldom reported. According to our experience, regional lymphatic metastasis rarely occurred in FSMs with the exception of lymphoma. Neither our series nor the 13 cases listed in Table 1 found regional lymphatic metastasis at initial diagnosis, which was also in support of this theme.
Our study also described four specific pathways of tumor invasion, which deepened the understanding of the clinicopathological characteristics of FSMs. Anatomically, the floor of the frontal sinus was the thinnest and easily invaded by tumor, which explained why frontal sinus lesions were more likely to invade downward the ethmoid sinus. And commonly lateral invasion from the ethmoid sinus to the orbit was owing to the thin lamina papyracea. On the other hand, the inner plate of frontal bone was thinner than the outer plate, which could lead to another common route with posteriorly invading the dura mater. Given the extensive infiltration of FSMs, we hypothesized that clinical target volume (CTV) should routinely include these high-risk areas. In addition, the unique tumor invasion pattern of primary FSMs made its symptoms and signs different from other sinonasal tumors. To our knowledge, the most common described symptoms at initial diagnosis included nasal obstruction, nasal discharge, epistaxis, mass in the nose, and facial pain . However, our data demonstrated that nasal obstruction occurred in only one patient, and ocular symptoms including proptosis as well as visual impairment were the most common, consistent with the high orbital invasion rate of our cohort.
The multimodality treatment consisting of surgery and radiotherapy had been shown to improve clinical outcomes of advanced-stage sinonasal tumors, compared with single-modality therapy [20, 24, 25]. Our study also adopted the unified treatment modality of surgery and adjuvant radiotherapy. Transfacial or craniofacial approach could provide a wide range of potential en bloc resection for anterior skull base tumors involving the dura mater . Whereas, craniofacial approach provided greater exposure to the ventral skull base, especially when the frontal lobe was invaded . In our study, three cases were treated with transfacial approach, one received endoscopic combined with transfacial approach, and other cases with invasion of frontal lobe underwent craniofacial resection. Even if the principle of en bloc resection was followed, the R0 resection rate was still extremely low, only 16.7%. In this condition, the treatment strategy of surgery and adjuvant radiotherapy obtained good clinical efficacy with the median survival time of 56 months, illustrating the importance of adjuvant radiotherapy and the value of comprehensive treatment. In an early single-center case study, Frew retrospectively analyzed six cases of frontal sinus SCC receiving radiotherapy alone, with a median survival time of only 13 months .
The existing literatures described that the overall treatment failure rates of sinonasal tumors ranged from 41–67% [21, 27, 28], and local recurrence was the predominant failure pattern. Likewise, our study yielded the similar results with a slightly lower treatment failure rate. Additionally, in the condition of only 2 cases receiving cervical prophylaxis irradiation, there was no regional lymph node failure in our cohort during the follow-up. Brownson et al also reported the regional lymphatic metastases rate of FSMs was less than 10% . Due to extremely rare regional lymph node metastases and failure, cervical prophylaxis irradiation might be not necessary for primary FSMs, which could help reduce treatment toxicities. In terms of surgical complications, although PORT was postponed in the two patients due to complications, it did not affect the clinical efficacy. As for radiation toxicities, although patient 3 experienced frontal necrosis and hearing loss, the patient received R2 resection with avoiding removal of orbital contents, thereby preserved part of the vision and developed no treatment failure, indicating that the organ-sparing surgery plus adjuvant radiotherapy might result in satisfactory outcomes. Overall, the complications and toxicities were tolerable for our cohort.
Despite our study provided long-term survival results of surgery combined with PORT for primary FSMs, there were still many limitations due to small sample size. Firstly, the case selection bias from retrospective analysis was particularly magnified in small sample studies, such as the distribution of pathologic type, age, and gender discussed previously. Thereafter, although all cases in this study adopted combined treatment modality of surgery and adjuvant radiotherapy, the surgical approach were not uniform, which affected inductive analysis of case series to a certain extent. Lastly, our experience was based on an inductive analysis of limited cases, therefore it was far from extrapolating conclusions in optimal treatment of primary frontal sinus malignancies.