Management of orbital invasion in esthesioneuroblastoma: 14 years’ experience

Esthesioneuroblastoma (ENB) is a rare malignant tumor of the nasal vault that is usually diagnosed at a locally advanced stage [1]. Orbital invasion is frequently observed in ENB involving the ethmoid sinus. It has been proven that orbital invasion is associated with a poor prognosis and is commonly evaluated as stage C disease, according to the Kadish/Foote staging system [2]. The prognostic value of the distinction between invasion of the bony orbit and of the deeper soft tissue has been reflected in the American Joint Committee on Cancer (AJCC) staging categories, which divide ethmoid and maxillary tumors and differentiate the role of bone orbital wall invasion (T3) from invasion of the anterior two-thirds (T4a) and orbit apex (T4b), at least for squamous cell carcinoma and adenocarcinoma [3, 4]. However, whether the prognostic value of the degree of orbital invasion is applicable to ENB remains an open question due to the rarity of ENB.

The periorbit plays an important role against invasion and is recognized as a “landmark” of orbital exenteration over time in sinonasal tumors [5‐7]. With the introduction of endoscopic surgery and advanced radiotherapy techniques [8], the indications for orbital exenteration are continuously changing. Agreement has not been reached on the degree of orbital invasion that is oncologically safe when sparing orbital contents. A recent study had showed that orbital preservation could be performed in cases of tumors not adherent to extraocular muscles [9]. However, the histology of sinonasal malignancies was extremely heterogeneous in previous studies [9‐11], and the evaluation of orbital invasion was unclear [11], thus raising the risk of statistical bias. Furthermore, the indication for orbital exenteration in squamous cell carcinoma or adenocarcinoma may not be generalizable to ENB due to their differences in biological characteristic and prognosis.

We believe that orbital preservation can be achieved with the assistance of radiotherapy, even if the extraocular muscles and eye globe are involved in ENB. In the current study, we retrospectively reviewed and summarized our therapeutic strategy over the past 14 years for 60 ENB patients with orbital invasion to clarify the specific degree of orbital invasion and to analyze its influence on survival and orbital preservation. To the best of our knowledge, this is the largest study in which treatment and prognostic factors have been assessed in patients with ENB invading the orbit.

Due to the rarity of ENB, there is limited data on this cancer in the literature. As far as we know, this is a retrospective study with the largest cohort of ENB with orbital invasion thus far within a single institution. Several interesting and new findings were discovered from this report. First, the prognostic value of distinction between invasion of the bony orbit and deeper soft tissue was found to exist in ENB. Second, the survival rate after radical radiation was comparable to the combination of surgery and radiotherapy among patients with aggressive tumors and stages (Foote stage of C/D). Third, no patient was managed with orbital exenteration, even in cases that extended to extraocular muscles or the eye globe.

There is no standardized staging system for ENB, and many staging systems have been proposed for ENB. The Kadish staging system [2] is still the most popular system because of its simplicity and ease of application. According to the Kadish system, tumors that extend beyond the nose and paranasal sinuses are designated as stage C [2]. Therefore, the system recognizes orbital invasion as a relatively negative prognostic factor, given that tumors with orbital invasion are classified as stage C. However, there are many criticisms of the Kadish system, and the prognosis for each stage is inconsistent among studies [13] because the details of local extension of the tumor were not assessed. Joshi et al. [14] used the National Cancer Database to evaluate the prognostic ability of the Kadish staging system. This multivariate analysis controlling for stage failed to demonstrate clear survival differences between stages in the Kadish system, which poorly predicted prognosis over a 10-year horizon. The prognostic value of the distinction between invasion of the bony orbit and deeper soft tissue had been reflected in the AJCC staging categories, which divide bone orbital wall invasion (T3) from invasion of the anterior two-thirds (T4a) and orbit apex (T4b) for sinonasal tumors of epithelial origin [3, 4]. In our study, we followed the classification method proposed by Iannetti [12] (stated in Material and Methods). Using this classification method, a univariate analysis showed that grade I orbital invasion was associated with better OS and PFS than was grade II/III. The outcome means that deeper orbital invasion is a negative prognostic factor in ENB. To our surprise, there was no significant difference between grade II and grade III in survival rate, and the 5-year OS of patients with involvement of the orbital apex was comparable to that of patients without involvement (62.3% vs. 70.2%, p = 0.173). Based on this observation, we believe that the Iannetti classification method could be a good reference for clinical treatment, but a long-term additional study with a larger sample size should be conducted to help determine whether orbital invasion is an independent prognosis factor in ENB.

The treatment strategy of ENB remains controversial. Due to the rarity of these tumors and the lack of prospective randomized controlled clinical trials, there is no generally accepted therapeutic regimen for ENB [15‐17]. Comprehensive treatment is usually recommended, as the majority of cases present with advanced ENB, and surgical resection followed by postoperative radiotherapy demonstrated better treatment outcomes with 5-year OS rates of 60–88% in previous retrospective reports [18‐20], compared to radiotherapy alone (29–54%) [15, 19, 21, 22]. Although previous reports indicated that comprehensive treatment was superior to radical radiotherapy, the results should be interpreted with caution, because patients with wider infringement of lesions may be given radical radiotherapy rather than surgery. Therefore, there was a significant case selection bias between various treatment modalities [15, 19]. The clinical data of 21 patients with T4 ENB treated with C-ion radiotherapy were retrospectively reviewed by Suefji [23]. The 3-year overall survival and local control rate were 88.4 and 83%, respectively. Nakamura et al. [24] described 42 consecutive patients who received proton beam therapy with curative intent for ENB. Twenty-eight (67%) patients had Kadish stage C and achieved a 5-year OS of 76%. In our study, 7 (50%) patients had a complete response among the definitive radiotherapy group. More interestingly, the abnormal signals of residual tumors which disappeared spontaneously during follow-up were found in 3 patients with PR. Radical radiotherapy still achieved a 5-year OS of 63.5%, which was higher than that of surgery plus postoperative radiation (58.2%). These results suggest that radical radiotherapy is not merely palliative but has therapeutic efficacy as a primary treatment for a notable percentage of locally advanced or unresectable ENBs.

For Kadish/Foote stage C tumors, there is little consensus regarding the timing of radiotherapy for a combination of surgery and radiation. The complex anatomical location, as well as visual and facial structures, is “challenging” in terms of performing radical surgery while preserving functional organs and improving local control rates. Only a few studies have been reported in terms of preoperative radiation in the treatment of sinonasal cancers. Erik et al. [25] reported 79 patients with sinonasal cancer who were treated with preoperative radiation, and orbital exenteration was performed in 7% of these patients. A total of 11,160 sinonasal malignancy patients were identified from the National Cancer Data Base for analysis by Robin [26]. The findings were validated in propensity score matching, and it is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin and improved OS. For ENB, Polin et al. [27] showed significant tumor reduction in two-thirds of patients treated with preoperative radiation with or without chemotherapy and increased recurrence-free survival in those responders. Sohrabi et al. [28] reported complete pathologic responses in two stage C ENB patients treated with neoadjuvant concurrent radiochemotherapy. In our series, preoperative radiotherapy yielded the most promising results, including a higher long-term survival, than did postoperative radiotherapy (5-year OS 79% for preoperative radiation vs. 58.2% for postoperative radiation, p = 0.215). Considering the high residual rate of primary surgery (76%), we believe that preoperative radiation not only improves the tumor resection rate but also increases the potential for orbital preservation surgery by reducing tumor mass and eliminating microscopic lesions at the periphery of the tumor. The treatment strategy of preoperative radiotherapy and/or chemotherapy followed by surgery for Kadish stage C/D disease was also advocated for by a European position paper on endoscopic management of tumors of the nose, paranasal sinuses and skull [29].

The indications for orbital exenteration are continuously changing, from invasion of orbital periosteum [30] to beyond the periosteum [6], to extraconal fat [10], and extraconal muscles [9]. Imola and Schramm [10] reported 66 patients in which the orbit was preserved, even in cases of limited involvement of extraconal fat. Orbital exenteration was performed in 12 cases, and similar survival rates were achieved in cases of orbital preservation and exenteration. In a cohort reported on by Lisan et al. [9], orbital preservation was undertaken in 66% of cases, whereas orbital exenteration was performed in cases of invasion of the extraocular muscles, ocular globe, or orbital apex. Local control rates and 5-year survival were similar in both groups. In previous studies, which include several pathological types [9‐11, 25] with varying prognoses, the evaluation of orbital invasion was ill defined [11, 25]. In our study, the histology was limited to ENB. Due to the good response to radiotherapy, no patient underwent orbital exenteration. The 5-year OS was 69% among all cases, which is consistent with the rates of 65–75% reported in previous studies [18‐20]. These results suggested that orbital preservation did not lead to poor survival rate, and invasion of extraocular muscles or the eye globe was not a contraindication for eye-sparing surgery in ENB.

In our study, lymph node status is the important prognostic factor affecting OS, DMFS, and PFS. Regarding 8 patients with N+, 7 patients underwent elective neck irradiation with no regional recurrence. According to this observation, we consider that patients in stage D disease with LN metastasis require only irradiation to the neck instead of neck dissection. Regarding patients with N0, ENB has a high rate of late regional recurrence (20–44%) [31, 32]. However, the value of prophylactic elective neck irradiation (PENI) for patients with N0 neck status is still unclear. In a large cohort (116 patients) reported by Yin et al. [33], PENI was an independent favorable predictor for regional controlling, and the author recommended PENI as a part of initial treatment strategy for patients with Foote stage B/C tumors. Two other studies hold a differing opinion that PENI plays a limited role in improving regional control [34, 35]. Our study showed that PENI improved the LRFS significantly from 58.1 to 100% (p = 0.004). Although the p- value was not statistically significant, the 5-year OS was still higher in patients treated with PENI than patients not treated with PENI.

Although patients who received chemotherapy had better LRFS compared to those who received treatment without chemotherapy in our study, the therapeutic effects of chemotherapy on ENB cannot be determined for the reason that the cohort lacked a standard chemotherapy protocol that was uniformly applied. Further clinical studies are needed to evaluate the value of chemotherapy for ENB. Our study had several other limitations. It was a retrospective analysis based on data from a single center. The Hyams grading system [36] that can be used as a prognostic indicator for ENB was not assessed in our study. A multicenter clinical trial is indispensable for further investigation.

Our data suggest that orbital invasion in grade II/III was significantly associated with adverse survival outcomes. Invasion of either the extraocular muscles or eye globe is not a contraindication for eye-sparing surgery. Primary radiotherapy achieved comparable survival to surgery plus radiotherapy in advanced and unresectable ENB. Prophylactic radiotherapy to the neck in patients with N0 significantly reduces the risk of regional recurrence.