Introduction

Esthesioneuroblastoma (ENB), also designated as olfactory neuroblastoma, is a rare malignant neoplasm of the sinonasal tract, originating from the olfactory neuroepithelium. ENB accounts for to 3–6% of nasal and paranasal sinus cancers [1, 2]. ENB affects individuals of all ages, with an apparent bimodal distribution, with peaks in the second and sixth decades of life [2]. It occurs in both genders and across ethnicities, with no apparent familial predisposition. As in other intranasal tumors, initial symptoms are non-specific and include nasal obstruction, epistaxis, cephalgia, hyposmia, exophthalmos and amaurosis, depending on the extension of the tumor to paranasal sinuses, orbital region and/or anterior skull base [2, 3]. ENB has no specific radiological findings, requiring a biopsy of the lesion to confirm the diagnosis by histoimmunopathology [2]. The modified Kadish system [4, 5] is commonly used for staging ENB. In stage A, the tumor is limited to the nasal cavity; in stage B, the tumor extends into the paranasal sinuses; in stage C, the tumor invades beyond the nasal cavity and paranasal sinuses and in stage D, it presents with distant metastases. The international TNM system [6] is also used for the staging of disease. Given the rarity of the tumor, the majority of articles published regarding the disease are retrospective reports, most often case reports or small heterogenous series [3, 7-10]. Therefore, there are no standard guidelines regarding its treatment. The few available studies reported better outcomes with a multimodal approach [11–14].

We aimed to review our institute’s experience in the treatment of ENB over 38 years and assess the survival outcomes.

Materials and methods

We conducted a unicentric retrospective review of 20 patients with histologically confirmed ENB, treated in our Institution between 1984 and 2022. Medical records of all patients were reviewed. Patients’ characteristics, clinical presentation of disease, staging and treatment were analyzed. The diagnosis of ENB was based on imaging findings and confirmed by histopathology. All patients were staged according to the modified Kadish system [4, 5] and the 8th edition of American Joint Committee on Cancer tumor–node–metastasis (AJCC/TNM) staging [6].

Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis. The site of recurrence and salvage therapies were recorded. Statistical analysis for OS and PFS was estimated by the Kaplan-Meier method using R statistical software v4.1.0. The Institutional Ethics Committee approved this study. The ethical standards displayed in the Declaration of Helsinki (1964) and its later amendments were followed.

Results

The patients’ characteristics and therapeutic approaches are described in Table 1. The median age was 51 years (20 to 76 years), with 40% of patients being over 60 years old at diagnosis. Sixty-five percent of patients were men. The most common symptoms at diagnosis were: nasal obstruction (78%), recurrent epistaxis (56%), headache (28%), rhinorrhea (28%), hyposmia (28%), proptosis (17%), facial/neck mass (17%), followed by dizziness (6%) and diplopia (6%).

According to the modified Kadish staging system, there were: 1 stage A patient (5%), 7 stage B patients (35%), 11 stage C patients (55%) and 1 stage D patient (5%). Regarding TNM staging, 3 patients presented early-stage disease (T1–2) and 17 advanced disease (T3–4), one of the latter had cervical metastasis (N3) at diagnosis. Seventeen patients underwent surgical resection, 10 of them received postoperative therapy [7 radiotherapy (RT) and 3 chemoradiotherapy (ChRT)]. The remaining 3 patients were treated with ChRT and chemotherapy (ChT), either alone or followed by ChRT. The majority of the patients (71.4%) treated with surgery alone were stage B at diagnosis. The remaining 2 stage B patients received surgery followed by adjuvant treatment. Of the 11 stage C patients, 7 (63.6%) underwent surgery and adjuvant treatment, 2 (18.2%) surgery alone, 1 (9.09%) systemic treatment and 1 (9.09%) ChRT. The patient with stage A at diagnosis was treated with surgery followed by RT, while the patient with stage D received neoadjuvant chemotherapy, followed by ChRT.

RT was delivered to the tumor bed and local extension, in the dose of 50 to 70 Gy, at 1.8–2 Gy/day, 5 days a week. One patient was treated with Cobalt-60, in the dose of 80 Gy. Until 2011, a total of 4 patients were treated with 3-dimensional conformal radiation therapy (3DRT). Afterward, 8 patients were treated with intensity-modulated radiation therapy [1 IMRT and 7 with volumetric modulated arc therapy (VMAT)]. ChT consisted of the combination of cisplatin (100 mg/m2) and etoposide (100 mg/m2), with dose adjustment if needed.

After the first line of treatment, the recurrence rate was 35% (locoregional recurrence in 6 patients and distance disease in 1 patient). The median time from the end of the first treatment to recurrence was 20.9 months. Five of the 7 patients treated with surgery alone had locoregional recurrence (Tab. 2). Two of these patients performed surgical re-excision, one without evidence of disease for 267 months after the second surgery and the other with disease progression and death 4.3 months afterwards. One of the patients received surgery and radiotherapy and remained alive without disease. One patient performed various surgical re-excisions and radiotherapy, dying with disease 127 months after the first surgery. One of the 5 patients who underwent surgery alone, received RT after relapse and stayed alive without evidence of disease 74 months after RT. Two patients treated with surgery combined with RT also relapsed, locoregionally and at a distance, respectively. Both died with evidence of disease more than 100 months after the first treatment. Three patients (15%) had persistence of disease after the initial treatment, one patient died 2 months later and the other 2 patients received additional treatment, surgery and radiotherapy, respectively. These patients remained alive, without evidence of disease and with stable disease, respectively, with a follow-up of 224 and 41 months.

After a median follow-up of 59.7 months (1.8 to 287 months), 8 patients had died, 1 patient was alive with evidence of disease and 11 patients were alive and free of disease. Median OS was 11 years, with a survival rate of 83.9% and 77.9% at two and five years of follow-up (Fig. 1). Two and five-year PFS rates were 76.7% and 61.0%, respectively (Fig. 2).

Figure 1. Overall survival for 20 patients with esthesioneuroblastoma using Kaplan-Meier analysis

Figure 2. Progression-free survival using Kaplan-Meier analysis

Discussion

ENB is a rare intranasal malignant tumor with origin in the olfactory neuroepithelium [1, 2]. The symptoms are nonspecific and associated with the site of invasion. Magnetic resonance imaging (MRI) and computed tomography (CT) are commonly used to assess the extension of disease [15]. The diagnosis is confirmed by histology and immunohistochemical tests, allowing the differential diagnosis from other tumors such as lymphoma, Ewing’s sarcoma, melanoma, rhabdomyosarcoma, extracranial meningioma, pituitary adenoma or undifferentiated nasosinusal carcinoma [16]. Histologically, the cells are small, with a round nucleus and scarce cytoplasm, surrounded by neurofibrillar matter and exhibiting pseudorosette or rosette arrangement in up to 50% of the samples [17].

There are no standard guidelines regarding the staging and the treatment of ENB, since the published articles on this theme are frequently retrospective studies, with small sampling [3, 7–10]. Most of the available data reported good outcomes with a multimodal approach, namely surgery, pre or postoperative radiotherapy and/or (neo)adjuvant chemotherapy [11–14]. Various retrospective studies and two meta-analyses demonstrated that a combined treatment improves the survival outcomes, especially in advanced stages [11–13, 18–20]. Open craniofacial resection used to be the gold standard surgical procedure, although, in the last years, endoscopic endonasal approaches have been preferred, mainly in the early stages [21]. Regarding RT, the literature recommends preoperative doses of 45 Gy and postoperative doses of 50 to 60 Gy, according to surgical margins. Doses of 65 to 70 Gy have been proposed for radical radiotherapy [12, 22]. Chemotherapy combined with radiotherapy has been described in some cases with more advanced stages and/or unresectable tumors [23–25]. The combination of cisplatin and etoposide is one of the most widely used in the treatment of ENB. Other agents include adriamycin, cyclophosphamide, vincristine, 5-fluorouracil and doxorubicin [23].

Besides treatment modality, other major prognostic factors influencing the ENB outcomes include the Hyams grade [26–28], presence of positive lymph nodes [18, 29–30] and/or distant metastases [14], staging [14, 18, 30] and extension of surgical resection (R0 or R1) [30]. Age at diagnosis [18], orbital invasion [29], intracranial extension [28], and dural involvement [31] were also described as prognostic factors for ENB.

In our study, 85% of patients underwent surgical resection alone or combined with adjuvant RT/ChRT. Most of the patients (5/7) submitted to surgery alone presented locoregional recurrence. From 10 patients treated with surgery combined with adjuvant treatment, only 1 patient presented locoregional recurrence and 1 recurrence at distance. After the first line of treatment, the persistence and recurrence rates were 15% and 35%, respectively. Our data is in accordance with the literature regarding local recurrence (30%) [10, 11, 14], and slightly lower for distance metastases (5%) compared with other studies [11, 14]. In the Dulguerov et al. [11] meta-analysis, local, regional, and distant recurrence rates were 29%, 16%, and 17%, respectively. In a recent study of a series of 187 patients treated for ENB, local recurrence was documented in 26% of patients, nodal recurrence in 14.5%, and distant recurrence in 25.5% [14]. In our series, OS was 83.9% and 77.9% at 2 and 5 years of follow-up, respectively. Two and 5-year PFS rates were 76.7% and 61.0%. The OS and DFS obtained in our study are in accordance with those described in the literature: 45–90% and 41-65% at 5 years, respectively [11, 12, 18, 32].

Conclusion

ENB is a rare intranasal malignant tumor, with no guidelines regarding its management. The different approaches of our institute in the treatment of ENB followed the progressive scientific understanding of the disease. We consider that a multimodal approach could be a good strategy for most patients, while unimodal treatment may be an option for very well selected patients. The retrospective design and the small number of patients were the main limitations of this study, making it challenging to perform reliable and, therefore, meaningful comparisons between different therapeutic approaches. Given the rarity of this entity, further studies, ideally prospective randomized studies, are needed to optimize the management of patients with ENB.

Conflict of interests

The authors declare no potential conflict of interest.

Funding

This publication was prepared without any external source of funding.

References