Tesi di Specializzazione in Otorinolaringoiatria
Outcome of Endoscopic versus Open Treatment of Esthesioneuroblastoma: a Meta-Analysis study
Relatore: Dott.ssa Giuditta Mannelli Candidato: Dott. Paolo Luparello
3 Indice 1 Introduction 1.1. Clinical presentation 1.2. Diagnosis 1.3. Staging 1.4. Histopathology 1.5. Grading 1.6. Treatment 1.7. Surgery 1.8. Radiotherapy 1.9. Chemotherapy
1.10. Management of the neck 1.11. Prognosis
2. Objective
3. Material and methods
4. Study characteristic and quality assessment 5. Statistical analysis
6. Results 7. Discussion 8. Conclusion 9. Bibliography
4
1. Introduction
Paranasal sinus malignancies comprise less than 5% of all head and neck cancers, and the incidence varies somewhere between 0.5 and 1.0 per 100,000 people in Western countries.
Esthesioneuroblastoma (ENB), also known as Olfactory Neuroblastoma, was first reported in 1924 by Berger and Luc, and it accounts for approximately 2-6% of nasal cavity and paranasal sinus cancer cases. ENB is an uncommon malignant tumor of the upper nasal cavity and anterior skull base. It is believed to arise from the olfactory neuroepithelium that lines over the cribriform plate, superior aspect of the nasal septum, middle turbinate, and superior turbinate. The olfactory neuroepithelium contains specialized receptor cells that mediate the sense of smell.
ENB may occour at any age, but has a slight male predominance and bimodal age presentation with two peaks at the second and sixth decade1.
1.1 Clinical Presentation
The ENB origin within the superior nasal cavity often results in patients having nonspecific symptoms such as unilateral nasal obstruction, reduced sense of smell or epistaxis which can be present for months prior to diagnosis2.
Extension into the orbit may give rise to double vision, proptosis, tearing, and decreased visual acuity. Intracranial extension may lead to neurological symptoms such as changes in mental status, headaches,
5
nausea and vomiting, seizures, and eventually coma and death. Other symptoms include ear pain and serous otitis media, which usually result from the obstruction of the eustachian tube.
Diagnosis of ENB with no involvment of cribriform plate should be a diagnosis of exclusion with often a delay in diagnosis. In most studies, the mean time from onset of symptoms to diagnosis of ENB ranges between 6–12 months. For this reason, many patients have advanced stage at the time of diagnosis. A high index of suspicion is therefore critical to achieve an accurate and timely diagnosis.
1.2 Diagnosis
A thorough physical exam and flexible fiber-optic endoscopic evaluation, complemented with both contrast-enhanced CT scan and MR imaging, represent the key in the diagnostic workup.
1. Particular attention should be dedicated to the neck examination; The incidence of neck metastases at presentation has been reported to be low, approximately 5–8%. However, the probability of developing subsequent recurrence in neck nodes has been reported to be 20–25%3.
On rare occasion, paraneoplastic symptoms due to ectopic hormone secretion were reported including Cushing Syndrome and hyponatremia secondary to adrenocorticotropic and antidiuretic hormone secretion respectively4-5
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are often complementary in characterizing the tumor and its extension into surrounding structures, especially to the orbit and the brain (Fig.1)
6
High-resolution CT scan remains the initial study of choice. It provides superior bony definition and allows evaluation of the integrity of bony structures surrounding the tumor, such as the orbit, skull base, septum, and palate. However, all patients with the confirmed or suspected diagnosis of ENB should have both CT and MRI with exceptions for only applying to very small and localized tumors. The main value of MRI lies in its ability to define the extent of the lesion and the involvement of surrounding soft structures, especially the orbit, skull base, dura, and brain parenchyma. It also helps in differentiating between tumor and adjacent inflammatory changes. Esthesioneuroblastoma is most typically hypointense compared to brain gray matter on T1-weighted MRI and it should enhance with gadolinium. T2-weighted images usually show an isointense or
7
hyperintense mass (Fig.2) This information is critical for proper preoperative surgical planning.
8
Due to the relatively high rate of neck involvement at presentation, a CT neck with intravenous contrast is routinely obtained to look for occult metastasis. Metastatic workup also includes chest and abdomen CT, as well as liver function tests. Alternatively, a Positron Emission Tomography (PET) scan could be obtained to rule out regional and distant metastases. WU et al. showed that the evaluation by positron emission tomography with CT (PET/CT) altered clinical staging in 3 out of 9 patients of their case series, and 7 out of 9 patients affected by ENB had PET positive scan6.
Intraoperative biopsy under general anesthesia is the recommended course of action to complete the diagnostic workup, and pre-operative imaging acquisition is mandatory to determine the vascularity of the mass7.
1.3 Staging
Several staging systems have been proposed with the attempt to create an uniform approach for predicting prognosis and treatment planning, but there is still no consensus on the best staging system for ENB. The goal of establishing a staging system for malignant tumors is to correlate disease extent and burden with its prognosis and guide treatment regimens. Unfortunately, there is no universally accepted staging system for ENB that has provided consistent information on prognosis, including overall survival.
The first and most popular staging system was described by Kadish in 1976 and is divided into 3 stages: Stage A tumor confined to the nasal
9
cavity; Stage B tumor extending to the paranasal sinuses; Stage C tumor extending beyond the paranasal sinuses (Tab.1)
Kadish staging for Olfactory Neuroblastoma
Stage Extent
A Lesion confined to nasal cavity
B Lesion confined to nasal cavity and
paranasal sinuses
C Lesion in nasal cavity with distant spread
The main limitation of this staging system is that it fails to account for metastases and that Stage C is too broad. The former limitation has been addressed by Morita et al. who amended the Kadish system by establishing a Stage D for tumors with regional and distant metastasis8
(Tab.2)
Staging system according to Kadish et al. And Morita et al.
Type Extent
A Tumor limited to the nasal cavity
B Tumor in the nasal cavity and
extending to the paranasal sinuses
C Tumor extends beyond the nasal
10
involving the cribriform lamina, the skull base, the orbitor the intracranial cavity
D Tumor with neck or distant
metastasis
Since the shortcomings of a broad Stage C, Biller et al. and then Dulguerov and Calcaterra established other staging systems based on a TNM format. These included a detailed description of the local extent of tumor was divided into 4 stages (Tab.3) A number of studies have shown that the Dulguerov and Calcaterra staging system9 predicted disease-specific survival better than the Kadish system.
Staging system according to Dulguerov et al. Stage Features
T1 Tumor involving the nasal cavity and/or paranasal sinuses (excluding sphenoid), sparing the most superior ethmoid cells T2 Tumor involving the nasal cavity and/or paranasal sinuses (including sphenoid), with extension to or erosion of the cribriform plate
T3 Tumor extending into the orbit or protruding into the anterior cranial fossa, without dural invasion
T4 Tumor involving the brain
N0 No cervical lymph node metastasis
N1 Any form of cervical lymph node metastasis M0 No metastasis
11
M1 Distant metastasis present
All these staging systems are based on CT, MR, and/or PET findings. Radiologic staging and tumor grading are not directly related. Kane et al. reported only 14% of all Kadish A tuomors were low grade based on Hyams’ grading (grades 1 and 2)10
1.4 Histopathology
On macroscopic evaluation, ENB are usually unilateral, polypoid, glistening, soft, reddish-grey masses covered by an intact mucosa; the cut surface appears greyish-tan to pinkish-red and hypervascularized. The tumor’s size ranges from under one centimeter (cm) to large masses involving the nasal cavity and invading the intracranial region. Diagnosis of ENB is usually difficult on conventional light microscopy and almost always it requires immunohistochemical (IHC) staining for definitive diagnosis. Low-grade esthesioneuroblastoma forms submucosal, sharply demarcated nests, lobules, or sheets of cells, often separated by richly vascular or hyalinized fibrous stroma. Pseudorosettes (Homer-Wright rosettes), with neoplastic cells palisading or cuffed around the central delicate fibrillar neural matrix, might be seen.
12
Tumor cells are often uniform, with sparse cytoplasm and round or ovoid nuclei with punctate salt-and-pepper chromatin and nucleoli that are either small or absent. ENB characteristically demonstrates fibrillary cytoplasm and interdigitating neuronal processes (neuropil), created by a syncytium of cells. Higher-grade tumors are characterized by tumor necrosis, pleomorphism, increased mitoses, decreased to absent neuropil, and a less overt lobular growth pattern. The tumor cells can arrange in gland-like rings or tight annular formations with a true lumen (Flexner-Wintersteiner rosettes). Rosettes alone are not diagnostic of esthesioneuroblastoma, although the Homer Wright rosettes are nearly pathognomonic in the nasal cavity when containing true neuropil. The mitotic rate is variable, but is usually low, especially in lower-grade tumors. Calcifications (concretion-like or psammomatous) may be seen, less frequently as the grade increases. Melanin pigment, ganglion cells, rhabdomyoblasts, divergent differentiation as islands of true epithelium (squamous pearls or gland formation), and clear-cell change may occasionally present in
13
esthesioneuroblastoma11. A number of immunohistochemical stains are
used to differentiate ENB from other tumors with similar histological features on light microscopy. The typical immunohistochemical profile includes diffuse staining for neuron-specific enolase12, synaptophysin, chromogranin A, CD56 (NCAM) and beta-tubulin, as well as variable S100 protein reactivity, which is typically in a sustentacular cell pattern highlighting only cells at the periphery of the nests, often limited in higher-grade tumors. Sustentacular cells may also be positive for GFAP. Calretinin staining (nuclear and cytoplasmic) has been reported in esthesioneuroblastoma but can also be seen in other sinonasal tumors13.
As many as one-third of esthesioneuroblastomas may also stain focally for cytokeratin (CAM5.2, CK18). Negative markers include CD45RB, CD99, p63, and FLl1. Proliferation marker studies reveal a variable Ki-67 proliferation index (2- 50%), and BCL2 expression increases with tumor grade14-15. In addition, HASH-1, a molecular marker expressed in
immature olfactory neurons, was shown to be also present in specimens of high-grade ENB. The significance and usefulness of this marker are still unknown.
1.5 Grading
Esthesioneuroblastoma is graded according to the Hyams system, based on examination of routine hematoxylin-eosin staining under light microscopy. This system has 4 grades ranging from Grade 1, which indicates well-differentiated tumors, to Grade 4, which indicates poor differentiation with no evidence of neuronal or neuroendocrine architecture based on the following characteristics: mitotic activity,
14
nuclear pleomorphism, rosette formation, necrosis, disorganized architecture, and sparse fibrillary matrix (Tab.4)
Hyams grading system Microscopic
features
Grade I Grade II Grade III Grade IV
Architecture Lobular Lobular ± Lobular ± Lobular Pleomorphism Absent/sligh
t
Present Prominent Marked
Neurofibrillar y matrix
Prominent Present May be present Present Rosettes Homer Wright Homer Wright Flexner-Wintersteine r Flexner-Wintersteine r
Mitoses Absent Present Prominent Marked
Necrosis Absent Absent Present Prominent
Glands May be present May be present May be present May be present Calcification Variable Variabl
e
Absent Absent
This grading is a reflection of the biology of ENB from the indolent least aggressive to the highly aggressive tumor16.
15
It is a subjective system and definitive separation between grades is arbitrary17. Therefore, there has been a tendency to group these categories
into low grade encompassing grade I/II and high grade involving III/IV to provide easier description of those tumors in correlation with prognosis. Another problem with this grading system is that high-grade poorly differentiated tumors may mimic other aggressive non-ENB tumors and are difficult to be separated from each other18. There has been growing
evidence in the literature that Hyams grading can be correlated with the outcome of ENB and, therefore, can be used as a prognostic indicator. High-grade tumors with Hyams grade III/IV were found to be associated with more aggressive locoregional disease and worse survival outcome compared to low-grade tumors16-19-20.
It suggested to be a good tool for selecting patients for adjuvant radiotherapy21.
Recently, there has been an attempt to update the Hyams grading trying to find other histological parameters that can be used as a prognostic indicator; necrosis and mitosis were found to be significant predictors of overall and disease-free survival. Also, glandular hyperplasia (which was not included in the original Hyams grading) combined with the absence
16
of spindle features and mitosis was found to be a positive prognostic indicator18 .
1.6 Treatment
The three options used for the treatment of esthesioneuroblastoma are surgery, external beam radiation, and chemotherapy. Often, treatment utilizes a combination of these modalities22. Treatment depends on the local tumor stage and whether or not there is regional or distant metastatic disease. Surgery alone is best reserved for patients with small tumors located in the sinonasal cavity without involvement of the skull base or orbit. For more advanced tumors, the most successful treatment includes surgery and radiation therapy with most Institutions favoring delivery of postoperative, rather than preoperative, radiotherapy; large and bulky tumors (T3 and T4) are treated with neoadjuvant concurrent chemo-radiotherapy followed by surgery. This allows for a potentially less invasive and less morbid surgical resection23. Although early reports on chemotherapy in ENB focused on patients with recurrent or metastatic disease, adjuvant chemotherapy is now commonly employed for patients with advanced local and regional disease.
17
1.7 Surgery
Treatment for ENB changed dramatically with the introduction of the combined transcranial and transfacial approach for tumors of the paranasal sinuses involving the anterior skull base. Resection with negative margins is a cornerstone of the treatment. The traditional surgical approach for ENB is craniofacial resection (CFR). This is a combined transcranial and transfacial approach, typically including a frontal craniotomy, and lateral rhinotomy or midfacial degloving. The objective is to achieve an en bloc resection of tumor and involved structures. It also involves removal of the cribriform plate, olfactory bulbs, roof of the ethmoid sinuses, medial maxillae, upper septum, and as much of the anterior cranial fossa dura as necessary. This approach has an advantage of excellent exposure and en block tumor resection and providing excellent reconstruction with vascularized pericranial flap. The advent of craniofacial resection is credited with increase in overall survival for ENB patients. Although the complication rate associated with CFR has decreased over the last few decades, postoperative morbidity (approximately 35%) and mortality (2-5%) with this procedure still remain relatively high. Over the past two decades, less invasive endoscopic techniques have become increasingly utilized. Initially, endoscopic approaches were used only for early stage tumors without or with minimal skull base invasion. With advances in endoscopic techniques and reconstruction methods, endonasal endoscopic approaches have been increasingly utilized even for advanced stages with extensive local invasion without the need of facial incisions24.
Pure endonasal approaches provide access to the anterior skull base and to both lamina papayracea walls laterally. Dura, olfactory tracts and bulbs
18
can be resected, including the involved brain parenchyma. However, extensive parenchymal brain invasion is considered a relative contraindication to the pure endoscopic approach and a concomitant frontal craniotomy might be considered in these cases. Controindication to pure endoscopic approaches includes involvement of the anterior table of the frontal sinus, skin and subcutaneous tissue, nasolacrimal sac, carotid artery, and extensive intraorbital and brain parenchymal invasion. Also, lateral extension above orbit and palatal invasion are considered contraindication to perform pure endoscopic approaches and the traditional craniofacial approaches are indicated24-25. Reconstruction of
the skull base is the main challenge following endoscopic resection of ENB to avoid cerebrospinal fluid (CSF) leak. Multilayer reconstruction should be addressed in every case. It is believed that the risk of postoperative CSF leak would be higher with endoscopic approaches compared to the traditional craniofacial ones, but recent large reports of endoscopic resection of sinonasal cancers showed a CSF leak incidence to be less than 5%26.
In a recent meta-analysis by Iavarone et al27., CSF leaks larger than 2 cm2
were more associated to neoplastic aetiologies and successfully treated using vascularized flaps; the pedicled nasoseptal flap (PNSF) is currently the workhorse of endoscopic skull base repair and it represents the principal advancement in endoscopic reconstruction by vascularized flap and represents the technique of choice for several authors. This systematic review data showed an overall success rate of 96% after the first endoscopic attempt of closure.
19
1.8 Radiotherapy
ENB has a high local failure rate, about 15% at 5 for Kadish stage A/B and 47% for Kadish C/D at 5 years of follow up. Therefore, most Institutions have adopted surgical resection followed by postoperative radiotherapy as a standard treatment approach. It has been shown that postoperative radiation improves local control of the disease. However, for early staged (Kadish A) disease with negative resection margins, the role of postoperative radiation therapy is still questionable and surgery alone might be enough (about 100% disease free survival at 5 years follow up)28.
The radiation dose used usually ranges between 55 and 65 Gy. With advancement of radiation technologies, conformal techniques like intensity-modulated radiotherapy and proton beam therapy have shown better outcomes improving local control and minimizing toxicity and complications to the nearby critical structures. Proton-beam therapy can provide better dose distribution compared with X-ray irradiation because of its physical characteristics, and is deemed to be a feasible treatment modality. A recent studi of Nakamura report a 5-year overall survival (OS) and progression-free survival (PFS) rates of 100% and 80% for Kadish A, 86 and 65% for Kadish B, and 76% and 39% for Kadish C, respectively. It conclude that proton therapy is achieved excellent local control and survival outcomes without serious adverse effects23.
20
1.9 Chemotherapy
The role of chemotherapy in ENB has not been clearly identified in the literature. Chemosensitivity of ENB was suggested owing to its biological similarities to other chemosensitive neural crest tumors like high-grade neuroendocrine tumor. Generally, chemotherapy may be considered in patients with advanced stage, high Hyams grade, extensive regional disease, distant metastases, positive margins, unresectable tumors, and recurrent tumors29. Adjuvant chemotherapy may add improvement in
locoregional control and prolonged median time to relapse; however, there is no added benefit in improving the overall survival30 .
1.10 Management Of The Neck
The overall rate of cervical lymph node metastases in ENB may reach up to 30% with level II being the most frequently involved31-32 .
Presence of cervical lymph nodes at time of presentation ranges between 5 and 8%3-33 .
Patients with N+ neck at initial presentation should be managed by neck dissection and postoperative radiotherapy at the same time of management of the primary tumor. ENB has a high rate of late regional recurrences. Although the use of postoperative irradiation for the primary tumor has been the standard treatment, the value of elective neck irradiation (ENI) for those with N0 neck is still not clear. All patients with nodal recurrence should be treated by neck dissection with postoperative radiation.
21
1.11 Prognosis
ENB has excellent survival outcomes with the reported 5-year overall survival is between 57–93%11-34-35-36-37-38 .
Despite the high rate of survival, ENB has a high recurrence rate, thus patients require long-term follow-up, up to 10-15 years. Locoregional recurrence represents the most common failure, taking place within the first 5-10 years of clinical follo-wup. The risk of loco-regional recurrence is higher among those patients presenting poor prognostic factors such as high Hyams grade, advanced Kadish staging, intracranial extension, and positive resection margins39-40 .
22
2 Objective
ENB is a rare malignant disease of the nasal sinus district, which, however, on the basis of the clinical-anatomical pathological characteristics, requires a specific therapeutic treatment to which a variable prognosis corresponds. Since it represents a rare malignancy, the experiences regarding the management and treatment reported in literature are sometimes not of a unique interpretation. The main problems are still represented by a late diagnosis (about a year after the appearance of non-specific symptoms), a marked tendency to loco-regional recurrence (14-20% at 5 years follow up)41-42 even over almost 15 years of clinical follow-up, and indications for salvage treatment in case of distant metastases. Recent series highlight the importance of endoscopic approach, since anterior skull base tumors are in rich to be controlled with correct oncological margins with endoscopic resection. Oncological training is critical for the success of patients managed via endoscopic endonasal surgery. Careful clinical and radiographic assessment, accurate staging, negative margin tumor resection and appropriate use of (neo)adjuvant therapy are crucial to successful outcomes.
The purpose of this review was to give an update of the most recent literatures’ results about ENB management, by analyzing and reporting each surgical technique outcomes, including a reliable discussion about still questionated issues such as indications to neck disease management and salvage procedures indications, in order to provide a comprehensive overview of the most recent advances in the treatment of this pathological condition.
23
3 Matherials and methods
The systematic review was performed using independently developed search strategies in literature review methodology, and it was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement (http://www.prisma-statement.org)43, to guarantee a scientific strategy of research to limit bias by a systematic assembly, critical appraisal and synthesis of all the most relevant studies published on this topic44-45.
The databases interrogated included PubMed Clinical Queries http://www.ncbi.nlm.nih.gov. Reference lists from identified articles were searched and cross-referenced to identify additional relevant articles, and national experts in the field were contacted to identify unpublished data. The search terms used were esthesioneuroblastoma AND olfactory neuroblastoma. The search was performed for the first time on April 2019 and was set to automatically update periodically until July 2019. Duplicates, reviews, conference abstracts, editorial, case report and non-English articles were excluded. The inclusion criteria were set a priori and deliberately kept wide to encompass as many articles as possible without compromising the validity of the results, and they included articles: (1) published from 2012 onwards; (2) reporting published series of patients with at least 5 years follow up; (3) reporting data about the type of procedure: open or endoscopic; (4) with a clear description of results. We filtered the studies to ensure that only paper with comparable data were included in the review; there are several case series in the literature which have published results of small numbers of cases spanning several years, but this is due to the rarity of the patology in question. All data were
24
independently extracted by two authors and quality assessed. Eligibility for inclusion was separately assessed and when in doubt discussed and decided by consensus. Abstracts were analyzed to identify papers that fulfilled inclusion criteria and a first qualitative and descriptive review-analysis of selected articles was carried on; whilst, exclusively, publications clearly describing their aim and objectives, their inclusion and exclusion criteria, with clear or detachable statistical data, reporting success rates and well describing the surgical techniques, were included in our meta- analysis.
25
4 Study characteristics and quality assessment
All included papers were graded using the NICE scoring scale for retrospective case series (Available at: http://www. nice.org.uk/nicemedia/pdf/Appendix_04_qualityofcase_series_form_pre op.pdf). This is a scoring scale with eight items, with each item scoring
zero or one based on the study methods (Yes = 1; No = 0). Scores of ≥ 6 are considered to indicate a good quality study, scores between four and five as fair and those studies with a score of three are treated as poor quality (Tab.5)
Quality assessment for case series
1 Case series collected in more then 1 center (i.e. multicentric study) 2 Is the hypotesis/aim/objective clearly described?
3 Are the inclusion and exclusion criteria (case definition) clearly reported?
4 Is there a clear definition of the outcome reported? 5 Were data collected prospectively?
6 Is there an explicit statement that patients were recruited consecutively?
7 Are the main findings of the study clearly described?
8 Are outcome stratified (i.e. by disease stage, abnormal test result, patient characteristics)?
26
5 Statistical analysis
Categorical variables were calculated in terms of frequencies and percentages, median, mean and standard deviation (SD) values, and confidence interval (CI) 95%.
For statistical analysis, Fisher’s exact test was used for statistical analysis of categorical data for the descriptive review, and a value of p < 0.05 was considered significant. The pooled estimate of each statistic was calculated after Freeman–Tukey double arcsine transformation to stabilize the variances. A random effect model was specified, using the method of DerSimonian and Laird, with the estimate of heterogeneity being taken from the inverse-variance fixed- effect model. Heterogeneity is also quantified using the I-squared measure. All analyses were performed using STATA version 13 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). The possibility of publication bias was evaluated with the Begg and Egger tests, as well as visual inspection of the funnel plot. When possible, results are described in accordance with the PRISMA guidelines for reporting meta-analyses, with 95% confidence intervals reported throughout. When studies have low heterogeneity (pragmatically, I < 25%), the differences between reported outcomes can be explained simply by the observed natural differences between patients. In this case, we can consider that all patients are part of the same larger pool. A fixed-effects meta-analysis is appropriate in which each patient is given approximately equal weight.
27
6 Results
The initial search yelded 845 studies in Medline. Non-English language works (n=152), studies published before year 2012 (n=411) and non-human articles (n=64) were excluded at first screening. Of the remaining 218 studies, at second screning 140 articoles were excluded; in particular 46 were review, 3 meta-analisys, 80 case-report and 11 letter to editor. Therefore, 78 articles were eligible for quantitative analisys; 46 studies were further excluded for the lack of data on the type of treatment and patient follow up. 32 articles reported outcome of 3180 patients and were included in the meta-analysis. The various stage of sistematically assessing the abstract and reason for exclusion from the review are described in Fig.4. As for their quality, as assessed by the quality assessment criteria outlined above, 7 papers scored six, 11 papers scored five and 14 papers scored four.
28
The study periods range from 84 to 420 months with a median of 204 months.
A total of 3180 patients were identified, among all, the 58,4% (n=1857) were male and 41,3% (n=1314) female. The median age was 49 years (range, 14-61 years).
29 KADISH STAGE DULGUEROV STAGE NECK MTS HYAMS GRADE A B C D UN K T1 T2 T3 T4 N+ LOW HIGH Song et al 201266 3 4 23 5 0 6 5 18 9 5 0 0 Petruzzelli et al 201567 5 12 15 0 0 2 10 8 11 1 0 0 Ow et al 201311 10 19 24 3 13 7 5 46 8 3 0 0 Nakagawa et al 201768 4 5 13 0 0 6 9 5 2 0 21 1 Miller et al 201869 0 1 31 6 0 NA NA N A NA NA 14 19 Konig et al 20171 0 6 11 3 0 3 8 6 3 NA 11 7 Klironomos et al 201849 2 2 4 2 0 NA NA N A NA 1 5 5 Kim et al 201870 8 6 14 0 0 NA NA N A NA 3 12 10 Joshi et al 201890 19 3 11 8 488 82 0 31 7 186 14 0 238 64 235 196 Jiang et al 201133 0 0 19 6 0 NA NA N A NA 7 0 0 Hwang et al 201671 1 8 18 8 0 NA NA N A NA 5 0 0 Harvey et al 201772 11 27 71 0 0 NA NA N A NA 8 61 48 Feng et al 201573 3 6 15 0 0 9 7 2 6 0 0 0 El Kababri et al 201474 0 5 6 0 0 NA NA N A NA 1 0 0 De Bonnecaze et al 201460 1 3 3 1 0 1 5 0 2 1 0 0 Zhang et al 201675 1 3 6 3 0 3 2 6 2 3 6 7 Rimmer et al 201438 20 18 52 5 0 26 27 11 31 NA 0 0 Bartel et al 201776 1 2 6 0 0 NA NA N A NA NA 5 4 Carey 201777 22 5 16 7 597 31 98 NA NA N A NA NA 259 210
30 Gram201878 4 1 7 0 0 NA NA N A NA 1 11 3 hollen 201579 0 7 17 2 0 NA NA N A NA 2 0 0 Kumar 201280 0 3 12 0 0 0 4 5 6 2 4 11 Mays 201781 8 26 1 0 0 14 7 12 2 0 24 10 Peng 201882 0 4 6 0 0 0 4 1 5 0 7 3 Modesto 2013 83 5 13 16 9 0 NA NA N A NA 11 0 0 Schmidt 201684 1 1 8 1 0 1 0 3 7 0 4 3 Tsang 201585 1 4 9 0 0 NA NA N A NA 1 0 0 Turri-Zanoni 2017554 11 19 37 0 0 16 18 5 28 NA 51 16 Venkatramani 201586 0 8 16 0 0 NA NA N A NA 8 0 0 Xiong 2017 87 23 48 113 3 0 NA NA N A NA 21 0 0 Yin 201688 1 23 89 0 0 NA NA N A NA 28 0 0 Yu 201889 7 8 20 3 0 NA NA N A NA 3 15 17 Total 54 9 57 7 176 7 17 3 111 41 1 297 26 8 360 179 745 570
31 SURGERY OUTCOME ENDO OPE N ADJ OS 5 y DFS 5 y OS 10 y DFS 10 y Song et al 201266 5 12 23 76 61,8 NA NA Petruzzelli et al 201567 11 20 25 78 84 72 NA Ow et al 201311 16 36 32 90 95 55 58 Nakagawa et al 201768 22 8 0 100 95,5 NA NA Miller et al 201869 38 NA 28 NA NA NA NA Konig et al 20171 NA 17 9 70,7 70,7 70,7 70,7 Klironomos et al 201849 10 0 4 NA NA NA NA Kim et al 201870 14 9 19 93,8 37,3 57,5 NA Joshi et al 201890 0 511 NA 81,9 NA 63,7 NA Jiang et al 201133 8 8 19 31 NA NA NA Hwang et al 201671 10 16 20 66,8 52,8 48,3 NA Harvey et al 201772 67 23 NA NA 85 NA 63 Feng et al 201573 24 0 27 80 70 80 70 El Kababri et al 201474 1 9 10 91 NA NA NA
32 De Bonnecaze et al 201460 8 0 8 87,5 75 NA 75 Zhang et al 201675 13 0 NA 46,2 NA NA NA Rimmer et al 201438 30 65 63 83,4 80 76,1 62,8 Bartel et al 201776 4 1 7 88,9 88,9 88,9 88,9 Carey 201777 882 0 589 76,2 NA NA NA Gram201878 14 0 8 90 NA NA NA hollen 201579 1 20 21 69 68 NA NA Kumar 201280 0 14 14 45 NA NA NA Mays 201781 24 11 25 93 89 81 78 Peng 201882 7 2 9 45 NA NA NA Modesto 2013 83 17 13 27 73 57 60 56 Schmidt 201684 6 4 6 90,9 100 68,2 46 Tsang 201585 14 0 NA 93 NA 93 NA Turri-Zanoni 2017554 53 14 52 91,6 78,8 85,1 62,5 Venkatramani 201586 12 0 NA 72,8 73,7 58 60 Xiong 2017 87 55 94 117 66,7 57,5 NA NA Yin 201688 28 37 109 65 73 NA NA Yu 201889 13 24 33 81 69 72 54 Total 1407,00 968,0 0 1272
Legend: ENDO(Endoscopic treatment); OPEN(craniofacial resection); ADJ(adjuvant treatment); OS(Overall Survival at 5 and 10 years); DFS(Disease Free Survival at 5 and 10 years)
33
- Factors relating to study population:
Of the total patients, 17,26 % (n=549) was Kadish stage A, 18,14% (n=577) stage B, 55,56% (n=1767) stage C, 5,44% (n=173) stage D and for 3,49 % (n=111) the stage was unknown. Classificated by Dulguerov Staging system, 12,92% (n=411) was T1, 9,34 %(n=297) T2, 8,43% (n=268) T3, 11,32% (n=360) T4. Not all the studies presented the Dulguerov classification, so the number of cases on the total is partial.
0 200 400 600 800 1000 1200 1400 1600 1800 2000 fre q u en za Stage
Frequenza per stadio
Dulguerov Kadish
34
Regarding the istological Hyams Grade, 23,42% (n=745) were low grade (grade I-II) and 17,92% (n=570) were high grade (grade III-IV), as shown in figure
Hyams
LOW HIGH
35
The following graphs show the distribution of cases based on age and Kadish staging system; Stage C is the more represented in our casuistic, and has a peak incidence between 50 and 60 years.
37
- Factors relating to treatment characteristics:
44,24% (n=1407) was subject to endoscopic treatment, 30,44% (n=968) to open surgical treatment, 1,57% (n=50) were subject to combined treatment and 18,33% (n=583) to non surgical treatment (radiotherapy +/- chemotherapy).
5,62% (n=179) were the patients presented at diagnosis with nodal metastasis.
18,33% (n=583) were the patients subjet to non surgical treatment (radiotherapy and/or chemotherapy) due to inoperability status for comorbidity or tumor extension, as shown in figure
Type of treatment
38
- Factors relating to post-operative complications and recovery:
Regarding the complication rate, it results in 2,48% (n=24) for open surgery treatment, in particular 7 cerebro-spinal fistula (CSF), 5 endocranial hypertension and pneumocephalus, 5 neurological deficit, 1 hematoma, 2 epistaxis and 4 cases of meningitis; for endoscopic treatment the complication rate was 1,28% (n=18), in particular 12 CSF, 1 hematoma, 1 frontal sinusitis, 3 meningitis and 1 brain necrosis.
0,00 500,00 1000,00 1500,00 endo open
Complication based on treatment
complication total
39
- Factors relating to post-surgical adjuvant treatment:
About 40% (n=1272) of patients did adjuvant radiotherapy or radio-chemotherapybased on tumor dimension (Kadisch stage C/D or Dulguerov T3/T4), positive margins, Hyams grading III or IV. For initial stage (Kadish A/B) it was developed only in case of positive margins or high grade lesions; no adjuvant treatment was done in case of severe comorbidities
- Factors relating to survivals
The median overall survival and disease free survival at 5 years were 76,4% (±3,17; IC 95% 69,95-82,97) and 74,38% (±3,41; IC 95% 67,25-74,98), respectively.
40
The median overall survival and disease free survival at 10 years were 70,59% (±3,23; IC 95% 63,69-77,49) and 64,99% (±3,15; IC 95% 58,12-71,85), respectively.
The median OS at 5 years for endoscopical and open treatment, based on the article that reported it, was 76,78% (±7,7; IC 95% 58,54-95,62) and 63,57% (±9,08; IC 95% 42,08-85,06), respectively.
41
7 Discussion
Surgical management of ENB is continuosly evolving, with contemporary endoscopic approaches complementing or in many cases replacing open approaches. Aggressive and combined modality therapy appears to be justified in patients at greatest risk of developing recurrence based on advance tumor stage and high pathologic grade. ENB requires prologed surveillance following treatment gives it tendency for late recurrence46. The current treatment approach for esthesioneuroblastoma is based on multiple case series demonstrating a survival advantage achieved with combination of surgery and adjuvant radiation over each modality alone. Many studies suggest that improved overall survival (OS) and disease free survival (DFS) are attributable to achieving gross total resection (GTR) with microscopically negative surgical margins. Before the introduction of the craniofacial technique for resection in the 1970’s, GTR of these tumors was rarely achieved, leading to long term OS rates less than 40%47.
Since then, many surgical approaches have been described, as a first line treatment, including modifications of the classic craniofacial resection, endoscope-assisted craniofacial resection and pure expanded endoscopic endonasal approaches48. The last approach has been increasingly
implemented the past two decades and shows promising results in ENB resection with high rates of local control49. Open approaches are
appropriate when there is disease lateral to the midpoint of the orbital roof, extensive involvement of the frontal sinus, and intraorbital disease. Extensive dural and intracranial involvement is not an absolute limitation. the endoscopic approach is associated with lower rates of complications, locoregional recurrence, distant metastasis, cause-specific mortality, and overall mortality compared with open approaches, with higher 5-year and
42
10-year rates of OS, DSS, locoregional control, and MFS reported for the endoscopic group compared to the open group. Five-year survival and recurrence rates were comparable to reported rates in the literature for the endoscopic group as well as the open group. This finding suggests that, although recurrence rates are similar between approaches, patients with recurrences in the endoscopic group are experiencing lower mortality compared with patients receiving open surgery. A potential explanation is that patients with disease are better salvaged in the endoscopic group after the development of recurrences. With the majority of endoscopic studies being more recent, this may be a result of improved salvage techniques, both surgical and nonsurgical, over time41. In our analysis, we found an OS rate at 5 years of 76,78 % for endoscopic treatment and 63,57% for craniofacial resection; this results not reach statistical rilevanrelevancere in line with the literature.
Multiple reposts have described the benefit of radiation therapy following endoscopic resection of ENB50-51. The need for adjuvant radiotherapy is particularly controversial in early stage (Kadish stage A) lesions with no evidence in the literature unequivocally substantiating a survival benefit. There is likely greater uniformity as to the need for adjuvant radiotherapy in the context of locally advanced (Kadish stage C) disease or positive/close resection margins. Intensity modulated radiation therapy is the most commonly administered radiotherapy modality, allowing for a higher, more conformal dose to the tumor bed while sparing highly sensitive neighboring structures such as the brain and orbit. One series has shown promising long-term survival outcomes using proton beam
43
radiation with lower radiationinduced toxicity compared with conventional radiotherapy52.
Few studies in the literature evaluate the role of neoadjuvant radiation accompanied by pure endoscopic resection. The 2016 study of Yin et al found no significant difference in 5 years OS between 11 patients who received neoadjuvant radiation and 51 who underwent surgery before radiation (91% and 79% respectively)53. In a recent study Turri Zanoni et al.54 evaluated the role of neoadjuvant chemotherapy (cisplatin/etoposide) in high grade tumor patients who were treated by minimally invasive endoscopic approach followed by adjuvant radiation therapy or radiochemotherapy. They concluded that neoadjuvant chemotherapy improves survival in patients affected by poorly differentiated tumors. Bias exists in many forms for patients treated at different centers and across long time period. The rationale of why some patients were given radiotherapy neoadjuvantly or adjuvantly and with or without chemotherapy cannot be answered. Disease factors, such as close margins, higher Hyams’ grades, more clinically extensive Kadish C stages might influence such decision making. As an alternative to traditional radiotherapy, Proton beam therapy (PBT) can provide a better dose distribution compared with conventional X-ray treatment because of its physical characteristics. Therefore, PBT may facilitate curative high-dose irradiation of the tumor, without increasing normal tissue toxicity. A recent study of Nakamura et al.55 gave as indication for patients with
Kadish A single modality treatment by surgery or PBT. For those with Kadish B, concurrent therapy of PBT and chemotherapy. For those with Kadish C, which extends beyond the paranasal sinus, induction chemotherapy followed by concurrent therapy of PBT. It found that local
44
control was achieved in 100% Kadish A patients. However, local control for Kadish B and C patients was achieved in 58% and 19%, respectively. The mean radiotherapy dose was 55.1 Gy.
Regarding the target therapy, a recent study has identified some molecular alterations (e.g., Wnt and cKIT/PDGFRA pathways) that are potentially treatable using novel therapeutic approaches. These identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatments in ENB56.
Although endoscopic approaches to skull base have historically been plagued by frequent occurrence of CSF leak, refiniments in repair technique have markedly improved surgical results. A systematic review by Fu et al41 including reports between 2000 and 2014 found no significant differences in CSF leak rate between craniofacial and endoscopic cases (10,3% and 12,7% respectively), indicating that the endoscopic approach is a safe treatment modality for ENB.
Neck metastasis is a poor prognostic factor that negatively affects survival. Neck metastasis in ENB is well described and there appears to be a predictable pattern of lymphatic spread, with most disease occurring in levels I to III. Metastatic disease can be evident at the time of diagnosis or it can be presented as recurrent disease. It has been reported to occour in 5 – 8% of patients at initial presentation and in 15 – 25% of patients as recurrence57.
Hyams high grade ENBs were more than twice as likely to metastasize to both neck or distant targets. Hyams grading may be an important preoperative factor for decisionmaking in this scenario, as HGH ENBs were 2.1 times more likely to lead to eventual neck metastasis58.
45
Emerging research addressing this question observes level II lymph nodes to be the most frequently involved, followed by levels I and III. Retropharyngeal lymph node involvement has been described, although its frequency is inconsistently demonstrated. The issue of elective node irradiation (ENI) for esthesioneuroblastoma has been a controversial topic. In the past, many institution did not include ENI in their standard treatment of patients because of the perception that there was a low incidence of nodal metastasis. Ferlito et al59 analyzed 494 cases from 26 Institutions and calculated a metastatic rate of 23% to the cervical lymph nodes. An initial treatment by neck dissection or prophylactic cervical radiotherapy should be discussed, especially for tumors of high grades (Hyams 3 or 4) or advanced stages, but there is limited evidence on the use of elective neck dissection or elective radiotherapy in the clinically and radiologically N0 neck60. A study by Jiang et al.61 evaluated the role
of elective neck irradiation. In this study, of 71 patients with clinically negative lymph nodes enlargement, 22 of those (31%) received elective radiation before surgical treatment. During the follow up period (mean 80,8 months) 13 patients developed lymph nodes recurrence. None of those 13 patients had elective node radiation. In this study elective node radiation was associated with improve 5 years regional nodal control but not with overall survival or disease free survival. It conclude that elective node radiation in patients presented with clinically negative lymph nodes reduce the risk of cervical node recurrence especially among young patients who presented with Kadish C disease. The weight of the current clinical evidence clearly demonstrates that esthesioneuroblastoma has a higher rate of nodal metastasis than previously thought, favoring the use of elective neck therapy. A second argument for elective neck
46
radiotherapy is the observation that lymph node metastasis are often associated with distant metastasis. In 1998 Koka et al62 reported that patients with cervical nodal involvement have a distant metastases rate of 86%, compared with 51% for those without cervical disease. These findings were reaffirmed in the metanalysis by Dulguerov et al63 in 2001
that demonstrated significantly reduced survival for patients presenting with cervical node involvement compared with those with node-negative disease (29% vs 64%). Therefore, deferring neck therapy until the discovery of nodal disease is less preferable to elective treatment of a clinically node-negative neck. Naples et al.57 in their review raised the
question of what type of elective neck dissection (END) should be performed if a surgical treatment of the neck is considered. Since there is a consistent pattern of spread to level I,II,III, that indicates that an elective supraomohyoid neck dissection would be most appropriate. Although disease recurrence has appeared in the retropharynx and parotid, most reports indicate cervical lymphatics as the most common site of recurrence. With END is possible to allow assessment of occult node metastasis. This may result in upstaging of some patients but, if occult disease is removed before it becomes clinically apparent, is intuitive that the regional control rate would be better. The other open question is the laterality of END; the nasal cavity has intrinsic laterality with the nasal septum as divider, but metastasis can occour bilaterally. In a report evaluating elective neck radiation, Monroe et al. treated bilateral neck without recurrence in all patients64. Naples et al, based on this evidence, hypothesize that the behavior of ENB recurrence is similar to oral squamous cell carcinoma in which any lesions that cross the midline are likely to have a propensity for either side of the neck, and bilateral elective
47
treatment should be considered. A study of Marinelli at al. confirm this, having found that nodal spread patterns predominantly were bilateral irrespective of the degree of laterality of the tumor65. It found that, on 24 patients, the most frequently involved nodal basins were ipsilateral level II (83%; 20 of 24), ipsilateral level I (54%; 13 of 24), contralateral level II (46%; 11 of 24), contralateral level I (21%; 5 of 24), and ipsilateral level III (21%; 5 of 24). Five patients developed retropharyngeal nodal involvement, and four patients developed parotid involvement. Furthermore, tumor volume, including subdivisions into extracranial and intracranial components, appeared to be a poor predictor for the pattern of nodal spread. So this study provides evidence that unilateral elective treatment of the neck cannot be justified by ENB laterality.
48
8 Conclusion
The indistinct symptoms of unilateral nasal obstruction, loss of sense of smell, epistaxis, epiphora, and headache combined with the rare annual incidence of 0.4 per million people and variability in treatment response, has made ENB a difficult entity to study at any single institution. Multidisciplinary management of this entity seems to be necessary. Surgery is still the main line of treatment and minimally invasive endoscopic resection appears to be the preferred choice over more invasive approaches.
The true value of electively treating the neck in ONB remains unknown. The rationale behind elective neck therapy is based on the frequent nodal spread to the neck and the concomitant increase in mortality.
Prospective studies are needed to evaluate a potential role for elective neck dissection versus elective neck radiation for patients with esthesioneuroblastoma
Considering the lack of standardized treatment guidelines, the potential advantages of targeted therapy approaches and the paucity of data exploring the molecular pathogenesis of ONB, could be explored potentially targetable biomarkers/pathways in a cohort of recurrent or metastatic ONBs. The identification of multiple protein biomarkers of response or resistance to classic chemotherapy and targeted therapy could be useful in optimizing the cytotoxic chemotherapy and further improving personalized treatment of ONB.
50
9. Bibliography
1. Konig M, Osnes T, Jebsen P, Folkvard Evensen J, Meling TR. Olfactory neuroblastoma:a single center experience. Neurosurg Rev. 2017 May
2. Saade RE, Hanna EY, Bell D. Prognosis and biology in esthesioneuroblastoma: the emerging role of Hyams grading system. Curr Oncol Rep. 2015 Jan;17(1):423 3. Banuchi VE, Dooley L, Lee NY, Pfister DG, McBride S, Riaz N, Bilsky NH, Ganly I, Shah JP, Kraus DH, Morris LGT. Patterns of regional and distant metastasis in esthesioneuroblastoma. Laryngoscope. 2016 July ; 126(7): 1556– 1561. doi:10.1002/lary.25862
4. Josephs L, Jones L, Marenette L, McKeever P. Cushing’s syndrome:an unusual presentation of olfactory neuroblastoma. Skull Base. 2008;18(01):073–6. https://doi.org/10.1055/s-2007-994291
5. Koo BK, An JH, Jeon KH, CHOI SH, Cho YM, Jang HC, et al. Two cases of ectopic adrenocorticotropic hormone syndrome with olfactory neuroblastoma and literature review. Endocr J. 2008;55(3):469–75. https://doi.org/10.1507/endocrj.K07E-005
6. Wu HB. Preliminary study for the evaluation of olfactory neuroblastoma using PET/CT. Clin Nucl ed 2011;36:894-8
7. Liermann J, Syed M, Held T, Bernhardt D, Plinkert P, Jungk C, Unterberg A, Rieken S, Debus J, Herfarth K, Adeberg S. Advanced Radiation Techniques in the Treatment of Esthesioneuroblastoma: A 7-Year Single-Institution's Clinical Experience. Cancers (Basel). 2018 Nov 20;10(11)
8. Kadish S olfactory neuroblastoma:a clinical analysis of 17 cases. Cancer 1976;37:1571-6)( Morita A Esthesioneuroblastoma: prognosis and management.Neurosurgery 1993;32:706-15
9. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol. 2001 Nov;2(11):683-90.) (Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970-1990. Laryngoscope. 1992 Aug;102(8):843-9
51 10. Kane AJ Post-treatment prognosis of patients with esthesioneuroblastoma. J
Neurosurg 2010;113:340-51
11. Ow TJ, Bell D, Kupferman ME, Demonte F, Hanna EY. Esthesioneuroblastoma. Neurosurg. Clin. N. Am. 2013 Jan;24(1):51-65
12. Trojanowski JQ, Lee V, Pillsbury N, Lee S. Neuronal origin of human esthesioneuroblastoma demonstrated with anti-neurofilament monoclonal antibodies. N. Engl. J. Med. 1982 Jul 15;307(3):159-61
13. Wooff JC, Weinreb I, Perez-Ordonez B, Magee JF, Bullock MJ. Calretinin staining facilitates differentiation of olfactory neuroblastoma from other small round blue cell tumors in the sinonasal tract. Am. J. Surg. Pathol. 2011 Dec;35(12):1786-93 14. Thompson LD. Olfactory neuroblastoma. Head Neck Pathol. 2009
Sep;3(3):252-9.) (Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod. Pathol. 2002 Mar;15(3):264-78
15. Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod. Pathol. 2002 Mar;15(3):264-78
16. Dublin AB. Imaging characteristics of olfactory euroblastoma. Skull Base. 2007;17(S 1):A091
17. Bradley PJ, Jones NS, Robertson I. Diagnosis and management of esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surg. 2003;11(2):112– 8. https://doi.org/10.1097/00020840-200304000-00009
18. Gallagher KK, Spector ME, Pepper J-P, McKean EL, Marentette LJ, McHugh JB. Esthesioneuroblastoma updating histologic grading as it relates to prognosis. Ann
Otol Rhinol Laryngol. 2014;123(5):353–8.
https://doi.org/10.1177/0003489414526368
19. Bell D, Saade R, Roberts D, Ow TJ, Kupferman M, DeMonte F,et al. Prognostic utility of Hyams histological grading and Kadish-Morita staging systems for esthesioneuroblastoma outcomes. Head Neck Pathol. 2015;9(1):51–9. https://doi.org/10.1007/s12105-014-0547-3
20. Kaur G, Kane AJ, Sughrue ME, Madden M, OhMC, Sun MZ. Theprognostic implications of Hyam’s subtype for patients with Kadish stage C esthesioneuroblastoma. J Clin Neurosci. 2013;20(2):281– 6.https://doi.org/10.1016/j.jocn.2012.05.029
52 21. Van Gompel JJLong-term outcome of esthesioneuroblastoma:Hyams’ grade
predicts patient survival J Neurol Surg B Skull Base 2012,73:331-6
22. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50
23. Nishimura H, Ogino T, Kawashima M, Nihei K, Arahira S, Onozawa M, Katsuta S, Nishio T. Proton-beam therapy for olfactory neuroblastoma. Int. J. Radiat. Oncol. Biol. Phys. 2007 Jul 01;68(3):758-62
24. Su SY, Kupferman ME, DeMonte F, Levine NB, Raza SM, Hanna EY. Endoscopic
resection of sinonasal cancers. Curr Oncol
Rep.2014;16(2):369.https://doi.org/10.1007/s11912-013-0369-6
25. Gallia GL, Reh DD, Salmasi V, Blitz AM, Koch W, Ishii M. Endonasal endoscopic resection of esthesioneuroblastoma: the Johns Hopkins Hospital experience and review of the literature. Neurosurg Rev. 2011;34(4):465–75. https://doi.org/10.1007/s10143-011-0329-2
26. Nicolai P, Battaglia P, Bignami M, Bolzoni Villaret A, Delù G, Khrais T, et al. Endoscopic surgery for malignant tumors of the sinonasal tract and adjacent skull base: a 10-year experience. Am J Rhinol. 2008;22(3):308–16. https://doi.org/10.2500/ajr.2008.22.3170
27. Iavarone A, Luparello P, Lazio MS, Comini LV, Martelli F, De Luca O, Santoro GP, Santoro R, Alderotti G, Mannelli G. The surgical treatment of cerebrospinal fistula: Qualitative and quantitative analysis of indications and results. Head Neck. 2019 Nov 4. doi: 10.1002/hed.25981
28. Saade RE, Hanna EY, Bell D. Prognosis and biology in esthesioneuroblastoma: the emerging role of Hyams grading system. Curr Oncol Rep. 2015;17(1):1–5)( Schwartz JS, Palmer JN, Adappa ND. Contemporary management of esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surgery. 2016;24(1):63–9. https://doi.org/10.1097/MOO.0000000000000220
29. Folbe A, Herzallah I, Duvvuri U, Bublik M, Sargi Z, Snyderman CH, e t a l . E n d o s c o p i c e n d o n a s a l r e s e c t i o n o f esthesioneuroblastoma: a multicenter
53
study. Am J Rhinol Allergy.2009;23(1):91–4.
https://doi.org/10.2500/ajra.2009.23.3269
30. Schwartz JS, Palmer JN, Adappa ND. Contemporary management of esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surgery. 2016;24(1):63–9. https://doi.org/10.1097/MOO.0000000000000220
31. HowellM, Branstetter B, Snyderman C. Patterns of regional spread for esthesioneuroblastoma. Am J Neuroradiol. 2011;32(5):929– 33.https://doi.org/10.3174/ajnr.A2401
32. Zanation AM, Ferlito A, Rinaldo A, Gore MR, Lund VJ,McKinney KA, et al. When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. Eur Arch Otorhinolaryngol. 2010;267(11):1667–71. https://doi.org/10.1007/s00405-010-1360-6
33. Jiang W, Mohamed AS, Fuller CD, Kim BY, Tang C, Gunn GB,e t a l . The r o l e o f e l e c t ive nodal i r r a d i a t i on for esthesioneuroblastoma patients with clinically negative neck.Pract Radiat Oncol. 2016;6(4):241–7. https://doi.org/10.1016/j.prro.2015.10.023
34. Bak M, Wein RO. Esthesioneuroblastoma: a contemporary review of diagnosis and management. Hematol Oncol Clin North Am.2012;26(6):1185–207. https://doi.org/10.1016/j.hoc.2012.08.005
35. Ozsahin M, Gruber G, Olszyk O, Karakoyun-Celik O, Pehlivan B,Azria D, et al. Outcome and prognostic factors in olfactory neuroblastoma:a rare cancer network study. Int J Radiat Oncol Biol Phys.2010;78(4):992–7. https://doi.org/10.1016/j.ijrobp.2009.09.019
36. Nishimura H, Ogino T, Kawashima M, Nihei K, Arahira S,Onozawa M, et al. Proton-beam therapy for olfactory neuroblastoma.Int J Radiat Oncol Biol Phys. 2007;68(3):758–62. https://doi.org/10.1016/j.ijrobp.2006.12.071
37. Bachar G, Goldstein DP, Shah M, Tandon A, Ringash J, Pond G, et al. Esthesioneuroblastoma: the Princess Margaret Hospital experience. Head Neck. 2008;30(12):1607–14. https://doi.org/10.1002/hed.20920
38. Rimmer J, Lund VJ, Beale T, Wei WI, Howard D. Olfactory neuroblastoma:a 35-year experience and suggested follow-up protocol.Laryngoscope. 2014;124(7):1542–9. https://doi.org/10.1002/lary.24562
54 39. Su SY, Bell D, Hanna EY. Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol.2014;18(S 02):S149–S56. https://doi.org/10.1055/s-0034-1390014
40. Ahmed S. Abdelmeguid. Olfactory Neuroblastoma. Head and Neck Cancers. Current Oncology Reports (2018) 20:7. https://doi.org/10.1007/s11912-018-0661-6
41. Fu TS, Monteiro E, Muhanna N, Goldstein DP, de Almeida JR. Comparison of outcome for open versus endoscopic approaches for olfactory neuroblastoma: a systematic review and individual participant data meta-analysis. Head Neck 2016;38(suppl 1):E2306-16
42. Roxbury CR, Ishii M, Gallia GL, Reh DD. Endoscopic Management of Esthesioneuroblastoma. Otolaryngol Clin N Am 49 (2016) 153–165
43. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A et al (2014) Preferred reporting items for systematc review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 349:g7647
44. Sedgwick P (2015) Meta-analysis: testing for reporting bias. BMJ 350:g7858 45. Goodman S, Dickersin K (2011) Metabias: a challenge for comparative
effectiveness research. Ann Intern Med;155:61–62
46. Schwartz JS, Palmer JN, Adappa ND. Contemporary management of esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surg. 2016;24:63-9 47. Levine PA, McLean WC, Cantrell RW. Esthesioneuroblastoma: the University of
Virginia experience 1960-1985. Laryngoscope 2009;96(7):742-6
48. Walch C, Stammberger H, Anderhuber W, Unger F, Kole W, Fetchinger K. The minimally invasive approach to olfactory neuroblastoma: combined endoscopic and stereotactic treatment. Laryngoscope 2000;110(4):635-40
49. Kliromonos G et al. Endoscopic management of Esthesioneuroblastoma: our experience and review of literature. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.09.011
50. Castelnuovo P, Bignami M, Delu G, Battaglia P, Bignardi M, Dallan I. Endonasal endoscopic resection and radiotherapy in olfactory neuroblastoma: our experience. Head Neck 2007;29(9):845-50
