Olfactory Neuroblastoma: Everything Radiologists Should Know

Review article

Raquel Navas-Campo1 Leticia Moreno Caballero1 Ana Gasos Lafuente1 Pilar Tobajas Morlana1 Eduardo Séez Valero1 María José Gimeno Peribáñez1

1 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

Abstract Olfactory neuroblastoma (ONB) is a rare malignant tumor that originates from olfactory neuroepithelial cells. Its early diagnosis is difficult due to the low specificity of symptoms. Imaging tests play an important role in the diagnosis and surgical planning of ONB; therefore, it is important that radiologists know the characteristic findings and the different classifications that will help to choose the most appropriate treatment for each tumor. Keywords Olfactory neuroblastoma, Esthesioneuroblastoma, Cancer of the Head and Neck, Computed Tomography, Magnetic Resonance Imaging

Introduction of life and the second peak in the sixth decade of life, some recent studies support a uniform distribution across all ages, Olfactory neuroblastoma (ONB) is a rare malignancy of the with a peak in the fifth and sixth decades of life.3,4,6.12,13 upper nasal cavity, also known as esthesioneuroblastoma, Nonspecificity of symptoms and local aggressiveness lead to esthesioneuroepithelioma, esthesioneurocytoma or olfactory the development of locally advanced disease with submuco- placode.1 It was first described by Berger et al.2 in 1924, and sal spread to the paranasal sinuses and the anterior cranial the most widely accepted term at this time is “olfactory neu- fossa through the cribriform plate in a large number of pa- roblastoma”.3,4 tients.14-16 Metastatic disease affects between 17% and 48% The exact origin of this tumor, as well as the location and of patients.17 Cervical lymph nodes are the most common cell type are under debate.5 Proposed anatomic sites of ori- sites of metastasis, with an incidence ranging between 20% gin include Jacobson organ (vomeronasal organ), the sphe- and 30%, followed by the lung, bone and, rarely, the liver, nopalatine ganglion, the ectodermal olfactory placode, Loci’s mediastinum, adrenal gland, ovary, spleen or parotid gland or ganglion, sympathetic ganglia of the nasal mucosa, and the even the breast.12,18-24 nasal mucosa itself. However, the most likely site of origin of Imaging plays an important role in the diagnosis and surgical ONB is the basal neural cells of the olfactory mucosa.5-7 This planning of ONB. Therefore, it is essential that radiologists is supported by the fact that neural filaments are present in know the characteristic findings of ONB on the various imag- tumor cells, as demonstrated by Trojanowaski et al.8 in 1982, ing modalities and the classifications that will help to choose and by molecular analysis, as demonstrated by Carney et al.9 the most appropriate treatment for each tumor. in 1995, with the expression of the Drosophila achaete-scute gene (hASH1), involved in immature olfactory neuronal development.5,6,10 Histology and immunohistochemistry This tumor accounts for approximately 2% to 3% of all intra- nasal malignancies.11 It affects both genders equally. It may Histologically, ONB is composed of small round blue cells occur at all ages and, although it was thought to have a bi- slightly larger than mature lymphocytes. These cells pos- modal age distribution with one peak in the second decade sess round-to-oval-shaped nuclei, with scanty cytoplasm and

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sharply defined chromatin. They also have layers of malignant There is growing evidence in literature that this classification cells organized into lobules through slender vascular fibrous may be used as an indicator for prognosis. High-grade tu- septa, true neural rosettes (Flexner– Wintersteiner type) and mors in Hyams classification have been found to be associ- pseudorosettes (Homer Wright type).23 ated with more aggressive locoregional disease and a worst The differential diagnosis of ONB includes all small round survival outcome than low-grade tumors.4,34,35 Furthermore, blue cell tumors occurring in the sinonasal tract. These in- Hyams classification may add value to guide the selection of clude epithelial neoplasms such as sinonasal undifferentiated adjuvant therapy.34 carcinoma, sinonasal neuroendocrine carcinoma, squamous carcinoma and melanoma; non-epithelial neoplasms such as rhabdomyosarcoma, lymphoproliferative tumors and benign Clinical manifestations lesions such as inverted papilloma and schwannoma.25 Differential diagnosis is possible, especially in cases of high- The most common presenting symptoms are nasal obstruc- grade lesions, only by immunohistochemistry.26 The tumor tion followed by recurrent epistaxis. Other symptoms include cells of ONB express neuronal markers such as synaptophy- headache, facial pain, hyposmia and rhinorrhea.36.45 Occa- sin, chromogranin or neuron-specific enolase, as well as cal- sionally, it may occur as an asymptomatic nasal mass that retinin, which differentiate them from other types of small is found incidentally.45 Advanced stage disease manifests round blue cell tumors.27,28 with symptoms related to local extension beyond the nose The cells in the periphery of the lobules are highly reactive and paranasal sinuses, such as epiphora, diplopy, proptosis for protein S100. Cytokeratin is usually negative, although in and loss of visual acuity.36,43-45 Rarely, patients may present some isolated cases it may exhibit an irregular expression.29 with symptoms of intracranial involvement, such as frontal lobe symptoms and seizures.38,45 On rare occasions, paraneo- plastic symptoms have been reported resulting from ectopic Histological Classification hormonal secretion, including Cushing syndrome and hypo- natremia secondary to adrenocorticotropic hormone (ACTH) The histological grading system proposed by Hyams et al.30 and antidiuretic hormone (ADH) secretion, respectively.45-48 (Table 1) was developed in 1988 as an important tool for Locally, advanced disease may present signs of invasion and prognosis, both of recurrence and survival..30,31 The criteria destruction of surrounding structures, such as the orbit, underlying this classification are the mitotic activity, native brain, facial soft tissues and skin.3,6,38 architecture conservation, matrix features, nuclear poly- Because of the nonspecificity of the early symptoms of ONB, morphism, the existence of rosettes and tumor necrosis.32 there is generally a delay in diagnosis, with an average time This grading system stratifies tumors into four groups rang- of 6 to 12 months between the onset of symptoms and di- ing from well differentiated (grade I) to least differentiated agnosis.3,6,19,38,49 (grade IV). This is a subjective complex system and sometimes definitive separation into grades becomes difficult. For this reason, there has been a tendency to group these categories Imaging Diagnosis into low-grade, comprising grades I and II, and high-grade, comprising grades III and IV, in order to provide and easier Imaging is very important in the diagnosis and staging of description of these tumors in correlation with prognosis.33 ONB. Generally, a combination of computed tomography

Table 1: The Hyams histological grading system. * HW rosettes: true rosettes (Flexner– Wintersteiner type). * FW Pseudoro- settes (Homer Wright type).

GRADE Preservation of Mitotic Nuclear Fibrillary Rosettes Necrosis lobular architecture index polymorphism matrix

I + None None Prominent HW rosettes None II + Low Moderate Present HW rosettes None III + / - Moderate Prominent Present FW pseudorosettes Rare IV + / - High Marked Absent None Frequent

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(CT) and magnetic resonance imaging (MRI) is required for 12).55 On MRI, ONB appears hypointense to gray matter on an optimal evaluation of the extent of the tumor.38,49 Both T1-weighted images and iso- to hyperintense to gray matter tests allow diagnosis, definition of the extent and stage of on T2-weighted images (Figs. 10-15).56 The tumor demon- the tumor and of the surgical approach, and monitoring and strates homogeneous enhancement except for areas of ne- evaluation of the treatment response. crosis or hemorrhage. In addition, MRI can differentiate the Thin-slice CT scan (1-mm slice thickness) with reconstruction tumor from entrapped secretions, which are hyperintense on in coronal and sagittal planes is the best initial imaging test T2-weighted images.53,55 The classic imaging findings include for assessing ONB. On CT, ONB appears as a homogeneous a “dumbbell-shaped” mass extending across the cribriform soft-tissue mass in the nasal vault with uniform and moderate plate (Fig. 12), with the narrow portion at the cribriform contrast enhancement (Figs. 1 and 2). Scattered speckled cal- plate. Peripheral tumor cysts (Figs. 5b, 12, 14, 16) and speck- cifications may be present (Figs. 2-4, 5a, 6).50 The main value led calcifications are quite characteristic of ONB.1 of CT is that it provides better definition of bone involvement MRI fat-saturated sequences help distinguish tumor from or- than MRI. CT helps to evaluate bone erosion of the cribriform bital fat and muscle. A smooth margin of the tumor-fat inter- plate, fovea ethmoidalis and lamina papyracea (Figs. 1-4, 5a, face suggests that the lesion is contained by periorbital fascia 8). However, bone remodeling without erosion may occur in (Fig. 15), while an irregular margin favors frank invasion of some cases due to the indolent growth pattern.3,35,49 CT scans the orbit.35,49,57 However, the definitive diagnosis of invasion generally show a lytic pattern and very rarely dominant hy- of dura and periorbital tissues is possible only at surgery.49 perostosis mimicking fibrous dysplasia.51 CT is also useful to Imaging of the neck in patients with ONB is crucial because assess regional neck and distant metastasis.52,53 neck lymph nodes metastases are found at presentation in MRI is the imaging modality of choice for a detailed evalua- 5% of patients.33 Furthermore, it has been estimated that tion of the locoregional extent and staging of the tumor. MRI over 23% of patients may develop cervical lymph node me- is superior to CT for defining the soft tissue extent (Fig. 9) tastasis.20 Howell et al.52 described a predictable pattern of with a better assessment of intracranial (Figs. 10-14), orbital metastasis to cervical lymph nodes, typically involving level (Figs. 14 and 15) and skull base involvement and of perineu- II lymph nodes (93%), with frequent involvement of level I ral invasion. 53,55 MRI has added value in distinguishing du- lymph nodes (57%), level III lymph nodes (50%) and retro- ral involvement from brain parenchymal involvement (Fig. pharyngeal lymph nodes (43%).

a b

Fig. 1 (a) Axial CT scan of the head without intravenous contrast. Homogeneous soft tissue space-occupying lesion occupying the left nasal cavity (white asterisk) and extending to the left choana (black arrow) with bone destruction and extension to the left maxillary sinus (black asterisk). (b) Axial CT scan of the head with iodinated intravenous contrast. After contrast administration, the lesion shows moderate enhancement.

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a b

Fig. 2 Axial CT scan of the head (a) without intravenous contrast and (b) with iodinated intravenous contrast. Homogeneous soft tissue mass with small speckled calcifications inside (black arrows), occupying the nasal cavities with bone destruction and extension into both maxillary sinuses (black asterisks), as well as caudal extension posterior to the nasopharynx (white asterisk).

a b

Fig. 3 (a) Axial CT scan of the head without intravenous contrast. Bulky soft tissue mass occupying the nasal cavities and involving both orbits (black asterisks), predominantly the right orbit and the sphenoidal sinus (white asterisks). The mass contains calcifications (black arrow). (b) Axial CT scan of the head with iodinated intravenous contrast. After intravenous contrast administration, the mass presents homogeneous moderate enhancement.

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Fig. 4 Axial CT scan of the head (a) without intravenous contrast and (b) with iodinated intravenous contrast. (c) Coronal multiplanar reconstruction (MPR) from CT scan of the head with iodinated intravenous contrast. Nasal cavity lesion with speckled calcifications inside (black arrows), enhancing with contrast and causing bone destruction with invasion of both orbits (black asterisks) and of the frontal sinus with frontal intracranial extension (white arrows). a b

Fig. 5 Axial CT scan of the head without intravenous contrast. (a) Bulky soft tissue mass with speckled calcifications inside (black arrows) occupying the nasal cavity and causing bone destruction extending to the right orbit and frontal sinus (black asterisk). (b) The mass also extends to the anterior cranial fossa, where it presents cystic content in its posterior pole (white asterisk) and perilesional edema (white arrow). Significant mass effect with compression of the left frontal horn and midline shift to the right. There is also presence of several associated sites of parenchymal bleeding (white arrowhead).

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a b

Fig. 6 (a) Axial CT scan of the head with iodinated intravenous contrast shows soft tissue mass with small speckled calcifications inside (white arrow), causing bone destruction with extraconal left intraorbital extension compressing the left medial rectus muscle (black asterisk), as well as extension to bilateral anterior ethmoidal cells. (b) Axial CT scan of the head with iodinated intravenous contrast. Extension of the soft tissue lesion to the left frontal sinus (white asterisk) with bone destruction (black arrow) and extracranial extension to the anterior fossa.

a b

Fig. 7 (a) Coronal MPR from CT scan of the head with iodinated intravenous contrast. Large soft tissue mass occupying the left nasal cavity with bone destruction and left intraorbital extension (black asterisk), extension to the left maxillary sinus (black arrow), destruction of the floor of the left frontal sinus and destruction of the left cribriform plate and intracranial extension (white arrow). (b) Coronal MPR from CT scan of the head with bone window. The scan shows destruction of the lamina papyracea, ethmoidal cells, left lacrimal bone, left orbital plate, left cribriform plate and the crista galli.

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a b

Fig. 8 Coronal MPR from CT scan of the head with iodinated intravenous contrast (a) soft tissue window and (b) bone window. Bulky mass occupying the nasal cavities with extension to both orbits, predominantly to the right orbit (black asterisk) and frontal sinus. Bone destruction of the lamina papyracea, orbital plate and cribriform plate. Parenchymal intracranial extension with extensive left frontal involvement (black arrow) and associated edema (white arrow), causing mass effect with subfalcine herniation and midline shift to the right (white arrowhead).

Fig. 9 Axial MRI of the head. (a) FLAIR sequence. (b) T2-weighted sequence. (c) Diffusion- weighted sequence and (d) T1-weighted sequence with paramagnetic contrast (Gadolinium). Space-occupying lesion located in the nasal cavity causing bone destruction and invasion of the left maxillary sinus (black asterisk). The mass exhibits moderately restricted diffusion and enhances after paramagnetic contrast administration.

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One of the most frequent distant metastases is to bone, based on the TNM system (table 4) with a more detailed de- with the spine being the most common site (86%).58 Cases scription of the local extension of disease and considering of asymptomatic bone metastases have been described and, distant metastases and spread to cervical lymph nodes. In T1, therefore, a bone scan should be included in the diagnostic the tumor involves the nasal cavity and/or paranasal sinuses work-up.33 (excluding the sphenoid), sparing the most superior eth- The evaluation of recurrent tumor must include both CT and moidal cells; in T2, the tumor involves the nasal cavity and/or MRI. The imaging characteristics of the recurrent tumor do paranasal sinuses, including the sphenoid, with extension to not differ from its appearance at initial presentation. The fol- or erosion of the cribriform plate; in T3, the tumor extends lowing follow-up protocol has been suggested for an early into the orbit or protrudes into the anterior cranial fossa with detection of recurrence: contrast-enhanced MRI performed no dural invasion and in T4, the tumor involves the brain. at 2 to 4 months after completion of all therapy. Then, MRI is Disease is classified as N0 if there is no cervical lymph node repeated every 4 to 6 months for 5 years and from then on- involvement, as N1 for any form of cervical lymph node in- wards, annually for the patient’s lifetime.59 The MRI protocol volvement, as M0, if there is no metastasis and as M1 if there used in our service consists of T1-, T2- and fat-suppressed is evidence of distant metastasis. T1-weighted images with and without contrast administration for sinonasal evaluation, and T1-weighted, T2-weighted, FLAIR, DW-EPI and T1-weighted sequences with contrast ad- Treatment ministration for brain evaluation. In addition, a chest radio- graph should be performed annually to exclude the presence The treatment modalities used and the expected outcomes of metastasis.59 depend on the tumor extension and histological grade. Ex- cept for cases of very early-stage and limited disease, multimodality therapy offers the best opportunity for cure.5 Imaging classification/Staging Surgery followed by radiation therapy is considered as the standard therapy by most expert centers.5,39 Several staging systems have been proposed for ONB, but no The traditional surgical approach for ONB is anterior craniofa- single system is universally accepted. cial resection, involving a bifrontal craniotomy combined with The first to propose a classification was Kadish. In this clas- a transfacial lateral rhinotomy.63 This surgical procedure is sification, tumors were divided into three categories accord- performed, if needed, by a team of neurosurgeons and oto- ing to their extension: Group A, the tumor is confined to the laryngologists. In the last two decades, endoscopic approach- nasal cavity; Group B, the tumor extends into the paranasal es have gained popularity, producing comparable oncologic sinuses; and Group C, the tumor extends beyond the para- outcomes, limiting surgical morbidity and the duration of nasal sinuses.18 hospital stay.64 Initially, these approaches were recommended This classification was modified in 1993 by Morita et al.,60 only for early-stage disease with minimal invasion of the skull who added stage D for the spread to cervical lymph nodes base. However, with advances in endoscopic techniques and and distant metastasis (Table 2).19,61 Some studies have re- reconstruction methods, they are being increasingly used for ported that the modified Kadish staging system may be a advanced-stage disease with extensive invasion, allowing useful predictor of survival.12,49 In their study, Jethanametest complete resection.65 et al.12 found that in this classification, lymph node involve- Contraindications for purely endoscopic approaches include ment and the age at the time of diagnosis were prognostic involvement of the anterior table of the frontal sinus, skin factors. However, the rarity of the disease makes it difficult to and subcutaneous tissue, the nasolacrimal sac, the carotid validate the staging systems, and the prognostic value of this artery and extensive intraorbital and brain parenchymal in- classification has not been confirmed in other studies such as vasion. Furthermore, lateral extension above the orbit and the one conducted by Konuthula et al.62 palatine invasion are also considered as contraindications for In 1990, Biller et al61 proposed an additional classification purely endoscopic approaches and, in such cases, traditional (Table 3), in which T1 indicates that the tumor involves the craniofacial approaches are indicated.63,66 Regardless of the nasal cavity and paranasal sinuses, excluding the sphenoid, approach, complete resection with negative margins should with or without erosion of the bone of the anterior cranial be achieved in all cases.63 fossa; in T2 the tumor extends into the orbit or protrudes into Postoperative radiation therapy has been shown to improve the anterior cranial fossa, in T3 the tumor involves the brain local control of disease. However, no benefit has been dem- with resectable margins, and in T4 the tumor is unresectable. onstrated in terms of long-term overall survival for adjuvant Dulgerov and Calcaterra19 proposed in 1992 a classification radiotherapy.13,62,67 Conformed radiotherapy techniques such

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a b

Fig. 10 Coronal MRI of the head. (a) T2-weighted sequence and (b) T1-weighted sequence. Space-occupying mass of slightly heterogeneous intensity, predominantly hyperintense to gray matter on T2-weighted sequence and slightly hypointense on T1-weigthted sequence, occupying the left nasal cavity. The scan shows bone destruction with destruction of the left lamina papyracea, extraconal left intraorbital extension with compression of the left medial rectus muscle and no apparent infiltration of the muscle (black arrow), infundibular extension to the medial wall of the left maxillary sinus (white arrow), destruction of the floor of the left frontal sinus with extension to the sinus, destruction of the left cribriform plate with extra-axial incra- cranial extension in the left frontobasal anterior fossa, apparently contained by the dura, with a doubtful dural disruption that might be an indication of minimal occupation of the subdural space (white arrowhead). a b

Fig. 11 Kadish stage C esthesioneuroblastoma. (a) and (b) Coronal T2-weighted MRI of the head. Bulky space-occupying lesion with heterogeneous signal intensity, located at the level of the nasal cavity (black asterisk), with bone destruction, invading orbits (white arrow), as well as paranasal sinuses (black arrow), nasopharynx and anterior brain fossa (white arrowhead), where peripheral cystic component is noticed (black arrowhead).

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Fig. 12 Axial MRI of the head. (a) T1-weighted sequence shows a lesion that is slightly hypointense to gray matter, occupies the left frontal sinus (black asterisk) and destroys the posterior wall of the sinus extending to the anterior cranial fossa (white arrow). (b) On the fat-suppressed T2-weighted image, the lesion is hyperintense to gray matter. (c) T1-weighted sequence with paramagnetic (Gadolinium) contrast and (d) fat-suppressed T1-weighted image with paramagnetic (Gadolinium) contrast. These sequences show a homogeneous enhancement of the lesion and evidence of subdural infiltration with no extension to the brain.

Fig. 13 Axial MRI of the head. (a) FLAIR sequence. (b) T2-weighted sequence. (c) Diffusion- weighted sequence and (d) T1-weighted sequence with paramagnetic (Gadolinium) contrast. Involvement of the anterior cranial fossa by a nasal cavity mass (black asterisk), causing significant mass effect at the encephalic level, with presence of peripheral cystic cavity (black arrow) and significant perilesional edema of finger-like morphology (black arrowhead), causing subfalcine herniation (white arrow). The mass has heterogeneous signal intensity, being hyperintense to gray matter on T2-weighted sequences, exhibiting moderately restricted diffusion and slight enhancement after paramagnetic contrast administration.

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Fig. 14 Axial MRI of the head. (a) T1-weighted sequence. (b) T2-weighted sequence. (c) T1- weighted sequence with paramagnetic (Gadolinium) contrast and (d) fat-suppressed T1- weighted sequence with paramagnetic (Gadolinium) contrast. Space-occupying mass that appears hypointense to gray matter on T1-weighted sequences and moderately hyperintense on T2-weighted sequences with heterogeneous contrast enhancement, occupying the left nasal cavity (black asterisk) and ethmoidal cells and destroying the left orbital plate, with extraconal intraorbital extension (white asterisk) and compression of the left medial rectus muscle with no apparent infiltration of the muscle. This can be better visualized on fat-saturated sequences (d), where a hypointense line can be seen between the lesion and the muscle (tumor-fat interface) (white arrows), suggesting that the lesion is contained within the periorbital fascia.

Fig. 15 Axial MRI of the head. (a) FLAIR sequence. (b) T2-weighted sequence. (c) Diffusion- weighted sequence and (d) T1-weighted sequence with paramagnetic (Gadolinium) contrast. Space-occupying mass located in the nasal cavity and ethmoidal cells, exhibiting bone destruction (black asterisk) and extraconal orbital invasion (white asterisk). The mass is slightly hyperintense to gray matter on T2-weighted sequences and exhibits moderate restricted diffusion and a slight enhancement after paramagnetic contrast administration.

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a b

Fig. 16 Axial CT scan of the head (a) without intravenous contrast and (b) with iodinated intravenous contrast. Parenchymal intracranial extension with extensive left frontal involvement occupying the midline. Brain parenchymal mass effect with surrounding edema (white arrows) and associated subfalcine herniation with midline shift to the right (black arrows). After intravenous contrast administration, a cystic component is seen in the left frontal region (white asterisk).

Table 2: Kadish classification modified by Morita et al.

STAGE DESCRIPTION

A Tumor confined to the nasal cavity. B Tumor extends into the paranasal sinuses C Tumor extends beyond the paranasal sinuses, including the cribriform plate, the skull base, the intracranial cavity and orbit. D Tumor with spread to cervical lymph nodes and/or distant metastasis.

Table 3: Biller’s classification.

GRADE DESCRIPTION

T1 Tumor involves the nasal cavity and paranasal sinuses, excluding the sphenoid, with or without erosion of the bone of the anterior cranial fossa T2 Tumor extends into the orbit or protrudes into the anterior cranial fossa. T3 Tumor involves the brain with resectable margins T4 Unresectable tumor

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Table 4: Classification based on the TNM system by Dulgerov and Calcaterra.

CLASSIFICATION DEFINITION

TUMOR T1 Tumor involves the nasal cavity and/or paranasal sinuses (excluding the sphenoid) sparing the most superior ethmoidal cells T2 Tumor involves the nasal cavity and/or paranasal sinuses, including the sphenoid, with extension to or erosion of the cribriform plate T3 Tumor extends into the orbit or protrudes into the anterior cranial fossa with no dural invasion T4 Tumor involves the brain

LYMPH NODES N0 No cervical lymph node involvement. N1 Any form of cervical lymph node involvement

METASTASIS M0 No metastases M1 Distant metastases

as intensity-modulated radiotherapy and proton-beam radia- surgery alone and surgery with adjuvant radiotherapy were tion have shown better outcomes, improving local control compared among the different modified Kadish stages, there and minimizing toxicity and complications in critical sur- was also no differences in survival between the two groups in rounding structures.5,68 stages A, B and D. However, for patients with Kadish stage C, In general, chemotherapy may be considered in patients with surgery with adjuvant radiotherapy had better survival rates advanced tumor stage, high Hyams grade, extensive regional than surgery alone.62 disease, distant metastasis, positive margins, unresectable tumors and recurrent tumors.69 There is no standard chemotherapy regime for treating ONB. Some authors reported the Conclusion use of cyclophosphamide, vincristine and doxorubicin, while others considered the use of cisplatin-based regimens.70 Olfactory neuroblastoma is a rare malignancy. The diagnosis Cisplatin in combination with etoposide appears to be the of this tumor is based on imaging tests, pathology examina- most widely accepted regimen used for ONB.71,72 Adjuvant tion and immunohistochemistry. Therefore, radiologists play chemotherapy may contribute to improve locoregional con- a crucial role in its diagnosis. For this reason, they should be trol and extend the mean time to relapse. However, it does aware of the characteristic findings on the different imaging not improve overall survival.68 tests (CT and MRI), and of the various staging systems avail- Overall survival rates are inconsistent between various stud- able for diagnosing its extension. Optimal therapy depends ies. Konuthula et. Al62 analyzed survival in 1,107 patients on the tumor extension and histological grade, with the using data from the National Cancer Database (NCDB) and treatment of choice being multimodality therapy with com- found that survival with different modalities of treatment was bined surgery and radiation with or without chemotherapy, not clear because of the low patient numbers. Although a although this depends on each center’s experience. combination of surgery and radiation therapy has been used most frequently and has been shown to have a survival of Ethical responsibilities around 65%, many patients are still being treated with sur- Protection of human subjects and animals. The authors gery or RT alone, as no statistically significant difference has declare that no experiments were performed on humans or been shown for the different treatment modalities. When animals for this investigation.

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Confidentiality of data.The authors declare that they have 17 Levine PA, McLeanWC, Cantrell RW. Esthesioneuroblastoma: the Univer- sity of Virginia experience 1960-1985. Laryngoscope. 1986;96(07):742– followed the protocols of their work center on the publica- 746 tion of patient data. 18 Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical Right to privacy and informed consent. The authors de- analysis of 17 cases. Cancer. 1976;37(03):1571–1576 19 Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience clare that no patient data appear in this article. 1970-1990. Laryngoscope. 1992;102(08):843–849 Sources of funding. There have been no sources of funding 20 Rinaldo A, Ferlito A, Shaha AR, Wei WI, Lund VJ. Esthesioneuroblastoma and cervical lymph node metastases: clinical and therapeutic implications. for this study. Acta Otolaryngol. 2002;122 (02):215–221 21 Monroe AT, Hinerman RW, Amdur RJ, Morris CG, Mendenhall WM. 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