Key points

Introduction

Esthesioneuroblastoma (ENB) was first described by Berger and Richard in 1924. It has been characterized as a rare malignant neoplasm of the sinonasal cavity that arises in the superior portion of the nasal vault. Since its first description, ENB has been referenced under several names, but the accepted terms at this time are “esthesioneuroblastoma” and “olfactory neuroblastoma.” The exact origin of this tumor, both the location and cell type, is under debate. Proposed anatomic sites of origin include Jacobson organ, the sphenopalatine ganglion, the ectodermal olfactory placode, Loci’s ganglion, sympathetic ganglia of the nasal mucosa, and the nasal mucosa itself. However, the most likely site of origin, and the one most generally accepted, is the basal neural cells of the olfactory mucosa. The olfactory epithelium is unique in the human nervous system in that it is capable of regeneration and the histologic organization of the olfactory organ reflects this ability. Several cell types are present: the mature olfactory neuroepithelial cells, a basal layer of stem cells that repopulate the differentiated epithelium, sustentacular supporting cells, and flat cells forming the ducts of Bowman in the olfactory lamina propria. ENB seems to be of neuronal or neural crest origin, this idea is supported by the neural filaments present in tumor cells. Also, molecular analysis suggests that ENB is derived from immature olfactory neurons.

Regardless of its origin, several factors have presented challenges to the characterization and treatment of ENB. First, the tumor is very rare, making it a difficult entity to study. Second, ENB can be difficult to differentiate from several other neoplasms. Third, ENB itself can demonstrate a wide spectrum of clinical behavior, ranging from relatively indolent to both locally aggressive and metastatic. Despite these challenges, the diagnosis and management of ENB has progressed significantly during the last 30 years.

Introduction

Esthesioneuroblastoma (ENB) was first described by Berger and Richard in 1924. It has been characterized as a rare malignant neoplasm of the sinonasal cavity that arises in the superior portion of the nasal vault. Since its first description, ENB has been referenced under several names, but the accepted terms at this time are “esthesioneuroblastoma” and “olfactory neuroblastoma.” The exact origin of this tumor, both the location and cell type, is under debate. Proposed anatomic sites of origin include Jacobson organ, the sphenopalatine ganglion, the ectodermal olfactory placode, Loci’s ganglion, sympathetic ganglia of the nasal mucosa, and the nasal mucosa itself. However, the most likely site of origin, and the one most generally accepted, is the basal neural cells of the olfactory mucosa. The olfactory epithelium is unique in the human nervous system in that it is capable of regeneration and the histologic organization of the olfactory organ reflects this ability. Several cell types are present: the mature olfactory neuroepithelial cells, a basal layer of stem cells that repopulate the differentiated epithelium, sustentacular supporting cells, and flat cells forming the ducts of Bowman in the olfactory lamina propria. ENB seems to be of neuronal or neural crest origin, this idea is supported by the neural filaments present in tumor cells. Also, molecular analysis suggests that ENB is derived from immature olfactory neurons.

Regardless of its origin, several factors have presented challenges to the characterization and treatment of ENB. First, the tumor is very rare, making it a difficult entity to study. Second, ENB can be difficult to differentiate from several other neoplasms. Third, ENB itself can demonstrate a wide spectrum of clinical behavior, ranging from relatively indolent to both locally aggressive and metastatic. Despite these challenges, the diagnosis and management of ENB has progressed significantly during the last 30 years.

Epidemiology

Malignancies of the sinonasal tract are rare, and ENB is uncommon even among neoplasms that fall within this category, accounting for roughly 3% of all tumors found in the nasal cavity. No apparent causal factors have been identified for this disease. There is, perhaps, a very slight male predominance reported among large series, with an approximate 55% male to 45% female distribution (Ow TJ, Hanna EY, Roberts DB, et al. Multimodality therapy optimizes long-term outcome in patients with esthesioneuroblastoma. Unpublished data, manuscript under review, 2012). ENB has been reported across several ethnicities, but published cases have been largely among the white population (Ow TJ, Hanna EY, Roberts DB, et al. Multimodality therapy optimizes long-term outcome in patients with esthesioneuroblastoma. Unpublished data, manuscript under review, 2012). Although some investigators have suggested that the age at which ENB develops has a bimodal distribution, this is not supported by recent large reviews, which more accurately suggest that the disease has been diagnosed across all decades, with a peak in the fifth or sixth decade.

Anatomy of the anterior skull base

The following is a brief description of the region of the anterior skull base. For more detail, the reader is referred to the work by Rhoton and the article by Pinheiro-Neto and colleagues. The anterior skull base can be divided into the medial and lateral compartments. The medial compartment is made up of the ethmoid, sphenoid, and frontal bones. The anterior-most aspect of the bony skull base is composed of the frontal bones, housing the pyramidal frontal sinuses. Inferiorly, the nasal cavity is found anteriorly and the sphenoid body housing the sphenoid sinus is found posteriorly. On the endocranial side, the crista galli is found at the midline. The gyri rectus, the anterior cerebral arteries, and the olfactory bulbs rest on the anteromedial base of the skull. Here, the roof of the ethmoid bone forms the cribriform plate anteriorly, where the olfactory rootlets pierce the bony skull base to enter the nasal cavity, and where an emissary vein traverses the foramen caecum. It is from this region the ENB is thought to arise. Posteriorly, the planum sphenoidale is found with the sella turcica housing the pituitary gland. Within the nasal cavity, the perpendicular plate of the ethmoid joins the vomer at the midline to make up the posterior nasal septum. The lateral plates of the ethmoid contribute to the medial orbital walls. The superior turbinates project from the roof of the ethmoid into the nasal cavity, lateral to the cribriform plate. The sphenoethmoid recesses and ostia to the sphenoid sinus can be found superior and posterior to the superior turbinates.

The lateral portion of the anterior skull base is the region of the orbit. Endocranially, the orbital gyri and middle cerebral arteries rest on the anterolateral skull base. The roof of the orbit is formed from the lesser wing of the sphenoid bone and the zygomatic bone. The inferior bony orbit is formed from the zygomatic, maxillary, and palatine bones. The medial wall of the orbit is formed from the maxilla, lacrimal bone, and ethmoid bones. There are several important foramina in the lateral portion of the anterior skull base. The anterior and posterior ethmoidal foramina are conduits for the branches of the ophthalmic artery bearing the same names, found traversing the superomedial orbital walls from the orbit to the superior nasal cavity. The supratrochlear foramen medially and the supraorbital foramen laterally house the neurovascular bundles superior to the orbits that supply the soft tissues of the forehead. In the posterior orbit, the optic canal is formed by the frontal bone and the lesser wing of the sphenoid, and the optic nerve and ophthalmic arteries are transmitted from intracranial to the orbit through this structure. The superior orbital fissure is found between the lesser wing and greater wing of the sphenoid. The oculomotor nerve (CN III), trochlear nerve (CN IV), lacrimal, frontal, nasociliary branches of the ophthalmic (CN V3) nerve, abducens nerve (CN VI), the ophthalmic vein, and sympathetic fibers from the cavernous sinus all pass through the superior orbital fissure. The inferior orbital fissure is found between the greater wing of the sphenoid and the anterior orbital floor formed by the maxillary and palatine bones. The maxillary nerve and its zygomatic branch, as well as the ascending branches from the pterygopalatine ganglion, can be found traversing the inferior orbital fissure. The adjacent infraorbital canal transmits the infraorbital artery and vein, which exit the infraorbital foramen to the soft tissues of the cheek.

Access to the anterior cranial base can be achieved via a bifrontal craniotomy, a subfrontal-transglabellar approach, a transnasal approach, and a transmaxillary-transnasal route. A detailed understanding of the anatomy of the midface, nasal cavity, paranasal sinuses, orbit, and anterior cranial fossa are crucial to successful surgery for ENB.

Clinical presentation

ENB, like all sinonasal tumors, can grow insidiously, and the common symptoms are very nonspecific and commonly associated with benign processes. A usual delay of 6 to 12 months between the onset of symptoms and diagnosis of ENB has been reported. Symptomatology is related to the anatomic structures affected by mass effect or local invasion. The most common presenting symptoms are nasal obstruction, followed by epistaxis. Other nasal symptoms include headache, facial pain, “sinusitis,” hyposmia or anosmia, or an asymptomatic nasal mass. Visual symptoms occur when the orbit is invaded and include diplopia, vision loss, proptosis, and epiphora. Intracranial invasion can rarely produce additional symptoms, including effects secondary to pituitary dysfunction, such as diabetes insipidus or hormonal disturbance, blindness secondary to effects on the optic nerves and chiasm, or neurologic symptoms secondary to mass effect or intracranial hypertension. Because symptoms associated with ENB are nonspecific and mimic those of benign sinonasal processes, an increased index of suspicion is crucial to improve early detection of these tumors. It has been suggested that unilateral symptoms and recurrent epistaxis for more than 1 to 2 months warrant more thorough investigation for a possible malignant process. It has been shown that patients with ENB present with unilateral symptoms more often than bilateral symptoms. One study has also compared patients diagnosed preoperatively with bilateral polyposis to those with unilateral polyps and found that neoplastic and malignant processes were exclusively diagnosed in the group with unilateral findings.

Diagnostic workup

Any patient with a history that is suspicious for a sinonasal tumor deserves a thorough neurologic, ophthalmologic, and head and neck examination. Cranial nerve abnormalities, including deficits in olfaction, facial paresthesias, ophthalmoplegia, and visual field deficits are concerning and should be noted. Middle ear effusion may be identified if the eustachian tube is obstructed. Proptosis and conjunctival injection are, of course, significant findings for orbital involvement. Nasal endoscopy is a necessity. Flexible fiberoptic endoscopy has the advantages of greater patient comfort, more facile assessment of the entirety of the nasal cavity, and the ability to concurrently evaluate the pharynx and larynx, whereas rigid nasal endoscopy offers the advantage of improved resolution and the ability to manipulate with a second instrument such as a suction or forceps.

After a mass is identified, imaging is needed for qualitative evaluation and staging. High-resolution sinus CT scan with intravenous contrast should be performed and the protocol should request thin (3 mm) sections through the skull base and paranasal sinuses. ENB metastasizes to the neck in 20% to 25% of cases, though only approximately 5% to 8% of patients present with cervical metastases. Therefore, a CT scan of the neck should be included in the diagnostic workup, as well, to evaluate for regional metastasis. Views in three dimensions—axial, coronal, and sagittal—are optimal, and a protocol amenable to image-guidance is useful if there is a consideration for endoscopic management. MRI is complementary and both imaging modalities are recommended. ENB is most typically hypointense compared with brain gray matter on T1-weighted MRI and should enhance with gadolinium. T2-weighted images show an isointense or hyperintense mass. Whereas CT scan is the optimal modality for evaluation of bony involvement (particularly the lamina papyracea, cribriform plate, and fovea ethmoidalis), MRI provides better discrimination between tumor and secretions and optimal evaluation of orbital and intracranial or brain parenchymal involvement.

After adequate examination on physical examination and imaging, biopsy is the next important step in securing a diagnosis. The authors generally recommend intraoperative biopsy under general anesthesia for any sinonasal mass, particularly lesions suspicious for malignancy, those deep in the nasal cavity, and those near the skull base or orbit. Biopsy is ideally performed after imaging has been reviewed to determine the vascularity of the mass. Bleeding from a vascular tumor is best managed in the operative setting. Because ENB can often be easily confused with several other sinonasal malignancies without careful immunohistologic characterization (see later discussion) it is best to reserve definitive management after thorough pathologic review on permanent section.

Histologic features

When the tumor is well-differentiated, ENB forms submucosal, sharply-demarcated nests or sheets of cells, often separated by richly vascular or hyalinized fibrous stroma. The cells are often uniform, with sparse cytoplasm and round or ovoid nuclei with punctuate (“salt-and-pepper”) chromatin and nucleoli that are either small or absent. The mitotic rate can be variable, but is usually low. ENB is characterized by fibrillary cytoplasm and interdigitating neuronal processes (neuropil). The cells can be arranged in glandular rings with a true lumen (called Flexner-Wintersteiner rosette) or pseudorosette (Homer-Wright pseudorosette). Examples of these characteristic features are presented in Figs. 1 and 2 .

Characteristic histologic features of lower grade ENB. ( A , B ) low-power (2×, 10×) magnification demonstrates monotonous cells growing in sharply demarcated nests and sheets. ( C ) High-power (40×) view demonstrates cells with round nuclei and punctuates “salt-and-pepper” chromatin embedded in a neurofibrillary stroma. See Hyams’ grading system (see Table 2 ).

Characteristic histologic features of higher grade ENB seen at ( A ) 2× magnification, ( B ) 10× magnification, and ( C ) 40× magnification with necrosis, increased mitotic activity and predominance of true-lumen, Flexner-Wintersteiner rosettes ( arrows ). Homer-Wright pseudorosettes ( arrowhead ) are more frequently seen in low-grade ENB. See Hyams’ grading system (see Table 2 ).

ENB can be more difficult to diagnose when the tumor is less differentiated, with increasing pleomorphism, higher mitotic rate, and areas of necrosis (see later discussion of Hyams’ grading), which can make this entity difficult to distinguish from other sinonasal tumors, particularly small blue cell tumors (see later discussion of sinonasal tumors considered in the differential diagnosis). In difficult cases, a panel of immunohistochemical markers is crucial to the establishment of a definitive diagnosis. ENB typically shows diffuse staining with neuron-specific enolase, synaptophysin, and chromogranin. Cytokeratins, glial fibrillary acid protein, neurofibrillary protein, β-tubulin, microtubule-associated protein, vimentin, epithelial membrane antigen, Leu-7 (CD57), and CD56 can all show variable reactivity. Desmin and myogenin, vimentin, and actin are negative, an important marker ruling out rhabdomyosarcoma. S-100 is variably positive, but positive cells are usually limited to the periphery of neoplastic nests, corresponding to sustentacular cells. This characteristic pattern differentiates ENB from sinonasal melanoma. FLI1 is negative, as is the EWS/FLI1 chimeric transcript, ruling out the rare diagnosis of peripheral neuroectodermal tumor or Ewing sarcoma. The typical immunohistochemistry panel and expected findings in ENB and other sinonasal tumors in the differential diagnosis are summarized in Table 1 . Typical staining patterns are exemplified in Fig. 3 .

Characteristic immunohistochemical staining of ENB. ( A ) Synaptophysin is diffusely positive. ( B ) S-100 highlights sustentacular cells. ( C ) Cytokeratin cocktail is negative.

Electron microscopy, though less commonly used, can be helpful in the diagnosis of ENB. Typical findings are tumor cells with cytoplasmic dense-core neurosecretory granules, and neurite-like cell processes containing neurofilaments or neurotubules.

Grading system

One grading system exists for ENB, which was described by Hyams in 1988. This system scores mitotic activity, nuclear polymorphism, amount of fibrillary matrix, rosette formation, and amount of necrosis seen. Categories are scored, and characteristics are organized into four tiers ( Table 2 ). When this system has been reviewed in the literature to compare grade to survival, grades I and II, and grades III and IV are often combined. Data supporting the value of this system for prognostication have been mixed. A report by Zafereo and colleagues did not find that Hyams’ grade was associated with disease-specific or recurrence-free survival. In Dulguerov and colleagues meta-analysis, only five studies were identified that evaluated Hyams’ grading, and collectively grade III and IV tumors were associated with decreased survival. Some flaws of the Hyams’ grading scale are that is subjective, leading to variable grading between pathologists, and there is sampling error when the entire tumor is not examined, as in a biopsy. Additionally, poorly differentiated tumors can be difficult to distinguish from other, more aggressive, tumors that are associated with a worse outcome than ENB.

Table 2

Grading scale according to Hyams

Grade	1	2	3	4
Architecture	Lobular	Lobular	Variable	Variable
Mitotic activity	Absent	Present	Prominent	Marked
Nuclear pleomorphism	Absent	Moderate	Prominent	Marked
Fibrillary matrix	Prominent	Present	Minimal	Absent
Rosettes	HW	HW	FW	FW
Necrosis	Absent	Absent	+/− Present	Common

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