Esthesioneuroblastoma

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CHAPTER 143 Esthesioneuroblastoma

Esthesioneuroblastoma, first described by Berger, Luc, and Richard in 1924,¹ is an uncommon neoplasm that arises from olfactory epithelium high in the nasal vault and frequently invades the skull base, cranial vault, and orbit. Although esthesioneuroblastoma accounts for up to 3% of intranasal neoplasms in some series, fewer than 400 unique cases have been reported in the world literature. The recent apparent increase in incidence is at least in part attributable to improvements in diagnostic imaging and pathologic recognition of this relatively rare entity. Because of the limited number of subjects treated in different eras of medical and surgical practice, in addition to nonuniform treatment schemes and follow-up, management recommendations regarding these tumors have been based largely on anecdotal data and limited series.

Pathology

The morphologic, ultrastructural, and immunohistochemical features of esthesioneuroblastoma are similar to those of neuroblastoma of the adrenal glands and sympathetic nervous system. Light microscopy reveals a lobular architecture with sheets of cells in a dense neurofibrillary background. Individual cells have round to oval nuclei with scant, poorly defined cytoplasm. Occasionally, olfactory rosettes or pseudorosettes are present. A grading system based on histology has been proposed as a prognostic tool but has achieved varying success (Table 143-1) (Fig. 143-1).²

TABLE 143-1 Hyams’ Histologic Grading System for Esthesioneuroblastoma

FIGURE 143-1 A, Photomicrograph of an esthesioneuroblastoma showing a lobular arrangement of cells with round to oval nuclei and poorly defined cytoplasm. B, Specimen from a higher grade tumor showing more cellularity with less tissue architecture.

Ultrastructurally, dense membrane-bound neurosecretory granules are seen along with neurofilaments and microtubules. On immunohistochemical staining, most esthesioneuroblastomas are positive for neuron-specific enolase (NSE), neurofilament, synaptophysin, chromogranin, and Leu-7 and variably positive for S-100. Although similar to neuroblastoma histologically, correlated coexpression of NSE and cytokeratin points to an epithelial rather than neural crest origin of these tumors.³

Clinical Findings

Patients with esthesioneuroblastoma are typically evaluated by the otolaryngologist for complaints of nasal obstruction or recurrent epistaxis. A fleshy, friable nasal mass is frequently noted, and hyposmia is often detected on formal testing. Other, less common initial symptoms and signs include headache, visual impairment, and rhinorrhea (Table 143-2). Males and females are affected equally.⁴^–⁶ The age at diagnosis has been reported to be 3 to 78 years with a bimodal distribution consisting of peaks in the second and fifth decades.⁷^,⁸ No geographic, environmental, or lifestyle risk factors have been clearly associated with increased risk for esthesioneuroblastoma.

TABLE 143-2 Initial Symptoms and Signs of Esthesioneuroblastoma

Nasal Obstruction

Epistaxis

Nasal mass

Hyposmia

Headache

Rhinorrhea

Visual acuity loss

Proptosis

Mental status changes

Neck mass

Tooth pain

Face pain

Face mass

Diplopia

Metastatic disease is present in 17% to 48% of patients with esthesioneuroblastoma at diagnosis.⁹^–¹² Cervical lymph nodes account for the majority of metastases; other locations include lung, bone, and much less commonly, liver, mediastinum, adrenal gland, ovary, spleen, parotid, central nervous system, and spinal epidural space.⁶^,¹³ In our experience, 8% of patients in whom esthesioneuroblastoma was detected had metastatic disease in the cervical lymph nodes, with cervical node disease eventually developing in 28%. Metastatic disease ultimately developed in some location in 37% of patients.

Patient Evaluation

Preoperative evaluation includes a thorough history and physical examination to determine the extent of the symptoms and concomitant medical conditions that might limit aggressive management. Evaluation by an otolaryngologist is warranted both to assess the extent of sinus and cervical disease and to provide a diagnostic biopsy specimen. A preoperative neuro-ophthalmologic evaluation should be performed to identify visual acuity or motility deficits and to document baseline function in patients with disease near orbital structures or in whom extensive surgical resection is anticipated (Table 143-3).

TABLE 143-3 Preoperative Evaluation of Patients with a Suspected Sinonasal Mass

History and physical examination, including systemic examination to evaluate for evidence of metastases

Computed tomography of the head and sinuses with and without contrast enhancement

Magnetic resonance imaging of the head with and without contrast enhancement

Otolaryngologic evaluation and biopsy to confirm the diagnosis

Positron emission tomography/computed tomography of the neck, chest, abdomen, and pelvis

Nuclear bone scan

Radiographic assessment of tumor begins with contrast-enhanced computed tomography (CT). Sinus disease and bony erosion are well depicted by CT. Erosion of the floor of the anterior fossa or orbital wall is common, and in such cases magnetic resonance imaging (MRI) is of utility in more clearly depicting the extent of soft tissue disease and better visualizing pathology near the orbital apex (Fig. 143-2). However, when the bone erosion depicted on CT is minimal, MRI is still strongly recommended because the extent of intracranial disease may be significant even with little visualized bony involvement. Adequate radiographic assessment allows preoperative classification of the tumor according to the scheme proposed by Kadish and modified by others (Table 143-4).^12,^14,¹⁵ As discussed later, this system has been correlated with outcome with some reliability.

FIGURE 143-2 Axial (A) and coronal (B) gadolinium-enhanced magnetic resonance images demonstrating a Kadish stage C esthesioneuroblastoma. Tumor extends from the ethmoidal sinuses and nasal vault through the cribriform plate and into the intracranial compartment (arrows).

TABLE 143-4 Modified Kadish Staging of Esthesioneuroblastoma

Stage A	Tumor confined to the nasal cavity
Stage B	Tumor extension to the paranasal sinuses
Stage C	Tumor beyond the nasal cavity and paranasal sinuses, including involvement of the cribriform plate, base of the skull, intracranial cavity, and/or orbit
Stage D	Tumor with metastases to the cervical lymph nodes and/or distant sites

Patients in whom metastatic disease is suspected should undergo a thorough evaluation for determination of the extent of disease and selection of adjuvant therapy. Such evaluation may include positron emission tomography/CT of the neck, chest, abdomen, and pelvis, as well as a bone scan.

Treatment

The relatively small number of reported cases of esthesioneuroblastoma has made it difficult to determine the impact of individual therapies. This effort has been further hampered by the changes in medical management, surgical technique, and technology over the past 50 years; patients in early reports were treated in a much different era of medicine than those in recent years. With the onset of interest in cranial base surgery, treatment paradigms have shifted from less aggressive surgical resection to more frequent total resections. More recently, interest has begun to shift to less invasive, endoscopic-assisted surgical intervention with adjuvant stereotactic delivery of radiotherapy or radiosurgery. Although experience with adjuvant therapies has been limited, some benefit appears to be gained from the use of radiotherapy and chemotherapy.

Radiotherapy

Early lesions (Kadish stage A or B) have been managed successfully with radiation therapy alone in some cases; Elkton and coauthors reported short-term local tumor control with radiation therapy alone in 17 of 21 stage A or B tumors.¹⁶ Their findings have been confirmed by others,¹⁷ but some have suggested that the use of radiation as a sole treatment modality be reserved for inoperable cases.⁷^,¹⁸ Anecdotal, unpublished cases of smaller tumors limited to the nasal cavity and successfully treated exclusively with biopsy and radiosurgery have been reported, although experience with this scheme is inadequately detailed and limited by short-term follow-up. However, based on our experience with the use of radiosurgery for focal areas of recurrent disease, primary definitive radiosurgery may be a valid plan for stage A and selected stage B tumors.

Preoperative radiotherapy has also been recommended. Theoretical benefits of preoperative radiation therapy include decreasing tumor mass and minimizing local tumor dissemination and distant metastases at the time of surgery by decreasing cell viability. Preoperative tumor irradiation has proved useful in sparing the orbital contents during surgery for paranasal sinus carcinoma.¹⁹ In doses of 50 to 60 Gy, radiation therapy has also been purported to decrease the likelihood of tumor recurrence. In a series from the Mayo Clinic, the incidence of recurrence of both high- and low-grade tumors was reduced by postoperative radiation treatment.⁸ A review of the recent literature revealed that just 20% of patients treated by radiotherapy and surgery had recurrence of tumor at 5 years versus 50% who underwent surgery alone. For patients with advanced or metastatic disease, adjuvant therapy may provide additional benefit. Improved outcomes have been reported for patients undergoing neck dissection and radiation therapy for cervical disease.⁵^,²⁰

Chemotherapy

Histologically and ultrastructurally, esthesioneuroblastoma shares features with other chemosensitive tumors such as neuroblastoma, small cell lung carcinoma, and primitive neuroectodermal tumor. Probably for this reason, similar chemotherapeutic regimens found to be effective for these other lesions have been used for esthesioneuroblastoma, with variable results. In one series of 7 patients, chemotherapy induced a partial response in 4 patients and no response in 3.⁶ Another study reported improvement after chemotherapy in 19 of 20 patients.²¹ A series from the Mayo Clinic demonstrated regression of disease after chemotherapy in 2 of 4 patients with Hyams’ grade III or grade IV tumors but in none of the 4 with lower grade lesions.²² Gross total tumor resection combined with chemotherapy has produced better outcomes than chemotherapy alone has, but this is confounded by the fact that patients who did not undergo attempted resection had more extensive disease at diagnosis. Typically, regimens include cyclophosphamide and vincristine, although doxorubicin is sometimes included. Platinum-based therapies have also been used with some favorable results. A few centers have used high-dose chemotherapy with bone marrow rescue and intra-arterial chemotherapy with some success as well.²³^–²⁶