eMedicine Specialties > Oncology > Carcinomas of the Central and Peripheral Nervous System

Esthesioneuroblastoma

Michael Somenek, MD, Resident Physician, Department of Otolaryngology, Rush University Medical Center
Nicholas C Shera, PhD, Freelance Medical/Scientific Writer; Guy J Petruzzelli, MD, PhD, MBA, FACS, The Charles Arthur Weaver Professor of Cancer Research, Professor and Senior Attending Physician, Director of Head, Neck, and Skull Base Surgery, Department of Otolaryngology, Rush University Medical Center

Updated: Oct 30, 2009

Introduction

Background

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare neoplasm originating from olfactory neuroepithelium. Approximately 1,000 cases have been identified since Berger and Luc described the first case in 1924.¹ Due to the rare and complex nature of ENB, multiple opinions exist regarding the etiology, optimal staging system, and treatment modalities. These tumors often display varying biologic activity ranging from indolent growth, with patient survival exceeding 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis, with survival limited to a few months.

Esthesioneuroblastoma. Coronal CT scan of the orbits and sinuses shows a large, enhancing, and expansile mass occupying the ethmoid air cells that is invading the cribriform plate and breaking through to the left anterior cranial fossa. Image courtesy of Michael Lev, MD.

Esthesioneuroblastoma. A 39-year-old man presented with 1 month of decreased vision, left facial numbness, and swelling. Physical examination demonstrated left-sided exophthalmos and blindness. He had also lost his sense of smell. Contrast-enhanced T1-weighted MRI demonstrated a large lesion that originated in the paranasal sinuses and extended through the cribriform plate into the anterior cranial fossa. He underwent a bifrontal craniotomy for resection of this tumor.

Pathophysiology

Esthesioneuroblastomas (ENBs) are undifferentiated tumors of neuroectodermal origin derived from the olfactory epithelium.² The tumor cells are mitotically active and are the precursor cells that develop into sustentacular and neuronal cells. Inconsistent histologic presentations initially led to controversy surrounding the exact histologic origin of ENBs, and this ambiguity can confound clinical and prognostic decisions. In essence, ENBs contain variable arrangements of their small cells. Additionally, there exists a variable presence (or absence) of true rosettes and neurofibrillary material.

To date, no certain genetic factor has been identified that can accurately assist in the diagnosis or predict prognosis. This is partially due to the ability to analyze cancer genomes on a whole genome basis. Recently, a tool called array comparative genomic hybridization was applied to the analysis of ENBs.³ Although many alterations were identified in this study, chromosomal gains in 7q11 and 20q and deletions in 2q, 5q, 6p, 6q, and 18q have been confirmed by at least 2 other studies. Interestingly, 20q is a region that has been implicated in other cancers, including breast, ovarian, and squamous cell carcinoma. Still, further experimentation will be required to determine the role of these genomic regions in ENB.

The demonstration of human achaete-scute homologue (HASH1) gene expression, although still investigational, could become the diagnostic procedure of choice.⁴ The HASH1 gene is involved in olfactory neuronal differentiation and is expressed in immature olfactory cells⁵ ; therefore, it could be useful in distinguishing ENB from other poorly differentiated small blue cell tumors.

Frequency

United States

The incidence of esthesioneuroblastoma in the United States follows trends observed worldwide.

International

Based on the reports in the literature, approximately 1,200 cases of esthesioneuroblastoma (ENB) have been identified since 1924. Interestingly, 80% of these have been identified in the last 25 years. However, the current data set cannot distinguish between a rising incidence and better recognition of the disease. ENB has an estimated incidence of 4 cases per 10 million individuals and accounts for approximately 5% of all sinonasal tumors. Similar incidence rates have been obtained through epidemiologic studies performed in Denmark.⁶ To our knowledge, no studies suggest a geographic deviation.

Race

• Esthesioneuroblastoma (ENB) does not show a predilection toward any individual race. ENB does not show familial prevalence and has been reported in all races and on all continents.

Sex

• Esthesioneuroblastoma (ENB) affects males and females with similar frequency.

Age

• Esthesioneuroblastoma (ENB) occurs in a wide range of age groups (3-90 y). There exists a bimodal peak of occurrence in the third and sixth decades of life.

Clinical

History

The symptoms of esthesioneuroblastoma (ENB) can be classified into nasal, neurologic, oral, facial, cervical, and ophthalmologic and are as follows:

• Nasal - Obstruction (70%), epistaxis (46%), discharge, unilateral polyp, anosmia
• Neurologic - Headache, nausea
• Oral (rare) - Mobile tooth, nonhealing tooth-extraction site, ill-fitting dental prostheses, ulceration
• Facial (rare) - Swelling, pain, anesthesia, trismus
• Cervical - Mass
• Ophthalmologic - proptosis, extraocular movement paralysis, and blindness,

Physical

Nasal examination, particularly if aided by endoscopy, reveals a reddish-gray tumor arising in the upper nasal fossa, which bleeds easily with instrumentation. Although this aspect is strictly different from the white, glistening appearance of benign nasal polyps, little differentiates esthesioneuroblastoma (ENB) from other nasal malignancies. Late findings may include signs related to extensive disease such as orbital, cranial, and cervical involvement.

Causes

No clear etiologic agent or exposure has been documented in humans; however, a single case of occupational exposure has been reported in a woodworker.⁷ Esthesioneuroblastoma (ENB) can be consistently induced by nitrosamine compounds in rodents. In cats with spontaneous ENB or in transgenic mice developing ENB, type C retroviral particles have been demonstrated and classified as feline and murine leukemia virus, respectively. The role of retrovirus sequences in human ENB remains to be evaluated.

Differential Diagnoses

Lymphoma, Non-Hodgkin
Malignant Melanoma
Metastatic Cancer, Unknown Primary Site
Plasmacytoma, Extramedullary

Other Problems to Be Considered

Nasal and paranasal squamous cell carcinoma
Sinonasal polyposis
Choanal polyp
Juvenile angiofibroma
Neuroendocrine carcinoma
Embryonal rhabdomyosarcoma
Undifferentiated sinonasal carcinoma
Ewing sarcoma

Workup

Laboratory Studies

• No specific lab studies confirm the diagnosis of esthesioneuroblastoma (ENB). Because surgery often is contemplated and because open nasal procedures are associated with significant bleeding and may involve blood transfusions, a complete blood count may be obtained, and the patient should be advised about preoperative blood donation.

Imaging Studies

Esthesioneuroblastoma. Coronal CT scan of the orbits and sinuses shows a large, enhancing, and expansile mass occupying the ethmoid air cells that is invading the cribriform plate and breaking through to the left anterior cranial fossa. Image courtesy of Michael Lev, MD.

Esthesioneuroblastoma. A 39-year-old man presented with 1 month of decreased vision, left facial numbness, and swelling. Physical examination demonstrated left-sided exophthalmos and blindness. He had also lost his sense of smell. Contrast-enhanced T1-weighted MRI demonstrated a large lesion that originated in the paranasal sinuses and extended through the cribriform plate into the anterior cranial fossa. He underwent a bifrontal craniotomy for resection of this tumor.

• CT scan
  • Standard radiographs do not have a role in the evaluation of esthesioneuroblastoma (ENB). A direct coronal fine-cut CT scan (3 mm) is the initial radiologic study of choice.
  • ENB lacks a specific radiologic appearance and is seen as a homogeneous soft tissue mass with uniform and moderate contrast enhancement (see Image 1).
  • CT images are essential for correct staging and should be evaluated carefully for erosion of the lamina papyracea, cribriform plate, and fovea ethmoidalis specifically.
  • Obstruction of the sinus-draining ostia results in an accumulation of nasal secretions, which tend to be difficult to differentiate from tumor tissue when viewed on CT scan.
  • An unusual but characteristic imaging feature of ENBs is the presence of cysts at the tumor-brain interface.⁸
• MRI
  • MRI often is necessary to better delineate sinonasal and intraorbital extension or an intracerebral extension.
  • Using MRI, ENB appears as hypointense to gray matter on T1-weighted images and isointense or hyperintense to gray matter on T2-weighted images (see Image 2).
  • Because details of bony erosion are better demonstrated by CT images, both studies usually are required in the majority of patients.
• Scintigraphy
  • Since most ENBs express somatostatin receptors, the use of scintigraphy with a radiolabeled somatostatin analog (¹¹¹ In-pentoctreotide [¹¹¹ In-DTPA-D-pheoctreotide]; Octreoscan) has been proposed. A preliminary study of this technique found it to be clinically useful, especially for discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery.⁹ The sensitivity and specificity remain unclear, however.

Other Tests

• No other diagnostic tests are necessary.

Procedures

• Biopsy
  • Grossly, esthesioneuroblastoma (ENB) appears as a gray to red mass in the nasal vault. The color usually is related to the extent of tumor vascularization, raising the possibility of profuse nasal bleeding following the biopsy procedure.
  • Taking a biopsy specimen should be deferred until completion of the radiologic studies to avoid swelling effects on accurate imaging and the inadvertent biopsy of other nasal tumors of neurogenic origin.
  • Biopsy and endoscopy should be performed under general anesthesia. The specimen should be sent for regular staining, as well as for immunohistochemistry and possibly electron microscopy.

Histologic Findings

Esthesioneuroblastomas (ENBs) can display various histologic presentations. The hallmark of well-differentiated ENBs is arrangements of cells into rosettes or pseudorosettes (sheets and clusters). True rosettes (Flexner-Wintersteiner rosettes) refer to a ring of columnar cells circumscribing a central oval-to-round space, which appears clear on traditional pathologic sections. Pseudorosettes (Homer-Wright rosettes) are characterized by a looser arrangement and the presence of fibrillary material within the lumen.

One common method of stratification is to separate ENBs into 2 distinct groups: neuroblastomas proper and neuroendocrine carcinomas. The first group, neuroblastomas proper, has a histologic presentation similar to that of peripheral neuroblastomas of childhood. This group of ENBs is composed of sheets of poorly demarcated groups of cells separated by fine connective tissue trabeculae. The cells are small and typically show no mitotic activity. Importantly, these masses contain fibrillary material between the cells. Rosettes of the Homer-Wright type are present. One observed feature on electron microscopy is the presence of a dendritic cytoplasmic process with accumulations of small dense core granules within the process.¹⁰

The unique feature of neuroendocrine carcinomas, the second class of ENBs, is admixture with glands. A neurofibrillary component is absent, and the growth pattern is that of solid nests without rosettes. In some cases, ENBs present as neoplastic cells that are intimately related to the basal epithelium of the glands, and a neurofibrillary component is not seen. The cells in these tumors are typically larger than those in neuroblastomas, and the growth pattern is that of solid nests without rosettes. Dense core granules similar to those of neuroblastoma are present in the cytoplasm and cytoplasmic extensions.

Further confounding accurate diagnosis is the fact that ENB is histologically similar to other small, round blue cell tumors. The acronym LEMONS (lymphoma, Ewing sarcoma, melanoma, olfactory/other [ENBs, rhabdomyosarcoma or Markel cell carcinoma], neuroblastoma, and small cell carcinoma) defines the other tumors from which ENB should be differentiated. Distinguishing ENBs from the other tumors is of paramount importance because the tumors respond differently to various treatment modalities.

The following list describes the outcome of each of these diseases with various
immunohistochemical tests.

• Esthesioneuroblastomas stain positive for S-100 protein and/or neuron-specific enolase, while the stain usually is negative for cytokeratin, desmin, vimentin, actin, glial fibrillary acidic protein, UMB 45, and the common leukocytic antigen. For difficult cases, electron microscopy can be useful. Common features are small, round neuroepithelial cells arranged in rosette or pseudorosette patterns, separated by fibrous elements. Rosettes consist of a central space ringed by columnar cells with radially oriented nuclei.
• Lymphoma can be excluded when the majority of tumor cells are negative for CD45 (the remaining positive cells demonstrate no atypical immunophenotype).
• Ewing sarcoma is positive for MIC2/CD99 gene products that result from an 11;22 translocation.¹¹
• Melanoma can be identified using a combination of immunohistochemical markers: MART-1/Melan-A, HMB-45, and S-100. S-100 is expressed in more than 95% of melanomas.
• Rhabdomyosarcoma displays a loss of chromosome 11 and stains positive for desmin (expressed in 95%), muscle-specific actin, and myoglobin.
• Markel cell carcinoma stains positively for low-molecular-weight cytokeratin 20 and NSE.
• Neuroblastoma often stains positive for NSE, synaptophysin, Leu7, and neurofilament protein. Elevated serum catecholamines are also suggestive of neuroblastoma.
• Small cell carcinomas stain positively for chromogranin, NSE, and synaptophysin (presynaptic nerve cell vesicles). Most small cell carcinomas are positive for TTF-1.

In summary, the pathologic distinction of poorly differentiated small neoplasms of the nasal cavity is difficult and is based on a panel of immunohistochemical stains and, if necessary, electron microscopy. To date, no specific immunocytologic stain identifies ENB; however, knowledge of the histochemistry of other related tumors can distinguish them. When ENB is suspected, diagnostic tests should include S-100 protein, neuron-specific enolase, chromogranin and/or synaptophysin, cytokeratin, desmin, actin, UMB 45, common leukocytic antigen, and myc-2 protein.

ENB can be graded histologically by the Hyams system, which is based on the preservation of lobular architecture, mitotic index, nuclear polymorphism, and the presence of fibrillary matrix, rosettes, and necrosis.¹² The Hyams system is based on 4 grades, which are described in Table 1, below.

Histopathologic Grading According to Hyams¹²

Staging

Tumor staging is an important guide for prognosis and therapy. Several staging systems, including Hymans (see Pathophysiology, above), Kadish, and TNM systems, have been proposed as a guide to choosing treatment modalities.

From a limited series of 17 patients, Kadish et al were the first to propose a staging classification for esthesioneuroblastoma (ENB).¹³ ENBs were divided into 3 categories: groups A, B, and C. Group A is limited to tumors of the nasal fossa; in group B, extension is to the paranasal sinuses; and group C is defined as extension beyond the paranasal sinuses and nasal cavity.

Some authors have noted that effectively stratifying patients with the Kadish system can be difficult. Recognizing these inadequacies, Morita et al in 1993 published a revised Kadish system that redefined stage C (consisting of local disease spreading beyond the paranasal sinuses) and included a stage D (distant metastasis).¹⁴

In 1992, Dulguerov and Calceterra proposed a classification based on the tumor, node, metastasis (TNM) system, which is predicated on CT and MRI findings that can be identified before treatment.¹⁵ Although this classification system has gained popularity, attempts have been made to further modify the Kadish system for ENB.

• TNM system, where T = tumor, N = node, and M = metastasis
  • T1 - Tumor involving the nasal cavity and/or paranasal sinuses (excluding sphenoid), sparing the most superior ethmoidal cells
  • T2 - Tumor involving the nasal cavity and/or paranasal sinuses (including the 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
  • M1 - Distant metastases present

Treatment

Medical Care

Due to the rarity and complexity of esthesioneuroblastoma (ENB), there exists considerable heterogeneity in treatment. Complete surgical resection of the tumor followed by radiation therapy is recognized by most studies as the optimal treatment. However, some institutions report success with alternative treatment sequences, including surgery without radiation. More recently, chemotherapy has been introduced in the therapeutic armamentarium. Because of the lack of any randomized trial comparing these treatment protocols, the available data can be summarized as follows:

• Single-modality therapy versus combined treatment
  • The literature gives little support to single-modality treatments; few studies advocate either surgery or radiation alone. Dulguerov’s 2001 meta-analysis clearly showed lower recurrence rates for the combination of surgery and radiotherapy.¹⁶
  • Some institutions advocate surgery alone for Kadish stage A tumors, whereas most suggest adjuvant radiotherapy for these lesions.
  • A few studies advocate neoadjuvant chemotherapy for Kadish C lesions.
  • Unlike most surgical specimens from the head and neck, specimens from the nasal cavity and paranasal sinuses, even en bloc, are difficult to orient, and surgical margins are difficult to analyze. Because one can rarely be completely confident of the adequacy of surgical margins, postoperative radiation to minimize the risk of local recurrence seems justified in almost all patients.
• Timing of surgery and radiation in combined therapy
  • Most institutions favor surgery as the first treatment modality, followed by postoperative irradiation.
  • Preoperative radiation results in the usual loss of definable tumor borders, which makes an en-bloc resection problematic. However, it has been noted that a theoretical advantage to preoperative radiation therapy is to convert an inoperable tumor to one that is amenable to resection. This theory is not widely supported.
• Radiation technique
  • Standard techniques include external megavoltage beam and a 3-field technique; an anterior port is combined with wedged lateral fields to provide a homogeneous dose distribution. The radiation portals are nowadays planned by integrating pretreatment CT or MRI imaging within the radiotherapy software.
  • The dose varies from 5500-6500cGy. The majority of patients receive < 6000 cGy. These doses are close to or exceed the maximum radiation dose recommended for sensitive structures such as the optic nerve, optic chiasma, brainstem, retina, and lens. Therefore, those patients are susceptible to cataract formation and glaucoma.
  • A possible role of proton beam radiotherapy, intensity-modulated radiotherapy, and stereotactic radiation has been suggested.^17,18 Several institutions have reported that intensity-modulated radiotherapy can provide good tumor control with low rates of radiation-induced toxicity, in children as well as in adults.^19,20 There are case reports describing the use of CT-guided interstitial high-dose-rate brachytherapy.²¹ However, prospective clinical trials confirming the efficacy of these modalities have not yet been completed.
• Role of chemotherapy
  • Chemotherapy is not recommended for routine treatment of ENB. Exceptions include palliative treatments or as part of a multimodality treatment in patients with advanced or metastatic disease.
  • The use of chemotherapy has been advocated by authors from the University of Virginia.²² In their protocol, patients with advanced disease (eg, Kadish stage C) are treated first with 2 cycles of cyclophosphamide (300-650 mg/m²) and vincristine (1-2 mg) with or without doxorubicin, followed by 50 Gy of radiotherapy, which then is followed by a craniofacial resection. With this regimen, the 5-year and 10-year actuarial survival rates are 72% and 60%, respectively. Similar results have been obtained without chemotherapy, and how much chemotherapy contributed to the cure rates is unclear.
  • Cisplatin-based regimens are preferred at the Mayo Clinic^23,24 and at the Gustave-Roussy Institute in France,²⁵ but even if ENBs are responsive to cisplatin, chemotherapy for high-grade tumors in the advanced setting is not curative.
  • At Harvard, the selected regimen is cisplatin (33 mg/m²/d) and etoposide (100 mg/m²/d) for 3 days. This has been followed by proton radiation in 9 patients, with excellent results.¹⁷ This is probably the only study that demonstrates convincingly the possibility of a nonsurgical treatment of ENB, although the patient population is small.
  • A more aggressive chemotherapy regimen was reported by Mishima et al.²⁶ In 8 of 12 patients receiving a combination of cyclophosphamide, doxorubicin, vincristine, and continuous-infusion cisplatin and etoposide followed by radiation, a complete response was achieved. Toxicity was acceptable, according to the authors.

Surgical Care

Surgery remains the primary treatment for esthesioneuroblastoma (ENB) and offers the best chance for locoregional control as well as survival. Both open and endoscopic craniofacial resection have achieved complete surgical resection with tumor-free margins. In the last 20 years, craniofacial resection followed by radiation therapy has been repeatedly referred to as the “gold standard” for treatment, and thus, other treatment modalities should be measured against it. Open craniofacial resection permits en-bloc resection of the tumor, with assessment of any intracranial extension and protection of the brain and optic nerves.

• The en-bloc resection should include the entire ipsilateral cribriform plate and crista-galli.
• The olfactory bulb and overlaying dura should be removed with the specimen.
• Preservation of the contralateral olfactory system, when possible, results in a preserved sense of smell in a few cases.
• A tumor that does not penetrate the orbit can be encompassed by resecting the lamina papyracea or even small segments of orbital periosteum.
• To avoid late frontal sinus mucocele formation, the posterior table of the frontal sinus should be taken down, the mucosa removed, and the cranial contents allowed to fill the defect.
• Repair of the dura is facilitated by the added exposure afforded by craniotomy. Although cranial floor defects as large as 4 cm may be present, bone grafts have not been necessary. The cranial floor is repaired by various techniques, including a pericranium flap, temporalis muscle and fascia transposition, or a layer of fascia lata held with thrombin glue. This prevents the herniation of cranial contents into the nasal cavity and the occurrence of cerebrospinal fluid leaks.
• Pneumocephalus has been prevented in the immediate postoperative period by the placement of a nasal trumpet in the operated nasal fossa, along with necessary packing, to vent any coughed or pressurized air away from the cranial cavity.
• Postoperative complications have been reported in 15-40% of cases. Major complications include (but are not limited to) frontal lobe abscess, infection, and intercranial hemorrhage.
• Endoscopic craniofacial resection (ECFR)
  • ECFR is being successfully performed and is now a widely accepted treatment modality.
  • Multiple studies have shown it to be a safe, feasible, and oncologically sound technique.^27,28,29,30
  • Initially, an endoscopic approach was limited to Kadish stages A and B; however, successful resections have been performed on stage C tumors.²⁷
  • The benefits of an endoscopic approach include decreased time in surgery, blood loss, morbidity, postoperative complications, and cost.
  • Excess bleeding can hinder the endoscopic approach.
  • Endoscopic resection followed by gamma-knife stereotactic radiosurgery has demonstrated positive outcomes.
  • Key features unique to the endoscopic approach include the following:
    • Creating generous sphenoidotomies and drilling off the sphenoid rostrum to make a common sphenoid sinus cavity allowing exposure to the planum sphenoidale.
    • A Draf type III, Lothrop-type, frontal sinusotomy communicating both frontal sinuses across the midline to expose a common frontal sinus cavity.
    • Using a high-speed cutting bur, performing an anterior fossa craniotomy bilaterally, from the planum posteriorly to the posterior wall of the frontal sinus anteriorly.
    • The dura is resected and a complete anterior fossa resection is performed. This includes bilaterally transecting the olfactory tracts.
    • A multi-layered dural reconstruction is performed, which includes an intradural inlay and overlay Alloderm graft, abdominal fat, and sealant. The multi-layered reconstruction is supported intranasally, with placement of packing under direct visualization and the balloon of a Foley catheter.
• Neck metastasis at presentation occurs in 5–7% of patients. When neck disease is diagnosed at the initial presentation, it should be treated surgically.
• In their literature review, Beitler et al found an incidence of delayed neck metastasis of 19%, but half of these patients also presented with local recurrence.³¹ Salvage treatment was successful in 70% of these patients. Contrary to the conclusion of Beitler et al, the authors do not consider that a 10% rate of delayed neck recurrence represents justification for elective neck dissection in all cases of ENB.

Consultations

Usually, patients with head and neck tumors are treated in academic centers with broad expertise with prospective treatment programs outlined in the multidisciplinary tumor board. Head and neck tumor boards usually include a head and neck surgeon and radiation and medical oncologists. Speech language pathologists, psychosocial oncologists, nutritional and social work support, and dental consultations are available. Maxillofacial and prosthetic consultants are incorporated as needed. The treatment protocol is decided in common, and each specialist performs his or her own specific task as described above.

• A craniofacial team, in which neurosurgeons form an essential part, usually manages an esthesioneuroblastoma (ENB) surgically. Most of the important complications after surgery concern the brain and calvarium; thus, close neurosurgical follow-up is necessary.
• For ENB, a preoperative ophthalmology evaluation is mandatory because the optic nerves are at risk during either radical surgery or radiation therapy. In addition, ophthalmologists can be helpful if partial intraorbital resection is contemplated. Dacryocystorhinostomy usually is performed during surgery, and ophthalmologists can provide help in this procedure and/or the postoperative evaluation of the lacrimal system.
• If an associated palate resection is contemplated, the upper dental prosthesis should be made before surgery and placed at the end of the procedure. This usually achieves a separation of the oral cavity from the nasal cavity and allows adequate oral nutrition. Adjustments of this prosthesis are required after ablation of the nasal packing and in response to tissue scarring and/or retraction that take place within 6 months after completion of treatment.

Diet

No specific postoperative dietary restrictions are required for patients with esthesioneuroblastoma (ENB).

• Following major surgery, patients tolerate only light meals during the first postoperative days.
• Patients with a history of constipation should be given stool softeners for the first postoperative week to prevent undue straining and allow the skull base repair to heal.

Activity

• Some surgeons routinely place a lumbar drain to decrease pressure on the dural repair. The authors tend to restrict CSF decompression to cases with significant dural sacrifice and replacement and/or when the base of skull repair is deemed fragile. As long as the drain remains in place, patients require strict bed rest.
• Otherwise, patients usually are out of bed on the first postoperative day.
• Patients should be advised to not blow their noses for several days and to open their mouth during sneezing and coughing to avoid the creation of pneumocephalus.

Medication

Chemotherapy as a treatment modality has historically been reserved for unresectable tumors, recurrence, or metastatic disease. Most reports suggest that chemotherapy is reserved as part of multimodality treatments. Palliative chemotherapy can be beneficial for relieving pain and obstruction or debulking tumors when surgery is not an option (either high risk or patient refusal of surgery).

Follow-up

Further Inpatient Care

• In the first 48 hours following craniofacial resection, regular neurosurgical evaluation is required. ICU monitoring for at least 24 hours also is necessary. Duration of the lumbar drainage is controversial, varying from intraoperative only to as long as 7 days.
• Aspiration of the nasal trumpets should be performed several times a day. Nasal packing is left in place for 5-7 days. Removal of large nasal packing is uncomfortable, and some pain medication could be administered before the procedure.

Further Outpatient Care

• Nasal irrigation with sterile isotonic sodium chloride solution begins within a few days after packing removal. Removal of nasal crusting should be performed regularly during initial postoperative visits. This problem is aggravated during radiotherapy but decreases in most patients after 1-2 years. It is a lifelong burden for which no good treatment or prevention is available.

• Craniotomy sutures are removed 7-10 days after surgery. If a facial incision has been used, sutures are removed after 5 days

Inpatient & Outpatient Medications

• Antibiotic prophylaxis is usually started before surgery for esthesioneuroblastoma and includes coverage for gram-positive bacteria. Because good intracerebral penetration is preferred, ceftriaxone often is a good choice. Postoperatively, the authors continue antibiotics while the nasal packing remains in place.

Complications

• Craniofacial resection for esthesioneuroblastoma (ENB) has been associated with a complication rate of 10-15%. Higher rates of complications (up to 30%) have been observed in cases of revision or salvage surgery or surgery following radiation or chemoradiation therapy.
  • The most frequent problems are infections, including abscess surrounding the bone flap; meningitis; and, less often, subdural or epidural abscess.
  • Meningitis sometimes is related to the presence of a cerebrospinal fluid leak, because the closure of the anterior skull base is not always watertight.
  • Pneumocephalus has been another difficult problem to prevent. Although self-limiting in most cases, pneumocephalus can result in brain compression and requires needle aspiration through the trephine bony holes.
  • Blindness, secondary to optic nerve injury, and death either from intracerebral bleeding or internal carotid injury have become exceptional.
• Inform patients that olfactory function is likely to be altered or absent after surgery. In addition, nasal crusting is a long-lasting problem that requires daily nasal irrigation for several years.
• Delayed complications include necrosis of the frontal bone flap, lacrimal drainage obstruction, and frontal sinus mucocele.
• Radiation-related complications also are rare and include lacrimal duct blockage and tearing, postradiation cataract, osteoradionecrosis of the frontal bone flap, radiation retinopathy, and blindness.

Prognosis

• Treatment results before the availability and use of modern diagnostic techniques were flawed, probably by the inclusion of cases of sinonasal undifferentiated carcinoma and sinonasal neuroendocrine carcinoma, 2 aggressive diseases associated with poor survival. The importance of correctly differentiating these cancers is highlighted in a recent report by Rosenthal et al.³²
• In recent series, the 5-year patient survival rates have varied from 50-80%, with the majority of large studies indicating patient survival rates of higher than 70%. In the 2001 meta-analysis by Dulguerov et al, the average 5-year survival was 45 ± 22% (range, 0-86%).¹⁶
• Whether the Kadish classification system has a definitive prognostic value remains unknown, but the available survival data for stages A, B, and C are 72%, 59%, and 47%, respectively. According to the Dulguerov staging system, the survival rates were 81% for T1, 93% for T2, 59% for T3, and 48% for T4.
• Prognostic survival factors that emerged in the meta-analysis by Dulguerov et al include lower Hyams histopathologic grade (56% for grades I-II vs. 25% for grades III-IV) and absence of neck lymph node metastasis (64% for N0 vs. 29% for N+).¹⁶
• Other possible but unconfirmed prognostic factors include a low proliferative index, the completeness of the surgical resection, and tumor shrinkage after induction chemotherapy.
• Survival data categorized according to treatment modality favored regimens that include surgery.
• The most frequent recurrence is local, with rates from 20-40% (29% in the Dulguerov et al meta-analysis). Craniofacial resection followed by radiation seems to result in fewer recurrences, a rate of approximately 10%. Salvage after local recurrence is possible in one third to one half of cases.
• Regional recurrence, while disease at the primary site remains under control, occurs in 15% of cases and is salvageable by further treatment in 25-50% of cases. Distant metastasis with locoregional control occurs infrequently (8%) and carries a dismal prognosis.
• Recurrence may occur years after the completion of treatment, often more than 10 years; therefore, prolonged follow-up is required, although the optimal frequency of medical visits and the necessity of radiologic studies have not been precisely determined.

Miscellaneous

Medicolegal Pitfalls

• Inadequate informed consent: Patients must understand that treatment of esthesioneuroblastoma (ENB) can be associated with serious complications, as previously outlined, because ENB is a cancer located in an area surrounded by essential structures, including the eye and optic nerve, internal carotid artery, and brain.
• Failure to diagnose the tumor at an early stage: ENB most often presents with benign rhinologic symptoms of congestion and mild self-limited epistaxis. Otolaryngologists should have a low threshold to perform office nasal endoscopy under topical anesthesia to carefully examine the entire sinonasal cavity.

Multimedia

Media file 1: Esthesioneuroblastoma. Coronal CT scan of the orbits and sinuses shows a large, enhancing, and expansile mass occupying the ethmoid air cells that is invading the cribriform plate and breaking through to the left anterior cranial fossa. Image courtesy of Michael Lev, MD.

Media file 2: Esthesioneuroblastoma. A 39-year-old man presented with 1 month of decreased vision, left facial numbness, and swelling. Physical examination demonstrated left-sided exophthalmos and blindness. He had also lost his sense of smell. Contrast-enhanced T1-weighted MRI demonstrated a large lesion that originated in the paranasal sinuses and extended through the cribriform plate into the anterior cranial fossa. He underwent a bifrontal craniotomy for resection of this tumor.

References

1. Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res. Jul-Aug 1997;17(4A):2683-706. [Medline].

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Keywords

esthesioneuroblastoma, ENB, olfactory neuroblastoma, esthesioneuroepithelioma, olfactory esthesioneuroma, esthesioneurocytoma

Contributor Information and Disclosures

Author

Michael Somenek, MD, Resident Physician, Department of Otolaryngology, Rush University Medical Center
Michael Somenek, MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas C Shera, PhD, Freelance Medical/Scientific Writer
Disclosure: Nothing to disclose.

Guy J Petruzzelli, MD, PhD, MBA, FACS, The Charles Arthur Weaver Professor of Cancer Research, Professor and Senior Attending Physician, Director of Head, Neck, and Skull Base Surgery, Department of Otolaryngology, Rush University Medical Center
Guy J Petruzzelli, MD, PhD, MBA, FACS is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Association for the Advancement of Science, American Association of Clinical Anatomists, American College of Surgeons, American Medical Association, American Society for Head and Neck Surgery, American Society of Clinical Oncology, Chicago Medical Society, North American Skull Base Society, Society of Surgical Oncology, Society of University Otolaryngologists-Head and Neck Surgeons, and Southwest Oncology Group
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

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