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

Esthesioneuroblastoma

Author: Pavel Dulguerov, MD, Assistant Professor, Division of Head and Neck Surgery, University of Geneva Medical School, Switzerland
Coauthor(s): Abdelkarim S Allal, MD, PD, Senior Lecturer and Consulting Staff, Division of Radiation Oncology, Geneva University Hospitals
Contributor Information and Disclosures

Updated: Aug 11, 2006

Introduction

Background

Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the nasal vault, believed to arise from the olfactory epithelium. In 1924, Berger and Luc first described the tumor in the French medical literature under the name esthésioneuroépithéliome olfactif. Because of the uncertainty surrounding its precise histological origin, various names have been ascribed to this tumor, but the only 2 terms used in recent publications are esthesioneuroblastoma and olfactory neuroblastoma.

Beyond the most appropriate naming, multiple opinions exist regarding its origin, diagnosis, and management. The source of this controversy stems primarily from the rarity of this unusual tumor and the fact that almost no individual clinician or even institution will treat more than a few patients each year with this diagnosis. Three other factors contribute to the controversy surrounding this neoplasm. First, this tumor exhibits varying biologic activity ranging from indolent growth with patients surviving with known tumor more than 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis and patient survival limited to a few months. The second factor involves problems with precise histologic diagnosis since esthesioneuroblastoma is often confused with other small, round cell undifferentiated neoplasms of the nasal cavity. Third, no universally accepted staging system is available (see Staging).

Pathophysiology

The exact cell of origin of esthesioneuroblastoma has been controversial. While a neuronal-neural crest origin is supported by the presence of neurofilaments in ENB, until recently, few arguments linked ENB directly to the olfactory epithelium.

The olfactory epithelium is a peculiar neurosensory organ because dying olfactory neurons are replaced by new ones, which exhibit a progressive maturation, not only during embryogenesis but also physiologically and when injured by trauma or environmental insults. The globose basal cells constitute a precursor population and express neural cell adhesion molecule (NCAM) and proteins coded by the mammalian analogue of Drosophila achaete-scute (MASH) gene. These progenitor cells differentiate in olfactory neurosensory cells, which exhibit a progressive maturation from the basal membrane to the epithelial surface. Each layer can be characterized by specific olfactory- and neuron-specific markers. Immature olfactory cells express GAP43, a 24-kd membrane-associated protein kinase C involved in polyphosphoinositide turnover. As these cells mature, they migrate toward the surface, send axons to the olfactory bulb, and express olfactory marker protein (OMP) and NCAM, but not GAP43.

In the mid 1990s, ENB was found to express HASH, the human homologue of the MASH gene, while staining negative for other olfactory epithelium markers. Further indirect evidence that ENB originates from olfactory stem cells can be derived from transgenic mice in which the SV40T oncogene was inserted under the OMP gene promoter region: these mice did not develop ENB but adrenal and sympathetic ganglia neuroblastoma. Therefore, the currently available evidence links ENB with the basal progenitor cells of the olfactory epithelium.

Inclusion of ENB within the Ewing sarcoma family of tumors or the primitive neuroectodermal tumors (PNET) was proposed because of the identification, in certain cases, of translocation t(11:22), which is regarded as a specific molecular abnormality for Ewing sarcoma. Recent studies using fluorescent in situ hybridization and reverse transcriptase polymerase chain reaction (PCR) have failed to confirm this translocation in ENB. Therefore, ENB should be seen as a distinct entity from PNET and the Ewing sarcoma family of tumors.

Most of the olfactory neuroepithelium is located at the cribriform plate; however, islands of olfactory mucosa may be found in the upper turbinates and the upper one third of the nasal septum as well as on the entire middle turbinate. On rare occasions, olfactory mucosa has been found in the inferior turbinates and in the maxillary sinus. This probably explains why a small percentage of early-stage tumors appear to be completely free of the cribriform plate.

Frequency

United States

ENB remains a rare disease.

International

In an extensive literature review, Broich et al found about 1000 new cases reported; however, several multiple publications on the same patients were included. Most cases (80%) were reported within the last 20 years. This is certainly the result of better recognition of this disease entity by pathologists, although the possibility of a rising incidence cannot be ruled out entirely.

In view of the lack of precise epidemiologic studies, the authors' data suggest an incidence of 1 case per 1,000,000 per year. Similar incidence figures were recently obtained in Denmark. Thus, the authors tend to think that ENB represents about 5% of all nasal malignant tumors.

Race

• ENB does not show familial prevalence and has been reported in all races and on all continents.

Sex

• ENB affects males and females with similar frequency.

Age

• ENB occurs in all age groups.

Clinical

History

Esthesioneuroblastoma (ENB) does not cause specific symptoms, similarly to most other nasal and paranasal malignancies. The symptoms can be classified into nasal, facial, oral, ophthalmic, neurological, and cervical. The unilateral nature of symptoms should raise the suspicion of a possible neoplasia. Symptoms of nasal and paranasal cancers are as follows:

• Nasal - Obstruction, epistaxis, discharge, unilateral polyp, anosmia
• Neurological - Headache, nausea
• Oral - Mobile tooth, nonhealing tooth extraction, ill-adapted dental prostheses, ulceration
• Facial - Swelling, pain, anesthesia, trismus
• Cervical - Mass
• The average delay between the appearance of the first symptom and the diagnosis is 6 months. The most frequent symptoms are a unilateral nasal obstruction (70%), followed by epistaxis (46%). These are banal symptoms, occurring in common nasal diseases, including long-term rhinosinusitis or allergic polypoid sinus disease. Many of these patients undergo sinus surgery, only to have the diagnosis established as an unexpected pathological finding. The importance of sending the totality of removed tissue during sinus surgery and the vigilance of the pathologist cannot be overemphasized.
• Further growth of the tumor can be directed laterally within the orbit and results in proptosis, extraocular movement paralysis, and blindness, or, it superiorly produces intracranial complications. Facial and oral symptoms are rare.
• Early referral for an intranasal biopsy is key to early diagnosis. A patient with a unilateral nasal obstruction and/or a recurrent epistaxis lasting longer than 1-2 months should undergo a thorough nasal evaluation by an otolaryngologist, although the cost-effectiveness of this approach has not been evaluated.

Physical

A nasal examination, particularly if aided by endoscopy, reveals a reddish-gray tumor arising in the upper nasal fossa, which bleeds easily during instrumentation. Although the aspect is strictly different from the white glistening appearance of benign nasal polyps, little differentiates ENB from other nasal malignancies.

Causes

No clear etiologic agent or exposure has been documented in humans. However, 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.

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• Skull Base Tumors (Neurosurgery)
• Neuroblastoma (Radiology)
• Malignant Tumors of the Nasal Cavity (Otolaryngology and Facial Plastic Surgery)