Olfactory neuroblastomas are uncommon small round cell tumors
of neuroendocrine origin
, which typically arise superiorly and laterally within the nose
, presumably from precursor cells
of the nasal neuroepithelium. Reflecting their neuronal lineage, immunohistochemical staining is positive for synaptophysin, neurofilament protein, S-100, chromogranin, and neuron-specific enolase.1
The histologic differential diagnosis
includes lymphoma, Ewing's sarcoma, and other poorly differentiated sarcomas and carcinomas. Although controversy remains, some investigators have reported an 11-22 chromosomal translocation common to esthesioneuroblastomas, Ewing's sarcomas, and other primitive neuroectodermal tumors.2,-4
Both clinical (Kadish) staging and pathological (Hyam's) grading systems are widely employed, but modifications have been proposed.5
Kadish staging correlates most strongly with disease-free and overall survival.2
may also be a poor prognostic sign, but no other epidemiologic or molecular genetic
markers outweigh the importance of Kadish stage.6,7
Survival is also truncated in patients with histologically high-grade tumors,2,8
but high-grade seems to predict responsiveness to chemotherapy.9
Because of the rarity of these tumors, there are no randomized, controlled trials or even single-arm prospective trials assessing different treatment approaches. Only small, retrospective, single-institution series and literature reviews are available to guide therapy. As a result, no consensus exists on optimum treatment.
Standard treatment has included initial surgery and adjuvant radiation therapy.10
Tumor infiltration of adjacent structures (orbits, sinuses, brain
via the cribriform plate) and metastatic spread to cervical lymph nodes (> 25% of patients) is common,6
and most patients present with Kadish state C tumors.10
As a result, combined craniofacial surgical approaches involving otolaryngologic, head and neck, and neurosurgical techniques are often required for optimum tumor removal.
Disease-free survival in a large retrospective series was 68.4% at 5 years,10
and 80.4% at 8 years in a more recent series.6
Overall survival may be as high as 50% at 10 years, but is dependent on histologic grade and staging.7,9
In the setting of recurrent or widely metastatic disease
, a variety of chemotherapeutic regimens have demonstrated activity.7,9,11
The largest experience is with platinum-based regimens, particularly cisplatinum and etoposide, using regimens similar to those used for small-cell lung cancer (eg, cisplatinum 60 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1, 2, and 3). Some authors have used higher doses of cisplatinum or substituted carboplatinum. Cyclophosphamide, thio-TEPA, and high-dose CAV with stem-cell support have also shown activity. Despite radiographic responses, however, the median survival in the setting of recurrent disease is poor (12 months), but may be dependent on the histologic grade of the tumor.8,9
Recently, neoadjuvant chemo- and radiotherapy have been advocated, and some authors
have proposed that neoadjuvant therapy should become the new standard of care.7,12
Potential benefits of this approach include facilitation of gross total tumor removal and longer disease-free survival. Response to neoadjuvant therapy
may also predict better overall survival.7
Summary and Recommendations
Esthesioneuroblastomas are uncommon, locally invasive, small round cell tumors typically arising in the vault of the nasal cavity. Standard treatment has included radical surgical removal followed by radiation
therapy, and in modern series is associated with 5- and 10-year overall survival
s of 80% and 50%. Advanced Kadish stage, Hyams grade, and possibly older age are associated with poorer long-term outcome.
A variety of chemotherapy regimens, particularly platinum-based ones, produce responses in advanced recurrent disease, but survival remains poor in this situation. Recent series have advocated neoadjuvant chemo- and radiotherapy, but supportive studies are lacking.
All data regarding treatment of esthesioneuroblastomas constitutes weak Class III (case series with historical controls) or Class IV (uncontrolled case series and expert opinion) evidence, and none of the treatment approaches carries more weight than a Practice Option. Multi-institution controlled trials are essential. In their absence, radical surgery followed by radiation therapy is an appropriate therapeutic approach for newly diagnosed patients. In patients with histologically high-grade tumors and metastatic disease at the time of diagnosis, or in patients in whom tumor cytoreduction could facilitate more complete surgical removal, 2-4 cycles of neoadjuvant chemotherapy may be considered. While many single- and multiagent regimens have shown some activity, conventional doses of cisplatin and etoposide are currently preferred.
Kleihues P, Burger PC, Scheithauer BW. Histological Typing of Tumours of the Central Nervous System. 2nd edition. Berlin: Springer-Verlag. 1993;25-26.
Miyamoto RC, Gleich LL, Biddinger PW, Gluckman JL. Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis. Laryngoscope. 2000;110:1262-1265.
Whang-Penn J. Translocation t (11:22) in esthesioneuroblastoma. Cancer Genet Cytogenet. 1987;1:155-159.
Mezzelani A, Tornielli S, Minoletti F, Pierotti MA, Sozzi G, Pilotti S. Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing's group. Br J Cancer. 1999;81:586-591.
Resto VA, Eisele DW, Forastiere et al. Esthesioneuroblastoma: the Johns Hopkins experience. Head Neck. 2000;22:550-558.
* Levine PA, Gallagher R, Cantrell RW. Esthesioneuroblastoma: reflections of a 21-year experience. Laryngoscope. 1999;109:1539-1543.
* Polin RS, Sheehan JP, Chenelle AG, et al. The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience. Neurosurgery. 1998;42:1029-1037.
Eriksen JG, Bastholt L, Krogdahl AS, et al. Esthesioneuroblastoma -- what is the optimal treatment? Acta Oncol. 2000;39:231-235.
McElroy EA Jr, Buckner JC, Lewis JE. Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience. Neurosurgery. 1998;42:1023-1027.
Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res. 1997;17:2683-2706.
Goldsweig HG, Sundaresan N. Chemotherapy of recurrent esthesioneuroblastoma. Case report and review of the literature. Am J Clin Oncol. 1990;13:139-143.
* Sheehan JM, Sheehan JP, Jane JA, Polin RS. Chemotherapy for esthesioneuroblastomas. Neurosurg Clin N Am. 2000;11:693-701.
* = multiple papers written by the same group, based on the same series of patients.