Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Esthesioneuroblastoma Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of neural crest origin arising from the olfactory sensory epithelium in the roof of the nasal fossa. The tumor was first described in 1924 by Berger et al, who reported in the French literature about "l'esthesioneuroepitheliome olfactif." The first English literature report of ENB came from Schall and Lineback in 1951. Since then less than 300 cases of ENB have been reported. This paucity of cases has hindered progress in the understanding and control of this dangerous cancer. The olfactory epithelium occupies the superior nasal fossa, covering the cribriform plate, superior nasal septum, and medial aspect of the supreme and superior turbinates. The area of olfactory epithelium is somewhat variable in man, and has been reported as low as the medial aspect of the middle turbinates. The epithelium is pseudostratified, and consists of bipolar sensory neurons, sustentacular, or support, cells, and undifferentiated basal cells. The exact cell of origin of ENB is not certain, but the multipotential basal cell is the favored candidate. Once arisen, ENB tends to spread submucosally in all directions to involve the paranasal sinuses, nasal cavity, and surrounding structures. The tumor is locally aggressive, and local recurrence strikes in up to 68% of cases regardless of initial treatment protocol. ENB also metastasizes widely by both hematogenous and lymphatic routes, with the neck being the most common site. Davis and Weissler reviewed the ENB literature since the early 1970s and found a cumulative cervical metastatic rate of 27%. Grossly, the tumor usually appears as a gray, pink, or red firm polypoid mass high in the nasal vault. ENB is highly vascular and bleeds profusely upon biopsy. Several authors recommend biopsy in the operating room for this reason. Microscopically, ENB has a variable appearance. In general, the tumor is histologically similar to malignant tumors of the sympathetic ganglia, adrenal medulla, and retina. The tumor is often difficult to identify definitively by conventional light microscopy and has been frequently misdiagnosed, most commonly as undifferentiated small cell carcinoma. Common features which aid in identification include: 1) small, round or oval blue neuroepithelial cells arranged in true rosette of pseudorosette patterns, separated by fibrous septa. Rosettes consist of a membrane-lined central space ringed by columnar cells with radially oriented nuclei. Pseudorosettes consist of a ring of blue cells around a tangle of neurofibrils. 2) surrounding stroma composed of undifferentiated nuclei and neurofibrillary cords; 3) marked microvascularity; 4) palisading of neuroepithelial cells around vessels. Mitotic figures are rare, and calcification and necrosis are sometimes seen. In the early study of ENB, much effort was expended defining histologic subtypes. Multiple studies have confirmed, however, that histologic subtype has no bearing on clinical tumor behavior or patient prognosis with ENB; therefore, all identified tumors are currently called esthesioneuroblastoma, or less commonly, olfactory neuroblastoma. Tumors are sometimes subclassified according to the presence or absence of rosettes and pseudorosettes. Currently, ENB is identified using a combination of clinical location, light microscopic appearance, and a battery of immunohistochemical stains, including chromogranin, synaptophysin, S-100 protein, and neuron-specific enolase. Occasionally, electron microscopy is used to confirm the presence of neuroblastoma. McGavran in 1970 and Taxy and Hidvegi in 1977 demonstrated neurosecretory granules containing catecholamine in ENB tumors examined by electron microscopy. This is a feature ENB shares with neuroblastomas in other anatomic locations, and is not a feature of normal olfactory epithelium. The advent of CT scanning has greatly enhanced the staging accuracy and therapeutic planning capability with regard to ENB. ENB has no classic radiologic features, but the tumor is typically a homogenous soft tissue mass with relatively uniform, moderately intense contrast enhancement, located in the superior nasal cavity. Bony erosion is frequently seen and usually accompanied by remodeling. Calcification may be seen. No clear etiology for ENB has been discovered. Herrold in 1963 did produce ENB in Syrian hamsters by administering the auto industry solvent diethylnitrosamine (DENA) by various routes. There is no documented connection, however, between exposure to DENA or to any other substance and development of ENB in man. ENB shows no clear racial, geographic, or sexual predilection, though some studies do indicate a slight male predominance. The tumor has been reported in all age groups. Elkon et al reviewed the world ENB literature from 1966 to 1979 and found a bimodal age distribution, with peaks in the 11 to 20 year range and the 51 to 50 year range. Bailey and Barton in 1975 reported a slight preponderance in the 10 to 40 year age range. Thawley et al state that ENB occurs predominantly in males 40 to 55 years old. Kadish et al in 1976 devised the currently popular staging system for ENB. Their system is as follows: Group A: tumor confined to the nasal cavity; Group B: tumor involving the nasal cavity and paranasal sinuses; Group C: tumor extension beyond the nasal cavity and sinuses. This staging system has been criticized for its over-simplicity and failure to adequately address metastases. Biller et al proposed a staging system based on the TNM classification: T1: tumor in the nasal cavity and sinuses (except sphenoid) with or without erosion of anterior cranial fossa bone; T2: periorbital or anterior cranial fossa extension; T3 brain involvement with resectable margins; T4 unresectable tumor. Dulguerov et al from UCLA in 1992 criticized Biller's system for assuming cribriform plate involvement in all cases and for requiring craniotomy for accurate staging. Their system, also following the TNM format, is based on CT and/or MRI findings: T1: tumor involving the nasal cavity and sinuses (except sphenoid), sparing the most superior ethmoidal cells; T2: tumor in the nasal cavity and sinuses (including sphenoid) with extension to or erosion of the cribriform plate; T3: tumor extending into the orbit or into the anterior cranial fossa (extradural); T4 tumor involving the brain. The object of any surgical staging system is to provide consistent information that guides treatment and prognosis. These new systems have yet to be used enough to assess their usefulness relative to the established Kadish system. Diagnosis of ENB requires a high index of suspicion and is ultimately based on biopsy. The most common complaint of ENB patients is unilateral nasal obstruction. Symptoms are typically present for months, and sometimes for years before presentation. Patients may have had multiple procedures for removal of "polyps." Another common symptom is recurrent epistaxis. Other symptoms include anosmia, facial pain, headache, proptosis, diplopia, syncope, and lethargy. The most common physical sign is a high nasal mass. As described, the mass is usually gray to pink or red, firm, and polypoid. It bleeds easily. Less common findings include neck mass, extraocular paralysis, or nasopharyngeal mass. If clinical suspicion is high, imaging studies, usually CT scan, may be ordered prior to biopsy in order to assess extent of tumor involvement. Biopsy can be performed in the clinic or the OR, but brisk bleeding is to be expected. Over the years, primary surgery, primary radiotherapy, and combined surgery and radiotherapy have been employed against ENB. Adjuvant chemotherapy has been tried with some success for recurrent, unresectable, and metastatic ENB. Chemotherapy has generally not been the first choice for resectable ENB, but a multitude of drugs have achieved cytoreduction in advanced cases in some studies. Polonowski et al from France reported a case of complete regression of recurrent ENB using a regimen of cisplatin and 5FU. More study is needed regarding the efficacy of chemotherapy in ENB. While ENB is moderately radiosensitive, and cures have been achieved with doses as low as 40 Gray, most successfully treated ENB patients have received 60 Gray or more of XRT, in addition to surgery. The therapeutic debate in ENB centers around primary surgery - with radiotherapy held in reserve for recurrences - , versus combination therapy. Elkon et al in 1979 reviewed 97 cases and concluded that both treatment options, as well as primary XRT, were equally effective in treating stages A and B. They found combination therapy more effective in Stage C patients. Dulguerov et al from UCLA advocate combination therapy in all cases, with radiotherapy administered post-operatively. Of 26 patients reviewed, they document 93% disease-free tumor control in those treated with a combination protocol, versus 14% control with surgery alone, and 40% control with XRT alone. Levine et al from UVA likewise advocate combination therapy, with pre-operative XRT, in all Stage A and B cases of ENB. They employ pre- and post-operative chemotherapy in Stage C cases. Biller et al, from Mt. Sinai, maintain that an adequate surgical resection yields results superior to combination therapy, and they hold radiotherapy in reserve for recurrences, unresectable tumors, and cases of incomplete excision. Regarding surgical therapy, most authors speak of the precraniofacial period (before the 1970s) and the craniofacial period. The combined craniofacial approach to esthesioneuroblastoma was first described by Doyle and Payton in 1971, and is championed by several authors for use in all operative cases of ENB. A frontal craniotomy is combined with lateral rhinotomy or midfacial degloving to achieve an en bloc resection of varying radicality, but which may include tumor, cribriform plate, olfactory bulbs, medial maxillae, septum, fovea ethmoidalis, ethmoid air cells, and as much anterior cranial fossa dura as necessary. If dural resection is performed, the defect can be sealed with a pericranial flap. Fat/fascia grafts are sometimes used as well, and the nasal defect can be further sealed with a split-thickness skin graft. Orbital exenteration is of course avoided if at all possible. While the advent of craniofacial resection is credited with uniformly improved disease-free survivals, not all authors insist on radical surgery in all cases. Extracranial approach with wide tumor margins may be sufficient in some limited tumors, like our case report, shown by imaging studies not to involve the cribriform plate. Recently the issue of elective neck treatment has been discussed in the literature. No answers have been offered, but given the 20-30% rate of cervical metastases, elective neck treatment with dissection or radiation in advanced cases deserves more study. Although the low number of cases makes interpretation of treatment results difficult, some figures have emerged from consolidated literature reviews. Five-year survival rates range from 50% to 65%. Five-year tumor-free rates are in the range of 20%. Local recurrence is the most common cause of treatment failure, occurring in up to 68% of patients. Metastases may be expected in 20% to 30% of patients, and may occur many years after initial treatment. A lifetime of close post-treatment follow-up is necessary. Twelve cases of ENB treated at The Methodist Hospital between 1980 and the present were reviewed. Six patients were male, and six were female. The age range was 11 to 71 years; average age was 49.6 years. Four patients were Kadish stage C, six were stage B, and two were Stage A. The most common symptom was unilateral nasal obstruction. One patient received primary radiotherapy, two underwent primary surgery, and nine underwent combination therapy. Eight patients underwent craniofacial resections, and three underwent extracranial resections. Follow-up times ranged from a few months to nine years. Of the 12 patients, there were 6 recurrences, for a recurrence rate of 50% Two patients suffered local recurrence, one had local and metastatic recurrence, and three suffered metastatic recurrence - all three of these patients had cervical involvement, yielding an overall cervical metastasis rate of 25%. Of the recurrences, 4 were initial stage B, and 2 were stage C. Of the 3 extracranial resections, 1 patient suffered local recurrence. Of the 8 craniofacial resections, 5 recurred. Of 9 patients treated with combination therapy, 4 suffered recurrence. Of 2 patients treated with primary surgery, both recurred. The 1 patient treated with primary radiotherapy had no recurrence and died of other causes. Our patient numbers are too small to draw firm conclusions from these results. Four patients have died of their disease, two are dead of other causes, two are still undergoing treatment, and four are alive with no evidence of disease, with a follow-up period from 6 months to 9 years. There are insufficient data to assess a 5-year survival rate for these patients. Esthesioneuroblastoma is an uncommon neuroectodermal malignancy of the olfactory epithelium, with an alarming propensity toward aggressive local recurrence and distant metastasis. ENB should be considered in any case of chronic unilateral nasal obstruction, particularly in a middle-aged patient. Once diagnosed, CT scan should be used to assess tumor involvement and plan therapy. Surgery is the mainstay of therapy, and tumors involving the cribriform plate should be excised via craniofacial resection. No definitive statement can be made regarding primary surgery versus combination therapy, but radiotherapy is certainly a useful modality in recurrent disease. Despite the best treatment, recurrences will happen; therefore, close, lifetime follow-up is essential. Case Presentation A 43 year-old Latin American man presented to the otolaryngology service with a greater than one year history of right nasal obstruction and occasional epistaxis. Physical examination and CT scan suggested the presence of a polyp in the right superior nasal cavity, and the patient underwent right endoscopic sinus surgery with removal of the presumed polyp from the medial aspect of the right middle turbinate. Final pathology was consistent with esthesioneuroblastoma. The patient subsequently underwent MRI of the head, which showed no intracranial extension or cribriform plate involvement. He was returned to the operating room, where he underwent right external ethmoidectomy, partial right medial maxillectomy, and right sphenoidotomy. Pathology revealed some residual tumor in the ethmoid specimen without bony invasion, and no evidence of maxillary tumor. The sphenoid was found to be clear at surgery. The patient tolerated the procedure well and was discharged home after three days. Bibliography Appelblatt NH, McClatchey KD. Olfactory neuroblastoma: a retrospective clinicopathologic study. Head Neck Surg 1982;5:108-113. Bailey BJ, Batron S. 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