1

Introduction

Olfactory neuroblastoma (ONB) is a rare and locally aggressive tumor of neural crest origin arising from the basal reserve cell of olfactory epithelium in the superior aspect nasal cavity . Since initially being described by Berger et al. in 1924, approximately 1400 cases have been accounted for in the literature . It remains a relatively uncommon neoplasm representing 3%–5% of all sinonasal malignancies with no race, gender, or age predilection. The origin within the superior nasal cavity often results in patients having nonspecific symptoms such as nasal obstruction, reduced sense of smell or mild epistaxis which can be present for months prior to diagnosis. Typically advanced disease is present at the time of diagnosis with involvement of the adjacent paranasal sinuses, orbit, or anterior cranial fossa. Several staging systems have been proposed in an attempt to create a uniform approach for predicting prognosis and treatment planning. The most commonly used classification was described by Kadish in 1976 which was later modified by Morita and colleagues . A later classification was described by Dulgeurov and Calcaterra which was based on a TNM classification, and incorporated CT scan and MRI imaging. The advantage of the TNM system is the integration of pretreatment imaging rather than the surgical staging required by the Kadish system .

Due to the rarity of this tumor, no large prospective studies have been developed to guide therapy. Treatment advances in the mid-1970’s led to the acceptance of craniofacial resection as a viable surgical alternative that demonstrated an increased disease-free survival. Therefore multiple treatment modalities including extra-cranial resection with or without radiotherapy, definitive radiation alone, definitive chemo-radiation, or combined intracranial-extracranial surgery (open craniofacial resection), and more recently transnasal intracranial-extracranial resection (endoscopic craniofacial resection) have been proposed . Chemotherapy was used in several studies as part of a tri-modality (chemotherapy, surgery, radiation, chemotherapy) approach with mixed success . Regardless of treatment modality, local regional and distant relapses occur frequently over even 10 years of follow up. Treatment with craniofacial resection and postoperative radiation therapy has demonstrated positive results in several studies . Current treatment protocols focus on multimodality regimens that include a combination of craniofacial resection, radiation, and chemotherapy. However, there is still a lack of agreement regarding the role of chemotherapy, particularly in advanced stage disease. Therefore, literature related this tumor consists primarily of case reports and pathological studies, case series with chart reviews, and meta-analyses. . We present a previously unreported case series of patients with ONB treated with primary surgery and provide a comprehensive analysis of the treatment outcomes.

2

Materials and methods

Following appropriate institutional review board assessment, this case series was collected from patients evaluated by the lead author (GJP) between February 1994 and March 2010. Review of prospectively collected data revealed 37 patients with histologically confirmed ONB. The diagnosis of ONB relied on the pathologic features that included microscopic findings of uniform small round blue cells with scanty cytoplasm and hyperchromatic round nuclei. Immunohistochemical staining with neuron-specific enolase, synaptophysin and S-100 protein was positive in all cases. Patient demographics, presenting symptoms, tumor extent, and histologic margin status on final pathologic studies, regional and distant metastasis, treatment regimen, and survival were collected from the medical record. All patients’ imaging studies were reviewed to confirm staging according to the Kadish and Dulgeurov staging systems. Five patients were excluded from further analysis for the following reasons ( Table 1 ), three patients presenting with altered mental status were found to have tumors that demonstrated unresectable parenchymal brain invasion or with evidence of distant metastases, one patient opted for treatment elsewhere, and one patient was referred for neck dissection for a delayed cervical metastasis following successful treatment of the primary at another institution. Thirty-two patients were definitively treated with curative intent and are the focus of this review. Endpoints of this study were disease-free survival and overall survivals and were calculated from the date of diagnosis. Overall and disease specific survival curves were developed with the Kaplan–Meier product limit methods and statistical significance was determined by the log-rank test. Statistical analysis was performed with the SAS proc lifetest software application. (SAS Institute, Cary, NC).

3

Results

3.2

Surgical treatment and complications

Initial treatment was primary concurrent chemo radiation in four patients followed by salvage open craniofacial resection in three. Twenty-eight patients had primary surgery. Of these, two patients had limited Kadish A disease isolated to the maxilla and lateral nasal wall and were treated early in the series with open medial maxillectomy. Twenty-six patients had surgical resection with either an anterior craniofacial approach, open (17) or endoscopic (9). Negative margins were achieved in 84% of patients (26/31). Open craniofacial resection was performed using standard bifrontal craniotomy with bilateral orbital osteotomies and en bloc resection of cirbiform plate, crista gali, fovea ethmoidalis anterior fossa dura and olfactory bulbs and tracts. Margins were assessed by frozen section and the anterior cranial base reconstruction was performed with a pericranial flap. The method of endoscopic craniofacial resection consisted of debulking freely mobile intranasal tumor, defining borders of resection margins, isolating anterior cranial base inferiorly with craniotomy (via the nasal cavity) where needed, dural resection as indicated, margin assessment (dura, olfactory tracts, brain, lateral nasal walls), and reconstruction with allograft dermis. In all cases of endoscopic craniofacial resection margins included the planum sphenoidale (developed with bilateral sphenoidotomies, resection of rostrum with exposure of planum), posterior wall frontal sinus (developed with bilateral Draff type 3 frontal sinusotomy), transection of nasal septum, and resection of involved lamina paparycea including bilateral total ethmoidectomies, resection of middle turbinates, and anterior ethmoid artery ligation. Table 3 summarizes the primary and adjuvant treatment programs.

Table 3

Treatment and outcome.

PT	Stage Kadish	TNM		Reconstruction	Status	Survival	Margins	Recurrence
1	A	T1, N0, M0	MM	Primary closure	NED	140.63	N	N
2	B	T2, N0, MO	OCFR + RT	Pericranial flap	NED	210.17	N	Y
3	C	T2, N0, M0	RT + OCFR	Pericranial flap	NED	248.23	N	N
4	B	T2, N0, M0	OCFR + RT	Pericranial flap	NED	184.00	N	N
5	B	T2, N0, M0	OCRF + RT	Pericranial flap	AWD	174.90	N	N
6	B	T3, N0, M0	OCRF + RT	Pericranial flap	DOD	30.03	N	N
7	B	T3, N0, M0	OCRF + RT	Pericranial flap	NED	219.70	P	N
8	C	T3, N0, M0	OCRF + RT	Pericranial flap	NED	176.97	N	N
9	A	T2, N0, M0	MM	Primary closure	NED	178.43	N	N
10	C	T4, N0, M0	RT + CT + OCFR	Pericranial flap	DOD	10.47	N	N
11	C	T4, N0, M0	RT + CT + OCRF	Pericranial flap	NED	61.07	N	N
12	C	T4, N0, M0	RT + CT + OCFR	Pericranial flap	NED	90.03	N	N
13	C	T2, N0, M0	OCFR + RT	Pericranial flap	AWD	104.67	P	Y
14	C	T4, N0, M0	OCFR + RT + CT	Radial forearm flap	DOD	6.53	N	N
15	C	T3, N0, M0	OCRF + RT	Pericranial flap	NED	140.13	N	N
16	C	T4, N0, M0	OCFR + CT + RT	Pericranial flap	DOD	124.77	P	Y
17	C	T3, N0, M0	OCFR + RT	Pericranial flap	DOD	89.73	N	N
18	B	T4, N0, M0	OCFR + RT	Pericranial flap	NED	74.20	P	N
19	B	T4, N0, M0	OCFR + RT	Pericranial flap	NED	43.47	N	N
20	A	T1, N0, M0	ECFR	Dermal graft	NED	69.30	N	N
21	B	T2, N0, M0	ECFR + RT	Dermal graft	NED	72.63	N	N
22	A	T2, N0, M0	ECFR	Dermal graft	NED	54.90	N	N
23	B	T2, N0, M0	ECFR + RT	Dermal graft	NED	88.20	N	N
24	A	T2, N0, M0	ECFR + RT	Dermal graft	NED	82.40	N	N
25	B	T3, N0, M0	OCRF + CT + RT	Pericranial flap	NED	78.83	N	N
26	C	T4, N2B, M0	OCFR + ND + CT + RT	Pericranial flap	DOD	10.47	P	Y
27	B	T3, N0, M0	ECFR + RT	Dermal graft	NED	71.63	N	N
28	B	T2, N0, M0	ECRF + RT	Dermal graft	NED	65.07	N	N
29	C	T4, N0, M0	CT + RT + OCRF	Pericranial flap	NED	68.03	P	N
30	A	T2, N0, M0	ECFR + RT	Dermal graft	NED	56.53	N	N
31	B	T2, N0, M0	ECFT + RT	Dermal graft	NED	43.70	N	N
32	C	T4, N1, M0	RT + CT	None	DOD	6.00	P	N

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