Ectopic Olfactory Neuroblastoma: Systematic Review of a Rare Clinical Entity among Sinonasal Tumors

Abstract

Objectives  Ectopic olfactory neuroblastoma is an uncommon manifestation of an already rare neoplasm. We aimed to systematically review the literature for cases of ectopic olfactory neuroblastoma to better characterize this rare disease entity and to present two new case reports.

Methods  A search of the PubMed and Embase databases was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify English-language articles reporting cases of ectopic olfactory neuroblastoma, published from 1955 through November 2021.

Results  Sixty-six cases of ectopic olfactory neuroblastoma were identified in 62 articles including the current review. Ectopic olfactory neuroblastoma arose in a wide age range (2–89 years) without significant sex predilection. It occurred most commonly in the ethmoid (25%), maxillary (25%), and sphenoid (16%) sinuses. Seventy-three percent of cases presented with low Hyams grade (I and II). The most common symptoms were nasal obstruction (32%) and epistaxis (32%). Paraneoplastic syndromes were observed in 27% of patients. The most common treatment was surgical resection followed by adjuvant radiotherapy. Overall, 76% of all patients were disease-free at the time of last follow-up. Locoregional recurrences and distant metastases were found in 19 and 5% of cases, respectively.

Conclusion  This systematic review describes previously reported cases of ectopic olfactory neuroblastoma, a disease entity with poorly understood characteristics. Physicians should consider olfactory neuroblastoma in the differential diagnosis for sinonasal masses, as their ectopic presentation may present considerable diagnostic and therapeutic difficulties. Patients with olfactory neuroblastoma may benefit from long-term follow-up and routine endoscopic examinations for surveillance of ectopic recurrences.

Introduction

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma (ENB), is an uncommon malignant tumor arising from the olfactory neuroepithelium in the sinonasal cavity. It was first characterized by Berger et al in 1924, ¹ and there have been over 1,000 cases reported in the literature to date. ² The tumors generally arise from the cribriform plate in the superior nasal cavity. ONB represents approximately 3% of all intranasal tumors and 5% of malignant nasal and paranasal sinus tumors. ^{3 4} The initial clinical presentation of ONB can be highly varied, although common presenting symptoms include nasal obstruction and epistaxis. Less commonly, nonspecific findings such as headache, paresthesia, and vision loss are observed, which can often lead to delayed diagnosis or misdiagnosis. ⁵ ONB has been described as a “great impostor” as it is often confused for other tumors of the head and neck region. ⁶ In rare cases, ONB has also been seen in association with various paraneoplastic syndromes including syndrome of inappropriate anti-diuretic hormone (SIADH) ⁷ and Cushing's syndrome. ⁸ Local recurrence is thought to occur in 20 to 30% of patients following treatment, ⁹ while regional recurrence in the neck occurs in around 14% of patients. ¹⁰ Distant metastatic spread is thought to occur in around 8% of all cases. ¹¹

The exact cell type from which ONB originates has not yet been clearly defined in the literature. The likely cell of origin is hypothesized to be the basal neural cells of the olfactory mucosa, ³ as almost all tumors arise from the cribriform plate region. ^{12 13} However, this does not adequately explain the etiology of ectopic ONB originating outside the nasal cavity, even though these cases are exceedingly rare. The first case of ectopic ONB was described in the literature by McCormack and Harris in 1955. ¹⁴ Since then, several cases of ONB originating outside of the olfactory neuroepithelium have been reported in the literature. ^{13 15 16 17 18} Due to its rarity, little is known about the presentation and disease characteristics of ectopic ONB.

In this review, we aim to better characterize ectopic ONB and familiarize clinicians with its unique diagnostic and therapeutic dilemmas. Herein, we present two new cases of ONB originating from the maxillary sinus and systematically review all previously published case series and reports of ectopic ONB.

Case Reports

Case Report 1

In 2015, a 20-year-old female presented with a 6-month history of right-sided nasal obstruction. Computed tomography (CT) of the sinuses was performed, which showed a 4.4 × 3.2 × 3.7 cm mass centered in the middle nasal cavity extending into the right maxillary sinus and right frontal recess with no intracranial invasion ( Fig. 1 ). On nasal endoscopy, a large right-sided sinonasal mass was visualized. A biopsy was performed, and pathology was suspicious for an inverted papilloma. A diagnostic angiogram showed significant vascularization of the mass. Hence, the patient underwent preoperative embolization before her tumor resection. She subsequently underwent a right endoscopic medial maxillectomy, ethmoidectomy, sphenoidotomy, and frontal sinusotomy. The entirety of the surgical resection was extradural. The mass was friable with a smooth encapsulated surface. Intraoperatively, the mass's primary site of attachment was noted to be within the maxillary sinus, and the tumor filled the maxillary sinus and right nasal cavity without any evidence of extension or invasion into other contiguous regions ( Fig. 1 ).

Fig. 1.

Preoperative computed tomography (CT) scan with ( A ) coronal and ( B ) axial slices showing a large mass filling the right maxillary sinus and nasal cavity measuring 4.4 cm in its largest diameter.

Histologic sections showed a tumor with lobular architecture composed of relatively monotonous small to medium cells forming occasional Homer-Wright rosettes. The tumor cells stained positive for synaptophysin, chromogranin, CD56, and MIB-1, and negative for keratin AE1/AE3 and CD45. This was consistent with Hyams grade II, Kadish stage B ONB. Histologic resection margins were negative.

A positron emission tomography-CT (PET-CT) performed at the 3-week postoperative period showed no evidence of residual locoregional or distant disease. The patient received adjuvant chemoradiation at an outside institution but attended routine postoperative visits at our hospital. She was free of disease 5 years after her surgical resection.

Case Report 2

In 2004, a 43-year-old female presented with 18 months of nasal obstruction and a right-sided nasal mass. She endorsed discolored rhinorrhea, right-sided anosmia, and intermittent facial pain. Partial smell preservation was noted on the contralateral side. Nasal endoscopy noted a friable mass filling the right nasal cavity. Magnetic resonance imaging (MRI) and CT imaging of the sinuses was performed and noted a large mass filling the right nasal cavity extending from the area of the olfactory cleft without frank invasion or evidence of metastasis. A biopsy was performed and was consistent with ONB, Hyams grade I. The tumor cells stained positive for synaptophysin and S-100, and were negative for Melan-A, HMB45, and cytokeratin A1/3.

The patient subsequently underwent right-sided endoscopic sinus surgery with skull base resection and multilayered skull base reconstruction. The resection was extradural, and surgical pathology confirmed negative resection margins, including negative dural biopsies. The multilayered skull base reconstruction included use of acellular dermis and a free septal mucosal graft. The patient subsequently completed intensity-modulated radiation therapy (5,220 cGy in 29 fractions) targeted at the skull base. The radiation field did not include the maxillary sinuses.

She was monitored with frequent PET-CT and MRI scans without any indications of recurrence until 2018. At the time, the patient reported mild recurrent right epistaxis. Visualization with endoscopy showed an exophytic area involving the right inferolateral maxillary sinus. Review of prior MRIs identified a mild nonspecific signal along the floor of the right maxillary sinus that was more prominent on more recent imaging.

Biopsy of the right maxillary sinus was performed, and histologic studies revealed a submucosal neoplasm composed of round to oval uniform cells with few mitotic figures and no necrosis, consistent with ONB. The tumor cells stained positive for synaptophysin and chromogranin and negative for cytokeratin 8/17, glial fibrillary acidic protein, and had a 1% Mib-1 proliferation index. This represented ectopic recurrence 14 years after treatment of her first ONB. Of note, there was no tumor noted in proximity of the maxillary sinus at the time of the initial resection to serve as a possible nidus for tumor recurrence in this area.

The patient underwent tumor resection with combined endoscopic medial maxillectomy and Caldwell-Luc approach. Multiple frozen section biopsies of margins were taken, which were all negative. The final pathology was consistent with T2N0M0, Hyams grade I, Kadish stage B ONB. Postoperatively, the patient completed 5,940 cGy of intensity-modulated radiation therapy in 33 fractions in 2019. Two years from the date of her tumor resection, the patient remained without evidence of disease recurrence.

Systematic Review Methods

Search Strategy

A systematic review of the literature on cases of ectopic ONB was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. According to the University of Southern California's Office for the Protection of Research Subjects, a case report does not meet the definition of human subjects' research requiring institutional review board (IRB) reviews, and as such, this study did not require IRB review.

PubMed and Embase databases were searched from inception to November 2021. The search was conducted on November 10, 2021. Search terms including olfactory neuroblastoma or esthesioneuroblastoma , in conjunction with disease location (e.g., ectopic , maxillary , ethmoid , sphenoid , sphenoclival , sellar , nasopharynx , or meatus ) were used to identify relevant articles.

Eligibility Criteria

The inclusion criteria were newly reported cases of ONB that had primary sites of attachment and appeared to originate outside of the olfactory epithelium/cribriform region. For cases of ectopic ONB recurring after resection of traditional nasal cavity ONB, the recurrence must have arisen more than 5 years after the original resection, at a different location than the original tumor, and outside of the initial surgical field. Non-English papers, articles with unclear tumor origin, and cases where the primary tumor arose from the olfactory mucosa but subsequently recurred in an ectopic location < 5 years after treatment were excluded. References of relevant articles were screened for any additional articles that would meet the criteria for inclusion in this review.

Three investigators (C.L., I.B., and L.T.) independently reviewed all identified records by titles and abstracts to determine eligibility for inclusion. Any discrepancies between the articles chosen for inclusion by the reviewers were resolved by consensus.

Data Extraction

Data was extracted systematically using a standardized form on Microsoft Excel (Microsoft Corporation, 2018). Information that was recorded for each case included patient demographics, location of the tumor, symptoms at presentation, diagnostic modalities utilized, tumor staging, primary treatment, adjuvant treatment, and long-term outcomes.

Results

A database search yielded 398 unique articles, with an additional 18 articles added after reviewing the references of included articles. ^{2 8 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70} Of those 416 articles, 61 were found to be suitable for inclusion based on the previously described inclusion and exclusion criteria, representing a total of 64 patient cases. All included articles were case reports except for one case series. With the addition of the two case reports we described above, there were a total of 66 cases of ectopic ONB included in this analysis ( Table 1 ). Fig. 2 shows the literature search process.

Table 1. Summary information of cases included in the systematic review ( n  = 66) .

Author	Age	Sex	Tumor location	Treatment	Recurrence a	Staging/Grading (Kadish/Hyams) b
McCormack and Harris (1955)	29	F	Ethmoid sinus	Surgery + radiotherapy	No	- / -
King (1959)	14	M	Nasopharynx	Surgery + radiotherapy	Locoregional recurrence	- / -
Church and Uhler (1959)	N/A c	N/A c	Maxillary alveolus	Surgery	Locoregional recurrence; 8 months after treatment	- / -
Mashberg et al (1960)	24	M	Maxillary sinus	Surgery	No	- / III
Becker and Jacox (1964)	51	M	Frontal sinus	Surgery	Locoregional recurrence; 3 years after treatment	- / -
Fitz-Hugh et al (1965)	53	F	Ethmoid sinus	Surgery + radiotherapy	No	- / -
Schochet et al (1975)	31	F	Parasella	Surgery + radiotherapy	No	- / -
Sarwar (1979)	31	F	Sella/Parasella	Surgery + radiotherapy	No	- / -
Pope et al (1980)	56	F	Ethmoid sinus	Surgery + radiotherapy	No	- / -
Meyrowitz et al (1984)	71	F	Maxillary sinus	Surgery + radiotherapy	Locoregional recurrence; 18 months after treatment	- / -
Woerner et al (1986)	2	M	Maxillary sinus	Chemoradiotherapy	No	- / -
Berman et al (1992)	11	F	Sphenoid sinus	Surgery + chemoradiotherapy	No	- / -
Feifel et al (1992)	47	F	Maxillary alveolus	Radiotherapy	Locoregional recurrence; 6 months after treatment	- / -
Myers et al (1994)	79	F	Maxillary sinus	Radiotherapy	Distant metastasis; 6 months after treatment	- / -
Chacko et al (1998)	62	F	Sphenoid sinus	Died before treatment	N/A	C / -
Roy et al (2000)	44	F	Sella	Surgery + radiotherapy	No	- / -
Miura et al (2001)	56	M	Ethmoid sinus	Chemoradiotherapy	Distant metastasis; 3 months after treatment	B / III
Sharma et al (2002)	40	M	Sphenoid sinus	Chemoradiotherapy	No	- / -
Chirico et al (2003)	59	F	Sphenoid sinus	Chemoradiotherapy	Unknown	- / II
Mariani et al (2004)	35	F	Sella	Surgery	No	A / II
Morris et al (2004)	63	M	Sphenoid sinus	Surgery	No	- / -
Yu et al (2004)	36	M	Ethmoid sinus	Radiotherapy	No	- / -
Kanno et al (2005)	39	F	Ethmoid sinus	Surgery + radiotherapy	Locoregional recurrence; 2 years after treatment	- / -
Sajko et al (2005)	57	F	Sella	Surgery + radiotherapy	No	- / -
Unal et al (2006)	14	F	Maxillary sinus	Surgery + chemotherapy	No	B / -
Butt and Olczak (2007)	52	M	Ethmoid sinus	Surgery + radiotherapy	Locoregional recurrence; 4 years after treatment	- / -
Lee et al (2007)	49	M	Multifocal: maxillary sinus; ethmoid sinus	Surgery	No	- / -
Lee and Kim (2007)	89	M	Inferior meatus	Radiotherapy	Locoregional recurrence; 5 months after treatment	A / IV
Josephs et al (2008)	48	M	Ethmoid sinus	Surgery + radiotherapy	No	C / -
J.H. Lin et al (2009)	40	M	Sella	Surgery + radiotherapy	No	- / -
Kodama et al (2009)	52	F	Maxillary sinus	Surgery + radiotherapy	No	C / II
H. Lin et al (2009)	64	F	Sphenoid sinus	Died before treatment	N/A	- / -
Chan et al (2009)	79	M	Sphenoid sinus	Surgery + radiotherapy	No	C / -
Seccia et al (2010)	69	F	Pterygopalatine fossa	Surgery + radiotherapy	No	- / -
Wormald et al (2011)	15	F	Ethmoid sinus	Surgery + radiotherapy	No	C / II
Wormald et al (2011)	60	M	Sphenoid sinus	Surgery + radiotherapy	No	B / II
Wormald et al (2011)	61	M	Nasopharynx	Surgery + radiotherapy	No	A / I
Wormald et al (2011)	12	M	Nasal floor	Surgery	No	- / -
Senchak et al (2012)	28	F	Middle turbinate	Surgery	No	- / I
Akinfolarin et al (2012)	33	M	Sphenoid sinus	Surgery + chemoradiotherapy	Distant metastasis; 5 months after treatment	- / -
Kumar et al (2013)	35	F	Lateral wall/middle meatus	Surgery + radiotherapy	No	B / III
Lopez et al (2013)	73	F	Maxillary sinus	Surgery + radiotherapy	Unknown	C / -
Gabbay et al (2013)	50	M	Ethmoid sinus	Surgery	No	- / -
Mayur et al (2014)	19	M	Ethmoid sinus	Surgery + chemotherapy	No	C / -
Squillaci (2014)	81	F	Ethmoid sinus	Surgery + chemotherapy	No	- / -
Abdel-Rahman and Kamal (2014)	55	M	Sphenoid sinus	Surgery + chemoradiotherapy	Unknown	- / -
Jiang et al (2015)	N/A c	M	Maxillary sinus	Surgery + radiotherapy	No	B / -
Purohit et al (2015)	62	F	Sphenoclival	Chemoradiotherapy	Locoregional recurrence; 6 months after treatment	C / III
Holmes et al (2016)	63	F	Maxillary sinus	Surgery	Unknown	- / IV
Leon-Soriano et al (2016)	41	M	Multifocal: ethmoid sinus; ethmoid sinus	Surgery + radiotherapy	No	B / II
Nakano et al (2017)	27	F	Ethmoid sinus	Surgery + chemoradiotherapy	No	- / -
Thomas et al (2016)	13	F	Maxillary sinus	Chemoradiotherapy	No	C / II
Zahedi et al (2017)	71	M	Sphenoclival	Surgery	No	- / -
Parrilla et al (2017)	31	M	Ethmoid sinus	Surgery + radiotherapy	No	B / -
Fosbøl et al (2018)	17	F	Maxillary sinus	Surgery + radiotherapy	No	- / I
Rasool et al (2018)	28	F	Maxillary sinus	Surgery + radiotherapy	No	- / I
Familiar and Azcutia (2019)	31	M	Sphenoid sinus	Chemoradiotherapy	No	C / I
Caldwell and Sato (2019)	15	M	Nasopharynx	Chemoradiotherapy	Locoregional recurrence; 3 months after treatment	D / I
Wong et al (2019)	17	F	Maxillary sinus	Surgery + radiotherapy	No	B / I
Mims et al (2020)	13	M	Lateral wall of nasal cavity	Surgery + radiotherapy	No	- / II
Peyneshki et al (2020)	66	M	Sella	Surgery + radiotherapy	No	- / II
Heiland and Heiland (2021)	35	M	Middle meatus	Surgery	No	B / -
Zhong et al (2023)	55	M	Nasopharynx	Surgery	Locoregional recurrence; 14 months after treatment	- / IV
Tudor et al (2021)	11	F	Maxillary sinus	Surgery + chemotherapy	Unknown	- / I
Lui et al (current study)	20	F	Maxillary sinus	Surgery + chemoradiotherapy	No	B / II
Lui et al. (current study)	57	F	Maxillary sinus	Surgery + radiotherapy	No	B / I

Abbreviations: F, female; M, male; N/A, not available.

^aAs reported at the time of each case's publication.

^bStaging and grading information as reported by each article.

^cInformation not reported by article.

Fig. 2.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart.

The average patient age at the time of presentation was 43 years old (range: 2–89 years), and the disease showed no major sex predilection, with 52% of cases arising in females ( Table 2 ). The most common locations of ectopic ONB outside of the nasal cavity were the ethmoid sinus (25%) and maxillary sinus (25%) ( Table 3 ). The next most common tumor locations were the sphenoid sinus (16%) and the sellar or parasellar areas (10%). Less common locations included atypical nasal cavity locations (9%), nasopharynx (6%), sphenoclival region (3%), alveolar process of the maxilla (3%), frontal sinus (1%), and the pterygopalatine fossa (1%). ONB affected the left (49%) and right side (47%) equally. In two cases, simultaneous multifocal disease was discovered with separate noncontiguous ONBs arising in both right- and left-sided locations. Upon diagnosis, the majority of cases with reported histologic Hyams grading ( n  = 26) were Hyams I (35%) or Hyams II (38%). In terms of Kadish classification, the majority of cases with reported staging ( n  = 25) presented as Kadish stage B (44%) or C (40%) ( Table 3 ).

Table 2. Demographic characteristics of patients with ectopic olfactory neuroblastoma.

Characteristic	Number of patients (%)
Age ( n  = 64)
Mean	43 y
Range	2–89 y
0–9	1 (2)
10–19	12 (19)
20–29	6 (9)
30–39	10 (16)
40–49	7 (11)
50–59	12 (19)
60–69	9 (14)
70–79	5 (8)
80–89	2 (3)
Sex ( n  = 65)
Male	31 (48)
Female	34 (52)

Table 3. Tumor features at time of initial presentation and diagnosis.

Characteristic	Number of patients (%)
Laterality ( n  = 49)
Right	23 (47)
Left	24 (49)
Multifocal a	2 (4)
Location ( n  = 68)
Ethmoid sinus	17 (25)
Maxillary sinus	17 (25)
Sphenoid sinus	11 (16)
Sellar/parasellar	7 (10)
Nasopharynx	4 (6)
Lateral wall	2 (3)
Alveolar process of maxilla	2 (3)
Sphenoclival	2 (3)
Frontal sinus	1 (1)
Middle turbinate	1 (1)
Middle meatus	1 (1)
Inferior meatus	1 (1)
Pterygopalatine fossa	1 (1)
Nasal floor	1 (1)
Grading/Staging
Hyams ( n  = 26)
I	9 (35)
II	10 (38)
III	4 (15)
IV	3 (12)
Kadish ( n  = 25)
A	3 (12)
B	11 (44)
C	10 (40)
D	1 (4)

^aBoth cases of multifocal disease involved two masses arising from a right- and left-sided location.

Clinical presentation most often involved symptoms of nasal obstruction (32%), epistaxis (32%), and headache (26%) ( Table 4 ). Central nervous system (vomiting, altered mental status) and ophthalmic (vision loss, cranial nerve VI palsy) symptoms were also present in some cases. Endocrine paraneoplastic syndromes were observed in 27% of the cases reported, with 12 cases of SIADH (18%) and 6 cases of ectopic Cushing's syndrome (9%).

Table 4. Presenting symptoms, primary treatment modalities, and outcomes of ectopic olfactory neuroblastomas.

Characteristic	Number of patients (%)
Symptoms at presentation
Nasal obstruction	21 (32)
Epistaxis	21 (32)
Headache	17 (26)
Paraneoplastic syndrome	18 (27)
SIADH	12 (18)
Ectopic Cushing's syndrome	6 (9)
Edema	11 (17)
Vision loss	9 (14)
Abducens nerve palsy	8 (12)
Vomiting	5 (8)
Altered mental status	5 (8)
Hypoesthesia	4 (6)
Primary treatment ( n  = 66)
Surgery alone	12 (18)
Surgery + radiotherapy	31 (47)
Surgery + chemotherapy	4 (6)
Surgery + chemoradiotherapy	5 (8)
Radiotherapy alone	4 (6)
Chemoradiotherapy	8 (12)
No treatment	2 (3)
Surgical approach ( n  = 52)
Open	25 (48)
Endoscopic	27 (52)
Post-treatment outcomes ( n  = 59)
Disease-free a	45 (76)
Locoregional recurrence	11 (19)
Distant metastases	3 (5)

Abbreviation: SIADH, syndrome of inappropriate anti-diuretic hormone.

^aDisease-free at time of original case report publication without any history of recurrence or metastasis.

The majority of cases were treated with surgery (79%), with or without adjuvant therapy. Eighteen percent of patients were treated with surgery alone, 47% with adjuvant radiotherapy, 6% with adjuvant chemotherapy, and 8% with adjuvant chemoradiotherapy. The remaining cases did not receive surgical treatment. Twelve percent of patients received chemoradiotherapy alone, 6% received radiotherapy alone, and 3% received no treatment. Of the 59 cases that underwent treatment and had known outcomes, 76% of patients remained disease-free at the time of original case publication, 19% had locoregional recurrence of disease within 5 years of initial treatment, and 5% had distant metastatic disease without neck involvement ( Table 4 ).

Discussion

To our knowledge, our review consisting of 66 confirmed cases is the most comprehensive report on ectopic ONB to date. We found that these tumors can occur at any age without any obvious sex predilection, and were most commonly found in the ethmoid sinus, maxillary sinus, sphenoid sinus, and sella turcica. Unlike primary site ONB, in which a majority of cases present with the classic findings of nasal obstruction and epistaxis, patients with ectopic disease only present with obstruction or epistaxis in roughly a third of cases. ⁷¹ Of note, 27% of patients presented with a paraneoplastic syndrome of either SIADH or Cushing's syndrome. These findings suggest that an ectopic ONB should be considered for sinonasal masses presenting atypically, and in situations where paraneoplastic syndromes are present and unaccounted for.

Staging and grading of ONBs is usually conducted via clinical (Kadish) and histological (Hyams) classification. Kadish staging is based on the location and extent of invasion of the tumor, with the modified version by Morita including four stages (A–D), such that Kadish stage D is associated with the worst prognosis. ⁷² Hyams proposed a grading scheme based on histological and clinical findings, including mitotic activity and tumor necrosis, with four grades in total (I–IV). Recent studies have mostly validated these classification systems, showing that a higher Kadish stage and Hyams grade of ONBs lead to higher rates of recurrence and lower rates of overall survival. ⁷³ In our two case reports, the tumors were classified as Kadish B/Hyams II and Kadish B/Hyams I, respectively. These low staging and grading classifications predict good overall outcomes, as observed in our cases. Since the Kadish staging system is based on the location of tumor, there may be a decrease in prognostic reliability when used for classifying ectopic ONBs, as the lowest Kadish stage is assigned to ONBs located solely in the nasal cavity. Ectopic cases arising outside of the nasal cavity often must be staged as at least Kadish B, even though some of these cases may represent tumors that are less aggressive and share a similar prognosis to nonectopic ENBs categorized as Kadish A. The Hyams grading system may therefore be more useful for predicting the aggressiveness of ectopic cases. However, further studies are necessary to evaluate the prognostic utility of the current classification systems when used in ectopic cases of ONB.

For the treatment of ectopic ONB, the most commonly reported modality was surgical resection with adjuvant radiotherapy. While open surgical approaches were more common overall, endoscopic resections have become more common in recent years. Generally, ectopic ONBs tended to be locally aggressive, so negative surgical margins should be confirmed. However, cervical lymph node involvement appears to be uncommon in ectopic ONB and was only reported in four cases. ^{34 36 51 65} Two of these cases were treated with neck dissection along with adjuvant therapy: chemoradiotherapy in one, and radiotherapy in the other. One case was treated with chemoradiation, and the final patient died before treatment was initiated. Regardless, prognoses were relatively favorable for these malignancies, considering that 76% of patients were disease-free at the time of case publication, recurrences developed locoregionally in 19% of patients within 5 years of treatment, and distant metastases were reported in only 5% of patients. As reported in this review, cervical lymph node involvement as well as locoregional recurrences in patients with ectopic ONB appear to be lower than the previously reported rates in the literature for nonectopic ONB. ^{9 10} However, these positive outcomes may be biased by the fact that most published cases reported follow-up periods of 5 years or less. It is possible that with more thorough long-term surveillance, the rate of recurrence could match that of typical ONB cases. As this disease entity is rarely encountered with few reports overall, the data surrounding initial presentation as well as long-term outcomes remains unclear which could explain the present report's lower than expected rates of cervical lymph node involvement and locoregional recurrence as discussed above. Nonetheless, the findings in this review suggest that early diagnosis and appropriate surgical and adjuvant therapy can lead to a good prognosis in these patients. Of note, there were two patients reported in the literature who had ectopic ONB occurring more than 10 years after treatment of a primary ONB, including our second case report. There have been rare instances of ONB developing following radiation exposure to the head and neck, with five cases currently reported in the literature to our knowledge. ^{74 75} The patient in our second case report originally had nonectopic disease treated with surgical resection and radiation therapy with subsequent ectopic ONB; however, the radiation field did not include the maxillary sinuses, so the case likely represents de novo ectopic ONB. As such, clinicians should be aware that patients with history of superior nasal cavity ONB may be at risk for disease recurrence in ectopic locations later in life, and would likely benefit from long-term, routine endoscopic sinonasal evaluations. Similarly, patients with prior head and neck radiation should be monitored closely for development of malignancies, including ectopic ONB, in previously irradiated tissue.

Our review found that regions reported to harbor ectopic disease included the paranasal sinuses, sellar and parasellar regions, atypical locations within the nasal cavity, nasopharynx, sphenoclival region, pterygopalatine fossa, and the alveolar process of the maxilla. While it is generally accepted that ONBs are of neural crest origin, the exact cell of origin remains unknown. Possible progenitors include cells from the pterygopalatine ganglion, the vomeronasal organ, the terminal nerve, autonomic ganglion in the nasal mucosa, and the basal cells of the olfactory epithelium. ^{3 4 65} Furthermore, the etiology of aberrant ectopic cases has yet to be determined. A leading hypothesis is that the olfactory neuroepithelium may deposit in ectopic locations during embryological development. An alternative hypothesis suggests that separate neuroendocrine cell populations that typically involute during fetal development can persist into adulthood and serve as the origin for ectopic ONB. ^{12 76} Further research is needed to elucidate the embryologic origins of ONB and the mechanism through which they may present in ectopic locations.

The main limitation of this systematic review is the quality of evidence included in the selected articles. Due to the rare incidence of ectopic ONB, the only descriptions of this disease found in the literature were either case reports or case series. Furthermore, there was significant heterogeneity in the amount and type of information reported on patient demographics, symptoms, treatment, outcomes, and follow-up periods among the included articles. As a result, this review can only comment on general characteristics of the disease without conducting any statistical analysis or drawing any definitive conclusions. The heterogeneity in reported information also made it difficult to accurately determine whether recurrences were local or regional in location, and therefore we reported recurrences either as locoregional or distant. Furthermore, although the ethmoid air cells and maxillary sinus were the most common locations for ectopic tumor sites in this systematic review, it is important to note that there are olfactory filaments extending down the length of the middle and superior turbinates. If these structures were primarily involved, then these cases may not necessarily represent ectopic tumors in the traditional sense. Finally, since the follow-up period reported in the majority of ectopic ONB cases in the literature was less than 5 years, future studies investigating outcomes and complications over a longer time course could help further guide the longitudinal management of patients with these tumors.

Conclusion

Although rare, ectopic ONB may be considered in the list differential diagnoses of sinonasal tumors as it can pose a significant diagnostic and therapeutic challenge. More than a quarter of patients with ectopic ONB may initially present only with symptoms of a paraneoplastic syndrome. Patients with primary ONB can have recurrence of disease in ectopic locations many years after initial remission and may benefit from long-term surveillance and careful endoscopic survey of the sinuses.