INTRODUCTION — Olfactory neuroblastoma, also referred to as esthesioneuroblastoma, is a rare malignant tumor of neuroectodermal origin with neuroendocrine differentiation. Olfactory neuroblastomas are thought to arise from the olfactory epithelium [1].
The clinical presentation, pathology, treatment, and follow-up of patients with olfactory neuroblastomas will be reviewed here. Other malignancies of the nasal cavity and skull base are discussed elsewhere. (See "Tumors of the nasal cavity" and "Paranasal sinus cancer" and "Chordoma and chondrosarcoma of the skull base".)
EPIDEMIOLOGY — Olfactory neuroblastoma makes up approximately two percent of all sinonasal tumors and has an incidence of 0.4 per million population [2]. In patients with olfactory neuroblastomas, the mean age at presentation is 53 years, with most cases occurring in patients between 35 and 70 years of age [3-7]. There is a moderate male predominance with a 59:41 male:female ratio in one series from the Surveillance, Epidemiology, and End Results (SEER) database [3].
CLINICAL MANIFESTATIONS — Nasal obstruction due to the presence of a mass is the most common symptom with olfactory neuroblastoma and is present in the majority of cases. Other manifestations of local disease include epistaxis, nasal discharge, and/or pain. When nasal symptoms are present, physical examination usually reveals a red-brown, polypoid mass located high in the nasal cavity.
Symptoms can also be due to invasion of adjacent structures. Examples of symptoms due to local extension of tumor include:
●Anosmia caused by tumor extension into the cribriform plate
●Pain, proptosis, diplopia, and excessive lacrimation due to orbital extension
●Ear pain and otitis media because of obstruction of the eustachian tube
●Frontal headache due to involvement of the frontal sinus
Rarely, patients with olfactory neuroblastomas may have paraneoplastic syndromes due to hormone production, including ectopic adrenocorticotropic hormone syndrome [4,5], hypercalcemia [6], syndrome of inappropriate antidiuretic hormone (SIADH) [7], and hyponatremia [4], as well as neurological paraneoplastic syndromes [8].
DIAGNOSIS AND STAGING — The diagnosis of olfactory neuroblastoma requires a tissue biopsy, which is usually obtained during detailed examination of the nasal cavity. Delayed diagnosis is common. (See 'Pathology' below.)
Staging — There is no uniformly accepted staging system for patients with olfactory neuroblastoma. The Kadish and the Dulguerov systems are most commonly used for staging patients with olfactory neuroblastoma.
Kadish system — The most widely used approach is the Kadish clinical staging system (table 1) [9]. As originally proposed, this was a three-tier classification based upon the extent of the primary tumor. This was subsequently modified to include a separate category for patients with lymph node or distant metastases [10]:
●Stage A – Confined to the nasal cavity
●Stage B – Involvement of one or more paranasal sinuses
●Stage C – Extension beyond the nasal cavity and paranasal sinuses
●Stage D – Regional lymph node or distant metastasis
Kadish stage C does not differentiate patients based on the extent of intracranial invasion. However, intracranial invasion with dural involvement has been shown to be a negative prognostic factor for local recurrence and metastasis [11,12].
Olfactory neuroblastoma are generally slow-growing tumors [13,14]. Patients present most frequently with local (Kadish stage A-C) disease and are less likely to present with regional lymph nodes or distant metastases (Kadish stage D disease) [15]. As examples, in a National Cancer Database (NCDB) analysis of 1167 patients, 34 percent had Kadish stage A or B disease (disease limited to the nasal cavity or sinuses), 53 percent had stage C disease, and 8 percent had stage D disease [16]. In a review of the Surveillance, Epidemiology, and End Results (SEER) registry, the overall rate of cervical lymph node metastasis was approximately 9 percent [3].
Dulguerov system — The Dulguerov system, based upon a modification of the tumor, node, metastasis (TNM) type of classification, may provide superior stratification of patients into prognostic groups (table 2) [17,18]. This was illustrated in a meta-analysis that compared the Kadish and Dulguerov systems using individual level data from 399 patients treated with primary surgery [18]. While higher stage with either system correlated with worse disease-free and overall survival, the Dulgueroy appeared to be a better discriminator of overall survival, especially among patients within the heterogeneous Kadish stage C group. However, not all studies have demonstrated superiority. One study of the NCDB comparing the Kadish, TNM, and modified Dulguerov systems in 883 patients with olfactory neuroblastoma showed no difference in survival outcomes between the three systems [19].
Imaging studies — Computed tomography (CT) and magnetic resonance imaging (MRI) help to differentiate tumor from other causes of nasal obstruction and are essential for tumor staging [20-22]. Origin from the superior nasal cavity medial to the middle turbinate is highly suggestive of olfactory neuroblastoma. Definitive diagnosis requires histologic examination of a biopsy or surgical specimen and may require electron microscopy and immunohistochemistry. (See 'Pathology' below.)
Imaging studies can identify regional or distant metastases at presentation and may include CT, MRI, positron emission tomography (PET), or somatostatin receptor-based image (SRI). These imaging modalities may have a role as an adjunct to staging in patients with locally advanced (Kadish C) or high-grade (Hyams grade III or IV) disease, where there is a significant risk of lymphatic metastases or distant disease. (See 'Hyams grading system' below.)
●CT – CT provides the best information about invasion into bony structures and permits detailed assessment of bony erosion or destruction, particularly of the cribriform plate. It can be difficult to differentiate tumor extension versus sinus obstruction with CT alone.
●MRI – MRI is more accurate for defining the margins of tumor extension into adjacent soft tissue areas, such as the anterior cranial fossa and the orbital tissues. It can also differentiate obstructed secretions from tumor in a sinus that is opacified on CT.
●PET/CT – PET/CT may be helpful in differentiating lymphatic metastases from benign lymphadenopathy when a borderline enlarged lymph node does not meet other criteria for malignancy, such as peripheral enhancement and/or central necrosis. Retropharyngeal lymph nodes are also at risk for metastatic disease, but level II lymph nodes are most frequently involved [23]. There are limited data for the role of PET/CT in identifying distant metastases [24]. In one study, PET correctly identified 17 of 20 extracranial metastases, including two distant metastases [25].
●SRI – Most olfactory neuroblastomas express somatostatin receptors, similar to well or moderately differentiated neuroendocrine carcinoma of other origins [26,27]. Observational studies consistently report detection of olfactory neuroblastoma by SRI such as indium in-111 pentetreotide (OctreoScan) or gallium Ga-68 DOTATATE PET-CT [26,28,29]. While these imaging modalities have not been formally studied in olfactory neuroblastoma, the use of SRI in conjunction with cross-sectional images is promising and could be offered for initial staging at diagnosis, following definitive therapy with surgery and/or radiotherapy to differentiate tumor and scar tissue, and to select patients for peptide receptor radioligand therapy. (See 'Peptide receptor radioligand therapy' below.)
PATHOLOGY
Hyams grading system — The Hyams histologic grading system grades tumors from I to IV based upon pathologic features such as mitotic activity and necrosis [30].
●Grade I tumors are characterized by a prominent fibrillary matrix, tumor cells with uniform nuclei, absent mitotic activity, and absent necrosis.
●Grade II tumors have some fibrillary matrix and exhibit moderate nuclear pleomorphism with some mitotic activity. There is no necrosis.
●Grade III tumors have a minimal fibrillary matrix and Flexner type rosettes are present. There are more prominent mitotic activity and nuclear pleomorphism, and some necrosis may be seen.
●Grade IV tumors have no fibrillary matrix or rosettes and show marked nuclear pleomorphism and increased mitotic activity with frequent necrosis.
Most studies have found a correlation between Hyams grade and prognosis [17,22,30,31]. In a meta-analysis that included five studies in which lesions were graded histologically, the mean five-year survival was 56 percent for those with low-grade lesions (Hyams I and II) versus 20 percent for those with high-grade lesions (Hyams III and IV) [31]. However, a Surveillance, Epidemiology, and End Results (SEER) study of 281 patients treated from 1973 to 2010 showed that patients with grade I and II tumors had a 10-year overall survival rate of 67 percent and that those with high-grade tumors (III and IV) had a 10-year overall survival rate of 34 percent. For high-grade tumors, multivariate analysis showed that Kadish stage predicted for worse disease-specific survival and that radiation independently predicted for improved disease-specific survival [32].
Histopathology — On gross examination, biopsy material from olfactory neuroblastoma is soft and hemorrhagic. Resection specimens may show a polypoid appearance. Microscopically, the tumor grows beneath the surface respiratory epithelium and may produce focal ulceration. The vascular supply is rich and fragile, accounting for the hemorrhagic gross appearance.
In low-grade (Hyams grade I or II) lesions, the tumors display a lobulated growth pattern with nests of tumor cells and intervening septae containing supportive sustentacular cells as well as small blood vessels. Fibrillary stroma comprised of axonal processes is often abundant and is a useful clue to the diagnosis (picture 1) [30,33]. Cytologically, the tumor cells will contain finely granular cytoplasm. The nuclei are classically round with evenly dispersed, finely speckled chromatin and inconspicuous nucleoli.
With increasing Hyams grade, the tumors develop a more sheet-like growth pattern with attenuation or loss of the sustentacular cells, greater nuclear pleomorphism, increased mitotic activity, and necrosis.
Homer-Wright pseudorosettes, which are composed of tumor cells surrounding a core of pink fibrillary material, are seen in one-half of olfactory neuroblastomas; true (Flexner type) rosettes, composed of tumor cells surrounding a central lumen, may be seen in higher-grade tumors.
Molecular findings — Comprehensive genetic profiling studies suggest that olfactory neuroblastoma is a genetically heterogeneous entity. While high frequency recurrent somatic mutations are uncommon, significant subsets of cases have been found to harbor mutations involving TP53, PIK3CA, NF1, and CDKN2A [34]. FGFR3 and CCND1 copy number alterations or amplifications have also been described in a significant minority of cases [35].
In a DNA methylation study of 66 cases, four discrete subgroups were identified. The largest group (42 cases) showed low methylation and corresponded to cases with classic, often low-grade, morphology. A second small group (four cases) was found to have increased global methylation without CpG island methylation and also corresponded to classic cases of olfactory neuroblastoma, often low grade. A third group (seven cases) demonstrated increased global as well as CpG island methylation with IDH2 point mutations. These tumors were found to have a similar methylation profile as the subset of sinonasal undifferentiated carcinomas (SNUC) harboring IDH2 point mutations. Tumors in this group were more likely to be high grade with variant morphology and display aberrant immunohistochemical findings. A fourth group (13 cases) contained tumors with a heterogenous pattern of methylation that was similar to various poorly differentiated tumors (eg, adenocarcinoma, squamous cell carcinoma) within the sinonasal tract. This subset of tumors was often high grade and displayed immunohistochemical evidence of epithelial differentiation [36].
Differential diagnosis — While low-grade olfactory neuroblastoma is apparent histologically, high-grade forms often require additional evaluation to refine the differential diagnosis, which includes neuroendocrine carcinoma, SNUC, melanoma, Ewing sarcoma, and metastatic tumors [37]. Misdiagnosis of "small blue cell" tumors occurs frequently and confounds the medical literature. In a series of 12 consecutive patients referred to a cancer center with a histologic diagnosis of olfactory neuroblastoma, 10 patients (83 percent) were misdiagnosed [38]. Distinguishing among these tumors may have therapeutic significance, since the biological behavior and prognosis may differ.
Immunohistochemistry is an important adjunct in the diagnosis of olfactory neuroblastoma. The tumor cells are typically highlighted by stains for Calretinin [39] as well as neuroendocrine markers (CD56, chromogranin, synaptophysin), while the sustentacular cells are immunoreactive for Sox10 and S100. In typical cases, stains for pancytokeratins (intermediate filaments associated with epithelial differentiation) are negative.
Tumors most commonly confused with olfactory neuroblastoma include:
●Sinonasal undifferentiated carcinoma – SNUC is an aggressive neoplasm that is derived from Schneiderian epithelium. It is composed of medium-sized, polygonal cells with round to oval hyperchromatic nuclei and a scant to moderate amount of eosinophilic cytoplasm. Tumor cells are arranged in nests, wide trabeculae, ribbons, and sheets, with surface dysplasia. Mitoses, necrosis, and vascular invasion are often present [40-42]. SNUC enters into the differential diagnosis of high-grade olfactory neuroblastoma, but in contrast to olfactory neuroblastoma, neurofibrillary stroma and pseudorosettes are absent, and the tumor cells will show evidence of epithelial differentiation by cytokeratin immunochemistry [41]. In cases of Hyams grade IV olfactory neuroblastoma, this distinction may be difficult, particularly in cases with aberrant cytokeratin expression. (See "Pathology of head and neck neoplasms", section on 'Sinonasal undifferentiated carcinoma'.)
Subsets of SNUC as well as high-grade olfactory neuroblastoma, sinonasal adenocarcinoma, and high-grade neuroendocrine carcinoma harboring IDH2 R172 point mutations have been identified. As such, significant biologic overlap between these entities exists, and their distinction in some cases may be arbitrary and irreproducible [43].
●Ewing sarcoma – Ewing sarcoma and related primitive neuroectodermal tumors (PNET) are characterized by the chromosomal translocation t(11;22) (q24;q12) [44]. In addition, Ewing sarcoma is MIC2 (CD99) positive. In one study of 69 round cell lesions of the sinonasal region (22 olfactory neuroblastomas, 17 malignant lymphomas, 9 Ewing sarcomas, 9 rhabdomyosarcomas, 3 SNUCs, 5 melanomas, and 4 pituitary adenomas), each of the cases of Ewing sarcoma was positive for MIC2; all other tumors were MIC2 negative [45]. Olfactory neuroblastomas also lack the t(11;22) translocation typically found in Ewing sarcoma [46]. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)
●Large cell neuroendocrine carcinoma – The distinction between high-grade olfactory neuroblastoma and large cell neuroendocrine carcinoma may be difficult as the morphologic overlap may be considerable. Histologically, these are both high-grade lesions. Neuroendocrine carcinoma more typically grows in irregular nests and sheets, exhibiting brisk mitotic activity and frequent necrosis. A lobular growth pattern is absent. The stroma is desmoplastic and fibrotic, without any fibrillary quality apparent histologically. Artifactual cytologic "crush" effect may be present.
Similar to olfactory neuroblastoma, large cell neuroendocrine carcinoma will label immunohistochemically with neuroendocrine markers (CD56, chromogranin, synaptophysin). In contrast to classic cases of olfactory neuroblastoma, immunohistochemical cytokeratin expression is typically seen and no evidence of sustentacular cells is present. As previously mentioned, some cases of both olfactory neuroblastoma as well as large cell neuroendocrine carcinoma have been found to harbor IDH2 point mutations and may represent a "grey zone" between these two entities [43].
TREATMENT — Surgery, radiation therapy (RT), and/or chemotherapy are all used in the treatment of olfactory neuroblastomas [47]. The optimal treatment paradigm has not been established in randomized clinical trials; observational studies generally have limited numbers of patients due to the rarity of this disease. Furthermore, the natural history of the disease necessitates prolonged observation to adequately assess the results of treatment [48]. There are limited data regarding genetic and molecular alterations in olfactory neuroblastoma to guide therapeutic decisions [34,35,49,50].
Primary tumor
Surgery — Surgery alone for the initial management of patients with an olfactory neuroblastoma is generally restricted to carefully selected patients with early stage (Kadish stage A) and low Hyams grade (I or II) disease because of the poor prognostic discrimination of available staging systems [19], the high risk of local recurrence, and the better results of a combined-modality approach that includes RT. (See 'Surgery plus RT' below.)
Multiple factors may be considered in choosing the optimal surgical approach, including tumor extent, patient comorbidities, reconstruction options, morbidity of surgery, and experience of the surgical team. Morbidities of surgical approaches can differ and should be considered in choosing the best surgical technique. Nonrandomized studies suggest equivalent disease-free survival with different surgical approaches as long as complete excision is achieved [51,52].
●Combined craniofacial versus transfacial approach – Surgical resection of olfactory neuroblastomas originally used a transfacial approach. However, multiple observational studies found that a combined craniofacial approach improved the ability to achieve an en bloc resection and resulted in better local control of disease and improved survival compared with a transfacial approach [17,31,47,53].
●Endoscopic versus open surgery – Advances in surgical techniques have led to the development of a minimally invasive endoscopic approach in carefully selected patients as a way to minimize complications and improve the cosmetic outcome [51,54-60]. A meta-analysis of olfactory neuroblastoma that included 361 patients in 23 published studies demonstrated a better survival rate for endoscopic surgery compared with open surgery, even when taking into account the year of publication [61]. Although the patient groups had similar follow-up, patients treated with endoscopic surgery had earlier-stage tumors, suggesting a selection bias. Another systematic review of 36 studies including 609 patients demonstrated that endoscopic surgery was associated with improved overall and disease-specific survival [52]. For patients with advanced Kadish stage (C/D), however, no difference in disease-free survival was detected. For patients with higher Hyams grade, endoscopic surgery was associated with superior overall and disease-specific survival. The availability and preference of surgical approach vary between institutions. An endoscopic surgical technique may be combined with a neurosurgical approach for the intracranial component of disease, or with RT.
●Extent of surgery – The extent of surgery may vary depending on tumor stage. Although superior outcomes have generally been observed with craniofacial resection (removal of mucosa, bone of the anterior cranial base, dura, and olfactory bulbs), lesser surgery (extradural resection with preservation of dura and olfactory bulbs) has been proposed for early stage (Kadish A/B) tumors with low Hyams grade as long as resection margins are negative [62]. Although attempts have been made to preserve olfactory function by performing a unilateral resection in patients with unilateral disease, this remains controversial, and there are insufficient data to make any conclusions [63].
Radiation therapy — Radiation therapy (RT) alone has been used for the initial treatment of patients with olfactory neuroblastoma in a number of series, but results have generally been less satisfactory than when RT is used in combination with surgery. RT alone is reserved for patients who are poor surgical candidates, and may include intensity-modulated radiation therapy (IMRT) or proton beam therapy.
A review of the literature identified 55 cases of olfactory neuroblastoma treated with RT alone [64]. Treatment was successful in preventing disease recurrence in all six cases with Kadish stage A disease at a median follow-up of over eight years. However, for patients with more extensive disease (Kadish stage B and C disease), treatment was successful in only 7 of 12 (58 percent) and 7 of 37 (19 percent) cases, respectively.
Highly conformal techniques, such as IMRT and proton beam therapy, are now standard to minimize toxicity to adjacent critical structures (retina, optic nerve, optic chiasm, brain stem and brain) [65]. Proton beam therapy has been utilized to reduce the dose of radiation to critical organs, and to reduce the integral dose to the region and, thus, further reduce toxicity, including radiation-induced malignancies [66-68]. There will likely never be prospective clinical trials comparing outcomes with proton beam therapy with outcomes with IMRT due to the rarity of olfactory neuroblastoma.
Proton beam therapy is also being studied as a way to escalate dose and, thus, improve tumor control, particularly in patients with positive margins or unresectable disease [69]. A systematic review and meta-analysis comparing clinical outcomes with charged particle therapy and conventional photon therapy in patients with malignant tumors of the nasal cavity and paranasal sinuses, including olfactory neuroblastoma, revealed significantly higher disease-free survival at five years (relative risk 1.44, 95% CI 1.01-2.05) and locoregional tumor control at longest follow-up (relative risk 1.26, 95% CI 1.05-1.51) with the use of proton beam therapy compared with IMRT [70]. However, there was greater neurological toxicity in patients receiving charged-particle therapy compared with photon therapy.
Proton beam therapy may be especially important in children with developing bone, soft tissue, and neurological structures, although olfactory neuroblastomas are extremely rare in this patient population [69]. (See 'Pediatric cases' below.)
Stereotactic radiosurgery has been used to treat recurrent disease. In one report of 31 locally recurrent tumors, 36-month tumor control was 89 percent with stereotactic radiosurgery [71].
Further details on the use of RT in head and neck cancer are discussed separately. (See "General principles of radiation therapy for head and neck cancer".)
Surgery plus RT — Observational studies generally indicate that the combination of surgery and radiation therapy (RT) improves disease-free and overall survival compared with either surgery or RT alone [31,72-74]. This combined modality approach is particularly important for patients with disease extending beyond the paranasal sinuses (Kadish stage C (table 1)) or those with positive surgical resection margins.
●For patients treated using combined modality therapy, the choice of surgical approach depends upon the size and extent of the primary tumor.
•Kadish stage A and B – Patients with Kadish stage A and B are typically offered endoscopic endonasal resection of the anterior cranial base.
•Kadish stage C – Patients with stage C disease are typically offered a combined approach of endoscopic and craniofacial resection; however, given data suggest equivalent outcomes as long as complete excision is achieved, the preference for surgical approach (endoscopic versus transcranial/transfacial approaches) varies between institutions and is dependent upon the experience of the surgical team [51].
Previously, a combined otolaryngologic and neurosurgical anterior craniofacial resection followed by postoperative RT was the most widely used approach for patients with localized olfactory neuroblastoma [4,31,47,75-78]. (See 'Surgery' above.)
●For those receiving postoperative RT, we suggest a minimum RT dose of at least 54 Gy in 30 treatments over six weeks [79,80].
Data supporting this approach are as follows:
●This combined modality approach is supported by a literature review and meta-analysis that included 390 patients from 26 studies published between 1990 and 2000 [31]. Among the 169 patients treated with a combination of surgery and RT, the reported five-year survival was 65 percent, whereas the reported five-year survival rates for the 87 patients treated with surgery alone and the 49 patients treated with radiation alone were 48 and 37 percent, respectively. Similar added benefit of RT over surgery alone was shown for high-grade tumors in a Surveillance, Epidemiology, and End Results (SEER) study of 281 patients treated from 1973 to 2010 [74].
●In one single-institution series, 70 patients were treated for olfactory neuroblastoma, including 77 percent with T3 or T4 disease and 38 percent with Kadish C or D disease [81]. Ninety percent had surgery as part of therapy, and 66 percent received postoperative RT alone or combined with neoadjuvant or adjuvant chemotherapy. The median follow-up was 7.6 years. Recurrent disease developed in 46 percent, and the median time to recurrence was 6.9 years. Patients with T3 or T4 disease treated with surgery alone had a median disease-specific survival of 88 months, whereas those who were treated with surgery and postoperative RT or chemoradiotherapy had a median survival of 219 months.
●In a single-institution series of 30 cases managed predominantly with craniofacial resection and postoperative RT, there were no recurrences in the 11 patients with Kadish A or B disease [75]. Among the 19 cases with Kadish C olfactory neuroblastomas, 9 patients eventually recurred; the 5- and 10-year relapse-free survival rates were 61 and 0 percent, respectively, although the 10-year overall survival rate was 74 percent, emphasizing both the high rate of late relapse in this subset of patients and the ability to salvage both local and regional relapses.
●In another series of 10 patients managed with craniofacial resection and postoperative proton beam RT, all 5 patients with negative resection margins remained free of disease [47]. However, four of the five patients with positive margins eventually recurred, including three after a disease-free interval of more than five years.
Chemotherapy — The role of chemotherapy (either before or after RT or surgery; or concurrently with RT) is not established. Numerous studies have evaluated various chemotherapy regimens in an effort to improve outcomes [82-90]. However, it is unclear whether this actually improves results compared with a combined craniofacial resection and RT [89]. In one study of 11 children, 10 received chemotherapy prior to local therapy, with a five-year overall survival in the group of 91 percent [91].
Management of the neck
Incidence — The cervical lymph nodes are the most frequent site of disseminated disease in patients with olfactory neuroblastoma. The incidence of cervical metastases at presentation is overall low (<10 percent) [51]. In a review of the SEER registry, the overall rate of cervical lymph node metastasis was approximately 9 percent [3]. In a retrospective review with long-term follow-up, 7 percent of patients presented with primary cervical metastases, and an additional 9 percent of patients developed delayed cervical metastases [92], which are frequently associated with failure at other sites [93,94].
Treatment approach — For patients who present with clinical or radiographic evidence of cervical lymph node metastases, treatment is typically surgical resection, with adjuvant RT as clinically indicated using an approach similar to other head and neck cancers. Patients with cervical lymph node metastases at diagnosis are at higher risk for distant metastatic disease and have a significantly worse prognosis than those without neck metastases (five-year survival 29 versus 64 percent), providing a rationale for this approach [3,95]. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)
For patients who present without lymph node involvement, the optimal treatment approach is uncertain even for those at high risk for developing disseminated disease. There are no clinical trials that directly compare elective treatment versus observation with salvage therapy for those who do relapse.
●Some experts advocate elective treatment of the neck with RT or selective lymphadenectomy, particularly in those at high risk of developing disseminated disease (Kadish stage C disease or Hyams grade III or IV disease). In one consensus statement based on a systematic review of the literature, for those patients with high-grade tumors and advanced local stage (dural invasion), elective treatment of the N0 neck was suggested to prevent long-term regional recurrence [51]. The rationale for immediate treatment is that this may represent the best opportunity to successfully control tumor [74,81,93].
●Other experts offer patients observation, with salvage surgery and/or RT if there is an isolated, delayed cervical lymph node metastasis. This approach is based upon the relatively low risk of developing isolated, delayed cervical lymph node metastases, improved screening with positron emission tomography (PET) scans, the ability to successfully treat many of these patients with salvage therapy (70 percent in the Mayo Clinic series), and the significant toxicity associated with elective cervical nodal RT [86,94]. Additionally, while elective neck irradiation can reduce the risk of locoregional nodal disease, it does not necessarily improve survival.
In patients with isolated neck recurrences, multimodality treatment (which includes surgery, RT, and chemotherapy) is of clinical benefit [94,96].
Systemic disease — The rarity of olfactory neuroblastomas, combined with the favorable prognosis following aggressive local and regional therapy, has resulted in only very limited experience for patients with disseminated disease. Cytotoxic chemotherapy appears to have activity in some patients, and newer molecularly targeted approaches may become an option as the biology of olfactory neuroblastomas is better understood.
In a systematic review and meta-analysis of 678 patients, 12 percent developed distant metastatic disease following initial definitive curative treatment of the primary tumor. The median time to the development of distant metastatic disease was 15 months and occurred as late as 276 months. The most common site of distant metastasis was bone (40 percent), followed by drop spinal metastasis (29 percent) and lungs (29 percent).
The distant metastasis-free survival varied by definitive treatment modality and Kadish stage. The six-month overall survival after the diagnosis of distant metastases was 63 percent. Overall survival was better for patients with drop metastases to the spinal cord, and patients with metastases to visceral organs had the worst overall survival. Patients treated aggressively for distant metastatic disease (using chemotherapy with surgery and/or RT) had a two-year overall survival of 63 percent [97].
Cytotoxic chemotherapy — There are limited data to recommend any specific chemotherapy regimen, given the rarity of this disease; such patients should be enrolled in clinical protocols whenever feasible.
A variety of chemotherapy agents have been evaluated in small series. These reports have included a mixture of patients with disseminated disease and with locoregional disease where chemotherapy was used alone or in combination with surgery and/or RT. Cisplatin-based combination regimens (particularly cisplatin and etoposide) have often been chosen, primarily because of their activity in patients with small cell lung cancer or related neuroendocrine-type tumors [98-108]. Non-platinum regimens, such as irinotecan plus docetaxel, or doxorubicin, ifosfamide, and vincristine, and temozolomide may also be active [107-109]. Responses in patients with disseminated disease have generally been of short duration. In patients with distant metastases, the addition of chemotherapy to surgery (with or without RT) was associated with improved overall survival [97].
Molecularly targeted therapy — An understanding of the molecular pathogenesis of olfactory neuroblastomas may lead to the use of targeted therapies in patients with advanced disease, although these approaches remain investigational.
●In one case report, treatment of a patient with advanced olfactory neuroblastoma using sunitinib resulted in stabilization of disease for 15 months after progression following maximal surgery and RT [110]. Immunohistochemistry of a tumor biopsy revealed expression of platelet-derived growth factor.
●Signaling in the sonic hedgehog pathway has been associated with tumor cell growth in patients with nevoid basal cell carcinoma and some other tumors. In at least one report, key genes in this pathway were activated in olfactory neuroblastoma cell lines but not in normal olfactory epithelium [111]. If this observation is confirmed, this may offer another target for specific therapy. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
Several studies have characterized additional mutations and alterations in additional pathways, which may lead to additional treatment options [34,35,50], including FGFR3 amplifications and alterations of PIK3CA, NF1, CDKN2A, CDKN2C, and other genes.
Radiation therapy — The approach to radiation therapy (RT) for brain, bone, and other visceral metastases in patients with olfactory neuroblastoma is similar to those used for other malignancies [104]. These treatment approaches are discussed separately. (See "Overview of the treatment of brain metastases" and "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors", section on 'Radiation therapy'.)
Peptide receptor radioligand therapy — The use of peptide receptor radioligand therapy (PRRT) in patients with metastatic olfactory neuroblastoma remains investigational. Limited case reports suggest that PRRT (which targets the somatostatin receptor) has efficacy in patients with recurrent or metastatic olfactory neuroblastoma, including those with heavily pretreated disease [112-115].
The use of PRRT in other malignancies (eg, neuroendocrine tumors) is discussed separately. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand therapy' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin receptor-expressing tumors'.)
Pediatric cases — Although olfactory neuroblastoma is more common in adults, it can also occur in children and adolescents. Such patients should be managed at an institution with multidisciplinary experience treating olfactory neuroblastoma. (See 'Clinical manifestations' above.)
For pediatric patients with olfactory neuroblastoma who present with advanced tumors, induction chemotherapy prior to surgery and RT has been recommended, as these patients have high observed response rates and long-term survival with this approach. In a review of 24 patients with pediatric olfactory neuroblastoma, neoadjuvant chemotherapy was administered to 13 patients with an 84 percent response rate [116]. A gross total resection was achieved in eight patients with primary surgery and four patients following neoadjuvant chemotherapy. Eighty-eight percent of patients received RT. Five-year disease-free survival of the entire group was 73 percent. In another study of 11 children treated with initial chemotherapy followed by surgery and then RT, five-year overall survival was 91 percent [91].
The use of RT in pediatric patients can induce late toxicities, particularly near sensitive neurological and bony structures that may not have reached full development. As an example, one study of eight patients treated with proton therapy demonstrated a four-year overall survival rate of 88 percent [69]. However, four patients had late radiation-related toxicities, including endocrine dysfunction, retinopathy, and optic neuropathy due to dose escalation.
Prognosis — The prognosis for patients with olfactory neuroblastoma is influenced both by the extent of disease and the pathologic grade. Patient age may also be a prognostic factor independent of tumor stage or treatment [117].
In a National Cancer Database (NCDB) analysis of 1167 patients, 34 percent of patients had Kadish stage A or B disease, while 53 percent had stage C and 8 percent had stage D disease [16]. The five-year overall survival rate for the entire series was 77 percent; for patients with Kadish stages A, B, C, and D, the five-year survival rates were 80, 88, 77, and 50 percent, respectively. Although there was a slight bias in terms of treating Kadish stage B patients, as 15 percent more received RT than stage A patients, this was not enough to account for the difference in survival between these two groups. One study of the NCDB comparing the Kadish; tumor, node, metastasis (TNM); and modified Dulguerov systems showed no difference in survival prediction with the three systems [19].
Data suggest a poorer prognosis in those with higher Hyams grade tumors [31,71,74,118]. A meta-analysis of the published literature from 1983 to 2018 looked at Hyams grade as a predictor of metastasis and overall survival [118]. The analysis included 525 patients for tumor metastases and 563 patients for overall survival. Neck metastasis was observed in 18 percent of high-grade Hyams and 8 percent of low-grade Hyams patients. Distant metastasis was noted in 21 percent of high-grade Hyams versus 9 percent of low-grade Hyams patients. Low-grade Hyams patients had 5- and 10-year overall survival rates of 81 and 64 percent, respectively, as compared with 61 and 41 percent, respectively, for high-grade Hyams patients. Taken as a whole, these data may imply that Hyams grade, when available, is more prognostic that Kadish stage, although Kadish stage may have prognostic relevance in high-grade Hyams tumors.
POSTTREATMENT SURVEILLANCE — There are no formal guidelines for appropriate follow-up after treatment for olfactory neuroblastoma. Extended clinical and imaging follow-up is indicated [4,47,75,76,119]. Approximately 10 to 20 percent of patients may experience local or regional recurrence for at least 10 years after initial therapy [119], and treatment of recurrences is associated with prolonged disease-free survival.
For posttreatment surveillance, we offer baseline magnetic resonance imaging (MRI) of the brain with attention to the face (for maxillofacial imaging of the nasal cavity and paranasal sinuses) and skull base at two to three months after treatment completion. MRI is then repeated at six-month intervals for approximately two years, followed by yearly examinations until five years after completing treatment. Positron emission tomography/computed tomography (PET/CT) and/or somatostatin receptor-based imaging (SRI) with either indium in-111 pentetreotide (OctreoScan) or gallium Ga-68 DOTATATE PET-CT may also be offered for detection of occult regional and distant metastases and for evaluation of marginally enlarged cervical lymph nodes. Clinical follow-up should continue beyond five years, with consideration of additional imaging in high-risk patients.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)
SUMMARY AND RECOMMENDATIONS
●Olfactory neuroblastoma, also known as esthesioneuroblastoma, is a neuroectodermal malignancy of the nasal cavity, which usually presents with locally invasive disease. Olfactory neuroblastomas have a marked tendency for late local and regional recurrences. (See 'Clinical manifestations' above.)
●For patients with locoregional disease, surgery has a primary role in the management of these patients, and the best results are associated with a combination of surgery and radiation therapy (RT). There are limited data for chemotherapy as part of planned multimodality therapy for initial treatment. (See 'Chemotherapy' above.)
•For select patients with Kadish stage A (table 1) and low Hyams grade (I or II) tumor, we suggest surgical excision as a single modality rather than surgery plus RT (Grade 2C). Endoscopic endonasal surgery is preferred for such early-stage tumors, with surgery limited to an extradural resection in selected cases. (See 'Surgery' above.)
•For patients with Kadish B and C primary tumors or advanced Hyams grade (III or IV), we suggest a combination of surgery and RT (Grade 2C). (See 'Surgery plus RT' above.)
-Patients with Kadish stage B tumors, are typically treated with endoscopic endonasal surgery due to less morbidity and equivalent oncologic outcomes.
-Patients with Kadish stage C tumors are typically treated using a combined approach of endoscopic and craniofacial resection. However, preference for surgical technique varies between institutions and is dependent on the experience of the surgical team.
●RT alone is reserved for patients who are poor surgical candidates, and it may include intensity-modulated radiation therapy (IMRT) or proton beam therapy. (See 'Radiation therapy' above.)
●For pediatric patients with olfactory neuroblastoma who present with advanced tumors, we offer induction chemotherapy prior to surgery and RT, as these patients have high observed response rates to induction chemotherapy. (See 'Pediatric cases' above.)
●Patients with olfactory neuroblastoma may develop recurrences 10 or more years following initial treatment. Thus, prolonged surveillance for evidence of local or regional recurrence is indicated. (See 'Posttreatment surveillance' above.)
•Aggressive local therapy with surgery and/or RT is indicated for patients with local recurrence without distant metastases, since a significant number of such patients may have prolonged disease-free survival.
•Surgery with or without RT is indicated for patients with cervical lymph node recurrence. Aggressive therapy in this setting can result in prolonged disease-free survival in some patients. (See 'Management of the neck' above.)
●Systemic treatment may provide clinically useful palliation of patients with advanced olfactory neuroblastoma who are not candidates for definitive surgery or RT. There are limited data to recommend any specific chemotherapy regimen; such patients should be enrolled in clinical protocols whenever feasible. (See 'Cytotoxic chemotherapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Derrick Lin, MD, Bruce E Brockstein, MD, and Jerome B Taxy, MD, who contributed to earlier versions of this topic review.
