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Olfactory Nerve Schwannoma: a case series with a systematic review of the literature focusing risk factors, etiology, clinical presentation, and management

  • Nazmin Ahmed , Gianluca Scalia , Giuseppe E. Umana , Sruthi Ranganathan , Samsul Arifin , Md Isma Azam , Mohammad Morshad Alam , Mohammed A. Azab , Minaam Farooq , Daniel Encarnacion-Santos , Bashir Ahammed , Oday Atallah and Bipin Chaurasia EMAIL logo
Published/Copyright: April 24, 2024
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Oncologie
From the journal Oncologie Volume 26 Issue 3

Abstract

Objective

Olfactory Nerve Schwannomas (ONS) affect cranial nerve I (CN I), responsible for the sense of smell. This systematic review aims to comprehensively examine the risk factors, etiology, clinical presentation, and management of ONS by analyzing 44 case reports/series published from 1978 to 2022.

Methods

Our systematic review utilized a comprehensive search strategy across various scientific databases, including PubMed, Scopus, and Web of Science in March 2023. The inclusion and exclusion criteria included minimum information on demographics (i.e., age), clinical presentation, syndrome, area involved, and extent of resection. The selected articles were case reports, so there is no question about bias. Articles were meticulously reviewed for the above information and underwent both qualitative and quantitative analysis.

Results

A total of 44 case reports/series, consisting of 45 patients, were included in this study (mean: 38.45). The anterior cranial fossa was the most frequently involved area (48 %). The most common surgical procedure was bifrontal craniotomy (n=16), followed by left frontal craniotomy (n=7). Approximately 95.5 % of patients underwent Gross Total Resection (GTR), while 4.5 % had Subtotal Resection (STR). Radiotherapy was applied to two patients. Olfactory function varied, with 35.5 % preserving it and 28.88 % experiencing damage or loss. Positive outcomes were observed in approximately 66.6 % of cases, with complications reported in 15 % of instances, including cerebrospinal fluid (CSF) rhinorrhea and diplopia.

Conclusions

Long-term follow-up and regular screening of patients are imperative. Further research is essential to elucidate the precise pathogenesis and to develop improved treatment modalities for ONS. This review provides a comprehensive overview of the current state of knowledge regarding ONS; however, as the disease is very rare, only case reports are available as a primary study, making it difficult to reach a strong conclusion.

Keywords: Olfactory Nerve Schwannoma; risk factors; etiology; clinical presentation; management

Introduction

Schwannomas are the most common benign, slow-growing nerve sheath tumors of peripheral nerves, including cranial nerves. They originate from Schwann cells, and the World Health Organization (WHO) classifies them as grade 1 tumors. Schwannomas can develop in any part of the nervous system containing Schwann cells [1, 2]. They are also known as neurinomas and neurilemmomas, and they offer a high chance of curative surgery. Schwannomas account for approximately 6–8 % of all intracranial tumors and are most frequently found in the posterior fossa of the brain. Only 1 % of Schwannomas progress to neurofibrosarcoma, a rare and serious form of cancer. Due to their encapsulated nature, surgical removal is often successful [3, 4]. Schwannomas can also occur outside of the cranial nerves, particularly on the flexor surfaces of the limbs [5].

The vestibular division of the VIII cranial nerve is where Schwannomas most commonly develop. Schwannomas and neurofibromatosis type II can both be caused by mutations that disrupt the function of the merlin protein. Schwannomas are S-100-positive, a characteristic of cells derived from neural crest cells. Olfactory Nerve Schwannomas (ONS) affect cranial nerve I (CN I), responsible for the sense of smell. The olfactory and optic nerves, lacking a Schwann cell layer, are unlikely to develop Schwannomas [6], [7], [8]. As the olfactory and optic nerves lack Schwann cells, Schwannomas theoretically cannot arise in these locations, raising questions about the true pathogenesis of this tumor [8].

Schwannomas typically affect older individuals, most commonly between the ages of 50 and 60, with no evidence of racial or gender preference [9, 10]. The rates are similar between males and females, with a higher incidence among Caucasians compared to non-Caucasians [10], [11], [12], [13]. While no confirmed causative factors have been identified for ONS, some environmental, genetic, and occupational factors have been implicated in Schwannoma development. Therefore, through this review, we have presented the risk factors for the development of ONS, their etiology, clinical presentation, and management strategies, thus enabling us to provide evidence-based recommendations for experts and significantly improve the management strategy.

Methods

A systematic search was performed across reputable academic databases, including PubMed, Scopus, and Web of Science. A combination of Mesh terms was used, including “Olfactory Nerve Schwannoma,” “Cranial Nerve I,” “Risk Factors,” “Etiology,” “Clinical Presentation,” and “Management,” to ensure the relevance and quality of the included studies. The search was conducted by two researchers of the team who independently carried out the entire procedure. Subsequently, the results were cross-checked by another member to control for bias. Case reports related to ONS published between 1978 and 2022 were considered for inclusion in this review. This extensive timeframe was chosen to provide a comprehensive overview of the existing literature on ONS. Data extraction was meticulously carried out, covering a range of key parameters, including patient demographics, clinical presentation, imaging findings, treatment modalities employed, and outcomes. The inclusion and exclusion criteria encompassed the minimum information on demographics (i.e., age), clinical presentation, syndrome, area involved, and extent of resection. This structured approach facilitated the systematic organization of data for analysis. The data collected were meticulously organized and synthesized by three researchers of the team, which involved creating tables to effectively present the findings. Both qualitative and quantitative analyses were conducted. The presentation of results followed the guidelines set out by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [14]. This included the construction of a study flow diagram to illustrate the study selection process and the presentation of structured findings (Figure 1). To ensure the review’s credibility and consistency, it was conducted by at least two independent reviewers who engaged in cross-reviewing to maintain rigor. This comprehensive methodology ensured a systematic and thorough exploration of the topic, enabling the synthesis of a comprehensive overview of ONS based on the findings of 44 case reports (Table 1).

Figure 1: Identification of studies via databases and registers.
Figure 1:

Identification of studies via databases and registers.

Table 1:

Reported cases of Olfactory Nerve Schwannoma and their management.

SI Author and year Pt Age Sex Syndrome Area involved Surgery Endoscopic approach Extent of resection Other therapies Reconstructio n of skull base Olfactory function Outcome
1 Ulrich et al. 1978 [15] 1 19 M Epilesy, partially blind, anosmia, diminished corneal reflex, hypesthenia Right anterior cranial fossa Right frontal craniotomy – GTR None NM NM Ocassional epileptic fit 3 years after operation. Visual field mildly improved.
2 Vassilouthis et al. 1980 [16] 1 17 M Pyrexia, headaches, nausea, confusion, and drowsiness Anterior cranial fossa Left frontal craniotomy – GTR None NM NM Less euphoric, no other neurological signs at 7th POD
3 Sato et al. 1985 [17] 1 23 M Convulsion Left anterior cranial fossa Subfrontal craniotomy – GTR None NM NM NM
4 Nagao et al. 1991 [18] 1 63 F Recent memory disturbed Anterior cranial fossa Left frontal craniotomy – GTR None NM NM NM
5 Bando et al. 1992 [4] 1 55 F Anosmia, impaired vision, and concentric contraction of visual field Anterior cranial fossa, nasal cavity, ethmoid sinus, and anterior skull base Bifrontal craniotomy – GTR None Dural allograft, pericranium Destroyed Uneventful
6 Takanobu et al. 1992 [19] 1 33 F None Anterior cranial fossa, left olfactory groove, ethmoidal sinus Bifrontal craniotomy – GTR None Inner table of frontal bone, dura, pericranium Preserved Patient developed bacterial meningitis which improved with antibiotics. Emotional lability lasted for 1 week
7 Sabel et al. 1995 [20] 1 17 M Convulsion, apathetic and drowsy Anterior cranial fossa Left fronto-temporal craniotomy – GTR None NM Destroyed The patient was well at 2 year F/U with no evidence of recurrence
8 Boyd et al. 1997 [10] 1 29 F Convulsion, headache, hyposmia Anterior cranial fossa. Cribriform plate, ethmoid air cell, nasofrontal duct Bifrontal craniotomy – GTR None Pericranium Destroyed Developed transient hemiparesis but improved at 3rd POD, no recurrence at 3 months F/U. Hyposmia persisted
9 Huang et al. 1997 [21] 1 33 M Headache, leathargy, LOC decreased eye vision Anterior cranial fossa Craniotomy – GTR None
10 Praharaj et al. 1999 [22] 1 45 M Headache, convulsion Right anterior cranial fossa Bifrontal craniotomy – GTR None NM Destroyed Postoperative CT scan demonstrated no residual of tumor
11 Gelabert et al. 2000 [23] 1 19 M Convulsion Left anterior cranial fossa, olfactory groove Left frontal craniotomy – GTR None
12 Tan et al. 2001 [24] 1 21 M Seizure, right lower limb monoparesis Anterior cranial fossa Subfrontal craniotomy – GTR None Autologous muscle, fascia and histoacry1 glue NM No recurrence at 12 months F/U
13 Tsai et al. 2001 [25] 1 31 F Headache, convulsion Anterior cranial fossa, olfactory groove Bifrontal craniotomy – GTR None NM Preserved No recurrence at 4 year F/U
14 Ramos Amador et al. 2002 [26] 1 24 F Hypoesthesia on the left side of face, impaired vision Anterior cranial fossa, left side of the cribriform plate Bifrontal craniotomy – GTR None NM NM NM
15 Carron et al. 2002 [27] 1 59 F Headache, rhinorrhea Anterior cranial fossa, cribriform plate, ethmoid sinus Bifrontal craniotomy Endoscopic transnasal biopsy GTR None Septal and turbinate flap, pericranium Destroyed CSF rhinorrhea, managed with lumbar drain for 5 days postoperatively
16 Prasad et al. 2004 [28] 1 19 M Anosmia, convulsion Anterior cranial fossa Frontoparietal craniotomy Colloidcyst resected by endoscope NTR Radiotherapy NM Preserved Patients tolerated radiotherapy with minimum side effects
17 Shenoy et al. 2004 [29] 1 55 M Seizure Anterior cranial fossa Left fronto-temporal craniotomy – GTR None NM Preserved NM
18 Yuen et al. 2004 [30] 1 33 F Seizure Right cribriform plate Right frontal craniotomy – GTR None NM NM NM
19 Murakami et al. 2004 [31] 1 30 M Headache Left anterior cranial fossa, cribriform plate Left frontal craniotomy – GTR None NM Preserved NM
20 Komoribayashi et al. 2005 [32] 1 38 F Seizure Left anterior cranial fossa Bifrontal craniotomy – GTR None NM NM NM
21 Yako et al. 2005 [33] 1 14 M Headache, vomiting, anosmia Anterior cranial fossa Bifrontal craniotomy and right orbital osteotomy – GTR None NM Destroyed Discharged with no new neurological deficit with no recurrence at 1 year F/U MRI
22 Adachi et al. 2007 [1] 1 49 F Seizure Left anterior cranial fossa, cribriform plate Left frontal craniotomy – GTR None NM Destroyed No recurrence in the 2 year F/U MRI
23 Daglioglu et al. 2008 [34] 1 21 M Psychotic behiviour, severe headache, bilateral papilloedema, spastic paraparesis Anterior cranial fossa, cribriform plate Bifrontal craniotomy – GTR None NM Preserved Developped seizure at 4th POD which was controlled with antiseizure medication. Neurologically improved significantly within 4 months of follow-up with no recurrence
24 Kanaan et al. 2008 [35] 1 14 M Personality changes, difficulty concentrating, headache, weight and taste loss Anterior fossa, left ethmoid sinus NM Endoscopic endonasal tumor biopsy followed by expanded endoscopic transplanum transcribriform approach NTR None Fat, dural substitute graft, septal mucosal flap NM Normal neurologialc function (with the exception of anosmia)
25 Rose et al. 2009 [36] 1 33 F Facial pain and nasal obstruction Frontal and sphenoid sinus, cribriform plate, ethmoid bone Bifrontal craniotomy Endoscopic endonasal approach GTR Radiotherapy with no success Preserved No recurrence at 12 months F/U.
26 Choi et al. 2009 [13] 1 39 F Headache, anosmia Right anterior cranial fossa, orbital wall, cribriform plate Bifrontal craniotomy – GTR None NM Improved No neurological deficit at 2 weeks F/U
27 Mirone et al. 2009 [37] 1 38 M Headache, drowsiness, amnesis Anterior cranial fossa, left cribiform plate Left frontal craniotomy – GTR None NM Preserved At follow-up, 18 months later, the patient remained well with no clinical or neuroradiological evidence of recurrence
28 Martínez-Soto et al. 2009 [38] 1 54 M Headache, dysphasia Anterior cranial fossa, cribiform plate Bifrontal craniotomy – GTR None Frontal periosteum NM Patient readmitted 1 month after the surgery due to CSF fistula which was managed with ventricular drainage followed by lumboperitoneal shunt
29 Figueiredo et al. 2009 [39] 1 49 M Headache, anosmia, optic atrophy Anterior cranial fossa, olfactory groove, ethmoid sinus Bifrontal craniotomy – GTR None Pediculate apneurosis Destroyed Developed CSF rhinorrhea and meningitis, treated with antibiotics and lumbar drain. Discharged with no additional neurological morbidity
30 Darie et al. 2010 [40] 1 28 F Complex partial seizures, emotional lability, anosmia Midline of anterior cranial fossa Left frontal craniotomy – GTR None Temporalis muscle flap, fibrin glue Preserved At one- and four-months follow-up, neurological examination was normal except for anosmia
31 Li et al. 2012 [41] 1 16 F Seizure Right anterior cranial fossa, olfactory groove, cribriform plate Right frontal craniotomy – GTR None NM Preserved Discharged 7 days after surgery without new neurologic deficits, and normal in follow-up visits.
32 Hayashi et al. 2013 [42] 1 39 F Hyposmia Left anterior cranial fossa Bifrontal craniotomy – GTR None NM Preserved No recurrence at 10 months F/U
33 Wang et al. 2014 [43] 1 38 F Intermittent vomiting, hyposmia Left anterior cranial fossa, ethmoidal sinus NM NM GTR None NM Destroyed Hyposmia persisted
34 Blake et al. 2014 [9] 1 38 NM None Left anterior cranial fossa, ethmoidal sinus NM NM GTR None NM NM NM
35 Kim et al. 2015 [44] 1 49 F Headache, nausea, vomiting Left anterior cranial fossa, cribriform plate Subfrontal craniotomy – GTR None NM Preserved No neurological deficit during discharge. No recurrence at 19 months F/U
36 Micovic et al. 2017 [45] 1 73 F Seizures, headache Right subfrontal region Subfrontal craniotomy – GTR None NM Preserved Patient was discharged with anosmia. On the follow-up examination after six months she regained olfaction.
37 Figueroa-Ángel et al. 2018 [46] 1 46 F Headache, tinnitus, vertigo right anterior cranial fossa, cribriform plate, right nasal cavity Bifrontal craniotomy – GTR None Bone fragment, scalp and tissue adhesive Destroyed No recurrence in follow up MRI
38 Taha et al. 2018 [47] 1 56 M Incidental finding during evaluation after RTA Right frontal intra- axial mass Right frontal craniotomy – GTR None No need of reconstruction, as mass was intra-axial Destroyed Anosmia, right optic atrophy and sixth nerve palsy persited postoperatively
39 Hadjigeorgiou et al. 2019 [48] 1 75 F Dementia including loss of orientation Right anterior cranial fossa, ethmoid sinus, nasal cavity Bilateral subfrontal approach – GTR None NM Preserved No tumor recurrence at 6 months F/U
40 Yoon et al. 2020 [49] 1 50 M Headaches, changes to personality, anosmia Anterior cranialfossa, cribriform plate Bifrontal craniotomy – GTR None NM NM NM
41 Benhoummad et al. 2021 [5] 1 33 NM Headache and left nasal obstruction Anterior cranial fossa, frontal and ethmoidal air sinus, left nasal cavity Transfacial; through a mid-frontal incision. Endoscopic endonasal approach GTR None Septal cartilage, fat graft, surgical, biological glue NM The patient did present a diplopia without any signs of meningitis or CSF rhinorrhea
42 Liao et al. 2021 [50] 1 55 F Right-sided rhinorrhea, epistaxis Right anterior nasal cavity NM Endoscopic endonasal approach GTR None NM Preserved No evidence of recurrence was observed.
43 Liu et al. 2022 [51] 2 55 M Left nasal obstruction, pain, and epiphora Left nasal cavity, ethmoid sinus, nasopharynx NM Endoscopic endonasal approach GTR None Vascularized mucosal flap of the nasal septum Preserved No recurrence was observed during the follow-up period of 19 months
44 Liu et al. 2022 [51] 50 F Nasal cavity obstruction, hyposmia, occasional ipsilateral hemorrhage, orbital swelling and pain, and nasal discharge Right nasal cavity, olfactory groove, cribriform plate NM Endoscopic endonasal approach GTR None Free flap of the middle turbinate Destroyed No recurrence was noted on CT, 6 months after the procedure.
45 Kasymov et al. 2022 [52] 1 55 M Impairment of smelling Anterior cranial fossa Left-sided lateral supraorbital craniotomy – GTR None NM Destroyed No recurrence was noted on MRI, 2 years after the procedure.

  1. NM, not mentioned; Pt, Patient.

Results

A total of 45 patients were included in this study (mean: 38.45) from 44 selected case reports/series, and their relevant characteristics were reported in Table 2. The median age, which represents the middle point when all ages are arranged in ascending order, is 33 years. While there is no specific mode (most frequently occurring age) as the ages vary, the standard deviation is approximately 16.7 years, indicating some variability in the ages of the patients. The dataset shows a gender distribution, with approximately 46.6 % of the patients being male and 48.8 % being female (Table 2).

Table 2:

Summary of demographics, clinical characteristics, and outcomes of Olfactory Nerve Schwannoma patients.

Category Description Percentage/value
Age Average age 38.4 years
Median age 33 years
Standard deviation 16.7 years
Gender ratio Male patients 46.6 %
Female patients 48.8 %
Common symptoms Seizures 36 %
Headaches 30 %
Olfactory disturbances 20 %
Visual disturbances 20 %
Confusion 20 %
Affected sites Anterior cranial fossa 48 %
Nasal cavity 15 %
Ethmoid sinus 15 %
Cribriform plate 15 %
Type of surgery Bifrontal craniotomy 35.5 %
Left frontal craniotomy 15.5 %
Extent of resection Gross total resection (GTR) 95.5 %
Subtotal resection (STR) 4.5 %
Olfactory function Preserved 35.5 %
Damaged or lost 28.8 %
Improved 2 %
Not specified 33.3 %
Outcome No recurrence 66.6 %
Complications (e.g., CSF rhinorrhea, diplopia) 15 %

ONS located solely in the nasal cavity is quite rare and can typically be distinguished from olfactory groove meningioma, hemangiopericytoma, esthesioneuroblastoma, and metastatic disease. Notably, while there was no evidence of nerve attachment during surgery, careful observation of the images from both patients revealed compression and thinning of the cribriform plate with local bone defects. In particular, Magnetic Resonance Imaging (MRI) commonly reveals a local intracranial protrusion of the tumor, suggesting the origin of the tumor. Very rarely, an intra-axial mass with a cystic component and perilesional edema, which mimic high-grade glioma, abscess, or metastasis. The most frequently involved area among the patients was the anterior cranial fossa, accounting for 48 % of cases. Other affected areas included the nasal cavity (15 %), ethmoid sinus (15 %), and cribriform plate (15 %). The most common surgical procedure was bifrontal craniotomy (n=16) followed by left frontal craniotomy (n=7). Approximately 95.5 % of patients underwent Gross Total Resection (GTR), while 4.5 % had Subtotal Resection (STR). Radiotherapy was applied to two patients. Among the patients, seizures were the most common symptom, occurring in approximately 36 % of cases. Other prevalent symptoms included headaches (30 %), olfactory disturbances (20 %), visual disturbances (20 %), and confusion (20 %). Olfactory function varied, with 35.5 % preserving it and 28.88 % experiencing damage or loss. Positive outcomes were observed in approximately 66.6 % of cases; however, it is important to note that some complications were reported, such as CSF rhinorrhea and diplopia, in some instances (15 %). A significant proportion of patients, approximately 95.5 %, underwent Gross Total Resection (GTR) of their tumors. About 4.5 % of cases underwent Subtotal Resection (STR) (Tables 1 and 2).

The risk factors and mechanism of ONS formation are not well discussed; in most cases, they are believed to result from sporadic mutations. The risk factors for ONS may include a family history of the tumor, the presence of neurofibromatosis type 2, and a genetic condition characterized by the formation of non-cancerous tumors that affect the nervous system. Despite the generally positive outcomes, there were instances of negative complications. One patient experienced occasional epileptic fits three years after the operation, although with a mild improvement in the visual field. Another patient exhibited less euphoria and no other neurological signs on the seventh postoperative day. Additionally, bacterial meningitis developed in one case, which improved with antibiotics; however, emotional lability persisted for a week. Another patient developed transient hemiparesis that improved by the third postoperative day, but hyposmia persisted at the three-month follow-up. CSF rhinorrhea occurred in two cases, one managed with a lumbar drain for five days postoperatively, and another with a seizure on the fourth postoperative day, controlled with antiseizure medication. Although most patients showed normal neurological function, anosmia persisted in several cases. Notably, some patients experienced anosmia and other complications postoperatively, but in a few instances, olfaction was regained after months. Additionally, some cases presented with persistent optic atrophy and sixth nerve palsy without evidence of recurrence (Table 2).

The blood supply is derived from the vessels through the cribriform plate. When the tumor becomes large enough, it can also recruit blood supply from falx. The left carotid angiography revealed that the tumor was supplied from the anterior ethmoidal artery. The left carotid artery angiogram showed a hyper-vascular mass mainly fed by the ethmoidal artery and partly by a few branches of both anterior cerebral arteries, which displaced the anterior cerebral arteries superiorly and posteriorly. Sometimes, an expanded corridor is needed for decompression. Kannan and his colleagues achieved near-total resection through an expanded endoscopic endonasal transplanum transcribriform approach, leaving a small part of the tumor that was adhered to the frontopolar branch of the anterior cerebral artery.

There is a shortage of epidemiological studies on ONS which leads to unclear results and sometimes missing information causing an obscure understanding of the condition and its management. The limited information on risk factors, postoperative complications, and incomplete description of surgical techniques hinder the ability to draw robust conclusions. Additionally, insufficient long-term follow-up and the absence of comparative analyses in reviewed case reports limit the assessment of treatment efficacy and the identification of prognostic factors.

Discussion

Etiology and risk factors

The exact cause and mechanism of ONS formation remain unknown. In most cases, they are believed to result from sporadic mutations. Since cranial nerves I and II (olfactory nerve and optic nerve, respectively) lack Schwann cells, questions arise regarding the cell of origin of Schwannomas in these locations. Most tumors are sporadic in nature, and no well-established predisposing factors have been observed. Risk factors for ONS may include a family history of the tumor, the presence of neurofibromatosis type 2, and genetic conditions characterized by non-cancerous tumor formation in the nervous system. Schwannomatosis, often seen in adults, can result in multiple Schwannomas. Gorlin-Koutlas syndrome is a complex genetic disorder associated with multiple tumors in the body, including multiple Schwannomas, and frequent exposure to ionizing and non-ionizing radiation [53], [54], [55]. Several factors have been identified as contributing to Schwannoma development: (a) Abnormalities in the gene(s) on chromosome 22. (b) Overproduction of Schwann cells enveloping the nerve. (c) Other genetic disorders, such as neurofibromatosis type 2 (NF2) and Gorlin-Koutlas syndrome, or a positive family history [56, 57].

Origin and pathophysiology

The olfactory and optic nerves are not susceptible to Schwannomas because they lack a Schwann cell coating. This raises questions about the true pathogenesis. To promote axonal growth, olfactory ensheathing cells (OECs) and Schwann cells both wrap unmyelinated axons of nerve fibers up to two exterior layers of the olfactory bulb [8, 20]. Two main hypotheses regarding the genesis of ONS are developmental and non-developmental origins. Developmental hypotheses speculate whether neural crest cells migrate within the central nervous system or mesenchymal pial cells transform into ectodermal Schwann cells. Non-developmental hypotheses propose that Schwann cells found in nearby structures like the perivascular nerve plexus, the meningeal branches of the trigeminal nerve, and the anterior ethmoidal nerves innervating the anterior cranial fossa and olfactory groove give rise to intracranial Schwannomas. Some researchers have concluded that the olfactory nerve contains Schwann cells originating from precursor cells found in the olfactory epithelium. The question of whether Schwann cells are present in the olfactory nerve remains a subject of debate. According to some authors, these tumors can develop from the unsheathing cells of the olfactory nerve and bulb, the embryonic terminal nerve, the nerve plexus of the dural vessels, or the fila olfactoria [58], [59], [60].

Symptomatology

The signs and symptoms of ONS may vary from one individual to another, with differences in the onset and progression of the tumor. Many individuals may have slow-growing tumors that remain asymptomatic and are only detected during radiological imaging studies of the head and neck region, often performed for unrelated health conditions. However, large tumors can cause significant signs and symptoms, sometimes accompanied by additional symptoms related to underlying conditions [61, 62]. Symptoms in individuals with ONS may include anosmia or hyposmia (most common), visual deficits, cognitive disturbances, seizures, rhinorrhea, headaches, motor and sensory dysfunction, intracranial hypertension, and sometimes may remain asymptomatic. Less common symptoms may encompass epilepsy, pyrexia, nausea, confusion, drowsiness, vomiting, epiphora, nasal discharge, among others. Additionally, facial droop and altered touch sensation on the face (facial paresthesia) may occur when the tumor compresses the facial nerve [15, 63].

Neuroimaging features

ONS may remain undiagnosed when they are asymptomatic and slow-growing, leading to delayed detection and diagnosis due to the gradual development of symptoms. Typically, tumors are identified when symptoms worsen suddenly, prompting healthcare providers to conduct radiological studies of the brain. Diagnosing ONS may involve several tests and examinations, including a comprehensive physical examination, thorough evaluation of the individual’s medical history, assessment of presenting signs and symptoms, and neurological, motor skills, and cognitive assessments [62], [63], [64]. ONS are slow-growing tumors, and the choice of imaging depends on their size. Initially, they affect the anterior and middle ethmoid air-cells unilaterally, appearing as masses in the superior olfactory recess. They can grow in any direction and tend to erode adjacent bone as they expand, with potential invasion into the orbits, anterior cranial fossa, and the opposing nasal cavity’s midline. Additionally, they can obstruct the ostia of the paranasal sinuses, leading to sinus blockage [65, 66].

Radiological imaging techniques

Plain X-ray

The initial imaging test utilized to assess structures with varying densities in different body areas is typically a plain X-ray. Imaging studies that may be conducted include X-rays of the head, neck, and vertebral column. A common feature observed in plain radiographs is well-circumscribed masses that displace surrounding structures without direct invasion, along with signs of fatty and cystic degeneration [67, 68].

Computed tomography (CT) scan

While CT scans are often the initial investigation, they are not as sensitive or specific as MRI for diagnosing Schwannomas. CT scans are particularly useful for evaluating skeletal changes near the tumor. Imaging characteristics include low to intermediate attenuation, strong contrast enhancement, and homogeneous or heterogeneous enhancement. Typically, a well-defined, lobulated mass lesion with solid and cystic areas and heterogeneous enhancement after contrast administration is observed on a CT scan. Calcification, absence of hyperostosis, and bone erosion are key indicators for detecting ONS on CT scans [69], [70], [71].

Magnetic resonance imaging (MRI)

MRI imaging shows varied T1 and T2 signal intensities. Signal characteristics include variable enhancement on T1, heterogeneous intermediate signal on T2, and moderate to intense intermediate signal (usually) on T1 with contrast (Gd). These lesions are characterized by well-circumscribed and encapsulated masses with low to intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The hyperintensity may be uniform or exhibit a target sign with a strong signal at the periphery of the lesion on T2-weighted images, reflecting the core fibrous tissue and surrounding myxoid tissue. When distinguishing ONS from other tumors in the anterior cranial fossa, such as olfactory groove meningioma, olfactory neuroblastoma, or low-grade astrocytoma, the differential diagnosis must be considered [72, 73].

Angiography

In many cases, ONS requires diagnostic techniques such as computed tomography and digital subtraction angiography. Angiograms can reveal tumor blush with prolonged opacification and arteriovenous shunting. Cerebral angiography involves injecting a dye into the bloodstream to visualize blood vessels on X-rays [74], [75], [76].

Cerebrospinal fluid analysis

A lumbar puncture or spinal tap may be performed, involving the removal of a sample of cerebrospinal fluid (CSF) from around the brain and spinal cord. The CSF sample is taken from the lower spinal cord using a thin needle and is checked for the presence of cancer cells [47, 77].

Tissue biopsy

Tissue biopsy can provide evidence of malignancy and identify the neural cell type involved. There are two methods for conducting a biopsy: (a) biopsy during a surgical procedure to remove the brain tumor; (b) stereotactic needle biopsy when the tumor is located deep within the brain or in a sensitive area [78, 79].

Differential diagnosis

ONS can often be confused with other conditions. Distinguishing between Schwannoma and meningioma may be possible based on the patient’s clinical characteristics, including their young age at presentation, bone scalloping on CT, the absence of the dural tail sign, and their low vascularity. Schwannomas typically exhibit positive immunohistochemical results for S-100 and negative results for epithelial membrane antigen (EMA). Differentiating these closely related entities remains a challenge because Olfactory Ensheathing Cells (OECTs) resemble ONS in radiological, clinical, and histological characteristics. Currently known IHC markers may not resolve the challenge, as both OECs and Schwann cells test positive for GFAP and S-100 while being negative for EMA. Therefore, new tools are needed to differentiate between OECTs and olfactory Schwannoma [80], [81], [82].

Management of ONS

While partial resection is an option because the tumor is benign and slow-growing, complete excision is typically the preferred approach. The use of adjunctive therapy is a good option, and patients generally have a good prognosis after complete tumor removal [80, 82].

Treatment modalities

Wait and watch approach: for individuals with small, slow-growing tumors that are asymptomatic, healthcare providers might choose a “watch and wait” approach. Brain scans may be performed to monitor the rate of tumor growth, and if the tumor is small and growing slowly, invasive procedures may not be necessary. Symptomatic treatment can involve the use of antiseizure medications, pain relievers, steroids (to reduce inflammation), and antidepressants [82].

Surgery: surgical excision and tumor removal are the primary treatments for ONS. Preserving nerve function affected by the tumor is a crucial criterion for surgery. The sub-frontal approach is typically used for most cases because it provides the best surgical access to the tumor. However, endoscopy or endoscopy assistance has been used in cases with or without a nasal sinus extension. Most of these cases underwent MRIs, and while Schwannomas were not initially considered in the differential diagnosis, the basal location of the lesion was considered. Surgical treatment options may include microsurgical techniques that can minimize damage to the affected nerve. In most cases, the tumor can be completely removed without damaging the nerve, as it primarily affects the nerve’s covering [3, 28, 36].

Endoscopic approach: ONS tumors are typically removed through a bifrontal transbasal technique, which may require significant brain manipulation or retraction to access the tumor. In cases where the Schwannoma tumor extends into the nasal sinuses, it is recommended to consider endoscopic surgery. ONS can be successfully removed using an expanded endoscopic endonasal transcribriform approach through a “keyhole craniectomy” in the ventral skull base. This method offers the shortest path to the anterior cranial base with no brain retraction. This has advantages in clearing the tumor-feeding arteries away before removal, early decompression of optic nerves, and resection of tumors in the optic canal, this approach is superior to the transcranial approach. The cons are, tumors that involve intra-cranial arteries cannot be removed totally [35, 75, 80].

Radiation therapy and chemotherapy: additional treatment options, such as chemotherapy and/or radiation therapy, may be considered if the tumor is malignant. The use of chemotherapy and radiation therapy is determined on a case-by-case basis by healthcare providers. Radiation therapy is used for bilateral Schwannomas and individuals in poor general health. Radiation therapy can have temporary side effects, including nausea and vomiting, hair loss, dry mouth, headaches, fatigue, changes in skin color, difficulty speaking and hearing, memory problems, and seizures. Long-term side effects may include memory loss, decreased brain function, and the emergence of stroke-like symptoms [5], [6], [7]. The decision to use chemotherapy as a treatment approach is also made on a case-by-case basis by healthcare professionals. Side effects of chemotherapy may include nausea and vomiting, mouth sores, hair loss, loss of appetite, fatigue, diarrhea, an increased risk of infection, and an increased risk of bruising [3].

Molecular targeted therapy: Merlin, also known as Schwannomin, is associated with the development of Schwannomas. Everolimus, temsirolimus, and the dual mTORC1 and mTORC2 inhibitor vistusertib (AZD2014) have shown promise in inhibiting Schwannoma growth in preclinical studies. In a phase II trial, 88 % of patients treated with bevacizumab and everolimus had stable disease (SD). Although 17 % of target meningiomas progressed, radiographic response (defined as a 20 % reduction from baseline) was reported in 5–10 % of Schwannomas and meningiomas. The first immunotherapeutic strategy for NF2 patients was recently tested in a clinical trial for individuals with progressing Schwannomas associated with the disease. Because merlin blocks downstream pathway activation and tyrosine receptor kinase-mediated signaling, several protein kinase inhibitors could help halt tumor development. In Schwannomas, the tumor-associated macrophage makes up most immunosuppressive cells [62, 82].

Prevention of Olfactory Nerve Schwannoma

There are no specific methods or guidelines for preventing the development of ONS. However, for individuals with a family history of the condition, genetic counseling and testing before family planning may be recommended. Regular health check-ups may help in early tumor detection. Preventive measures may include reducing exposure to ionizing radiation, avoiding smoking, minimizing the risk of injury, effective management of infections, and maintaining a healthy body mass index [23, 61, 66].

Complications and outcome

Complications from ONS may include permanent damage to the olfactory nerve, leading to the loss of smell and facial droop. Psychological distress, malignant transformation, genetic disorders, and post-surgery complications such as muscle, nerve, and blood vessel damage can also occur. Infections at the surgical wound site and tumor recurrence after surgery are common complications. Chemotherapy and radiation therapy can have side effects that vary depending on the type of treatment. After the complete removal of Schwannoma, complications are rarely observed, and in a few cases, olfaction may return. Occasionally, symptoms, especially anosmia, may recur after surgery [66, 69, 71].

Policy implications limitations and future research

The field of ONS has significant knowledge gaps. The findings of this research have substantial implications for clinical practice and policy development regarding ONS management. Our study underscores the importance of early detection and diagnosis of ONS, highlighting the need for healthcare providers to be vigilant about potential risk factors such as family history or genetic predispositions to nervous system tumors. From a policy standpoint, our results show the necessity for further research into ONS etiology, risk factors, and long-term outcomes to inform evidence-based guidelines. However, this research has limitations that require acknowledgment. Primarily relying on case reports introduces selection bias and limits generalizability. The small sample size and retrospective data collection further constrain the robustness of the findings. Additionally, the heterogeneity in patient demographics and treatment modalities across cases may weaken the results. Moreover, the lack of long-term follow-up data impedes assessing treatment efficacy and identifying prognostic factors.

Addressing these knowledge gaps requires focused future research. Investigations should delve into the pathophysiology and origin of olfactory Schwannoma, and introduction of molecular studies for deeper insights. Clear diagnostic criteria for various ONS types are needed to enhance diagnostic accuracy, alongside efforts to refine differential diagnosis methods. Research into minimally invasive and endoscopic surgical techniques is essential for improving surgical outcomes. Furthermore, exploring targeted therapies, immunotherapies, and molecular approaches may offer novel treatment avenues. Understanding ONS risk factors and preventive strategies can aid in reducing its incidence.

Conclusions

ONS is a rare and challenging condition that affects the olfactory nerve. Its rarity, unique characteristics, and lack of comprehensive research make it a topic of interest and concern for both clinicians and researchers. Current diagnostic methods, including imaging and histopathology, are essential but need further refinement to improve accuracy. Treatment options are primarily surgical, with adjunctive therapies considered in specific cases. Research gaps in the pathophysiology, origin, diagnostic criteria, differential diagnosis, surgical techniques, and treatment options must be addressed in the future to enhance patient outcomes and overall management of this rare condition.

Corresponding author: Bipin Chaurasia, MS, Department of Neurosurgery, Neurosurgery Clinic, Birgunj, Nepal, Phone: +97779845454636, E-mail:

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: The authors confirm their contribution to the paper as follows: study conception and design: NA, GS, GEU, SR, SA, MIA, MMA, BC; data collection: MMA, MAA, MF, DES; analysis and interpretation of results: NA, MMA, BA, OA; draft manuscript preparation: NA, GS, MMA, BC, SA. All authors reviewed the results and approved the final version of the manuscript.

  4. Competing interests: Authors state no conflict of interest.

  5. Research funding: The study did not receive any funding from any organizations.

  6. Data availability: The data and other materials from this study will be made available by the corresponding author upon reasonable request.

  7. Registration and protocol: The conducted review is simplified due to the rarity of the disease. There is no primary research available other than case series. Therefore, this review constitutes a systematic analysis of existing case reports. Consequently, we did not register a protocol for this review; however, we prepared a brief protocol before commencing the research at the Ibrahim Cardiac Hospital & Research Institute.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/oncologie-2023-0586).

Received: 2023-12-12
Accepted: 2024-03-31
Published Online: 2024-04-24

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/oncologie-2023-0586
Keywords for this article
Olfactory Nerve Schwannoma; risk factors; etiology; clinical presentation; management
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Review Articles
  3. How to optimize the immune checkpoint blockade therapy for cancers?
  4. The role of intratumoral microorganisms in the progression and immunotherapeutic efficacy of head and neck cancer
  5. The emerging significance of RNA 5-methylcytosine modification in human cancers
  6. Overview and new insights of lysine-specific histone demethylase 1 in colorectal cancer: promoting epithelial-mesenchymal transition and stemness features of cancer stem cells
  7. Research Articles
  8. Olfactory Nerve Schwannoma: a case series with a systematic review of the literature focusing risk factors, etiology, clinical presentation, and management
  9. Exploring the bladder tissue microbiome in patients with muscle-invasive bladder cancer using 2bRAD-M sequencing
  10. Schizandrin A enhances the sensitivity of gastric cancer cells to 5-FU by promoting ferroptosis
  11. Establishment and refinement of a DEN-induced hepatocellular carcinoma model in rats
  12. Identification of hypoxia-immune-related signatures for predicting immune efficacy in triple-negative breast cancer
  13. The HSP90AB1-mediated upregulation of IDO1 can promote the progression of colorectal cancer
  14. Time to initiation of adjuvant chemotherapy and survival in patients with stage II and III rectal cancer not receiving total neoadjuvant therapy
  15. SPOP attenuates the proliferation, invasion, and migration of choriocarcinoma JAR cells by promoting KIF23 degradation
  16. Short Commentaries
  17. Advances and costs in oncology: where is the balance?
  18. Liquid biopsy as a new era in endometrial cancer
  19. Is an immune-oriented use of radiation therapy possible? An increasingly open question under the spotlight of immunotherapy
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