Olfactory Neuroepithelium Research Articles

Olfactory Neuroblastoma With Divergent Differentiation: Contemporary Management of Unusual Pathology and Literature Review.

Olfactory neuroblastoma (ON; Esthesioneuroblastoma) is a malignant tumor that arises from the olfactory neuroepithelium. Very rarely, ON can histologically display a biphenotypic pattern, with only 7 cases reported in the literature to date. We describe a case of this poorly understood entity and review the patient's histology, pathology, and treatment. An 85-year-old man presented with endoscopy and imaging findings of a sinonasal mass arising from the olfactory cleft. Biopsy and further pathological review established Hyams grade 3 and Kadish stage C tumor. The patient underwent combined endoscopic and open-approach resection due to the involvement of the nasal bone and subsequent adjuvant radiation therapy. Specimen contained Flexner-Wintersteiner rosettes and stained positive for the neuroendocrine marker synaptophysin consistent with ON. A second, epithelial component pattern of goblet cells and mucin was observed suggesting divergent differentiation. We are the first group to report next-generation sequencing of this tumor, which revealed a pathogenic mutation in PIK3CA and a likely pathogenic variant in RUNX1 (AML1). ON with divergent differentiation is very rare, and more robust studies characterizing molecular drivers and pathology may aid in clinical management.

Olfactory neuroblastoma

Originating from the olfactory neuroepithelium, olfactory neuroblastoma is a rare malignant tumor of the nasal cavity that typically affects adults between the ages of 35 and 70. Clinical presentation predominantly consists of nonspecific symptoms such as nasal obstruction, nasal drainage or epistaxis, thus illustrating the need for a thorough diagnostic workup. In addition to a complete head and neck examination, rigid nasal endoscopy, biopsy and imaging are necessary to establish a definitive diagnosis as well as plan for treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) are the primary imaging modalities utilized to assess for bony invasion and soft tissue involvement, respectively. Hyams grading system provides a histologic assessment of disease severity while various staging systems correlate severity of disease to anatomic location/progression. Treatment relies on both surgical intervention and radiation. In addition, ongoing research trials are investigating therapeutic targets. Given the risk of recurrence, extended post-treatment surveillance remains necessary.

Prosaposin/Saposin Expression in the Developing Rat Olfactory and Vomeronasal Epithelia

Prosaposin is a glycoprotein widely conserved in vertebrates, and it acts as a precursor for saposins that accelerate hydrolysis in lysosomes or acts as a neurotrophic factor without being processed into saposins. Neurogenesis in the olfactory neuroepithelia, including the olfactory epithelium (OE) and the vomeronasal epithelium (VNE), is known to occur throughout an animal’s life, and mature olfactory neurons (ORNs) and vomeronasal receptor neurons (VRNs) have recently been revealed to express prosaposin in the adult olfactory organ. In this study, the expression of prosaposin in the rat olfactory organ during postnatal development was examined. In the OE, prosaposin immunoreactivity was observed in mature ORNs labeled using olfactory marker protein (OMP) from postnatal day (P) 0. Immature ORNs showed no prosaposin immunoreactivity throughout the examined period. In the VNE, OMP-positive VRNs were mainly observed in the basal region of the VNE on P10 and showed an adult-like distribution from P20. On the other hand, prosaposin immunoreactivity was observed in VRNs from P0, suggesting that not only mature VRNs but also immature VRNs express prosaposin. This study raises the possibility that prosaposin is required for the normal development of the olfactory organ and has different roles in the OE and the VNE.

The IL-4-IL-4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell.

IL-4 and IL-13 have non-redundant effects in olfaction, with loss of smell in mice evoked only by intranasal administration of IL-4, but not IL-13. IL-4-evoked pathophysiological effects on olfaction is independent of compromised structural integrity of the olfactory neuroepithelium. IL-4-IL-4Rα signaling modulates neuronal crosstalk with immune cells, suggesting a functional link between olfactory impairment and neuroinflammation. Abbreviations: IL, interleukin; KO, knock-out; wk, week; WT, wild-type.

Features of clinical and morphological diagnosis of esthesioneuroblastoma

The incidence of malignant neoplasms in Russia and the world is growing, and among the many malignant tumors of the main localizations, there are rare forms of cancer, mentioned in the literature as a description of single cases. Such diseases include a malignant neuroepithelial tumor arising from the olfactory neuroepithelium of the nasal cavity – esthesioneuroblastoma (ENB), which accounts for only 3 to 6% of cases of malignant neoplasms of the nasal cavity and paranasal sinuses. In due to the rarity of this disease, there are certain difficulties in the clinical and morphological diagnosis of ENB, there is no coding of it in the ICD, and there are no uniform standards of treatment. The article presents the results of a retrospective analysis of the features of clinical and morphological diagnosis of esthesioneuroblastoma. The study was conducted using the database of the Volgograd Regional Clinical Oncology Dispensary from 2003 to 2023. At the initial histological examination, the diagnosis of esthesioneuroblastoma was established only in 6 patients (66.6 %), in three patients (33.4 %) other forms of the malignant process were diagnosed, which did not correspond to clinical manifestations. Immunohistochemical (IHC) data confirm the greatest correspondence of the immunophenotype to olfactory neuroblastoma, G3 (according to Hyams) M9522/33. The study showed that the use of IHC for differential diagnosis is mandatory and allows for more accurate identification of esthesioneuroblastoma.

Neural stem/progenitor cells from olfactory neuroepithelium collected by nasal brushing as a cell model reflecting molecular and cellular dysfunctions in schizophrenia

Objectives Neural stem/progenitor cells derived from olfactory neuroepithelium (hereafter olfactory neural stem/progenitor cells, ONSPCs) are emerging as a potential tool in the exploration of psychiatric disorders. The present study intended to assess whether ONSPCs could help discern individuals with schizophrenia (SZ) from non-schizophrenic (NS) subjects by exploring specific cellular and molecular features. Methods ONSPCs were collected from 19 in-patients diagnosed with SZ and 31 NS individuals and propagated in basal medium. Mitochondrial ATP production, expression of β-catenin and cell proliferation, which are described to be altered in SZ, were examined in freshly isolated or newly thawed ONSPCs after a few culture passages. Results SZ-ONSPCs exhibited a lower mitochondrial ATP production and insensitivity to agents capable of positively or negatively affecting β-catenin expression with respect to NS-ONSPCs. As to proliferation, it declined in SZ-ONSPCs as the number of culture passages increased compared to a steady level of growth shown by NS-ONSPCs. Conclusions The ease and safety of sample collection as well as the differences observed between NS- and SZ-ONSPCs, may lay the groundwork for a new approach to obtain biological material from a large number of living individuals and gain a better understanding of the mechanisms underlying SZ pathophysiology.

Early results of transnasal endoscopic nerve transfer for olfactory neuroepithelium stimulation

Early results of transnasal endoscopic nerve transfer for olfactory neuroepithelium stimulation

Clinical outcomes for olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare malignant tumor arising from the olfactory neuroepithelium. The standard of care for ONB is surgical resection; however, detailed treatment protocols vary by institution. Our treatment protocol consists of endoscopic skull base surgery (ESBS) for endoscopically resectable cases and induction chemotherapy followed by craniotomy combined with ESBS for locally advanced cases, with postoperative radiotherapy performed for all cases. Chemoradiotherapy (CRT) is performed in unresectable cases. In this study, we evaluate our treatment protocol and outcomes for ONB. A retrospective review of patients with ONB was conducted. Outcomes included survival outcomes and perioperative data. Fifteen patients (53.6%) underwent ESBS, 12 (42.9%) underwent craniotomy combined with ESBS, and 1 (3.6%) received CRT. The 5- and 10-year overall survival rates for all patients were 92.9% and 82.5%, respectively, with a median follow-up period of 81 months. The 5- and 10-year disease-free survival rates were 77.3% and 70.3%, respectively, and the 5- and 10-year local control rates were 88.2% and 80.2%, respectively. Patients undergoing ESBS demonstrated a significantly shorter operating time, period from operation to ambulation, hospitalization period, and less blood loss than those undergoing craniotomy combined with ESBS. Our treatment protocol was found to afford favorable outcomes. Patients who underwent endoscopic resection showed lower complication rates and better perioperative data than those who underwent craniotomy combined with ESBS. With appropriate case selection, ESBS is considered a useful approach for ONB.

Personalized Approach to Olfactory Neuroblastoma Care.

Olfactory neuroblastoma (ONB) is an uncommon neuroendocrine malignancy arising from the olfactory neuroepithelium. ONB frequently presents with nonspecific sinonasal complaints, including nasal obstruction and epistaxis, and diagnosis can be obtained through a combination of physical examination, nasal endoscopy, and computed tomography and magnetic resonance imaging. Endoscopic resection with negative margins, with or without craniotomy, as necessary, is the standard of care for definitive treatment of ONB. Regional metastasis to the neck is often detected at presentation or may occur in a delayed fashion and should be addressed through elective neck dissection or radiation. Adjuvant radiotherapy should be considered, particularly in the case of high grade or tumor stage, as well as positive surgical margins. Systemic therapy is an area of active investigation in both the neoadjuvant and adjuvant setting, with many advocating in favor of induction chemotherapy for significant orbital or intracranial involvement prior to surgical resection. Various targeted immunotherapies are currently being studied for the treatment of recurrent or metastatic ONB. Prolonged locoregional and distant surveillance are indicated following definitive treatment, given the tendency for delayed recurrence and metastasis.

Overexpression of miR-25 Downregulates the Expression of ROBO2 in Idiopathic Intellectual Disability.

Idiopathic intellectual disability (IID) encompasses the cases of intellectual disability (ID) without a known cause and represents approximately 50% of all cases. Neural progenitor cells (NPCs) from the olfactory neuroepithelium (NEO) contain the same information as the cells found in the brain, but they are more accessible. Some miRNAs have been identified and associated with ID of known etiology. However, in idiopathic ID, the effect of miRNAs is poorly understood. The aim of this study was to determine the miRNAs regulating the expression of mRNAs that may be involved in development of IID. Expression profiles were obtained using NPC-NEO cells from IID patients and healthy controls by microarray. A total of 796 miRNAs and 28,869 mRNAs were analyzed. Several miRNAs were overexpressed in the IID patients compared to controls. miR-25 had the greatest expression. In silico analysis showed that ROBO2 was the target for miR-25, with the highest specificity and being the most down-regulated. In vitro assay showed an increase of miR-25 expression induced a decrease in ROBO2 expression. In neurodevelopment, ROBO2 plays a crucial role in episodic learning and memory, so its down-regulation, caused by miR-25, could have a fundamental role in the intellectual disability that, until now, has been considered idiopathic.

Transcriptomic Signatures of Neuronally Derived Extracellular Vesicles Reveal the Presence of Olfactory Receptors in Clinical Samples from Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) is defined as an injury to the brain by external forces which can lead to cellular damage and the disruption of normal central nervous system functions. The recently approved blood-based biomarkers GFAP and UCH-L1 can only detect injuries which are detectable on CT, and are not sensitive enough to diagnose milder injuries or concussion. Exosomes are small microvesicles which are released from the cell as a part of extracellular communication in normal as well as diseased states. The objective of this study was to identify the messenger RNA content of the exosomes released by injured neurons to identify new potential blood-based biomarkers for TBI. Human severe traumatic brain injury samples were used for this study. RNA was isolated from neuronal exosomes and total transcriptomic sequencing was performed. RNA sequencing data from neuronal exosomes isolated from serum showed mRNA transcripts of several neuronal genes. In particular, mRNAs of several olfactory receptor genes were present at elevated concentrations in the neuronal exosomes. Some of these genes were OR10A6, OR14A2, OR6F1, OR1B1, and OR1L1. RNA sequencing data from exosomes isolated from CSF showed a similar elevation of these olfactory receptors. We further validated the expression of these samples in serum samples of mild TBI patients, and a similar up-regulation of these olfactory receptors was observed. The data from these experiments suggest that damage to the neurons in the olfactory neuroepithelium as well as in the brain following a TBI may cause the release of mRNA from these receptors in the exosomes. Hence, olfactory receptors can be further explored as biomarkers for the diagnosis of TBI.

Adrenocorticotropic hormone Secreting Olfactory Neuroblastoma producing Ectopic Cushing’s Syndrome

Olfactory neuroblastoma is a rare sinonasal tumour of neuroendocrine type arising from olfactory neuroepithelium. Cushing`s syndrome is a clinical entity occurring due to elevated serum cortisol levels which is commonly due to exogenous steroids. Ectopic ACTH giving rise to endogenous Cushing’s syndrome requires vigilant evaluation in recognition of ectopic site. This syndrome gives rise to multitude of metabolic derangements with high morbidity which warrants early evaluation and management.

A nasal cell atlas reveals heterogeneity of tuft cells and their role in directing olfactory stem cell proliferation.

The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic, and their relationship to the other specialized epithelial cells is unclear. Here, we establish that the family of MVCs comprises tuft cells and ionocytes in both mice and humans. Integrating analysis of the respiratory and olfactory epithelia, we define the distinct receptor expression of TRPM5+ tuft-MVCs compared with Gɑ-gustducinhigh respiratory tuft cells and characterize a previously undescribed population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we used an integrated single-cell transcriptional and protein analysis. Inhalation of Alternaria induced mucosal epithelial effector molecules including Chil4 and a distinct pathway leading to proliferation of the quiescent olfactory horizontal basal stem cell (HBC) pool, both triggered in the absence of olfactory apoptosis. Alternaria- and ATP-elicited HBC proliferation was dependent on TRPM5+ tuft-MVCs, identifying these specialized epithelial cells as regulators of olfactory stem cell responses. Together, our data provide high-resolution characterization of nasal tuft cell heterogeneity and identify a function of TRPM5+ tuft-MVCs in directing the olfactory mucosal response to allergens.

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons

BackgroundVenezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied.MethodsWe utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure.ResultsWe found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS.ConclusionsOur results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

Biomarkers in Alzheimer's Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Alzheimer's disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.

A case of olfactory ganglioneuroblastoma in a dog: immunohistochemical comparison with olfactory neuroepithelia and olfactory neuroblastomas.

In the present study, histopathological and immunohistochemical findings of olfactory ganglioneuroblastoma in a dog were compared to those of canine olfactory neuroepithelia and neuroblastomas. Olfactory ganglioneuroblastoma consists of ganglion cell-like tumor cells with Schwannian stroma and neuroblast-like tumor cells. Immunohistochemically, ganglion cell-like tumor cells were immunopositive for synaptophysin, β3-tubulin, and tyrosine hydroxylase, Schwannian stroma was immunopositive for GFAP and SOX2, and neuroblast-like tumor cells were immunopositive for OLIG2, β3-tubulin, SOX2, cytokeratin AE1/AE3, and p63. The immunohistochemical results of olfactory neuroepithelia and olfactory neuroblastomas were similar to those of neuroblast-like tumor cells. These results suggest that the ganglion cell-like tumor cells in the present case have a sympathetic neuron immunophenotype, whereas neuroblast-like tumor cells have an olfactory neuroepithelial immunophenotype.

Olfactory neuronal precursors as a model to analyze the effects of melatonin in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder of great importance affecting millions globally and its prevalence will triple in the following decades. Therefore, analysis and identification of substances which can effectively reduce the pathological process of this disease in different study models are crucial. Melatonin works as a multitasking substance and some of its activities could be used to target the neurodegenerative process of AD. These include, but not limited to, its potent antioxidant activity, regulation of sleep-wake rhythms (important for the consolidation of memory and cognition) and its action as a neurotrophic growth factor that promotes differentiation and neuronal proliferation. To evaluate the effects of melatonin at cellular level in AD, it is essential to have a study model that reflects the pathological process occurring in the CNS. In this, review we summarize the potential use of olfactory neuronal precursors derived from olfactory neuroepithelium directly obtained from patients for such purposes.

Rare case of mortality after hemorrhagic property of esthesioneuroblastoma

Esthesioneuroblastoma is a tumor arising from olfactory neuroepithelium with an incidence of four per million. This case presents a rare nasal cavity neoplasm with hemorrhagic properties that may lead to significant sequelae. We present a 69-year-old male patient who presented with worsening altered mental status over the past 6-7 months. His Glasgow coma scale was a nine, showing a large mass centered at the cribriform plate with extension intracranially, sinonasal cavity, and bilateral orbits on diagnostics. Bifrontal craniotomy was performed one day after admission with resection of the tumor in the cranial fossa and intranasally, and decompression of the brainstem, frontal lobes, and third ventricle. After surgery, the patient was managed in the intensive care unit but continued to deteriorate. He was confirmed to have no meaningful brain activity and eventually deceased seven days after admission. Depending on the tumor stage, esthesioneuroblastoma can have a favorable prognosis with proper therapies. Different surgical techniques for ENB lead to the question of which therapeutic modality is the best because of the tumor's gross hemorrhagic properties. With adjunctive radiation therapy and/or chemotherapy, more research can bring light to proper surgical techniques.

Antiviral Functions of Type I and Type III Interferons in the Olfactory Epithelium.

The olfactory neuroepithelium (OE) is one of the few neuronal tissues where environmental pathogens can gain direct access. Despite this vulnerable arrangement, little is known about the protective mechanisms in the OE to prevent viral infection and its antiviral responses. We systematically investigated acute responses in the olfactory mucosa upon exposure to vesicular stomatitis virus (VSV) via RNA-seq. VSVs were nasally inoculated into C57BL/6 mice. Olfactory mucosae were dissected for gene expression analysis at different time points after viral inoculation. Interferon functions were determined by comparing the viral load in interferon receptor knockout (Ifnar1-/- and Ifnlr1-/-) with wildtype OE. Antiviral responses were observed as early as 24 h after viral exposure in the olfactory mucosa. The rapidly upregulated transcripts observed included specific type I as well as type III interferons (Ifn) and interferon-stimulated genes. Genetic analyses demonstrated that both type I and type III IFN signaling are required for the suppression of viral replication in the olfactory mucosa. Exogenous IFN application effectively blocks viral replication in the OE. These findings reveal that the OE possesses an innate ability to suppress viral infection. Type I and type III IFNs have prominent roles in OE antiviral functions.

Effects of Endoscopic Sinus Surgery on Olfactory Function.

To review the effects of endoscopic sinus surgery and endonasal approaches to the skull base on olfaction. Advancements in endonasal endoscopic approaches to the sinuses and skull base allow for direct treatment of a variety of sinonasal and skull base diseases. However, these extended approaches will often require manipulation of normal anatomical structures and the olfactory neuroepithelium. Depending on the planned procedure and extent of disease, the prognosis of olfactory perception can vary significantly among patients. Endoscopic sinonasal surgical procedures may impact olfaction. Optimizing olfactory function requires proper surgical techniques, gentle handling of tissue, and perioperative care. Surgeons must discuss objectives and manage patient expectations. Routine olfactory assessment is crucial in surgical work-up and follow-up. Preserving anatomical structures while addressing the obstruction of the olfactory cleft helps to prevent decreased olfactory threshold. However, smell identification and discrimination do not always correlate with sinonasal anatomy.