Genetic and transcriptional evolution alters cancer cell line drug response.

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.

Decreased patient comorbidities and post-operative complications in technology-assisted compared to conventional total knee arthroplasty.

PURPOSE: The use of computer-assisted and robotic surgery was developed to improve component position and outcomes of total knee arthroplasty (TKA). The goal of this study is to identify differences in patient demographics, comorbidities, and complications between technology-assisted and conventional TKA. METHODS: A Nationwide Inpatient Sample database was used to identify patients who underwent technology-assisted and conventional TKA from 2016 to 2018. Analysed variables include demographics, length of stay (LOS), payer-status, geographic region, comorbidities, complications, and mortality. Univariate and multivariate analyses were performed to identify differences between both groups. RESULTS: The analysis includes 2,208,434 TKA patients, of which 2,054,879 (93.05%) were conventional and 153,555 (6.95%) were technology assisted. Patients undergoing technology-assisted TKA were more likely to be older than 65 years, had higher median income quartile, and had surgery in urban teaching hospitals. Patients were less likely to undergo technology-assisted TKA if they were female gender, had Medicare payer status, were black race, were obese, were living in rural location, or had higher Charlson comorbidity score and baseline comorbidities. Technology-assisted TKA patients had shorter LOS, and fewer pulmonary and infection complications. CONCLUSION: Patients undergoing technology-assisted TKA are being carefully selected with less baseline comorbidities, improved health, and living in urban areas. Subsequently, those carefully selected patients are discharged home, have a shorted hospital LOS, and have fewer complications compared to conventional TKA. Rural patients, black race and female gender are less likely to undergo technology-assisted TKA, further emphasizing the healthcare disparity for that segment of the population. LEVEL OF EVIDENCE: Therapeutic level III.

Potential role of chitinase-3-like protein 1 (CHI3L1/YKL-40) in neurodegeneration and Alzheimer's disease.

Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.

SvABA: genome-wide detection of structural variants and indels by local assembly.

Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABA's performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs and substantially improves detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (<1000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types and found that short templated-sequence insertions occur in ∼4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized (50-300 bp) SVs.

CloneSifter: enrichment of rare clones from heterogeneous cell populations.

BACKGROUND: Many biological processes, such as cancer metastasis, organismal development, and acquisition of resistance to cytotoxic therapy, rely on the emergence of rare sub-clones from a larger population. Understanding how the genetic and epigenetic features of diverse clones affect clonal fitness provides insight into molecular mechanisms underlying selective processes. While large-scale barcoding with NGS readout has facilitated cellular fitness assessment at the population level, this approach does not support characterization of clones prior to selection. Single-cell genomics methods provide high biological resolution, but are challenging to scale across large populations to probe rare clones and are destructive, limiting further functional analysis of important clones. RESULTS: Here, we develop CloneSifter, a methodology for tracking and enriching rare clones throughout their response to selection. CloneSifter utilizes a CRISPR sgRNA-barcode library that facilitates the isolation of viable cells from specific clones within the barcoded population using a sequence-specific retrieval reporter. We demonstrate that CloneSifter can measure clonal fitness of cancer cell models in vitro and retrieve targeted clones at abundance as low as 1 in 1883 in a heterogeneous cell population. CONCLUSIONS: CloneSifter provides a means to track and access specific and rare clones of interest across dynamic changes in population structure to comprehensively explore the basis of these changes.

Hearing loss prevalence and hearing health among school-aged children in the Canadian Arctic.

OBJECTIVE: Hearing loss is an important health concern in Canada's Arctic. The objective of this research was to provide information on the prevalence of childhood hearing loss in Nunavut. DESIGN: This cross-sectional study involved comprehensive audiologic assessments of school-aged children in six communities to determine overall and community-specific prevalence of hearing loss. Data were collected about hearing aid use and factors affecting use through a parent questionnaire. STUDY SAMPLE: Assessments were completed for 644 children in kindergarten to grade 6. RESULTS: 124 (19.3%) children had hearing loss of ≥ 30 dB HL at one or more frequencies in at least one ear (93.5% conductive loss). Applying a Canadian prevalence study definition, 148 (23.5%) children had hearing loss. Tympanic membrane perforations were present in 36.8% (n = 28) of children with unilateral and 45.8% (n = 22) with bilateral loss. CONCLUSIONS: The prevalence of hearing loss in Canada's North was almost three times that reported for non-indigenous children. One in five school-aged children was found to have hearing loss that is likely to affect classroom learning and social/emotional development. A hearing health strategy tailored to this population is critically needed.

Assays of Monitoring and Measuring Autophagic Flux for iPSC-Derived Human Neurons and Other Brain Cell Types.

Autophagy is a highly conserved, cytoprotective, catabolic process induced in response to conditions of cellular stress and nutrient deprivation. It is responsible for the degradation of large intracellular substrates such as misfolded or aggregated proteins and organelles. This self-degradative mechanism is crucial for proteostasis in post-mitotic neurons, requiring its careful regulation. Due to its homeostatic role and the implications, it has for certain disease pathologies, autophagy has become a growing area of research. We describe here two assays that can be used as part of a tool kit for measuring autophagy-lysosomal flux in human iPSC-derived neurons.One way to measure autophagic flux is through a western blotting assay, which can be used to analyze two important autophagy proteins: microtubule-associated protein 1 light chain 3 (LC3) and p62. In this chapter, we describe a western blotting assay for use in human iPSC neurons that can be used to quantify these two proteins of interest to measure autophagic flux.In addition to conventional western blotting techniques, more sophisticated tools have come available to readout autophagic flux in a sensitive and high-throughput manner. In the latter portion of this chapter, we describe a flow cytometry assay which utilizes a pH-sensitive fluorescent reporter which can also be used to measure autophagic flux.

Characteristics of persistent postural perceptual dizziness patients in a multidisciplinary dizziness clinic.

BACKGROUND: Persistent Postural Perceptual Dizziness (PPPD) is a newly defined condition which was added to the International Classification of Vestibular Disorders in 2017. Little is known about its impact on patients. OBJECTIVE: The goal of this study was to analyze the symptomology, epidemiology and impact of PPPD on patients. METHODS: A retrospective chart review was done to identify patients who attended the Multidisciplinary Dizziness Clinic (MDC) and were diagnosed with PPPD. Responses to demographic questions, health-related quality of life surveys and several well-validated questionnaires commonly used to assess dizziness severity were analyzed. RESULTS: One hundred patients were diagnosed with PPPD between March 2017 and January 2019, of which 80%(80/100) were females. The average Dizziness Handicap Index score was 60.3±19.0. Responses to the Patient Health Questionnaire classified 53 patients (53/99;53.5%) as moderately to severely depressed. Sixty-four patients (64/100;64.0%) were minimally or mildly anxious according to the Generalized Anxiety Disorder scale. The average Vertigo Symptom Scale score was 24.1/60. The average Situational Vertigo Questionnaire score was 2.00. Forty-nine (49/100;49.0%) patients had migraine symptoms according to the Migraine Screen Questionnaire. CONCLUSIONS: In conclusion, patients with PPPD display important handicap and an elevated risk of depression, anxiety and migraines.

Biogenesis of JC polyomavirus associated extracellular vesicles.

JC polyomavirus (JCPyV) is a small, non-enveloped virus that persists in the kidney in about half the adult population. In severely immune-compromised individuals JCPyV causes the neurodegenerative disease progressive multifocal leukoencephalopathy (PML) in the brain. JCPyV has been shown to infect cells by both direct and indirect mechanisms, the latter involving extracellular vesicle (EV) mediated infection. While direct mechanisms of infection are well studied indirect EV mediated mechanisms are poorly understood. Using a combination of chemical and genetic approaches we show that several overlapping intracellular pathways are responsible for the biogenesis of virus containing EV. Here we show that targeting neutral sphingomyelinase 2 (nSMase2) with the drug cambinol decreased the spread of JCPyV over several viral life cycles. Genetic depletion of nSMase2 by either shRNA or CRISPR/Cas9 reduced EV-mediated infection. Individual knockdown of seven ESCRT-related proteins including HGS, ALIX, TSG101, VPS25, VPS20, CHMP4A, and VPS4A did not significantly reduce JCPyV associated EV (JCPyV(+) EV) infectivity, whereas knockdown of the tetraspanins CD9 and CD81 or trafficking and/or secretory autophagy-related proteins RAB8A, RAB27A, and GRASP65 all significantly reduced the spread of JCPyV and decreased EV-mediated infection. These findings point to a role for exosomes and secretory autophagosomes in the biogenesis of JCPyV associated EVs with specific roles for nSMase2, CD9, CD81, RAB8A, RAB27A, and GRASP65 proteins.

Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.

We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53WT) but showed alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A and RB1 early in tumor evolution and with later-occurring extrachromosomal amplicons. All pHGGs exhibited at least one simple-SV signature, but complex-SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with complex-SV signatures were associated with shorter overall survival independent of histone mutation and TP53 status. These data provide insight into the impact of SVs on gliomagenesis and the mechanisms that shape them.

Generation of Human Neurons and Oligodendrocytes from Pluripotent Stem Cells for Modeling Neuron-Oligodendrocyte Interactions.

In Alzheimer's disease (AD) and other neurodegenerative disorders, oligodendroglial failure is a common early pathological feature, but how it contributes to disease development and progression, particularly in the gray matter of the brain, remains largely unknown. The dysfunction of oligodendrocyte lineage cells is hallmarked by deficiencies in myelination and impaired self-renewal of oligodendrocyte precursor cells (OPCs). These two defects are caused at least in part by the disruption of interactions between neuron and oligodendrocytes along the buildup of pathology. OPCs give rise to myelinating oligodendrocytes during CNS development. In the mature brain cortex, OPCs are the major proliferative cells (comprising ~5% of total brain cells) and control new myelin formation in a neural activity-dependent manner. Such neuron-to-oligodendrocyte communications are significantly understudied, especially in the context of neurodegenerative conditions such as AD, due to the lack of appropriate tools. In recent years, our group and others have made significant progress to improve currently available protocols to generate functional neurons and oligodendrocytes individually from human pluripotent stem cells. In this manuscript, we describe our optimized procedures, including the establishment of a co-culture system to model the neuron-oligodendrocyte connections. Our illustrative results suggest an unexpected contribution from OPCs/oligodendrocytes to the brain amyloidosis and synapse integrity and highlight the utility of this methodology for AD research. This reductionist approach is a powerful tool to dissect the specific hetero-cellular interactions out of the inherent complexity inside the brain. The protocols we describe here are expected to facilitate future studies on oligodendroglial defects in the pathogenesis of neurodegeneration.

Morphology of the Greater Trochanter: An Assessment of Anatomic Variation and Canal Overhang.

BACKGROUND: Varus malposition is a risk of early failure in total hip arthroplasty. The degree to which the tip of the greater trochanter (GT) overhangs the canal can increase this risk. Although we know proximal femoral anatomy is variable, no study has addressed variations in medial overhang of the GT on plain radiographs. METHODS: All low anteroposterior pelvis radiographs more than 1 year were reviewed 3 times by 2 orthopaedic surgeons and one radiologist. The canal width (CW) was measured 10 cm below the lesser trochanter. Canal overhang (CO) was defined by the distance between the lateral medullary canal and a parallel line beginning at the most medial aspect of the GT. The overhang index (OI) is defined as the percentage of the canal overhung by the GT. RESULTS: The mean CW was 13.5 mm, mean CO 16.4 mm, and mean OI 1.22. Hips were then classified as the following: (A) OI < 0.5 (n = 8), (B) OI 0.5-1.0 (n = 78), (C) OI 1.0-1.5 (n = 191), and (D) OI > 1.5 (n = 68). Intraobserver reliability was excellent for all measures: 0.89 (confidence interval: 0.87-0.91) for CW, 0.96 (0.95-0.97) for CO, and 0.97 (0.97-0.98) for OI. Interobserver reliability was good for CW 0.75 (0.70-0.79) and excellent for CO 0.90 (0.88-0.92) and OI 0.95 (0.94-0.96). CONCLUSIONS: Variations in the morphology of the proximal femur can predispose to varus component malposition. The degree to which the GT overhangs the canal can be quantified and classified based on plain films. This can aid in preoperative planning and help guide intraoperative proximal femoral preparation.

Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.

Correction to: HPV DNA in saliva from patients with SCC of the head and neck is specific for p16-positive oropharyngeal tumours.

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed.

Diagnosing subtle palatal anomalies: Validation of video-analysis and assessment protocol for diagnosing occult submucous cleft palate.

INTRODUCTION: Submucous cleft palate (SMCP) classically involves bifid uvula, zona pellucida, and notched hard palate. However, patients may present with more subtle anatomic abnormalities. The ability to detect these abnormalities is important for surgeons managing velopharyngeal dysfunction (VPD) or considering adenoidectomy. OBJECTIVES: Validate an assessment protocol for diagnosis of occult submucous cleft palate (OSMCP) and identify physical examination features present in patients with OSMCP in the relaxed and activated palate positions. METHODS: Study participants included patients referred to a pediatric VPD clinic with concern for hypernasality or SMCP. Using an appropriately encrypted iPod touch, transoral video was obtained for each patient with the palate in the relaxed and activated positions. The videos were reviewed by two otolaryngologists in normal speed and slow-motion, as needed, and a questionnaire was completed by each reviewer pertaining to the anatomy and function of the palate. RESULTS: 47 patients, with an average age of 4.6 years, were included in the study over a one-year period. Four videos were unusable due to incomplete view of the palate. The most common palatal abnormality noted was OSMCP, diagnosed by each reviewer in 26/43 and 30/43 patients respectively. Using the assessment protocol, agreement on palatal diagnosis was 83.7% (kappa = 0.68), indicating substantial agreement, with the most prevalent anatomic features being vaulted palate elevation (96%) and visible notching of hard palate (75%). CONCLUSION: The diagnosis of subtle palatal anomalies is difficult and can be subjective. Using the proposed video-analysis method and assessment protocol may improve reliability of diagnosis of OSMCP.

HPV DNA in saliva from patients with SCC of the head and neck is specific for p16-positive oropharyngeal tumours.

BACKGROUND: Human papillomavirus (HPV) is an important cause of head and neck squamous cell carcinoma (HNSCC), especially in young people. These tumours overexpress p16 and respond well to treatment. The rapid detection of HPV in patients with HNSCC may expedite treatment when p16 status is not immediately available. METHODS: Saliva-based DNA collection kits and nested polymerase chain reaction (PCR) were used to determine the HPV status of 62 individuals with biopsy-proven HNSCC. Immunohistochemistry was used to determine tumour p16 status. RESULTS: A total of 62 patients were included in the study. Twenty-nine samples (47%) were positive for HPV DNA, the majority of which were high risk (HR) subtypes (79%). Patients who tested positive for HR HPV were more likely to have a tumour arising in the oropharynx compared to a non-oropharyngeal site (74 vs 26%; p = 0.003). A positive HR HPV saliva assay was 100% specific (95% CI 59-100%) and had a 100% positive predictive value (95% CI 75-100%) for a p16 positive tumour arising in the oropharynx. In contrast, a negative HR HPV assay had a 96% negative predictive value (95% CI 80-100%) for tumours arising in a non-oropharyngeal site. Independent of site, the saliva assay had a sensitivity of 77% (95% CI 54-91%) and a specificity of 94% (95% CI 77-99%), respectively, for a p16 positive tumour. CONCLUSION: We show that a saliva based assay is an effective method for detecting HPV in patients with HNSCC and that a positive HR HPV test is highly specific for p16 positive tumours arising in the oropharynx. This simple and rapid test could be used in cases where a biopsy of the primary tumour is not readily available.

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors.

BACKGROUND: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. METHODS: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. RESULTS: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. CONCLUSION: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Tablet Audiometry in Canada's North: A Portable and Efficient Method for Hearing Screening.

BACKGROUND: Access to hearing health care is limited in many parts of the world, creating a lack of prompt diagnosis, which further complicates treatment. The use of portable audiometry for hearing loss testing can improve access to diagnostics in marginalized populations. Our study objectives were twofold: (1) to determine the prevalence of hearing loss in children aged 4 to 11 years in Iqaluit, Nunavut, and (2) to test and demonstrate the use of our tablet audiometer as a portable hearing-testing device in a remote location. STUDY DESIGN: Prospective cross-sectional observational. SETTING: Remote elementary schools in 3 Canadian Northern communities. SUBJECTS AND METHODS: Tablet audiometers were used to test hearing in 218 children. Air conduction pure tones thresholds were obtained at 500, 1000, 2000, and 4000 Hz. Children with hearing loss ≥30 dB in either ear were referred for audiology services. RESULTS: Tablet audiometry screening testing revealed abnormal results in 14.8% of the study participants. No significant difference in the rate of hearing loss was seen by sex; however, the rate of hearing loss decreased significantly with increasing age. The median duration of the hearing test was 5 minutes 30 seconds. CONCLUSIONS: Of the study population, 14.8% tested positive for hearing loss based on our interactive tablet audiometer. In this setting, the tablet audiometer was both time efficient and largely language independent. This type of testing is valuable for providing much-needed hearing health care for high-risk populations in rural and remote areas where audiology services are often unavailable.

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Atypical presentation of sinonasal cellular schwannoma: a nonsolitary mass with osseous, orbital, and intracranial invasion.

Objective Sinonasal cellular schwannoma represents < 4% of head and neck schwannomas. These benign tumors are typically confined to the nasal cavity or ethmoid sinus. We describe an atypical case of sinonasal cellular schwannoma with diffuse paranasal sinus involvement and both intraorbital and intracranial extension. Results A 62-year-old woman presented with a 6-month history of right orbital proptosis and right-sided headache. Subsequent imaging revealed an invasive paranasal sinus mass extending through the skull base and displacing the right orbit. Preoperative biopsies were not diagnostic but revealed a spindle cell lesion suspicious for malignancy based on lack of encapsulation, infiltration of the sinonasal submucosa, and osseous invasion. The patient underwent open skull base surgery, and pathology confirmed a S100-positive nonencapsulated cellular schwannoma. Conclusion An atypical case of sinonasal cellular schwannoma with intracranial extension is reported. Its presentation is contrary to the common view that these are isolated solitary lesions of the nasoethmoid region. We suggest that sinonasal cellular schwannoma be considered in the differential diagnosis of a poorly defined invasive paranasal sinus mass, particularly following biopsy.