Neuroectodermal Differentiation Research Articles

SALL3 mediates the loss of neuroectodermal differentiation potential in human embryonic stem cells with chromosome 18q loss

Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, because cells that have acquired specific genetic abnormalities experience a selective advantage invitro. These abnormalities are highly recurrent in hPSC lines worldwide, but their functional consequences in differentiating cells are scarcely described. In this work, we show that the loss of chromosome 18q impairs neuroectoderm commitment and that downregulation of SALL3, a gene located in the common 18q loss region, is responsible for this failed neuroectodermal differentiation. Knockdown of SALL3 in control lines impaired differentiation in a manner similar to the loss of 18q, and transgenic overexpression of SALL3 in hESCs with 18q loss rescued the differentiation capacity of the cells. Finally, we show that loss of 18q and downregulation of SALL3 leads to changes in the expression of genes involved in pathways regulating pluripotency and differentiation, suggesting that these cells are in an altered state of pluripotency.

Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency

Enhancers bind transcription factors, chromatin regulators, and non-coding transcripts to modulate the expression of target genes. Here, we report 3D genome structures of single mouse ES cells as they are induced to exit pluripotency and transition through a formative stage prior to undergoing neuroectodermal differentiation. We find that there is a remarkable reorganization of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. In the formative state, genes important for pluripotency exit establish contacts with emerging enhancers within these multiway hubs, suggesting that the structural changes we have observed may play an important role in modulating transcription and establishing new cell identities.

Optical Genome Mapping Reveals Genomic Alterations upon Gene Editing in hiPSCs: Implications for Neural Tissue Differentiation and Brain Organoid Research.

Genome editing, notably CRISPR (cluster regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), has revolutionized genetic engineering allowing for precise targeted modifications. This technique's combination with human induced pluripotent stem cells (hiPSCs) is a particularly valuable tool in cerebral organoid (CO) research. In this study, CRISPR/Cas9-generated fluorescently labeled hiPSCs exhibited no significant morphological or growth rate differences compared with unedited controls. However, genomic aberrations during gene editing necessitate efficient genome integrity assessment methods. Optical genome mapping, a high-resolution genome-wide technique, revealed genomic alterations, including chromosomal copy number gain and losses affecting numerous genes. Despite these genomic alterations, hiPSCs retain their pluripotency and capacity to generate COs without major phenotypic changes but one edited cell line showed potential neuroectodermal differentiation impairment. Thus, this study highlights optical genome mapping in assessing genome integrity in CRISPR/Cas9-edited hiPSCs emphasizing the need for comprehensive integration of genomic and morphological analysis to ensure the robustness of hiPSC-based models in cerebral organoid research.

Diffuse Pediatric-Type High-Grade Glioma H3-/IDH-wildtype with MYCN Deletion and Constitutional Mismatch Repair Deficiency: Case Presentation

Diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3/IDH WT) is a heterogeneous entity that is currently defined by a combination of highly malignant morphology, glial or primitive neuroectodermal differentiation, and a number of molecular features. Depending on the DNA methylation profile in pHGG H3/IDH WT, three molecular subgroups are distinguished, one of which (pHGG MYCN) is characterized by amplification of the indicated gene. We report a unique case of pHGG H3/IDH WT in a 19-year-old girl with a deletion of the MYCN gene and constitutional mismatch repair deficiency syndrome.

Renal Ewing sarcoma with extensive neuroectodermal differentiation: Case report and literature review

Abstract Ewing sarcoma with renal localization is one of the rarest members of the Ewing sarcoma family with less than 200 cases reported in the Medline database. Considering the fact that the majority of data published on the Ewing sarcoma with neuroectodermal differentiation is obtained through a few case reports and case series, it becomes understandable why we currently have no universally accepted treatment regimens. Case summary: A 33-year-old patient presented to the Emergency Department with right lumbar pain following a mild trauma and an episode of macroscopic hematuria. Physical examination confirmed hematuria and flank pain and a palpable flank mass was identified. MRI showed a cystic lesion of the upper pole of the right kidney of 127/110/123 mm. After prior agreement of the multidisciplinary team, a 3D laparoscopic right radical nephrectomy was done. The histopathological diagnosis revealed an Ewing sarcoma with extensive neuroectodermal differentiation staged as pT3N1M0L1V2R0. Despite swift implementation of the chemotherapy protocol, the progression of the disease was quickly noted. Currently, one year after diagnosis, the disease is still progressing despite the chemotherapy treatment, the patient being a third line chemotherapy candidate. As renal localization of Ewing sarcoma with extensive neuroectodermal differentiation is extremely rare, multimodal treatment strategies must be established by a multidisciplinary team. Despite its aggressive biological behavior, a proper therapeutic management might increase patient life expectancy.

Cell Differentiation and Aging Lead To Up-Regulation of FTO, While the ALKBH5 Protein Level Was Stable During Aging but Up-Regulated During in vitro-Induced Cardiomyogenesis.

FTO and ALKBH5 proteins are essential erasers of N6-adenosine methylation in RNA. We studied how levels of FTO and ALKBH5 proteins changed during mouse embryonic development, aging, cardiomyogenesis, and neuroectodermal differentiation. We observed that aging in male and female mice was associated with FTO up-regulation in mouse hearts, brains, lungs, and kidneys, while the ALKBH5 level remained stable. FTO and ALKBH5 proteins were up-regulated during experimentally induced cardiomyogenesis, but the level of ALKBH5 protein was not changed when neuroectodermal differentiation was induced. HDAC1 depletion in mouse ES cells caused FTO down-regulation. In these cells, mRNA, carrying information from genes that regulate histone signature, RNA processing, and cell differentiation, was characterized by a reduced level of N6-adenosine methylation in specific gene loci, primarily regulating cell differentiation into neuroectoderm. Together, when we compared both RNA demethylating proteins, the FTO protein level undergoes the most significant changes during cell differentiation and aging. Thus, we conclude that during aging and neuronal differentiation, m6A RNA demethylation is likely regulated by the FTO protein but not via the function of ALKBH5.

"PRRX1-rearranged mesenchymal tumors": expanding the immunohistochemical profile and molecular spectrum of a recently described entity with the proposed revision of nomenclature.

Since the publication of the 2020 World Health Organization classification of soft tissue and bone tumors, the classification of "fibroblastic" tumors has expanded to include a novel subset of tumors characterized by PRRX1::NCOA1/2 gene fusions. These tumors defy conventional classification and are morphologically distinct, characterized by a multi-nodular growth of bland spindle cells suspended in a myxo-collagenous stroma with mild cytologic atypia, "staghorn-like" vessels, and variable perivascular hyalinization. Mitotic activity is rare, and necrosis is not identified. Herein, we present six additional cases of PRRX1-rearranged mesenchymal tumors, including five cases with PRRX1::NCOA1 fusion and one case with PRRX1::KMT2D fusion. Three cases (3/6, 50%) demonstrated focal co-expression of S100 protein and SOX10, thereby expanding the immunohistochemical profile of this emerging entity. Like prior reported cases, there was no evidence of malignant behavior on short-term follow-up. The novel fusion, PRRX1::KMT2D, further expands the molecular spectrum of this entity and leads to a proposed revision of the provisional nomenclature to "PRRX1-rearranged mesenchymal tumor" to both accommodate non-NCOA1/2 fusion partners and allow for the possibility of partial neural or neuroectodermal differentiation.

Y-complex nucleoporins independently contribute to nuclear pore assembly and gene regulation in neuronal progenitors.

Besides assembling nuclear pore complexes, the conduits of nuclear transport, many nucleoporins also contribute to chromatin organization and gene expression, with critical roles in development and pathologies. We previously reported that Nup133 and Seh1, two components of the Y-complex subassembly of the nuclear pore scaffold, are dispensable for mouse embryonic stem cell viability but required for their survival during neuroectodermal differentiation. Here, a transcriptomic analysis revealed that Nup133 regulates a subset of genes at early stages of neuroectodermal differentiation, including Lhx1 and Nup210L, encoding a newly validated nucleoporin. These genes are also misregulated in Nup133▵Mid neuronal progenitors, in which nuclear pore basket assembly is impaired. However, a four-fold reduction of Nup133, despite also affecting basket assembly, is not sufficient to alter Nup210L and Lhx1 expression. Finally, these two genes are also misregulated in Seh1-deficient neural progenitors only showing a mild reduction in nuclear pore density. Together these data reveal a shared function of Y-complex nucleoporins in gene regulation during neuroectodermal differentiation, apparently independent of nuclear pore basket integrity.

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma.

In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood. We retrospectively included 19 EwS samples (17 patients). Affymetrix gene expression was correlated with maximal standardized uptake value (SUVmax) using machine learning, linear regression modelling, and gene set enrichment analyses for functional annotation. Expression of five genes correlated (MYBL2, ELOVL2, NETO2) or anticorrelated (FAXDC2, PLSCR4) significantly with SUVmax (adjusted p-value ≤ 0.05). Additionally, we identified 23 genes with large SUVmax effect size, which were significantly enriched for "neuropeptide Y receptor activity (GO:0004983)" (adjusted p-value = 0.0007). The expression of the members of this signaling pathway (NPY, NPY1R, NPY5R) anticorrelated with SUVmax. In contrast, three transcription factors associated with maintaining stemness displayed enrichment of their target genes with higher SUVmax: RNF2, E2F family, and TCF3. Our large-scale analysis examined comprehensively the correlations between transcriptomics and tumor glucose utilization. Based on our findings, we hypothesize that stemness may be associated with increased glucose uptake, whereas neuroectodermal differentiation may anticorrelate with glucose uptake.

S-100 Negative Granular Cell Tumor of Oral Cavity with Aggressive Clinical Behavior

Abstract Introduction/Objective Granular cell tumors (GCTs) are neoplasms with neuroectodermal (Schwann cell) differentiation that is typically benign and cured by surgical excision. These tumors characteristically display strong expression of S-100 protein. Similar tumors without expression of S-100 protein are called “S-100 negative granular cell tumors.” The few reported cases of S-100 negative GCT in the oral cavity describe indolent clinical behavior. We report a case of a 49-year-old male with recurrent S-100 negative GCT in the oral cavity. Methods/Case Report The patient presented initially with a mass in the hard palate, which was resected and diagnosed as an S-100 negative GCT. One year later, the patient developed severe epistaxis and anemia (hemoglobin 7.2 g/dL). A large tumor of the hard palate was the source of bleeding. It was resected and diagnosed as recurrent S-100 negative GCT. Histologically, this tumor consists of small nests of epithelioid to spindled cells with moderately abundant granular eosinophilic cytoplasm, round central nuclei with vesicular chromatin and distinct eosinophilic nucleoli, and significant mitotic activity. The cells are immunoreactive for SOX10 and negative for S-100, melan-A, keratin AE1/AE3, p40, synaptophysin, smooth muscle actin, desmin, and myogenin. Results (if a Case Study enter NA) N/A Conclusion S-100 negative GCTs are rare, and only a few case reports describe their involvement in the oral cavity. We report this case because of its rarity and aggressive clinical behavior. Recognition of this entity and its potential for locally aggressive growth is important. Management of this tumor by complete excision seems advisable.

Dyslexia associated gene KIAA0319 regulates cell cycle during human neuroepithelial cell development.

Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.

Decoding the dynamic H3K9cr landscapes during neural commitment of P19 embryonal carcinoma cells

Histone lysine crotonylation (Kcr) is a novel hydrophobic histone acylation modification, and we recently report its crucial roles in neural differentiation. However, it is still unclear how histone Kcr involve in early neural commitment. Here, we systematically investigate the H3K9cr landscapes during neuroectodermal differentiation of pluripotent P19 embryonal carcinoma cells (ECCs). We reveal that the genome-wide changes in H3K9cr favor neural fate specification, and identify potential co-factors binding H3K9cr. We also uncover that H3K9cr collaborates with H3K9ac to regulate gene expression changes. Our results provide novel insights into the epigenetic mechanisms underlying neural commitment.

Oxidative stress as a candidate mechanism for accelerated neuroectodermal differentiation due to trisomy 21

The ubiquity of cognitive deficits and early onset Alzheimer's disease in Down syndrome (DS) has focused much DS iPSC-based research on neuron degeneration and regeneration. Despite reports of elevated oxidative stress in DS brains, few studies assess the impact of this oxidative burden on iPSC differentiation. Here, we evaluate cellular specific redox differences in DS and euploid iPSCs and neural progenitor cells (NPCs) during critical intermediate stages of differentiation. Despite successful generation of NPCs, our results indicate accelerated neuroectodermal differentiation of DS iPSCs compared to isogenic, euploid controls. Specifically, DS embryoid bodies (EBs) and neural rosettes prematurely develop with distinct morphological differences from controls. Additionally, we observed developmental stage-specific alterations in mitochondrial superoxide production and SOD1/2 abundance, coupled with modulations in thioredoxin, thioredoxin reductase, and peroxiredoxin isoforms. Disruption of intracellular redox state and its associated signaling has the potential to disrupt cellular differentiation and development in DS lending to DS-specific phenotypes.

Retroperitoneal blue cell round tumor (Ewing sarcoma in a 35years old male)- case report.

IntroductionEwing sarcoma is a highly aggressive tumor. It's common presentation is primary bone tumor, but very rarely as soft tissue sarcoma both of which are under the spectrum of Ewing sarcoma family of tumors (EFT).Case presentationA 35 years old male who presented with advanced locally spreading tumor. He was diagnosed after presenting with epigastric pain and melena, CT abdomen revealed the retroperitoneal mass. CT guided core biopsy taken and was diagnosed as Ewing sarcoma. The patient presented with mass already grown so he was not a surgical candidate. Patient was managed symptomatically till he was sent for palliative care in a Sarcoma centre in Jordon and passed away on October 2021.DiscussionEwing Sarcoma family of tumors are group of small round blue cell tumors that are histogenetically related. The better known is Ewing ‘s sarcoma (EWS). It is a malignant small blue round cell tumor with variable degree of neuroectodermal differentiation. Retroperitoneal tumor are mostly malignant and accounts for one third of soft tissue sarcoma. They usually present as large masses at the time of the diagnosis. So they do not produce symptoms until they grow large enough to compress or invade contagious structures.ConclusionES-EWS is an aggressive tumor with high incidence of local recurrence and distant metastasis that's why is was given its poor prognosis characteristic. Multimodality treatment including surgical resection, chemotherapy and High dose radiotherapy will help in better survival rate.

Malignant gastrointestinal neuroectodermal tumor in head and neck: two challenging cases with diverse morphology and different considerations for differential diagnosis.

Malignant gastrointestinal neuroectodermal tumor (MGNET) is a sarcoma typically involving the gastrointestinal tract with neuroectodermal differentiation and EWSR1-ATF1/CREB1 fusions. Recently, rare MGNET cases were reported in extragastrointestinal sites. We identified 2 cases of MGNET arising in unprecedented laryngeal and intracranial locations, respectively. Both cases showed spindle and epithelioid tumor cells with amphophilic to clear cytoplasm and occasionally prominent nucleoli, arranged in solid, fascicular, and pseudoalveolar patterns. Case 1 exhibited moderate to marked nuclear atypia and focal intraepithelial component. In contrast, case 2 comprised predominantly low-grade epithelioid cells with extensive pseudopapillary structures. Both tumors showed an S100/SOX10-positive and HMB45/melan-A-negative immunoprofile as well as EWSR1-ATF1 fusion. A chief obstacle in diagnosing case 1 was the histologic and immunophenotypic resemblance to melanoma. The striking pseudopapillary architecture and the intracranial location of case 2 rendered differential diagnoses including meningioma and ependymoma. With the peculiar locations and morphology, these cases posed great diagnostic challenge.

ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export.

The pluripotent state is not solely governed by the action of the core transcription factors OCT4, SOX2, and NANOG, but also by a series of co‐transcriptional and post‐transcriptional events, including alternative splicing (AS) and the interaction of RNA‐binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize its role in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, mouse ZFP207 does not transcriptionally regulate neuronal and stem cell‐related genes but exerts its effects by controlling AS networks and by acting as an RBP. Our study expands the role of ZFP207 in maintaining ESC identity, and underscores the functional versatility of ZFP207 in regulating neural fate commitment.

Sinonasal mass lesions: A clinicopathological study with p63 and p16 immunohistochemical expressions.

The worldwide annual incidence of carcinomas of the sinonasal tract is 0.5 to 1.0 patients per 100,000 per year. P63 plays a role in epithelial development and is used as a marker for basal and myoepithelial cells. Expression of p16 occurs as a result of functional inactivation of the retinoblastoma protein (pRb) by the human papilloma virus (HPV) E7 protein. This study aims to study the histological spectrum of benign and malignant sinonasal mass lesions and to study the immunohistochemical expression of p63 in different type of sinonasal mass lesions. It also aims to ascertain the incidence of high-risk HPV in primary sinonasal mass lesions with p16 immunohistochemistry and delineate the histological spectrum of HPV-related sinonasal lesions. This cross-sectional study was conducted on 80 cases from June 2018 to June 2020 at a tertiary care hospital. Clinical history including demographic parameters were collected in the study proforma. The gross findings of the specimens noted and histopathological examination by H&E staining done. Immunohistochemistry staining for p63 and p16 expression was performed on all cases. Most common age group affected was 41-60 years with male:female ratio of 1.67:1. Nonneoplastic lesions (38.7%) comprised majority of the cases followed by benign neoplastic lesions (31.3%) and malignant neoplastic lesions (30%). Among the malignant neoplastic lesions, p63 showed positive expression in 75% (p = 0.005) and p16 showed positive expression in 41.7% (p = 0.023). Among benign and nonneoplastic lesions, p63 showed positivity in 21.4% (p = 0.000) and p16 showed positivity in 44.6% (p = 0.040). We analyzed p63 and p16 expression in varied lineages like carcinomas, papillomas, and neuroectodermal differentiation arising from the sinonasal tract and also in relation to other clinicopathological parameters. This study revealed p63 expression was associated more with the squamous cell carcinomas and nasopharyngeal carcinomas. Sinonasal tract malignancies are also associated with HPV infections that are identifiable by p16 immunostaining and, thus, could provide new prospects in identifying any definite biological and clinical characteristics associated with HPV as well as advancement in the targeted therapies for this patient population.

Endoderm and mesoderm derivatives in embryonic stem cell differentiation and their use in developmental toxicity testing

Embryonic stem cell differentiation models have increasingly been applied in non-animal test systems for developmental toxicity. After the initial focus on cardiac differentiation, attention has also included an array of neuro-ectodermal differentiation routes. Alternative differentiation routes in the mesodermal and endodermal germ lines have received less attention. This review provides an inventory of achievements in the latter areas of embryonic stem cell differentiation, with a view to possibilities for their use in non-animal test systems in developmental toxicology. This includes murine and human stem cell differentiation models, and also gains information from the field of stem cell use in regenerative medicine. Endodermal stem cell derivatives produced in vitro include hepatocytes, pancreatic cells, lung epithelium, and intestinal epithelium, and mesodermal derivatives include cardiac muscle, osteogenic, vascular and hemopoietic cells. This inventory provides an overview of studies on the different cell types together with biomarkers and culture conditions that stimulate these differentiation routes from embryonic stem cells. These models may be used to expand the spectrum of embryonic stem cell based new approach methodologies in non-animal developmental toxicity testing.

The Transcription Factor NF-κB in Stem Cells and Development.

NF-κB (nuclear factor kappa B) belongs to a family of transcription factors known to regulate a broad range of processes such as immune cell function, proliferation and cancer, neuroprotection, and long-term memory. Upcoming fields of NF-κB research include its role in stem cells and developmental processes. In the present review, we discuss one role of NF-κB in development in Drosophila, Xenopus, mice, and humans in accordance with the concept of evo-devo (evolutionary developmental biology). REL domain-containing proteins of the NF-κB family are evolutionarily conserved among these species. In addition, we summarize cellular phenotypes such as defective B- and T-cell compartments related to genetic NF-κB defects detected among different species. While NF-κB proteins are present in nearly all differentiated cell types, mouse and human embryonic stem cells do not contain NF-κB proteins, potentially due to miRNA-dependent inhibition. However, the mesodermal and neuroectodermal differentiation of mouse and human embryonic stem cells is hampered upon the repression of NF-κB. We further discuss NF-κB as a crucial regulator of differentiation in adult stem cells such as neural crest-derived and mesenchymal stem cells. In particular, c-REL seems to be important for neuronal differentiation and the neuroprotection of human adult stem cells, while RELA plays a crucial role in osteogenic and mesodermal differentiation.

SALL-4 and Beta-Catenin Expression in Sinonasal Teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (SNTCS) is a rare, aggressive malignancy that displays a heterogeneous combination of malignant blastema-like, epithelial and mesenchymal components. Its exact histogenesis is unknown with hypotheses ranging from true germ cell derivation to origin from pluripotent stem cells. However, despite this tumor's multiphenotypic histology, which includes frequent glandular, squamous, and neuroectodermal differentiation similar to adnexal germ cell tumors, SNTCS appears to have some differences from adnexal teratomas. For example, unlike adnexal teratomas, SNTCS has never been described as a component in a mixed germ cell tumor. Accurate recognition of SNTCS is difficult due to its rarity and histologic overlap with other sinonasal tumors. It is even more problematic on biopsy, since not all elements may be present in small samples. SNTCS can also share similar staining patterns with other neoplasms in the differential diagnosis. A recent study found nuclear β-catenin expression in a single TCS, but this has yet to be confirmed in additional cases. SALL-4, a marker of germ cell tumors, has not been examined. We performed β-catenin and SALL-4 immunohistochemistry on whole sections of 7 SNTCS and 19 other sinonasal neoplasms to assess whether β-catenin and SALL-4 are of utility in establishing a diagnosis of SNTCS. Intensity of expression and percentage of staining was noted for each tumor. For SNTCS, distribution of staining within each histologic component (immature neuroectodermal, epithelial, and mesenchymal) was also documented. Nuclear β-catenin expression was not identified in any SNTCS, with all cases demonstrating membranous expression (6 cases) or cytoplasmic and membranous expression (1 case). SALL-4 immunohistochemistry, however, was relatively sensitive (85.7%) and specific (89.5%) for SNTCS. SALL-4 expression was also identified in one poorly differentiated neuroendocrine carcinoma and one case of sinonasal undifferentiated carcinoma. SALL-4 appears to have utility in distinguishing SNTCS from other high grade sinonasal tumors.