Turner Syndrome with Y Chromosome and Germ Cells: A Case Report Highlighting the Need to Prioritize Individualized Care.

Turner syndrome (TS) is a genetic condition in phenotypic females in which the individual has one intact X chromosome and the second sex chromosome is absent or structurally alteredComponents of Y chromosome (e.g., 45,X/46,XY) have been found in 5-15% of patients with TS; these patients are often referred to as having "Turner syndrome with Y" (TS+Y). The presence of Y chromosome material increases risk for development of gonadal tumors. Historically, prophylactic gonadectomy has been recommended in this population to prevent malignancy, and patients were presumed infertile due to the presence of streak gonads with no germ cells (GCs). More recently, studies have reported on spontaneous puberty and menarche in TS+Y patients suggesting the presence of viable GC and ovarian function. Our institution offers patients with TS+Y the option of experimental gonadal tissue cryopreservation (GTC) at the time of gonadectomy. We present a unique case of a young girl with TS+Y who had GCs present in her gonads and underwent experimental GTC at the time of gonadectomy.

Pediatric Chordoma: A Tale of Two Genomes.

Little is known regarding the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed whole exome and mitochondrial DNA (mtDNA) genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole genome sequencing datasets of 80 adult skull base chordoma patients. In the pediatric chordoma cohort, 81% percent of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared to the rest of the mtDNA genes (p=0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (p<0.0001). Furthermore, a progressive increase in heteroplasmy of non-synonymous mtDNA mutations was noted in patients with multiple tumors (p=0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (p<5.9e-07 and p<0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.

Postmortem Protocols of Implantable Neurosurgical Devices: A Cross-Sectional Survey.

BACKGROUND: Implantable devices are increasingly more common for management of movement disorders, pain, and epilepsy. These devices are often complex and constructed of nonbiodegradable or hazardous materials. Therefore, proper postmortem handling of these devices is exceedingly important. Unfortunately, there is no consolidated resource available for postmortem neuromodulation device protocols. Thus, we surveyed and catalogued the protocols for implantable devices to summarize proper postmortem device protocols for implantable neurosurgical devices currently on the market. METHODS: We performed a cross-sectional study of companies producing commonly implanted neurosurgical devices. Using information from company websites, user manuals, and catalogs we categorized devices into 3 groups: A (formal recommendation for explantation), B (recommendation for explantation without formal company protocol), and C (explantation is not necessary). We then compiled the data into a stoplight diagram, providing a clear postmortem disposal algorithm for each device category. RESULTS: Twelve companies were queried regarding 46 devices. Postmortem protocols were available for 50% (23/46) of devices; the remaining devices did not have formal recommendations. Overall, 50% of devices were classified as category A "red light" on the stoplight diagram based on recommendations, 10.9% as category B "yellow light," and the remaining 39.1% were classified as category C "green light" indicating they are safe to bury or cremate. CONCLUSIONS: Evolution in therapies and growth in functional neurosurgery has expanded the range of implantable neurosurgical devices. We provide an educational document summarizing their postmortem protocols. This resource aims to aid health-care providers and encourage proper disposal practices during burial or cremation.

Reworking Classification of First Branchial Cleft Anomalies.

OBJECTIVES: To evaluate the clinical features of first branchial cleft anomalies (BCAs) and their relationship to pre-operative imaging, pathologic data, and post-operative surveillance outcomes. Additional aims were to assess the validity of the Work classification and describe features of recurrent cysts. METHODS: Records for 56 children (34 females, 22 males; age at surgery of 5.6 ± 4.4 years) collected over a 12-year period (2009-2021) were reviewed. Imaging and pathologic slides were re-reviewed in a blinded fashion by experts in those respective areas. Parents were contacted via telephone to obtain extended follow-up. An alternate classification method based on the presence (type II) or absence (type I) of parotid involvement is provided. RESULTS: Only 55% of first BCAs could be successfully classified using Work's method. First BCAs within the parotid were more likely to present with recurrent infections, involve scarred tissue planes and lymphadenopathy, and demonstrate enlarged lymphoid follicles on pathology. The overall recurrence rate was 16%, and recurrence was 5.3 times more likely when external auditory canal cartilage was not resected. Preoperative imaging was useful for predicting the extent of surgery required and the presence of scarred tissue planes. CONCLUSION: First BCAs within the parotid gland involve more difficult and extensive surgical resection and the potential for morbidity related to facial nerve dissection. Appropriately aggressive surgical resection, which may include the resection of involved ear cartilage, is necessary to prevent morbidity related to recurrence. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:459-465, 2024.

Embryonal and pineal tumours.

Embryonal and pineal tumours represent a diverse group of central nervous system (CNS) neoplasms. While many of the small round blue cell tumours that make up the embryonal neoplasms share similar histologic qualities, there are several morphologic and cytologic characteristics that are useful in distinguishing different tumour types. Similarly, pineal parenchymal tumours represent clinically diverse tumours, ranging from benign to overtly malignant. The most recent iteration of the World Health Organization Classification of CNS Tumours expanded greatly on the significance of molecular alterations in brain tumour diagnostics. In this article, we summarize the salient cytologic and histologic features of CNS embryonal and pineal tumours, and highlight diagnostically relevant molecular alterations within each tumour type.

ROS1 Alterations as a Potential Driver of Gliomas in Infant, Pediatric, and Adult Patients.

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.

WDR82-Mediated H3K4me3 Is Associated with Tumor Proliferation and Therapeutic Efficacy in Pediatric High-Grade Gliomas.

Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that the trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. A reduction in H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and the expression of genes associated with stem cell features, cell proliferation, the cell cycle, and DNA damage repair. A reduction in WDR82-mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82-mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve the prognosis for children with malignant gliomas.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

An adolescent case of sellar osteochondromyxoma in the setting of spondyloepiphyseal dysplasia.

PURPOSE: Osteochondromyxomas (OMX) are rare congenital bone tumors that have only been described in the context of Carney complex syndrome (CNC). Data on OMX as a separate entity and in association with other disorders remain limited, making both diagnosis and treatment difficult. METHODS: A case report of a 17-year-old female diagnosed with sellar OMX is presented in the setting of spondyloepiphyseal dysplasia (SED). We discuss the radiographic and histopathological interpretations in addition to reviewing the current literature on OMX. RESULTS: A successful gross total resection of the tumor was achieved via an endonasal endoscopic transsphenoidal approach. A diagnosis was established radiographically and pathologically. CONCLUSION: The diagnosis and treatment of OMX are best achieved via tissue biopsy. Following confirmed osteochondromyxoma cases long term for recurrence and outcomes will be essential in understanding its natural tumor history and in establishing standard treatments.

Neuroblastoma Arising in an Immature Teratoma of the Ovary in a 13-Year-Old.

Somatic malignancies arising in mature teratomas are exceedingly rare entities and even more so are those arising in immature teratomas. Here, we present a unique case of a 13-year-old who initially underwent ovarian sparing cystectomy for a 7.7 cm left ovarian mass with a pre-operative diagnosis of mature cystic teratoma. Histologically, all 3 germ cell layers were present and immature neuroepithelial tubules were also identified. Subsequent sections revealed a nodular lesion composed of neuropil, neuroblasts with a spectrum of maturation, and Schwannian-type stroma. The neuroblasts were diffusely positive for PHOX2B. Neuroblastoma arising in an immature teratoma has only been described in the literature once previously in an adult patient.

Pediatric benign triton tumor of trigeminal nerve: a case report and literature review.

PURPOSE: Benign triton tumors (BTTs) in the pediatric population are extremely rare occurrences. Paucity of data on BTTs poses both diagnostic and therapeutic challenges, particularly when found intracranially. METHODS: A case report of a 10-year-old male diagnosed with incidental maxillary trigeminal (V2) BTT is presented. We discuss radiographic and histopathological interpretations. Furthermore, we provide a brief review of current literature and historical background on pediatric trigeminal BTT diagnosis, histopathology, and management. RESULTS: Successful gross total resection of the tumor was achieved via Dolenc approach to the cavernous sinus. Management options with consideration of outcomes from the few prior cases reported in the literature are presented. CONCLUSION: Treatment of trigeminal nerve tumors requires a broad differential diagnosis and understanding rare tumors is essential in the diagnosis and treatment algorithm.

Major Features of the 2021 WHO Classification of CNS Tumors.

Advances in the understanding of the molecular biology of central nervous system (CNS) tumors prompted a new World Health Organization (WHO) classification scheme in 2021, only 5 years after the prior iteration. The 2016 version was the first to include specific molecular alterations in the diagnoses of a few tumors, but the 2021 system greatly expanded this approach, with over 40 tumor types and subtypes now being defined by their key molecular features. Many tumors have also been reconceptualized into new "supercategories," including adult-type diffuse gliomas, pediatric-type diffuse low- and high-grade gliomas, and circumscribed astrocytic gliomas. Some entirely new tumors are in this scheme, particularly pediatric tumors. Naturally, these changes will impact how CNS tumor patients are diagnosed and treated, including clinical trial enrollment. This review addresses the most clinically relevant changes in the 2021 WHO book, including diffuse and circumscribed gliomas, ependymomas, embryonal tumors, and meningiomas.

Plasma next-generation sequencing for diagnosis of amebic liver abscess in a non-endemic area.

Amebic liver abscess (ALA) is a common condition in the developing world but is rare in the United States without a clear exposure risk. It is even less common to develop in an infant. The diagnosis of ALA can be logistically difficult and often requires invasive procedures and testing with slow turnaround times. We present an 18-month-old boy initially admitted with fever, abdominal pain, and diarrhea with rapid progression to respiratory failure. He was found to have a significant pleural effusion accompanying a large solitary liver lesion with abdominal ascites. There was no infectious exposure history or travel history, and thus pyogenic liver abscess was suspected, and aspiration performed while he was on empiric antimicrobials. The bacterial culture was negative. Molecular testing with 16 s and 18 s rRNA PCR on the fluid were non-diagnostic. The diagnosis of Entamoeba histolytica was confirmed within 48 hrs via plasma next-generation sequencing. Serum IgG for E histolytica resulted positive multiple weeks after the patient was discharged. The patient made a full recovery after metronidazole and paromomycin. This case illustrates the need to maintain ALA in the differential diagnosis for liver abscess in an infant even in the absence of risk factors. Additionally, plasma next-generation sequencing may play a role in more rapid diagnosis of ALA and has the potential to reduce the need for more invasive testing.

Pediatric spinal intramedullary anaplastic myxopapillary ependymoma: a case report.

A 6-year-old girl presented with a 1-week history of progressive upper and lower extremity weakness and bilateral upper extremity dysesthesia. Imaging demonstrated a 4.7 × 1.2-cm enhancing intramedullary lesion in the cervical spine from level C2 to C5 with associated cystic components and syringomyelia. The patient underwent a C2-C5 laminoplasty, with gross total resection of the intramedullary lesion. Histological analysis showed small to medium-sized epithelioid cells, with predominantly a solid architecture focally infiltrating into the adjacent spinal cord tissue. Focal papillary differentiation was present along with peri-vascular pseudorosettes, mucin microcysts, and globules of dense collagen. Focal anaplasia was noted with mitosis (5/10 HPF), focal necrosis, and elevated Ki67 10-15%. These findings were consistent with a myxopapillary ependymoma with anaplastic features. CSF cytology was negative for tumor cells. MYCN amplification was not present. She was treated with targeted proton-beam radiation therapy. This is the fourth case of an intramedullary anaplastic myxopapillary ependymoma to date, and the first case in the cervical spine reported in the literature.

Continued Basal Zone Expansion After Resolution of Eosinophilia in a Child With Eosinophilic Esophagitis on Benralizumab.

ABSTRACT: A 20-year-old woman presented with dysphagia at 8 years of age. She underwent esophagogastroduodenoscopy with biopsies (EGD), which was diagnostic of eosinophilic esophagitis. Diet elimination resulted in improvement in symptoms, reduction in eosinophilia, and resolution of basal zone hyperplasia (BZH) on repeat EGD; however, food reintroduction resulted in recurrence of eosinophilia. Subsequently, her pulmonologist started benralizumab, a monoclonal antibody against the interleukin-5 receptor (IL5Rα) on eosinophils, for her asthma. Seven months after starting benralizumab, she underwent EGD for persistent dysphagia, which was notable for resolution of esophageal eosinophilia but demonstrated marked BZH in association with high numbers of CD3+ T cells and tryptase+ mast cells. She transitioned to dupilumab and had resolution of dysphagia. EGD was performed 10 months after starting dupilumab and demonstrated resolution of BZH and mast cell inflammation with significant reduction in T cells. Review of other patients at our center treated with biologics, most commonly dupliumab, reveals varying degrees of BZH in association with mostly CD3+ lymphocyte inflammation. Mast cells and T cells appear to be capable of coordinating mucosal inflammation and symptoms of EoE independent of eosinophilia in a subset of patients.

Primary Biphasic Hepatic Sarcoma in DICER1 Syndrome.

DICER1 tumor predisposition syndrome is a rare genetic disorder that predisposes individuals to multiple benign and malignant neoplasms. The phenotype is vast and includes pleuropulmonary blastoma (PPB), thyroid nodules, cystic nephroma, Wilms tumor, ovarian Sertoli-Leydig cell tumor, and medulloepithelioma, among others. Herein, we describe a patient with a DICER1 germline pathogenic variant presenting with two neoplasms that are not commonly encountered in the context of DICER1 syndrome. The first tumor is a multiloculated cystic hepatic lesion with a biphasic pattern, composed of cysts lined by bland biliary type (CK19-positive) epithelium surrounded by a condensation of sarcomatous spindled cell proliferation in a myxoid stroma. This neoplasm resembled PPB or cystic nephroma with malignant transformation. The second tumor is a chest nodule consistent with low-grade hidradenocarcinoma. Although it is difficult to speculate with just a single case, these unusual neoplasms occurring in particular at a young age raises the possibility that they can be inherent to, and thus, be part of the DICER1 tumor predisposition syndrome phenotype.

Benign skull and subdural lesions in patients with prior medulloblastoma therapy.

PURPOSE: To report on our institutional cohort of patients and review the literature of medulloblastoma patients who developed skull/subdural-based lesions following treatment. METHODS: Following institutional review board (IRB) approval, we retrospectively reviewed the medical records of four children with a history of treated medulloblastoma who developed non-specific skull-based/subdural lesions incidentally found on surveillance imaging. RESULTS: Biopsies of the lesions proved the pathology to be low grade and included inflammatory myofibroblastic tumor, cortical fibrous defect consistent with fibroma, fibrous tissue, and fibrous dysplasia. The finding of calvarial or subdural fibrous lesions in children following therapy for medulloblastoma was noted in four out of 201 (136 with available follow-up data) medulloblastoma patients seen or discussed in our institution over the past 10 years. CONCLUSIONS: These lesions can grow over time and pose a differential diagnostic challenge with metastatic disease when identified. The skull and subdural space should be scrutinized for secondary lesions on surveillance imaging of patients with medulloblastoma who have received craniospinal irradiation as knowledge of this benign occurrence will assist with management.

Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma.

Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRß, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

The Essentials of Molecular Testing in CNS Tumors: What to Order and How to Integrate Results.

PURPOSE OF REVIEW: Molecular testing has become essential for the optimal workup of central nervous system (CNS) tumors. There is a vast array of testing from which to choose, and it can sometimes be challenging to appropriately incorporate findings into an integrated report. This article reviews various molecular tests and provides a concise overview of the most important molecular findings in the most commonly encountered CNS tumors. RECENT FINDINGS: Many molecular alterations in CNS tumors have been identified over recent years, some of which are incorporated into the 2016 World Health Organization (WHO) classification and the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) updates. Array-based methylation profiling has emerged over the past couple of years and will likely replace much of currently used ancillary testing for diagnostic purposes. A combination of next-generation sequencing (NGS) panel and copy number array is ideal for diffuse gliomas and embryonal tumors, with a low threshold to employ in other tumor types. With the recent advances in molecular diagnostics, it will be ever more important for the pathologist to recognize the molecular testing available, which tests to perform, and to appropriately integrate results in light of clinical, radiologic, and histologic findings.