Case report: A unique presentation of a high-grade neuroepithelial tumor with EWSR1::PATZ1 fusion with diagnostic, molecular, and therapeutic insights.

Background: EWSR1::PATZ1 fusion tumors are exceedingly rare in the central nervous system with only 14 prior cases documented. PATZ1 fusion neuroepithelial tumors are beginning to be recognized as a distinct molecular class of neoplasms that most often occur in children and young adults. These tumors are polyphenotypic, show diverse morphologic features, may be low- or high-grade, and tend to have an intermediate prognosis. Case presentation: Herein, we present an unusual case of a high-grade neuroepithelial tumor in a young man with an EWSR1::PATZ1 fusion. This case is unique because the tumor appears to have undergone high-grade transformation from a persistent low-grade glioma, which has yet to be reported. Furthermore, this case is the first to document concurrent RB1 loss, SMAD4 loss, and TP53 inactivation in this tumor type, which correlates with high-grade transformation. Fortunately, this patient is alive 2.5 years after treatment and 18.5 years after initial presentation, which provides a unique window into how these tumors clinically behave over a long follow-up period. Finally, we discuss the altered molecular pathways that are a result of the EWSR1::PATZ1 fusion and discuss potential therapeutic targets. Conclusion: Awareness of the emerging entity of PATZ1 fusion neuroepithelial tumors is important not only for accurate diagnostic and prognostic purposes but also for predicting response to therapy.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Primary central nervous system tumor treatment and survival in the United States, 2004-2015.

INTRODUCTION: Brain tumor treatment and survival information is generally limited in large-scale cancer datasets. We provide a clinical investigation of current patterns of care and survival estimates for central nervous system (CNS) tumors treated in the United States. METHODS: We analyzed the National Cancer Database from 2004-2015 for all patients with diagnosis of primary CNS tumors. We describe patient demographics, treatment modality, and analyzed survival estimates. RESULTS: 512,168 patient tumor records were examined. The most common histology was meningioma (43.6%), followed by glioblastoma (22.0%), and nerve sheath tumors (10.6%). Patients had a median age of 60 years, with a female (57.9%), white (85.0%), and non-Hispanic (87.8%) predominance. Tumors were reported as World Health Organization (WHO) grade I for 55.9% of the patients, grade II for 5.9%, grade III for 4.4%, grade IV for 24.3%, and grade unknown or not applicable for 9.4%. Overall, 56% underwent surgical procedures, 30.4% received radiation, and 20.6% received chemotherapy. Radiation plus chemotherapy and surgery was the most common treatment modality in high-grade tumors (40.5% in WHO grade III and 49.3% in WHO grade IV), while surgery only or watchful waiting was preferred in low-grade tumors. Older age, male gender, non-Hispanic origin, higher number of comorbidities, and lower socioeconomic status were identified as risk factors for mortality. CONCLUSIONS: Our analysis provides long-term survival estimates and initial treatment decisions for patients with CNS tumors in hospitals throughout the United States. Age, comorbidities, gender, ethnicity, and socioeconomic characteristics were determinants of survival.

Initial management of meningiomas: Analysis of the National Cancer Database.

BACKGROUND: Meningiomas are the most common central nervous system tumor. We describe current trends in treatment and survival using the largest cancer dataset in the United States. METHODS: We analyzed the National Cancer Database from 2004 to 2014, for all patients with diagnosis of meningioma. RESULTS: 201,765 cases were analyzed. Patients were most commonly White (81.9%) females (73.2%) with a median age of 64 years. Fifty percent of patients were diagnosed by imaging. Patients were reported as grade I (24.9%), grade II (5.0%), grade III (0.7%), or unknown WHO grade (69.4%). Patients diagnosed by imaging were older, received treatment in community facilities, had higher Charlson-Deyo score, and a lower rate of private insurance. Watchful waiting was the most common treatment modality (46.7%), followed by surgery only (40%). Grade II and III patients were more likely to receive therapy. Watchful waiting increased from 35.2% in 2004 to 51.4% in 2014. Younger age, male gender, private insurance, and treatment in academic facilities were determinants for receipt of surgery and/or radiation. Median survival was 12.6 years, higher in histologically confirmed cases (13.1 years). Older patients, Blacks, males, those that received radiation plus surgery, and were treated in community facilities had an increased risk of mortality. CONCLUSIONS: Over half of patients were diagnosed by imaging, suggesting a higher role of clinical determinants over histological confirmation in treatment decisions. Watchful waiting as initial management is increasing. Our survival analysis favored histological confirmation. Patients receiving radiation and surgery had an increased risk of mortality.

Distribution and Quantity of Sites of John Cunningham Virus Persistence in Immunologically Healthy Patients: Correlation With John Cunningham Virus Antibody and Urine John Cunningham Virus DNA.

Importance: Although seroepidemiological studies indicate that greater than 50% of the population has been infected with John Cunningham virus (JCV), the sites of JCV persistence remain incompletely characterized. Objective: To determine sites of JCV persistence in immunologically healthy individuals. Design, Setting, and Participants: Tissue specimens from multiple sites including brain, renal, and nonrenal tissues were obtained at autopsy performed in the Department of Pathology at the University of Kentucky from 12 immunologically healthy patients between February 9, 2011, and November 27, 2012. Quantitative polymerase chain reaction was performed on the tissue specimens and urine. Serum JCV antibody status was determined by enzyme-linked immunosorbent assay. Main Outcomes and Measures: The detection and quantification of JCV from the tissues by quantitative polymerase chain reaction illuminated sites of viral persistence. These results were correlated with JCV antibody levels. Results: Autopsies were performed on 12 individuals, 10 men and 2 women, ranging in age from 25 to 75 years (mean, 55.3 years). Seven of 12 individuals were JCV antibody seropositive based on absorbance units. Serostatus was associated with amounts of JCV DNA in urine and its tissue distribution. John Cunningham virus DNA was found in 75% of genitourinary tissue samples from donors (18 of 24) with high JCV antibody levels, 13.3% of donors with low levels i(4 of 30), and 0% of seronegative persons (0 of 32). In nongenitourinary tissues, JCV DNA was detected in 45.1% of tissue samples of donors (32 of 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), and 0% of seronegative persons (0 of 43). Genitourinary tissues had higher copy numbers than other sites. John Cunningham virus DNA was detected in urine of seronegative individuals in a research-grade assay. Conclusions and Relevance: Persistent (latent or actively replicating) JCV infection mostly predominates in genitourinary tissues but distributes in other tissues at low copy number. The distribution and copy numbers of the virus appear to correlate with urinary JCV shedding and serostatus.