The World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition, 2021: A Critical Analysis.

In 2021 the World Health Organization issued the fifth edition of its classification of the tumors of the central nervous system. This revision made many significant changes in the overall structure of the tumor taxonomy, as well as utilizing to a greatly increased reliance on molecular genetic data to specify the various diagnoses described in the classification, and to add some new tumor types. This represents a trend following the pioneering introduction of certain required genetic alterations for particular diagnoses encoded in the 2016 revision of the preceding fourth edition. In this chapter I describe the major changes and comment on their significance, and highlight some areas which are, at least to me, controversial. The major tumor categories discussed include gliomas, ependymomas, and embryonal tumors, but all tumor types included in the classification are addressed to the extent necessary.

Anaemia worsens early functional outcome after traumatic brain injury: a preliminary study.

OBJECTIVE: To determine early effects on outcome from traumatic brain injury (TBI) induced by controlled cortical impact (CCI) associated with anaemia in mice. HYPOTHESIS: Outcome from TBI with concomitant anaemia would be worse than TBI without anaemia. METHODS: CCI was induced with electromagnetic impaction in four groups of C57BL/6J mice: sham, sham+anaemia; TBI; and TBI+anaemia. Anaemia was created by withdrawal of 30% of calculated intravascular blood volume and saline replacement of equal volume. Functional outcome was assessed by beam-walking test and open field test (after pre-injury training) on post-injury days 3 and 7. After functional assessment, brains removed from sacrificed animals were pathological reviewed with haematoxylin and eosin, cresyl violet, Luxol Fast Blue, and IBA-1 immunostains. RESULTS: Beam-walking was similar between animals with TBI and TBI+anaemia (p = 0.9). In open field test, animals with TBI+anaemia walked less distance than TBI alone or sham animals on days 3 (p < 0.001) and 7 (p < 0.05), indicating less exploratory and locomotion behaviours. No specific pathologic differences could be identified. CONCLUSIONS: Anaemia associated with TBI from CCI is associated with worse outcome as measured by less distance travelled in the open field test at three days than if anaemia is not present.

Osteochondroma mimicking meningioma: case report and literature update.

We report a case of an osteochondroma in a 47-year-old woman presenting with a 2-month history of thoracic back pain that radiated down her left arm. Based on imaging features, the osteochondroma was initially thought to represent a calcified meningioma. The unusual features of the case include the location of the tumor, patient age, the erosion of the vertebra, and the confusing neuroradiological features. We review reported cases in which a solitary costal osteochondroma impinges on the neural foramina or central spinal canal and we discuss reasons for the misdiagnosis in our case.

Synchronous ovarian and endometrial carcinomas in a patient with Rubinstein-Taybi syndrome: a case report and literature review.

Rubinstein-Taybi syndrome is characterized by distinctive facial and limb features and is associated with several types of tumors. A 29-yr-old woman with this syndrome presented with a large, complex ovarian mass. She was subsequently diagnosed with a low-grade serous carcinoma of the ovary and an endometrioid adenocarcinoma of the uterus. Rubinstein-Taybi syndrome is an autosomal dominant, multiple congenital anomalies-mental retardation syndrome. Two genes, CREBBP and EP300, have been found to be associated with this disorder, although some cases do not have an identifiable cause. These genes code for proteins that acetylate histone tails, an epigenetic modification that serves to control transcription. They also serve as cofactors to several transcription factors and modulate p53. Although these patients have a predisposition to benign and malignant neoplasms, no malignant gynecologic neoplasm has been described thus far. Although no significant evidence linking CREBBP and EP300 to gynecologic malignancies has yet been found, some studies have suggested that hypoacetylation of histones may be involved in endometrial and ovarian carcinomas.

Brainstem disconnection: two additional patients and expansion of the phenotype.

Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.

The crisis in the pathology subspecialty fellowship application process: Historical background and setting the stage.

The process whereby pathology residents apply for fellowships for subspecialty training after residency has long been fraught with multiple problems. This paper reviews the history of the creation of such fellowships, as tied to requirements for eligibility for certification by the American Board of Pathology, going back to the inception of the Board in 1948. The problems with fellowship applications began to appear in conjunction with changes in Board requirements for basic certification, revolving around the "fifth year" or "credentialing year" requirements, and have created a situation where now residents mostly apply for fellowships while still in the second of their 4-year AP/CP residency. The pressures to apply ever-earlier, to accept offers with short intervals between offer and expiration, and how this damages programs, as well as residents, are reviewed. This paper is a companion to a larger examination of the current status of this problem, which also explores some means to ameliorate or eliminate those problems.

Neuropathology and Ophthalmological Pathology of Fatal Central Nervous System Injuries in Young Children: Forensic Neuropathology of Deaths of Children Under Age 2, 2008-2016, in Central Missouri.

Nonaccidental head injuries are significant causes of morbidity and mortality among young children. Despite broad agreement among medical experts, controversies remain over diagnostic criteria, including from autopsies, because of opinions expressed by a small group of expert witnesses who testify for defendants in suspected child homicide cases. We reviewed 249 autopsies in children 2 years old and younger from the files of our Medical Examiner office in the University of Missouri School of Medicine done between January 1, 2008 and December, 31, 2016. Because of gradually instituted mandatory examination of spinal cords and retinas, we had 127 autopsies with brain examinations by a neuropathologist plus retinal examinations of which 67 also had spinal cord examinations. Results were correlated with clinical records, police and EMS reports, and imaging. We found that subdural hematomas, cerebral edema, and retinal hemorrhages were mostly limited to autopsy findings in children who suffered from fatal head trauma, whether accidental (3 cases) or inflicted (14); they were not encountered in cases of homicide by other mechanisms or from natural diseases including infections, brain tumors, SIDS/SUID, or SUDC. Two cases with no other evidence of head trauma had focal retinal hemorrhages. We advocate for examination of retinas and spinal cords in all autopsies of children in this age group.

The pathology fellowship application crisis: The current state and suggestions for remediation.

Problems within the Pathology fellowship application process in the US have been recognized and reported for years. Recently, members of the Graduate Medical Education Committee (GMEC) of the Association of Pathology Chairs (APC) and collaborators collected survey data from the residents themselves and the fellowship programs, as represented by both the fellowship program directors (members of the Fellowship Directors Ad Hoc Committee, FDAHC) and the program administrators (members of the Graduate Medical Education Administrators Section, GMEAS). These data are presented and discussed, and potential steps to resolve some of the problems around fellowship applications in pathology are presented.

Validation of Bromodomain and Extraterminal proteins as therapeutic targets in neurofibromatosis type 2.

Background: Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by development of schwannomas on the VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors. The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study. Methods: A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation of the BET BRD4, phospho-kinase arrays and immunohistochemistry (IHC) of BRD4 in vestibular schwannomas. Results: JQ1 inhibited proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased sensitivity of cells to JQ1. Loss of function experiments identified BRD4, and to a lesser extent BRD2, as BET family members mediating the majority of JQ1 effects. IHC demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. Analysis of signaling pathways effected by JQ1 treatment suggests that the effects of JQ1 treatment are mediated, at least in part, via inhibition of PI3K/Akt signaling. Conclusions: NF2-deficient Schwann and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. Our results suggest BRD4 regulates PI3K signaling and likely impedes NF2 schwannoma growth via this inhibition. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group.

BACKGROUND: Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of 3. Stratification of patients by risk group may allow toxic treatment to be avoided. METHODS: Seventy-six patients diagnosed with medulloblastoma and enrolled on CCG-9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or nondesmoplastic. Nonparametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates, and the log-rank test was used to compare survival according to histologic subtype. RESULTS: Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77% ± 9% and OS of 85% ± 8% compared with EFS of 17% ± 5% and OS of 29% ± 6% for patients with tumors in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy. CONCLUSIONS: Children less than 3 with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy.

Isolation and characterization of a population of stem-like progenitor cells from an atypical meningioma.

The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to subpopulations of less-differentiated cells residing within the tumor. These subpopulations of tumor cells have tumor-initiating properties and may be isolated from heterogeneous tumors when sorted or cultured in defined medium. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. We identify a tumor-initiating population from an atypical meningioma, termed meningioma-initiating cells (MICs). These MICs self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted at 1000 cells into the flank regions of athymic nude mice. Immunohistochemistry reveals stem-like protein expression patterns similar to neural stem and progenitor cells (NSPCs) while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Microarray and pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16(INK4A)), p14(ARF), and CDKN2B (p15(INK4B)). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. The isolation and identification of a tumor-initiating cell population capable of forming meningiomas demonstrates a useful model for understanding meningioma development. This meningioma model may be used to study the cell hierarchy of meningioma tumorogenesis and provide increased understanding of malignant progression.

SARS-CoV-2 detection by reverse transcriptase polymerase chain reaction testing: Analysis of false positive results and recommendations for quality control measures.

Testing for SARS-CoV-2 has become a critical component for the management of the COVID-19 pandemic. Reverse transcriptase polymerase chain reaction (RT-PCR) assays are currently the predominate method for testing. Quality control (QC) measures utilize known positive and known negative controls to ensure the adequacy of extraction and RT-PCR steps but do not evaluate all components of testing. We have conducted a quality assurance review of our RT-PCR testing for COVID-19 to determine the rate of false positive results in asymptomatic patients and causes for these errors. DESIGN: We have developed a quality control procedure in which all specimens from asymptomatic unexposed persons with SARS-CoV-2 positive tests were retested. When a second test was "non-detected" a third test was performed and a root cause analysis of the erroneous result undertaken. RESULTS: In the study period, 24,717 samples were tested and 6251 were from asymptomatic patients. Of the 288 initial positive tests, 20 (6.9%) were negative on retesting. Review of cycle threshold curves, technologists' records, location of specimen on testing plates and relationships with high viral load specimens was undertaken. Analysis revealed technologists' errors (misplacement of specimen in testing plate or contamination) and cross contamination from high viral load specimens in adjacent wells of testing plates were common causes for false positive results. DISCUSSION: SARS-CoV-2 RT-PCR testing is associated with a small number of false positive results, most easily recognized in asymptomatic non-exposed patients. Implementation of a limited retesting protocol identifies clinically significant testing errors and allows review and improvement of laboratory procedures.

Reliability of Magnetic Resonance Spectroscopy and Positron Emission Tomography Computed Tomography in Differentiating Metastatic Brain Tumor Recurrence from Radiation Necrosis.

BACKGROUND: Clinical and/or neuroimaging changes after whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for metastatic brain tumor(s) present the clinical dilemma of differentiating tumor recurrence from radiation necrosis. Several imaging modalities attempt to answer this clinical question, including magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) computed tomography (CT). We evaluated our experience regarding the ability of MRS and PET CT to differentiate tumor recurrence from radiation necrosis in patients who have received WBRT or SRS. METHODS: We retrospectively reviewed records of 242 patients with previous WBRT or SRS to identify those who had MRS and/or PET CT to differentiate tumor recurrence from radiation necrosis. Patients were sorted into true-positive, false-positive, false-negative, and true-negative groups on the basis of imaging interpretation and clinical course combined with surgical pathology results or reaction to nonsurgical treatments including SRS, dexamethasone, or observation. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were then calculated. RESULTS: Of 25 patients presenting such diagnostic questions, 19 were evaluated with MRS and 13 with PET CT. MRS sensitivity was 100%, specificity was 50%, and accuracy was 81.8%, whereas PET CT sensitivity was 36.4%, specificity was 66.7%, and accuracy was 42.9%. CONCLUSIONS: MRS has better accuracy than PET CT and a high negative predictive value, therefore making it more useful in distinguishing recurrent tumor from radiation necrosis. We encourage correlation with symptoms at imaging to aid in clinical decision making.

Bilateral Vision Loss with p-ANCA Associated Lymphocytic Vasculitis.

Purpose: To describe a case of p-ANCA associated vasculitis in a patient with bilateral vision loss with no systemic symptoms or signsMethods: A descriptive review of a caseResults: We report a case of bilateral sequential vision loss in a 73-year-old woman who had no constitutional symptoms except headache and was found to have positive p-ANCA and lymphocytic infiltration on bilateral temporal artery biopsy. Despite the early administration of systemic corticosteroids, the visual outcome was unfavorable.Conclusion: It is important to consider ANCA associated vasculitides when temporal artery biopsy does not support GCA.

Herpes in the Heart: A Case of Widely Disseminated Intrauterine Herpes Simplex Virus Infection Involving Neonatal Myocardium in a 23-Week Gestationally Aged Neonate.

We report a rare case of disseminated herpes simplex virus (HSV) infection in an extremely preterm neonate. Herpes Simplex Virus-2 (HSV-2) is the leading cause of genital ulcer disease in adults and is the most common cause of neonatal herpes, a rare infection associated with long-term neurologic impairment and high mortality. HSV-2 can be transmitted perinatally via direct mucosal or skin contact. Most neonates are infected intrapartum. However, intrauterine transmission does occur, though rarely. The pattern of dissemination described in our patient differs from previous case reports. Most reports indicate that intrauterine HSV infections have a typical triad of cutaneous manifestations, ophthalmologic findings, and neurologic involvement. However, we report the first case of intrauterine disseminated HSV infection in the heart.

Clinical outcomes of resecting scarpa's ganglion during vestibular schwannoma surgery.

Vestibular schwannomas are slow-growing tumors arising from the Schwann cells of the vestibular nerve. Scarpa's ganglion, the vestibular nerve ganglion, is located within the internal auditory meatus. Surgical treatment of vestibular schwannomas carries the potential of resecting Scarpa's ganglion along with the tumor. No prior studies have evaluated outcomes based on the presence of Scarpa's ganglion within tumor specimens. The neurosurgery patient records were queried for patients who underwent surgical resection of vestibular schwannomas at the University of Missouri Healthcare between January 1, 2008 and December 31, 2018. Inclusion criteria consisted of minimum age of 18, imaging demonstrating an eighth nerve tumor, surgical resection thereof, and a final pathological diagnosis of WHO grade I schwannoma. Data were collected retrospectively. The histological slides of the tumors were reviewed, and the presence or absence of the ganglion was noted. Outcomes analyzed included postoperative dizziness, hearing, and facial nerve function. Fifty-two patients met inclusion criteria. Ten (19%) resected tumors contained portions of the ganglion. No difference in risk of resection of ganglion occurred based on the surgical approach (p = 0.2454). Mean follow-up duration was 24.6 months ± 26.2 standard deviation. No differences in postoperative hearing or dizziness (p = 0.8483 and p = 0.3190 respectively) were present if Scarpa's ganglion was resected. House-Brackmann classification of facial nerve function at last follow-up was similar (p = 0.9190). Resection of Scarpa's ganglion with vestibular schwannomas does not increase risk of post-operative dizziness, facial nerve weakness, or hearing loss.

Assessing interobserver variability and accuracy in the histological diagnosis and classification of cutaneous neurofibromass.

BACKGROUND: Cutaneous neurofibromas (cNFs) are the most common tumors in people with neurofibromatosis type 1 (NF1) and are associated with reduced quality of life. There is currently no widely accepted standardized language for describing cNFs clinically or histopathologically. The objective of this study was to evaluate interobserver agreement across pathologists in describing and reporting of neurofibromas involving the skin. METHODS: Twenty-eight (H&E)-stained slides of cNF were scanned using an Aperio XT scanner. The digital images were reviewed by 6 pathologists, who entered free text of up to a 200 word description for each case into a REDcap database. Responses were analyzed for the most commonly used terms based on frequency, as well as agreement (reported as concordance) between reviewers. RESULTS: A set of the terms most commonly used by pathologists for the histological classification of cNF along with areas of agreement and disagreement have been identified. The study shows that there was strong agreement across reviewers that not all neurofibromas involving the skin are cutaneous neurofibromas and regarding the presence or absence of atypical features and heterologous elements. Areas of less concordance were identified and include cNF subtypes, definition of extension and pattern of growth, as well as the distinction of a cNF from a plexiform without an intraneural component involving skin. CONCLUSIONS: This work is the first step towards development of a robust classification system and devising "gold standard" histopathologic diagnostic criteria for cutaneous neurofibromas.

Extraneural Metastasis of Primary Glioma Occurring in a Setting of Occupational Ionizing Radiation Exposure.

Malignant gliomas account for 60% of all primary brain tumors in adults. Glioblastoma Multiforme (GBM) is the most common primary glial tumor with a dismal prognosis and a median survival of approximately 14 months. Extra-neural metastases from primary brain tumors are unusual with an incidence rate of less than 2%. This has been attributed to factors such as short survival, lack of true lymphatics in the CNS, and physical barriers provided by the dura, extracellular matrix, and basement membrane. Although most GBMs occur sporadically, there is a known association with therapeutic radiation exposure and with work in nuclear disaster cleanup. To our knowledge, no case of GBM with metastasis occurring in a patient with occupational radiation exposure currently exists in the literature. In this article, we present a case of GBM with lung metastasis occurring in a 51-year-old Caucasian male, whose history is significant for occupational exposure to ionizing radiation, and review the literature on GBM risk factors and potential mechanisms of metastasis.