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Emerging evidence from autopsy studies indicates that interface astroglial scarring (IAS) at the gray-white matter junction is a pathological signature of repeated blast brain injury in military personnel. However, there is currently no in vivo neuroimaging test that detects IAS, which is a major barrier to diagnosis, prevention, and treatment. In 27 active-duty U.S. Special Operations Forces personnel with high levels of cumulative blast exposure, we performed translocator protein (TSPO) positron emission tomography (PET) using [ 11 C]PBR28 to detect neuroinflammation at the cortical gray-white matter interface, a neuroanatomic location where IAS has been reported in autopsy studies. TSPO signal in individual Operators was compared with the mean TSPO signal in a control group of nine healthy civilian volunteers. We identified five Operators (18.5%) with TSPO signal at the cortical gray-white matter interface that was more than 2 standard deviations above the control mean. Cumulative blast exposure, as measured by the generalized blast exposure value, did not differ between the five Operators with elevated TSPO signal and the 22 Operators without elevated TSPO signal. While the pathophysiologic link between neuroinflammation and IAS remains uncertain, these preliminary observations provide the basis for further investigation into TSPO PET as a potential biomarker of repeated blast brain injury., (© The Author(s) 2024. Published by Mary Ann Liebert, Inc.)

2023 was an important year for research in traumatic brain injury (TBI), particularly as it concerned interests in neuropathology. After reviewing the literature, we present the advancements that we felt were of particular importance to the neuropathology community. Highlighted are articles that report upon: (1) the first large-cohort assessment for the neuropathology of intimate partner violence, (2) the assessment of chronic traumatic encephalopathy (CTE) in young athletes, (3) the observation of cortical sulcal depth vascular changes in CTE, (4) a proposal for a tau immunohistochemical panel to evaluate complex cases of CTE in the context of multiple tauopathies, (5) the relationship of TBI and/or CTE with TDP-43 pathology, (6) repetitive TBI inducing pathology in C9orf72 -transgenic mice, (7) radiologic patterns of head and neck injury following vehicular underbody blast exposure, (8) chronic alterations in brain metal content following repetitive impact TBI, (9) neurovascular unit injury following low-level blast exposure, and finally (10) an assessment of Muhammad Ali's clinical history leading to the conclusion that he suffered from young-onset, idiopathic Parkinson Disease. We close our writing with in memoriam to Dr. Byron A. Kakulas, a renowned figure in the neuropathology of spinal cord injury who we lost in 2023., Competing Interests: The authors do not have any conflict of interest to declare.

Chronic traumatic encephalopathy (CTE) is defined by perivascular neuronal phosphorylated-tau accumulation at cortical sulcal depths. CTE has been mainly described in the context of repetitive, impact-type traumatic brain injury (rTBI), principally from contact sports. Rarely, CTE has been associated with single TBIs, including in relationship to healed leucotomy sites in brains from formerly institutionalized psychiatric patients without documented rTBI. Given that leucotomy principally involves severing of white matter, this could suggest involvement of axonal injury in CTE pathophysiology. We present three cases wherein isolated CTE pathology was identified adjacent to distinct white matter lesions. Case 1 is a 41-year-old man with history of hereditary hemorrhagic telangiectasia and resection of a cerebral arteriovenous malformation (AVM). Case 2 is a 46-year-old man with glioblastoma. Case 3 is a 52-year-old man with a remote cerebral infarct. Isolated CTE lesions were found adjacent to the aforementioned pathologies in each case. Additional CTE lesions were not identified despite extensive sampling. Multiple age-related tau astrogliopathy (ARTAG)-like lesions were also identified at other sulcal depths near the AVM resection site in Case 1. These cases may provide insights regarding the pathophysiology of the CTE pathognomonic lesion and the development of ARTAG-like pathology adjacent to long-standing mass lesions., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Background: Comprehensive analysis of brain tumor incidence and survival in the Veteran population has been lacking., Methods: Veteran data were obtained from the Veterans Health Administration (VHA) Medical Centers via VHA Corporate Data Warehouse. Brain tumor statistics on the overall US population were generated from the Central Brain Tumor Registry of the US data. Cases were individuals (≥18 years) with a primary brain tumor, diagnosed between 2004 and 2018. The average annual age-adjusted incidence rates (AAIR) and 95% confidence intervals were estimated per 100 000 population and Kaplan-Meier survival curves evaluated overall survival outcomes among Veterans., Results: The Veteran population was primarily white (78%), male (93%), and between 60 and 64 years old (18%). Individuals with a primary brain tumor in the general US population were mainly female (59%) and between 18 and 49 years old (28%). The overall AAIR of primary brain tumors from 2004 to 2018 within the Veterans Affairs cancer registry was 11.6. Nonmalignant tumors were more common than malignant tumors (AAIR:7.19 vs 4.42). The most diagnosed tumors in Veterans were nonmalignant pituitary tumors (AAIR:2.96), nonmalignant meningioma (AAIR:2.62), and glioblastoma (AAIR:1.96). In the Veteran population, survival outcomes became worse with age and were lowest among individuals diagnosed with glioblastoma., Conclusions: Differences between Veteran and US populations can be broadly attributed to demographic composition differences of these groups. Prior to this, there have been no reports on national-level incidence rates and survival outcomes for Veterans. These data provide vital information that can drive efforts to understand disease burden and improve outcomes for individuals with primary brain tumors., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2023.)

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life., (2023.)

2022 was a productive year for research in traumatic brain injury (TBI) and resultant neuropathology. After an extensive review, we present related studies and publications which we felt were of particular importance to the neuropathology community. First, 2022 was highlighted by important advancements in the diagnosis and, moreover, our understanding of chronic traumatic encephalopathy (CTE). Important publications include a pair concluding that CTE primarily concerns neuronal accumulation of phosphorylated tau ( ptau ), but that glial ptau accumulation often helps to facilitate diagnosis. In addition, a new large community study from Australia continues the indication that CTE is relatively uncommon in the community, and the first large-cohort study on brains of military personnel similarly demonstrates that CTE appears to be uncommon among service members and does not appear to explain high rates of neuropsychiatric sequelae suffered by the warfighter. The causation of CTE by impact-type TBI was supported by the application of the Bradford Hill criteria, within the brains of headbutting bovids, and interestingly within an artificial head model exposed to linear impact. Finally, a large-scale analysis of APOE genotypes contends that gene status may influence CTE pathology and outcomes. In experimental animal work, a study using mouse models provided important evidence that TDP-43 facilitates neurodegenerative pathology and is implicated in cognitive dysfunction following TBI, and another study using a swine model for concussion demonstrated that evidence that axonal sodium channel disruption may be a driver of neurologic dysfunction after concussion. Finally, we end with memoriam to Dr. John Q. Trojanowski, a giant of neurodegenerative research and an important contributor to the neurotrauma literature, who we lost in 2022., Competing Interests: The authors do not have any conflict of interest to declare.

Background. Frozen sections (FS) are common in neurosurgery to address varied clinical concerns. Artifacts in central nervous system (CNS) FS can be severe and affect or hinder interpretation. We performed a case-control study using a semiquantitative scale: the Histologic Preservation Score (HPS), and a quantitative scale: the Ice Crystal Vacuolization Score (ICVS), to compare the histologic quality yielded by snap- versus cryostat freezing techniques. Material and Methods. All specimens were sectioned in 2 halves, one half was used for FS and the other for permanent evaluation. HPS assigns a distortion score to the FS sample using the non-frozen half as the comparator: 1  =  minimal, 2  =  slight, 3  =  moderate, 4 & 5  =  severe. The ICVS is the average size in µm of the 5 largest vacuoles/0.05 mm 2 , evaluated on digitized slides. Results. 86 CNS-FS were collected: 22 snap- and 64 cryostat-FS. Significant differences in HPS: 2.28 versus 2.84 ( p <0.05 ) and ICVS 7.47 versus 14.56 ( p   <   0.001 ) were obtained for snap- versus cryostat-FS, respectively. HPS and ICVS showed a strong correlation: R 2  = 0.63, p   <   0.0001. Histologic distortion was worse for neuroglial than mesenchymal tissue by both methods; however, a significant difference was only observed in cryostat-FS: HPS: 3.23 versus 2.33, p   <   0.001 ; ICVS: 16.86 μm versus 10.26 μm, p   <   0.001 . Conclusion. Snap-FS yields better histologic quality than cryostat-FS for CNS-FS, and the difference is more pronounced in neuroglial samples. HPS and ICVS correlate strongly, indicating that the histologic quality is inversely proportional to water-crystallization. These results may apply to other areas of surgical pathology.

There are currently no non-invasive imaging methods available for astrogliosis assessment or mapping in the central nervous system despite its essential role in the response to many disease states, such as infarcts, neurodegenerative conditions, traumatic brain injury and infection. Multidimensional MRI is an increasingly employed imaging modality that maximizes the amount of encoded chemical and microstructural information by probing relaxation (T1 and T2) and diffusion mechanisms simultaneously. Here, we harness the exquisite sensitivity of this imagining modality to derive a signature of astrogliosis and disentangle it from normative brain at the individual level using machine learning. We investigated ex vivo cerebral cortical tissue specimens derived from seven subjects who sustained blast-induced injuries, which resulted in scar-border forming astrogliosis without being accompanied by other types of neuropathological abnormality, and from seven control brain donors. By performing a combined post-mortem radiology and histopathology correlation study we found that astrogliosis induces microstructural and chemical changes that are robustly detected with multidimensional MRI, and which can be attributed to astrogliosis because no axonal damage, demyelination or tauopathy were histologically observed in any of the cases in the study. Importantly, we showed that no one-dimensional T1, T2 or diffusion MRI measurement can disentangle the microscopic alterations caused by this neuropathology. Based on these findings, we developed a within-subject anomaly detection procedure that generates MRI-based astrogliosis biomarker maps ex vivo, which were significantly and strongly correlated with co-registered histological images of increased glial fibrillary acidic protein deposition (r = 0.856, P < 0.0001; r = 0.789, P < 0.0001; r = 0.793, P < 0.0001, for diffusion-T2, diffusion-T1 and T1-T2 multidimensional data sets, respectively). Our findings elucidate the underpinning of MRI signal response from astrogliosis, and the demonstrated high spatial sensitivity and specificity in detecting reactive astrocytes at the individual level, and if reproduced in vivo, will significantly impact neuroimaging studies of injury, disease, repair and aging, in which astrogliosis has so far been an invisible process radiologically., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Biopsies of the liver, lung, and kidney are performed for many indications, including organ dysfunction, mass lesions, and allograft monitoring. The diagnosis depends on the sample, which may or may not be representative of the lesion or pathology in question. Further, biopsies are not without risk of complications. Autopsies are a resource for assessing the accuracy of biopsy diagnoses and evaluating possible complications. Herein, we aimed to compare liver, lung, and kidney biopsy diagnoses with those from autopsies conducted soon after the procedure and to assess the contribution of biopsy to mortality. A 28-year search of our database identified 147 patients who were autopsied after dying within 30 days of a liver, lung, or kidney biopsy. The concordance of the biopsy diagnosis with the autopsy findings was determined. Finally, medical records were reviewed to determine the likelihood that a biopsy contributed to the patient's death. The contribution of the biopsy to death was categorized as "unlikely," "possible," or "probable." Overall concordance between biopsy and autopsy diagnoses was 87% (128/147), including 95% (87/92), 71% (32/45), and 90% (9/10) for liver, lung, and kidney biopsies, respectively. Concordance was lower for biopsies of suspected neoplasms versus non-neoplastic diseases. Lung biopsy concordance was higher for wedge biopsy versus needle or forceps biopsy. A biopsy was determined to at least "possibly" contribute to death in 23 cases (16%). In conclusion, an autopsy is an important tool to validate liver, lung, or kidney biopsy diagnoses. Confirmation of biopsy diagnoses via post-mortem examination may be particularly valuable when patients die soon after the biopsy procedure. Furthermore, an autopsy is especially useful when patients die soon after a biopsy in order to determine what role, if any, the procedure played in their deaths. Though biopsy complications are uncommon, a biopsy may still contribute to or precipitate death in a small number of patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Priemer et al.)

The brain of a 58-year-old woman was included as a civilian control in an ongoing autopsy study of military traumatic brain injury (TBI). The woman died due to a polysubstance drug overdose, with Coronavirus Disease 2019 (COVID-19) serving as a contributing factor. Immunohistochemical stains for β-amyloid (Aβ), routinely performed for the TBI study, revealed numerous, unusual neocortical Aβ deposits. We investigated the autopsied brains of 10 additional young patients (<60 years old) who died of COVID-19, and found similar Aβ deposits in all, using two different Aβ antibodies across three different medical centers. The deposits failed to stain with Thioflavin-S. To investigate whether or not these deposits formed uniquely to COVID-19, we applied Aβ immunostains to the autopsied brains of COVID-19-negative adults who died with acute respiratory distress syndrome and infants with severe cardiac anomalies, and also biopsy samples from patients with subacute cerebral infarcts. Cortical Aβ deposits were also found in these cases, suggesting a link to hypoxia. The fate of these deposits and their effects on function are unknown, but it is possible that they contribute to the neurocognitive sequelae observed in some COVID-19 patients. Our findings may also have broader implications concerning hypoxia and its role in Aβ deposition in the brain., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The year 2021 was highlighted by many notable advancements in the field of neurotrauma and associated neuropathology. After a thorough review of the new literature, we call attention to what we feel are among the most impactful studies and publications. In brief, 2021 was marked by published consensus papers related to the diagnosis of chronic traumatic encephalopathy (CTE) and its clinical counterpart, traumatic encephalopathy syndrome. There was also progress toward our understanding of the impact of traumatic brain injury (TBI) on the general population, and how strongly CTE pathology may, or may not, commonly underlie long term clinical sequelae following TBI. Next, a critical new study has identified that acetylated tau protein, which has been found to be increased in the brains of Alzheimer's disease and CTE patients, can be induced by TBI, is neurotoxic, and that its reduction via already-existent therapeutics is neuroprotective. There are also several important updates that pertain to military and blast TBI, particularly as they pertain to establishing causality of interface astroglial scarring. In addition, and for the first time, a specific signature for diffuse axonal injury has been identified in ex vivo tissues using multidimensional magnetic resonance imaging, providing promise for the clinical diagnosis of this lesion. Finally, several important radiologic studies from 2021 have highlighted long-standing structural reductions in a number of brain regions following both mild and severe TBI, emphasizing the need for neuropathologic correlation. We end by highlighting an editorial piece discussing how TBI is portrayed in entertainment media and how this impacts public perception of TBI and its consequences., Competing Interests: The authors do not have any conflict of interest to declare.

Background: Persistent neuropsychiatric sequelae may develop in military personnel who are exposed to combat; such sequelae have been attributed in some cases to chronic traumatic encephalopathy (CTE). Only limited data regarding CTE in the brains of military service members are available., Methods: We performed neuropathological examinations for the presence of CTE in 225 consecutive brains from a brain bank dedicated to the study of deceased service members. In addition, we reviewed information obtained retrospectively regarding the decedents' histories of blast exposure, contact sports, other types of traumatic brain injury (TBI), and neuropsychiatric disorders., Results: Neuropathological findings of CTE were present in 10 of the 225 brains (4.4%) we examined; half the CTE cases had only a single pathognomonic lesion. Of the 45 brains from decedents who had a history of blast exposure, 3 had CTE, as compared with 7 of 180 brains from those without a history of blast exposure (relative risk, 1.71; 95% confidence interval [CI], 0.46 to 6.37); 3 of 21 brains from decedents with TBI from an injury during military service caused by the head striking a physical object without associated blast exposure (military impact TBI) had CTE, as compared with 7 of 204 without this exposure (relative risk, 4.16; 95% CI, 1.16 to 14.91). All brains with CTE were from decedents who had participated in contact sports; 10 of 60 contact-sports participants had CTE, as compared with 0 of 165 who had not participated in contact sports (point estimate of relative risk not computable; 95% CI, 6.16 to infinity). CTE was present in 8 of 44 brains from decedents with non-sports-related TBI in civilian life, as compared with 2 of 181 brains from those without such exposure in civilian life (relative risk, 16.45; 95% CI, 3.62 to 74.79)., Conclusions: Evidence of CTE was infrequently found in a series of brains from military personnel and was usually reflected by minimal neuropathologic changes. Risk ratios for CTE were numerically higher among decedents who had contact-sports exposure and other exposures to TBI in civilian life than among those who had blast exposure or other military TBI, but the small number of CTE cases and wide confidence intervals preclude causal conclusions. (Funded by the Department of Defense-Uniformed Services University Brain Tissue Repository and Neuropathology Program and the Henry M. Jackson Foundation for the Advancement of Military Medicine.)., (Copyright © 2022 Massachusetts Medical Society.)

Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change  (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC., (© 2022. The Author(s).)

Individuals with dementia may come to forensic autopsy, partly because of non-natural deaths (e.g. fall-related), and/or concerns of abuse/neglect. At the New York City Office of Chief Medical Examiner (NYC OCME), brains from such cases are submitted for neurodegenerative disease (ND) work-up. Seventy-eight sequential cases were evaluated using a recently published condensed protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer disease (AD), a cost-cutting innovation in diagnostic neuropathology. ND was identified in 74 (94.9%) brains; the most common were AD (n = 41 [52.5%]), primary age-related tauopathy (n = 26 [33.3%]), and Lewy body disease ([LBD], n = 25 [32.1%]). Others included age-related tau astrogliopathy, hippocampal sclerosis of aging, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, argyrophilic grain disease, and Creutzfeldt-Jakob disease. 26.8% of AD cases involved a non-natural, dementia-related death, versus 40.0% for LBD. Finally, 70 (89.7%) cases had chronic cerebrovascular disease, 53 (67.9%) being moderate-to-severe. We present a diverse distribution of NDs notable for a high rate of diagnoses associated with falls (e.g. LBD), a potential difference from the hospital neuropathology experience. We also report a high burden of cerebrovascular disease in demented individuals seen at the NYC OCME. Finally, we demonstrate that the aforementioned condensed protocol is applicable for a variety of ND diagnoses., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

This article focuses on neuropsychiatric clinical expression and neuropathology associated with chronic traumatic encephalopathy (CTE), which is thought to develop years after traumatic brain injury. The incidence, prevalence, additional risk factors, and pathophysiology remain largely unknown. CTE is considered a tauopathy because the endogenous brain protein tau, in its hyperphosphorylated state (p-tau), defines the predominant neuropathological findings and may underlie aspects of cell toxicity, synapse and circuit dysfunction, and clinical signs and symptoms. We discuss pathophysiological mechanisms possibly affecting p-tau accumulation. Finally, we interweave how clinical features and neuroanatomical sites associated with CTE potentially intersect with posttraumatic stress disorder., Competing Interests: Disclosure The opinions expressed herein are those of the authors and are not necessarily representative of those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the US Army, Navy, or Air Force., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context.—: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting., Objective.—: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy., Design.—: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses., Results.—: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited., Conclusions.—: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic., (© 2021 College of American Pathologists.)

Context.—: Electronic cigarettes are handheld devices that heat an inner liquid containing chemicals to be aerosolized and inhaled, and have become a popular alternative to conventional cigarettes. Their use, termed vaping, has been linked to severe injury, with 2711 cases of associated lung injury and 60 deaths reported to the Centers for Disease Control and Prevention at the time of writing. Published case reports and series have emerged detailing clinical and imaging characteristics of vaping-induced lung injury. However, the pathologic characteristics of these induced injuries are still being established, particularly findings occurring over time., Objective.—: To illustrate the autopsy findings of an older patient who died of vaping-induced injury after prolonged symptomology and to provide a review of the most recent literature regarding the basic science, epidemiology, clinical presentation, imaging characteristics, and pathology of vaping-induced lung injury., Data Sources.—: Autopsy case and peer-reviewed literature., Conclusions.—: Vaping-induced lung injury has emerged as a public health issue, and this case represents a rare opportunity to evaluate this issue at autopsy. Most commonly, the injury has been attributed to tetrahydrocannabinol product use as opposed to nicotine. This case demonstrates that as today's young and relatively healthy "vapers" grow older and develop the comorbidities that come with advanced age, there is serious risk of chronic lung damage from vaping that could result in death. Further observations and studies, particularly autopsy evidence, are clearly important to understand the possible outcomes., (© 2020 College of American Pathologists.)

Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors., Competing Interests: M.H. has consulted or served on an advisory board for Celgene, Abbvie, BTG International, and NewLink Genetics. M.L. has research support from Arbor, BMS, Accuray, DNAtrix, Tocagen, Biohaven, and Kyrin-Kyowa, and has consulted for Tocagen, SQZ Technologies, VBI, and Stryker. The authors declare that there are no competing interests., (Copyright © 2020 by S. Karger AG, Basel.)

Arteriovenous malformations (AVM) of the brain are considered congenital. Most AVMs are presumably sporadic; however, rare familial cases occur and they may be observed in certain genetic disorders. We sought to determine the frequency of KRAS mutations and their association with clinicopathologic characteristics. We searched our neuropathology database from 2014-2017 for resected AVMs of the brain or dura mater. Twenty-one AVMs were tested (12 females, 9 males; average age: 32 years). KRAS mutations were found in 6/21 cases (28.5%). Five mutations were p.G12 V, and one p.G12C. The KRAS-mutant group contained 4 females and 2 males, with an average age of 28 years, compared to 34 years in the non-mutant group (P = .54). The average AVM size in the KRAS-mutant group was 3.9 cm, compared to 3.1 cm in the non-mutant group (P = .52). There were no histologic differences between KRAS-mutant and non-mutant cases. In summary, KRAS mutations occur in almost one-third of brain AVMs. KRAS p.G12 V was the most common mutation identified. We also demonstrate the first reported instance of a KRAS p.G12C mutation in a brain AVM. The mean age of patients with KRAS-mutant AVMs was lower than the non-mutant group, and the mean size larger. Histologic characteristics were equally distributed between KRAS-mutant and non-mutant groups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Fine needle aspiration (FNA) diagnoses are usually confirmed via surgical pathology or via evaluation of clinical outcomes. However, such confirmation may not occur for patients who die shortly after FNA, and autopsy may be a useful quality assessment tool in these cases. Also, there is little data investigating the relationship between FNA and mortality. We sought to demonstrate the autopsy as a quality assessment tool for the FNA and assess the contribution of FNA to mortality in patients who die soon after the procedure., Methods: A search of our database was performed from 1992 to 2016 for patients who were autopsied after dying within 30 d of an FNA. Concordance between findings from FNA, autopsy, and any intervening surgical pathology material was determined. Finally, a subjective determination of the likelihood that FNAs contributed to deaths was made by reviewing autopsy reports. The contribution was categorised as either "unlikely", "possible", or "probable"., Results: Fifty-eight patients (average age = 58 y) met the search criteria. Thirty-six (62%) patients had malignancies. Surgical pathology material was obtained concurrently or following FNA in 20 cases (34%). There was 73% concordance between FNA and autopsy findings, which compares to 80% concordance between FNA and surgical pathology diagnoses. The FNA was determined to be at least possibly contributory to death in 7/58 cases (3 cases designated as "probable," and 4 as "possible")., Conclusion: Autopsy can be used to validate FNA diagnoses and, like surgical pathology, confirms that FNA diagnoses are mostly accurate. However, in a small number of patients, FNA can precipitate death., (© 2018 Wiley Periodicals, Inc.)

Background: Small-cell carcinoma (SCC) of the urinary bladder frequently appears alongside urothelial carcinoma, suggesting common clonality. TERT promoter mutations have been recently implicated in urothelial carcinogenesis., Objective: To investigate the degree to which TERT promoter mutations are involved in SCC of the urinary bladder, the linked tumorigenesis between urothelial carcinoma and SCC of the urinary bladder, and the molecular distinctions between SCC of the urinary bladder and of the prostate., Design, Setting, and Participants: We investigated TERT promoter mutations in 53 cases of SCC of the urinary bladder and in 26 cases of SCC of the prostate using laboratory-based studies of tissue samples and clinical data., Outcome Measurements and Statistical Analysis: We measured the frequency of TERT promoter mutations in SCCs of the urinary bladder and prostate, and concordance of the mutation status between concurrent urinary bladder SCC and urothelial carcinoma., Results and Limitations: TERT promoter mutations were detected in 29/53 (55%) cases of urinary bladder and 0/26 (0%) cases of prostate SCC. Of 25 cases with concurrent urinary bladder SCC and non-small-cell components, all cases harbored identical TERT promoter mutation status in both phenotypes., Conclusions: TERT promoter mutations are found in more than half of urinary bladder SCCs. Mutation status is also identical in urothelial carcinoma and SCC components of concomitant malignancies, providing evidence of a common clonality. TERT promoter mutation status can differentiate SCC of the urinary bladder from prostate SCC, suggesting potential diagnostic use., Patient Summary: Small-cell carcinoma of the urinary bladder shares a common clonal origin with conventional urothelial carcinoma and may arise from a heterogeneous subclone. TERT promoter mutations may have utility as a differential biomarker for determining the primary site of a genitourinary small-cell carcinoma., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Chordomas are neoplasms that typically arise from midline skeletal structures and rarely originate within the intradural compartment of the CNS. A chordoma arising from the corpus callosum has not been previously described. The authors report the surgical management of a chordoma originating within the splenium of the corpus callosum. To determine the incidence and distribution of intracranial intradural chordoma, a literature search for additional cases was performed. MEDLINE was searched using the MeSH keyword "chordoma," yielding 2010 articles. These articles were screened for cases of primary intradural chordoma rostral to the craniocervical junction, which led to the identification of 46 relevant articles. The authors report the case of a 69-year-old man who initially presented with nonspecific neurological symptoms including spatial disorientation and cognitive decline. These symptoms eventually prompted intracranial imaging, including MRI, which revealed a ring-enhancing, heterogeneous, cystic mass localized within the splenium of the corpus callosum and extending into the bilateral ventricles. The lesion was believed to represent a high-grade glioma and the patient underwent a left interhemispheric approach and subtotal resection. After pathologic evaluation confirmed a diagnosis of an anaplastic chordoma, the patient underwent further resection. A gross-total resection (GTR) was achieved with a transfalcine approach to the contralateral portion of the tumor. Postoperatively, the patient had a partial left homonymous quadrantanopsia, but was otherwise at his neurological baseline. Proton beam radiotherapy was performed to the resection cavity but diffuse intraventricular disease ensued. The results of a literature search suggest that a chordoma arising in the corpus callosum has not been previously described. The present case demonstrates that chordomas can occur in the corpus callosum, and illustrates the utility of a transfalcine approach for GTR of lesions in this location, as well as the need for improved strategies to prevent intraventricular dissemination.

Thymomas are associated with autoantibody formation. The most common are anti-acetylcholine receptor antibodies, which correspond to myasthenia gravis (MG). Other autoantibodies, such as antistriational antibodies, can occur, but their relation to clinical syndromes is frequently uncertain. The etiology of antistriational antibodies is also poorly understood. In this case, a 61-year-old man with a history of thymoma was admitted with respiratory failure. The patient was positive for anti-acetylcholine receptor antibodies and antistriational antibodies. He developed cardiogenic shock and died within 2 days despite aggressive therapy. Laboratory studies revealed elevated cardiac enzymes and marked IgG elevation against Coxsackie A virus serotypes 9 and 24. Subclinical IgG elevations against additional Coxsackie A and Coxsackie B virus serotypes were also noted. Autopsy revealed lymphohistiocytic infiltrates with multinucleated giant cells in the myocardium and skeletal muscles, including the diaphragm. Giant cell polymyositis and myocarditis is a rare, lethal complication in patients with thymoma and MG. The pathogenesis is uncertain. An autoimmune process, possibly elicited by antistriational antibodies, has been suggested. The coexistence of antistriational antibodies and Coxsackie viral serologies has not been reported. This case may suggest that giant cell polymyositis and myocarditis in patients with thymoma and MG is a postviral autoimmune process.

Aims: Accurate histological diagnosis and classification of germ cell tumours (GCTs) is key to informing successful therapeutic and surveillance strategy. The modern therapeutic approach for yolk sac tumour (YST) is highly curative. Because YST takes on a large morphological spectrum, it can be confused for other GCT subtypes as well as somatic carcinomas, particularly when YST presents in an extragonadal or a metastatic setting. Currently available immunohistochemical markers are limited by suboptimal sensitivity and specificity. We reported recently that ZBTB16 is a sensitive and specific marker for testicular YST. ZBTB16 is absent in other GCTs and in most common somatic carcinomas, including those of gastrointestinal, pancreatobillary, respiratory, genitourinary and gynaecological tracts. The purpose of this study is to investigate the diagnostic utility of ZBTB16 in the settings of metastatic and extragonadal YST., Methods and Results: We studied 32 archived metastatic and four extragonadal primary YSTs as well as 51 somatic malignancies for their immunohistochemical expression of ZBTB16. For comparison, α-fetoprotein (AFP) and glypican-3 were also studied in parallel. Our results demonstrated an overall sensitivity of 91.6% for ZBTB16 in detecting metastatic and extragonadal YSTs. The non-YST elements (teratoma and embryonal carcinoma) in 15 YST-containing metastatic mixed GCTs were non-reactive. With the exception of occasional myoepithelial cells of salivary gland carcinoma, all the 51 somatic malignancies were negative for ZBTB16., Conclusions: ZBTB16 is a sensitive and specific marker for YST and is diagnostically superior to AFP and glypican-3 in metastatic and extragonadal settings., (© 2017 John Wiley & Sons Ltd.)

Background: Radical orchiectomy specimens present a unique set of challenges for pathology assessment owing to their rarity and complexity. This study compares second opinion pathology reports generated at a single, large academic institution to primary reports from outside hospitals., Methods: A database search was conducted for orchiectomy cases that were sent to our institution for management of testicular cancer from 2014 to 2015. Cases sent for consultation without a finalized diagnosis from the outside hospitals were excluded. A total of 221 consecutive cases were evaluated for comparison of final diagnoses between the outside institution and central pathology review., Results: This study revealed significant discrepancy involving multiple parameters between original and second opinion pathology reports. Of 221 cases of germ cell tumors assessed, 31% showed some discrepancy of histologic subtype. Overall, reporting of lymphovascular invasion changed in 22% of cases; of those, initially called positive 23% were changed to negative and of those initially called negative 12% were changed to positive. Although the overall discrepancy for spermatic cord invasion was 9%, an initial positive diagnosis was negated 35% of the time. The pathologic stage was altered in 23% of cases, mostly secondary to differences interpreting lymphovascular and spermatic cord invasion., Conclusion: Pathologists evaluating orchiectomy specimens should be aware of the major pitfalls in classification and staging, many of which may affect patient management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The paratestis (PT) is defined by the testicular tunics, epididymis, spermatic cord, rete testis, and embryonic remnants. It gives rise to a large diversity of pathologies, including those of soft tissue, which may prompt orchiectomy. We performed a 17-year search of our database for orchiectomies for a PT soft-tissue mass. In a total of 4741 orchiectomy specimens, 138 orchiectomies were performed for primary neoplastic or nonneoplastic masses of the PT soft tissue or had an incidental PT soft-tissue mass. Of these, 65.9% were neoplastic. The mean age was 40.2 years (range: <1 to 87 years) and was similar for neoplastic and nonneoplastic lesions. The most common malignancies were rhabdomyosarcoma (31/63 malignancies), liposarcoma (19/63), and leiomyosarcoma (5/63), with the former occurring in younger patients (average: 18.3 years). No malignancies were incidental. The most common benign neoplasm was spermatic cord lipoma (24/28 of benign neoplasms); however, most were incidental. This was followed by leiomyoma (3/28) and hemangioma (1/28). The most common nonneoplastic lesions were adrenal rests (22/47 nonneoplastic cases); however, all were incidental findings. Of 47 nonneoplastic masses, 22 prompted orchiectomy, and of these, the most common diagnosis was fibrous/nodular periorchitis (11/47). Of 88 nonincidental lesions, 25 were either benign neoplasms (3/25) or nonneoplastic (22/25). These data indicate that PT soft-tissue neoplasms prompting orchiectomy are disproportionately rhabdomyosarcomas, though these are principally in young patients. In older patients, malignancies are more frequently liposarcomas. However, almost one-third of orchiectomies performed for PT soft-tissue masses yield benign lesions, indicating an opportunity to reduce unnecessary procedures.

Neuroendocrine neoplasms of the prostate represent a multifarious group of tumors that exist both in pure forms and associated with prostatic adenocarcinoma. Morphologically, neuroendocrine cells in prostate neoplasms can range from being indistinguishable from surrounding prostate adenocarcinoma cells to having high-grade neuroendocrine appearances similar to neuroendocrine malignancies of other organs. On the molecular level, neuroendocrine malignancies arising in the setting of prostate adenocarcinoma have been the subject of a large amount of recent research, most of which has supported the conclusion that neuroendocrine malignancy within the prostate develops as a transdifferentiation from prostate adenocarcinoma. There has not, however, been substantial investigation into rare, pure neuroendocrine malignancies and the possibility that these tumors may have a different cell of origin and molecular genesis. Here, we discuss the morphologic spectrum of malignant neuroendocrine prostate neoplasms and review the most recent molecular data on the subject of malignant neuroendocrine differentiation in prostatic adenocarcinoma. In reflection of the most recent data, we also discuss diagnostic classification of prostate neuroendocrine tumors with reference to the 2016 World Health Organization (WHO) classification. We discuss the reporting of these tumors, placing emphasis on the differentiation between pure and mixed neuroendocrine malignancies so that, in the least, they can be easily identified for the purposes of future clinical and laboratory-based investigation. Finally, we suggest a designation for an unclassifiable (or not otherwise specified) high-grade neuroendocrine prostate malignancy whose features do not easily place it into one of the WHO diagnostic entities.