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Acute hemorrhagic leukoencephalitis (AHL) is an acute, hemorrhagic demyelinating disease thought to be caused by an immune-mediated process. Acute hemorrhagic leukoencephalitis is both diagnostically challenging and fatal in the majority of cases. We present two cases of AHL unexpectedly diagnosed at autopsy. These cases demonstrate the often nonspecific and challenging nature of AHL clinical presentation, review neuropathological mimics, and emphasize the importance of considering this diagnosis in the forensic setting.

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

Primary extracranial meningiomas are rare neoplasms, frequently misdiagnosed, resulting in inappropriate clinical management. To date, a large clinicopathologic study has not been reported. One hundred and forty-six cases diagnosed between 1970 and 1999 were retrieved from the files of the Armed Forces Institute of Pathology. Histologic features were reviewed, immunohistochemistry analysis was performed (n = 85), and patient follow-up was obtained (n = 110). The patients included 74 (50.7%) females and 72 (49.3%) males. Tumors of the skin were much more common in males than females (1.7:1). There was an overall mean age at presentation of 42.4 years, with a range of 0.3–88 years. The overall mean age at presentation was significantly younger for skin primaries (36.2 years) than for ear (50.1 years) and nasal cavity (47.1 years) primaries. Symptoms were in general non-specific and reflected the anatomic site of involvement, affecting the following areas in order of frequency: scalp skin (40.4%), ear and temporal bone (26%), and sinonasal tract (24%). The tumors ranged in size from 0.5 up to 8 cm, with a mean size of 2.3 cm. Histologically, the majority of tumors were meningothelial (77.4%), followed by atypical (7.5%), psammomatous (4.1%) and anaplastic (2.7%). Psammoma bodies were present in 45 tumors (30.8%), and bone invasion in 31 (21.2%) of tumors. The vast majority were WHO Grade I tumors (87.7%), followed by Grade II (9.6%) and Grade III (2.7%) tumors. Immunohistochemically, the tumor cells labeled for EMA (76%; 61/80), S-100 protein (19%; 15/78), CK 7 (22%; 12/55), and while there was ki-67 labeling in 27% (21/78)

Guam ALS/PDC is a severe tangle forming disorder endemic to Guam with features overlapping such neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease (PD), progressive supranuclear palsy (PSP), ALS, corticobasal degeneration (CBD) and pallido-ponto-nigral degeneration (PPND). Since the prevalence is declining, we examined brain tissue from 35 clinically diagnosed Chamorro patients with ALS/PDC and two Chamorro controls autopsied between 1946 and 2006, to determine if distinct variations in the pathology could be identified up to this time. Although the age at autopsy increased by 4.5-5 years per decade, we identified no qualitative differences in pathological deposits with antibodies against tau, ubiquitin, A beta, alpha-synuclein and TDP-43, indicating that these more recently identified proteins have been involved in the neuropathogenesis over the past 6 decades. Tau and TDP-43 positive neuronal, oligodendroglial and astrocytic inclusions involving multiple nerve fiber tracts occurred in both the ALS and PDC types, reinforcing the concept that these forms are part of the same disorder. The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place.

The central nervous system atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant tumor with a heterogeneous immunohistochemical profile and with some morphologic similarity to central nervous system primitive neuroectodermal tumors (PNET). Although several studies have investigated double immunolabeling in PNET, we are aware of no studies of double labeling of ATRT. A total of 10 ATRT from surgical and consultation materials at the Children's Hospital of Philadelphia were selected and stained for a variety of antigens using indirect immunofluorescence to detect single and double labeling. Most tumor cells showed only single labeling; rare cells showed double labeling as follows: 70% of tumors coexpressed (VIM) and glial fibrillary acidic protein (GFAP), 30% smooth muscle actin and GFAP, 20% epithelial membrane antigen (EMA) and VIM, 20% EMA/GFAP, and 20% EMA/SMA. These results are discussed in view of current debates over the histogenesis of CNS PNET and ATRT, and in reference to the classification of rhabdoid tumors as an entity or phenotype.

Telepathology is the practice of digitizing histological or macroscopic images for transmission along telecommunication pathways for diagnosis, consultation, or continuing medical education. Previous studies have addressed static versus dynamic imaging in several specimen types with a wide variety of systems and communication pathways. The goal of this paper was to assess the validity of a Web-based telepathology system for frozen section consultation within the Army Medical Department. The system provides real-time, dynamic remote control of a robotic microscope over standard Internet connections. Oftentimes, a solo pathologist is called on to provide diagnostic services without the support of immediate second or expert consultation during an intraoperative consultation. The use of telepathology is attractive because it provides an opportunity for pathologists to obtain immediate consultation. For purposes of the study, 120 consecutive frozen section cases were diagnosed at a distance using the system. Intraobserver agreement between the telepathology diagnosis and glass slide diagnosis was observed. Diagnostic agreement was 100% for a wide variety of specimens. This study suggests that such a system will help support pathologists located at distant sites.

The first influenza pandemic of the twenty-first century was caused by a swine-origin, influenza A (H1N1) virus that contained genes from human, swine, and avian influenza A viruses [4]. It has long been recognized that a small subset of influenza patients develops neurologic complications [1]. Central nervous system (CNS) pathology in influenza virus infection is thought to be indirect and multifactorial [15] and whether H1N1 infects the brain or cerebrospinal fluid (CSF) remains controversial [2]. The current model is that H1N1 triggers a cytokine storm that disrupts the blood–brain barrier and activates glial cells. Subsequent disseminated intravascular coagulation (DIC) and liver and renal dysfunction triggered by hypercytokinemia may also contribute to CNS damage [15]. A number of clinical syndromes affecting the CNS have been described in the context of influenza infection. Although these syndromes have overlapping features and can be caused by other viruses and toxic agents, they have specific clinical, radiological, and laboratory criteria for their diagnosis and the pathogenesis and predisposing factors differ. Classical Reye’s syndrome is a non-inflammatory encephalopathy with associated hepatic microvesicular fatty change and hyperammonemia, and is usually precipitated by the use of salicylates [5]. Reye’slike syndrome occurs at a younger age and does not have the microvesicular fatty change and mitochondrial abnormality of classical Reye’s syndrome [13] and it is not associated with salicylate use. Hemorrhagic shock and encephalopathy syndrome (HSES) occurs in infants, and there is associated fever, shock, DIC, hepatic and renal dysfunction, and the brain shows edema with occasional intracranial hemorrhage [3]. Acute necrotizing encephalopathy (ANE) was first described in Japan in 1995 [8], and then subsequently in other countries [7, 16]. MRI and autopsy studies show bilateral symmetrical infarcts in the thalamus, basal ganglia, cerebellar and cerebral white matter, and brainstem tegmentum. CSF protein is typically elevated and the mortality rate is high. Some infants have complex febrile seizures at the onset, followed by delayed involvement of bilateral frontal lobes or the entire cerebral hemisphere [12]. Recently, familial and recurrent ANE has been described and is associated with mutation in the Ranbinding protein gene (RANBP2) [10]. Like earlier influenza pandemics, the recent pandemic of novel influenza A (H1N1) infection has resulted in a number of cases with neurological complications [2, 7, 16]. The purpose of the present study was to document the changes present in the brains of fatal H1N1 virus patients to determine if cases without documented neurologic A. Mukherjee and J.E.G. Peterson contributed equally to this work.

Erdheim-Chester disease (ECD) is an uncommon, systemic xanthogranulomatous disorder, with distinct clinicopathological features, that is rarely expected preoperatively. We describe a case that presented in the brain of a 26-yr-old male patient and clinically mimicked the appearance of a neoplasm. The final diagnosis was a surprise. In retrospect, the diagnosis was suggested by the intraoperative "squash" preparations, which demonstrated a mixed cellular proliferation of lymphohistiocytic elements and large, multinucleated cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm. To the best of our knowledge, this is the first report detailing the cytopathological features of ECD.

Generalized perforating granuloma annulare is characterized by 1 to 4 mm umbilicated papules on the extremities, and is most commonly seen in children and young adults. Trans-epithelial elimination of mucinous, degenerating collagen fibers and surrounding palisading lymphohistiocytic granulomas are important histologic features. Perforating sarcoidosis and perforating granuloma annulare may be difficult to differentiate because of a similar clinical appearance and the presence of sarcoidal granulomas in biopsy specimens. A particularly high incidence of perforating granuloma annulare has been reported in the Hawaiian Islands.

Wilms’s tumor gene (WT1) is overexpressed in a variety of hematologic malignancies and solid tumors. Recently, WT1 protein has been considered as a molecular target of cancer immunotherapy for several solid tumors and as a tool for monitoring minimal residual disease in leukemia patients. There are only few investigations on WT1 expression in central nervous system neoplasms, which suggest that the WT1 gene may play an important role in tumorigenesis of primary astrocytic tumors and that high-grade tumors express high levels of WT1 proteins. We examined 50 low-grade and high-grade gliomas using tissue microarray and immunohistochemical methods to identify WT1 protein, P53, Ki-67, GFAP, NFP, EGFR, nestin, and Neu-N expression. WT1 and nestin shared overlapping expression in all gliomas and were increased in high-grade examples, highlighting their potential use as diagnostic and prognostic tumor markers. Our results support the combined role of WT1 and nestin in glial tumorigenesis and progression.

✓Ependymomas are glial tumors that occur most often in children. In adults, ependymomas most often appear in the spinal cord. The World Health Organization recognizes several rare ependymoma subtypes, including the giant cell ependymoma of the terminal filum. The authors describe an unusual case of a posterior fossa giant cell ependymoma in an 89-year-old man presenting with vertigo and disequilibrium. Only seven cases of this tumor have been reported in the literature to date. The authors discuss the clinical presentation, radiological findings, pathological considerations, and surgical intervention in this patient and review the relevant literature.

We report the rare finding of trimyelia with divergent cord pathways in a 33 5/7-week-old fetus who died shortly after spontaneous vaginal delivery.The main autopsy findings were three separate and distinct spinal cords, arising from the medulla and exiting through three separate foramina magni. The two lateral cords coursed toward each upper extremity and the medulla split into two halves that rejoined to form a central cervical cord. Further evaluation of this anomaly revealed agenesis of the cerebellar vermis and cystic dilation of the fourth ventricle. Microscopic cross-sections of the two lateral cords demonstrated well-formed central canals, white matter, and central gray with motor neurons. Sections of the abnormal mid-cervical cord demonstrated abnormally structured cord parenchyma without central canals.Some features were consistent with iniencephaly; however, defects of the occipital bone, anterior spina bifida, and shortening of the spinal cord were absent. Although agenesis of the cerebellar vermis and cystic dilation of the fourth ventricle indicate Dandy-Walker syndrome, other features such as hydrocephalus, agenesis of the corpus callosum, infundibular hamartomas, and malformations of the inferior olives or an occipital encephalocele were absent. The possible pathogenesis of this intriguing pathological entity is briefly discussed.

In clinical practice, molecular analysis of tumor specimens is often restricted by available technology for sample preparation. Virtually all current methods require homogenization of tissues for molecule extraction. We have developed a simple, rapid, nondestructive molecule extraction (NDME) method to extract proteins and nucleic acids directly from a single fixed or frozen tissue section without destroying the tissue morphology. The NDME method is based upon exposure of micron-thick tissue section to extraction buffer with the help of heating and/or intact physical forces (ultrasound and microwave) to facilitate release of macromolecules into the buffer. The extracted proteins and nucleic acids can be used directly without further purification for downstream SDS-PAGE analysis, immunoblotting, protein array, mass spectra protein profiling, PCR, and RT-PCR reactions. Most importantly, the NDME procedure also serves as an antigen retrieval treatment, so that after NDME, the same tissue section can be used for histopathological analyses, such as H&E staining, immunohistochemistry, and in situ hybridization. Thus, the NDME method allows, for the first time, both histological diagnosis and molecular analysis on a single tissue section, whether it is from frozen or fixed tissue specimens.

BACKGROUND Published research on the clinicopathologic features of extraventricular ependymal neoplasms of the cerebral hemispheres has been scant. METHODS Thirty-two archival cases were studied to investigate the prognostic impact of clinicopathologic parameters including flow cytometry, the proliferation (Ki-67) labeling index, and p53 expression. RESULTS Among these 32 cases were 2 subependymomas, 19 ependymomas, and 11 anaplastic ependymomas. No significant gender predilection was observed, and 45% of patients were in their second or third decade of life. The left cerebral hemisphere was 1.5 times more commonly involved. On available imaging studies, lesions were often cystic, with or without a mural nodule. Tumors expressed glial fibrillary acidic protein (87%), S-100 protein (77%), cytokeratin (43%), and epithelial membrane antigen (17%). Ki-67 proliferation index paralleled tumor grade. Immunoreactivity for p53 protein was observed in the 2 cases of subependymoma, in 10 of 11 anaplastic ependymomas, and in 6 of 17 ependymomas. Flow cytometry performed in 27 tumors revealed diploidy in 20 cases and aneuploidy in 4 cases (3 anaplastic and 1 classic ependymomas), with S-phase fraction ranging from 0.2–9.7. Eleven subjects were additionally treated with radiotherapy, and 3 with chemotherapy. Follow up was available in 25 (78%) patients. CONCLUSIONS The results of the current study suggest that there is no significant relation between histopathology, Ki-67 proliferation index, p53 immunolabeling, tumor ploidy, and biologic behavior. Cancer 2005. Published 2005 by the American Cancer Society.

To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identiWed. While these Wndings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classiWed as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the speciWcity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal 45 Ca 2+ uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These Wndings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These Wndings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD. Published by Elsevier Inc.

"Primary" ear and temporal bone meningiomas are tumors that are frequently misdiagnosed and unrecognized, resulting in inappropriate clinical management. To date, a large clinicopathologic study of meningiomas in this anatomic site has not been reported. Thirty-six cases of ear and temporal bone meningiomas diagnosed between 1970 and 1996 were retrieved from our files. Histologic features were reviewed, immunohistochemical analysis was performed (n = 19), and patient follow-up was obtained (n = 35). The patients included 24 females and 12 males, aged 10-80 years (mean, 49.6 years), with female patients presenting at an older age (mean, 52.0 years) than male patients (mean, 44.8 years). Patients presented clinically with hearing changes (n = 20), otitis (n = 7), pain (n = 5), and/or dizziness/vertigo (n = 3). Symptoms were present for an average of 24.6 months. The tumors affected the middle ear (n = 25), external auditory canal (n = 4), or a combination of temporal bone and middle ear (n = 7). The tumors ranged in size from 0.5 to 4.5 cm in greatest dimension (mean, 1.2 cm). Radiographic studies demonstrated a central nervous system connection in 2 patients. Histologically, the tumors demonstrated features similar to those of intracranial meningiomas, including meningothelial (n = 33), psammomatous (n = 2), and atypical (n = 1). An associated cholesteatoma was identified in 9 cases. Immunohistochemical studies confirmed the diagnosis of meningioma with positive reactions for epithelial membrane antigen (79%) and vimentin (100%). The differential diagnosis includes paraganglioma, schwannoma, carcinoma, melanoma, and middle ear adenoma. Surgical excision was used in all patients. Ten patients developed a recurrence from 5 months to 2 years later. Five patients died with recurrent disease (mean, 3.5 years), and the remaining 30 patients were alive (n = 25, mean: 19.0 years) or had died (n = 5, mean: 9.5 years) of unrelated causes without evidence of disease. We conclude that extracranial ear and temporal bone meningiomas are rare tumors histologically similar to their intracranial counterparts. They behave as slow-growing neoplasms with a good overall prognosis (raw 5-y survival, 83%). Extent of surgical excision is probably the most important factor in determining outlook because recurrences develop in 28% of cases.

Intraventricular neoplasms are readily seen on cross-sectional images, but the myriad possibilities may make a focused differential diagnosis elusive. Consideration of the tissue within and composing the ventricular lining and the clinical findings provide the means to limit the differential diagnosis when analyzing an intraventricular mass on an imaging study. Ependymomas are typically calcified, are more common in children, are more common in the fourth ventricle, and show intense enhancement on contrast-enhanced images. Subependymomas and central neurocytomas have an affinity for the anterior portion of the lateral ventricle, and both commonly demonstrate a heterogeneous cystic appearance on cross-sectional images. Subependymomas are more common in older adults, whereas central neurocytomas are more common before 40 years of age. Subependymal giant cell astrocytomas always lie near the foramen of Monro and are characterized by frequent calcification, intense enhancement on contrast-enhanced studies, and the presence of other stigmata seen in tuberous sclerosis. When a mass is centered on the choroid plexus, a highly vascular tumor-either choroid plexus papilloma, choroid plexus carcinoma, meningioma, or metastasis-should be suspected. The characteristic heavily lobulated appearance of a choroid plexus tumor favors this diagnosis over other possibilities, although it is not always possible to distinguish between the more common benign form, the choroid plexus papilloma, and the less common malignant counterpart, the choroid plexus carcinoma. By using clinical, demographic, and imaging findings, one can significantly limit the differential diagnosis for many of the most common intraventricular neoplasms.

Senile plaques (SP) and neurofibrillary tangles (NFT) are the lesions characteristic of Alzheimer's disease (AD). In this study, we examined variation in the proportion of individuals who had these lesions by race, age, and gender in a series of 138 autopsies conducted at the Office of the Chief Medical Examiner of the State of Maryland between 1990 and 1998. Cases were selected on the bases of age between 40 to 79 years and non-natural manner of death, and included 73% males, 61% subjects < 65 years of age, and 42% African Americans. Observations were conducted on histologic sections of the hippocampus, entorhinal cortex, and inferior temporal cortex stained with silver (Hirano method) and immunostained for Abeta-amyloid. We found that SP and NFT are strongly associated with age. These lesions begin to appear in the early to late 40s, depending on the anatomic location, and become common in the 6th decade, preceding by one to two decades the age at which AD becomes clinically prevalent. No difference in the prevalence of SP or NFT was found by gender or between whites and African Americans. The latter is in contrast to epidemiologic studies that suggest AD is more prevalent in African Americans than in whites.

We report a case of an extragonadal yolk sac tumor in a superior scrotal mass. Testicular ultrasonography was normal preoperatively and after chemotherapy. Serum a-fetoprotein was initially increased to 344.55 ng./ml. (normal 0 to 15) but it returned to normal after surgery and chemotherapy.