Pediatric skull inflammatory myofibroblastic tumor: a rare case report and literature review.

Inflammatory myofibroblastic tumors (IMTs) represent rare neoplasms, particularly infrequent in the pediatric skull. We present a novel case of a newborn male with a 5 cm right temporal mass and discuss current diagnostic and treatment options for IMTs. A multidisciplinary effort to surgically remove the lesion was successful, and the patient's skull defect healed without neurological deficits. The etiology of IMTs remains elusive, with proposed associations with chromosomal mutations in the anaplastic lymphoma kinase (ALK) gene. Surgical excision remains the primary treatment for IMTs. Promising pharmacological treatments, like Crizotinib, warrant further research into understanding potential alternatives in IMT management.

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

Infarction with associated pseudosarcomatous changes mimics anaplasia in otherwise grade I meningiomas.

We describe a morphologically distinct pattern of tumor infarction and associated sarcoma-like changes, mimicking focal anaplasia, in otherwise WHO grade I meningiomas. The described cases (n = 9) all demonstrated a discrete spindle-cell (pseudosarcomatous) component with brisk mitotic activity (12-14 mitoses/10 HPF), elevated Ki-67 (mean 75.5 ± 25.0%, quantified), absence of PR, SSTR2A, or EMA expression, and potential SMA expression (50%). Despite these high-grade features, all nine patients remained free of progression or recurrence post resection (follow-up mean: 49.8 months). In contrast, among a comparison (control) cohort of consecutive WHO grade II and III meningiomas (n = 16), as expected, progression rate was high (68.8%, P = 0.002, Fisher's exact, average time to progression = 25 months, follow-up mean: 39.8 months). While necrosis was a frequent feature among atypical/anaplastic meningiomas (12/16, 75%), and elevated mitoses and proliferative index were present consistent with histologic grade, a well-defined zonal pattern with pseudosarcomatous component was not present among these tumors. DNA methylation-based analysis readily distinguished meningiomas by copy number profiles and DNA-based methylation meningioma random forest classification analysis (meningioma v2.4 classifier developed at University of Heidelberg); all pseudosarcomatous cases analyzed (4/9) matched with high level calibrated classifier score to "MC benign-1", with isolated loss of chromosome 22q identified as the sole copy number alteration. In contrast, multiple chromosomal losses were detected among the comparison cohort and classifier results demonstrated good concordance with histologic grade. Our findings suggest that pseudosarcomatous alterations represent reactive changes to central meningioma infarction, rather than focal anaplasia, and further support the use of DNA methylation-based analysis as a useful adjunct for predicting meningioma behavior. These indolent tumors should be distinguished from their atypical and anaplastic counterparts.

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis.

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series. METHODS: We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes. RESULTS: The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group. CONCLUSIONS: Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity.

Fatal and widespread skeletal myopathy confirmed morphologically years after initiation of simvastatin therapy.

A patient is described in whom fatal myopathy occurred, and its cause appears to be the consequence of simvastatin therapy.

Symmetric Bihemispheric Postmortem Brain Cutting to Study Healthy and Pathological Brain Conditions in Humans.

Neuropathologists, at times, feel intimidated by the amount of knowledge needed to generate definitive diagnoses for complex neuropsychiatric phenomena described in those patients for whom a brain autopsy has been requested. Although the advancements of biomedical sciences and neuroimaging have revolutionized the neuropsychiatric field, they have also generated the misleading idea that brain autopsies have only a confirmatory value. This false idea created a drastic reduction of autopsy rates and, consequently, a reduced possibility to perform more detailed and extensive neuropathological investigations, which are necessary to comprehend numerous normal and pathological aspects yet unknown of the human brain. The traditional inferential method of correlation between observed neuropsychiatric phenomena and corresponding localization/characterization of their possible neurohistological correlates continues to have an undeniable value. In the context of neuropsychiatric diseases, the traditional clinicopathological method is still the best possible methodology (and often the only available) to link unique neuropsychiatric features to their corresponding neuropathological substrates, since it relies specifically upon the direct physical assessment of brain tissues. The assessment of postmortem brains is based on brain cutting procedures that vary across different neuropathology centers. Brain cuttings are performed in a relatively extensive and systematic way based on the various clinical and academic contingencies present in each institution. A more anatomically inclusive and symmetric bi-hemispheric brain cutting methodology should at least be used for research purposes in human neuropathology to coherently investigate, in depth, normal and pathological conditions with the peculiarities of the human brain (i.e., hemispheric specialization and lateralization for specific functions). Such a method would provide a more comprehensive collection of neuropathologically well-characterized brains available for current and future biotechnological and neuroimaging techniques. We describe a symmetric bi-hemispheric brain cutting procedure for the investigation of hemispheric differences in human brain pathologies and for use with current as well as future biomolecular/neuroimaging techniques.

Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway.

Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.

Erdheim-Chester disease mimicking a primary brain tumor. Case report.

Erdheim-Chester disease (ECD) is a rare systemic histiocytic disease. The authors present a case report detailing the presentation and treatment of a 26-year-old man diagnosed with seizures and a well-circumscribed temporoparietal mass that had been demonstrated on imaging studies. Both preoperative and intraoperative diagnoses were consistent with a low-grade astrocytic neoplasm. Subsequent pathological examination indicated a histiocytic proliferation positive for CD68 and factor VIII, and negative for CD1a and S100, with Touton giant cells characteristic of ECD. This case represents the first isolated occurrence of intracranial ECD and its potential to mimic glial neoplasms.

Basic pathology of the peripheral nerve.

Peripheral nerve pathology encompasses a complex array of disease processes that are poorly understood. This article provides a substrate for communication between pathologists and radiologists who are involved in the diagnosis and treatment of patients with peripheral neuropathy. The article is organized into sections on normal histology, routine morphologic techniques used in the study of peripheral nerve, and the basic disease patterns, followed by a brief discussion of selected neuropathies.

Erdheim-Chester disease of the brain: cytological features and differential diagnosis of a challenging case.

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.

Primary extracranial meningiomas: an analysis of 146 cases.

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), <3% of cells were positive. The differential diagnosis included a number of mesenchymal and epithelial tumors (paraganglioma, schwannoma, carcinoma, melanoma, neuroendocrine adenoma of the middle ear), depending on the anatomic site of involvement. Treatment and follow-up was available in 110 patients: Biopsy, local excision, or wide excision was employed. Follow-up time ranged from 1 month to 32 years, with an average of 14.5 years. Recurrences were noted in 26 (23.6%) patients, who were further managed by additional surgery. At last follow-up, recurrent disease was persistent in 15 patients (mean, 7.7 years): 13 patients were dead (died with disease) and two were alive; the remaining patients were disease free (alive 60, mean 19.0 years, dead 35, mean 9.6 years). There is no statistically significant difference in 5-year survival rates by site: ear and temporal bone: 83.3%; nasal cavity: 81.8%; scalp skin: 78.5%; other sites: 65.5% (P = 0.155). Meningiomas can present in a wide variety of sites, especially within the head and neck region. They behave as slow-growing neoplasms with a good prognosis, with longest survival associated with younger age, and complete resection. Awareness of this diagnosis in an unexpected location will help to avoid potential difficulties associated with the diagnosis and management of these tumors.

Mesencephalic cryptococcal abscesses presenting with parkinsonism as an initial manifestation of AIDS.

Parkinsonism has been associated with HIV/AIDS and cerebral cryptococcal disease, but to date there has been no report of histological cryptococcal lesions in the substantia nigra (SN) in a patient with parkinsonism. We report on a case of a 63-year-old man who presented with tremor, gait disturbance, and mask-like facies, and showed cryptococcal meningoencephalitis with cryptococcal abscesses in the SN at autopsy, without Lewy bodies or significant degeneration of the SN neurons. Parkinsonism also represented the first manifestation of AIDS in this previously undiagnosed patient. This case highlights the importance of considering infectious etiologies in patients presenting with parkinsonism, and underscores the need for autopsy in evaluation of patients with new or unexplained movement disorders. Movement disorders in association with AIDS and mesencephalic mass lesions are discussed.

Primary ear and temporal bone meningiomas: a clinicopathologic study of 36 cases with a review of the literature.

"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.

Double immunolabeling of central nervous system atypical teratoid/rhabdoid tumors.

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.

Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.

Cree leukoencephalopathy is a rapidly fatal infantile autosomal recessive leukodystrophy of unknown cause observed in the native North American Cree and Chippewayan indigenous population. We found in the brain of affected individuals the typical foamy cells with the oligodendroglial phenotype described in central hypomyelination syndrome/vanishing white matter, a syndrome related to mutations in the genes encoding the five subunits of the eucaryotic translation initiation factor eIF2B. In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B.