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Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer’s disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the “amygdala region” rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

Astrocytes with multiple micronuclei (“Creutzfeldt cells”) in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high‐grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico‐radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell‐rich GBMs were IDH‐wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich‐GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH‐wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.

Background Choriocarcinoma coexisting with or after normal pregnancy is extremely rare. To our knowledge, our case report is the first time cerebral mycotic pseudoaneurysms from choriocarcinoma have been proven angiographically. Case Description A 38-week pregnant 26-year-old woman presented with an acute left frontal hemorrhage. She underwent emergency cesarean section, followed by hematoma evacuation and resection of what grossly appeared to be a medium-sized arteriovenous malformation at the time of surgery. Angiogram before and after resection showed no obvious vascular pathology. One month later, she returned with status epilepticus, and an acute parenchymal hematoma posterior to the surgical resection cavity was identified. Angiography showed a multilobulated pseudoaneurysm along the left middle cerebral artery. This was resected and found on histopathology to have choriocarcinoma within and around the blood vessels. Serum human chorionic gonadotrophin levels increased daily. Pan computed tomography showed a left lung lobular mass. The diagnosis was stage 4 World Health Organization score 9 high-risk metastatic choriocarcinoma requiring radiation followed by multiagent chemotherapy. Two weeks later, she had another seizure. An angiogram showed an unruptured pseudoaneurysm along the right posterior cerebral artery, which was embolized. Conclusions Metastatic choriocarcinoma is rarely considered during a viable pregnancy but is almost always fatal if unrecognized. Early recognition enhances the chances of cure with chemotherapy. Arteriovenous malformations are typically considered in young women with intracerebral hemorrhages and have higher risk of rupture in pregnant women, but physicians should also be aware of metastatic choriocarcinoma and the development of mycotic aneurysms in peripartum women with intracerebral hemorrhages.

Context.—The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. Objective.—To summarize and discuss the most significant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. Data Sources.—The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. Conclusions.—The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists.

The histologic expression of epithelial and organ-related immunohistochemical markers in primary sellar region tumors has received little attention to date. This lack of empirical data may lead to mistaken assumptions in the evaluation of sellar region neoplasms. To address this issue, the frequency and specificity of epithelial (cytokeratin 7(CK7), CK20) and organ-related differentiation markers (gross cystic disease fluid protein-15 (GCDFP-15), thyroid transcription factor-1 (TTF-1), Napsin A, paired box 8 (PAX-8), hepatocyte paraffin 1 (HepPar1) and estrogen receptor (ER)) were studied in 40 patients with adenomas comprising five hormonal sub-types. Non-parametric statistical procedures were used to examine associations between marker expression and tumor sub-type. CK7 and CK20 immunoreactivity were seen in 48% and 8% of tumors, respectively, although never in a diffuse pattern. CK20 expression was nearly exclusive to corticotrophs, whereas CK7 frequently highlighted cells with dendritic-type morphology. The specificity of organ-related differentiation markers was 100% (monoclonal Napsin A, GCDFP-15 and TTF-1), 97% (HepPar1 and PAX-8), 90% (polyclonal Napsin A) and 72% (ER); no tumors demonstrated significant co-expression of these organ-related markers with either CK7 or CK20. The first major conclusion of this study is that CK7 staining in adenoma is more frequent than has been previously than has been previously described. CK7 immunoreactive cells often displayed a dendritic-type morphology, including within large macroadenomas, which raises the question as to whether these represent tumor cells with folliculo-stellate cell-type differentiation, as these also have dendritic cell-type morphology and express CK7 in non-neoplastic glands. The second major conclusion, which confirms earlier findings, is that CK20 staining is a very infrequent immunohistochemical finding in adenomas that is virtually limited to corticotrophs and thus is helpful in diagnostic confirmation of that sub-type. The final conclusion is in regard to those features that separate adenomas from sellar region metastases: adenomas do not demonstrate significant expression of TTF-1, monoclonal Napsin A, PAX-8, HepPar1 or GCDFP-15, nor do they exhibit diffuse expression of CK7 and CK20.

Subependymoma is a rare subtype of benign ependymal neoplasm with distinct histological features. Anaplastic transformation has not yet been reported in this tumor to date. We present here a very unusual case of a 62-year-old woman with recurrent subependymoma of the fourth ventricle with multiple atypical histological features. Histologically, the resected recurrent tumor showed characteristic small cell clusters and nests of ependymal cells with an interspersed gliofibrillary matrix as seen in a classic subependymoma. In addition, there were very unusual histological features, including multiple areas of necrosis, microvascular proliferation, thrombosed blood vessels, and scattered mitotic figures. No coexisting ependymoma component of higher World Health Organization (WHO) grade was present. Immunohistochemically, MIB-1 labeling index was high, with up to 15% in the highest areas. Review of this patient's initial tumor, which was resected 6 years prior to recurrence, demonstrated features of a typical classic subependymoma without atypical features or a secondary tumor component. Subependymomas are known to be low-grade tumors and are usually cured if completely excised. The tumor presented here is unique in that several atypical pathological features were found in an otherwise typical subependymoma. Our case may represent anaplastic transformation of subependymoma, although no such examples have been reported to date.

Context.—Intraoperative evaluation of lesions in the central nervous system requires the correlation of clinical, radiologic, and histologic data and knowledge of clinicopathologic entities and their common locations. Advances in neuroimaging during the last 20 years have revolutionized the diagnosis and treatment of central nervous system diseases. The diagnosis and treatment of patients have improved because of these changes and have allowed access to regions that were previously inaccessible. These new approaches have placed the pathologist in a key role in the diagnosis and treatment of patients with central nervous system lesions. Assessment of the adequacy of the material, particularly for stereotactic biopsies, is necessary, and a combination of cytologic imprint preparations and frozen sections are often used. This review discusses many of the issues involved in intraoperative consultation and provides a simplified approach to the differential diagnosis of a variety of central nervous system lesions that may be encountered intraoperatively. Objective.—To provide guidelines for and address potential pitfalls in the intraoperative management of the central nervous system. Data Sources.—Author's experience and pertinent literature. Conclusions.—Careful assessment of the gross specimen coupled with prudent use of frozen sections and cytologic imprint preparations is pivotal to reducing intraoperative error rates and preventing needless anxiety for the patient.

Training of neuropathologists varies worldwide. Systems range from highly organized specialist and subspecialist education with national certification, to regulated training with diploma recognition, to informal apprenticeships in neurological hospitals and no formal recognition. This overview compiles and summarizes the history of regulated training systems, the status of neuropathology within various countries' medical systems and the manner in which neuropathologists are trained. Anecdotal evidence suggests that countries with regulated systems of neuropathology training and an active professional organization are more likely to have an adequate supply of diagnostic specialists and a vibrant research community. The different training systems reflect the style of medical services delivery in the respective countries. In general, the existence of formal neuropathology training systems occurs only in countries with relatively high levels of per capita health expenditures, reflecting the development of medical specialization overall. Evolving diagnostic technologies and major international research endeavors, whose goals are to understand structure and function of the human brain, demand that neuropathology training is more than simply diagnostic histopathology.

Hemangioblastomas (HBs) account for nearly a tenth of all posterior fossa neoplasms and can be the presenting finding in patients with von Hippel-Lindau (VHL) syndrome. HB must be differentiated from renal cell carcinoma (RCC), also seen in VHL, as the distinction between these lesions dictates the management of these patients. Currently inhibin A and RCC marker have been used in the diagnosis of HB and metastatic RCC, both with inconsistent results. Additional immunohistochemical markers including CD10, PAX-2, D2-40, and FLi-1 have been shown to have potential for the distinction of these two entities. Fifteen cerebellar HBs and 17 metastatic clear cell RCCs to the brain were selected for the study. All cases were immunostained with RCC marker, inhibin, CD10, PAX-2, D2-40, and Fli-1. The staining patterns were scored based on intensity and extent of tumor staining. In the differentiation of HB and metastatic RCC, D2-40 and RCC marker proved to be poor markers with less than 50% of HBs and RCCs, respectively, showing positive staining. PAX-2 and CD10 were superior to RCC marker in the diagnosis of metastatic RCC, with PAX-2 having better specificity. Fli-1 failed to stain tumor cells in both HBs and RCC. Inhibin A, in combination with PAX-2, showed to be the most useful markers to differentiate HB from metastatic RCC.

We describe the clinical course and postmortem pathological findings in a patient with essential tremor (ET) treated with deep brain stimulation (DBS) for 12 years. This 75 year old woman had a 13-year history of progressive ET prior to implantation of bilateral quadripolar DBS electrodes in the region of her ventral intermediate thalamic nuclei in 1996, producing immediate relief of arm tremor. Histopathological examination of the brain, performed 12 years after the initial implantation, demonstrated electrode catheter tracts rimmed by 20-25 micron fibrous sheaths, with multinucleated giant cells and reactive gliosis. Lymphocytic infiltration was seen by L26 immunoreactivity with CD3 (T cells) staining predominating over CD20 (B cells). Cerebellar axonal spheroids and Purkinje cell loss were found. The minimal foreign body reaction and gliosis around the electrodes 12 years after implantation supports the long-term safety of DBS. The case represents the longest reported follow-up with autopsy examination after DBS and confirmed histological changes associated with ET.

An atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal tumor most often occurring in the posterior fossa in children younger than 3 years of age. Adult cases of AT/RT are very rare, and 27 cases with a diagnosis of either AT/RT or (malignant) rhabdoid tumor have been reported to date. The authors report an adult case of an AT/RT occurring in the pineal region with molecular cytogenetic and immunohistochemical confirmation. A 33-year-old woman presented with a 2-month history of headache and blurred vision progressing to diplopia, and was admitted emergently due to deteriorating mental status. An MR image showed a heterogeneously enhancing mass involving the posterior third ventricle and pineal region with mild hydrocephalus. She underwent a subtotal resection of the tumor and was then treated with chemoradiation. Thirteen months after surgery, she was still alive with radiological evidence of recurrence/residual lesions. Histological sections showed epithelioid cellular sheets of rhabdoid tumor cells with scattered mitotic figures. Immunohistochemically, the tumor cells were diffusely and strongly positive for epithelial membrane antigen and vimentin, and showed focal expression of glial fibrillary acidic protein, pancytokeratin, and neurofilament protein. Loss of nuclear immunoreactivity for INI1 protein was observed. Fluorescence in situ hybridization analysis showed monosomy 22. Histologically, this tumor consisted exclusively of epithelioid tumor cells with rhabdoid features. The differential diagnoses include rhabdoid glioblastoma, metastatic carcinoma, and rhabdoid meningioma. Molecular testing to identify monosomy 22 or deletions of the chromosome 22q11 containing the INI1/hSNF5 gene and/or immunohistochemical staining with INI1 antibody is of great importance for the diagnosis of this tumor.

This study focuses on the epidemiology, clinical manifestations, risk factors, diagnosis and outcome of all cases of central nervous system (CNS) fungal infections in a tertiary center. Medical records of 18 patients of culture-proven CNS fungal infections were retrospectively reviewed from 2000 to 2007, including 12 isolated from the cerebrospinal fluid (CSF) and seven from tissue biopsy. Patient demographic data included 10 males and eight females. The mean age was 55 years (range: 24-89 years). All but one patient were immunocompromised. Fungal organisms isolated from CSF included: Cryptococcous neoformans (8 patients), Coccidioides immitis (3 patients), and Aspergillus versicolor (1 patient). Histopathology of seven biopsy cases revealed groups of pigmented golden-brown fungal forms in three cases; three cases showed septate fungi, two of which had melanin in their walls; and one case showed multiple round spherules. These cases on microbiological cultures grew Coccidioides immitis (1 patient), Aspergillus fumigatus (1 patient), Cladophialophora bantiana (2 patients), Fonsecaea monophora (1 patient) and Scedosporium apiospermum (2 patients). Five of the seven fungal organisms isolated from tissue biopsies were dematiaceous fungi. Twelve patients died after a period of a few weeks to months, two were lost to follow-up, and four are alive with severe neurological sequelae. CNS fungal infections in our cohort were more common in patients post-transplant and with hematologic malignancies. In our series, rare dematiaceous fungi are emerging agents for cerebral mycosis. The outcome of CNS fungal infections is poor despite vigorous antifungal therapy.

We present a rare case of an adult patient without seizures who is found to have a ganglioglioma occurring in the cerebellopontine angle. A 52-year-old woman with ataxia, headaches, and falling episodes underwent neuroimaging. Magnetic resonance imaging (MRI) revealed a smooth, somewhat lobulated mass in the left cerebellopontine angle. The mass was hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging, and did not enhance after administration of gadolinium. Left retromastoid craniectomy was performed, and the mass was noted to be exophytic from the brain stem. The exophytic component was resected. Light microscopic findings were consistent with ganglioglioma. This was confirmed with immunohistochemical studies. Ganglioglioma is a rare tumor of the central nervous system that typically presents with seizures in children and young adults. Occurrence of this tumor in the cerebellopontine angle is extremely unusual; this rarity is magnified by its occurrence in an adult patient without a history of seizures. Our case illustrates that ganglioglioma should be considered in the differential diagnosis of cerebellopontine angle masses at any age. This appears to be especially true when dealing with masses that are non-enhancing on imaging.

To describe the cytologic features of myxopapillary ependymoma (MPE) on intraoperative smears, to analyze cytomorphologic parameters that may help in reaching the diagnosis and to discuss differential diagnosis.Touch imprint smears of 13 MPE cases were reviewed and graded semiquantitatively for 14 cytomorphologic parameters; cellularity, myxoid background, isolated/dispersed tumor cells, "hyaline globules (HGs)," fibrillary cytoplasmic processes, papillary structures, perivascular pseudorosettes, epithelioid tumor cells (ETCs), intracytoplasmic mucin, intranuclear inclusions, nuclear grooves, mitosis, cytologic atypia and hemosiderin-laden macrophages.Cytologic examination revealed variably cellular specimens composed of isolated and loosely aggregated tumor cells with round to oval or occasionally spindle-shaped nuclei; evenly distributed, finely granular chromatin; and fibrillary processes admixed with occasional ETCs. Most of the cases showed prominent fibrillary processes and occasional ETCs with at least a focal myxoid background. HGs and hemosiderin-laden macrophages were often seen. Papillary structure, a histologic hallmark of MPE, was rarely observed.Dual glial and epithelioid properties of tumor cells, well-known features of "regular" ependymomas, and a distinctive myxoid background with HGs strongly support a diagnosis of MPE and are of great help in excluding other mimics (e.g., other variants of ependymoma, metastatic mucinous adenocarcinoma, metastatic adenoid cystic carcinoma and chordoma).

Carcinoma metastatic to the pituitary gland is infrequent and has been reportedly detected in approximately 1% of pituitary surgical cases. It may masquerade as a pituitary adenoma both clinically and radiologically.A 49-year-old man presented with a 1-month history of severe headache, diplopia and blurred vision. Neurologic examination revealed bitemporal hemianopsia and left sixth nerve palsy. The initial radiologic diagnosis based on magnetic resonance imaging was pituitary adenoma. A biopsy of the lesion was performed. While intraoperative frozen section examination could not completely exclude an "atypical" pituitary adenoma, cytologic touch imprint findings were diagnostic of metastatic small cell carcinoma. Subsequently, additional workup revealed that the patient had a mass lesion in the right lung and right-sided mediastinal lymphadenopathy on chest computed tomography. This was a rare case of pituitary metastasis as the first manifestation of an occult malignancy.For intraoperative diagnosis at the time ofpituitary surgery, cytologic imprints can be used reliably to make a diagnosis not only of pituitary adenoma but also of metastatic lesions. It is appropriate in current neuropathology practice that the imprint method be used as the sole modality for intraoperative consultation for pituitary lesions.