Tumor‐to‐tumor metastasis to the central nervous system

Tumor‐to‐tumor metastasis is a well‐recognized phenomenon. Meningioma is the most common intracranial host tumor, with the breast and lung being the most common primary sites. We report herein two such cases of metastasis from pulmonary adenocarcinoma and malignant melanoma (MM) of vulva, respectively. Case 1: a 69‐year‐old female smoker who had a history of right upper lobectomy of lung for adenocarcinoma presented with a headache and altered mental status, and was found to have a left temporal contrast‐enhancing mass with massive surrounding edema on MRI. The resection specimen revealed foci of metastatic adenocarcinoma within a microcystic meningioma. Case 2: a 75‐year‐old woman with a history of radical vulvectomy for MM died of widespread systemic metastasis of MM. At autopsy, a 2.5 × 2 × 2 cm firm nodule attached to the falx was incidentally found, with focal black discoloration at the periphery of the mass. Histologic examination showed a fibroblastic meningioma with a focus of metastatic MM. Case 1 is the first case report describing a microcystic variant of meningioma harboring metastatic carcinoma. Although MM is one of the most common metastatic brain tumors, MM‐to‐meningioma metastasis is reportedly extremely rare, but can occur.     

Hickam's dictum: Angiosarcoma‐to‐meningioma metastasis

Tumor‐to‐tumor metastasis is a seldom reported phenomenon whereby a neoplasm seeds within another histologically distinct tumor, with only 84 cases documented in the literature. We hereby describe the case of a 95‐year‐old woman who died of widespread metastases identified as a primary hepatic angiosarcoma on autopsy, and the interesting finding of a seeding foci within a dural meningioma. Although meningiomas are the most common intracranial neoplasms to harbor such a phenomenon, this is to our knowledge the first case where an angiosarcoma was identified as the donor tumor.     

Glioblastoma with tumor‐to‐tumor metastasis from lung adenocarcinoma

Glioblastoma is a tumor with widely variable morphology. It may rarely show pseudoepithelial components or true epithelial differentiation. Metastasis to glioblastomas have been previously reported, but were unsupported by immunohistochemical or molecular analyses. Herein we describe a glioblastoma with carcinomatous foci in a patient with no past clinical history of tumors outside the central nervous system. The carcinomatous foci expressed epithelial, but not glial markers. Therefore, whole‐body imaging was carried out to verify the presence of carcinoma. A lung mass was biopsied and it resulted as primary lung adenocarcinoma. Carcinomatous foci of glioblastoma and lung adenocarcinoma had the same KRAS mutation which was absent in glial areas of the glioblastoma. Thus, glioblastoma with tumor‐to‐tumor metastasis was diagnosed. This case demonstrates that, albeit rare, metastases to glioblastoma may occur, and they should be considered in the differential diagnosis of glioblastoma with carcinomatous foci. Even when the past clinical history is negative, the presence of carcinoma should be investigated to rule out glioblastoma with tumor‐to‐tumor metastasis.     

Bidirectional Brain‐gut‐microbiota Axis in increased intestinal permeability induced by central nervous system injury

Central nervous system injuries may lead to the disorders of the hypothalamic‐pituitary‐adrenal axis, autonomic nervous system, and enteric nervous system. These effects then cause the changes in the intestinal microenvironment, such as a disordered intestinal immune system as well as alterations of intestinal bacteria. Ultimately, this leads to an increase in intestinal permeability. Inflammatory factors produced by the interactions between intestinal neurons and immune cells as well as the secretions and metabolites of intestinal flora can then migrate through the intestinal barrier, which will aggravate any peripheral inflammation and the central nervous system injury. The brain‐gut‐microbiota axis is a complex system that plays a crucial role in the occurrence and development of central nervous system diseases. It may also increase the consequences of preventative treatment. In this context, here we have summarized the factors that can lead to the increased intestinal permeability and some of the possible outcomes.     

Extracranial metastasizing solitary fibrous tumors (SFT) of meninges: Histopathological features of a case with long‐term follow‐up

Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle‐aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is exceptional in patients with meningeal solitary fibrous tumors and has been clinically reported in a handful of cases only and their histopathological features have not been investigated in detail. In this report, we describe the detailed clinico‐pathological features of a meningeal solitary fibrous tumor presenting during a 17‐year follow‐up period, multiple intra‐, extracranial relapses and lung metastases.     

Lung carcinoma metastasis presenting as a pineal region tumor

An autopsy case is reported of pineal metastasis from lung adenocarcinoma, which is a rare manifestation of the disease. A 75‐year‐old man who had been found to have a lesion in the lung by chest CT 2 years previously, became aware of head heaviness and then suffered consciousness disturbance. Brain MRI revealed a solitary mass in the pineal region with hydrocephalus. At autopsy a midsagittal section of the brain disclosed a well‐circumscribed mass consisting of epithelial cells occupying the third ventricle. Although it should be recognized that such metastasis is very rare, the present case provides further information that might be useful for diagnosis.     

Childhood radiation‐associated atypical meningioma with novel complex rearrangements involving chromosomes 1 and 12

Meningiomas are recognized as the most common late complication following radiotherapy. However, cytogenetic studies in childhood atypical radiation‐induced meningioma are sporadic, mainly because this condition generally occurs after a long latent period. In the present study we show the results of conventional and molecular cytogenetics in a 14‐year‐old boy with a secondary atypical meningioma. Apart from numerical changes, we found complex aberrations with the participation of chromosomes 1, 6 and 12. The invariable presence of loss of 1p was demonstrated by fluorescent in situ hybridization (FISH) analysis with probes directed to telomeric regions and by comparative genome hybridization (CGH). Previous cytogenetic studies on adult spontaneous and radiation‐associated meningiomas showed loss of chromosome 22 as the most frequent change, followed by loss of the short arm of chromosome 1. To the best of our knowledge this is the first report of highly complex chromosome aberrations in the pediatric setting of meningioma.     

Ki‐67 proliferative index predicts clinical outcome in patients with atypical or anaplastic meningioma

Meningiomas represent the second most common central nervous system neoplasms in adults and account for 26% of all primary brain tumors. Although most are benign, between 5% and 15% of meningiomas are atypical (grade II) whereas 1–2% are anaplastic meningiomas (grade III). Although histological grade is the most relevant prognostic factor, there are some unusual cases in which establishing a diagnosis of high‐grade meningioma following 2000 World Health Organization (WHO) histological criteria is extremely difficult. Therefore, the aim of the present study was to evaluate the predictive value of Ki‐67 labeling index and its contribution to current WHO classification in predicting tumor recurrence and overall survival in patients with high‐grade meningiomas. A total of 28 patients (with 16 atypical meningiomas and 12 anaplastic meningiomas) were evaluated for demographic, clinical, radiological and therapeutic variables, and for Ki‐67 immunohistochemistry. Median Ki‐67 labeling index in the whole series was 7.0 (0.5–31.5) with no differences with respect to the histological grade (P = 0.87). In the univariate analysis, Ki‐67 labeling index and postoperative Karnofsky performance status were identified as significant prognostic factors of tumor recurrence and overall survival. The multivariate analysis demonstrated that Ki‐67 labeling index is the only independent predictor of both tumor recurrence and overall survival. More importantly, this predictive value was maintained in both patients with atypical and patients with anaplastic meningioma.     

Interleukin‐1β protects astrocytes against oxidant‐induced injury via an NF‐κB‐Dependent upregulation of glutathione synthesis

Astrocytes produce and export the antioxidant glutathione (GSH). Previously, we found that interleukin‐1β (IL‐1β) enhanced the expression of astrocyte system x_c^?, the transporter that delivers the rate‐limiting substrate for GSH synthesis—cyst(e)ine. Herein, we demonstrate directly that IL‐1β mediates a time‐dependent increase in extracellular GSH levels in cortical astrocyte cultures, suggesting both enhanced synthesis and export. This increased GSH production was blocked by inhibition of nuclear factor‐κB (NF‐κB) activity but not by inhibition of p38 MAPK. To determine whether this increase could provide protection against oxidative stress, the oxidants tert‐butyl hydroperoxide (tBOOH) and ferrous sulfate (FeSO₄) were employed. IL‐1β treatment prevented the increase in reactive oxygen species produced in astrocytes following tBOOH exposure. Additionally, the toxicity induced by tBOOH or FeSO₄ exposure was significantly attenuated following treatment with IL‐1β, an effect reversed by concomitant exposure to l ‐buthionine‐S,R‐sulfoximine (BSO), which prevented the IL‐1β‐mediated rise in GSH production. IL‐1β failed to increase GSH or to provide protection against t‐BOOH toxicity in astrocyte cultures derived from IL‐1R1 null mutant mice. Overall, our data indicate that under certain conditions IL‐1β may be an important stimulus for increasing astrocyte GSH production, and potentially, total antioxidant capacity in brain, via an NF‐κB‐dependent process. GLIA 2015;63:1568–1580     

Stimulation of glucocorticoid‐induced tumor necrosis factor receptor family‐related protein ligand (GITRL) induces inflammatory activation of microglia in culture

Glucocorticoid‐induced tumor necrosis factor receptor family‐related protein ligand (GITRL) is a member of the tumor necrosis factor superfamily (TNFSF) and is known to act as a costimulator in the immune system by binding to GITR. GITRL is expressed in endothelial cells, dendritic cells, macrophages, and B cells, but it is not known whether GITRL is expressed in brain microglia cells. Here, we investigated the expression of GITR and GITRL and their potential role in microglia cells. Using BV‐2 mouse microglia cells and mouse primary microglia cultures, we have demonstrated that 1) both GITR and GITRL are expressed in microglia cells; 2) stimulation of GITRL induces inflammatory activation of microglia on the basis of production of nitric oxide (NO) and expression of inducible nitric oxide synthase, cyclooxygenase‐2, CD40, and matrix metalloproteinase‐9; 3) GITRL‐mediated microglial NO production partially depends on p38 MAPK, JNK, and nuclear factor‐κB pathways; and 4) GITRL stimulation also induces microglia cell death. These results indicate that GITR and GITRL are functionally expressed on brain microglia and that the stimulation of GITRL can induce inflammatory activation of microglia. The GITR/GITRL system may play an important role in neuroinflammation. © 2010 Wiley‐Liss, Inc.     

Correlative evidence that tumor cell‐derived caveolin‐1 mediates angiogenesis in meningiomas

Since it has recently been reported that caveolin‐1 (cav‐1) may favor the progression of prostatic and renal cancers by stimulating tumor neoangiogenesis, we thought it of interest to analyze the correlation between cav‐1 expression and tumor microvessel density (MVD) in meningiomas. In the present study we quantified cav‐1 expression by immunohistochemistry and used CD105 immunohistochemical staining to measure MVD. Sixty‐two formalin‐fixed, paraffin‐embedded, surgically resected meningiomas were submitted to the analysis. On the basis of cav‐1 immuno‐expression, cases were subdivided into meningiomas displaying a low (n = 34) and a high (n = 28) cav‐1 immuno‐expression, respectively. Mann–Whitney test showed that a significantly higher MVD was present in the cases with a high cav‐1 expression than in those with a low expression (mean 24.44 vs. 41.28 microvessels/mm²) (P = 0.0001). Moreover, Spearman test revealed a significant positive correlation between cav‐1 rate of expression and MVD counts in the meningiomas of our series (r = 0.390; P = 0.0023). Therefore, our study demonstrates the existence of an association between cav‐1 expression and neoangiogenesis in meningiomas, suggesting that cav‐1 may mediate the progression of these tumors by stimulating the angiogenic process. Besides, it is known that the progression of meningiomas is paralleled by an increase in MVD. The clarification of cav‐1 role in the neoangiogensis of meningiomas may open new insights about the possibility of novel therapeutic strategies in these neoplasias.     

Immunocytochemical analysis of glucose transporter protein‐1 (GLUT‐1) in typical,brain invasive,atypical and anaplastic meningioma

Glucose transporter‐1 (GLUT‐1) is one of the major isoforms of the family of glucose transporter proteins that facilitates the import of glucose in human cells to fuel anaerobic metabolism. The present study was meant to determine the extent of the anaerobic/hypoxic state of the intratumoral microenvironment by staining for GLUT‐1 in intracranial non‐embolized typical (WHO grade I; n = 40), brain invasive and atypical (each WHO grade II; n = 38) and anaplastic meningiomas (WHO grade III, n = 6). In addition, GLUT‐1 staining levels were compared with the various histological criteria used for diagnosing WHO grade II and III meningiomas, namely, brain invasion, increased mitotic activity and atypical cytoarchitectural change, defined by the presence of at least three out of hypercellularity, sheet‐like growth, prominent nucleoli, small cell change and “spontaneous” necrosis. The level of tumor hypoxia was assessed by converting the extent and intensity of the stainings by multiplication in an immunoreactive score (IRS) and statistically evaluated. The results were as follows. (1) While GLUT‐1 expression was found to be mainly weak in WHO grade I meningiomas (IRS = 1–4) and to be consistently strong in WHO grade III meningiomas (IRS = 6–12), in WHO grade II meningiomas GLUT‐1 expression was variable (IRS = 1–9). (2) Histologically typical, but brain invasive meningiomas (WHO grade II) showed no or similarly low levels of GLUT‐1 expression as observed in WHO grade I meningiomas (IRS = 0–4). (3) GLUT‐1 expression was observed in the form of a patchy, multifocal staining reaction in 76% of stained WHO grade I‐III meningiomas, while diffuse staining (in 11%) and combined multifocal and areas of diffuse staining (in 13%) were only detected in WHO grades II and III meningiomas, except for uniform staining in angiomatous WHO grade I meningioma. (4) “Spontaneous” necrosis and small cell change typically occurred away from the intratumoral capillary network embedded within the pattern of GLUT‐1 staining. Taken together, GLUT‐1 staining cannot be applied as a substitute for histologic grading in order to predict tumor behavior. However, assessment of tumor hypoxia in association with “spontaneous” necrosis and foci of small cell change may substantially contribute to the neuropathologic diagnosis of WHO grades II and III meningioma.     

Rosai‐Dorfman disease isolated to the central nervous system: A report of six cases

We reviewed the diagnosis and treatment of six patients with CNS Rosai‐Dorfman disease (RDD). Lesions were located in the cerebral convexity, middle cranial base, parasaggital, petrous orbit, and thoracic spine. Preoperatively, all the lesions were misdiagnosed as meningioma. Histopathology of all CNS lesions showed a characteristic feature called emperipolesis, where small lymphocytes or plasma cells were engulfed in histiocyte cytoplasm. Total resection of lesions was performed in all cases, and at an average follow‐up of 15 months, all patients are alive and well with no evidence of recurrence. Preoperative diagnosis of CNS RDD is challenging. Surgical removal of lesions is an effective treatment. More research is needed to clarify the effectiveness of other treatment options such as radiosurgery and corticosteroid therapy.     

Immunohistochemical analysis of cyclooxygenase‐2 and brain fatty acid binding protein expression in grades I‐II meningiomas: Correlation with tumor grade and clinical outcome after radiotherapy

This study was done to evaluate the association of cyclooxygenase 2 (COX‐2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I‐II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I‐II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX‐2 and BFABP were performed on formalin‐fixed paraffin‐embedded tissues. COX‐2 expression was significantly associated with BFABP status and both COX‐2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX‐2 status were prognostic in progression‐free survival. Patients with moderate or strong COX‐2 expression had worse outcome than those with negative or weak COX‐2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX‐2 has prognostic significance in intracranial grades I‐II meningiomas following radiotherapy.     

Anterior pituitary gland synthesises dopamine from l‐3,4‐dihydroxyphenylalanine (l‐dopa)

Prolactin (PRL) is a hormone principally secreted by lactotrophs of the anterior pituitary gland. Although the synthesis and exocytosis of this hormone are mainly under the regulation of hypothalamic dopamine (DA), the possibility that the anterior pituitary synthesises this catecholamine remains unclear. The present study aimed to determine if the anterior pituitary produces DA from the precursor l ‐3,4‐dihydroxyphenylalanine (l ‐dopa). Accordingly, we investigated the expression of aromatic l ‐amino acid decarboxylase (AADC) enzyme and the transporter vesicular monoamine transporter 2 (VMAT2) in the anterior pituitary, AtT20 and GH3 cells by immunofluorescence and western blotting. Moreover, we investigated the production of DA from l ‐dopa and its release in vitro. Then, we explored the effects of l ‐dopa with respect to the secretion of PRL from anterior pituitary fragments. We observed that the anterior pituitary, AtT20 and GH3 cells express both AADC and VMAT2. Next, we detected an increase in DA content after anterior pituitary fragments were incubated with l ‐dopa. Also, the presence of l ‐dopa increased DA levels in incubation media and reduced PRL secretion. Likewise, the content of cellular DA increased after AtT20 cells were incubated with l ‐dopa. In addition, l ‐dopa reduced corticotrophin‐releasing hormone‐stimulated adrenocorticotrophic hormone release from these cells after AADC activity was inhibited by NSD‐1015. Moreover, DA formation from l ‐dopa increased apoptosis and decreased proliferation. However, in the presence of NSD‐1015, l ‐dopa decreased apoptosis and increased proliferation rates. These results suggest that the anterior pituitary synthesises DA from l ‐dopa by AADC and this catecholamine can be released from this gland contributing to the control of PRL secretion. In addition, our results suggest that l ‐dopa exerts direct actions independently from its metabolisation to DA.     

A new method for analysing transition to psychosis: Joint modelling of time‐to‐event outcome with time‐dependent predictors

An active area in psychosis research is the identification of predictors of transition to a psychotic state among those who are assessed as being at high risk of psychosis. Many of the potential predictors are time dependent in the sense that they may change over time and are measured at a number of assessment time points. Examples are various psychopathological measures such as negative symptoms, positive symptoms, depression, and anxiety. Most research in transition to psychosis has not made use of the dynamic nature of these measures, probably because suitable statistical methods and software have not been easily available. However, a relatively new statistical methodology is well suited to include such time‐dependent predictors in transition to psychosis analysis. This methodology is called joint modelling and has recently been incorporated in mainstream statistical software. This paper describes this methodology and demonstrates its usefulness using data from one of the pioneering studies on transition to psychosis.