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ABSTRACT: Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms.
American Journal of Clinical Pathology 03/2013; 139(3):345-9. · 2.60 Impact Factor
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ABSTRACT: Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG → ATG, lysine → methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG → AGG, glycine → arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype.
Journal of Neuro-Oncology 01/2013; · 3.21 Impact Factor
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ABSTRACT: CRX (OTX3) is a transcription factor of the OTX homeobox family, whose expression and function is essential for the development and differentiation of retinal and pineal cells. Among human cancers, CRX seems to be selectively expressed only by retinoblastomas and pineal tumors. In our immunohistochemical analysis, performed on 89 primary and metastatic central nervous system tumors, we found that CRX is strongly expressed by normal pineal tissue as well as by pineal parenchymal tumors. Other than pineal tumors, we observed CRX positivity not only in a few medulloblastomas but also in atypical teratoid/rhabdoid tumors and in small cell lung carcinoma metastasis, in which photoreceptor differentiation has not been reported so far. In conclusion, CRX could represent a potential routine immunohistochemical marker in surgical neuropathology for the differential diagnosis of tumors of the pineal region. However, owing to the significant percentage of negative cells in some pineal tumors of our series, CRX negativity does not definitively rule out the diagnosis of a pineal parenchymal tumor, particularly in case of small biopsy specimens.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 12/2012; · 1.63 Impact Factor
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ABSTRACT: Primary Hodgkin's lymphomas of the central nervous system (CNS) as well as cerebral involvement as the first manifestation of a systemic Hodgkin's disease are very rare. CNS involvement usually occurs in patients with advanced or relapsing systemic disease. Because primary CNS Hodgkin's lymphoma may present unexpected and sometimes misleading clinical and neuroradiological features, the description of unusual cases is important for expanding the awareness of this rare disease of the central nervous system. We describe three cases of primary Hodgkin's lymphoma of the CNS with peculiar features. None of the three patients had a previous clinical history of systemic Hodgkin disease. Case 1 and case 2 presented an unusual localization in the cerebellar hemisphere and in the brainstem, respectively. The third case occurred as a temporal lesion in the settings of a Richter transformation of a chronic lymphocytic leukemia.
Acta Neurochirurgica 11/2012; · 1.52 Impact Factor
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Neuropathology 10/2012; · 2.02 Impact Factor
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Brain Pathology 09/2012; 22(5):737-40. · 3.99 Impact Factor
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ABSTRACT: Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glioneuronal tumors included in the revised WHO classification of central nervous system tumors, showing partial histological similarities to pilocytic astrocytomas. To evaluate potential similarities at the molecular level between these tumors, we analysed a series of 10 RGNT for the presence of KIAA1549-BRAF fusions using interphase fluorescence in situ hybridisation. However, we found no cases showing KIAA1549-BRAF gene fusion or BRAF (V600E) mutation. Our data support the hypothesis that RGNT may represent a distinct entity among the glioneuronal tumors of the central nervous system, with molecular features different from pilocytic astrocytomas.
Journal of Neuro-Oncology 07/2012; 110(1):21-5. · 3.21 Impact Factor
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ABSTRACT: Aim: Primary melanocytic tumours are uncommon neoplasms of the central nervous system. Although similarities with uveal melanomas have been hypothesized, data on their molecular features are limited. Methods: In this study, we investigated the mutational status of BRAF (V600E) , KIT, GNAQ, GNA11, N-RAS and H-RAS in a series of 19 primary melanocytic tumours of the CNS. Results: We identified six cases harbouring mutations in the hotspot codon 209 of the GNAQ gene and two cases with mutations in the hotspot codon 209 of the GNA11 gene. Two mutations in codon 61 of N-RAS were also found. In the SSCP analysis, no shifts corresponding to BRAF(V600E) mutations or suggesting activating mutations in the KIT gene were observed. Conclusions: In primary melanocytic tumours of the CNS, GNA11 and N-RAS mutations represent a mechanism of MAPK pathway activation alternative to the common GNAQ mutations. On the other hand, BRAF(V600E) mutations and activating KIT mutations seem to be absent or very rare in these tumours. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Neuropathology and Applied Neurobiology 07/2012; · 3.80 Impact Factor
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Tim Müller, Marco Gessi,
Anke Waha,
Lukas Jan Isselstein,
Daniel Luxen,
Dorothee Freihoff,
Johannes Freihoff,
Albert Becker,
Matthias Simon,
Jennifer Hammes,
Dorota Denkhaus,
Anja zur Mühlen,
Torsten Pietsch,
Andreas Waha
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ABSTRACT: The recent identification of isocitrate dehydrogenase 1 (IDH1) gene mutations in gliomas stimulated various studies to explore the molecular consequences and the clinical implications of such alterations. The Cancer Genome Atlas Research Network showed evidence for a CpG island methylator phenotype in glioblastomas that was associated with IDH1 mutations. These alterations were associated with the production of the oncometabolite, 2-hydroxyglutarate, that inhibits oxygenases [ie, ten-eleven translocation (TET) enzymes involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC)]. We investigated 60 gliomas for 5hmC presence, 5-methylcytosine content, TET1 expression, and IDH1 mutation to gain insight into their relationships on a histological level. Of gliomas, 61% revealed no immunoreactivity for 5hmC, and no correlation was observed between IDH1 mutations and loss of 5hmC. Interestingly, expression of TET1 showed remarkable differences regarding overall protein levels and subcellular localization. We found a highly significant (P = 0.0007) correlation between IDH1 mutations and nuclear accumulation of TET1, but not with loss of 5hmC. Of 5hmC-negative gliomas, 70% showed either exclusive or dominant cytoplasmic expression, or no detectable TET1 protein (P = 0.0122). Our data suggest that the loss of 5hmC is a frequent event in gliomas, independent of IDH1 mutation, and may be influenced by the nuclear exclusion of TET1 from the nuclei of glioma cells.
American Journal Of Pathology 06/2012; 181(2):675-83. · 4.89 Impact Factor
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ABSTRACT: 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.
Neuropathology 04/2012; · 2.02 Impact Factor
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ABSTRACT: OBJECTIVES/HYPOTHESIS: The prognosis for laryngeal squamous cell carcinoma (LSCC) has not shown any improvement in the last 30 years because of inadequate prognostic stratification. Therefore, the detection of reliable molecular markers may have a significant impact on clinical practice. As promising data regarding HER1/EGFR have been published, the purpose of the present study was to elucidate the role of the other receptors of the HER family. STUDY DESIGN: Retrospective. METHODS.: We used quantitative immunohistochemistry to evaluate the expression pattern of the HER4 receptors cytokeratin (CK)-14, CK-17, and proliferating cell nuclear antigen in 67 LSCCs and assessed correlations with various prognostic parameters. RESULTS.: HER1 levels inversely correlated with those of HER2-4. The negative prognostic value of HER1 was confirmed, and a protective role for HER2-4 was found. Specifically, the overexpression of HER4 and its nuclear localization are protective and are associated with a better prognosis. CONCLUSIONS.: Semiquantitative evaluation of HER2-4 provides predictive information that can be combined with HER1 expression data for molecular characterization of LSCC. The pattern of localization of HER4 is an easily evaluable qualitative parameter with a clear correlation with prognosis. The immunohistochemical methods described in this article are reliable, reproducible, and potentially translatable to clinical practice.
The Laryngoscope 03/2012; 122(8):1724-33. · 1.75 Impact Factor
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ABSTRACT: Pilocytic astrocytoma is the most frequently occurring brain tumor during childhood. It is classified as grade I by the World Health Organization and may rarely evolve into higher-grade tumors. Frequent genetic abnormalities documented in astrocytomas in children are gains on chromosomal arm 7q. Duplications at 7q34 lead to a fusion between genes KIAA1549 and BRAF resulting in constitutive activation of the BRAF kinase. The BRAF gene is located on chromosome 7q34 and a pseudogene has been identified on chromosome Xq13. We have developed a simple and sensitive pyrosequencing method for the determination of the BRAF copy number in clinical samples. The approach is based on the simultaneous amplification of a DNA fragment contained in exon 11 of BRAF and the respective pseudogene that is used as an internal control. Three different bases in the PCR product allow precise sequence assessment of products originating from the BRAF gene and the respective pseudogene and a calculation of gene copy numbers. After the calibration of the assay on 78 control DNA samples, 42 clinical PA samples were analyzed for variation in copy numbers by pyrosequencing and for fusion gene expression by reverse transcription-polymerase chain reaction. The results obtained from tumor DNA by the developed assay and the established reverse transcription-polymerase chain reaction assays show a high concordance. In summary, we have established a pyrosequencing-based assay allowing precise detection of BRAF copy numbers in DNA extracted from clinical samples.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 09/2011; 20(3):148-57. · 1.58 Impact Factor
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ABSTRACT: Medulloblastoma (MB) is the most common malignant primary brain tumour in childhood. Metastatic disease (M+) at diagnosis is the most important negative prognostic clinical marker and, despite craniospinal irradiation and intensive chemotherapy, it remains one of the leading causes of treatment failure. To date, few clinical and biological data have been evaluated to obtain an additional prognostic profile for these high-risk patients. In this study, 169 patients with metastatic MB registered in the multicentre HIT2000 trial of the German Society of Pediatric Oncology and Haematology (GPOH) have been investigated to determine the importance of p53 protein expression in predicting survival. At a median follow-up of 4.1 years, 159 patients with p53-negative tumours had significantly better four-year event-free survival (EFS) and progression-free survival (PFS) (56 ± 11, 59 ± 4%) than 10 patients with p53-positive tumours (40 ± 16, 40 ± 16%; P = 0.018 for EFS, P = 0.007 for PFS, respectively). Furthermore, four-year overall survival (OS) of children with p53-negative tumours was higher than for children with p53-positive tumours (72 ± 4 vs. 35 ± 18%, P = 0.05). Three of the p53-positive MBs harbored a point mutation in the TP53 gene. p53 protein assessment by immunohistochemistry may be a useful tool for sub-stratification of metastatic high-risk MB patients.
Journal of Neuro-Oncology 07/2011; 106(1):135-41. · 3.21 Impact Factor
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ABSTRACT: Ependymomas are rare brain tumors representing about 3% of all intra-cerebral and spinal neoplasms. The WHO classification recognizes various rare histological ependymoma variants (i.e., lipidized ependymoma, giant cell ependymoma, etc.). However, a detailed analysis of a larger series of such cases is still lacking. We analyzed 13 case of ependymoma presenting unusual histological features. The data analysis of our series and its comparison to the cases published in literature did not reveal any close association between these features and the clinical parameters (such as age or localization). Moreover, some of these features can be found combined in individual tumors, suggesting that these variants may represent a spectrum of differentiation rather than true specific entities. However, awareness on these rare histological patterns in ependymomas is necessary in the differential diagnosis with other primary or secondary brain tumors.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 07/2011; 459(4):423-9. · 2.49 Impact Factor
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ABSTRACT: Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glio-neuronal tumors included in the revised WHO classification of CNS tumors and show histopathological features similar to pilocytic astrocytomas. To evaluate at molecular level potential affinities between these tumors, we investigated a case of RGNT, arising in the cerebellum of a young patient, for the presence of transcriptional products originating from the KIAA1549-BRAF fusion. However, the analysis did not show any fusion. Further studies in larger RGNT case series are needed in order to demonstrate the possible presence of KIAA1549-BRAF fusion and better delineate its relationship with pilocytic astrocytomas.
Neuropathology 04/2011; 31(6):654-7. · 2.02 Impact Factor
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ABSTRACT: The development of an acardiac twin in a monochorionic multiple pregnancy is a rare and severe complication of abnormal placental vascular anastomoses. These malformed fetuses present with a very bizarre morphology and a plethora of different malformations. However, all acardiac twins show either a complete absence or an anlage of the heart. Cerebral development is usually poor. We report, according to our review of the literature, for the first time, a very unusual case of acardius with features of acardius amorphus and acormus (fused head and malformed axial skeleton without macroscopically detectable internal organs) with lobar holoprosencephaly and intracerebral pigmented retina-like tissue.
Pediatric and Developmental Pathology 04/2011; 14(5):411-7. · 0.99 Impact Factor
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ABSTRACT: Advances in understanding the molecular basis of primitive neuroectodermal tumors of the central nervous system (CNS-PNET) biology are critical to improve patient outcome. Recently, new data on their molecular features have been reported, suggesting that supratentorial PNET (s-PNET) in adult patients may represent a specific tumor entity among CNS-PNETs. In this study, we analyzed the clinicopathologic and molecular features of 12 cases of s-PNET in adult patients. The follow-up analysis showed that these tumors have an aggressive clinical behavior. At the histopathologic level, they resembled their pediatric counterpart, showing a variable spectrum of neuronal differentiation. These cases did not show astrocytic differentiation; therefore, they did not qualify for the differential diagnosis of glioblastoma variants. The tumors were also screened for mutation of TP53, IDH1, IDH2, and β-catenin, using single strand conformation polymorphism-based and sequencing assays, and were analyzed for c-myc/N-myc gene copy numbers with a quantitative polymerase chain reaction-based method. The strand conformation polymorphism-based mutational analysis showed that 5 tumors harbored TP53 mutations. In 2 cases, a mutation at codon 132 of the IDH1 gene was also found. No mutations of the β-catenin or IDH2 genes were identified. No cases presented c-myc or N-myc amplifications. Only 1 case presented overexpression of epidermal growth factor receptor. In conclusion, our data show a high incidence of TP53 mutations in this group of tumors and show, in comparison with pediatric s-PNET, the absence of amplification of the c-myc/N-myc genes, indicating that s-PNET in adult patients may represent a specific subset of tumors among CNS-PNETs.
The American journal of surgical pathology 03/2011; 35(4):573-82. · 4.06 Impact Factor
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Acta Neuropathologica 11/2010; 121(2):283-5. · 9.32 Impact Factor
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ABSTRACT: The primitive neuroectodermal tumours of central nervous system (CNS-PNET) are a heterogeneous group of neoplasms, occurring in the CNS and composed of undifferentiated or poorly differentiated neuroepithelial cells which may display divergent differentiation along neuronal, astrocytic and ependymal lines. The WHO classification includes in this group of tumours also ependymoblastomas and medulloepitheliomas. Several groups have reported examples of CNS-PNET with combined histological features of ependymoblastoma and neuroblastoma, defined as 'embryonal tumour with abundant neuropil and true rosettes'. The presence of the amplification of chromosome region 19q13.42, common in both ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes, suggests that they represent a histological spectrum of a single biological entity.
We examined 24 cases of ependymoblastoma/embryonal tumour with abundant neuropil and true rosettes (EPBL/ETANTR) for the presence of mutations of TP53 and β-Catenin and for amplification of c-myc/N-myc.
The single strand conformation polymorphism-mutational screening did not identify any mutation in exons 5 to 8 of the TP53 gene. However, we found a point mutation affecting codon 34 (GGA → GTA) of β-Catenin gene resulting in a Glycine → Valine substitution. No cases presented c-myc/N-myc amplification.
EPBL/ETANTRs show molecular features different from other CNS-PNET and medulloblastomas. The presence of alterations in the β-Catenin/WNT pathway seems to be noteworthy due to the close relationship between this pathway and miR-520g encoded in chromosome 19q13.42 region amplified in these tumours.
Neuropathology and Applied Neurobiology 11/2010; 37(4):406-13. · 3.80 Impact Factor
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Andrey Korshunov,
Marc Remke, Marco Gessi,
Marina Ryzhova,
Thomas Hielscher,
Hendrik Witt,
Vivienne Tobias,
Anna Maria Buccoliero,
Iacopo Sardi,
Marina Paola Gardiman, [......],
Andreas E Kulozik,
Olaf Witt,
Sverre Mork,
Andreas von Deimling,
Otmar D Wiestler,
Felice Giangaspero,
Marc Rosenblum,
Torsten Pietsch,
Peter Lichter,
Stefan M Pfister
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ABSTRACT: Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior.
Acta Neuropathologica 08/2010; 120(2):253-60. · 9.32 Impact Factor
