Palisading Necrosis Research Articles

High-grade astrocytoma with piloid features in the conus medullaris: a rare presentation of a new World Health Organization diagnosis. Illustrative case.

Neuroepithelial tumors with histological features of pilocytic astrocytoma (PA), increased mitotic activity with high-grade features of microvascular proliferation, and palisading necrosis have often been designated as anaplastic PAs. High-grade astrocytoma with piloid features (HGAP) was recently classified as its own entity by the World Health Organization (WHO) in 2021, after being grouped under anaplastic PA. This rare tumor typically arises in the cerebellum. The authors present the case of a patient with HGAP in the conus medullaris, a rare occurrence, with only 17 reported HGAP cases in other parts of the spinal cord. An 83-year-old female patient presented with progressive lower-extremity weakness over 2 weeks. Subsequent imaging revealed an intramedullary spinal cord mass near the conus. Histopathological analysis confirmed a neuroepithelial tumor. Chromosomal microarray revealed the diagnosis of HGAP, an exceedingly unusual tumor to be found near the conus. The tumor characteristics showed uniformly low cellularity and low proliferation of medium-sized ovoid cells with elongated nuclei, embedded in a loose pilocytic matrix. This report presents the case of a patient with HGAP in the conus medullaris, a new WHO diagnosis that needs to be included in the differential diagnosis for conus masses. https://thejns.org/doi/10.3171/CASE24390.

Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis.

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

Clinical, pathological, and molecular features of central nervous system tumors with BCOR internal tandem duplication

Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1–3 bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.

Prognostic Effect of CDKN2A Homozygous Deletion and Beclin 1 in Isocitrate Dehydrogenase Mutant Glial Tumors

ABSTRACT Background: In the updated World Health Organization Classification of Central Nervous System Tumors, the presence of CDKN2A/2B homozygous deletion is now recognized as the indicative of Grade 4 in isocitrate dehydrogenase (IDH) mutant astrocytomas, and it is associated with a poor prognosis in Grade 4 astrocytomas. Conversely, Beclin 1, a crucial protein in autophagy initiation, exhibits a bidirectional effect on tumor progression and suppression. The objective of this study is to evaluate CDKN2A homozygous deletion in IDH mutant astrocytomas of varying grades, to compare it with microvascular proliferation (MVP) and palisading necrosis, and to analyze the relationship between these findings and Beclin 1 expression, subsequently comparing them with prognosis. Subjects and Methods: CDKN2A homozygous deletion and Beclin 1 expression were analyzed in 32 cases with IDH-mutant diffuse astrocytomas of Grades 2, 3, and 4. Results: CDKN2A homozygous deletion was detected in one of 10 patients with Grade 2 and in 8 of 17 patients with Grade 4. Beclin 1 was positively stained in 2 of Grade 2 astrocytomas, 4 of Grade 3 astrocytomas, and 9 of Grade 4 astrocytomas. While Beclin 1 expression was present in 5 of 9 cases with CDKN2A homozygous deletion, no expression was observed in four cases. Conclusion: In this study, the prognostic significance of CDKN2A homozygous deletion alone was found to be lower compared to the deletion in combination with MVP and/or necrosis. At the same time, Beclin 1 expression was determined to exert no prognostic significance alone, while it was found to exert a poor prognostic effect in combination with CDKN2A homozygous deletion.

PATH-04. TRANSFORMATION OF GRADE 2 OLIGODENDROGLIOMA TO GLIOSARCOMA WITH RAPID AND EXTENSIVE PROGRESSION: CASE REPORT.

Abstract Transition of WHO grade 2 oligodendroglioma to gliosarcoma is rare. We report a case of a 40 year-old gentleman with WHO grade 2 oligodendroglioma, isocitrate dehydrogenase enzyme (IDH)-mutant, 1p/19q co-deletion positive, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, tumor mutational burden of 5 mutations/megabase, with microsatellite stability. He underwent rapid and extensive transformation to WHO grade 4 glioblastoma with gliosarcomatous features, mesenchymal subclass on DNA methylation, IDH-wild type, 1p/19q co-deletion negative, MGMT promoter methylated. He was diagnosed with bi-hemispheric multifocal partially enhancing, T2-FLAIR hyperintense lesions. Pathology revealed WHO grade 2 oligodendroglioma. He enrolled on a clinical trial to receive proton radiation (45 Gray in 25 fractions) to the involved tumor sites. Three weeks after initiation of radiation, he developed headache, imbalance, and confusion. MRI brain 3 weeks after completion of radiation revealed worsening enhancement, edema, and a new region of non-enhancing T2-FLAIR hyperintensity. Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC). Four cycles of PC were completed with observations of gradual clinical and radiographic worsening after each cycle. Re-resection of multifocal tumor for tissue diagnosis and tumor debulking revealed progression to WHO grade 3 oligodendroglioma with high mitotic activity and regions of palisading necrosis. Two weeks postoperatively, malignant cerebral edema developed, requiring left sided decompressive craniectomy. Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis. Autopsy revealed extensive bi-hemispheric involvement of WHO grade 4 glioblastoma. Our patient demonstrated unusually rapid clinical and radiographic progression within one month after completion of radiation. Other reported cases in the literature have documented progression at 1 to 5 years after initial treatment. Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.

Intratumoral thrombosis as a histological biomarker for predicting epidermal growth factor receptor alteration and poor prognosis in patients with glioblastomas.

Intratumoral thrombosis is a specific finding in glioblastomas and considered the origin of palisading necrosis. Its distribution and contribution to the glioblastoma pathophysiology and systemic thrombosis are obscure, although deep vein thrombosis is a common complication in glioblastoma cases. Clinicopathological and genetic analyses were performed on 97 glioblastoma tissue specimens to elucidate the role of thrombotic events and associated molecular abnormalities. Morphologically, intratumoral thrombosis was observed more frequently in vessels composed of single-layered CD34-positive endothelium and/or αSMA-positive pericytes in the tumor periphery, compared to microvascular proliferation with multi-channeled and pericyte-proliferating vessels in the tumor center. Intratumoral thrombosis was significantly correlated with the female sex, high preoperative D-dimer levels, and epidermal growth factor receptor (EGFR) amplification. The presence of one or more thrombi in 20 high-power fields was a predictive marker of EGFR amplification, with a sensitivity of 81.5% and specificity of 52.6%. RNA sequencing demonstrated that the group with many thrombi had higher EGFR gene expression levels than the group with few thrombi. The tumor cells invading along the vessels in the tumor periphery were positive for wild-type EGFR but negative for EGFRvIII, whereas the cells around the microvascular proliferation (MVP) in the tumor center were positive for both wild-type EGFR and EGFRvIII. Intratumoral thrombosis is an independent poor prognostic factor. Aberrant but exquisitely regulated EGFR can induce thrombosis in non-MVP vessels in the tumor invasion area and then promote palisading necrosis, followed by hypoxia, abnormal angiogenesis, and further tumor cell invasion.

A Blinding Glioma

A 12-year-old girl presented with no light perception in the right eye. Ultrawide-field retinal imaging (Fig A) revealed a grayish papillary mass expanding into the vitreous cavity, ghost retinal vessels, and deep retinal hemorrhages. Brain magnetic resonance imaging showed a left-sided parieto-occipital tumor crossing the midline (Fig B, arrows) with an enlarged right optic nerve (arrowhead). Pathologic examination found highly cellular glial and microvascular proliferation, palisading necrosis, numerous mitoses (Fig C, arrow) (Hemalun Phloxin Saffron staining, left), and diffuse expression of the mutation H3F3A G34R (right).

CNS tumor with BCOR internal tandem duplication: Clinicopathologic, molecular characteristics and prognosis factors

The central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR ITD) is a recently identified rare tumor entity, the complete morphologic characteristic, genetic alteration, classification, clinical outcomes and optimal treatment for this tumor entity have not been fully clarified. Here, two new cases of CNS tumor with BCOR ITD were reported and the clinicopathologic, molecular characteristics, and prognosis were analyzed through reviewing of the reported literature. The histological features included a clear border with adjacent brain parenchyma, an extensively microcystic background, and the cells with round to oval nuclei containing delicate chromatin, ependymoma-like perivascular pseudorosettes, and palisading necrosis. Immunohistochemical features showed strong and diffuse positive expression for BCOR, scattered positive expression for OLIG2, and negative expression for GFAP, Syn, and EMA. PCR and direct DNA sequencing analysis identified exon 15 ITD of the BCOR gene in both cases. Interestingly, both cases revealed two duplication segments, which had not been reported in the literature. A review of the literature shows that CNS tumor with BCOR ITD has a poor prognosis with a median survival of 1.7 years; surgical gross total resection is a good prognostic factor. A combination of radiation treatment and chemotherapy, while trending towards significance, does not reach statistical significance. On the contrary, the OS is not associated with age, gender, and tumor location. In conclusion, CNS tumor with BCOR ITD is a rare tumor entity with characteristic morphologic and molecular features and a poor prognosis. The optimal treatment strategies need further studies.

HGG-23. The presence ofROS1 fusions are not limited only to infantile hemispheric glioma.

INTRODUCTION: Diffuse pediatric-type high-grade gliomas are diffuse gliomas with histological features of malignancy, typically occurring in children, and infants. For these tumors, precise classification, identification of prognostic and predictive factors requires molecular analysis. The ROS proto-oncogene 1 (ROS1) gene encodes a receptor tyrosine kinase that is involved in chromosomal rearrangements in numerous malignancies, and may be an attractive therapeutic target, since specific inhibitors have been approved for several neoplasms. Molecular evaluation including detection of ROS1 fusions in pediatric gliomas are not included in standard diagnostic tests so far, therefore data on its significance is still limited. We present two cases of pediatric ROS1 fusion-positive brain tumors. METHODS AND RESULTS: The patient no.1 was 1 year old boy with disseminated brain lesions. Histopathological examination displayed the presence of a neoplasm, which was composed of round and spindle-shaped cells with palisading necrosis, mitotic activity, and microvascular proliferation. The patient no.2 is 9 years old girl with tumor located in left frontal lobe. Microscopically, the neoplasm revealed the presence of oligodenroglial-like component with microvascular proliferation, and high mitotic activity. Targeted gene sequencing panel - Ampliseq Childhood Cancer Panel for Illumina was used to detect diagnostic and targetable gene fusions. In both of patients ROS1:GOPC gene fusions were detect. Identified fusions allowed to established diagnosis - infant-type hemispheric glioma with ROS1 fusion (patient no 1) and - diffuse pediatric-type high grade glioma with ROS1 fusion (patient no 2). CONCLUSIONS: Our results indicate, that the presence of ROS1 fusions are not limited to the infant-type hemispheric gliomas only and may play a role in other glioma entities. It may be worth to include this biomarker in the diagnostic panel of pediatric brain tumors to establish a more precise diagnosis and a potential therapeutic target. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064).

Glioblastoma following Hemorrhagic Stroke: A Case Report

Objective: To report a glioblastoma (GBM) case preceded by a hemorrhagic stroke. Methods: This case reported a 53-year-old male presenting at at Murni Teguh Memorial Hospital, Medan, Indonesia, with a chief complaint of an altered mental state. The condition had been worsened for two weeks. On anamnesis, he was identified to have experienced intracerebral hemorrhage in January 2020. A follow-up head computed tomography scan was conducted in September 2020, showing a normal condition of the brain. Other oncogenic risk factors were not found. Due to convulsion in October 2020, the patient underwent a magnetic resonance imaging examination showing a cystic right temporoparietooccipital lesion and cerebral edema. Craniotomy tumor removal surgery was performed while the tumor was further examined for histopathological findings. The tumor was diagnosed as glioblastoma with microvascular proliferation and palisading necrosis. Results: There was some associations between hemorrhagic stroke and glioblastoma development. Conclusion: GBM preceded by hemorrhagic stroke is a rare case that can be diagnosed thoroughly by complete clinical and adjunct examinations.

The histopathological approach to granulomatous skin lesions

Granulomatous inflammation of skin and subcutaneous tissue are common in India. An identical histological picture is produced by several causes. Present study aims at classifying infectious granulomas based on histomorphology and special staining and developing a proper approach for making a specific etiological diagnosis. To classify the granulomatous dermatitis and a simple diagnostic histological approach has been worked out based on morphology of granuloma, presence of caseous necrosis, palisading necrosis, location of the granuloma and use of special stains. A prospective study of skin biopsies with granulomatous inflammation over a period of 2 years is done. Histologically lesions were divided into six subtypes:-Tuberculoid, foreign body type, histoid, necrobiotic, suppurative and sarcoidal type. On basis of morphological features and special staining each type was further subclassified and a specific diagnosis was given. Among 580 skin biopsies, 175 cases (30.17%) were of granulomatous skin lesions. On histopathological typing Tuberculoid type of granuloma was the most common type (62/175 cases, 35.43%) of which leprosy (40/62 cases, 64.52%) was the commonest etiology identified. Infections form an important etiology of granulomatous skin inflammation (120/175 cases, 68.57%) of which leprosy (82/120 cases, 68.33%) is the leading etiology in our study. Adequate clinical work-up in combination with pathological resources help in correctly approaching a granulomatous skin lesion and reaching a specific etiologic diagnosis.

Clinical relevance of molecular subgrouping of gliomatosis cerebri per 2016 WHO classification: a clinicopathological study of 89 cases.

The extremely invasive phenotypes and genotypes related to progression of gliomatosis cerebri (GC) remain unclear although GC has been removed as an independent entity from the 2016 WHO classification. Hence, categorization of GC under the current WHO molecular classification is essential, and the molecular subgroups that might contribute to GC progression should be compared with the histopathological differences between initial and new lesions identified during follow-up. Analyses of IDH1/2 and TERTp mutations and 1p/19q co-deletion, and immunohistochemistry of IDH1-R132H, ATRX, p53 and galectin-3 were performed. Anaplastic astrocytoma, IDH-wildtype (AA-IDHwt) was the common molecular subgroup (52.8%), followed by diffuse astrocytoma, IDH-wildtype (DA-IDHwt) and AA, IDH-mutant (AA-IDHmt) (each 16.9%), DA-IDHmt (7.9%), glioblastoma (GBM)-IDHwt (3.3%) and GBM-IDHmt (2.2%). Approximately 92% of the AA-IDHwt lesions progressed to histologically confirmed GBM in the newly enhanced lesions harboring the TERTp mutation and expressing galectin-3. Similar to primary GBMs, GC-related GBMs that progressed from the IDHwt subgroups showed microvascular proliferation, palisading necrosis or thrombotic occlusion, implying that a subset of IDHwt subgroups may evolve to overt GBM. Molecular subgrouping did not provide the perfect prediction for the survival of GC patients. The AA-IDHwt group showed worse overall and progression-free survival (PFS) than the AA-IDHmt group. Biopsy plus radiotherapy, chemotherapy and temozolomide treatment for DA-IDHwt, and resection plus radiotherapy and temozolomide treatment for AA-IDHwt prolonged PFS. In conclusions, majority of GC was of the AA-IDHwt subgroup, which progressed to GBM. Molecular subgroups may assist in the selection of treatment modalities, because "GC pattern" still remains as a special growth of gliomas in WHO 2016 classification without established treatment guideline.

Spontaneous development of intratumoral heterogeneity in a transposon-induced mouse model of glioma.

Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding(t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

GlioblastomaMultiforme: A clinico-pathological analysis

Background: Aim of the study was to classify Glioblastoma Multiforme (GBM) and its variants on histology and analyze their clinico-pathological features. Better understanding of the heterogeneous nature of GBM and its variants may provide improved treatment paradigms, prognostic classification and approaches towards molecular targeted treatments.Materials and Methods:40 cases of GBM were analyzed retrospectively and prospectively, covering a period of 8 years (January 2008- July2015). Cases were analyzed on the basis of clinical presentation, histopathological features and radiological reports. Results: Of the 40 cases of GBM, the Conventional GBM, GBM with oligodendroglial component, Giant Cell GBM accounted for 26, 9 and 3 cases respectively. While there was 1 case each of Gliosarcoma and P-NET variants. Conventional GBM most commonly presented with Headache (69.2%) and paresis (57.7%) whereas GBMO patients presented with convulsions. On radiology, the variants of GBM cannot be distinguished as the findings were similar in all of them. Non-palisading necrosis was predominantly present in Conventional GBM (61.5%) and palisading necrosis in GBMO (66.7%).Conclusion:Histopathology remains the main tool for differentiating the variants as radiological differentiation is not possible due to similar appearing features.DOI: 10.21276/APALM.1658

Glial fibrillary acidic protein, CD34, Ki-67, and p53 immunohistochemistry expression study to estimate the concordance between the morphology and the awarded grades of the brain gliomas

Background: The 2007 WHO grading system of gliomas recognizes four prognostic grades of the latter. Based exclusively on morphological patterns, this classification remains unsatisfactory with rates of diagnostic conflicts between pathologists ranging from 20% to 50%, particularly between Grades II and III. Misestimating the grade implies impertinent care decisions. We evaluated the concordance between grades and morphological characteristics of our series. Methods: Our study is a retrospective covering 3 years and wherein the biopsies of 32 formalin-fixed paraffin-embedded brain gliomas were explored. The histopathological diagnosis had been revised, and all cases were stained by immunohistochemical (IHC) technique with glial fibrillary acidic protein (GFAP), Ki-67, p53, and CD34 tumor markers. Comparisons were made between the grades and the IHC results and between the latter and the morphological characteristics of the studied gliomas. We used Kolmogorov–Smirnov test for normal distribution, Chi-square test of Pearson and Fisher test for qualitative variables, Mann–Whitney U-test, and Kruskal–Wallis test for continuous variables. The significance is retained for P< 0.05. Results: GFAP is expressed in all of the 32 studied tumors. Our markers are more expressive in high-grade gliomas (GFAP [P = 0.149], Ki-67 [P = 0.001], p53 [P = 0.012], and CD34 [P = 0,004]). Labeling index increases with the cellular density (Ki-67 [P = 0.001], p53 [P = 0.031]) and with the mitotic activity (Ki-67 [P = 0.001], p53 [P = 0.056]). CD34 is more expressive in the presence of endothelial-capillary proliferation (P = 0.02), of palisading necrosis (P = 0.015), and of nonpalisading necrosis (P = 0.076). Ki-67 is more specific and more sensitive than p53 (P < 0.001). The value of ideal expression of Ki-67 proposed for our sample is 8.5% (P < 0.001). It allows 93.7% of specificity and 75% of sensibility and separates the low grade (I, II) of the high grade (III, IV). Conclusion: The results prove the concordance of the established grades and gliomas morphology of our series.

Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Glioblastoma occurring at the site of a previous medulloblastoma following a 5-year remission period

We describe a case of a 14-year-old boy who developed a cerebellar and brainstem glioblastoma 5 years after treatment for a medulloblastoma. The patient first presented in 2003 with 9 months of vomiting and a 9-kg weight loss. A head MRI showed a heterogeneously enhancing posterior fossa mass with hydrocephalus. Gross total resection was performed and the tumor was consistent with a classic medulloblastoma. Postoperative chemotherapy and craniospinal radiation was administered. The patient remained tumor-free until 2008, at which time he presented with right-sided weakness and numbness, left eye pain, vomiting and weight loss. Imaging showed abnormalities within the posterior pons, medulla, inferior cerebellar peduncles, cerebellar hemispheres and cervicomedullary junction with expansion of the medulla and cervical spinal cord. Due to the location of the lesion, biopsy was felt to be too risky and was avoided. Despite receiving chemotherapy, his symptoms continued to worsen and he died 4 months later. Post mortem examination limited to the brain and spinal cord confirmed the radiographic extent of the tumor. Microscopic examination showed a highly cellular infiltrative glial neoplasm with extensive palisading necrosis. A diagnosis of glioblastoma was rendered. The question of whether the first and second tumors were related is of potential clinical and academic interest. The first tumor was synaptophysin-positive and GFAP-negative, consistent with medulloblastoma. The second tumor was synaptophysin-negative and focally GFAP-positive, consistent with glioblastoma. The glioblastoma displayed EGF receptor amplification, and interestingly, it also displayed MYCN amplification; both tumors showed low level PTEN deletion. The medulloblastoma displayed a signal pattern consistent with an isochromosome 17q, while the glioblastoma showed some cells with an isochromosome 17q signal pattern amid a background of cells with abundant chromosomal instability. The relationship between these two tumors, particularly with regard to various molecular events, is discussed.

Co-occurrence of Idiopathic Granulomatous Hepatitis and Primary Biliary Cirrhosis

Purpose: Purpose: To report a possible association between idiopathic granulomatous hepatitis and primary biliary cirrhosis (PBC). Methods: Review of two cases Case 1: A 42 year old asymptomatic woman had an elevated alkaline phosphatase, 343 IU (normal <130), a positive antimitochondrial antibody, titer 1:64, and 20% eosinophils. Liver biopsy demonstrated florid bile duct lesions with minimal fibrosis, consistent with Stage II PBC. She was treated with methotrexate 15 mg weekly (ursodiol was unavailable at the time). Six months later her alkaline phosphatase was normal, 75 IU. 15 years after the diagnosis of PBC the patient presented with one week of fevers, chills, and night sweats. Her alkaline phosphatase was elevated, 313 IU. Liver biopsy showed numerous granulomas with giant cells throughout the liver lobule with some areas of palisading necrosis and intense inflammation, consistent with a diagnosis of idiopathic granulomatous hepatitis. The methotrexate dose was increased to 22.5 mg per week. Her symptoms remitted, alkaline phosphatase returned to normal, and liver biopsy was essentially normal. Case 2: A 42 year old female with fatigue was referred for evaluation of abnormal liver function tests. Her alkaline phosphatase level was slightly elevated, 149 IU (normal <125). Antimitochondrial antibody was negative. Liver biopsy showed a granulomatous type inflammation of the portal tracts consistent with idiopathic granulomatous hepatitis. She was treated with oral methotrexate; two and seven years later liver biopsies and alkaline phosphatase levels were essentially normal. 12 years after diagnosis of idiopathic granulomatous hepatitis, alkaline phosphatase was 284 IU, antimitochondrial antibody was strongly positive (113.2 units by ELISA; normal <20), and liver biopsy showed bile duct inflammation and occasional fibrous bridging, consistent with a diagnosis of Stage II-III PBC. Ursodiol therapy was initiated. Alkaline phosphatase has since ranged from 115 - 149 IL (normal <130). Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, and granulomas in portal and lobular regions of the liver. We describe the first reported case of idiopathic granulomatous hepatitis occurring in a patient with PBC, as well as the first known diagnosis of PBC in a patient with idiopathic granulomatous hepatitis. Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. The cause of both diseases is unknown.

Primary Cerebellar Pilocytic Astrocytoma With Anaplastic Features in a Patient With Neurofibromatosis Type 1 -Case Report-

A 70-year-old woman with neurofibromatosis type 1 (NF-1) presented with a primary cerebellar pilocytic astrocytoma (PA) with anaplastic features manifesting as worsening headache and ataxia. Magnetic resonance (MR) imaging on admission showed a diffusely enhanced solid mass in the left cerebellar hemisphere, although MR imaging showed no abnormalities 2 years before admission. Histological examination after gross total removal of the tumor exhibited a biphasic pattern with marked Rosenthal fibers, together with some malignant features including frequent mitoses and invasive growth pattern. The final diagnosis was PA with anaplastic features. Previous PA cases with mitotic activity and endothelial proliferation, and/or palisading necrosis have been classified as anaplastic PA (or PA with anaplastic features). In the present case, the tumor histology corresponded to this designation. The present case indicates that PAs with anaplastic features can occur in patients with NF-1.