Diffuse Fibrillary Astrocytoma Research Articles

Isocitrate Dehydrogenase and Alpha Thalassemia/Mental Retardation, X-linked Mutation Status in Human Gliomas at a Tertiary Care Hospital in Southern India: A Cross-sectional Study

Introduction: The molecular subtyping of human gliomas in the current World Health Organisation (WHO) 2021 classification highlights the diagnostic and prognostic significance of neoplastic entities. This subsequently contributes to a better understanding of immunohistochemistry markers in various glioma patients. Aim: The study aimed to determine the Isocitrate Dehydrogenase (IDH1) gene mutation and Alpha Thalessemia/Mental retardation X-linked (ATRX) mutation in gliomas through immunohistochemistry and clinically categorise them into various subgroups. Materials and Methods: The present cross-sectional study was conducted in the Department of Pathology and Neurosurgery on 50 glioma samples collected from patients who underwent surgery at ESIC Medical College and Super Speciality Hospital in Hyderabad, Telangana, India from June 2018 to June 2023. Histopathological evaluation and Immunohistochemistry (IHC) study for IDH1 and Alpha Thalessemia/Mental retardation X-linked were performed on all patients. Clinical variables such as age, gender, duration of symptoms, and clinical presentation were collected from medical records and tabulated. Results: Total 50 cases of glioma were studied. The expression of IDH1 wild type was observed in 30 (60%) cases, which was more common than IDH1 mutation observed in 20 (40%) cases. The mean age in the study was 41.9 years, with a majority of male patients 33 (66%). IDH1 mutation was commonly observed in diffuse fibrillary astrocytomas (34%) followed by 12% of cases in anaplastic Astrocytomas. Glioblastoma was the most common histopathological diagnosis in 40% of cases, but the observed IDH mutation was least frequent in glioblastomas. Out of the 20 glioblastoma cases, only one tested positive for IDH mutation. In contrast, ATRX loss was predominantly seen in glioblastomas, with three out of the five positive cases. IDH1 mutation was more common in adults than in children, and a female preponderance (60%) was noted. ATRX mutation was observed in only 10% of cases. Conclusion: The IDH1 and ATRX are reliable prognostic markers, and their analysis through immunohistochemistry provides a practical and dependable method for categorising gliomas compared to molecular analysis, thus assisting clinicians in achieving promising treatment outcomes.

LGG-21. Durability of response to targeted therapies in pediatric low-grade gliomas: A multi-institution retrospective review

Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.

Histopathological Spectrum of Neoplastic and Non Neoplastic Brain Lesions at a Tertiary Care Centre in South IndiaA Retrospective Observational Study

Introduction: Brain lesions can be caused by varied etiological factors like neoplastic, infectious, inflammatory and vascular diseases. Accurate diagnosis in very important for correct neurosurgical treatment. A retrospective histopathological study of brain lesions is of utmost importance because as it can demonstrate the changes in the spectrum of brain lesions,burden of disease in the community, can reveal the possible risk factors and can suggest probable treatment methods for various neoplastic and non neoplastic brain lesions. Aim: To evaluate the incidence, age distribution, gender distribution, and histopathological spectrum of neoplastic and non neoplastic lesions of brain. Materials and Methods: This retrospective study was conducted in the Department of Pathology at Narayana Medical College, Nellore, Andhra Pradesh, India, from January 2019 to December 2021. Total 216 cases were studied. The tumours were classified under World Health Organization (WHO) classification. To test the mean difference between the groups, Independent sample t-test was done. Results: Out of 216 cases, 180 (83%) were neoplastic and 36 (17%) were non neoplastic lesions. The male: female ratio was 1.03:1. Non neoplastic lesions were common in males (22, 61.11%), while neoplastic lesions were common in females (92, 51.11%). The most common age group affected was 41-50 years (55, 25.46%). Astrocytoma (41, 22.77%) followed by meningioma (40, 22.22%) were the common neoplastic tumours and haematoma(7, 19.44%) was the most common non neoplastic lesion in adults. Common tumour in children (<18 years) was diffuse fibrillary astrocytoma (3/11, 27.27%)and chronic inflammatory pathology was the common non neoplastic lesion (2/11, 18.18%). Conclusion: Majority of cases were seen in 41-50 years age group. Astrocytoma was the common neoplastic tumour and haematoma was the common non neoplastic lesion in adults. Diffuse fibrillary astrocytoma was the common tumour and chronic inflammatory pathology was the common non neoplastic lesion in children.

Primary spinal intramedullary astrocytomas; long-term outcomes and literature review

BackgroundSpinal cord astrocytomas are rare intramedullary tumors. The optimal management of these rare tumors is still controversial. In addition, the different histopathological subclassification and diversity in management protocols complicated the outcome of the disease. We aim to present our long-term outcome of different subtypes of spinal astrocytomas and contribute to the overall understanding of this rare disease. MethodsA retrospective descriptive cohort study of surgical cases managed between June 2001 and December 2019 was carried out. We included the clinical, radiological studies, histological findings, treatment strategies, and surgical outcomes for all operated patients with histologically proven intramedullary spinal astrocytoma. American Spinal Injury Association (ASIA) impairment scale was used to assess the neurological status of patients. ResultsA total of 21 patients were identified. The patients’ median (IQR) age at the time of surgery was 22 years (range 2–63 years). Gross total resection (GTR), subtotal resection (STR), and extended biopsy with duraplasty (Ext. Bx) were the surgical options. Two main categories were identified: diffuse fibrillary astrocytoma (DFA) in 11 patients and pilocytic astrocytoma (PA) in the other 10 patients. Postoperative adjuvant radiotherapy (RT) was used in 9 patients. The median (IQR) follow-up period was 69 months (range 2–237 months). ConclusionConcerning the subclassification of spinal astrocytoma, each group, DFA & PA, has a different natural history and proposed management profiles. Early intervention is highly advocated to provide stability or improvement in the neurological outcomes in the long term. Laminectomy with extended safe resection is the recommended surgical intervention for cases of PA. On the other side, limited safe resection is the choice for DFA patients of any grade. Radiation therapy should be preserved only to DFA when resection is incomplete, has high-grade tumors, or in cases of recurrences.

Heat shock factor 1 in brain tumors: a link with transient receptor potential channels TRPV1 and TRPA1.

Novel data report a "cross-talk" between Heat-Shock Factor 1 (HSF1) and the transient receptor potential vanilloid 1 cation channel (TRPV1) located in the cell membrane, introducing these channels as possible drug targets for the regulation of HSF1 activation. This study aims to investigate the co-expression of TRPV1 and HSF1 in human brain tumors. Additionally, the expression of the transient receptor potential ankyrin 1 channel (TRPA1), which is co-operated with TRPV1 in a plethora of cells, was studied. Immunohistochemical staining for HSF1, TRPV1 and TRPA1 expression was quantitatively analyzed in paraffin-embedded semi-serial tissue sections from 74 gliomas and 71 meningiomas. mRNA levels of HSF1, TRPV1 and TRPA1 were evaluated using real-time PCR. Although HSF1 was significantly increased compared with TRPV1/TRPA1 (p ≤ 0.001) in both gliomas and meningiomas, high co-expression levels for HSF1, TRPV1 and TRPA1 were found in 62.50% of diffuse fibrillary astrocytomas (WHO, grade II), 37.50% of anaplastic astrocytomas (WHO, grade III), 16.32% of glioblastomas multiforme (WHO, grade IV), and 42.25% of meningiomas (WHO, grade I and II). Correlation analysis revealed a relationship of HSF1 with TRPV1/TRPA1 in diffuse fibrillary astrocytomas (WHO, grade II) and benign meningiomas (WHO, grade I) contrary to glioblastomas multiforme (WHO, grade IV) and high grade meningiomas (WHO, grade II). Importantly, TRPA1 and TRPV1 expression levels were significantly increased in meningiomas compared with astrocytic tumors (p < 0.05). In conclusion, HSF1 and TRPV1/TRPA1 co-expression may be implicated in the pathogenesis of human brain tumors and should be considered for the therapeutic approaches for these tumors.

A single-centre observational study of 124 surgically managed glioma patients: molecular subtyping and its correlation with clinico-radiological profile

Background: The World Health Organization (WHO) 2016 classification incorporated molecular subtyping in glioma, highlighting the diagnostic and prognostic significance. The study aims to determine the isocitrate dehydrogenase (IDH-1) gene, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, and tumor suppressor gene-53 (p53) mutation in glioma and their correlation with various clinical and radiological parameters.Methods: In this prospective observational study, histopathological slides of glioma (2017-2018), were analyzed for IDH-1, ATRX and p53 mutations and their correlation with various clinical and radiological parameters.Results: IDH-1 mutation was found in 48 (38.7%), ATRX loss in 38 (30.6%) and p53 mutation in 40 (32.5%) patients. The expression of IDH-1 was significantly higher (43.7%) in adults; however, no significant difference was seen with gender. Also 51.2% of patients, who presented with seizures, showed IDH-1 expression; and 27.7% of patients, who had neurological deficit also showed IDH-1 expression. IDH-1 expression was high in glioma located at insula (73.3%) and parietal lobe (71.4%); while ATRX loss was seen in glioma located at insula (80%). Intraventricular glioma characteristically lacks all three markers: IDH-1 expression, p53 overexpression and ATRX loss. IDH-1 expression and p53 overexpression was seen mainly in diffuse fibrillary astrocytoma, oligodendroglioma, anaplastic astrocytoma and glioblastoma.Conclusions: Molecular subtyping is of paramount importance in glioma management. IDH-1 mutation is commonly observed in adults and patients presenting with seizures. The duration of symptoms correlates with IDH-1 and ATRX mutations. Intraventricular tumors lack all three mutations.

The expression level of cannabinoid receptors type 1 and 2 in the different types of astrocytomas.

Astrocytomas, the most prevalent primary brain tumors, can be divided by histology and malignancy levels into four following types: pilocytic astrocytoma (grade I), diffuse fibrillary astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (grade IV). For high grade astrocytomas (grade III and grade IV), blood vessels formation is considered as the most important property. The distribution of cannabinoid receptors type 1 (CB1) and cannabinoid receptor type 2 (CB2) in blood vessels and tumor tissue of astrocytoma is still controversial. Asrocytoma tissues were collected from 45 patients under the condition of tumor-related neurosurgical operation. The expression of CB1 and CB2 receptors was assessed using immunofluorescence, quantitative real-time RT-PCR and western blotting. The results indicated an increased expression of CB1 receptors in tumor tissue. There was a significant difference in the mount of CB2 receptors in blood vessels. More was observed in the grade III and glioblastoma (grade IV) than astrocytoma of grade II and control. This study suggested that, the expression increase of cannabinoid receptors is an index for astrocytoma malignancy and can be targeted as a therapeutic approach for the inhibition of astrocytoma growth among patients.

MiRNA expression profiling in human gliomas: upregulated miR-363 increases cell survival and proliferation.

The role of microRNAs (miRNAs) in glioma biology is increasingly recognized. To investigate the regulatory mechanisms governing the malignant signature of gliomas with different grades of malignancy, we analyzed miRNA expression profiles in human grade I-IV tumor samples and primary glioma cell cultures. Multiplex real-time PCR was used to profile miRNA expression in a set of World Health Organization (WHO) grade I (pilocytic astrocytoma), II (diffuse fibrillary astrocytoma), and IV (glioblastoma multiforme) astrocytic tumors and primary glioma cell cultures. Primary glioma cell cultures were used to evaluate the effect of transfection of specific miRNAs and miRNA inhibitors. miRNA microarray showed that a set of miRNAs was consistently upregulated in all glioma samples. miR-363 was upregulated in all tumor specimens and cell lines, and its expression correlated with tumor grading. The transfection of glioma cells with the specific inhibitor of miR-363 increased the expression level of tumor suppressor growth-associated protein 43 (GAP-43). Transfection of miR-363 induced cell survival, while inhibition of miR-363 significantly reduced glioma cell viability. Furthermore, miRNA-363 inhibition induced the downregulation of AKT, cyclin-D1, matrix metalloproteinase (MMP)-2, MMP-9, and Bcl-2 and upregulation of caspase 3. Together, these data suggest that the upregulation of miR-363 may play a role in malignant glioma signature.

Diffuse Intrinsic Brainstem Tumor in an Infant

Brainstem gliomas constitute 10% to 20% of all pediatric tumors of the central nervous system, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors is benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill defined, especially in the neonates. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Thus, we report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem fibrillary astrocytoma, treated with vinorelbine (30 mg/m/d on days 0, 8, and 22), a vinca alkaloid that has shown activity against glioma. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas as this patient showed significant clinical improvement over a short period of time.

Pediatric and Adult Gliomas: How Different Are They?

Recently, I was discussing the treatment of a pediatric patient who had gliomatosis cerebri. A pediatric neuro-oncologist, one of my respectable friends, insisted on chemotherapy with temozolomide. Because the histologic type was anaplastic astrocytoma (as determined by open biopsy), many would consider radiotherapy the primary option; thus, there was an exciting discussion. On another occasion, the same colleague and I were discussing a pediatric patient with a symptomatic diffuse astrocytoma of the posterior thalamus; this time as well, he insisted on a trial of chemotherapy with carboplatin and vincristine. My colleague's philosophy is that because pediatric gliomas are different from adult gliomas, chemotherapy to defer or avoid radiotherapy is reasonable in cases of low-grade and sometimes even high-grade glioma. Maybe my colleague is right regarding the difference between pediatric and adult gliomas. There have been numerous reports showing substantial differences in the molecular features underlying pediatric and adult high-grade gliomas. Pediatric and adult glioblastomas were shown to be clearly distinguished by frequent gain of chromosome 1q and lower frequency of chromosome 7 gain and 10q loss in the pediatric form. Platelet-derived growth factor receptor-α (PDGFR-α) was found to be the predominant gene subject to focal amplification in childhood high-grade gliomas.1,2 Among the pediatric low-grade gliomas, pilocytic astrocytoma is the predominant histologic type and diffuse astrocytomas are quite rare. In this issue of Neuro-Oncology, Stokland et al. from the Children's Brain Tumour Research Centre, University of Nottingham, UK, report on 639 pediatric patients with low-grade gliomas, 63.7% of which were pilocytic astrocytomas and only 5.9% of which were diffuse fibrillary astrocytomas.3 The predominance of the former type is consistent with other evidence. For instance, in the Brain Tumor Registry of Japan, the incidence of pilocytic astrocytomas peaks in patients between 5 and 9 years old, while that of diffuse astrocytomas peaks in patients between 40 and 44 years old. In the Central Brain Tumor Registry of the United States (CBTRUS), 1,834 pediatric patients (those between 0 and 19 years old) with pilocytic astrocytomas are registered, while only 101 cases of diffuse astrocytoma are found in the pediatric population. Therefore, pediatric low-grade gliomas are mostly pilocytic astrocytomas, and adult low-grade gliomas are mostly diffuse astrocytomas. Pilocytic astrocytomas and diffuse astrocytomas are classified as WHO grades I and II, respectively. However, pilocytic astrocytoma is not a precursor of diffuse astrocytoma, as there is a distinct difference between the molecular features of the two. There appears to be no role for either TP53 mutations or aberrant PDGF signaling in the development of pilocytic astrocytomas, in contrast to the role of TP53 mutations and increased expression of PDGF-A and PDGFR-α as common, early events in the formation of diffuse astrocytomas.4 Pilocytic astrocytomas also differ from diffuse astrocytomas in their altered and increased expression of immune response genes. Hierarchical clustering analysis using a set of 1,176 genes distinguished pilocytic astrocytomas from diffuse astrocytomas and oligodendrogliomas.5 Pilocytic astrocytomas are also different from the diffuse astrocytomas clinically, as evidenced by the fact that histology is one prognostic factor in pediatric low-grade gliomas.3 Fear of radiation-induced adverse effects has been used to justify the use of chemotherapy for unresectable pilocytic astrocytomas. A number of chemotherapy regimens have been used to delay the need for radiotherapy, including carboplatin and vincristine. A recent randomized trial, Children's Oncology Group A9952, compared the combination of carboplatin and vincristine with the combination of procarbazine, thioguanine, lomustine, and vincristine and reported 5-year event-free survival rates of 40%-50%. More than 400 low-grade gliomas were registered, and 83% of them were pilocytic astrocytomas.6 However, although a small study is under way, the role of chemotherapy in the management of pediatric diffuse astrocytomas remains unclear. In adult diffuse astrocytomas, a randomized study comparing radiotherapy and temozolomide is now ongoing in Europe and North America. Yes, pediatric and adult gliomas are different. Pediatric and adult high-grade gliomas are biologically different. On the other hand, differences between pediatric and adult low-grade gliomas are mainly due to the difference in their histologies. Whether pediatric diffuse astrocytomas are chemosensitive remains unproven. The UK study reported in this issue also suggests that, because of the small number of diffuse astrocytomas in the pediatric population, international cooperation will be needed to address the issue of the optimal management of this entity.

Pediatric low-grade gliomas.

Pediatric low-grade gliomas encompass a heterogeneous set of tumors of different histologies. Cerebellar pilocytic astrocytomas occur most frequently followed by supratentorial diffuse fibrillary astrocytomas. Recent research has implicated activation of the RAS/RAF/MEK pathway in tumorigenesis of these tumors. Surgery is the mainstay of therapy. Overall survival rates for patients whose tumors are completely resected are 90% or greater, 10 years from diagnosis. Conversely, most optic pathway/hypothalamic, deep midline, and brain stem gliomas have minimal potential for resection; these tumors can be difficult to treat and deserve special attention. Combination chemotherapy is currently recommended as front-line adjuvant treatment for progressive or recurrent tumors. Second-line radiotherapy can also improve overall survival but is associated with more frequent and significant neurocognitive, endocrine, and other long-term toxicities.

Factors influencing activities of daily living using FIM–FAM scoring system before starting adjuvant treatment in patients with brain tumors: results from a prospective study

Patients with brain tumors have varied degree of functional and psychological impairments because of factors relating to the tumor or to the treatment they receive. The functional independence measurement and functional activity measurement system (FIM-FAM) is an activity of daily living (ADL) scoring system that may be able to determine impairments in different domains objectively. From August 2007 to April 2008, 150 consecutive adult (>18 years) primary brain tumor patients (median age 40 years; male 88, female 62) registered in a general out-patient neuro-oncology clinic were accrued and detailed data were recorded. Seventy percent had malignant tumor (66% high-grade and 34% low-grade; 70% intra-axial). Glioblastoma (GBM) (23.3%), anaplastic astrocytoma (AA) (18.7%), and diffuse fibrillary astrocytoma (18.7%) were the commonest histologic subtypes. The common sites for tumors included frontal region (30.7%), posterior fossa (12%), and left parietal region (11.3%). A detailed baseline pre-radiotherapy (pre-RT) ADL assessment was done with the FIM-FAM scoring system, which has seven domains with 30 sub-domains (maximum and minimum total scores are 210 and 30). The mean total FIM-FAM score of the entire patient population was 167.5 (range 30-208). Scores in self care, sphincter control, mobility items, locomotion, communication items, psychological, and cognitive item domains were 39.49, 10.95, 22.70, 16.44, 28.93, 18.96, and 30.1, respectively. Univariate analysis showed total FIM-FAM scores not significantly different with age (< or =35 years vs. >35 years; P = 0.994), sex (male versus female; P = 0.133), and grade of the tumor (high-grade versus low-grade; P = 0.142) but were significantly higher in patients with a Karnofsky performance score (KPS) of > or =70 as compared with <70 (P = 0.001), neurological performance scale (NPS) of 0 or 1 vs. 2 or 3; P = 0.001), disease type (benign versus malignant; P = 0.001), and site of disease (cerebral versus cerebellar; P = 0.024). Multivariate analysis confirmed these findings for KPS (P = 0.001) and NPS (P = 0.012) only. Age was a significant factor for poorer cognitive function (P = 0.005), psychological (P = 0.045), and self care function (P = 0.001). A trend for correlation between tumor sites with the corresponding function as assesses on the FIM-FAM score was observed. Mobility domain scores were poor for left parietal domain and psychosocial for frontal lobe lesion. Pearson correlation test demonstrated a significant correlation between KPS and NPS with FIM-FAM scores (P = <0.001). Average time to perform the FIM-FAM was 15-20 min. FIM-FAM system is relatively simple, easy to perform in routine clinical practice and may be used as a tool for assessment of rehabilitation program. There is strong correlation with age, type of tumor, and site of disease with different functional and cognitive domain impairment.

Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

BackgroundNeurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue.MethodsFormalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined.ResultsModerate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade-dependent manner (p < 0.05). Interestingly, a statistically significant (p < 0.05) reverse relationship between Trk receptors LIs and pc-Jun/pJNK LIs was noted in some glioblastomas multiforme.ConclusionIn the context of astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression may promote tumor growth independently of grade. Furthermore, activation of JNK pathway may contribute to progression towards malignancy. Considering the fact that regional tumor heterogeneity may be a limiting factor for immunohistochemical studies, the significance of the reverse relationship between Trk receptors and pc-Jun/pJNK LIs with respect to biological behavior of human astrocytomas requires further evaluation.

Bilateral thalamic astrocytoma

We present a 68-year-old woman who presented with symptoms of frontotemporal dementia. Brain MRI revealed tumor mass in both thalami and according to WHO classification, the tumor corresponded to diffuse fibrillary astrocytoma grade II. This case points to the role of neuroimaging in patients presenting with classical symptoms of dementia.

HTERT immunopositivity patterns in the normal brain and in astrocytic tumors

Accumulating data about the impact of hTERT in astrocytic tumor carcinogenesis and recent evidence about its association with disease outcome prompt the evaluation of this molecule with methods applicable in routine pathology practice. In this study, we investigated hTERT protein expression with immunohistochemistry (IHC) and the NCL-hTERT antibody in 49 astrocytic tumors. Results were validated with the assessment of hTERT mRNA (relative quantification, identification of splice variants, in situ hybridization). Specific nuclear hTERT immunostaining patterns (IPs) were characterized as patterns As (single large dot) and Am (multiple dots) without nucleoplasm staining and pattern B (nucleoplasm staining with or without dots), corresponding to low and high relative hTERT expression values (P<0.0001). Low- and high-grade astrocytic tumors were found positive for hTERT in 74 and 85% of cases, respectively. Heterogeneity in the distribution of hTERT-positive cells was observed in all tumors. The prevailing nuclear IPs differed significantly between pilocytic astrocytomas (pattern As) and the rest of histologic types up to glioblastoma (patterns Am and B) (P<0.0001). The described nuclear IPs were also observed in non-neoplastic cells. Positive endothelial cells were found in astrocytic tumors of all grades, even when tumor cells showed no hTERT immunoreactivity. A subset of mature normal neurons was positive for hTERT (pattern As), suggesting a role for this molecule in neuronal maintenance in the adult brain. The nuclear hTERT IPs described here may reflect the functional status of non-neoplastic brain and neoplastic astrocytic cells and support the model of a continuum in the development of glioblastomas from diffuse fibrillary astrocytomas.

AP-1 and heat shock protein 27 expression in human astrocytomas.

In previous work we have shown that the expression of heat shock protein 27 (Hsp27) is associated with anaplastic potential of astrocytomas (Anticancer Res 1997, 17:2677-2682). Heat shock protein-coding genes have been found to have a putative AP-1 (activator protein-1)-binding site in their promoter region and the synthesis of these proteins is induced by the same extracellular stimuli that also activate AP-1 (a homo/heterodimer of members of the Jun and Fos families). In order to detect the putative relation of Hsp27 with AP-1 activation in human astrocytomas we examined eighty astrocytic tumors with different grades of malignancy for c-Jun, c-Fos, and Hsp27 expression. Six pilocytic astrocytomas (WHO grade I), 15 diffuse fibrillary astrocytomas (WHO grade II), 19 anaplastic astrocytomas (WHO grade III), and 40 glioblastomas multiforme (WHO grade IV), were studied by immunohistochemistry using monoclonal and polyclonal antibodies directed against human Hsp27, c-Fos, and active (phosphorylated) forms of c-Jun (p-c-Jun). Monoclonal antibodies against the phosphorylated forms of the over-expressed MAP kinases JNK (c-Jun N-terminal kinase) (p-JNK) and p38 (p-p38) were also used. Overexpression of p-c-Jun, c-Fos and p-JNK was observed in the majority of glioblastomas (grade IV) whereas only minimal expression was noted in diffuse fibrillary astrocytomas (grade II). Hsp27 expression was observed only in the tumor specimens where c-Jun and c-Fos were co-expressed. AP-1/Hsp27 co-expression was associated with ascending grading of malignancy and it was independent of the proliferation index of the tumors. Our findings suggest that during malignant progression of astrocytomas there is activation of signal transduction cascade(s) culminating in AP-1 induction.

Cerebellar astrocytomas: a 24-year experience.

Cerebellar astrocytomas are the most benign tumors of the CNS. Seventy to eighty percent are found in children. We report on 38 children under 18 who had cerebellar astrocytoma in the posterior fossa and were treated by a multidisciplinary team in our Neurosurgical Department from January 1974 to December 1997. We included all patients in whom the histopathological diagnosis was astrocytoma, regardless of malignancy. The diagnostic methods used were pneumoventriculography, cranial X-rays, CT scan, and MRI. All patients were treated surgically. Neither radiotherapy nor chemotherapy was indicated in patients with pilocytic or fibrillary astrocytomas. A greater prevalence was observed in female (25/38; 66%) than in male (13/38; 34%) patients. Histopathological results revealed 27 (71%) pilocytic astrocytomas, 8 (21%) diffuse fibrillary astrocytomas, 1 (2%) anaplastic astrocytoma and 2 (6%) glioblastomas. These tumors were more frequently located in the right cerebellar hemisphere; increased intracranial pressure syndrome was the most frequent form of clinical presentation. Total tumor resection was obtained in 29 (83%) cases and subtotal resection in 9 (17%). In 6 (16%) cases, ventriculoperitoneal shunts were placed to control persistent hydrocephalus after tumor excision. The most frequent complication was increased ataxia. The mortality rate was 8.5%.

Aberrant Localization of the Neuronal Class III b-Tubulin in Astrocytomas A Marker for Anaplastic Potential

c Background.—The class III b-tubulin isotype (bIII) is widely regarded as a neuronal marker in development and neoplasia. In previous work, we have shown that the expression of bIII in neuronal/neuroblastic tumors is differentiation dependent. In contrast, the aberrant localization of this isotype in certain nonneuronal neoplasms, such as epithelial neuroendocrine lung tumors, is associated with anaplastic potential. Objective.—To test the generality of this observation, we investigated the immunoreactivity profile of bIII in astrocytomas. Design.—Sixty archival, surgically excised astrocytomas (8 pilocytic astrocytomas, WHO grade 1; 18 diffuse fibrillary astrocytomas, WHO grade 2; 4 anaplastic astrocytomas, WHO grade 3; and 30 glioblastomas, WHO grade 4), were studied by immunohistochemistry using anti-bIII monoclonal (TuJ1) and polyclonal antibodies. A monoclonal antibody to Ki-67 nuclear antigen (NC-MM1) was used as a marker for cell proliferation. Antibodies to glial fibrillary acidic protein (GFAP) and BM89 synaptic vesicle antigen/synaptophysin were used as glial and neuronal markers, respectively. Results.—The bIII immunoreactivity was significantly greater in high-grade astrocytomas (anaplastic astrocytomas and glioblastomas; median labeling index [MLI], 35%; interquartile range [IQR], 20%‐47%) as compared with diffuse fibrillary astrocytomas (MLI, 4%; IQR, 0.2%‐21%) (P , .0001) and was rarely detectable in pilocytic astrocytomas (MLI, 0%; IQR, 0%‐0.5%) (P , .0001 vs high-grade astrocytomas; P , .01 vs diffuse fibrillary astrocytomas). A highly significant, grade-dependent relationship was observed between bIII and Ki-67 labeling and malignancy, but this association was stronger for Ki-67 than for bIII (bIII, P , .006; Ki-67, P , .0001). There was co-localization of bIII and GFAP in neoplastic astrocytes, but no BM89 synaptic vesicle antigen/synaptophysin staining was detected. Conclusions.—In the context of astrocytic gliomas, bIII immunoreactivity is associated with an ascending gradient of malignancy and thus may be a useful ancillary diagnostic marker. However, the significance of bIII-positive phenotypes in diffuse fibrillary astrocytomas with respect to prognostic and predictive value requires further evaluation. Under certain neoplastic conditions, bIII expression is not neuron specific, calling for a cautious interpretation of bIII-positive phenotypes in brain tumors. (Arch Pathol Lab Med. 2001;125:613‐624)

Age-dependent rate of anaplastic transformation in low-grade astrocytoma.

Age and histologic grade are interrelated characteristics of diffuse fibrillary astrocytomas, because the peak age incidence rises with increasing grade. The relationship between age and grade may be explained if age determines the rate of anaplastic progression in astrocytomas. The authors tested this hypothesis by determining the interval between diagnosis of low-grade astrocytoma and progression to high-grade astrocytoma in patients of various ages. A two-way scatterplot of age at initial diagnosis versus interval to anaplastic progression demonstrated a strong negative correlation (n = 24; Pearson correlation coefficient = -0.83; Spearman correlation coefficient = -0.79; p < 0.001 for both values). It was concluded that the rate of anaplastic progression in low-grade astrocytoma is directly correlated with patient age.

Low-grade supratentorial astrocytomas in adults: Management, immunohistochemical analysis and long-term follow-up

A retrospective review of supratentorial, low-grade astrocytomas in adults over a 10-year period (1983–1993) was performed. All 62 patients had computed tomography and surgery with histological and immunohistochemical analysis of the tumour. Radiotherapy was administered to all patients, regardless of the extent of surgical resection. Multivariate analysis showed that age of the patient at the time of surgery ( P=0.008) and female sex ( P=0.031) were the most important indicators of improved survival. No significant survival advantage was found with any particular symptom or symptom duration. Neither presence of a tumour cyst nor site of the tumour affected survival. Histological grading (St Anne-Mayo system) found 61 grade II astrocytomas (98%) and one grade I tumour. Six tumours (10%) were protoplasmic astrocytomas and 56 cases (90%) were diffuse fibrillary astrocytomas. Proliferation index derived from Ki-67 antibody staining and the presence of p53 protein expression were not significantly correlated with survival. Most patients underwent biopsy (79%) with 8% undergoing subtotal and 13% total resection. Increased extent of surgical removal showed a trend towards an improved survival ( P=0.05). No survival advantage was found with increasing radiotherapy dose. Median survival in the study population was 5.1 years, with survival rates of 70% at 2 years and 53% at 5 years. The follow-up period ranged from 1 to 10.5 years. Younger age, female sex and the extent of surgical resection are important prognostic factors in the management of low-grade astrocytomas, whereas the efficacy of postoperative radiotherapy needs further evaluation. The prognostic significance of Ki-67 and p53 expression in low-grade astrocytomas remains to be determined.