Heterogeneous group of neuroectodermal tumors that arise from the glia, the supporting cells of he central nervous system.

Gliomas account for half of all intrinsic brain tumors.

Account for approximately 70% of 22,500 new malignant primary brain tumors in adults in the U.S.

Low grade gliomas, I, and II, include pilocytic, astrocytoma, and ganglioglioma, and hi grade  III and IV include anaplastic astrocytoma, and glioblastoma.

Approximately 20,000 new cases of gliomas diagnosed annually in the US, and account for the majority of deaths from primary brain tumors.

The incidence of gliomas spans the age spectrum: from childhood to older adults.

Gliomas is the leading cause of cancer death and children 0-14 years, and is among the top three causes of cancer deaths for adolescents and young adults aged 15-39 years, and rank seventh for cancer deaths among adults age greater than 40 years.

Account for 30% incidence of primary CNS tumors, which relates to 26 per 100,000 adults 20 years older (Central Brain Tumor Registry of the United States).

Malignant gliomas are the most common type of primary malignant brain tumor, accounting for 80% of patients in the annual incidence of 5.26 per 100,000 population or 17,000 new cases a year.

Incidence of malignant glioma approximately 5 per 100,000 people.

Incidence slightly increased over the past two decades.

High-grade gliomas represent the largest fraction of newly diagnosed primary brain tumors.

Patients with gliomas have a high disease burden compared to patients with other malignancies.

Increasing incidence noted, especially among the elderly, as result of improved imaging techniques.

Glioblastomas account for approximately 60-70% of malignant gliomas, 10-15% anaplastic astrocytomas, anaplastic ((oligodendrogliomas)) and anaplastic oligoastrocytomas 10%, and less common lesions of anaplastic ependymomas and anaplastic gangliogliomas account for the rest of the tumors.

Represent 42% of primary CNS tumors with more than three-fourths being malignant.

40% more common in men and twice as more common in white people than in blacks.

Median age for glioblastomas is 64 years and for anaplastic astrocytomas is 45 years.

Anaplastic gliomas are classified as grade 3 malignant tumors by WHO classification: and include the anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma or mixed glioma.

Anaplastic gliomas are highly aggressive lesions and tend to occur in young adults.

Anaplastic gliomas usually recur or progress to grade 4 lesions, glioblastomas, within several years of diagnosis regardless of surgery, radiation therapy or chemotherapy.

Anaplastic astrocytoma is account for 3.2% of primary brain tumors, anaplastic oligodendrogliomas account for 1.2% of primary brain tumors, while glioblastomas account for 20.3% of primary brain tumors (Central Brain Tumor Registry of the U.S.).

Anaplastic gliomas are often heterogeneous and harbor more malignant foci than sampled by biopsy specimens, and are not usually amenable to complete resection.

Anaplastic mixed gliomas have a prognosis intermediate between anaplastic oligodendroglioma and anaplastic astrocytoma.

For the majority of lesions no cause is known.

Only established risk factor is ionizing radiation.

Not clearly related to cell phone use.

Patients with atopy have a reduced risk.

Gene polymorphisms affecting DNA repair and cell cycle regulation implicated in tumor development.

Approximately 5% have family history.

Surgical specimens are evaluated for atypical cells, mitoses, endothelial proliferation and necrosis for staging purposes.

Grade 1 refers to lesions without above characteristics.

Grade 2 lesions refer to lesions that usually have atypical cells.

Grade 2 gliomas eventually become aggressive, tumors, infiltrating normal brain tissue with accelerated tumor growth and neovascularization.

Histologically grade 2 IDH mutant astrocytomas are composed of well-differentiated neoplastic astrocytes with moderately increased cellularity and atypia.

Gliomas with IDH mutation have an unbalanced translocation between chromosomes 1 and 19 are defined as oligodendrgliomas, whereas IDH mutant gliomas without one p/19q code deletion are defined as astrocytomas.

Grade 3 astrocytomas, formally, termed, anaplastic astrocytomas, have increased cellularity, nuclear atypia, and marked mitotic activity.

The combination of chemotherapy and radiation are standard care for postoperative treatment of patients with IDH mutant grade 3 gliomas and for patients with IDH mutant grade 2 gliomas who are considered high risk for progression.

Grade 4 astrocytomas previously termed, IDH mutant glioblastomas,  have necrosis and/or microvascular proliferation.

Diffuse infiltrating low-grade gliomas are classified as WHO grade 2 tumors and include ologodendrogliomas and astrocytomas.

Diffuse infiltrating low-grade tumors are relatively rare lesions, accounting for only 5% of all primary brain tumors and 15% of all gliomas.

Compared with high-grade gliomas grade 3 and four, patients typically present at a younger age, with peak incidence between 35 and 44 years.

The most typical presentation of diffuse infiltrating low-grade gliomas are seizures, most commonly occurring in patients with oligodendrogliomas.

Low grade glioma includes astrocytomas, oligodendrogliomas and mixed gliomas classified as grade 2.

Low-grade glioma is associated with worse outcomes with the IDH-1/2 wild-type molecular findings: these lesions tend to represent the more aggressive glioma that will progress rapidly to glioblastoma.

IDH1 and IDH 2 are enzymes that convert isocitrate to alpha ketoglutarate through oxidative decarboxylation.

IDH1/2Mutations introduced a gain of function activity to the enzyme that leads to accumulation of 2hydroxybutyrate.

Low low grade IDH mutant gliomas develop additional mutations to drive progression to a higher grade IDH mutant gliomas.

Approximately 2500 people in the US have a diagnosis of IDH mutated grade 2 glioma each year:

These patients tend to be young with the median age of 40 years, and most have tumor related epilepsy, and a tumor that may affect cognition, employment in other aspects of life.

These tumote typically become refractory to treatment, and are eventually fatal, belying their  designation is a low-grade glioma.

A subset of lesions have endothelial proliferation and cellular atypia which are well circumscribed and slow growing and are considered low grade.

Low grade glioma refers to in either grade 1 or grade 2.

Low grade glioma represents the spectrum of tumoric types of histologic features.

Low-grade gliomas affect both adults and children.

The predominant histological type of glioma found in children is a grade 1 tumor juvenile pilocytic astrocytoma and is curable by complete surgical resection.

Low grade glioma incidence 6 per 1 million population.

Low grade lesions originate from glial brain tissue and are predominantly astrocytic or oligodendrglial differentiation.

Low-grade glioma in adults have an incidence of 0.8 to 1.2 per 100,000.

Low-grade glioma cause unknown.

Patients with low-grade gliomas are commonly diagnosed incidentally during imaging evaluations for headache, vertigo and head trauma.

Patients with low-grade gliomas have longer survival than patients with high-grade gliomas with a median survival of 13 years with treatment.

Low grade gliomas: WHO grade II astrocytoma (15-25%), WHO grade II(5-18%), oligoastrocytoma WHO grade II (10-19%),ependymoma WHO grade II (3-9%), and rare entities neurocytomas (0.2-0.5%) and subependymomas.

Low-grade II gliomas are invasive and cannot be completely resected surgically, and residual tumor cells always present distal to the margin of resection.

Mutations in the genes encoding metabolic enzymes isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are present in nearly all grade 2 diffuse gliomas in adults.

Focal neurological abnormalities are less common than seen in high-grade gliomas , secondarily to its slow growth rate and infiltrating nature.

Ultimately grade II lesions undergo malignant degeneration and ultimately are fatal.

Grade 3 and 4 lesions are considered malignant.

Low grade glioma survival not improved by early radiotherapy.

Low grade glioma surgical resection benefits have not been shown.

In patients with high risk low grade glioma treated with radiotherapy provarbazinr, lomustine, and vincristine compared with radiotherapy alone showed improved overall survival but  significant adverse effects.

Low grade glioma usually nonenhancing, ill-defined and difficult to measure.

Low grade glioma survival rate 50-60% at 5-years.

Low-grade glioma median survival rate rages between 7.5 years and 10 years, and a 5-year survival probability between 55-86%.

Low-grade glioma cannot be cured by any current treatment protocol (2010).

Because of diffuse brain infiltration, low-grade gliomas are usually not considered surgically curable.

Low-grade gliomas-grade II, display significant variability in critical behavior.

Survival time in low-grade gliomas has a median survival time range from a few to more than 10 years.

Effect on survival from surgery on low-grade gliomas is unclear.

In a study of low-grade gliomas, treatment at a center that favored early surgical resectionwas associated with better overall survival than treatment at a center that favored biopsy and watchful waiting (Jakola AS et al).

In the above study the median follow-up was seven years and the overall survival was significantly better with early surgical resection, with a median survival of 5.9 years in the biopsy and observe group, and in the surgical resection group, the median survival was not yet reached.

Low grade glioms prognosis depends on: age, tumor grade, and extent of resection.

Low-grage glioma, oligodendroglioma type with loss of heterozygosity on chromosomes 1p and 19q, IDH mutations have a distinctly more favorable prognosis and higher therapeutic response rate.

Oligodendrogliomas are IDH mutant tumors that arise from oligodendroglioma precursors, and are divided into two tumor grades two and three.

Oligodendrogliomas demonstrate chromosome arm, 1p/19q codeletion.

Mutations in either IDH1or IDH2 occur up to 80% of grade 2 and 3 diffuse gliomas and carry more favorable prognosis compared with IDH wild type tumors.

In grade 2 and 3 gliomas there is more concordance with molecular signatures of IDH, 1p/19q and TP53 status than with histological findings.

Codeletion of 1p/19q is prognostic for outcome to alkylating chemotherapy.

Isocitrate dehydrogenase-1(IDH1) mutation is associated with improved outcome and possibly predictive of chemotherapy effectiveness.

O6-methyguanine-DNA methytransferase (MGMT) promoter methylation predictive for benefit from alkylating chemotherapy in anaplastic glioma.

MGMT Promoter methylation is a significant prognostic biomarker for high-risk  low-grade glioma progression, and response to temozolomide and radiotherapy.

Amplification of epidermal growth factor mutation and deletion of PTEN, and mutation in telomerase reverse transcriptase (TERT) are diagnostic for high-grade glioma.

Trisomy of chromosome 7 and loss of chromosome 10 and its q arm associated with impaired outcome.

Low-grade glioma progresses to to higher grade lesions, with more aggressive behavior, with increased frequency with advancing age.

Low grade glioma has the least number of molecular abnormalities compared to high grade glioma with more chromosomal and molecular changes.

Low grade glioma grade I in children are often benign indolent lesions of childhood like pilocytic astrocytomas and gangliogliomas.

Low grade lesions mainly affect young adults characterized by slow growth, high degree of cellular differentiation and diffuse infiltration of the surrounding brain tissue.

Low grade gliomas in adults comprise 25% of all adult diffuse astrocytomas.

High grade-has an incidence of approximately 5 in 100,000 per year and represents about 40% of primary brain tumors in adults.

High grade-about 50% are glioblastomas.

High-grade malignant glioma accounts for 8-10% of pediatric brain tumors and is regularly fatal.

Gliomas account for approximately 45% of all pediatric tumors of the CNS.

High grade III or IV malignant gliomas are the most common primary brain tumors and their incidence is increasing.

High-grade tumor survival rates in children has not improved in 30 years with a three-year event free survival among children with newly diagnosed tumors treated with radiation and chemotherapy is 11-22%: recurrent Median‘s life expectancy is only 5.6 months.

Derived from connective tissue matrix, neuroglial cells, that provide support for neurons and respond to brain injury.

Staging based on degree of cellularity, mitoses, nuclear atypia, proliferation and the presence of necrosis with higher grade correlated with worsening prognosis.

Mutations in p53 tumor suppressor gene are frequent, with partial or complete loss of its locus on chromosome 17p.

Grade III glioma median survival 3-5 years.

High-grade tumors will almost invariably recur and the median survival from recurrence ranges from only 3-6 months.

Gliomal tumor resection bleeding to cure is anecdotal, and even major heroic resections, including hemispherectomies, have failed to cure patients.

Surgical resection tries to remove as much tumor as possible without damaging eloquent areas of the brain, such as those involved in motor, sensory, lying which, vision, and memory functions.

However, increased extent of tumor resection does correlate with patient survival.

Benefit of increased resection is increased in stronger and younger patients.

Macdonald Criteria for response assessment in high-grade gliomas:

Complete response: complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks, no new lesios, no corticosteroids and stable or improved clinical process.

Partial response: 50% or greater decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions, stable or reduced corticosteroid dose, and stable or imporved clinically.

Stable disease: does not qualify for complete or partial response, or progression, and stable clinical state.

Progression: 25% or greater increase in the sum of the products of the perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.

The above criteria were developed for CT scans of the brain and have been extrapolated to brain MRI, now the standard modality to assess treatment in high-grade gliomas.

Lower grade gliomas are often hypodense on T1 weighted imaging and hyperintense on T2/flare.

Macdonald criteria uses two-dimensional measurements.

Treatment for all grades of IDH mutant astrocytomas initially involves maximal safe resection of the non-enhancing fluid attenuated, inversion recovery signal abnormalities on MRI.

unfortunately, because of the diffuse nature of the disease, surgery is not curative and postoperative treatment. Decisions are made on the basis of tumor grade, extent of resection, and patient characteristics.

If total gross resection is achieved, patients with grade 2 astrocytomas younger than 40 years are observed with serial MRIs.

In this younger population, postoperative radiotherapy and chemotherapy are reserved for tumor recurrence.

For patients with IDH mutant grade 2 astrocytoma who are older than 40 years or who had a subtotal resection and have a higher risk of recurrence, and are usually offered radiotherapy with concomitant prochlorperazine lomistine, and  incristine or temozolomide chemotherapy.

For grade 3 astrocytomas the addition of one year of adjuvant temozolomide chemotherapy to radiotherapy significantly increases median progression free survival from 19 to 42.8 months and the five-year survival rate increase from 44 to 56%: not confirmed in other studies.

The median survival for patients with grade 2 to 3 astrocytomas is 6 to 10 years, whereasas that for patients with grade 4 astrocytomas is approximately 32 months.

A meta-analysis of 12 randomized trials with 3004 patients demonstrated that adjuvant nitrosoureas generated slightly longer median survival times, but no difference in long-term survival time in high-grade gliomas (Stewart LA).

Bevacizumab for recurrent grade 2 and grade 3 gliomas is ineffective(van den Bent).

Among pediatric patients with low-grade glioma with BRAFV 600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression free survival and there is safety profile in standard chemotherapy is first-line therapy.

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