Glioma

Tumors of the central nervous system comprise approximately 2% of all adult cancers but are the second most common cancer in children (26%). Gliomas account for approximately 81% of all primary malignant brain tumors. They are more common in Western Europe and Southeast Asia. In addition, they are more common in populations predominantly of northern European ancestry in Australia, New Zealand, and the United States. Gliomas are also 40-50% more common in adult men than women. Adults older than 65 years have the highest rate of higher grade and more aggressive gliomas, while lower grade and less aggressive forms are more common in younger adults, especially between 20 and 40 years of age. Little is know about the cause and risk factors for glioma and other tumors of the central nervous system High therapeutic doses of ionizing radiation in the treatment of cancer or, historically, fungal infection of the skin (tinea) in the head region, have been associated with cancer development (mainly of meningioma, and to some extent glioma). Several inherited cancer syndromes have been associated with increased risk of glioma, such as Neurofibromatosis type 1 and 2, Tuberous sclerosis, Li-Fraumeni syndrome, Maffuci syndrome and Ollier diseases, and Melanoma-neural system tumor syndrome.

Gliomas present with a variety of symptoms: headaches, seizures, nausea and vomiting, changes in intellectual functioning (memory loss, personality changes), problems with movement, vision loss.

Gliomas comprise a complex and heterogeneous group of tumors classified according to the suggested cell of origin, growth pattern (diffuse or more circumscribed), molecular features, and malignancy grade. They encompass diffuse astrocytic and oligodendroglial tumors, other astrocytic tumors such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, or subependymal giant cell astrocytoma, ependymal tumors, and other rare glioma subtypes, e.g. chordoid glioma of the third ventricle, angiocentric glioma, astroblastoma. Examples of other non-glial tumors of the central nervous system are choroid plexus tumors, neuronal and mixed neuronal-glial tumors, tumors of the pineal region, embryonal tumors, meningiomas, tumors of the sellar region, germ cell tumors, hematological malignancies, tumors of the cranial and paraspinal nerves.

Diffuse astrocytic and oligodendroglial tumors (diffuse gliomas) are the most common types of glioma. Broadly, they are classified as oligodendroglioma and astrocytoma, encompassing anaplastic subtypes, and glioblastoma as the most malignant variant of astrocytoma. Their further classification is based not just on histological features but, also on molecular alterations, mainly mutations in IDH1, IDH2, ATRX, TP53, and H3F3A genes, and deletion of 1p and 19q chromosome arms.

Oligodendrogliomas represent approximately 15% of gliomas. They are diffusely infiltrating, slowly growing gliomas characterized by uniform cell architecture and increased numbers of delicate, branching blood vessels. The tumor cell nuclei are mainly round and regular and often surrounded by an artifactual perinuclear clearing that results in the so-called "fried egg" appearance. Increased cellularity, mitotic activity, nuclear pleomorphism, necrosis, and endothelial proliferation are present in high-grade oligodendrogliomas (anaplastic oligodendrogliomas, grade III). Besides histological features, the main criteria for the classification of oligodendrogliomas is the presence of IDH mutation in combination with obligatory co-deletion of 1p and 19q chromosome arms.

Astrocytomas represent approximately one third of all gliomas. They are diffusely infiltrating tumors composed of atypical astrocytes with a varying degree of nuclear atypia and a variable amount of cytoplasm, sometimes with processes creating a fibrillary background. Mitotic activity, necrosis, and vascular proliferation are also variably present. Morphological features of glioma are highly variable and several phenotypically different cell types exist, including gemistocytic astroglial cells. Gemistocytic cells resemble a morphological alteration that can also be found in reactive astrocytes and is characterized by eosinophilic, voluminous cytoplasm, and eccentric nuclei. A four-tiered grading is based on morphological features such as cellularity, nuclear atypia, mitotic rate, endothelial proliferation, and necrosis. Diffuse astrocytoma, grade II is characterized by slight cellular atypia and low mitotic activity. Anaplastic astrocytoma, grade III is characterized by increased cellular atypia and mitotic activity. Glioblastoma, grade IV astrocytoma is additionally characterized by microvascular proliferation, thrombosis in blood vessels, and necrosis. Glioblastoma can develop as primary, de novo high-grade glioma or through a malignant progression of diffuse astrocytoma. The new classification of all astrocytomas, important for prognosis of such patients, prompts evaluation of mutations in IDH1, IDH2, ATRX, TP53, and H3F3A genes, and deletion of 1p and 19q chromosome arms.

The distinction between different forms of brain tumors is mainly based on morphological features, but immunohistochemistry plays an important role to distinguish between different tumor types. In neuropathological diagnostics, antibodies directed towards proteins such as Glial Fibrillary Acidic Protein (GFAP), Olig2, S-100, Synaptophysin, neurofilament, MAP2, p53, and the proliferation marker Ki-67 (MKI67) are commonly used. Antibodies against ATRX and mutated forms of IDH1 (IDH R132H) and histone H3 (H3K27M) are used to detect the respective mutations. Analysis of deletion of 1p and 19q chromosome arms is done by Multiplex Ligation Dependent Probe Amplification (MLPA) or, less commonly by fluorescent in situ hybridization.

The therapy and prognosis of patients with glioma depend on tumor type, location of the tumor (sometimes preventing surgical removal), and malignancy grade. Diffuse gliomas often cannot be removed completely due to their invasive growth. They usually recur and undergo malignant progression. The 5-year overall survival is better in lower grade than in high-grade tumors, being 82, 54, 22 and 3% for grade I, II, III, and IV, respectively. High-grade gliomas are aggressive tumors and without curative treatment. Analysis of methylation of the promoter of MGMT gene, which encodes for a DNA repair enzyme, is important for the prediction of response to chemotherapy with alkylating agents, e.g. Temozolomidem which is the first choice pharmacological therapy for patients with malignant gliomas.