Astrocytomas are the most common (over 70%) of all primary intracranial neoplasms.

Spinal astrocytomas are discussed elsewhere.

The world health organization (WHO) currently recognizes multiple astrocytic tumor variants.

They may be classified according to their cytologic characteristics, viz., fibrillary, protoplasmic or gemistocytic; or according to their location, viz., cerebral, hypothalamic, cerebellar or brainstem. The latter classification apart from location is also based upon considerations, partly, of cell type and partly of growth and behavior of the tumor.

Although tumor composition is often heterogenous, fibrillary astrocytes are by far the most frequently observed. Astrocytes show a stellate arrangement of fine fibrillary processes. Their nuclei are oval with scattered chromatin. Diffuse cerebral astrocytomas are composed of cells with this appearance, and are predominantly of the fibrillary type. These tumors may contain microcysts and foci of dystropic calcification.

Identifying the presence of these morphological subtypes, however, appears to have little value in terms of predicting prognosis.

A possible exception is the 9% to 19% of astrocytomas composed predominantly of gemistocytic cells.

In such cases, gemistocytic cell content in excess of 60% has been associated with aggressive neoplastic behavior and a poorer prognosis. Microscopically, the cells are large, globoid, and packed with a hyaline cytoplasm, and eccentric nuclei with coarse chromatin and conspicuous nucleoli. They show glial fibrillary acidic protein (GFAP) positivity.

Protoplasmic variant, the least common variant (<1% of all astrocytomas), involves cerebral hemisphere superficially. Histologically homogenous population of small astrocytes with few delicate processes.

Over the years, the notion that histological characteristics are useful as predictors of neoplastic aggressiveness has come to be accepted. As a result, current classification systems assign distinct tumor grades based on the presence, absence, and degree of specific observable histological criteria. These criteria commonly include the overall degree of tumor cellularity, extent of cellular and nuclear pleomorphism, frequency of mitotic activity, and presence or absence of necrosis and endothelial proliferation.

In the WHO four tier system, similar weight is given to the presence of nuclear atypia, mitoses, endothelial proliferation, and necrosis. In the absence of these criteria, the grade of 0 is assigned. If any of the criteria can be identified, a grade of 1 is aligned. Successive grades up to 4 are assigned upon subsequent identification of any of the remaining criteria. Using this system, the proportionate distribution of all astrocytomas has been found to be 4.1% grade 1, 23% grade 2, 16% grade 3, and 57% grade 4.

We follow Daumas- Duport (St. Anne/Mayo,1988) system. This scheme is restricted to astrocytomas and glioblastomas. The following histological abnormalities are used to place tumors in 4 grades: nuclear atypia, mitosis, endothelial proliferation,

and necrosis. The system is very reproducible and the grade is strongly correlated with survival.

However, when describing the histological grade of astrocytic tumors, communication is often simplified by use of of the terms' low grade astrocytoma', 'anaplastic astrocytoma', and 'glioblastoma mutiforme'. Despite variability among the grading systems, the distinction between low grade astrocytoma, and anaplastic astrocytoma is commonly made based on the presence of mitoses and increased cellularity. Similarly, glioblastoma multiforme and anaplastic astrocytoma are frequently distinguished based on the presence of necrosis and endothelial proliferation.

Individual variants of astrocytoma may display both age and location related predilections.

For example, the majority of pilocytic astrocytomas occurs in childhood population and involves the cerebellum.

A tendency to the diagnosis of higher tumor grades is found with increasing patient age. This is reflected by the presence of peak incidences for low grade astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme during the third, fourth, and fifth decades of life, respectively. Further, the overall incidence of astrocytomas, regardless of grade, is seen to rise proportionately with age, peaking during the fifth to sixth decades of life.

Clinical features of this condition commonly include headaches, nausea, papilledema, and blurred vision. Symptoms such as these are of limited value for predicting tumor location, although they may play a valuable role in prompting patients to seek medical attention. Other symptoms experienced by patients with astrocytomas are primarily determined by the location and size of the tumor involved. Supratentorial lesions present with seizures and focal neurological deficits, such as, dysphasia and hemiparesis. In cases involving the posterior fossa, ataxia, dysmetria, and nystagmus, are frequently found. Astrocytomas involving the brainstem are often notable for the production of a variety of symptoms, including cranial nerve deficits and limb weakness. in the presence of large tumors or obstructed cerebrospinal fluid (CSF) circulation, evidence of increased intracranial pressure may be seen.

In general magnetic resonance imaging is superior to computerized tomography to evaluate their composition and relationships with nearby anatomical structures. Conversely, CT is more sensitive for revealing characteristics such as hemorrhage and intratumoral calcification. Despite the excellent radiographic methods available, however, imaging studies are often unreliable for discriminating among the individual historical grades and variants of astrocytoma.

The use of post operative imaging (within 48 hours), particularly MRI with gadolinium, is invaluable is assessing completeness of resection and detecting recurrence.

The astrocytoma, anaplastic astrocytoma, and glioblastoma are regarded as a spectrum of diffuse astrocytic tumors with common molecular genetic abnormalities. The presence of multiple characteristic genetic mutations, whether inherited or acquired, has been associated with the oncogenesis of astrocytomas. Some have also theorized that the accumulation of specific genetic mutations brings about the further progression of low grade neoplasms to higher degrees of malignancy. For example, deletion mutations of chromosome 17 (17p) and, less frequently, chromosome 22 (22q), are known to be present among a large number of astrocytomas regardless of grade. Other mutations 13 (13q), 9 (9p), and 19(19q), possibly reflecting later transformative events. Moreover, deletion mutations of chromosome 10 (10q) are found almost exclusively among glioblastomas, suggesting that they are involved in the transition to the highest grades of malignancy.

In astrocytic tumors, the transition to glioblastoma is associated with upregulation of the epidermal growth factor receptor (EGFR) gene found on chromosome 7. It has been proposed that mutation common to high grade astrocytomas specifically that of chromosome 10q may be involved in the stimulation of EGFR gene expression or the disinhibition of its regulation.

Significant interest has been generated in utilizing the presence of these characteristic genetic alterations for the purpose of predicting aggressive tumor behavior. In the future, the use of cytogenetic techniques is likely to play an increasing role in the treatment of neoplasms, such as the astrocytoma.

Low grade Astrocytoma:

The term 'low grade astrocytoma’ is given to a group of astrocytic tumors with a relatively well-differentiated histological appearance. Among these are included typical low grade astrocytoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and subependvmal giant cell astrocytoma. Although strictly intended to imply uniform astrocytic cell composition, low grade neoplasms of mixed oligodendroglioma-astrocytoma cell content are also occasionally included in this category.

Pilocytic and low-grade astrocytomas are encountered most frequently, accounting for 43% of astrocytomas as a whole.

The median age of patients with low grade gliomas is approximately 35 years. There is a biphasic age distribution, with two peak incidences at 6 to 12 years, and 26 to 46 years, with a slight male preponderance.

Most low grade astrocytomas in adults arise supratentorially; half are of typical histology, with the remaining consisting of pilocytic astrocytomas and mixed oligodendrogliomas-astrocytomas in nearly equal proportions.

Involvement of the hemispheres is more common than that of deeper structures, such as the basal ganglia and brainstem.

When hemispheric in location, frontal lobe involvement is more prevalent than temporal or parietal lobe involvement.

Infratentorial lowgrade astrocytomas occur most commonly in the cerebellum of children. Whereas low grade cerebellar astrocytomas account for 15% to 18% of all intracranial tumors among children, they account for only 1% of those among adults. The pattern of cerebellar involvement is unihemispheric in approximately 30%, bihemispheric in 34%, and vermian in 16% of cases. Histologically, the vast majority, approximately 85% of lowgrade cerebellar astrocytomas are pilocytic.

For practical purposes, pilocytic astrocytomas are commonly given separate consideration from typical low grade astrocytomas as they have been associated with a more favorable prognosis. In addition to the cerebellum, pilocytic astrocytomas (juvenile type) commonly involve the hypothalamus and optic pathways, constituting the majority of tumors referred to as hypothalamic and optic gliomas. Pilocytic astrocytomas diagnosed during the first two decades of life are predominantly cerebellar. In contrast, those found in adults are most often supratentorial. When located supratentorially, the temporal lobes, frontal lobes, and basal ganglia are most commonly involved. Pilocytic astrocytomas are typically diagnosed earlier in life than low grade astrocytomas, with mean ages ranging from 14 to 18 years, and from 30 to 37 years, respectively.

Signs and symptoms observed at the time of diagnosis are primarily related to tumor location. 60% of them present with seizures, twice as frequently as the high grade ones. They are one of the common causes of intractable epilepsy.

Other recent advances in neuroimaging help for further evaluation.

On gross examination, low grade astrocytomas are typically poorly circumscribed and may be similar in appearance to the surrounding non neoplastic tissues. On histological examination, mildly increased cellularity and slight pleomorphism are present, but notably absent are changes such as mitosis and extensive atypia, which are characteristic of high-grade astrocytomas. On microscopic examination, fibrillary astrocytes are most often observed, though multiple astrocytic morphologies may also be present. Neoplastic cells can be seen to diffusely infiltrate surrounding tissues. Nonneoplastic tissue elements may become incorporated, or trapped within the tumor mass. This phenomenon may on occasion give false impression of mixed tumor.

Many consider a complete resection to be curative for pilocytic astrocytomas with the use of postoperative irradiation offering little additional benefit. furthermore, some have advocated withholding radiation treatment, even if subtotal resection is obtained initially, reserving radiation for tumor recurrence or surgery limited biopsy. The timing and extent of resection is controversial. A similar argument has been made for the treatment of typical low grade astrocytomas in both children and adults.

Restrictions on the use of radiation treatment among young children have been recommended due to high degree of associated morbidity. Additionally, some have implicated radiation as a cause of the mutational events leading to increased aggressiveness. Despite this, some have found post operative radiation useful in typical low-grade astrocytomas, even in cases of total resection. Still others have argued that the benefit of completely resecting typical low grade astrocytomas remains unproven, instead advocating the use of focused radiation therapy alone as initial treatment.

The use of chemotherapeutic agents for the treatment of low grade astrocytomas is controversial, with studios citing little improvement over the results achieved with conventional therapies alone.

These studies have recommended reserving chemotherapeutic agents for cases of inoperable low grade astrocytomas or as a means of obviating the morbidity associated with cerebral irradiation in children.

The prognosis for patients with low grade astrocytomas varies with tumor location and histology.

Regardless of supra or infratentorial location, pilocytic tumors are associated with the most favorable prognosis, with 5 and 20 year survival rates of 85% to 86% and 79% to 82%.

Although varying with supra and infratentorial location, the prognosis for other low grade astrocytomas is much less favorable.

Those in a supratentorial location have been found to carry 5 and 10 year survival rate of 51% to 56% and 23% to 39% respectively. In contrast, those occurring in the cerebellum are associated with still poorer outcomes, with survival rates at both 5 and 10 years of 7%.

Histologically, the microcystic change is recognized to be a regressive feature and indeed one does not witness much cellular activity in such regions. The cytoplasm is scanty and fibrillar and the nuclei small and monomorphic.  Another feature of slow growth and thus seen in low grade astrocytomas is the formation of thick smooth cytoplasmic extensions of glial cells, called Rosenthal bodies. They were believed to represent degenerating astrocytes.

Other factors predictive of improved outcome include younger age, seizure at presentation, and lack of preoperative fixed neurological deficit.

Tumor recurrence is often associated with malignant progression and is a common cause of mortality among patients with low grade astrocytoma. The frequency is thought to be highest among patients with typical low grade astrocytoma, occurring in 57% to 72% of cases. Factors that have been associated with an increased rate of an increased rate of recurrence include subtotal resection and the presence of oligodendroglial tumor components. additionally, some believe that malignant progression of low grade astrocytomas is more prevalent among adults.

Research efforts for the low grade astrocytomas focus on developing chemotherapy regimens that control tumor growth with fewer side effects on other organs of the body. Because these tumors grow slowly, the strategy is to give less intensive chemotherapy over long periods of time.

For older children and those whose tumors progress despite chemotherapy, new radiation techniques are under study to “focally” deliver therapy with minimal effects on the normal brain.

Subependymal giant cell astrocytoma (SEGA):  discussed elsewhere.

Pleomorphic Xanthoastrocytoma (PXA):

They are rare(<1%), typically, develops in children and young adults.

Invasion of the overlying dura in superficial lesions is common. Occasionally,

skull may be eroded. Temporal lobe is the commonest site, followed by the parietal, occipital, and the frontal lobes.

The median survival for patients diagnosed with anaplaslic astrocytoma ranges from 15 to 28 months, with projected 1, 2, and 5 year survival rates of 60% to 80%, 38% to 64%, and 35% to 46%, respectively. Aggressive resection has shown higher survival; some have found little improvement with radical excision and place a greater emphasis on the radiotherapy and chemotherapy.

The use of postoperative radiation has been shown to prolong survival in patients with anaplastic astrocytomas, often to a greater degree than when used for the treatment of glioblastoma multiforme. In addition, some authors have advocated the use of alternate treatments, such as brachytherapy, radiosensitizers, and chemotherapeutic agents both initially and at recurrence. However, others have found these alternate modalities to be of little extra benefit and rely more heavily on conventional forms of treatment.

For high grade tumors, new approaches on trial, include use of new chemotherapy drugs, high doses of chemotherapy following radiation therapy, and gene therapy to make the tumor cells more sensitive to chemotherapy. A major problem in treatment is that the high dose chemotherapy also kills cells in the bone marrow that produce healthy blood. This raises the risk of severe infection and slows down the delivery of chemotherapy. Gene therapy approaches are being developed to protect bone marrow from these side effects so that chemotherapy can be given more intensively to fight the rapid tumor growth.

Genetherapy and immunotherapy are still under in the experimental stage.

As with other astrocytic tumors, primary site recurrence is the most common cause of mortality.

Factors thought to correlate with improved outcome in patients with anaplastic astrocytoma include younger age, higher preoperative performance scores, and presentation with seizures. Additionally, some have found improved outcomes among patients previously diagnosed with lower grade astrocytic tumors in comparison to patients in whom an anaplastic astrocytoma has arisen de novo.

Glioblastoma multiforme (GBM):

First recognized by Virchow, in 1863, and described later as 'spongioblastoma multiforme', this, the most malignant neoplasm in the human body. Glioblastoma multiforme is the least differentiated and most aggressive form of astrocytoma.  

It accounts for 15% to 23% of all primary intracranial tumors.

Furthermore, it constitutes 35% of gliomas, 66% to 87% of high grade astrocytomas, and 50% of all astrocytomas, making it the most common astrocytoma.

Patients diagnosed with glioblastoma multiforme are most commonly in their fifth or sixth decade of life.

The diagnosis is made less frequently in younger age groups and rarely in children, where GBM account for less than 9% of all

Most GBMs contain a centrally located, hypoxic area of necrosis that develops as the tumor mass outgrows its blood supply. This hypoxic zone is concentrically enveloped by hypercellular neoplastic tissue and surrounding edematous white matter. The more malignant astrocytomas have been found to have features histologically indistinguishable from glioblastoma multiforme and thus there is a a controversy against assigning a separate name for this tumor, as there is no such cell as a glioblast.

WHO currently recognizes two histological variants of glioblastoma:

candidates or have tumors that involve eloquent or deep structures. Alternate modalities are needed in such cases.

Reoperation for recurrence in selected patients who have had favorable results to initial treatment may be considered.

Postoperative radiation has been found to be helpful. Radiotherapy, age, and performance status have been demonstrated to be the three most significant prognostic factors. Usual total dose is 60 Gy. Newer techniques, such as, dose fractionation, stereotactic radiotherapy, heavy particle radiotherapy, and brachytherapy have also been used with no evidence to suggest a better outcome.

As compared to radiotherapy, role of chemotherapy is limited. However, it is currently used in the young and in recurrence after radiotherapy.  ‘Standard’ chemotherapy has been a nitrosourea based regimen. Newer promising chemotherapy includes Temozolomide and CPT-11.

Newer therapies, such as, genetherapy and immunotherapy are under trial.

Prognosis for patients with glioblastomas have shown little improvement despite the use of multiple treatment modalities, including surgery, whole brain, local, and focused radiation( brachytherapy); radiosensitizing agents, and other forms of chemotherapy have not helped. Median life expectancies of 8 to 10 months after diagnosis are common, along with 1, 2, and 5-year survival rates of 30% to 44%, 10% to 12%, and 2.5% to 5% respectively.

Survival rates cited for children are similar to those for adults.

The most common cause of mortality among patients with glioblastoma regardless of age is recurrence.

Younger patients with seizures at presentation, lack of focal neurological deficit, and complete tumor resection favor a better prognosis.

satellite lesions) or Disconnected (no detectable microscopic connection)', and as 'Synchronous (if present on initial presentation) or Metachronous (if developed during follow-up. They are termed multiple, if present at the same time but are separate spatially, and multicentric, if they are independent spatially as well as temporarily.

Although multiple astrocytomas may arise independently within a single patient, the majority are probably represent the presence of a single neoplastic disease.

Reportedly, the multifocality occurs in 2.3% to 9.1% of cases.

Anaplastic astrocytoma has more infiltrative growth than does GBM thus multifocal glioma occur more frequently in AA than GBM.

Proteins responsible for tumor cell attachment & migration are - myelin, ECM protein, Merosin, fibronectin, laminin.

Leptomeningeal gliomatosis:

Diffuse subarachnoid dissemination of intracranial tumors is termed leptomeningeal gliomatosis. This condition often results from the presence of a high grade intracranial neoplasm that has gained access to the CSF by virtue of its proximity to the ventricles or cisterns. In such cases, patients may experience a variety of symptoms, including mental status changes, headache, cranial nerve deficits, and back pain.

Diagnosis is by CSF cytology. Radiology may be negative.

Therapeutic measures employed include craniospinal radiation, and systemic or intrathecal chemotherapy. Survival rates are generally poor and primarily related to histology of the and its responsiveness to treatment. With respect to astrocytic tumors, limited success has been achieved in the treatment of leptomeningeal gliomatosis involving anaplastic astrocytomas.

However, the prognosis for patients with leptomeningeal gliomatosis resulting from GBM is bleak, with survival rates generally measured in terms of weeks.

Extraneural metastasis:

Among adults, astrocytomas have the distinction of being the intracranial neoplasm most likely to metastasize outside the CNS. However, even with astrocytomas, metastasis is rare. The extraneural presence of metastases is frequently associated with previous craniotomy or a diversionary shunting procedure. It is by virtue of these routes the metastatic cells are believed  to gain access to extradural lymphatic and vascular tissues. However, a prior dural disruption is not strict requirement. These cases are a result of invasion of intracranial vascular structures, such as venous sinuses.

The most common sites for extraneural metastases include lung, lymph nodes, and bone.

In those who have had shunt  procedures done, the abdomen should also be considered a potential site.

The probablity of metastases appears to be related to the degree of tumor anaplasia, with GBM more likely to metastasize than others. Survival rates for such patients are poor, ranging from 6 months to 2 years after the time of diagnosis. Chemotherapy, although of minimal benefit to survival, is advised to improve the quality of life.