Astrocytomas: pathogenesis, symptoms, diagnosis, and treatment

Astrocytic Tumors

Brain tumor is one of the most lethal forms of cancers with more than 13,000 deaths every year in the United States. Though we are still a long way from developing medical interventions that promise total recovery, advancements in the diagnostic methods such as MRS, ultrasonic aspiration and in surgical procedures such as intraoperative neuronavigation, Gamma Knife radiosurgery, etc., have improved the precision for the surgeon and outcome for the patient to a significant extent. It is hoped that our increasing understanding of the molecular pathology of the disease propelled by the huge amount of research devoted to the field would lead to developing a successful treatment plan for astrocytoma and all other forms of brain tumors in the near future.

Introduction

Brain tumor is one of the dangerous forms of cancer and in the United States alone more than 200,000 people are affected by it every year. Of these, primary brain tumors account for around 40,000 cases. Statistics indicate that approximately 13,000 people die of brain tumor every year making up 2% of all cancer related deaths in the U.S. [IRSA]Tumors are classified as primary or secondary based on the location of their origin. Cancers that originate within the brain cells are called primary tumors and those that are derived from other parts of the body into the brain are called metastatic or secondary brain tumors. Glial cells are the cells that nourish, insulate and support the neurons. They also form part of the blood brain barrier. Tumors derived from the glial cells account for 44.4% of all primary forms of brain tumor. Astrocytoma or tumors derived from the astrocyte cells account for 11.3% of all primary brain and CNS tumors and 21.6% of all gliomas. [BTS] Let us have a brief overview of Astrocytoma, the condition, it's pathogenesis, diagnosis and treatment methods.

The Glial Cells

The brain is made up of two important cell types namely the neurons and the glial cells. While the neurons have action potential and constitute the main functional mechanism for the brain the glial cells are by no means less important. In fact the glial cells exceed neurons in number by 10 to 50 times. [ISCID] There are different types of glial cells namely astrocytes, oligodendrocytes and ependymal cells. The astrocytes are star shaped cells, which nourish, insulate and support the neurons. Astrocytes also perform cleanup operations by digesting dead neuron cells. Glioma is a collective term that refers to tumors that originate from these glial cells. Astrocytomas, Ependymomas, Oligodendrogliomas are the different types of gliomas derived from the corresponding cell types. [IRSA]

Tumor Grades

Besides the basic classification of malignant and benign forms, tumors are also classified based on the rate of development and appearance. The WHO classifies grade 1 tumor as normal under the microscope and with a very slow growth rate. These tumors can be effectively managed by surgery. Grade 2 tumors have a slightly faster growth rate and cellular abnormalities are clearly visible under microscopic observation. These tumors can affect neighboring cells and carry the risk of developing into higher-grade tumors. Grade 3 tumors are classified as malignant tumors, which grow rapidly and affect neighboring tissues at a fast rate. Grade 4 tumors are the most deadly in terms of their growth. They spread very fast and affect a large area. They are called necrotic tumors as they have dead cells in the center and they grow new blood vessels to sustain their rapid proliferation. [IRSA]

Astrocytomas are classified into four types based on the above-mentioned grading. Pilocytic Astrocytomas are first grade astrocytomas that predominantly affect pediatric patients. Astrocytes are found along with rosenthal fibers and eosinophilic granular bodies. The lesions that appear in the brain tissue are referred to as "juvenile pilocytic astrocytoma." This condition accounts for 85% of cerebellar tumor. The preferred sites for this tumor include the cerebellum, cerebral hemispheres, ganglia, thalamus and the optic nerve. Fibrillary Astrocytoma is a grade-2 astrocytoma and it is not circumscribed. It is well differentiated and affects adjoining cells and is a tumor of the fibrillary or gemistocytic neoplastic astrocytes. In around 60% of the Patients diagnosed with this condition P53 mutations have been observed. It is found that this type of astrocytoma is common among patients who have Li-Fraumeni syndrome. (patients with inherited P53 mutation) Anaplastic Astrocytomas is a grade 3 astrocytoma and is a malignant form. This type shows increased cellularity and distinct nuclear atypia. This tumor is characterized by high TP53 mutations. Typically in this tumor, most of the genes that are concerned with cell progression are altered.

The Glioblastoma Multiforme, a grade 4 and most malignant form of astrocytoma is anaplastic and composed of pleomorphic astrocytic tumor cells showing intense mitotic activity. Glioblastoma is the most common form of brain tumor accounting for 12% to 15% of all tumors and around 60% of all astrocytic tumors. There are two types of Glioblastoma as Dr. Vinay says, "One type begins as a low- or intermediate-grade astrocytoma and changes into a glioblastoma," the other type, known as the denovo form, seems to start out as a glioblastoma. This seems to be due to the differences in the genetic changes that trigger the growth of these tumors." [CancerWise] it predominantly affects the cerebral hemispheres and has a high incidence rate for people between 45 and 70 years of age. The GBM is also one of the most complex forms of tumor where a single gene cannot be implicated as the precursor. To quote Dr. Vinay again, "there does not appear to be a single genetic basis that could explain the disease that we have been able to find. While genetics seems to play a role, it doesn't seem to be a 'one-hit' problem, like certain leukemias that can be traced to one gene; it's more like multiple hits that take place over a period of time." [CancerWise] Amplification of the EGFR (epidermal growth factor receptor) is found in approximately 40% of primary gliblastoma cases. Mutations of the PTEN gene are also observed in 45% of primary gliblastomas. [NCI]

Pathogenesis

There is no clearly identified molecular pathology for astrocytoma. Research is still focused on understanding the molecular pathologies underlying astrocytoma. However, research has indicated the following genetically derived pathologies. The following genes: PTEN/MMAC1, DMBT1 (deleted in malignant brain tumor-1), EGFR, TP53, P16, PDGFR, and retinoblastoma cell-cycle regulatory gene have all been indicated in the onset of astrocytoma. Though, today, alterations in these genes are well-known, the cause for these abnormal gene alterations remain unknown. The most commonly identified causes are the deletion of tumor suppressing genes such as p53, retinoblastoma, p16 as well as the addition of tumor promoting genes such as PDGFR, and EGFR.[Medscape] Mutation to the P53 tumor suppressor gene is an important factor in tumor development. Studies have shown that the P53 mutations are the most common among humans and hence carry a risk potential for developing cancers. Since the P53 gene is responsible for cell cycle regulation, which includes induction of apoptosis, aberration in the gene results in uncontrolled cell growth.[Nobuaki Ishii]

Studies have also implicated RNA binding proteins in the pathogenesis of astrocytoma. The link between over expression of tyrosine kinase (which is a chief regulator found in malignant astrocytes) and the RNA posttranscriptional modifications are being closely studied. [Pamela a. Silver. PhD] in Glioblastma multiforme (GBM), the most lethal form or grade 4 astrocytoma, researchers have observed aberrations on chromosome 10 resulting in the loss of tumor suppressing genes such as PTEN/MMAC1 along with other similar genes that regulate P. I3 Kinase and PKB/Akt pathways. Animal Studies have also attested that the P. I3 kinase (phosphoinositide-3-kinase) in particular has a vital role in defining and regulating the number and size of the cells in tissues. [Karen T. Barker] Further, molecular studies have also revealed the overexpression of tumor promoting genes such as EGFR and other Growth factor receptors that activate P21 - RAS signalling pathways. Also deletion of PTEN and a resultant increase in phosphorylated PKB/Akt has been shown to result in an increase in cell size. Hence downregulation of PI3 Kinase, PTEN, overexpression of EGFR and PFGFR, are some of the possible molecular pathologies. [Medscape]

Symptoms and Diagnosis

There are many different symtoms associated with astrocytoma or any type of brain tumor in general. Because there is an increase in intra-cranial pressure due to the increased cell mass, headache is a commonly observed symptom. Nausea, vomitting, dementia, changes in personality and mood swings are also observed. However, symptoms are mostly associated with the position of the tumor within the brain. For example, tumor in the occipictal lobe would result in visual hallucinations and impairment while a tumor positioned in the parietal lobe will lead to impaired motor functions. Diagnosis of astrocytoma involves a complete examination by the physician followed by a series of tests such as MRI, CT scan, angiogram and biopsy. The MRI uses a magnet, radio waves and computer to create high quality 3d images of the brain. The MRI is considered the best choice as it has a 81% to 100% specificity as compared to the CT scan which has 72% to 100% specificity. Using MRS chemical composition of the tumor and the metabolite intensities can also be ascertained along with the morphological characterisitcs. Thus MRI provides better information which is useful in grading the tumor. For grade 4 astrocytoma's spectroscopic studies reveal high Cho, high lipid, high lactate and low NAA values. However, the MRI testing is time consuming (40 to 90 minutes) and is problematic for claustrophobic patients. [eMedicine] Biopsy of the affected brain tissue will also help in determining the nature of the abnormal tissue growth.

Treatment

Treatment for astrocytoma includes, surgery, chemotherapy, radiation and gluco corticoid medication. Treatment improves the survival rates for patients and the type of treatment depends on the growth and location of the tumor. First grade tumors such as Pilocytic Astrocytomas are easily treated by resection. In most cases removal of the affected part would be sufficient. However, if the location of the tumor makes surgery an impossible choice then the condition is treated by chemotherapy and radiotherapy. In fibrillary, anaplastic astrocytoma and Glioblastoma complete removal by surgery is followed by chemotherapy and radiation. Total cure is possible for Pilocytic Astrocytomas after surgery while the prognosis for fibrillary astrocytoma depends on whether or not the tumor cells are transformed into more malignant types. Also recurrence is high in fibrillary astrocytoma.

With the advancements in medical technology such as intraoperative neuronavigation that allows the surgeon to see the surgical region on the computer screen, and the use of high power microscopes to magnify the surgical zone, it is possible to limit damage to adjacent healthy tissues while doing a tumor resection. Radiation therapy may be both external and internal. In the later case, radioactive materials are implanted near the tumor zones. It is now common to use biodegradable BCNU polymer wafer implants for radiation therapy. Also, the use of scalpel for tissue extraction can be eliminated by using the 'ultrasonic aspiration' method. Ultrasonic waves are focused on the tumor area to break it down and the fragments are removed by suction. [IRSA]

Radiosurgery

Stereotactic radiosurgery is a non-invasive form of therapy, which can be done in a session by a neurosurgeon. The aim of the therapy is to destroy the tumor cells by concentrating a series of cobalt 60 beams from different angles onto a spot. Since individual beams are not strong enough to destroy healthy cells the therapy does not affect healthy cells that is passes thorough but only affects the area on the brain where all the beams converge (the tumor zone). However, this therapy has its limitations and only an area of 4 cm can be treated at any one time so it might involve multiple sessions. Radiosurgery is typically recommended for patients who do not have the need for surgical intervention. However, this therapy is also used post surgery to remove traces of tumor cells that might still exist. Though the radiation does not destroy healthy cells, multiple sessions of radiotherapy are not recommended for children in view of the possible long-term damage to a brain which is still in the developmental stage. [IRSA]