Astrocytomas

Patrick J. Kelly, M.D., FACDS
Professor and Chairman
Department of Neurological Surgery
New York University Medical Center
550 First Ave
New York, N.Y. 10016
email: surg@mcns04.med.nyu.edu

Glial Neoplasms comprise the majority of primary intracranial tumors. These affect about 14,000 Americans annually. Glial tumors are divided into a classification scheme based on cell type-usually based on the supposed cell of origin. Thus, astrocytomas are derived from astrocytes, Oligodendrogliomas derived from oligodendroglial cells and mixed gliomas or oligoastrocytomas are derived from both astrocytes and oligodendroglial elements. The following discussion concerns astrocytomas only and is presented in hopes that it will provide some insight into the classification and treatment of these tumors.

Types

In general astrocytic tumors are classified according to histologic grade. There is some confusion among pathologists on the proper system for tumor grading. This can result in confusion for physicians, research protocols and especially for patients. Below I will try to clarify the classification issue as this is extremely important for understanding the tumor and its prognosis.

The astrocytoma is derived from a normal supporting cell in the brain called the astrocyte. In a patient with one of these tumors, the cells in the astrocytoma tumor are no longer normal; and the degree of this abnormality is used to determine the tumor's grade. The tumor's grade determines the prognosis of the tumor. Astrocytomas are graded from 1 to 4, with grade 1 being the slowest growing and grade 4 being the most rapidly growing and malignant lesions. The following descriptions refer to the appearance of the tumor under the pathologist's microscope.

Grade 1: In these tumors astrocytic tumor cells are usually normal in appearance except that there are more of them than normally seen in microscopic examinations of brain tissue. Usually grade 1 astrocytomas produce epileptic seizures as their only symptom since their presence is irritating to surrounding brain tissue. They can also become quite large since they are well tolerated by the brain. However, when the mass effect of the tumor and the mass of the brain combine within the non-yielding skull cavity; a rise in pressure inside the skull results. This can cause headaches, paralysis, personality change, coma and death. The prognosis for grade 1 astrocytomas is generally good. Sometimes surgery to reduce mass effect is required, however. Patients with grade 1 astrocytomas have been known to live 30 years or more following diagnosis. Radiation therapy is probably not appropriate in these tumors. The CT and MRI appearance of these lesions is shown in

Figure 1a,b
(44Kb) (CT) (137Kb) (MRI).

Pilocytic astrocytomas: These benign astrocytomas tend to occur in children and young adults, are histologically circumscribed . Despite the fact that many are located in the thalamus and other important subcortical locations, they can be completely resected by computer assisted stereotactic technique with excellent postoperative results. These lesions exhibit prominent enhancement on CT or on MR imaging with gadolinium (as shown in Figures 2A and 2B). The histologic borders are usually defined accurately by the contrast enhancement.

Figure 2a,b
(44Kb) (CT) (137Kb) (MRI)

Grade 2: In grade 2 tumors, tumor cells are slightly abnormal in appearance as well as increased in number. The variations in appearance of these cells is referred to as pleomorphism. There should be no mitotic figures (indications that the cells are dividing) and no necrosis (dead tissue). In general, these tumors are made up of isolated tumor cells within functioning brain tissue. On imaging studies these lesions show hypodensity on CT and prolongation of T1 and T2 on MRI as shown in Figures 3A and 3B. They only very rarely exhibit contrast enhancement.

Figure 3a,b,c
(37Kb) (CT) (119Kb) (MRI). (60Kb) (MRI).

Removal of the tumor is, in fact, removal of this "sick" brain tissue. These tumors are, therefore, usually biopsied only; unless they are located in unimportant brain tissue- in which case they can be removed ( as in the case shown in Figure 3). In addition, these lesions (tumors) rarely produce paralysis.

There remains some debate on the place for radiation therapy and chemotherapy in these tumors. However, recent studies have shown that 5 year survival in grade 2 astrocytomas without treatment is about 34%; and with treatment (radiation therapy): about 70%. Therefore most centers recommend radiation therapy after a grade 2 astrocytoma is diagnosed by biopsy or some other surgical procedure.

Grade 3: These and Grade 4 astrocytomas are frequently referred to as malignant astrocytomas. They exhibit contrast enhancement on imaging studies. Frequently, the contrast enhancing mass is surrounded by a zone of hypodensity on CT and prolonged T1 and T2 on MRI as shown in Figure 4. This zone is frequently called "edema" and it is edematous brain parenchyma infiltrated by isolated tumor cells.

Figure 4a,b,c
(34Kb) (CT) (54Kb) (MRI) (117Kb) (MRI)

In another classification scheme these are referred to as anaplastic astrocytomas. In grade 3 tumors, cells are not only abnormal in appearance but some show evidence of mitosis. Mitosis is the cellular process by which cells divide; where one cell becomes two. Mitoses are apparent to the pathologist as the surgical specimen is reviewed under the microscope. Some of the cells in the tumor infiltrate into brain tissue- similar to the picture seen with grade 1 and grade 2 astrocytomas; other cells stay put and continue to divide and destroy the brain parenchyma in which they reside as the joined cells for a mass of solid tumor tissue. When the tumor tissue is formed in important brain areas, neurological deficits corresponding to that area result because the brain tissue in that area is destroyed by the evolving tumor tissue mass. For example, a grade 3 astrocytoma forming in the central area of the brain, with formation of solid tumor tissue in the motor area will produce weakness and paralysis on the opposite side of the patient's body ( remember that the left side of the brain controls the right side of the body and vice versa).

Treatment for grade 3 astrocytomas involves establishing the diagnosis by surgery or stereotactic biopsy and follow-up with radiation therapy and chemotherapy. The average survival of patients with grade 3 astrocytomas is 18 months with treatment.

Grade 4: Grade 4 astrocytomas ( frequently referred to as glioblastomas or glioblastoma multiforme) are the most malignant variety of these tumors. They are made up of cells which infiltrate brain tissue with a region (and in some cases regions) of solid tumor tissue within the zone of infiltrated brain tissue. Mitoses are frequently noted by the pathologist as the surgical specimen is examined. In addition, regions of necrosis (dead tissue) are also noted- where the tumor has grown so fast that parts of it has outpaced its blood supply. These tumors induce the formation of new but abnormal blood vessels which when identified are also important in establishing the diagnosis. The CT and MRI demonstrate a contrast enhancing mass with a hypodense center (which corresponds to necrosis) surrounded by a zone of hypodensity on CT and prolonged T1 and T2 on MRI which corresponds to infiltrated parenchyma as shown in Figure 5.

Figure 5a,b,c
(35Kb) (CT) (97Kb) (MRI) (94Kb) (MRI)

The grade 4 astrocytoma has the worst prognosis of all: 17 weeks average (mean) survival after diagnosis without treatment; 30 weeks average survival with biopsy followed by radiation therapy; 37 weeks average survival following surgical removal of most of the tumor tissue component of the tumor and radiation therapy and 51 weeks average survival following stereotactic volumetric resection of the tumor tissue component and radiation therapy. The prognosis for any patient with a malignant astrocytoma (grade 3 or 4) is also very dependent upon age (older people do not live as long as young patients) and performance status ( patients who are neurologically normal and independent live longer than patients who have a neurological deficit). Chemotherapy has been shown to add several weeks on to the survival. Radiation implants (brachytherapy) have also been shown to increase survival but more than half of these patients require another operation to remove dead tissue resulting from the radiation.

Therapy for Astrocytomas

With only a few exceptions (notably, pilocytic astrocytomas) astrocytomas are not curable tumors with any of the treatment methods available to us today. These treatment modalities consist of surgery which establishes the diagnosis and in some cases can remove a significant part of the tumor, radiation therapy, usually given in daily "fractions" of about 200 rads per day (5 days a week) over a 6 week course and chemotherapy ( many agents are available and being evaluated in many clinical "trials" around North America).

Surgical Procedures

Conventional Craniotomy with internal decompression

Here the patient's skull is opened and a surgeon guided by his own hand-eye coordination, knowledge of anatomy, qualitative interpretation of the CT and/or MRI and the appearance of the lesion from normal brain attempts to remove as much of the tumor as possible. The goals are to reduce intracranial pressure and reduce tumor burden.

Stereotactic Biopsy

A probe is inserted by means of a stereotactic frame into the CT and/or MRI defined tumor target in an attempt to obtain a specimen of the lesion for histologic diagnosis.

Stereotactic Volumetric Resection

This is a less invasive procedure than a conventional craniotomy. A virtual tumor volume (determined by the CT and MRI defined boundaries of the lesion) is established in a computer. The surgical procedure is simulated on the computer beforehand to determine the safest and most effective surgical approach. At surgery an opening in the skull is much smaller than with other types of neurosurgery and the removal of the tumor is guided by computer generated images, usually transmitted into a heads-up display unit mounted on the operating microscope. These computer generated images are superimposed over the surgical field and indicate to the surgeon where tumor stops and normal brain tissue begins. This helps the surgeon establish a plane between tumor and brain tissue for a more complete (and safer) removal of the lesion.

Radiation Therapy

Conventional External Beam: Modern radiation therapy for astrocytomas is delivered in multiple fractions by means of a linear accelerator (LINAC) . A planning CT or MRI scan is done to assist in targeting the radiation beams from the LINAC to encompass tumor plus a 2-3cm margin. Although there are variations in protocols between institutions, most patients receive between 6000 and 6500 rads delivered over a six week period of time (5 days per week).
Stereotactic Interstitial Irradiation: Radiation is delivered to a CT and/or MRI defined tumor volume by means of multiple stereotactically implanted radiation seeds (Iridium 192, Iodine 125, Palladium 103). Acting together these radionuclide sources produce a radiation dose field which is fitted to the volume of the tumor so that the tumor gets a lethal dose of radiation while the surrounding brain tissue receives much less because of the dose fall-off away from the sources. Radiation is delivered in a lower dose rate (typically 40 to 50 rads per hour) than in conventional external beam irradiation (200 rads per minute) which is theoretically safer for normal brain tissue surrounding the tumor. However, this form of radiation requires a surgical procedure to place the sources and they are frequently removed after the desired dose of radiation has been delivered. Commonly, interstitial irradiation is used as a "boost" to the radiation doses delivered by external beam radiation therapy.
Stereotactic Radiation Therapy: This type of external beam radiation therapy is delivered by a LINAC in multiple fractions but with the patient's head secured in a relocatable stereotactic frame which increases the accuracy.

Chemotherapy

There are many chemotherapy protocols under investigation in Phase II and Phase III clinical trials. Chemotherapy is usually considered in patients who have tolerated surgery and radiation therapy. Standard chemotherapeutic agents include BCNU, Procarbazine and Cisplatin. These will be discussed in further installments.

There are many experimental therapies- none of which have been shown to be curative yet. These include brachytherapy (stereotactic interstitial irradiation), stereotactic radiosurgery (focused one shot high dose irradiation to the tumor), immunotherapy ( where lymphocytes conditioned to attack brain tumor cells are injected into the tumor or cavity made by surgical removal of part of the tumor) and most recently gene therapy ( where the brain is infected by a genetically engineered virus which attacks tumor cells). Clinical trials are underway for the evaluation of all of these.