Gemistocytic Astrocytoma of the Frontal Lobes
Patient #11 emphasizes the importance of the differential diagnosis of a patient with a rapidly progressive dementia. According to the family, the patient was normal until three months prior to presentation. His initial symptoms consisted of progressive problems with memory, followed by gait problems, and finally incontinence. This presentation suggests a process involving frontal and temporal lobes bilaterally. The patient had evidence of disinhibition which could also reflect frontal lobe dysfunction.
The differential diagnosis included:
On admission to our service, an MRI of the head revealed a large mass in both frontal lobes crossing the corpus callosum ("butterfly tumor"). A CT scan performed later also revealed a large mass occupying most of the frontal lobes, greater on the right, with a slight amount of calcification.
With spread of the lesion across the corpus callosum, as well as the associated edema, mass effect, and slight calcification, a glioma, especially an astrocytoma, was felt to be the most likely diagnosis. Other conditions with similar presentations on MRI include lymphomas, infections, or white matter inflammatory conditions. These would, however, show enhancement with contrast, which this lesion did not.
Although the imaging studies were consistent with an astrocytoma, there was a small chance that another disease process might be present. The situation was discussed with the family, who wanted to be assured that the patient did not have a treatable condition. Neurosurgery was consulted and a stereotactic biopsy was obtained from the right frontal lobe. The biopsy confirmed the presence of a gemistocytic astrocytoma.
Following the biopsy, the patient became more obtunded and developed a left hemiparesis. The patient had a DVT in the left leg. Because the patient was post-operative, IV heparin could not be initiated. The family, considering the prognosis, decided not to opt for radiation or chemotherapy. The patient remained stable and plans were made to transfer the patient to a nursing home close to the family.
The involvement of the CNS by malignancies is not uncommon. Metastasis from sites outside the CNS (e.g. lung, breast, colon etc.) accounts for the majority of CNS neoplasms in adults. During the course of their disease, about 20% of patients with cancer will develop metastatic disease to the CNS.
Primary neoplasms of the CNS account for about 12,000-14,000 new cases every year. They are more common in children, and rank 2nd in number in the list of malignancies seen in that age group. Of the primary CNS tumors 40% are gliomas and the majority of these are of astrocytic origin (75-90%). Other glial tumors include oligodendrogliomas, ependymomas, and primitive neuroectodermal tumors (PNET).
There are many classification systems in use. Classification is based on the broad range of histopathological features which can be seen. This varies from low grade astrocytomas to glioblastoma multiforme. This is important for understanding the differences in incidence, location, presentation, clinical course, and outcome. The World Health Organization (WHO) classification is perhaps the most widely used, and separates astrocytomas into 4 main types:
The St. Anne/Mayo classification is another system in use. The main difference is that the WHO Grade 2 is further subdivided into Grades 1 & 2 and Pilocytic astrocytomas are classified separately. This classification is based on a point system for various histological features seen and is thought to be more predictive of patient survival (Duport et al.).
Following the discovery of tumor oncogenes and tumor suppressor genes for colon cancer, genetic models for tumors in other organ systems have been developed. Astrocytomas have been found to be associated with several gene alterations, including amplification of oncogenes and mutations or deletions in several tumor suppressor genes.
Amplification of epidermal growth factor (EGF) is one of the most consistent alterations found in about 25-50% of tumors, and is more common in more anaplastic tumors. Rearrangements in the EGF receptor can be found in about 40% of cases, along with amplification of EGF. As a result of the rearrangement, the EGF binding domain is deleted. The exact effect of this is unclear. However, an antibody to this mutant EGF receptor may be helpful in diagnosis. This also holds the potential for using monoclonal antibodies conjugated with radionuclides and toxins to be directed against the tumor. Other amplifications seen include those of Platelet Derived Growth Factor (PDGF) and the MDM2 gene.
Aside from amplification of genes, several tumor suppressor genes have been identified. One of the most important ones is p53. This is found on chromosome 17p13.1. Loss of the short arm of chromosome 17 is seen in about 30% of astrocytomas and are seen in much higher frequency in higher grade astrocytomas (60% in GBM compared to 40% in anaplastic astrocytomas). There is also evidence that a second tumor suppressor gene is located on chromosome 17.
Other chromosomal abnormalities include loss of one allele of chromosome 10 (60% in GBM compared to 25% in anaplastic astrocytomas). Loss of short arm of chromosome 9 is seen in 30-50% of GBM and anaplastic astrocytomas. There is also a higher incidence of astrocytomas in neurofibromatosis type 1.
Astrocytomas tend to progress from more differentiated and less malignant tumors to less differentiated and more malignant tumors. This is thought to be due to progressive development and accumulation of genetic alterations. It is believed that the p53 mutation probably occurs early and then subsequent mutations start appearing. Loss of one allele of chromosome 11 and amplification of EDGF is thought to occur in the later stages of transformation.
The different grades of Astrocytomas as presented in the World Health Organization (WHO) classification are as follows:
The clinical features result from the destruction of underlying normal brain tissue, and can be extremely variable depending upon the location of the tumor and the specific structures that are compromised. Focal findings in a patient with headaches should prompt further studies. As the tumor grows, symptoms can become more marked. Gliomas have a predilection for traveling across white matter, and may present with symptoms of a dementia. The white matter spread is called gliomatosis cerebri and could be mistaken for PML, MS etc. Gliomas also can spread via the CSF leading to leptomeningeal gliomatosis. These patients may present with cranial neuropathies, obstructive hydrocephalus, compressive myelopathies, radiculopathies etc. Spread outside the CNS is extremely rare, but may spread to the peritoneal cavity in patients with shunts.
Diagnosis is based on imaging and confirmed by biopsy. Low grade astrocytomas show decreased attenuation on CT scans and decreased signal on T1 MRI but increased signal on T2 MRI. There is normally very little enhancement with contrast. Radiographically, it may sometimes be difficult to differentiate from reactive gliosis due to a nonneoplastic process. Calcification may be present in about 15% of astrocytes and can help in differentiation. Anaplastic astrocytomas usually have indistinct borders and moderate amounts of associated edema. Enhancement and hemorrhage vary with the amount of neovascularity and endothelial proliferation. Glioblastoma multiforme characteristically demonstrate a heterogenous appearance. These tumors have no distinct wall, a large amount of associated edema, and cystic areas which can be seen on imaging studies. They may cross to the other cerebral hemisphere, giving rise to the characteristic "butterfly tumor". Final diagnosis is usually made by stereotactic biopsy. A diagnosis can be made in 92-98% of cases, and the morbidity and mortality for biopsy is low (0-3%).
The prognosis for patients with astrocytomas depends on the malignant potential and stage of the tumor. Surgical resection, chemotherapy and radiation are currently the mainstays of therapy.
Surgical Resection: The main indications for surgery include confirmation of the diagnosis and resection of tumors with the aim of prolonging survival or achieving a cure. Cytoreduction (removal of neoplastic tissue) has been shown to improve the response to chemotherapy. It is postulated to help by removing areas of tumor which would otherwise be inaccessible to chemotherapeutic medications and also by reducing radioresistant cells. In some tumors, like juvenile pilocytic astrocytomas, surgical resection can produce complete cures. More infiltrative and malignant neoplasms, such as glioblastoma multiforme, benefit to a lesser degree because total resections are almost impossible to achieve.
Radiation Therapy: Radiation therapy is thought to be the most effective therapy following surgical resection for malignant gliomas, low grade gliomas, and recurrent tumors. It has been shown in several trials that the dose of radiation delivered has a bearing on long term survival. In a randomized trial of patients with malignant gliomas (by the Medical Research Council Brain Tumor Working Party in England), using doses of radiation (60 Gy compared to 45 Gy), median survival improved from nine months to 12 months if the dose was increased from 45 Gy to 60 Gy. In a study from the Mayo Clinic, a similar dose response was seen in low grade gliomas following surgical resection. Many different kinds of delivery systems are employed. These include:
Chemotherapy: Chemotherapy involves the administration of drugs before or after resection and/or radiation. Results from most studies show only modest increases in survival with adjuvant chemotherapy (Brain Tumor Cooperative Group). Less malignant neoplasms seem to respond better then more malignant tumors. Nitrosoureas are the drugs of choice for gliomas, and BCNU has been shown to be the most effective for glioblastomas. In addition to the conventional methods of administering chemotherapy (IV), there have been some new and novel delivery systems which have been developed:
Biological Therapies: A variety of newer techniques are being tried for the treatment of astrocytomas. These include the following:
There are three main types of viruses in use - retroviruses, adenoviruses, and herpes viruses. All of these have advantages and disadvantages. HSV vectors have the advantage of being extremely neurotrophic and are therefore more selective in their infection. HSV vectors can also hold larger genes compared to the other kind of viruses. There are also different kinds of genes which can be bound to the vectors. There are "cytotoxic genes" whose products will cause direct cell death. There are also "cytostatic genes" whose products will inhibit cellular proliferation.
An example of a novel gene strategy is to incorporate into a viral vector the cDNA for an enzyme which does not influence normal cell function, but could convert an inactive drug into an active one. This strategy is now being employed on an experimental basis for brain tumors. Herpes simplex vectors (HSV) have been produced containing thymidine kinase (TK) which is normally absent in human brain cells. TK is present in viruses and can phosphorylate nucleotides in viruses as well as guanine analogues such as gancyclovir. The HSV is injected into tumors in the brain. The patient is then given gancyclovir which is phosphorylated by those cells expressing thymidine kinase. The phosphorylated guanine nucleotide (gancyclovir) is incorporated into DNA, mainly in rapidly dividing cells. The unusual nucleotide in DNA prevents normal DNA replication as well as also possibly inhibiting DNA polymerase, ultimately leading to tumor cell death. Normal cells are less likely to divide rapidly so that the guanine analogue is not incorporated into DNA, and neurons, for example will be spared. These new gene therapies provide a bold new approach for this important field.
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