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Neurosurg Focus 12 (2):Article 1, 2002, Click here to return to Table of Contents

Low-grade tumors

M. BEATRIZ S. LOPES, M.D., AND EDWARD R. LAWS, JR., M.D. Departments of Pathology (Neuropathology) and Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia

Low-grade tumors of the central nervous system constitute 15 to 35% of primary brain tumors. Although this cate- gory of tumors encompasses a number of different well-characterized entities, low-grade tumors constitute every tumor not obviously malignant at initial diagnosis. In this brief review, the authors discuss the pathological classification, diagnostic procedures, treatment, and possible pathogenic mechanisms of these tumors. Emphasis is given in the neu- roradiological and pathological features of the several entities.

KEY WORDS • • • treatment outcome

Low-grade of the brain represent a large pro- toses. The pilocytic (juvenile) astrocytoma is a character- portion of primary brain tumors, ranging from 15 to 35% istic, more circumscribed lesion occurring primarily in in most reported series.1–5 They include a remarkable di- childhood and with a predilection for being located in the versity of lesions, all of which have been lumped together cerebellum. It usually appears as a cystic tumor with a under the heading of "low-grade glioma." This category mural nodule. The tumor tissue itself may have features of includes virtually every tumor of glial origin that is not microcystic degeneration and Rosenthal fibers which are overtly malignant at the time of initial diagnosis. degenerative structures in the astrocytic processes. Other reasonably common types of low-grade gliomas include CLASSIFICATION OF GLIOMAS the low-grade and the low-grade , which is usually anatomically related to the Table 1 provides a classification of low-grade tumors of ventricular ependymal lining. the central nervous system. The most common low-grade There is a large variety of uncommon tumors also cate- glioma is the ordinary astrocytoma. Once divided into fib- gorized as low-grade gliomas. The is rillary and protoplasmic subtypes, this lesion currently is very frequently found in the context of NF Type 1. It can thought to be derived from ordinary , and it usu- occur as an "anterior" lesion that affects one or both optic ally occurs as a relatively homogeneous but infiltrative le- nerves, primarily evolving in the optic nerve sheath, or a sion. Closely related is the mixed glioma (mixed oligoas- "posterior" lesion that involves the optic chiasm and occa- trocytoma) that consists of both astrocytoma cells and sionally the hypothalamus. In approximately 40% of pa- oligodendroglioma phenotypes in varying proportions. tients harboring these lesions evidence of NF Type 1 is The subcategory "low-grade" tends to exclude those le- observed.2 sions with features of a high degree of pleomorphism, Another genetically related low-grade glioma is the necrosis, or vascular proliferation, or large numbers of mi- subependymal giant cell astrocytoma associated with tu- berous sclerosis. The characteristic location as well as its Abbreviations used in this paper: CT = computerized tomo- association with giant cells help define this lesion. There graphy; EEG = electroencephalogram; GFAP = glial fibrillary acid- are some indolent tumors categorized as low-grade glio- ic protein; MR = magnetic resonance; NF = ; mas that commonly present with . They include SEGA = subependymal giant cell astrocytoma; WHO = World two mixed neuronal–glial tumors: the , Health Organization. which may also be cystic and partially calcified, and the

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TABLE 1 TABLE 2 Classification of low-grade tumors of the central nervous system Modalities used in the diagnosis of glioma

gliomas neurological exam: papilledema, localizing signs astrocytoma (astrocytoma WHO Grade II; low-grade astrocytoma, EEG: focal changes, delta activity, epileptiform discharges ordinary astrocytoma) CT scan & MR imaging oligodendroglioma (oligodendroglioma WHO Grade II; low-grade angiography (when indicated) oligodendroglioma) lumbar puncture (generally not indicated) mixed (mixed oligoastrocytoma WHO Grade II; low-grade mixed glioma) (juvenile pilocytic astrocytoma; WHO Grade I) optic nerve glioma pleomorphic xanthoastrocytoma (WHO Grade II) DIAGNOSTIC PROCEDURES FOR LOW-GRADE subependymal giant cell astrocytoma (WHO Grade I) GLIOMAS ependymoma (variants: cellular, papillary, clear cell) myxopapillary ependymoma A summary of diagnostic procedures is provided in Table 2. In patients presenting with disorders, papilloma EEG can be used to diagnose the disease. The characteris- neuronal & mixed glial–neuronal tumors gangliocytoma tic EEG appearance of a low-grade glioma includes slow central or delta waves as well as any associated epileptiform ganglioglioma activity. Currently the most commonly used diagnostic dysembryoplastic neuroepithelial tumor modality is the imaging study, usually MR imaging, desmoplastic infantile ganglioglioma which provides exquisite detail both of the anatomy of the lesion and often of its pathophysiology (Tables 3 and 4). A stereotactic biopsy sampling procedure is commonly performed in attempts to diagnose presumed low-grade dysembryoplastic neuroepithelial tumor, which is usually gliomas detected by imaging studies. These biopsy proce- located in the temporal lobe. The pleomorphic xanthoas- dures are usually effective; however, because the patho- trocytoma is a characteristic superficial tumor also associ- logical findings are occasionally equivocal, one must al- ated with seizures. These lesions ordinarily have quite a ways be concerned with a sampling error in tumors that low proliferative activity and often can be controlled by contain areas of differing degrees of malignancy. treatment with radical but subtotal resection alone. The is a peculiar and uncommon TREATMENT OF LOW-GRADE GLIOMAS tumor, likely of neuronal derivation. These tumors are fre- quently associated with the third ventricle and also have In a significant proportion of detected low-grade glio- an indolent course. mas the patients may be appropriate candidates for con- Some investigators classify choroid plexus papillomas servative management. Patients harboring these lesions together with the gliomas. These tumors arise from the can be treated with anticonvulsant medication and re- choroid plexus, either in the lateral ventricles, the third peated neurodiagnostic imaging studies, withholding in- ventricle, or the fourth ventricle, and frequently present as tervention until there has been a change either clinically or obstructive masses. radiologically. Partial resection may be appropriate for some low-grade , particularly those that are near important areas of the brain. Partial resection can CLINICAL FEATURES OF LOW-GRADE result in long-term favorable results in patients with pilo- GLIOMAS cytic astrocytomas, dysembryoplastic neuroepithelial tu- It is clear that the location of the lesion tends to be the mors, and some and pleomorphic xantho- most important factor in determining the nature of the astrocytomas. symptoms and signs. Because these lesions are usually Radical or total resection is the surgical procedure of slow growing, seizures may be the presenting clinical choice for all forms of glioma, because in many of the symptom and may precede the diagnosis by many years. Seizures are particularly likely to occur in cases in which the lesions involve the temporal and the frontal lobes. TABLE 3 Visual symptoms are relatively common in low-grade Magnetic resonance imaging features of low-grade astrocytoma gliomas, depending on the actual location of the tumor, and its involvement of the optic apparatus or optic pathways. pathological features detectable cysts In cases of slowly progressive lesions that expand to necrosis affect important areas of the brain, the patients may pre- hemorrhage sent with progressive neurological deficits such as hemi- edema paresis, sensory changes, or difficulty with speech and blood–brain barrier disruption language. lesion analysis In cases in which lesions occlude or obstruct the ce- circumscribed compared w/ infiltrative unifocal compared w/ multifocal or diffuse rebrospinal fluid pathways, the patients may present with “benign” compared w/ “malignant” progressive signs of increased intracranial pressure.

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TABLE 4 Magnetic resonance imaging features of various types of low-grade tumors

MR Imaging

Tumor Type T1-Weighted Gadolinium Enhancement low-grade astrocytoma hypointense none low-grade astrocytoma, optic nerve glioma isointense, expansive little or none & low-grade oligoastrocytoma (infiltrative) hyperintense, homogeneous indistinct borders slight pilocytic astrocytoma hyperintense, well demarcated, cystic yes ganglioglioma cystic, isointense or hyper- yes intense borders heterogeneous heterogeneous patients with these tumors complete removal of the lesion more recent laboratory work seems to support the concept can result in cure. On occasion, cortical mapping or awake that there may be a single precursor cell that can differen- surgery may be helpful in allowing complete resection to tiate into neuronal elements and into all types of glial ele- be accomplished without producing unacceptable neuro- ments as well. logical deficits. It is clear that some astrocytomas are the result of genet- The role of radiotherapy remains quite controversial in ic disturbances, particularly those associated with known the management of most low-grade gliomas (Table 5). Al- genetically linked diseases. Tumorigenesis may be the re- though there is some evidence that low-grade ordinary sult of oncogene activity, but more commonly it is the astrocytomas may benefit from , radio- result of the loss of tumor suppressor genes. Both of these therapy has not been applied in a consistent fashion, and mechanisms are being investigated using the techniques the dose-response relationship is not clear. Some investi- of molecular biology and molecular neuropathology. gators have used radiosurgery in an attempt to provide Like their more malignant counterparts, most low-grade more focused delivery of radiation for low-grade gliomas, gliomas tend toward invasiveness, and only occasionally and in the future this may prove to have a role in com- are they truly well-circumscribed lesions. The inherently bined management protocols. invasive nature of many of these tumors suggests that Because these lesions do not have features of anaplasia, surgery alone may not be adequate to provide long-term the role for is limited. In an attempt to control and that multimodality approaches may be ulti- avoid radiotherapy in very young patients, some chemo- mately more effective. It is true, however, that some forms therapy programs have been advocated. In patients with of low-grade gliomas are basically indolent hamartoma- clear signs of tumor progression despite prior therapy, tous lesions that have very little growth potential and very chemotherapy may also be considered; nitrosourea agents little ability for malignant transformation. It is evident that seem to be the most logical choices at the present time. accurate histopathological diagnosis is critical in deter- Occasionally other experimental therapies have been used mining both prognosis and recommendations for therapy in the management of low-grade glioma. These include (Table 6). interstitial brachytherapy, immunotherapy, photodynamic Although many of these lesions are considered benign, therapy, and hyperthermia. the authors of natural history studies have tended to show that they actually behave in a rather aggressive fashion, PATHOGENIC FEATURES and the prognosis for many of them is guarded. In cases of ordinary astrocytomas the 5-year survival rate is approxi- At one time it was thought that the most common low- mately 50%, and the tendency toward malignant progres- grade gliomas, namely astrocytomas and oligodendrogli- sion over time is clear. Table 7 summarizes the results of omas, arose from separate precursor cells. The results of a number of retrospective studies designed to estimate the frequency of malignant degeneration in patients with as- trocytoma who are followed over time.

TABLE 5 Controversies in the management of low-grade gliomas HISTOLOGICAL FEATURES OF LOW-GRADE GLIOMAS radical excision compared w/ stereotactic biopsy sampling radiotherapy Examples of the key features of the histopathology of is it effective? low-grade gliomas are given in Figs. A–M. Click to view: what dose is ideal? pilocytic astrocytoma (Figs. A1–A10), diffuse low-grade what methods should be used? astrocytoma (Figs. B1–B20), pleomorphic xanthoastro- radiosurgery cytoma, subependymal giant cell astrocytoma, and oligo- does it have a role? chemotherapy dendroglioma (Figs. C1–E9), mixed oligoastrocytoma, is it appropriate? ependymoma, myxopapillary ependymoma, and choroid which drugs are effective? plexus papilloma (Figs. F1–I2), ganglioglioma, dysembry- what treatment regimens or combinations are appropriate? oplastic neuroepithelial tumor, gangliocytoma, central neu- is metabolic imaging useful in follow-up and treatment decisions? rocytoma (Figs. J1–M4).

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TABLE 6 trol from those that will undergo malignant transforma- Prognostic factors and pathological features in patients with tion. Tumor receptor studies and tumor genetic studies low-grade astrocytomas may allow various forms of intervention in which novel agents and novel strategies are used. Gene therapy may Favorable Unfavorable play a role in the treatment of low-grade gliomas as well age ≤ 40 yrs age ≥ 40 yrs as in the more malignant tumors, because they both prob- single cyst/mural nodule ably share many of the same genetic predispositions. seizures as presenting problem increased intracranial pressure Management of these lesions remains a challenge and circumscribed lesion diffuse or multifocal lesion should be treated as scientifically based as possible. There homogeneous on enhanced imaging heterogeneous is a continuing need for careful and continued follow-up functional status normal functional status impaired hypometabolic on PET* hypermetabolic on PET studies. pilocytic gemistocytic microcystic References normal vascular pattern microvascular endothelial proliferation 1. Afra D, Muller W, Benoist G, et al: Supratentorial recurrences necrosis of gliomas. Results of reoperations on astrocytomas and oligo- mitosis dendrogliomas. Acta Neurochir 43:217–227, 1978 *PET = positron emission tomography. 2. Kleihues P, Cavenee WK (eds): Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000 3. Laws ER Jr, Taylor WF, Clifton MB, et al: Neurosurgical man- CONCLUSIONS agement of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 61:665–673, 1984 Major research efforts are directed toward the biologi- 4. Muller W, Afra D, Schroder R: Supratentorial recurrences of cal behavior of these interesting lesions. The authors of gliomas. Morphological studies in relation to time intervals some studies have suggested that metabolic imaging may with astrocytomas. Acta Neurochir 37:75–91, 1977 help differentiate those tumors destined for long-term con- 5. Piepmeier J, Christopher S, Spencer D, et al: Variations in the natural history and survival of patients with supratentorial low- grade astrocytomas. 38:872–879, 1996 TABLE 7 6. Soffietti R, Chio A, Giordana MT, et al: Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neuro- Studies reporting malignant transformation in low-grade glioma surgery 25:686–692, 1989 7. Vertosick FT Jr, Selker RG, Arena VC: Survival of patients Malignant with well-differentiated astrocytomas diagnosed in the era of Authors & Year Transformation (%) computed tomography. Neurosurgery 28:496–501, 1991 Weir & Grace, 1976 10.3 8. Weir B, Grace M: The relative significance of factors affecting Muller, et al., 1977 30.5 Grade I postoperative survival in astrocytomas, grades one and two. 44.6 Grade II Can J Neurol Sci 3:47–50, 1976 Afra, et al., 1978 17.9 Grade I 31.4 Grade II Manuscript received April 24, 2001. Laws, et al., 1984 49 Accepted in final form January 17, 2002. Soffietti, et al., 1989 79.2 Address reprint requests to: M. Beatriz S. Lopes, M.D., Depart- Vertosick, et al., 1991 56 ment of Pathology-Neuropathology, University of Virginia, PO Piepmeier, et al., 1996 42.9 Box 800214, Charlottesville, Virginia 22908–0214.

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