I vened an international group of neuropathologists to

Transcription

1 Revision of the World Health Organization Classification of Brain Tumors for Childhood Brain Tumors LUCY BALIAN RORKE, MD,' FLOYD H. GILLES, MD,t RICHARD L. DAVIS, MD,* AND LAURENCE E. BECKER, MDS COMMITTEE ON PATHOLOGY, PEDIATRIC BRAIN TUMOR WORKSHOP A classification for childhood brain tumors based upon revision of nomenclature of all brain tumors published by the World Health Organization (WHO) in 1979 is proposed. Applicability of the WHO classification scheme was tested in a combined study of the clinical and pathologic features of approximately 3300 brain tumors in children. It was found to be adequate for many of the neoplasms but unsuitable for a significant proportion, including a number of complex cerebral tumors for which there was no appropriate name. Nomenclature of poorly differentiated or densely cellular neuroepithelial tumors was simplified to reflect the current state of knowledge of neuroembryology and neuro-oncology, although the Committee members recognized that such a proposal would likely perpetuate the longstanding and continuing controversy relative to the nature and origin of these neoplasms. Cancer 56: , N 1976, the World Health Organization (WHO) con- I vened an international group of neuropathologists to develop a unified classification of brain tumors in an attempt to consolidate the diverse systems then in use. Their deliberations culminated in publication of a monograph in 1979 that outlined and illustrated the new classification system.' At about the same time, Gilles called attention to the need for more data concerning histologic prognostic factors in childhood neoplasm and suggested that classification of brain tumors in children might be based upon clusters of histologic features rather than upon the old system of categorization based upon the predominant putative cell type forming the bulk of the neoplasm. A group of pathologists from ten children's hospitals in the United States and Canada therefore agreed to provide material to Gilles and co-workers for a combined study of the clinical and pathologic features of approximately 3300 brain tumors in children. A major aspect of the Presented at the American Cancer Society Conference: Pediatric Brain Tumor Workshop, Niagara-on-the-Lake, Ontario, Canada, June From the *Department of Neuropathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, the?department of Neuropathology, Children's Hospital of Los Angeles, Los Angeles, the $Department of Neuropathology, University of California at San Francisco, San Francisco, California, the Division of Neuropathology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada. Address for reprints: Lucy B. Rorke, MD, The Children's Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA study included simultaneous review of all slides, using a dual-head microscope, by Drs. Rorke and Davis, whose assignment was the diagnosis of each tumor according to the WHO classification scheme. The usefulness and applicability of the WHO system for tumors in children was thus tested. It was found to be adequate for many of the tumors but unsuitable for a significant proportion. There were, for example, a number of complex cerebral neoplasms for which there was no appropriate name. As a part of this Workshop, this committee was invited to propose a classification system of childhood brain tumors that might be acceptable to pathologists and understandable to clinicians. It was decided to use the experiences of Rorke and Davis, in conjunction with the broad experience of the other committee members, and to adapt the WHO system of nomenclature specifically for classification of brain tumors in children. This proposal is made with considerable trepidation, as our disagreement with the WHO Committee of neuropathologists on several fundamental issues may be construed as a gross impertinence. Nevertheless, we are sufficiently convinced that revisions are justified by advances in knowledge of the nature and behavior of central nervous system tumors in children, and recognize that new data may necessitate future changes. Few, if any, classification systems currently in use can be regarded as perfect. They are, rather, dynamic, everchanging tools that help organize thoughts about collective observations which, by necessity, must change as new information becomes available. It is conceivable, 1869

2 1870 CANCER October I Supplement 1985 Vol. 56 TABLE I. Location of Tumors Interfacing with the Nervous System Site Designation Central nervous system parenchyma I Hemispheres (superficial) a Frontal Parietal Temporal Occipital Thalamus and/or basal ganglia b H ypothalamus/chiasm C Antenor optic pathways d lntraventricular Pineal region e f Brain stem Cerebellum g h Brain stem and cerebellum (including cerebellopontine angle and middle cerebellar peduncle) i Spinal cord (level and site, if known) j Intradural, extramedullary jl Meninges I1 lntradural a Extradural b Parasellar region 111 Skull and/or vertebral column IV Orbit (eye) V Peripheral nervous system VI for example, that analysis of Gilles data within the next few years may justify abandonment of this system altogether. If such a change would clarify our perception of the biology and treatment of brain tumors in children, we should embrace it without hesitation. Rationale Brief discussion of several fundamental points is in order before presentation of the classification system outlined below. This is primarily a histologic classification based not only upon light microscopic features of the tumors, but upon findings obtained by use of immunohistochemical techniques and electron microscopy when appropriate. We recognize the extraordinary heterogeneity of both individual cell morphologic features and tissue patterns of many tumors within the same general diagnostic category. For example, the variable appearance of tumors called ependymoma is remarkable indeed, and it is difficult to convey the diversity of patterns by written descriptions alone. We maintained the convention of placing a tumor within a specific category on the basis of the predominant cell type, unless different cell types appeared to contribute essentially equally to formation of the tumor, in which case it was a mixed tumor, e.g., oligoastrocytoma. However, the general class assignments do not necessarily represent a unitary entity and may be subject to change. Application of a grading system to denote the degree of histologic malignancy is widely used. However, in view of the fact that tumors of the nervous system are often biologically malignant but histologically benign or, conversely, may manifest cellular features of anaplasia but respond favorably to treatment, we believed that it would be appropriate to designate only whether a tumor is or is not anaplastic. This scheme, therefore, does not use the modifying terms benign or malignant. Instead, a category of anaplastic was used for neoplasms that display those histologic features. Designation of tumor site is important, as this appears to be related to prognosis. It is wellestablished, for example, that a child with a cerebellar astrocytoma has a better prognosis than does a child with a histologically similar tumor located in the cerebrum. Therefore, we recommend designation of site as listed in Table 1 along with the histologic diagnosis. For example, if the tumor is a cerebellar astrocytoma the diagnosis would be Astrocytoma (pilocytic), Ih. Finally, there was general agreement on diagnostic terms except for those applied to poorly differentiated or densely cellular neuroepithelial tumors. In view of the long-standing and continuing controversy among neuropathologists relative to the nature and origin of these neoplasms, it is not surprising that considerable time and energy were devoted to nomenclature that would be acceptable, not only to all Committee members, but also to others who would be using the classification system. The Committee members agreed on many basic principles, but found the semantic aspects almost insurmountable. Lengthy discussion finally culminated in a compromise decision to use quotation marks around the word primitive to indicate the controversial nature of this problem. See Definitions and Comments for IC, below. We attempted as much as possible to retain the original WHO definitions. Those categories and definitions left unchanged or changed slightly are designated by asterisks. I. Tumors of Neuroepithelial Tissue A. Glial Tumors 1. Astrocytic tumors a. *Astrocytoma (fibrillary, protoplasmic, pilocytic, gemistocytic, xanthomatous) Astrocytoma is a tumor composed predominantly of astrocytes with variable numbers of

3 No. 7 SESSION V Rorke et a/ intracytoplasmic intermediate filaments demonstrated by antisera to glial fibrillary acidic protein (GFAP). The histologic subclassification depends on the appearance of the individual tumor cells and on the patterns they form with each other and with other tissue elements. Because of regional histologic variability and the uncertain relationship of histologic pattern and biological behavior, these tumors are simply designated astrocytoma. However, if there is predominance of one pattern, the appropriate adjective should be used. Of the histologic subtypes of astrocytoma, the pilocytic pattern is most common in children and is most often located in the cerebellum. Supratentorial sites are most common in the diencephalon and optic nerve. These tumors are slowly growing, focally infiltrative neoplasms that often invade the subarachnoid space. They may be cystic or solid. Those in the cerebellum in particular have a good prognosis. The classic histologic features present a biphasic pattern that consists of a dense arrangement of cells with oval nuclei with fine chromatin and elongated unipolar or bipolar processes that tend to form parallel bundles adjacent to loosely structured microcystic areas. Astrocytes in these areas have small round-to-oval nuclei, occasionally with a denser chromatin pattern and a small perikaryon from which delicate stellate processes extend to anastamose with processes from neighboring cells. There is an irregular pattern of blood vessels that may be hyalinized. Endothelial proliferation is not uncommon, especially in the walls of cysts, but this feature does not signifj. malignancy. Rosenthal fibers and eosinophilic intracytoplasmic droplets are commonly found. Nuclei are sometimes enlarged, hyperchromatic, and pleomorphic; however, if mitoses are not present, this feature does not signify anaplasia. The xanthomatous variant, to which the name pleomorphic xanthoastrocytoma has been given, is a tumor that occurs primarily in children and young adults? These are primarily supratentorial tumors that tend to grow within the leptomeninges and invade the brain via the Virchow-Robin spaces, and in a diffise manner. They are characterized histologically by a moderately cellular pleomorphic population of neoplastic cells, many of which are enormous and lipidized. The cells contain both fat and GFAP-positive material. Lymphocytes and plasma cells are often abundant. Mitotic activity is inconspicuous, and the patients have a good prognosis. b. Anaplastic astrocytoma A tumor formed by astrocytes demonstrating varying degrees of pleomorphism, increased cellularity, and a variable number of mitotic figures, anaplastic astrocytoma may contain foci of necrosis, but they are not of the pseudopalisading type. This tumor is distinguished from the ghoblastoma multiforme (see IA6). c. *Subependymal giant cell tumor (tuberous sclerosis) Subependymal giant cell tumor is a periventricular, usually circumscribed tumor that is composed of giant, often fusiform cells with various degrees of astrocytic and/or neuronal differentiation.)- A perivascular arrangement may be conspicuous, and calcification is frequent. The tumor often arises from the medial part of the floor of the lateral ventricle, occludes the foramen of Monro, and typically occurs in young patients as part of the tuberous sclerosis complex. d. Gigantocellular glioma A tumor of infancy and childhood dominated by large, bizarre astrocytes but lacking other features of anaplasia such as mitoses, pseudopalisading, or vascular proliferation, gigantocellular glioma often has a conspicuous fibrovascular stroma. 2. Oligodendroglial Tumors a. Oligodendroglioma Oligodendroglioma present a spectrum of histologic anaplasia that had been divided previously into 2, 3, or 4 grades. This classification assigns two grades, recognizing that the grading of oligodendrogliomas is incomplete and that subsequent studies may suggest additional grades. The welldifferentiated oligodendroglioma is an infiltrating lesion that may be macroscopically poorly defined or well-circumscribed. The lesion is noted microscopically for monotony of

4 1872 CANCER October I Supplement 1985 Vol. 56 round nuclei with moderately prominent nucleoli and scant mitotic activity. Perineuronal satellitosis is frequently conspicuous. Calcification is observed in most cases. A distinctive network of angular capillaries is frequently seen. A distinctive feature in lesions in which autolysis has occurred is artifactual perinuclear halos, which create a fried-egg appearance. This appearance is, however, not necessary for the diagnosis. Necrosis and vascular proliferation are uncommon. b. Anaplastic oligodendroglioma Anaplastic oligodendroglioma is a markedly densely cellular lesion with abundant necrosis and vascular proliferation. Nuclei vary in size but are generally larger and more hyperchromatic, and contain coarser chromatin and more prominent nucleoli than those in the welldifferentiated lesion. Mitotic activity is also more frequent. Although some oligodendroglial neoplasms present with pseudopalisading around necrotic foci and therefore merge cytologically with the glioblastoma, most anaplastic oligodendrogliomas fall short of this state. Many oligodendrogliomas include cells with astrocytic characteristics. These include both cells with prominent glassy cytoplasm, signet ring cells, as well as conventional fibrillary astrocytes with more elongated processes. The former cells frequently contain bundles of filaments that are strongly positive for glial fibrillary acidic protein. This classification considers these lesions to be oligodendrocytes. Lesions with a significant component of fibrillary astrocytes, however, should be regarded as mixed gliomas (see IA5). 3. Ependymal tumors a. *Ependymomas Ependymomas are common tumors in childhood. They typically project from an ependymal surface, most commonly the floor of the fourth ventricle or lateral and third ventricles. They may also arise in the cerebellopontine angle, the region of the central canal of the spinal cord, or from the filum terminale, although such tumors are rare in this latter site in children. The majority of ependymomas appear to be histologically mature, but they carry a poor prognosis in children. Ependymomas are highly vascular tumors composed predominantly of ependymal cells that form rosettes (structures resembling the central canal of the spinal cord), canals (structures resembling the walls of ventricles), and perivascular rosettes (arrangements of cells with processes oriented toward the wall of a blood vessel, the gliovascular structure). Structures that resemble central canals or ventricular linings are diagnostic but infrequent. The perivascular pseudorosette is the more common feature, but this tumor may exhibit a diverse range of histologic patterns that make diagnosis difficult. The neoplastic cells may contain eosinophilic intracytoplasmic granules, and the otherwise welldifferentiated examples may contain scattered mitotic figures. These tumors may contain cartilage, calcium deposits, or dysplastic bone. These tumors often contain GFAp6 and at the ultrastructural level contain zonulae adherentes, cilia with basal bodies, and microvilli. Ependymomas frequently have cells that by light microscopy closely resemble oligodendrocytes. By light microscopy, therefore, some of these lesions qualify as mixed gliomas. However, ultrastructurally, these oligodendrocytes have features of ependymal cells. b. Anaplastic ependymoma An anaplastic ependymoma is an ependymoma composed in whole or part of cells with anaplastic features such as nuclear atypia, high nuclear/cytoplasmic ratio, multiple nuclei, and most often with a marked increase in number of mitotic figures. Necrosis and vascular endothelial proliferation may also be seen. c. Myxopapillary ependymoma Myxopapillary ependymoma occurs virtually exclusively in the region of the cauda equina and originates from the filum terminale or the conus medullaris. It is composed of ependymal cells often arranged in a perivascular papillary manner around central cores of acellular hyaline connective tissue. The stroma is highly vascular, and hemorrhages are frequent. Mucin is often demonstable in the cytoplasm of the tumor cells and in the walls of blood vessels. Material

5 No. 7 SESSION V * Rorke et al with a similar staining reaction in the stroma may be so prominent that the architecture is blurred. 4. Choroid plexus tumors a. *Choroid plexus papilloma Choroid plexus papilloma is an intraventricular papillary tumor usually composed of a single layer of low columnar or cuboidal cells that lie upon a basement membrane that covers a delicate vascular connective tissue core. Sometimes they are heavily mineralized. Even though these tumors are histologically mature, they may seed widely throughout the central nervous system. b. Anaplastic choroid plexus papilloma (carcinoma) A malignant tumor arising from the choroid plexus, either by anaplasia in a choroid plexus papilloma, or de novo, anaplastic choroid plexus papilloma show varying degrees of anaplasia, which may increase with time. They may arise in any ventricle or site of choroid plexus, although in children they are seen most frequently in the lateral ventricles. 5. Mixed gliomas Mixed gliomas contain a prominent mixture of two or three types of glial cells. They occur most commonly in the cerebrum in children. a. Oligoastrocytoma Oligoastrocytoma contains a conspicuous mixture of oligodendroglial cells and astrocytes. The oligodendroglial cells may be isolated or occur in patches, but some patches of at least six oligodendroglial cells must be present. The astrocytic cytoplasm may be sparse or abundant. Either component (oligodendroglia or astrocytic) may predominate, and the name may be modified accordingly. Distinct vascular patterns and calcification may be present but are not requisite diagnostic criteria. 1. Anaplastic oligoastrocytoma If either component is anaplastic, the adjective is added to the name. b. Ependymoastrocytoma Ependymoastrocytoma contains perivascular pseudorosettes in addition to astrocytes. The perivascular pseudorosette is a structure with a small blood vessel that is centrally located, surrounded by a narrow or wide, centric or eccentric, perivascular halo of a nucleus-free zone, which is in turn surrounded by nuclei of the tumor cell. The astrocytic component of this tumor must be external to the perivascular pseudorosettes, as the radially oriented eosinophilic fibrils within the pseudorosette are often plasma thromboplastin (PTAH)-, Holzer-, or GFAPpositive. If the astrocytic component predominates, the name is reversed accordingly. The astrocytic cytoplasm may be sparse or abundant. These cells are GFAP-positive. Ependymal tubules may be present but are not requisite diagnostic criteria. Ultrastructural study confirms ependymal nature of the cells as described.' 1. Anaplastic ependymoastrocytoma If either component is anaplastic, the appropriate adjective is added. c. Oligoastroependymoma Oligoastroependymoma contains distinct regions with each of the three glial cell types. Patches of oligodendroglial cells, with or without dispersed individual oligodendrocytes, interspersed with perivascular pseudorosettes and regions of astrocytes (with or without prominent cytoplasm) are all present. 1. Anaplastic oligoastroependymoma If any component is anaplastic, the appropriate adjective is added. d. Oligoependymoma Oligoependymoma contains prominent patches of oligodendrocytes and perivascular pseudorosettes without an appreciable astrocytic component. 1. Anaplastic oligoependymoma If either cellular component is anaplastic, the appropriate adjective is added. e. Subependymoma-subependymal glomerate astrocytoma A special type of mixed tumor consisting of astrocytes and ependymal cells that arises

6 1874 CANCER October 1 Supplement 1985 Vol. 56 beneath the lining of the fourth or lateral ventricles, subependymoma-subependymal glomerate astrocytomas were thought to be small, asymptomatic incidental nodules discovered at necropsy in middle-aged or elderly individuals. However, large, symptomatic examples occur in children and, even though composed of mature cells, they have a poor prognosi~.~*'~ The tumor contains clusters of nests of nuclei interspersed in a background of fine or coarse fibrils. Nuclei are round or oval, and clear distinction as astrocytic or ependymal is difficult. Overall, the density of nuclei is low except in the nodules of nuclei. There is only slight-to-moderate pleomorphism, as most of the nuclei are uniform in shape. Vacuoles, mineralization, and microcysts may be present but are not requisite diagnostic criteria. There is no known anaplastic subset of this tumor. Ultrastructural studies disclose presence of glial filaments, microvilli, and zonulae adherente~.~.' I f. Gliofibroma A rare tumor of infancy and childhood, gliofibroma is composed of intermingled, welldifferentiated astrocytes and fibroblast^.'^^'^ The two cell types are often surrounded by the same basal lamina, collagen, and reticulin fibers, and gliofibrils are abundant. The tumor displays no evidence of anaplasia. 6. Glioblastomatous tumors a. *Glioblastoma multiforme Glioblastoma multiforme is an anaplastic, highly cellular, pleomorphic tumor containing necrosis and endothelial proliferation. It is composed of very diverse cells that sometimes resemble one or more of the glial cell types, but more often are only recognizable as neoplastic cells. Perinecrotic pseudopalisades are usually prominent. Mitotic figures may be abundant, but may not be found at all. b. Giant cell glioblastoma The giant cell subset of glioblastoma is set apart because it contains cells, often multinucleated, with exceedingly large pleomorphic nuclei lying in a population of smaller cells. The cells may be ordered in regular fascicular arrays or may be jumbled. Reticulin is sometimes abundant but is not a requisite diagnostic criterion. Otherwise, the tumor displays the features of a glioblastoma multiforme. c. *Glioblastoma with a sarcomatous component Glioblastoma with a sarcomatous component is formed by a mixture of glioblastoma and fibrosarcoma. The latter is thought to arise from vascular mesenchyme. 7. Gliomatosis cerebri The gliomatosis cerebri class of central nervous system neoplastic processes is unique and can only be diagnosed with certainty at necropsy. It is comprised of diffuse gliomatous proliferation located in multiple sites within the nervous system. Neoplastic glial cells of diverse origins and patterns may be located in forebrain, hindbrain, or spinal cord. The neoplastic cells may range from isolated single pleomorphic or hyperchromic cells to widespread, diffuse, or nodular involvement by cells of single or several lineages. It may contain foci of glioblastoma. B. Neuronal Tumors Four types of tumors, each of which contains mature-appearing ganglion cells, constitute the category of neuronal tumors. 1. Gangliocytoma Gangliocytoma is a tumor composed almost entirely of ganglion cells, some of which contain two or more nuclei. The background glial component is inconspicuous. There may be a prominent mesenchymal component, calcification, and/or cyst formation. Neurofilament protein (NFP) may be abundant in these tumors, and the glial component is positive for GFAP. Electron microscopy confirms the ganglion cell and glial features of the cells. These tumors occur most commonly in the cerebral hemispheres in childhood and often announce their presence by the onset of seizures. They appear to be slowly growing neoplasms and are generally associated with a good prognosis. The mass effect may be produced largely by a cyst. A curious lesion confined to the cerebellum, and more likely a malformation than a true neoplasm, is the dysplastic gangliocytoma described by Lhermitte and Duclo~.'~ It is included among tumors because of its tendency to present as a mass lesion, occasionally during late

7 No. 7 SESSION V Rorke et al ~hildhood. ~, ~ Affected folia may or may not be enlarged. Microscopically, it is characterized by a diffise scattering of abnormal large neurons thought to be derived from granule cells. 2. Anaplastic gangliocytoma Anaplastic gangliocytoma is a tumor composed almost entirely of ganglion cells, as described above, but which displays anaplastic features. 3. Ganglioglioma Ganglioglioma is composed of both ganglion cells and neoplastic glia, usually astrocytes. The ganglion cell component is often unevenly distributed such that some portions contain a prominent population, whereas none are seen in other regions. They may be arranged diffisely or form clusters. The tumor may have a prominent connective tissue component. Penvascular lymphocytes are common. These tumors, like the gangliocytoma, tend to grow slowly and have a good prognosis. They are often cystic. Immunocytochemical and electron microscopic features are as outlined above for gangliocytoma. 4. Anaplastic ganglioglioma Anaplastic ganglioglioma is the anaplastic form of the ganglioglioma described above. Anaplasia generally affects the glial component and may manifest features of glioblastoma multiforme. C. Primitive Neuroectodermal Tumors Tumors in the primitive neuroectodermal category are most frequently located in the cerebellum and are among the most common tumors of childhood. They are, without question, the focus of greatest debate as well. The controversy dates back to 1925 when the prototype tumor in this group, the medulloblastoma, was described by Bailey and Cushing. Hypotheses regarding the cell of origin and the nature of the tumor were advanced by Bailey and Cushing and continued to be proposed many years Details of the issues in question are too complex to review in this context, but the essence of the problem may be found in other report^.'^-^' Briefly, it may be summarized as follows: Is the cerebellar medulloblastoma derived from a multipotential external granule cell and hence unique to the cerebellum, or is it basically similar to tumors that have a similar appearance and biologic behavior but grow in the cerebrum, pineal region, or spinal cord and are known by a variety of different names? When considered together, certain facts emerge: (1) tumors identical in appearance to medulloblastoma may arise in the pineal gland, cerebrum, or spinal cord; (2) the biologic behavior of these tumors is similar; (3) aside from the apparently undifferentiated cells, these tumors, regardless of site of origin, may contain cells that display features of neoplastic astrocytes, oligodendrocytes, ependymal cells, neuronal cells, melanocytes, or mesenchymal cells, such as smooth or striated muscle. Some tumors may contain more than one mature or immature cell type; and (4) the cerebellar medulloblastoma is a heterogenous neoplasm that usually exhibits a variety of histological features.22 There appear to be several fundamental unresolved questions at the heart of the controversy: (1) Is the cell of origin unique to the portion of the nervous system in which the tumor arises, e.g., external granule cell in cerebellum, pineoblast in pineal gland, etc.. or does it arise from a primitive or undifferentiated cell common to all portions of the nervous system, including the pineal gland; or (2) Do the tumors arise from a single primitive multipotential neuroepithelial cell that has the capacity to differentiate into one or more types of neural cell such as astrocyte, ganglion cell, or even melanocyte? Or, alternatively, do the tumors originate from a clone of cells, some of which are already committed to become astrocytes or neurones or simply to remain as undifferentiated neoplastic cells; or (3) The possibility also exists that these tumors do not arise from primitive neuroepithelial cells; rather, the apparently undifferentiated or primitive cells is a previously mature transformed neoplastic cell. Until such time as there is incontrovertible scientific evidence in support of one view, the nosologic problem will persist. In our opinion, the evidence to date indicates that there is a group of central nervous system tumors that most commonly occur in childhood and that are primarily composed of primitive or undifferentiated neuroepithelial cells. They often display considerable histologic heterogeneity and may contain a variable number of cells that are morphologically identifiable as astrocytes, oligodendrocytes, ependymal cells, neurones, melanocytes, or even mesenchymal cells. The nomenclature that we propose for this group of tumors enclosed the word primitive within quotation marks to direct attention to the unresolved questions outlined above, and we believed also

8 1876 CANCER October I Supplement 1985 Vol. 56 that a simple description of the recognizable types within these tumors would be more acceptable than an interpretive diagnosis such as primitive neuroectodermal tumor with astrocytic differentiation. 1. Primitive neuroectodermal tumor, not otherwise specified (NOS) Primitive neuroectodermal tumors, NOS occur most commonly in the midline region of the cerebellum but may be located anywhere within the central nervous system, including the pined gland. They tend to spread widely within the central nervous system through subarachnoid pathways and rarely metastasize outside the nervous system, most commonly to bone. These tumors are composed of poorly differentiated neuroepithelial cells that consist of small, round nuclei surrounded by a minimal rim of cytoplasm, or larger cells with round or oval nuclei set within a more obvious perikaryon, which may be eosinophilic and have a tapered end. Nuclei are rich in chromatin and may contain one, or sometimes two, nucleoli. The background has a pink granulofibrillar character or may be absent. Mitotic figures are often conspicuous and sometimes bizarre. The cells in some instances form Homer Wright rosettes. The tumors may have a variable fibrovascular stroma, may contain foci of necrosis or multinucleated tumor cells, and sometimes contain clusters of or individual macrophages. These tumors contain no GFAP- or NFP-positive neoplastic cells, and electron microscopy shows the tumor to be composed of undifferentiated cells with large nuclei, rt nucleoli, and scanty cytoplasm with inconspicuous organelles. 2. Primitive neuroectodermal tumor with a. Astrocytes Primitive neuroectodermal tumors with astrocytes may be characterized by a variety of histologic patterns. The astroglial cells are less densely packed than are the undifferentiated cells and are separated by a more neuropillike stroma. The transitional zone between the fields of primitive cells and the astroglial elements may be indistinct or sharply defined. At times there is a striking lobular pattern, often associated with growth of cells in rows. These are similar to what has been described as the desmoblastic variety of med~lloblastoma,~~ but the cells in these regions do not rest upon reticulum. The glial cells may resemble immature forms or may be easily recognizable as neoplastic astrocytes. These cells stain positively for GFAP and display ultrastructural features characteristic of astroglia. Areas of tumor consisting of the undifferentiated cells are also present as described in 1. Pseudopalisading and pseudorosettes may be seen. b. Oligodendroglia Tumors containing poorly differentiated neuroepithelial cells and oligodendroglia are basically similar to those described in 1 but contain areas in which apparently neoplastic oligodendrocytes are recognizable. Most commonly, these foci are made up of small oligodendroglia with the typical fried-egg appearance; they rarely display features of anaplasia. The GFAP stain is negative, and electron microscopic features are as described for undifferentiated cells and oligodendroglia. c. Ependymal cells Ependymal cell tumors include those previously called ependymoblastoma and are composed of the poorly differentiated neuroepithelial cells described above and the ependymal rosettes or canals; only a few such structures may be present. Immunoperoxidase stain for GFAP may or may not be positive. Ultrastructural features include elongated junctional devices, rosette-like arrangements, microvilli, cilia, and basal bodies.24 An unusual variant of this tumor can only be diagnosed on ultrastructural examination. It displays a biphasic cellular pattern: some portions are easily recognized poorly differentiated neuroepithelial cells, whereas other areas are composed of larger cells with a moderate-to-large deep pink perikaryon, round nuclei, and a prominent nucleolus. These cells generally have distinct cytoplasmic borders, tend to be discrete, and have no background granulofibrillar stroma. They do not form ependymal rosettes or pseudorosettes, and on light microscopy evoke no suspicion of their ependymal nature. d. Neuronal cells Neuronal cell tumors are largely made up of the poorly differentiated neuroepithelial cells and a generally small but variable number of immature or mature ganglion cells. The latter

9 No. I SESSION V Rorke et al must be differentiated from preexisting neurons. Occasionally, small areas of the neoplasm look like small neuronal hamartomas. Immunoperoxidase stain for NFP is usually positive, and ultrastructural study reveals presence of clear or dense core vesicles, synapses, cilia with pattern, and blunt cytoplasmic processes that contain abundant actin filaments, microtubules, or large clear vesicles that resemble growth cones of developing nerve cell^.^'-^^ Some of these tumors may be histologically indistinguishable from the peripheral neuroblastoma. e. Other (melanocytes, mesenchymal) Rarely, a primitive neuroectodermal tumor may contain cells with melanin pigment in fields in which papillary and/or tubular formations contrast sharply with other typical-appearing areas. The pigmented cells are low columnar or cuboidal in character. The melanin-bearing cells do not always form these tubular structures but may be scattered amidst nonpigmented, poorly differentiated cell^.^' These rare tumors are primarily located within the cerebellar vermis and disseminate widely through cerebrospinal fluid pathways. A second rare variant of primitive neuroectodermal tumor is one in which a component of the neoplasm is mature or immature striated muscle; smooth muscle has also been reported in these The precise nature of this variant has also been subject to controversy. Some investigators believe that they are teratoid t~mors ~,~~.~~ others regard them as mixed neuroepithelialmesenchymal neoplasm^^^-^'; still others suggest that primitive neuroectoderm may have a myogenic potential and hence regard them as a differentiated medull~blastoma.~~ A PTAH stain is useful for demonstration of cross-striations. Immunohistochemical studies for myoglobin are positive; GFAP and/or NFP may be present. Ultrastructural examination of portions containing the muscle fibers confirm the presence of neoplastic muscle fiber^.^^"^ f. Mixed cellular elements A small number of these primitive neuroectodermal tumors may contain a combination of cellular structures as described under a-e. 3. Medulloepithelioma Medulloepithelioma is a rare tumor of infancy and childhood that most often occurs in cerebral hemispheres but which may also arise in brain stem, cerebellum, or peripheral nerve.23*3942 The central nervous system tumor follows a biologically malignant course, generally disseminating widely through subarachnoid pathways. a. Medulloepithelioma, NOS Medulloepithelioma, NOS has a distinctive histologic appearance that is characterized by structures recapitulating the embryonic neural tube. Columnar cells form stratified tubular or papillary structures that rest upon a sharply defined external limiting membrane. There is a periodic acid-schiff (PAS)-positive internal membrane that resembles an internal limiting membrane as well. Mitotic figures are abundant. The ultrastructure of these tumors is basically that of the fetal neural tube. Cells have minimal cytoplasm with few organelles and no cilia or microvilli. Nuclei are chromatin-rich, and cell junctions are primitive.43 b. Medulloepithelioma with 1. Astrocytes 2. Oligodendrocytes 3. Ependymal cells 4. Neuronal cells 5. Other (melanocytes, mesenchymal including cartilage and bone) 6. Mixed cellular elements The morphologic variations observed in the medulloepithelioma reflect the multipotential nature of this most primitive embryonic tumor. As such, it may display any or all components of nervous system differentiation. Nomenclature thus reflects these possibilities and requires no further elaboration relative to light microscopic, immunocytochemical, or ultrastructural features beyond those already delineated above. D. Pineal Cell Tumors Problems in the nosology of neoplasms arising in the pineal gland have been addressed in detail.- Tumors are separated into two major groups: teratomatous or germ cell type and those

10 1878 CANCER October I Supplement 1985 Vol. 56 derived from the neuroepithelial anlage of the gland itself, i.e., the pineal parenchymal tumors. An additional small proportion consists of other types of central nervous system tumors such as astrocytoma, glioblastoma multiforme, choroid plexus papilloma, meningioma, efc., which may arise within the pineal gland. Only those tumors derived from the pineal parenchyma are considered in this section. Rubinstein separated these into two categories, pineoblastoma and pineocyt0ma,4~*~~ and noted that the pineoblastoma is composed of uniform sheets of immature, poorly differentiated cells resembling medulloblastoma, whereas the pineocytoma display a lobular architecture resembling the normal pineal gland. Unfortunately, distinction between the two may be difficult, as transitional forms are frequent or the patterns may coexist. Moreover, both types may differentiate: the pineoblastoma along pineocytic or retinoblastomatous lines, and the pineocytoma in astrocytic and/or neuronal directions. They may also contain melanin.45*46 Separation of these two types of tumors is important as their biologic behavior is different, although the long-range prognosis for children with pineal tumors is generally poor. In our experience, children with pineoblastoma often have disseminated disease at presentation and survive for a shorter period in contrast to those with pineocytoma; tumor disseminates much later in the course and survival may be prolonged in children with pineocytoma. 1. Primitive neuroectodermal tumor (pineoblastoma) (see C above) For reasons already outlined above, we regard the tumor diagnosed by others as pineoblastoma as a primitive neuroectodermal tumor arising from the neuroepithelial anlage of the pineal. Histologic features of these tumors are therefore as described with one addition. Those that display retinoblastomatous differentiation contain rosettes of the Flexner-Wintersteiner variety and/or fleurettes. Fleurettes are flower-like arrangements of cells undergoing photoreceptor differentiation. These structures resemble those of cone cells radiating from an attachment girdle of external limiting membrane of zonulae adherentes when examined with the electron mi~roscope.~ Ultrastructural study also reveals giant club-shaped cilia with a microtubular pattern. 2. Pineocytoma a. *Pinemytoma, NOS Pineocytomas, NOS are pineal parenchymal tumors displaying a lobular pattern. The cells may be of uniform size and have a polar process that radiates toward a blood vessel. Application of the Achuc6rro-Hortega silver carbonate technic demonstrates club-like expansions at their tips. Neoplastic cells in some of these tumors may range in size from small to large. b. Pineocytoma with ganglion cells Some of the tumors contain large rosettes that appear different from Homer Wright rosettes?8 The centers contain delicate argyrophilic cell processes, some of which have a terminal bulb. Ultrastructural features suggest that they are small mature neurons. c. Pineocytoma with astrocytes Histologic features of pineocytoma with astrocytes are as described under 2a, but with the added feature of neoplastic astrocytes. 11. Tumors of Meningeal and Related Tissues A. Meningioma This classification restricts the term meningioma to a neoplasm found only in the meninges, or meningeal rests, as occasionally found in the skull, along peripheral nerves, or in the skin. Meningiomas are relatively uncommon in childhood. Central nervous system meningiomas are smooth, lobulated masses that tend to be broadly attached to the dura although they may be intraventricular or in the spinal epidural space, especially in children. Although meningiomas may adhere to the pial surface, invasion of the brain is exceptional in the histologically welldifferentiated lesion. Adjacent bone may be involved with tumor or may exhibit an osteoblastic response. These tumors may encase cerebral vessels or cranial nerves. Meningiomas display a variety of histologic patterns, the majority of which have no prognostic significance.

11 No. 7 SESSION V * Rorke et al Meningioma, NOS This category of meningioma, NOS includes the common major subtypes of meningioma such as meningotheliomatous (syncytial), fibroblastic, transitional, psammomatous, angiomatous, and cystic. The meningotheliomatous type is formed by sheets of cells with indistinct borders. Nuclei are oval, have a delicate chromatin pattern and a small nucleolus, and closely resemble arachnoid cap cells. Cytoplasmic invagination into nuclei (pseudoinclusions) and true intranuclear inclusions are common. The fibroblastic type is formed by spindle-shaped cells that resemble fibroblasts. Fibrous connective tissue in these tumors may be calcified. Arachnoidal whorl-like structures are not common in either of these two subtypes. The transitional pattern is a combination of syncytial and fibrous elements. The former form lobules or whorls. The psammomatous subtype is one in which the bulk of the mass is composed of psammoma bodies; a few neoplastic cells remain. A cell in mitosis may rarely be encountered. Other subtypes have been described, and the reader is referred to Kepes excellent monograph on the ~ubject.4~ Ultrastructural features are also described in detail by Kepes, the major characteristic of which consists of complex interdigitations of plasma membranes. 2. Papillary meningioma The papillary meningioma has a distinctive appearance because of the orientation of neoplastic cells to blood vessels. Such orientation produces radiating penvascular structures similar in some respects to that of the ependymoma. Reticulin fibers may be seen within these radiations. The nuclei are round and resemble those of other meningiomas, although they may be slightly more hyperchromatic and are more likely to be found in mitotic division. Although the lesion may not have overt microscopic features of malignancy, recurrence and late metastases are frequent. 3. Anaplastic meningioma The diagnosis of anaplastic meningioma is assigned to lesions that have either (1) clear-cut histologic evidence of anaplasia in an otherwise unequivocal meningioma or (2) anaplastic features that develop over time in a previously well-differentiated lesion. Anaplastic lesions are noted for invasion of the cerebral parenchyma where a marked astrogliosis may be observed. In contrast to the typical meningioma, the anaplastic lesion has cells whose nuclei are larger and plumper and contain prominent nucleoli. Mitotic figures are not difficult to find. In some instances, elongated cells assume a more sarcomatous appearance, although the cells usually remain plump and lack the well-defined fascicular arrangement of the fibrosarcoma. Necrosis may be prominent. B. Meningeal Sarcomatous Tumors 1. *Meningeal sarcoma, NOS (primary meningeal sarcomatosis) Meningeal sarcoma, NOS is a diffuse proliferation within the subarachnoid space of undifferentiated small, anaplastic, presumably mesenchymal, cells. 2. Rhabdomyosarcoma or leiomyosarcoma Rhabdomyosarcoma or leiomyosarcoma is a rare tumor that occurs primarily in the posterior fossa of children and is composed of striated or smooth muscle. 3. Mesenchymal chondrosarcoma The rare mesenchymal chondrosarcoma tumor presents as a multilobulated mass attached to the dura and seems to favor the anterior fossa in infants and children. It resembles soft tissue chondrosarcomas elsewhere, but may be difficult to diagnose if no cartilaginous differentiation is present. It may be confused with a neuroepithelial tumor, as cells may form Homer Wright-like rosettes. However, its mesenchymal character becomes obvious by the use of trichrome stains. The tumor tends to recur and may invade the brain.% 4. *Fibrosarcoma A tumor composed of spindle cells, reticulin, and collagen, fibrosarcoma may show a welldifferentiated fascicular pattern or cellular disarray and anaplasia. 5. Others Other types of sarcomatous lesions such as xanthosarcoma (malignant fibroxanthoma) could occur in children although they have not yet been described. C. Primary Melanocytic Tumors 1. Malignant melanoma

12 1880 CANCER October 1 Supplement 1985 Vol. 56 Primary malignant melanoma may occur in the leptomeninges in a focal site or diffusely in the intracranial and intraspinal spaces as an isolated event or, more frequently, in association with cutaneous or ocular nevi. Intracranial lesions associated with the skin lesions are usually present in childhood and present as a diffuse, and less commonly focal, proliferation of malignant melanocytes. Similar lesions occur in adults, where it can be difficult to exclude a metastatic nature. 2. Melanomatosis The nervous system of infants or children with certain phakomatosis such as basal cell nevus syndrome may contain diffuse meningeal or parenchymal perivascular nests of melanocytes that more commonly represent hamartomatous, non-space-occupying growths. 3. Melanocytic tumors, miscellaneous Melanocytic tumors, miscellaneous include the so-called pigmented meningioma, melanotic schwannoma, melanotic neurofibroma, efc. They occur primarily in the intramedullary or intradural extramedullary compartment of the spinal cord. The pigmented meningioma is related to cutaneous nevocellular nevi *Tumors of Nerve Sheath Cells A. *Neurilemmoma (Schwannoma, Neurinoma) Neurilemmoma is a tumor composed of spindle-shaped cells considered to be Schwann cells. These are encapsulated, sometimes cystic, tumors. Dense cellular areas showing true palisades (Antoni A pattern) alternate with more loosely structured areas that may contain lipid (Antoni B pattern). Nerve fibers can usually be found stretched over the capsule but not within the tumor. In exceptional cases melanin pigmentation is found. B. *Anaplastic Neurilemmoma (Schwannoma, Neurinoma) A rare malignant counterpart of the neurilemmoma, anaplastic neurilemmoma is characterized by loss of the usual architecture and by excessive numbers of mitotic figures. C. *Neurofibroma Neurofibroma is a localized or diffuse tumor consisting of a mixture of Schwann cells and fibroblasts with loosely arranged collagen fibers and mucoid material, forming an intersecting pattern of wavy fascicles in which neurites may be demonstrable. Antoni A and B patterns may rarely be seen. These tumors usually occur as a component of von Recklinghausen s disease. D. *Anaplastic Neurofibroma (Neurofibrosarcoma, Neurogenic Sarcoma) Anaplastic neurofibroma is the malignant counterpart of the neurofibroma. Transformation of a neurofibroma into a sarcoma is a recognized complication of von Recklinghausen s disease. Classify according to local current standards. IV. Primary Malignant Lymphomas V. Tumors of Blood Vessel Origin A. *Hemangioblastoma Hemangioblastoma is a tumor composed of blood vessels that are separated by stromal cells with clear cytoplasm. The stromal cells often contain sudanophilic material. In spite of its name, this tumor is a well-differentiated growth that rarely, if ever, undergoes anaplasia. It most commonly occurs in the cerebellum but may be found in brain stem, spinal cord, or cerebrum. It may be part of Lindau s syndrome or of von Hippel-Lindau disease. B. *Hemangiopericytoma Hemangiopericytoma is a vascular tumor in which the endothelium of the capillary channels is separated by a basement membrane from masses of cells with oval nuclei, variable chromatin, and poorly defined cell boundaries. The center of the nucleus is pale in some cells. Pericellular and perivascular reticulin is abundant. Mitoses are frequent. These tumors may or may not be attached to dura. They tend to be aggressive in their growth; they may recur or invade adjacent tissues.

13 No. 7 SEsSlONV Rorke et a/, 1881 C. Neoplastic Angioendotheliosis-Angiosarcoma A rare neoplasm composed of vasculature of which the endothelial cells show varying degrees of nuclear atypia and mitotic activity, the most anaplastic varieties may be so cellular that the vascular component is obscured. Tumors of this type occur in conjunction with similar involvement of skin and/or visceral structures and are considered part of widely disseminated neoplasia of endotheli~rn.~~~~~ VI. Germ Cell Tumors Germ cell tumors occur most often in.the pineal or other midline region And are most commonly found in infants and children. They tend to extend into neighboring structures or may seed along cerebrospinal fluid pathways. A. *Germinoma Germinoma is a tumor composed of large primitive, spheroidal cells indistinguishable from the testicular seminoma and oviuian dysgerminoma. These cells often contain one or two large eosinophilic nucleoli. Mitotic activity is variable. Lymphoid cells are a prominent feature in its stroma. Fibrous and granulomatous reactions, including multinucleated giant cells, may be found. B. *Embryonal Carcinoma Embryonal carcinoma is composed of cells of primitive epithelial appearance, often with clear cytoplasm growing in a variety of patterns: acinar, tubular, papillary, and solid. Alpha-fetoprotein is often demonstrable by immunohistochemistry; human chorionic gonadotrophin may be identified as C. *Choriocarcinoma Choriocarcinoma is a highly malignant tumor composed of elements identical with syncytiotrophoblast and cytotrophoblast. D. Endodermal Sinus Tumor The endodermal sinus tumor h& several patterns, the most common of which is characterized by a reticular arrangement of primitive epithelial cells, distinctive papillary structures resembling the endodermal sinuses of the rodent s placenta, and hyaline globules, both intracellular and e~tracellular. ~ These tumors are strongly positive for alpha-fetoprotein and may also contain human chorionic gonadotrophin. E. Teratomatous Tumors 1. Immature teratoma Immature teratoma is a malignant form of teratoma that contains immature structures resembling those of the embryo; mature elements are also present in most of the casess4 2. Mature teratoma Mature teratoma is a tumor composed exclusively of mature elements resembling tissues derived from two or more of the embryonic germ 1aye1-s. ~ 3. Teratocarcinoma Teratocarcinoma is basically a mature teratoma in which one or more epithelial components may exhibit anaplasia. F. Mixed Germ Cell Tumors Most germ cell tumors occur in pure form; however, each may also be mixed with one or more other typess4 VII. Malformative Tumors A. *Craniopharyngioma Craniopharyngioma is a tumor considered by some to originate from vestigial remnants of the craniopharyngeal duct (Rathke s pouch). Two histologic features are recognized. stratified squamous epithelium, frequently lining a cyst; and ameloblastomatous (adamantinomatous) tissue forming more solid areas. Calcification, ossification, and inflammatory reaction are common. Astrogliosis and Rosenthal fibers in the vicinity of the tumor are Frequent. These tumors typically occur in the suprasellar or intrasellar regions and grow into the hypothalamus or third ventricle.

14 1882 CANCER October I Supplement 1985 Vol. 56 B. *Rathke s Cleft Cyst Rathke s cleft cyst lesions usually arise within the sella and are lined by cuboidal, often ciliated, epithelium identical with the lining of small cysts frequently found between the pars anterior and the infundibular process. C. *Epidermoid Cyst An epidermoid cyst is lined by keratin-producing squamous epithelium. The contents are brittle, white, and pearly, and the cysts are referred to as pearly tumors or cholesteatomas. The cysts occur in several particular locations of the cranial cavity, including the dipla& The cerebellopontine angle is a frequent site. Malignant transformation is rare. D. *Demoid Cyst A dermoid cyst is lined by keratin-producing squamous epithelium and contains skin appendages. It frequently occurs in a median location and may communicate with the skin via a sinus tract. The contents are smeary or cheesy and may include hair and rarely teeth. E. *Colloid Cysts of the Third Ventricle (Paraphyseal Cyst, Neuroepithelial Cyst) Colloid cysts of the third ventricle occur in the region of the foramen of Monro, near the choroid plexus, and are lined by ciliated columnar or cuboidal epithelium that may become flattened under pressure. F. *Enterogenous and Respiratory Cysts Enterogenous and respiratory cysts are lined by mucin-secreting (enterogenous) or ciliated respiratory epithelium. G. *Other cysts Other cysts include arachnoid cysts, ependymal-lined cysts, and neuroglial-lined cysts. Cysts in the pineal gland are usually neuroglial-lined. H. *Lipoma Lipoma is a localized mass of adipose tissue found over the corpus callosum and in the cauda equina, spinal canal, quadrigeminal plate, and hypothalamus. Masses of adipose tissue are frequently associated with spinal dysraphic states. I. *Granular Cell Tumor (Choristoma) Granular cell tumor is a mass of cells with eosinophilic granular cytoplasm found in the pars nervosa of the pituitary gland. J. Hamartoma 1. Neuronal Neuronal hamartoma is a collection of mature neurons arranged in a disorganized manner. Although most common in or near the hypothalamus, it can occur elsewhere. 2. Glial Glial hamartoma is a malformation composed of disorganized glial elements most common in the ventral subarachnoid space at the level of the infundibulum and optic tract. These have thickwalled blood vessels. 3. Neuronoglial Neuronoglial hamartoma is a malformation composed of disorganized neuronal and glial elements. 4. Meningioangioneurinomatosis A local proliferation of arachnoidal cells, blood vessels, and Schwann cells often associated with other features of neuroectodermal dysplasia, meningioangioneurinomatosis may occur at any level and may present as a mass lesion before the first year of life.5 VIII. Tumors of Neuroendocrine Origin A. Pituitary Tumors 1. Pituitary adenoma Adenomas of the anterior pituitary have been classically diagnosed by light microscopy with the use of routine stains as well as special histochemical techniques for demonstration of granules in the alpha and beta cells. It is now recognized that immunohistochemical techniques are required

15 No. 7 SESSION V - Rorke et al for an accurate classification of these tumors for identification of hormones produced by the tumor cells. See Kovacs et al. for further 2. Pituitary carcinoma An adenocarcinoma may arise in the anterior lobe of the pituitary: rarely there may be anaplasia and obvious mitotic activity (although mitoses may be seen in adenomas), but diagnosis is usually based upon clinical behavior. B. Paraganglioma Although paraganglioma usually extends into the intracranial cavity from a contiguous site, there are reports of this type of tumor arising in the pineal, pituitary, or cauda equina region.5s These display features similar to those described for those that arise more typically in the head and neck.59 Large neurons may also be present. IX. Local Extensions from Regional Tumors The type should be specified according to primary diagnosis. X. Metastatic Tumors XI. Unclassified Tumors A small percentage of tumors, when examined by standard light microscopic techniques, cannot be placed in one of the above categories. Immunocytochemical methods and electron microscopy assist in defining the nature of some tumors, but a fraction may remain nameless even after all avenues of investigation have been exhausted. Under these circumstances, it seems prudent to provide a descriptive diagnosis rather than to create a novel name. Classification of Brain Tumors in Children I. Tumors of neuroepithelial tissue A. Glial tumors 1. Astrocytic tumors a. Astrocytoma (fibrillary, protoplasmic, gemistocytic, pilocytic and xanthomatous) b. Anaplastic astrocytoma c. Subependymal giant cell tumors (tuberous sclerosis) d. Gigantocellular glioma 2. Oligodendroglial tumors a. Oligodendroglioma b. Anaplastic oligodendroglioma 3. Ependymal tumors a. Ependymoma b. Anaplastic ependymoma c. Myxopapillary ependymoma 4. Choroid plexus tumors a. Choroid plexus papilloma b. Anaplastic choroid plexus tumor (carcinoma) 5. Mixed gliomas a. Oligoastrocytoma 1. Anaplastic oligoastrocytoma b. Astroependymoma I. Anaplastic ependymoastrocytoma c. Oligoastroependymoma 1. Anaplastic oligoastroependymoma d. Oligoependymoma I. Anaplastic oligoependymoma e. Subependymoma-subependymal glomerate astrocytoma f. Gliofibroma

16 1884 CANCER October I Supplement 1985 Vol Glioblastomatous tumors a. Glioblastoma multiforme b. Giant cell glioblastoma c. Gliosarcoma 7. Gliomatosis cerebri B. Neuronal tumors 1. Gangliocytoma 2. Anaplastic gangliocytoma 3. Ganglioglioma 4. Anaplastic ganglioglioma C. Primitive Neuroepithelial tumors 1. Primitive neuroectodermal tumor, not otherwise specified (NOS) 2. Primitive Neuroectodermal tumor, with a. Astrocytes b. Oligodendrocytes c. Ependymal cells d. Neuronal cells e. Other (melanocytic, mesenchymal) f. Mixed cellular elements 3. Medulloepithelioma a. Medulloepithelioma, NOS b. Medulloepithelioma with: 1. Astrocytes 2. Oligodendrocytes 3. Ependymal cells 4. Neuronal cells 5. Other (melanocytic, mesenchymal) 6. Mixed cellular elements D. Pineal cell tumors I. Primitive neuroectodermal tumor (See C above) (pineoblastoma) 2. Pineocytoma 11. Tumors of meningeal and related tissues A. Meningiomas I. Meningioma, NOS 2. Papilhry meningioma 3. Anaplastic meningioma B. Meningeal sarcomatous tumors I. Meningeal sarcoma, NOS 2. Rhabdomyosarcoma or leiomyosarcoma 3. Mesenchymal chondrosarcoma 4. Fibrosarcoma 5. Others C. Primary melanocytic tumors 1. Malignant melanoma 2. Melanomatosis 3. Melanacytic tumors, miscellaneous 111. Tumors of nerve sheath cells A. Neunlemmoma (schwannoma, neunnoma) B. Anaplastic neunlemmoma (schwannoma, neunnoma) C. Neurofibroma D. Anaplastic neurofibroma (neurofibrosarcoma, neurogenic sarcoma) 1V. Primary malignant lymphomas Classify according to local current standards V. Tumors of blood vessel origin A. Hemangioblastoma B. Hemangiopencytoma C. Neoplastic Angioendotheliosis-angiowcoma

17 No. 7 SESSION V Rorke et al VI. Germ cell tumors A. Germinoma B. Embryonal carcinoma C. Choriocarcinoma D. Endodermal sinus tumor E. Teratomatous tumors 1. Immature teratoma 2. Mature teratoma 3. Teratocarcinoma F. Mixed VII. Malformative tumors A. B. C. D. E. F. G. H. 1. J. VIII. Craniopharyngioma Rathke s clef? cyst Epidermal cyst Dermoid cyst Colloid cyst of third ventricle Enterogenous or bronchial cyst Cyst, NOS Lipoma Granular cell tumor (choristoma) Hamartoma I. Neuronal 2. Glial 3. Neuronoglial 4. Meningioangioneurinomatosis Tumors of neuroendocrine origin A. Tumors of anterior pituitary 1. Adenoma 2. Pituitary carcinoma B. Paraganglioma IX. Local extensions from regional tumors Type to be specified according to primary diagnosis X. Metastatic tumors XI. Unclassified tumors REFERENCES 1. Ziilch KG. Histological typing of tumors of the central nervous system. Geneva: World Health Organization, Kepes JJ. Xanthomatous lesions of the central nervous system: Definition, classification and some recent observations. In Zimmerman HW, ed. Progress in neuropathology, vol. 4. New Yo& Raven Press, 1979; Bender BL, Yunis EJ. Central nervous system pathology of tuberous sclerosis in children. Ultrasfruci Pathol 1980; 1: Nakamura Y, Becker LE. Subependymal giant cell tumor: Astrocytic or neuronal? Acla Neuropalhol (Berl) 1983: 60: Bonnin JM, Rubinstein U, Papasozomenos SCh, Marangos PJ. Subependymal giant cell astrocytoma: Significance and possible cytogenetic implications of an immunohistochemical study. Acta Neuropaihol (Berl) 1984; 62: Bonnin JM, Rubinstein U. Immunohistochemistry of central nervous system tumors. J Neurosurg 1984; 60: Poon TP, Hirano A, Zimmennan H. Electron microscopic atlas of brain tumors. New York Grune & Stratton, 197 I. 8. Kawano N, Yada K, Aikara M, Yagishita S. Oligodendrogliomalike cells (clear cells) in ependymoma. Acfa Neuropafhol (Berl) 1983; 62: Rea GL, Akenon RD, Rockswald GL, Smith SA. Subependymoma in a 2% year old boy. J Neurosurg 1983; 59: Scheithauer BW. Symptomatic subependymoma: Report of 21 cases with review of the literature. J Neurosurg 1978: 49: Moss TH. Observations on the nature of subependymoma: an electron microscopic study. Neuropathol Appl Neurobiol 1984; Friede RL. Gliofibromz A peculiar neoplasia of collagen forming glia-like cells. J Neuroputhol Exp Neurol : Iglasias JR. Richardson EP Jr, Callia F, Santac A, Garcia MC, Redondo C. Prenatal intramdullary gliofibroma. Acfa Neuroputhol (Berl) 1984; Lhermitte J, Duclos. Sur un ganglioneurome diffuse du cortex du cervelet. Bull Assoc Fr Etude Cancer 1920; 9: Roessman U, Wongmongkont T. Dysplastic gangliocytoma of cerebellum in a newborn. J Neurosurg 1984; Ambler M, Pogacar S, Sidman R. Lhermitte-Duclos disease (Granule cell hypertrophy of the cerebellum): Pathological analysis of the first familial cases. J Neuropathol Exp Neurol 1969; 28: Bailey P, Cushing H. Medulloblastoma cerebellk A common type of midcerebellar glioma of childhood. Arch Neurol Psychialry 1925: Rubinstein U. The cerebellar medulloblastoma: Its origin, differentiation, morphological variants, and biological behavior. In Vincken PJ, Bruyn GW, eds. Tumors of the Brain and Skull, Part 111. New York: Elsevier, 1975; 9: Rubinstein LW. Cytogenesis and differentiation of primitive central neuroepithelial tumors. J Neuropathol Exp Neurol 1972; 31: Rorke, LB. The cerebellar medulloblastoma and its relationship

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