Review Articles
Surgical Neuropathology Update A Review of Changes Introduced by the WHO Classification of Tumours of the Central Nervous System, 4th Edition Daniel J. Brat, MD, PhD; Joseph E. Parisi, MD; Bette K. Kleinschmidt-DeMasters, MD; Anthony T. Yachnis, MD; Thomas J. Montine, MD, PhD; Philip J. Boyer, MD, PhD; Suzanne Z. Powell, MD; Richard A. Prayson, MD; Roger E. McLendon, MD; for the Neuropathology Committee, College of American Pathologists
● Context.—The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. Objective.—To summarize and discuss the most signifi-
cant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. Data Sources.—The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. Conclusions.—The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists. (Arch Pathol Lab Med. 2008;132:993–1007)
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tumor types and a more current understanding of neoplastic behavior.3
he World Health Organization (WHO) classification of central nervous system (CNS) tumors has entered its 4th edition with the recent publication of the WHO Classification of Tumours of the Central Nervous System. 1,2 Like its predecessors, the newly revised version has been much anticipated, in large part because this particular classification system maintains a high level of international acceptance and consistency with its continuous periodic updates. Its concise, thorough style is highly popular among pathologists, clinicians, and trainees. The 4th edition has introduced a substantial number of changes to the previous edition that reflect both the recognition of new brain Accepted for publication February 8, 2008. From the Departments of Pathology and Laboratory Medicine, Emory University, Atlanta, Ga (Dr Brat); the Mayo Clinic, Rochester, Minn (Dr Parisi); the University of Colorado at Denver and Health Sciences Center, Denver (Drs Kleinschmidt-DeMasters and Boyer); the University of Florida, Gainesville (Dr Yachnis); the University of Washington, Seattle (Dr Montine); Methodist Hospital, Houston Tex (Dr Powell); the Cleveland Clinic, Cleveland, Ohio (Dr Prayson); and Duke University, Durham, NC (Dr McLendon). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Daniel J. Brat, MD, PhD, Department of Pathology and Laboratory Medicine, Emory University Hospital, G-169, 1364 Clifton Rd NE, Atlanta, GA 30322 (e-mail:
[email protected]). Arch Pathol Lab Med—Vol 132, June 2008
For editorial comment, see p 906. The editors have been receptive to suggestions to clarify the grading system employed by WHO by adding a new introductory chapter titled, ‘‘WHO Grading of Tumours of the Nervous System.’’ It explains that the histologic grade, as used by WHO, is meant to communicate a ‘‘stage of malignancy’’ that will predict biologic behavior. Thus, by WHO criteria, grade I CNS tumors are generally well circumscribed, slowly progressing, and can often be cured by resection; grade II lesions are typically infiltrative with low proliferation, but have a higher likelihood of recurrence; grade III tumors are histologically malignant and generally require more aggressive adjuvant therapy; and grade IV tumors are highly malignant and can be rapidly fatal. The 4th edition of WHO has introduced 7 changes in the grading of CNS neoplasms from the 3rd edition, some of which are minor and some of which have substantial implications (Table 1). The 4th edition is also deliberate in its attempt to distinguish individual types of brain tumors as entities, variWHO CNS Tumor Classification—Brat et al 993
Table 1.
Significant Changes in the World Health Organization (WHO) 2007 Brain Tumor Classification*
Grading Changes Anaplastic oligoastrocytomas with necrosis: now designated glioblastoma with oligodendroglial component, WHO grade IV. Brain invasion by a meningioma: now an independent criterion for WHO grade II. Atypical choroid plexus papilloma: criteria defined with designation of WHO grade II. Pineocytoma: now classified as WHO grade I; pineal parenchymal tumor of intermediate differentiation: now WHO grade II or III; pineoblastoma remains WHO grade IV. ● Gangliogliomas: classified as WHO grade I or III; grade II designation has been eliminated. ● Cerebellar liponeurocytoma: now designated WHO grade II tumor. ● Anaplastic hemangiopericytoma, WHO grade III: criteria established for distinguishing from hemangiopericytoma, WHO grade II. ● ● ● ●
● ● ● ● ● ● ● ● ● ● ●
New Entities, Variants, Patterns of Differentiation, and Syndromes Angiocentric glioma, WHO grade I Pituicytoma, WHO grade I Spindle cell oncocytoma of the adenohypophysis, WHO grade I Papillary glioneuronal tumor, WHO grade I Rosette-forming glioneuronal tumor of the fourth ventricle, WHO grade I Pilomyxoid astrocytoma, WHO grade II Extraventricular neurocytoma, WHO grade II Papillary tumor of the pineal region, WHO grades II–III Glioneuronal tumor with neuropil-like islands, WHO grades II–III Small cell glioblastoma, WHO grade IV Rhabdoid tumor predisposition syndrome
Other Classification Changes ● Medulloblastoma: variants include large cell, anaplastic, extensive nodularity, and desmoplastic/nodular; myogenic differentiation (previously medullomyoblastoma) and melanotic differentiation (previously melanotic medulloblastoma) are now considered morphologic patterns. ● CNS PNETs: reorganized to include CNS/supratentorial PNET (including neuroblastomas and ganglioneuroblastomas), medulloepithelioma, and ependymoblastoma. ● Giant cell glioblastoma and gliosarcoma: now classified variants of glioblastoma. ● Hemangioblastoma: now has its own chapter as an entity, apart from von Hippel-Lindau disease. ● Olfactory neuroblastoma and peripheral neuroblastomas: no longer included in the CNS classification. * CNS indicates central nervous system; PNET, primitive neuroectodermal tumor.
ants, or patterns of differentiation, and some of the reorganization of this edition reflects this attempt. An entity represents a unique clinicopathologic form of neoplastic disease and is given its own chapter. Variants of a brain tumor represent an important subtype of an entity with different biologic properties or clinical behavior and are given a major subsection within a chapter. Patterns of differentiation of a tumor represent a particular cellular morphology that may or may not correspond with distinct clinical behavior. There have been 10 new entities, variants, and tissue patterns, as well as 1 new genetic syndrome, added to the 4th edition (Table 1). In addition, there has been substantial reorganization of some established brain tumor types in an attempt to contemporize the classification. A recent review and mini-symposium have introduced these changes to the neuropathology community.2,4–7 The purpose of the current review is to summarize and discuss the most important updates in the 4th edition for the general practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns of differentiation, and syndromes; and (3) changes in the classification of existing brain tumors. GRADING CHANGES OF ESTABLISHED ENTITIES Anaplastic Oligoastrocytoma/Glioblastoma With Oligodendroglioma Component, WHO Grade IV The infiltrating gliomas consist of astrocytomas, oligodendendrogliomas, and oligoastrocytomas, with each category having its own grading system in the WHO classification. The grading schemes for the histologically ‘‘pure’’ astrocytomas and oligodendrogliomas in the 4th edition 994 Arch Pathol Lab Med—Vol 132, June 2008
remain largely the same as in the 3rd edition. Of note, there have been some fairly substantial changes incorporated into the grading of oligoastrocytomas that will affect both grade and classification. As in the past, oligoastrocytomas are designated as tumors that contain distinct regions of oligodendroglial and astrocytic differentiation. The minimal percentage of each component required for the diagnosis of a mixed glioma has been debated.8 In the prior WHO edition, the criteria for anaplastic oligoastrocytoma (WHO grade III) included ‘‘features of anaplasia,’’ which were listed as nuclear atypia, cellular pleomorphism, high cellular density, high mitotic activity, microvascular proliferation and necrosis.3 These features could be present in the astrocytic component, the oligodendroglial component, or both. The results of recent clinicopathologic investigations have suggested that this grading scheme could be improved by dividing anaplastic oligoastrocytomas into prognostically distinct groups based on the presence of necrosis.9–11 Miller et al10 studied the overall survival of 215 patients with anaplastic oligoastrocytoma as it related to age, sex, type of surgical procedure, necrosis, and endothelial hyperplasia. Necrosis was present in 33% of these tumors, and endothelial proliferation was noted in 66%. Median survival was significantly shorter in patients with anaplastic oligoastrocytomas with necrosis (22.8 months; 95% confidence interval, 14.9–33 months) than with anaplastic oligoastrocytomas that lacked necrosis (86.9 months; 95% confidence interval, 48.4–129 months). In contrast, the presence of endothelial proliferation was not found to be prognostically important among anaplastic mixed tumors. Thus, these data indicated that patients WHO CNS Tumor Classification—Brat et al
with anaplastic oligoastrocytomas with necrosis had shorter survival and that these tumors should be considered grade IV tumors rather than grade III. It can be debated whether anaplastic oligoastrocytomas with necrosis should be considered ‘‘oligoastrocytoma, grade IV’’ or should be classified as ‘‘glioblastoma with an oligodendroglial component, grade IV.’’ In the 4th edition, the WHO classification indicates that oligoastrocytomas with necrosis should be classified as glioblastoma with oligodendroglioma component, WHO grade IV. This topic is discussed in chapters on both anaplastic oligoastrocytoma and glioblastoma. In the latter, glioblastoma with oligodendroglioma component is described as a pattern of differentiation in glioblastoma.1 It is critical to highlight that although the above noted grading change applies to anaplastic oligoastrocytomas with necrosis, there is not a comparable change in grade when necrosis is present in an anaplastic oligodendroglioma. Necrosis in an anaplastic oligodendroglioma was not associated with a shorter survival, and the grade of such neoplasms remains WHO grade III.1,10 Meningioma With Brain Invasion, WHO Grade II WHO grading schemes for meningiomas have traditionally designated tumors as ‘‘meningioma, WHO grade I,’’ ‘‘atypical meningioma, WHO grade II,’’ or ‘‘anaplastic (malignant) meningioma, WHO grade III,’’ depending upon the presence of histopathologic features that indicate increasingly aggressive behavior. In the 3rd edition, the criteria for atypical meningioma, WHO grade II included a mitotic index of 4 or more per 10 high-power fields (HPFs) or more than 3 of the following features: increased cell density, small cells with a high nuclear-cytoplasmic ratio, prominent nucleoli, sheetlike growth pattern, and geographic necrosis.3 In that edition, the presence of brain invasion was listed as a feature that indicated an increased likelihood of recurrence and/or aggressive behavior, but was not formally included as a criterion for grade II or grade III (Figure 1). Prior to 1997, most grading systems for meningioma considered brain invasion the best evidence of ‘‘malignancy.’’ Perry et al12,13 studied the prognostic significance of brain invasion in a large series of patients who had been diagnosed previously with ‘‘malignant meningioma’’ due to the presence of brain invasion, histologic anaplasia, or metastasis. On the basis of a multivariate analysis of histopathologic features and their relationship to tumor recurrence and patient survival, the authors concluded that brain invasion indicated a greater likelihood of recurrence and should be considered one of the diagnostic features of grade II meningioma. Brain invasiveness was not associated with the same increased mortality rate as grade III meningiomas with anaplastic features. This study suggested that the diagnosis of grade III, malignant meningioma should be reserved for those tumors that were frankly anaplastic (ie, having carcinoma or sarcoma-like histology) and/or contain 20 or more mitoses per 10 HPFs.13 Due in large part to the strength of evidence in these studies, WHO has adopted a grading scheme for meningiomas that incorporates their findings, as brain invasion is now considered an independent diagnostic criterion for the designation of WHO grade II meningioma (Table 2). Arch Pathol Lab Med—Vol 132, June 2008
Choroid Plexus Neoplasms, WHO Grades I–III The 2000 edition classified choroid plexus papillomas as WHO grade I and choroid plexus carcinomas as WHO grade III. These diagnostic entities are at opposite ends of the choroid plexus neoplastic spectrum, with papillomas being benign tumors that can be cured by resection and carcinomas being malignant neoplasms that behave aggressively and require adjuvant therapy. The previous edition recognized that there was a subset of papillomas with worrisome histologic features and designated them ‘‘atypical choroid plexus papilloma,’’ but there was not a designated grade or clinical correlation, and criteria for this designation were not well developed. A recent clinicopathologic study of a large number of nonmalignant choroid plexus neoplasms investigated the histologic features of these neoplasms as they related to tumor recurrence, including mitoses, increased cellularity, nuclear pleomorphism, solid growth, and necrosis.14 On multivariate analysis, the presence of 2 or more mitoses per 10 HPFs was found to be the sole diagnostic criterion that was significantly predictive of tumor recurrence. There was a trend toward an increased risk of recurrence if any of these atypical histologic features were present. The WHO classification now includes ‘‘atypical choroid plexus papilloma, WHO grade II’’ as a diagnostic category and indicates that the presence of mitotic activity (ⱖ2 mitoses per 10 HPFs) should be used to establish this diagnosis in a lowgrade papillary neoplasm (Figure 2). It also indicates that other atypical features may be present, but not required, for the diagnosis. Pineal Parenchymal Tumors, WHO Grades I–IV In the previous edition of the WHO classification, the section on pineal parenchymal tumors included ‘‘pineocytoma, WHO grade II’’ and ‘‘pineoblastoma, WHO grade IV.’’ The previous edition did not include a grade I designation for a pineal parenchymal tumor. There was a separate chapter on ‘‘pineal parenchymal tumor of intermediate differentiation,’’ which described a tumor that fell in between the grade II and grade IV tumors in its degree of differentiation and displayed moderate to high cellularity, mild nuclear atypia, and occasional mitoses. The criteria for this set of tumors were not detailed, there was no grade designated, and there was no indication of the prognostic significance associated with this tumor classification. In the current edition, 2 major changes have been introduced. First, the histologically bland ‘‘pineocytoma,’’ which is composed of mature neoplastic pineocytes, is now considered to be a WHO grade I neoplasm. Second, a much more complete description of pineal parenchymal tumor of intermediate differentiation has been given that is based on careful clinicopathologic investigation of a large series of these uncommon tumors.15,16 Such intermediate differentiation neoplasms account for at least 20% of pineal parenchymal tumors. They contain sheets or large lobules of uniform cells with moderate nuclear atypia and low to moderate mitotic activity. There may be transitions from rosette-bearing areas (more typical of pineocytoma) to diffuse, sheetlike growth. The vast majority contain 2 or fewer mitoses per 10 HPFs, and MIB-1 proliferation indices range from 3% to 10%. The 5-year survival of pineal parenchymal tumor of intermediate differentiation is 39% to 74%. Some investigations have indicated that these intermediate differentiation tumors fall into WHO CNS Tumor Classification—Brat et al 995
Figure 1. Meningioma with brain invasion. A, Brain invasion by meningioma is noted as large tongues of tumor infiltrating into the superficial brain parenchyma (hematoxylin-eosin, original magnification ⫻200). B, Immunohistochemistry for glial fibrillary acidic protein highlights the brain parenchyma entrapped by the tongues of invading meningioma (original magnification ⫻100). Brain invasion is a diagnostic feature of World Health Organization grade II meningioma in the 4th edition. Figures provided by Dr Arie Perry. Figure 2. Atypical choroid plexus tumor. Atypical choroid plexus tumors are World Health Organization grade II tumors and display 2 or more mitoses per 10 high-power fields. A sheetlike growth pattern (A) (hematoxylin-eosin, original magnification ⫻200) and nuclear atypia (B) (hematoxylin-eosin, original magnification ⫻600) are commonly noted but not necessary for the diagnosis.
2 prognostic groups, and short survival is associated with tumors displaying a high mitotic index (⬎6 per HPF), mitoses, necrosis, and a lack of neurofilament protein staining.15,16 The current WHO classification has designated these tumors as WHO grade II or III but has not provided strict criteria to distinguish between the 2 grades. Ganglioglioma, WHO Grade I or III Ganglioglioma grading has been slightly altered in the 4th edition. In the previous edition, gangliogliomas were classified as either WHO grade I or II, and anaplastic gangliogliomas were considered WHO grade III.3 In the current classification, the WHO grade II has been eliminated. Thus, gangliogliomas are now designated WHO grade I, and anaplastic gangliogliomas remain grade III.1 Grading of gangliogliomas has typically has been assigned based 996 Arch Pathol Lab Med—Vol 132, June 2008
on characteristics of the glial component of the neoplasm. However, the standard criteria that have been used for grading of astrocytomas (eg, mitotic activity, microvascular proliferation, and necrosis) appear to less reliably predict the clinical behavior of gangliogliomas.17 Although the 3rd edition allowed for the grading of gangliogliomas as grade I, II, or III, specific criteria to distinguish among the grades were not provided. One of the largest and most comprehensive investigations of supratentorial gangliogliomas suggested that grade II tumors contain cellular atypia (increased cellularity, conspicuous pleomorphism), microvascular proliferation, or an elevated MIB-1 labeling index (ⱖ5%). Grade III neoplasms in this investigation included the additional findings of necrosis and an MIB-1 proliferation index of 10% or more.17 Although the numbers of patients in the grade II and grade III groups were WHO CNS Tumor Classification—Brat et al
World Health Organization (WHO) Grading of Meningiomas
the cerebellar liponeurocytoma is now considered a grade II tumor.
WHO Grade I Benign meningioma Histologic variant other than clear cell, chordoid, papillary, and rhabdoid Lacks criteria of grades II and III meningiomas
Hemangiopericytoma, WHO Grade II and Anaplastic Hemangiopericytoma, WHO Grade III Hemangiopericytomas (HPCs) of the CNS are most frequently associated with cranial or spinal dura. These dura-based HPCs are now clearly recognized as a distinct entity, separate from meningioma.1 This distinction is critical, since HPCs are biologically aggressive, with high rates of recurrence (⬎60%) and metastasis (23%–64%).20,21 More recent studies have shown improved patient outcomes, most likely due to the increased recognition of this entity and advances in radiotherapy.22 Central nervous system HPCs can have considerable histologic and immunohistochemical overlap with dura-based solitary fibrous tumors (SFTs).23,24 Indeed, in the soft tissue literature, there has been a trend toward merging HPCs into the SFT category.25 In the CNS, however, those dural tumors that have been classified as SFTs generally have an indolent clinical behavior and a potential for surgical cure, whereas CNS HPCs are more malignant by comparison.20,24 In the WHO 3rd edition, hemangiopericytoma was listed as either a WHO grade II or III neoplasm, but criteria to distinguish between the grades were not provided. The 4th edition has introduced criteria for the diagnosis of anaplastic hemangiopericytoma, WHO grade III, which include a high mitotic activity (ⱖ5 per 10 HPFs) and/or necrosis, and 2 or more of the following features: hemorrhage, moderate to high nuclear atypia, and high cellularity.1,20 Prior studies have demonstrated that dura-based HPCs with these ‘‘anaplastic’’ features recurred earlier and more frequently than those that did not and also had higher rates of metastasis. The investigations that support these criteria for grading HPCs were performed in 1991, well before the publication of the 3rd edition, yet they were not incorporated into the WHO grading of HPCs in the 3rd edition.20 Thus, unlike other grading changes introduced into the 4th edition, which were based on new
Table 2.
WHO Grade II Atypical meningioma Mitotic index ⱖ4 per 10 high-power fields or At least 3 of 5 parameters: Sheeting architecture (loss of whorling and/or fascicles) Small cell formation (high N/C ratio) Macronucleoli Hypercellularity Spontaneous necrosis (i.e., not induced by embolization or radiation) or Brain invasion or Clear cell meningioma or Chordoid meningioma WHO Grade III Anaplastic (malignant) meningioma Mitotic index ⱖ20 per 10 high-power fields or Frank anaplasia (sarcoma, carcinoma, or melanoma-like histology) or Papillary meningioma or Rhabdoid meningioma * N/C indicates nuclear/cytoplasmic.
relatively small, this investigation demonstrated that the histologic grade was significantly associated with the recurrence-free survival rate. The data in this study are compelling, yet the conclusions will need to be independently validated. Presently, the WHO classification has excluded grade II as a designation for gangliogliomas. In the 4th edition, gangliogliomas are designated WHO grade I, and anaplastic gangliogliomas are designated WHO grade III. Cerebellar Liponeurocytoma, WHO Grade II The cerebellar liponeurocytoma is a rare, well-differentiated neurocytic tumor of the cerebellum that arises in adults and typically shows focal or regional lipomatous differentiation (Figure 3). This tumor type has low proliferative potential and a favorable outcome, especially when compared to medulloblastoma, the primitive neuroectodermal tumor of the cerebellum from which the liponeurocytoma needs to be distinguished. The cerebellar liponeurocytoma was included in the 3rd edition as a WHO grade I neoplasm. With increasing recognition of this entity and longer clinical follow-up periods in its investigation, it has become clear that these tumors have a rate of recurrence that is higher than previously thought and not compatible with a grade I designation. A review of the literature has indicated that as many as 60% of these tumors will recur within periods ranging from 1 to 12 years.18,19 There are currently no accepted histologic features of liponeurocytoma that can be relied upon to distinguish tumors with a low versus high risk for recurrence. In light of the substantial rate of tumor recurrences, Arch Pathol Lab Med—Vol 132, June 2008
Figure 3. Cerebellar liponeurocytoma, World Health Organization (WHO) grade II. These cerebellar tumors show sheetlike growth of well-differentiated neurocytic tumor cells and contain regions that demonstrate unambiguous lipomatous differentiation (hematoxylin-eosin, original magnification ⫻200). WHO has designated this tumor as grade II in the 4th edition. WHO CNS Tumor Classification—Brat et al 997
Figure 4. Angiocentric glioma. A, This rare tumor is composed of bipolar, spindled cells radiating toward a central vessel (hematoxylin-eosin, original magnification ⫻400). Neoplastic cells can also be noted within the central nervous system parenchyma between involved vessels, sometimes forming nodules. B, Immunohistochemistry for epithelial membrane antigen shows a dotlike pattern in perivascular cells, suggesting an ependymal derivation (original magnification ⫻600). Figure 5. Pituicytoma. A, Axial, postcontrast magnetic resonance image demonstrates a solid, circumscribed, and homogenously enhancing tumor in the suprasellar space. B, Pituicytomas are noted on hematoxylin-eosin sections as a compact, noninfiltrative proliferation of low-grade, bipolar spindle cells with pink cytoplasm arranged in interlacing fascicles (original magnification ⫻400). C, Pituicytomas are typically glial fibrillary acidic protein positive by immunohistochemistry (original magnification ⫻400).
data, the criteria for distinguishing grades II and III HPCs in the 4th edition were included by the authors and editors based on their judgment of the strength of previously existing studies. NEW CODIFIED ENTITIES, VARIANTS, PATTERNS, AND SYNDROMES Angiocentric Glioma, WHO Grade I Angiocentric glioma was only recently described, yet the unique clinical, radiologic, and pathologic features led to its acceptance as a new entity.26,27 This tumor occurs most frequently in children and young adults as a slowly growing, cerebral hemispheric mass. Nearly all patients have a longstanding history of epilepsy. Tumors occur in the frontal, temporal, or parietal lobes, and are usually centered in the cortex. On magnetic resonance imaging 998 Arch Pathol Lab Med—Vol 132, June 2008
(MRI), angiocentric gliomas are T2- or fluid-attenuated inversion recovery (FLAIR) hyperintense but generally lack contrast enhancement. The defining histologic feature of angiocentric glioma is the presence of monomorphous, bipolar tumor cells intimately associated with vessels of involved cortex and white matter (Figure 4). The elongate, slender cells are often oriented parallel to vessels, sometimes expanding perivascular spaces with streaming arrays of either single or multilayered cells. In some examples, tumor cells are radially oriented to vessels in a pattern highly reminiscent of ependymal pseudorosettes. A similar tendency to accumulate perpendicularly beneath the pia mater is seen in a small subset of tumors, giving them a palisading appearance. Cytologically, the tumor cells are uniform, spindle-shaped with oval or elongated nuclei and speckled WHO CNS Tumor Classification—Brat et al
chromatin as well as pink, tapering cytoplasm. Mitoses are generally absent, and the MIB-1 proliferation index ranges from 1% to 5%. Immunoreactivity is consistently strong for glial fibrillary acidic protein (GFAP), S100, vimentin, and a ‘‘dotlike’’ pattern for epithelial membrane antigen— a pattern typical of ependymoma (Figure 4). Ependymal differentiation has also been shown by ultrastructure, which demonstrates microlumen formation, microvilli, cilia, and complex, zipperlike intermediate junctions. The behavior of those tumors documented thus far suggests a stable clinical course and probable cure by surgical resection alone. The majority of patients undergoing subtotal resections have shown stable, residual tumor on MRI.26,27 Therefore, angiocentric glioma has been given a WHO grade I designation. Pituicytoma, WHO Grade I Pituicytomas are rare tumors that arise in the posterior pituitary or stalk and present as sellar or suprasellar masses in adults. In the past, the term pituicytoma has been applied to numerous nonrelated low-grade tumors that occur in the sellar/suprasellar region. Pituicytomas have only recently been described as a unique entity with specific histopathologic and immunohistochemical features, and on this basis have been added to the WHO classification.28 The signs and symptoms of pituicytomas include visual disturbances, hypopituitarism, and headache. On computed tomography scans or MR images, pituicytomas are solid and circumscribed and show homogenous contrast enhancement (Figure 5).28 Histologically, they are composed of bipolar spindle cells arranged in interlacing fascicles or storiform pattern. Their fusiform to plump cells possess moderate to abundant eosinophilic cytoplasm. Nuclei are moderate in size, are often oval or elongate, and show no significant atypia. Mitoses are rare to absent. Unlike pilocytic astrocytomas, pituicytomas lack Rosenthal fibers and eosinophilic granular bodies. Pituicytomas are distinguished from granular cell tumor tumors by the absence of cytoplasmic granularity attributable to lysosomes and from spindle cell oncocytoma by a lack of abundant mitochondria. Pituicytomas are believed to be derived from the pituicyte, the supporting glial cell of the posterior pituitary, in keeping with the localization of pituicytomas in the stalk and posterior lobe. As such, its cells are immunoreactive for vimentin, S100 protein, and GFAP.28,29 MIB-1 labeling indices are low, ranging from 0.5% to 2%.28,30 In most cases, these circumscribed tumors can be surgically resected. When tumors are strongly adherent to critical surrounding structures, only subtotal resection can be achieved. In these cases, slow regrowth is typical. These tumors have been designated WHO grade I. Spindle Cell Oncocytoma of the Adenohypophysis, WHO Grade I The spindle cell oncocytoma was first described as a unique neoplasm of the sella in 2002.31 This rare type of pituitary tumor occurs chiefly among adults and is noted on MRI as a solid, contrast-enhancing mass of the sellar and suprasellar spaces. Symptoms can include pituitary insufficiency, visual field defects, or headaches. The most distinguishing morphologic feature of this neoplasm is the presence of plump, eosinophilic spindled or epithelioid cells arranged in fascicles and demonstrating classic oncocytic features (Figure 6). With hematoxylin-eosin stains, Arch Pathol Lab Med—Vol 132, June 2008
the cytoplasm is granular and pink, whereas ultrastructural studies show abundant mitochondria. The tumor cells are cytologically low grade and generally lack any mitotic activity. By immunohistochemistry, the tumors show expression of S100, epithelial membrane antigen, and vimentin, with an MIB-1 proliferation index that averages 3%. These tumors are circumscribed, and a total surgical resection can usually be achieved. Although the number of reported cases is low, and long-term follow-up is not available, the current data suggest these tumors are benign in their clinical course. In the rare cases that have recurred, proliferative indices were elevated.32 Currently, spindle cell oncocytomas have been designated WHO grade I. Papillary Glioneuronal Tumor, WHO Grade I The papillary glioneuronal tumor was introduced to the literature in 1998 and recognized as a variant of ganglioglioma in the 2000 WHO edition.33–35 Increased recognition of its unique morphologic and clinical features has led to its classification as a new entity in the 4th edition. Papillary glioneuronal tumors arise predominantly in the cerebral hemispheres of adults, where they are seen on MRI as well-circumscribed, contrast-enhancing lesions with little mass effect or surrounding edema. Common clinical presentations include seizures, headaches, and other focal neurologic manifestations related to tumor location. The histopathologic and immunohistochemical features of these circumscribed, noninvasive tumors are distinctive (Figure 7). There is an obvious papillary or pseudopapillary architecture at low magnification, which on closer inspection is due to the collection of 2 distinct cell types surrounding a central fibrovascular core. The innermost layer of cells is composed of small, cuboidal cells with eosinophilic cytoplasm and round nuclei, whereas the outer layer in between the papillae contains larger clear cells with a neurocytic or ganglioid appearance. Immunohistochemistry highlights the biphasic nature of these papillary structures by demonstrating strong GFAP labeling of the inner layer and strong reactivity for neuronal markers (synaptophysin or NeuN) in the outer layer. Both the inner glial cells and the outer neuronal cells are cytologically low grade, and mitoses are either difficult to find or absent. The MIB-1 proliferation index is low (1%–2%). Although these are rare tumors, and clinical follow-up is limited, the current data on outcome are favorable, and these tumors have been designated WHO grade I. Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle, WHO Grade I The rosette-forming glioneuronal tumor of the fourth ventricle is a new entity that has only slowly emerged in the literature due to its prior classification with other lowgrade mixed glial and neuronal tumors.36,37 This rare tumor is found exclusively in the posterior fossa, where it arises in the midline, usually occupying a substantial fraction of the fourth ventricle, and it is noted by MRI as a circumscribed, solid mass with heterogeneous contrast enhancement (Figure 8). It occurs most often in adults who present with headache, ataxia, or hydrocephalus due to obstructed cerebrospinal fluid flow. On microscopic examination, tumors are biphasic, with clearly defined and spatially separate neurocytic and glial components. The neurocytic component contains a homogeneous population of small, clear cells that are arranged in either a roWHO CNS Tumor Classification—Brat et al 999
Figure 6. Spindle cell oncocytoma. A, Individual tumor cells are cytologically low grade and demonstrate classic oncocytic features, including abundant eosinophilic and granular cytoplasm (hematoxylin-eosin, original magnification ⫻400). By immunohistochemistry, tumor cells express S100 (B) (original magnification ⫻400) and epithelial membrane antigen (C) (original magnification ⫻400). D, Numerous mitochondria are noted within the cytoplasm on ultrastructural studies (electron microscopy, original magnification ⫻4000).
setted pattern with large central spaces or papillae around central vessels (Figure 8). A microcystic component with a blue mucinous extracellular matrix may be present as well. Delicate processes form a neuropil matrix adjacent to tumor cells and extending to central vessels. The glial component of this tumor is solid and composed of highly fibrillated cells that resemble those of pilocytic astrocytoma. Also like pilocytic astrocytoma, this glial component may have an oligodendroglioma-like tissue pattern, microcysts, Rosenthal fibers, and eosinophilic granular bodies. Both the neuronal and glial elements are histologically low grade, and these tumors do not generally display overt invasive properties. Mitoses are only rarely encountered, and the MIB-1 proliferation index ranges from 1% to 3%. The current experience with these tumors suggests they are clinically benign, with low rates of recurrence and little propensity for malignant transformation. They have been suggested to behave as WHO grade I neoplasms. Pilomyxoid Astrocytoma, WHO Grade II The pilomyxoid astrocytoma (PMA) is a tumor of early childhood or adolescence that was introduced into the lit1000 Arch Pathol Lab Med—Vol 132, June 2008
erature nearly 10 years ago.38 These tumors are now considered a variant of pilocytic astrocytoma, with characteristic clinical, neuroimaging, and pathologic features. Pilomyxoid astrocytomas most often arise in hypothalamic region, with symptoms referable to that site, including failure to thrive, developmental delay, vomiting, and feeding difficulties. In older children, headaches, nausea, and visual symptoms are more common.39 By MRI, these tumors are well-circumscribed, generally solid, and homogenously contrast-enhancing midline masses in the suprasellar and hypothalamic region (Figure 9). The histologic appearance of PMA is dominated by a hypercellular, monomorphous population of piloid cells that are typically embedded within a rich myxoid matrix and often display an angiocentric arrangement (Figure 9). The PMA has a compact architecture, with only a slight tendency for peripheral infiltration of adjacent brain. Individual tumor cells have elongate fibrillar processes, are moderate in size, and contain hyperchromatic nuclei with only modest nuclear pleomorphism. Mitotic figures can be noted but are not abundant. The diagnosis of PMA is WHO CNS Tumor Classification—Brat et al
Figure 7. Papillary glioneuronal tumor. A, Hematoxylin-eosin stains demonstrate a biphasic papillary tumor with an inner layer of cells having a flattened or cuboidal appearance and an outer layer between papillae composed of larger clear cells with bland nuclei (original magnification ⫻400). The inner layer stains intensely for glial fibrillary acidic protein by immunohistochemistry (B) (original magnification ⫻400), whereas the outer layer stains for synaptophysin (C) (original magnification ⫻400). Figure 8. Rosette-forming glioneuronal tumor of the fourth ventricle. A, Axial, postcontrast magnetic resonance image demonstrates a midline, heterogeneously contrast-enhancing mass occupying the fourth ventricle. B, The neurocytic component of this tumor shows a homogeneous population of small clear cells that are arranged in a rosetted pattern with large central spaces (hematoxylin-eosin, original magnification ⫻400). A smaller microcystic component with basophilic mucin is also present. C, Immunohistochemistry for synaptophysin highlights both the delicate neuropil within rosettes and the neurocytic tumor cells (original magnification ⫻600).
made only when this tissue pattern is predominant, since focal myxoid or angiocentric cell arrangement may be noted in typical pilocytic astrocytoma or infiltrating astrocytoma. Unlike ordinary pilocytic astrocytoma, PMAs typically lack a biphasic appearance, do not contain Rosenthal fibers, and only exceptionally contain eosinophilic granular bodies. Immunohistochemically, PMAs label strongly and diffusely for GFAP and vimentin but are typically negative for the neuronal markers neurofilament and chromogranArch Pathol Lab Med—Vol 132, June 2008
in. Synaptophysin immunoreactivity has been reported in a subset of PMAs, especially in a perivascular distribution.40 The MIB-1 labeling index is often around 5%. The relation of PMA to pilocytic astrocytoma is still debated. Reports of hybrid tumors that contain components of both conventional pilocytic astrocytoma and PMA suggest that the 2 tumors are related and belong in the same category. This concept is reflected in the new WHO classification, with PMA categorized as a variant of pilocytic astrocytoma. Pilomyxoid astrocytomas are associated with a more WHO CNS Tumor Classification—Brat et al 1001
Figure 9. Pilomyxoid astrocytoma. A, Coronal, postcontrast magnetic resonance image demonstrating a contrast-enhancing mass near the midline in the hypothalamic region, which is typical for pilomyxoid astrocytoma. B, These tumors are composed of bipolar, highly fibrillated tumor cells that have an angiocentric pattern and often display an abundance of clear or bluish, mucoid matrix in the background (hematoxylin-eosin, original magnification ⫻200). Figure 10. Extraventricular neurocytoma. A, Coronal, postcontrast magnetic resonance image reveals a solid and cystic, contrast-enhancing mass in the frontoparietal lobe with no connection to the ventricular system. B, Hematoxylin-eosin stains show a sheetlike growth of well-differentiated neurocytic tumor cells with monotonous nuclei and a neuropil matrix, similar or identical to central neurocytoma (original magnification ⫻400). C, Tumor cells stain strongly for synaptophysin by immunohistochemistry (original magnification ⫻400).
aggressive clinical course than typical pilocytic astrocytoma, resulting in a WHO grade II designation.39,41,42 Extraventricular Neurocytoma, WHO Grade II The central neurocytoma is a well-defined clinicopathologic entity that has been recognized previously in WHO classifications.3 These tumors occur primarily in young adults and have a stereotypic location within the lateral ventricles in the region of the foramen of Monro. They have a consistent pattern of neuronal differentiation and usually carry a favorable clinical prognosis.43 Occasionally, 1002 Arch Pathol Lab Med—Vol 132, June 2008
tumors with histopathologic features similar or identical to those of the central neurocytoma arise outside the ventricles, usually within the cerebral hemispheres but also in other regions throughout the neuraxis (Figure 10).44–51 These tumors clearly fall outside the classic definition of central neurocytoma and have been referred to as extraventricular neurocytoma (EVN).44 Extraventricular neurocytomas have been included in the 4th edition as a variant of central neurocytoma.1 These tumors occur most commonly in the cerebral hemispheres of adults, where they are noted on MRI as solitary, circumscribed, someWHO CNS Tumor Classification—Brat et al
Figure 11. Papillary tumor of the pineal region. A, Axial postcontrast magnetic resonance image demonstrates a circumscribed, contrast-enhancing mass centered in the pineal gland and associated with hydrocephalus. B, Microscopically, these tumors show a papillary architecture, with elongate columnar cells containing abundant eosinophilic or clear cytoplasm extending to central fibrovascular cores (hematoxylin-eosin, original magnification ⫻400). C, Tumor cells are strongly immunoreactive for cytokeratin (AE1/3, original magnification ⫻400). Figure 12. Glioneuronal tumor with neuropil-like islands. A, Well-differentiated neurocytic tumor cells with clear cytoplasm and round nuclei form a rim around a neuropil-like island that is largely devoid of cells (hematoxylin-eosin, original magnification ⫻400). B, The central neuropil of the central island as well as the rosette-forming neuronal tumor cells stain positive for synaptophysin by immunohistochemistry (original magnification ⫻400).
times cystic, and variably contrast enhancing. Like their central counterparts, neurocytic tumor cells are arranged in sheets, clusters, ribbons, or rosettes, and in association with fine neuropil dispersed in broad zones that separate cell aggregates (Figure 10). In distinction to central neurocytoma, which rarely has true ganglion cells present, this cell type can be identified in more than half of EVNs. Strong synaptophysin immunoreactivity of tumor cells is typical, and focal GFAP reactivity may also be seen. Like the central neurocytoma, the EVN has been designated WHO grade II.1,2 Previous studies have suggested that the recurrence rate of EVN is low when no atypical features are present.44 The presence of necrosis, vascular proliferation, elevated mitotic activity (ⱖ3 per 10 HPFs) or subArch Pathol Lab Med—Vol 132, June 2008
total resection have been associated with increased risk of recurrence. Papillary Tumor of the Pineal Region, WHO Grades II–III The papillary tumor of the pineal region (PTPR) is a recently described rare tumor type with a characteristic localization and histopathology. These tumors occur exclusively in the pineal region of children and adults, where they are noted on neuroimaging as large, circumscribed, contrast-enhancing masses (Figure 11).52,53 Their clinical and neuroimaging features are similar or identical to pineocytoma, and PTPR were undoubtedly referred to as papillary pineocytomas in the past. The distinctive papillary appearance of these tumors results from the radial WHO CNS Tumor Classification—Brat et al 1003
arrangement of large, cuboidal or columnar epithelioid cells around central, often hyalinized blood vessels (Figure 11). Individual cells have abundant pale or eosinophilic cytoplasm and round to oval cytoplasm. Necrotic foci are occasionally encountered, and the mitotic index ranges from 0 to 10 per 10 HPFs. The histogenesis of PTPR has been debated, in part because of the unique histopathologic appearance and immunohistochemical profile of these tumors. Tumors are strongly and consistently immunoreactive for cytokeratins and also show labeling for S100, vimentin, and MAP2.54 Unlike classic ependymoma, PTPRs show only focal labeling for GFAP or lack it completely, and the dotlike reactivity for epithelial membrane antigen that is typical of ependymoma is rarely seen in PTPR. The ultrastructural findings of ependymal and neuroendocrine features have suggested that these tumors may have specialized ependymal derivation, perhaps arising from the subcommissural organ. Papillary tumors of the pineal region have a substantial rate of recurrence, and among the cases recorded, tumor progression has occurred in 72%, with a subset of these causing death. A specific WHO grade has not been given, and criteria for grading have not been established, yet it has been suggested that PTPRs correspond to grade II or III. Glioneuronal Tumor With Neuropil-like Islands, WHO Grades II–III The glioneuronal tumor with neuropil-like islands, often referred to as the ‘‘rosetted’’ glioneuronal tumor, is a type of infiltrating astrocytoma with characteristic clusters of well-differentiated neuronal elements that form rosetted structures embedded in a central neuropil matrix.55 These morphologically intriguing tumors, first described in 1999, have thus far been noted to affect adults (25–40 years). The large majority have involved the cerebral hemispheres, but an intramedullary case has also been reported.56 They are characterized on MRI as nonenhancing, T1-hypointense, and T2-hyperintense, similar in pattern to grade II or III infiltrating gliomas. On microscopic examination, these tumors are characterized by a glial component similar or identical to an infiltrating astrocytoma. This element can be fibrillary, gemistocytic, or protoplasmic in its differentiation and ranges from moderate to high in its cellularity. Mitoses can be identified in the glial component, and the MIB-1 index ranges from 2.0% to 8.2%. Grading is based on findings within the infiltrating astrocytic element and generally corresponds to WHO grade II or III. The more distinctive components are the neuropil-like islands that are rimmed in a rosetted fashion by well-differentiated neurocytes and atypical neuronal forms (Figure 12). The central neuropil of these islands is intensely synaptophysin immunoreactive, whereas the rosette-forming neuronal elements are synaptophysin and NeuN positive. Less often, ganglion cell differentiation can be seen, and a single example composed mainly of proliferating neuronal nodules has been reported.56,57 This glioneuronal tumor variant is characterized clinically by recurrence after surgery and is capable of fatal progression. Additional cases will be required to define whether the distinctive features of these neoplasms have a bearing on outcome. They appear to behave in a manner that corresponds to their infiltrating astrocytoma component. While it can occasionally manifest with WHO grade II features, currently the glioneuronal tumor with neuropil-like islands is clas1004 Arch Pathol Lab Med—Vol 132, June 2008
Figure 13. Small-cell glioblastoma. Hematoxylin-eosin sections demonstrate a highly cellular infiltrative glial neoplasm composed of cells with scant cytoplasm, uniform nuclei that are round to slightly elongate, and displaying a high degree of mitotic activity (original magnification ⫻400).
sified as a distinctive tissue pattern of anaplastic astrocytoma and has been included within this chapter of the WHO 4th edition. Small Cell Glioblastoma, WHO Grade IV The small-cell glioblastoma is a recently recognized pattern of differentiation of glioblastoma (GBM) with welldefined clinical, morphologic, and genetic features.58,59 These tumors generally arise in the cerebral hemispheres of adults. On MRI, they are T2-hyperintense, reflecting diffuse infiltration and edema. While the majority show contrast enhancement, a subset do not. Small-cell GBMs contain a high density of neoplastic cells with scant cytoplasm, uniform, deceptively bland nuclei that are round to slightly elongate, and a high proliferation index (Figure 13). Foci of necrosis and microvascular proliferation may be small or not fully developed. Because of the cellular monotony and slightly rounded nuclear shape, small-cell GBMs can have a great deal of morphologic similarity to anaplastic oligodendroglioma and may require ancillary tests to diagnose correctly. This distinction is important, since small-cell GBMs are more malignant (WHO grade IV) than anaplastic oligodendroglioma (WHO grade III). Small-cell GBMs are characterized by a high frequency of epidermal growth factor receptor (EGFR) amplification and chromosome 10 loss, but have intact chromosome 1p and 19q. In contrast, anaplastic oligodendrogliomas show the opposite genetic alterations, having a high frequency of 1p/19q deletions but only rare EGFR amplifications and chromosome 10 loss. Whether the small-cell morphology has prognostic significance requires further investigation. These tumors are designated as a pattern of GBM in the 4th edition and are WHO grade IV. Rhabdoid Tumor Predisposition Syndrome The new WHO includes chapters on well-defined genetic syndromes that are associated with an increased risk for developing CNS tumors, including neurofibromatosis 1 and 2, von Hippel-Lindau disease, tuberous sclerosis complex, Li-Fraumeni syndrome, Cowden disease, Turcot syndrome, and nevoid basal cell carcinoma syndrome. The WHO CNS Tumor Classification—Brat et al
4th edition adds to this list the rhabdoid tumor predisposition syndrome (RTPS).1 This syndrome is characterized by germline mutations of the INI1 gene (22q11.2) and is manifested by a marked predisposition to the development of malignant rhabdoid tumors of infancy and early childhood.60,61 The atypical teratoid/rhabdoid tumor (AT/RT), a tumor fully described in the section on embryonal tumors in the 4th edition, is by far the most common CNS malignancy associated with this syndrome, but other tumors, including medulloblastoma, choroid plexus carcinoma, and primitive neuroectodermal tumors (PNETs), have been reported. Up to one third of AT/RTs are thought to arise in the setting of RTPS, and the majority of these occur within the first year of life. The most common non-CNS malignancy of RTPS is the malignant rhabdoid tumor of the kidney, which is also noted in infancy. The RTPS is highly suggested in those clinical scenarios that involve the synchronous occurrence of renal malignant rhabdoid tumor and AT/RT, the finding of bilateral malignant rhabdoid tumors of the kidney or the occurrence of malignant rhabdoid tumors in 2 or more siblings. Immunohistochemical evaluation of AT/RT for the INI1 protein (using the BAF47 antibody) shows a loss of labeling in tumor cell nuclei but retention of nuclear labeling in nonneoplastic cells, such as endothelial cells.62 Importantly, there are many malignant neoplasms of the CNS that can have ‘‘rhabdoid’’ morphology, including glioblastoma, meningioma, and carcinomas. These tumors show retention of the INI1 protein and are not thought to have INI1 mutations or be a component of the RTPS.63,64 The diagnosis of RTPS is established with certainty by sequencing of the INI1 gene on tissue representing the patient’s germline. Because of the risk associated with the RTPS, it is recommended that the germline status of the INI1 allele be investigated in each new case of AT/RT. The sporadic form of AT/RT is characterized by the same spectrum of INI1 mutations that are seen in the germline of RTPS. In either case, the second INI1 allele is believed to be lost by deletion as the second tumorigenic step. SHIFTS IN CLASSIFICATION Medulloblastoma/PNET Classification The section of the WHO Classification on Embryonal Tumours in the 4th edition has been substantially altered in its organization from the 2000 edition in an attempt to consolidate entities with similar histopathologic features, genetic alterations, and clinical behavior.1,3 The previous edition included individual chapters for medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma, all of which are primitive neuroectodermal neoplasms of the cerebellum. It has been concluded that medulloblastoma with myogenic differentiation is not a unique entity because it has genetic alterations similar to other forms of medulloblastomas, and myogenic differentiation can be seen in other medulloblastoma variants. The same holds true for melanotic differentiation in medulloblastoma. Thus, the current edition now describes medulloblastoma with myogenic differentiation (previously medullomyoblastoma) and medulloblastoma with melanotic differentiation (previously melanotic medulloblastoma) as patterns of differentiation that can be seen in medulloblastoma, rather than as unique entities. In addition to medulloblastoma with myogenic differArch Pathol Lab Med—Vol 132, June 2008
entiation and medulloblastoma with melanotic differentiation, the medulloblastoma section also contains expanded descriptions of large-cell medulloblastoma, anaplastic medulloblastoma, medulloblastoma with extensive nodularity, and desmoplastic/nodular medulloblastoma. In the new edition, each is considered a distinct variant of medulloblastoma and has been assigned a specific International Classification of Diseases for Oncology code. The previous edition also included individual chapters on ependymoblastoma, supratentorial PNETs, and medulloepithelioma, with the implication that each of these was a unique tumor entity. These primitive tumor types are known to occur throughout the neuraxis (not only in the supratentorial compartment) and each is now thought to represent a form of PNET that contains a distinctive pattern of differentiation. In the 4th edition, these tumors have been consolidated under one heading in a chapter titled ‘‘Central Nervous System Primitive Neuroectodermal Tumours.’’ There are now major subsections defining CNS/supratentorial PNET (which also includes neuroblastoma and ganglioneuroblastoma), medulloepithelioma, and ependymoblastoma. The chapter on AT/RT remains the last chapter in the embryonal tumor section. Other Notable Classification Changes in the New Edition ● Giant cell glioblastoma and gliosarcoma are now formally included as variants of glioblastoma, whereas they each had their own chapter in the 3rd edition. ● An attempt was made to classify tumors of ‘‘uncertain origin,’’ such that gliomatosis cerebri has now been placed in the astrocytic tumors section in the 4th edition, whereas it was located in the ‘‘Glial Tumours of Uncertain Origin’’ chapter in the 3rd edition. ● Chordoid glioma of the third ventricle, angiocentric glioma, and astroblastoma were placed in ‘‘Other neuroepithelial tumours.’’ ● Hemangioblastoma has its own chapter as a tumor entity and is classified among ‘‘Other neoplasms related to the meninges’’ in the 4th edition. As in the previous edition, there is also a discussion of this tumor type in the chapter on von Hippel-Lindau disease. ● Olfactory neuroblastoma (esthesioneuroblastoma) and peripheral neuroblastomas of the adrenal and sympathetic nervous system are no longer a part of the WHO classification of the CNS tumors section in the 4th edition. CONCLUSIONS It is useful to periodically reconsider the grading and categorization of brain tumors; WHO has met this challenge, now with 2 updates in the past 10 years. These exercises challenge us to reconsider previous assumptions and acknowledge gaps in knowledge while still attempting to improve the classification of these complex diseases. Clearly, the understanding of brain tumors has advanced, as reflected in the new WHO 4th edition. Some of the changes introduced will have an impact on the practice of general surgical pathologists and neuropathologists, whereas others may go largely unnoticed. Perhaps most significant for the generalist are the changes in grading for oligoastrocytomas and meningiomas, since these are commonly encountered brain tumors in the adult population. Importantly, those mixed oligoastrocytomas that are anaplastic and contain necrosis have now been categorized as GBM with oligodendroglioma component, WHO CNS Tumor Classification—Brat et al 1005
WHO grade IV. Those meningiomas that show histologic evidence of brain invasion are now formally recognized as WHO grade II. The changes in the classification of embryonal tumors are also notable, since these are frequently encountered pediatric brain tumors. The chapters on medulloblastoma and PNETs have been consolidated to include variants that were once considered unique entities, thereby simplifying classification, but also reflecting our current understanding of the biology, genetics, and clinical behavior of these neoplasms. Other changes in the 4th edition include the addition of uncommon tumor types that will rarely, if ever, be encountered by most diagnostic pathologists, including pituicytoma, angiocentric glioma, spindle cell oncocytoma of the adenohypophysis, and papillary tumor of the pineal region. There is much to be learned in the field of neurooncology, and no doubt significant changes will be made in the 5th edition of this important brain tumor classification system. In planning the next edition, more experience will be gained with pineal tumors, gangliogliomas, and choroid plexus neoplasms, since the current grading systems are based on a limited, although excellent, number of investigations. A better understanding of the natural history and the significance of atypical features is needed for pleomorphic xanthoastrocytomas. The current edition seems to contain a plethora of new glioneuronal tumors with complex, descriptive names, including the papillary glioneuronal tumor, the rosette-forming glioneuronal tumor of the fourth ventricle, and the glioneuronal tumour with neuropil-like islands. Future studies may bring clarification to the proper classification of these and other brain tumors. References 1. Louis DN, Ohgaki H, Weistler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press; 2007: 309. 2. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl). 2007;114:97– 109. 3. Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:314. World Health Organization Classification of Tumours. 4. Rosenblum MK. The 2007 WHO classification of nervous system tumors: newly recognized members of the mixed glioneuronal group. Brain Pathol. 2007; 17:308–313. 5. Fuller GN, Scheithauer BW. The 2007 revised World Health Organization (WHO) Classification of Tumours of the Central Nervous System: newly codified entities. Brain Pathol. 2007;17:304–307. 6. Brat DJ, Scheithauer BW, Fuller GN, Tihan T. Newly codified glial neoplasms of the 2007 WHO Classification of Tumours of the Central Nervous System: angiocentric glioma, pilomyxoid astrocytoma and pituicytoma. Brain Pathol. 2007; 17:319–324. 7. Roncaroli F, Scheithauer BW. Papillary tumor of the pineal region and spindle cell oncocytoma of the pituitary: new tumor entities in the 2007 WHO classification. Brain Pathol. 2007;17:314–318. 8. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer. 1997;79:1381–1393. 9. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24:2715–2722. 10. Miller CR, Dunham CP, Scheithauer BW, Perry A. Significance of necrosis in grading of oligodendroglial neoplasms: a clinicopathologic and genetic study of newly diagnosed high-grade gliomas. J Clin Oncol. 2006;24:5419–5426. 11. Smith SF, Simpson JM, Brewer JA, et al. The presence of necrosis and/or microvascular proliferation does not influence survival of patients with anaplastic oligodendroglial tumours: review of 98 patients. J Neurooncol. 2006;80:75–82. 12. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol. 1997;21:1455– 1465. 13. Perry A, Scheithauer BW, Stafford SL, Lohse CM, Wollan PC. ‘‘Malignancy’’
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Solitary fibrous tumors in the central nervous system: a clinicopathologic review of 18 cases and comparison to meningeal hemangiopericytomas. Arch Pathol Lab Med. 2003; 127:432–439. 25. Gengler C, Guillou L. Solitary fibrous tumour and haemangiopericytoma: evolution of a concept. Histopathology. 2006;48:63–74. 26. Lellouch-Tubiana A, Boddaert N, Bourgeois M, et al. Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI. Brain Pathol. 2005;15:281–286. 27. Wang M, Tihan T, Rojiani AM, et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol. 2005;64:875–881. 28. Brat DJ, Scheithauer BW, Staugaitis SM, Holtzman RN, Morgello S, Burger PC. Pituicytoma: a distinctive low-grade glioma of the neurohypophysis. Am J Surg Pathol. 2000;24:362–368. 29. Figarella-Branger D, Dufour H, Fernandez C, Bouvier-Labit C, Grisoli F, Pellissier JF. Pituicytomas, a mis-diagnosed benign tumor of the neurohypophysis: report of three cases. Acta Neuropathol (Berl). 2002;104:313–319. 30. Kowalski RJ, Prayson RA, Mayberg MR. Pituicytoma. Ann Diagn Pathol. 2004;8:290–294. 31. Roncaroli F, Scheithauer BW, Cenacchi G, et al. ‘Spindle cell oncocytoma’ of the adenohypophysis: a tumor of folliculostellate cells? Am J Surg Pathol. 2002; 26:1048–1055. 32. Kloub O, Perry A, Tu PH, Lipper M, Lopes MB. Spindle cell oncocytoma of the adenohypophysis: report of two recurrent cases. Am J Surg Pathol. 2005; 29:247–253. 33. Komori T, Scheithauer BW, Anthony DC, et al. Papillary glioneuronal tumour: a new variant of mixed neuronal–glial neoplasm. Am J Surg Pathol. 1998; 22:1171–1183. 34. Bouvier-Labit C, Daniel L, Dufour H, et al. Papillary glioneuronal tumour: clinicopathological and biochemical study of one case with 7-year follow up. 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WHO CNS Tumor Classification—Brat et al 1007
