Ependymomas and Choroid Plexus Tumors

8  Ependymomas and Choroid Plexus Tumors Christine E. Fuller, MD

Definitions and Synonyms  145 Brief Historical Overview  145 Ependymal Tumors  145 Choroid Plexus Tumors  157

Ependyma and choroid plexus play critical structural and biologic functions within the central nervous system (CNS); the neoplasms that recapitulate these cell types are the most common intraventricular and intramedullary spinal cord tumors. This chapter covers the various categories of ependymal and choroid plexus neoplasms and presents a practical approach to differentiating these tumors from possible diagnostic mimics in both adult and pediatric patients. Special attention is given to ancillary techniques that are useful in diagnostically challenging cases, as well as to controversial issues of histologic grading.

Definitions and Synonyms Ependymomas represent a group of gliomas with morphologic and ultrastructural evidence of predominantly or exclusively ependymal differentiation, as opposed to a growing list of tumors with only partial or limited ependymal features. The latter include astroblastoma, chordoid glioma, papillary tumor of the pineal region, pilomyxoid astrocytoma, and angiocentric glioma. The 2016 World Health Organization (WHO) classification scheme1 recognizes the following ependymal tumor categories: subependymoma (WHO grade I), myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II) including a number of variants, and anaplastic ependymoma (WHO grade III). In addition, ependymoma, RELA fusion positive, is a newly recognized aggressive entity that includes the majority of supratentorial ependymomas occurring in children and young adults. The previous category of “ependymoblastoma” is now mostly incorporated into the new diagnosis of embryonal tumor with multilayered rosettes, either with or without C19MC alteration, although ependymoblastic rosettes can also be seen occasionally in other embryonal tumor subtypes, such as atypical teratoid/rhabdoid tumor (see Chapter 12). Intraventricular neoplasms recapitulating choroid

plexus epithelium include choroid plexus papilloma (WHO grade I), atypical choroid plexus papilloma (WHO grade II), and choroid plexus carcinoma (WHO grade III).2

Brief Historical Overview Dating back to early perspectives,3 our concepts of ependymoma histogenesis have been related to embryology and the stages of normal ependymal cell development. This “stem cell” or “progenitor cell” theory of tumorigenesis proposes that radial glia, the multipotent neuroglial progenitor cells, give rise to multiple different populations of elongate unipolar and bipolar cells termed tanycytes; fetal ependymal tanycytes directly give rise to mature ependymocytes, whereas the more highly specialized cells of the circumventricular organs and choroid plexus are ultimately derived from this same developmental pathway.4 Choroid plexus tumors and ependymomas (including the various histologic subtypes) clearly recapitulate specific cell types found at various stages in this ontologic sequence. In more recent years, our focus relative to the accurate classification of ependymomas and choroid plexus tumors has shifted from one centered primarily upon development of objective histologic criteria to one that takes advantage of high-resolution genetic and epigenetic classifiers. A number of prognostically relevant molecular “signatures” have been uncovered, as have potential therapeutic targets; these will be explored later in this chapter. It should come as no surprise that the most recent WHO revision1 emphasizes a combined histologic/ molecular approach to tumor classification, with the inclusion of new molecularly defined entities such as RELA fusion-positive ependymoma. It is quite likely that subsequent tumor classifications will markedly expand upon this theme. Despite these triumphs, the concepts of atypical choroid plexus papilloma and ependymoma grading (including the issue of focal anaplasia) remain unresolved and await further clarification.

Ependymal Tumors

Incidence and Demographics Ependymomas represent slightly less than 10% of all neuroepithelial tumors; they are the most common primary tumor of the spinal cord and the third most common pediatric CNS tumor, accounting for up 145

Ependymomas and Choroid Plexus Tumors

Abstract

Background The 2016 Revised Fourth Edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System recognizes the following ependymal tumor categories: subependymoma (WHO grade I), myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II) including a number of variants, and anaplastic ependymoma (WHO grade III). In addition, ependymoma, RELA fusion positive, is a newly codified entity that includes the majority of pediatric supratentorial ependymomas. Tumors of choroid plexus include choroid plexus papilloma (WHO grade I), atypical choroid plexus papilloma (WHO grade II), and choroid plexus carcinoma (WHO grade III). Design The aim of this chapter is to summarize current knowledge pertaining to ependymal and choroid plexus lesions.

Outcome Clinical, epidemiologic, radiologic, and pathologic features of the various recognized ependymal and choroid plexus neoplasms are presented in detail, special attention given to histologic grading and identification of specific tumor variants. Useful ancillary diagnostic studies (immunohistochemistry, ultrastructural and molecular analyses) are also covered, as are differential diagnostic, prognostic, and treatment considerations. Xanthogranuloma of the choroid plexus is also discussed.

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Conclusion This chapter comprehensively covers the various categories of ependymal and choroid plexus neoplasms and presents a thoughtful approach to differentiating these tumors from possible diagnostic mimics in both adult and pediatric patients.

Keywords ependymoma anaplastic ependymoma choroid plexus papilloma choroid plexus carcinoma myxopapillary ependymoma subependymoma ependymoma, RELA fusion positive

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Practical Surgical Neuropathology to 30% of intracranial tumors in children younger than 3 years of age.1 They display a bimodal age distribution, with peak incidences at ages 6 and 30 to 40 years, respectively. The vast majority of pediatric ependymomas arise intracranially, but more than 60% of adult ependymomas are centered in the spinal cord.5 Ependymomas have an equal gender distribution, though they are nearly twice as common in Caucasians as in African Americans. Though most are sporadic, they may also be seen as part of neurofibromatosis type 2, nearly all with cervical spinal localization (see Chapter 22). Subependymomas are often incidental autopsy findings in the brains of older adults and represent approximately 10% of all ependymal tumors. They are uncommon in children.6 In contradistinction, anaplastic ependymomas are far more frequent in the pediatric age group. Arising predominantly in adults, only 10% to 20% of myxopapillary ependymomas manifest in children. They show a 2 : 1 male–female bias.7,8

Localization and Clinical Manifestations Accumulating data suggest that despite the histopathologic similarities, supratentorial, posterior fossa, and spinal ependymomas are biologically and genetically distinct entities.9 In children, the most common site of involvement (predominantly WHO grade II and III categories) is the posterior fossa/fourth ventricle followed by supratentorial location, the latter showing an equal mix of primarily paraventricular and intraparenchymal tumors.10 Supratentorial tumors (including ependymomas and subependymomas) more frequently involve paraventricular tissues of the lateral ventricles than the third ventricle. Intracranial ependymomas often become symptomatic when their growth results in blockage of cerebrospinal fluid (CSF) pathways, causing signs and symptoms related to hydrocephalus and increased intracranial pressure. These include ataxia, headache, nausea and vomiting, strabismus, irritability, and altered mental status; macrocephaly and bulging fontanels may be encountered in affected infants. Clinical signs and symptoms of anaplastic ependymoma are similar to those of low-grade ependymoma, although they tend to develop in an accelerated fashion. As noted, a subset of supratentorial ependymomas will entirely lack ventricular involvement, being instead centered within the subcortical white matter or superficial cortex,11–13 or rarely at various intracranial extra-axial locations.14–16 Of note, superficial cortical ependymomas typically occur in young adults and are typically associated with seizures; mixed histologic features have been described in some, including features reminiscent of angiocentric glioma, schwannian-like nodules, and variant morphologies including clear cell, tanycytic, myxopapillary, giant cell, and anaplastic ependymoma.12,13,17 Ependymal tumors may arise at any level of the spinal cord, though certain histologic subtypes have preferred locations. For example, conventional ependymomas, including the tanycytic variant, typically manifest as central intramedullary tumors within the thoracic/cervicothoracic region,18 whereas subependymomas more often arise within the cervical cord in an eccentric fashion.19 Spinal ependymomas are only rarely anaplastic. Myxopapillary ependymomas invariably arise in the region of the filum terminale; infrequent sites of origin include other spinal cord levels, intracranial sites (both intraventricular and intraparenchymal), and subcutaneous sacrococcygeal areas.20–25 As opposed to the typically benign behavior of intradural myxopapillary ependymomas, the soft tissue variant has a relatively high incidence of systemic metastases. Any of the spinal ependymal tumors may cause back pain and motor or sensory deficits, depending on their specific anatomic involvement. Rare extraneural sites for ependymomas include the ovaries, mediastinum, and sacrococcygeum. Ependymomas and anaplastic ependymomas occasionally metastasize via subarachnoid spread to seed other spinal and intracranial locations; rare extracranial metastases have also been reported.26 Pediatric 146

myxopapillary ependymomas more often disseminate through the CSF pathways, a feature not typical of the adult counterpart.7 Although they uncommonly recur, pure subependymomas do not otherwise show metastatic potential.6

Radiologic Features and Gross Pathology Conventional ependymomas commonly involve several contiguous spinal segments (three, on average) and grow as sausage-shaped centrally situated intramedullary tumors with discreet margins. The majority are hyperdense by computer tomography (CT) and isointense to hypointense on T1-weighted but hyperintense on T2-weighted magnetic resonance imaging (MRI), with uniform contrast enhancement; rostral and caudal cysts (“syringomyelia”) are frequently encountered (Fig. 8.1A).27,28 Intracranial tumors are also sharply demarcated. Those in the posterior fossa typically arise within or near the fourth ventricle, with somewhat more variable and heterogeneous contrast enhancement, occasionally with cystic components. These neoplasms commonly extend through the fourth ventricular foramina into the basal cisterns. Intratumoral hemorrhage or calcifications (or both) are also quite common, and obstructive hydrocephalus is frequently encountered5,29,30 (Fig. 8.1B). Supratentorial examples are more often cystic and may not be associated with a nearby ventricle (Fig. 8.1C). As noted, myxopapillary ependymomas are characteristically wellcircumscribed lesions arising in the conus medullaris/cauda equina/filum terminale region. Unlike conventional ependymomas, the majority of these lesions are hyperintense on T1-weighted MRI due to their mucin content31 (Fig. 8.1D). They are also hyperintense on T2-weighted imaging (Fig. 8.1E), are brightly enhancing on postcontrast images, and may show cystic changes (particularly in intracranial examples) or hemorrhage. Subependymomas are sharply demarcated nodular lesions bulging into the ventricles or arising eccentrically within the spinal cord (unlike classic ependymomas, which tend to be central); they show variable signal characteristics on MRI and CT. They are most often hypointense on T1-weighted and hyperintense on T2-weighted imaging, with faint to no contrast enhancement.32 Similar to other ependymal tumors, foci of calcium or hemorrhage may be present19,30,33 (Fig. 8.1F). On gross inspection, most ependymomas are soft tan to gray masses with well-defined borders. They may be partially cystic or contain areas of hemorrhage, necrosis, or calcification. Anaplastic examples may show evidence of frank intraparenchymal invasion, although it is often difficult to discern adherence versus invasion grossly. Myxopapillary ependymomas are lobulated, soft, gray to tan, and often encapsulated. In contrast, subependymomas are firm and lobulated or nodular, but nonencapsulated.

Histopathology Ependymomas have a wide morphologic spectrum with many recognized variants. However, nearly all of them share a few features, such as sharp demarcation from adjacent CNS and the presence of perivascular pseudorosettes (Table 8.1). Subependymoma and myxopapillary ependymoma (both WHO grade I lesions) are presented first, followed by conventional WHO grade II ependymomas and the multiple variants therein, and lastly, the features of anaplastic ependymoma (WHO grade III). RELA fusion-positive ependymomas will be presented in detail within the genetics section. Intraoperative cytology and smear preparation findings are included where applicable.

Histologic Variants and Grading

Subependymoma (WHO Grade I) Subependymomas are hypocellular, nodular tumors composed of collections of cytologically bland cells with round to oval nuclei set within

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Fig. 8.1  (A) Spinal ependymoma. T1-weighted postcontrast magnetic resonance image (MRI) showing uniformly enhancing intramedullary cervical spinal tumor. The low-density regions below are consistent with an associated syrinx. (B) Intracranial ependymoma. T1-weighted postcontrast MRI showing well-demarcated fourth-ventricular tumor with heterogeneous enhancement and cyst formation. (C) Supratentorial ependymoma. Contrast-enhanced T1-weighted MRI showing a large partially cystic intraparenchymal mass in the right frontal lobe. (D, E) Myxopapillary ependymoma. Classic cauda equina/filum terminale location with heterogeneous mass containing hyperintense foci on both T1-weighted (D) and T2-weighted (E) MR images. (F) Subependymoma. T1-weighted MRI showing sharply demarcated nodular lesion within the lateral ventricle.

wide expanses of coarse fibrillar matrix (Fig. 8.2A). This distinctive appearance resembles ependymal nuclear cytology embedded in an astrocytoma-like background. The neoplastic cells have a tendency to cluster, and microcysts are common, the latter encountered mostly in lateral ventricular examples (Fig. 8.2B). This pattern of focal cell clustering together with expansive intervening fibrillar zones lacking cell bodies is highly characteristic of subependymoma. As the name implies, these tumors arise directly beneath the ventricular surface, and, therefore, it is not uncommon to see a lining of normal ependymal cells over the tumor. Intratumoral hemorrhage or hemosiderin-laden macrophages and calcifications are frequently encountered, often accompanying sclerotic vessels and focal “degenerative atypia.”6,34,35 True ependymal rosettes, ependymal canals, and perivascular pseudorosettes are lacking, as is significant mitotic activity and endothelial proliferation; necrosis is uncommon, but has no prognostic significance when encountered. The cytologic findings are similar.36 Importantly, 5% to 20% of subependymomas harbor foci of classic or, rarely, even

anaplastic ependymoma. When such foci are tiny, they are probably of limited clinical relevance, but if they comprise a significant portion of the tumor (e.g., >10%), they should be graded according to the highest grade component (e.g., “combined ependymoma-subependymoma, WHO grade II”). Myxopapillary Ependymoma (WHO Grade I) Myxopapillary ependymomas (MPE) characteristically show a variably papillary architecture with central blood vessels, surrounded by cuboidal to spindled glial cells radially arranged around an intermediate layer of Alcian blue–positive myxoid stroma (see Fig. 8.2C). Some lesions exhibit a more compact fascicular pattern with intermixed mucin-rich microcysts and occasional perivascular pseudorosettes (Fig. 8.2D). Degenerative changes, including vascular hyalinization, are often prominent and may occasionally mask the more typical myxoid nature of this lesion.37,38 Some cases also feature rounded to spiculated collagen “balloons” that may be highlighted with trichrome, reticulin, and periodic acid–Schiff 147

Practical Surgical Neuropathology Table 8.1  Clinicopathologic and Neuroimaging Findings of Ependymal Tumors Tumor Type

Clinical Presentation

Neuroimaging

Histology

Ancillary Studies

Subependymoma (WHO grade I)

Often asymptomatic, but may present rarely with obstructive hydrocephalus

Sharply demarcated nodular intraventricular lesions or arising eccentrically within the spinal cord; variable CT and MRI findings; enhancement uncommon, but many have calcification

Hypocellular glial tumor with bland nuclei, cell clustering, and microcysts (in lateral ventricle); perivascular pseudorosettes and ependymal rosettes/canals are lacking; may show calcification, hemosiderin-laden macrophages, and nuclear pleomorphism

IHC—positive for GFAP, S-100, NCAM and NSE (often weak), and patchy dot-like EMA EM—typical features of ependymal differentiation as described elsewhere in table

Myxopapillary ependymoma (WHO grade I)

Back pain and/or sensory/ motor deficits

Cauda equina/conus/filum region well-circumscribed lesion, hyperintense on T1- and T2-weighted MRI with intense contrast enhancement

Myxoid stroma-rich papillary structures with central often hyalinized blood vessels surrounded by radially arranged cuboidal to elongated glial cells; some contain distinctive eosinophilic “balloons”

IHC—positive for GFAP, S-100, vimentin, and CD99; majority positive for COX-2; EMA-negative EM—typical features of ependymal differentiation as described elsewhere in table, plus interdigitating cell processes and microtubular aggregates bound by rough endoplasmic reticulum

Ependymoma (WHO grade II)

Spinal: back pain and/or sensory/motor deficits Intracranial: hydrocephalus with signs/symptoms of increased intracranial pressure or seizures for cortical examples

Spinal: centrally situated intramedullary tumors with discreet margins; CT-hyperdense; MRI T1-isointense to hypointense, T2-hyperintense, with uniform enhancement postcontrast; rostral and caudal cysts Intracranial: sharply demarcated, often partially cystic, heterogeneous contrastenhancing and similar T1 and T2 to spinal lesions

Conventional—solid moderately cellular tumor with variable glial to epithelial features, noninfiltrative growth pattern, true ependymal rosettes/ canals (infrequent), and/or perivascular pseudorosettes (frequent) Tanycytic—elongated spindled bipolar cells, fascicular architecture, inconspicuous pseudorosettes Clear cell—sheets of cells with rounded nuclei and abundant surrounding clear cytoplasm, branching capillaries, perivascular pseudorosettes; numerous mitoses and endothelial proliferation often present (most are WHO grade III) Papillary—cuboidal to columnar cells resting upon central finger-like projections of gliofibrillary “stroma”

IHC—positive for GFAP, S-100, vimentin; punctate, dot-like, or ring-like positivity for EMA; dot or membranous CD99 and D2-40 staining; lack of intratumoral neurofilament positive processes indicative of solid growth; L1CAM staining in some supratentorial cases EM—zipper-like intercellular junctional complexes, occasional cilia, surface and intraluminal microvilli

Anaplastic ependymoma (WHO grade III)

Similar to ependymoma but with more rapid onset

Similar to ependymoma, often with microinfiltration into surrounding tissues

Hypercellularity and numerous mitoses, microvascular proliferation, and palisading necrosis; solid growth centrally but often with focal microinfiltration at edges

Similar to grade II ependymoma; L1CAM staining in most supratentorial cases

COX-2, Cyclooxygenase-2; CT, computed tomography; EM, electron microscopy; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; IHC, immunohistochemistry; MRI, magnetic resonance imaging; NCAM, neural cell adhesion molecule; WHO, World Health Organization.

(PAS) stains (Fig. 8.2E and F). Despite the name, papillary growth pattern can be fairly inconspicuous in some myxopapillary ependymomas; nevertheless, the distinctive perivascular hyalinization and mucoid degeneration are typically found. Mitotic figures are uncommon, with necrosis and endothelial proliferation usually being absent. Rare anaplastic and giant cell variants have been described in case reports.39,40 Cytologic preparations typically recapitulate the histologic findings noted earlier, containing metachromatic material, bland nuclear morphology, and often papillary formations.41 Ependymoma (WHO Grade II) Ependymomas classically manifest as moderately cellular glial tumors showing sharp demarcation from the surrounding brain parenchyma (Fig. 8.3A) The cytologic characteristics of the tumor cells vary considerably, some displaying glial properties with elongated fibrillary processes, while others display epithelioid features reminiscent of non-neoplastic ependymocytes lining the ventricular surfaces. Key architectural features 148

include a solid (i.e., noninfiltrative) growth pattern, perivascular pseudorosettes (anuclear zones formed by the processes of tumor cells radially arranged around blood vessels) (Fig. 8.3B), and true ependymal rosettes and canals. The latter consist of cuboidal to columnar tumor cells surrounding a central rounded (rosette) or elongate (canal) lumen (Fig. 8.3C). Although more specific for ependymoma than the perivascular pseudorosettes, true rosettes and canals are seen in only a minority of cases (5% to 10%). Mitotic activity is low (<5/10 HPF) and both palisading necrosis and microvascular proliferation are absent in these grade II tumors. However, geographic infarct-like zones of necrosis are relatively common and do not influence the prognosis.5,42 Pleomorphic nuclei may be present, but this feature alone does not justify a higher grade designation. Degenerative changes may also include hemorrhage, calcification, myxoid degeneration, and vascular hyalinization. Cartilage,43,44 bone,45 lipoma-like features (from fat accumulation),46,47 neuropil-like islands,48 and cells with melanin,49 signet ring,50 oncocytic,51 granular cell,52 giant cell morphology,53–55 or eosinophilic intracytoplasmic inclusions56 have

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Fig. 8.2  Histologic features of grade I ependymal tumors. (A, B) Subependymoma. Hypocellular, vaguely lobulated neoplasm with clustered cytologically bland nuclei, densely fibrillar background, and microcysts. (C, D) Myxopapillary ependymoma. Papillary and solid structures containing abundant myxoid stroma and radially arranged elongated glial processes surrounding hyalinized blood vessels. (E, F) Myxopapillary ependymoma. Collagen balls on H & E (E) and PAS (F) stains.

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Fig. 8.3  Histologic features of conventional (WHO grade II) ependymoma. (A) Sharp circumscription from surrounding brain parenchyma and presence of perivascular pseudorosettes with nuclear-free zones surrounding blood vessels. (B) Perivascular pseudorosettes. (C) Numerous true ependymal rosettes with open lumina. (D) Squash preparation showing bland bipolar cells with long fibrillary processes and perivascular pseudorosettes.

all been described. Cytologic preparations of ependymomas typically contain cohesive clusters of cells with epithelioid to fibrillar cytoplasm and containing bland oval to rounded nuclei. Perivascular pseudorosettes and, rarely, true rosettes may be seen41 (Fig. 8.3D). Cellularity of ependymomas varies greatly from case to case and even regions within the same case. Markedly hypercellular examples that lack microvascular proliferation, palisading necrosis, or an elevated mitotic rate have been previously designated as “cellular ependymoma,” but this is no longer considered a true variant in the latest WHO classification, as there is extensive overlap with otherwise conventional ependymomas as previously described.1 Perivascular pseudorosettes are typically well formed at least focally, but true rosettes and canals are generally lacking in these hypercellular ependymomas, which may mimic medulloblastoma or other embryonal neoplasms at lower magnification (Fig. 8.4A and B). The following variants of conventional WHO grade II ependymoma have been well characterized: Tanycytic Ependymoma. This variant has a particular predilection for the spinal cord, where the differential diagnosis is aided by 150

the fact that radiologic features are similar to conventional spinal ependymomas. Typified by elongated spindled bipolar cells possessing thin eosinophilic fibrillary processes, it has been theorized that this variant most closely resembles the primitive radial glia-like tanycytes.4,57 With a predominantly fascicular architecture, only focal perivascular pseudorosettes, and lack of true ependymal rosettes, tanycytic ependymoma may resemble a variety of other nervous system tumors (particularly pilocytic astrocytoma and schwannoma), thus providing a formidable diagnostic challenge18,57–59 (Fig. 8.4C). Nuclear pleomorphism may be prominent in some cases, though this clearly represents a degenerative feature given the generally innocuous biologic behavior exhibited by these tumors. Cytologic smear preparations may be similarly confusing, harboring cells with long, thin processes and oval to spindle-shaped nuclei closely resembling pilocytic astrocytoma. Ancillary testing is frequently needed to accurately classify this uncommon ependymoma. Papillary Ependymoma. This uncommon ependymoma variant is characterized by single or multiple layers of cuboidal to columnar cells resting on central finger-like projections of gliofibrillary “stroma” (Fig. 8.4D); fibrovascular cores are not a feature, and the

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Fig. 8.4  Histologic features of WHO grade II ependymoma variants. (A, B) This ependymoma is hypercellular but lacks endothelial proliferation and increased mitotic activity. (C) Tanycytic ependymoma. Fascicular pattern of elongated spindle cells with less conspicuous pseudorosettes. (D) Papillary ependymoma. Papillary structures contain gliofibrillary “stroma.” (E) Clear cell ependymoma. Sheets of cells with abundant clear cytoplasm interrupted by vague perivascular pseudorosettes.

epithelial-like surfaces tend to be smooth in contour.5,60 In many cases, the architecture is more “pseudopapillary,” resulting from loss of cellular cohesion except immediately adjacent to blood vessels. Smear preparations likewise tend to have an epithelioid quality. Clear Cell Ependymoma. Preferentially arising in a supratentorial location in pediatric and young adult patients,26,61 clear cell ependymoma contains sheets of cells with rounded nuclei and abundant surrounding clear cytoplasm mimicking oligodendroglioma, but with a discrete margin in relation to adjacent brain. The presence of thin, branching “chicken-wire” capillaries may add to this diagnostic challenge. Perivascular pseudorosettes may be subtle, but are invariably present, whereas true rosettes are absent26,61,62 (see Fig. 8.4E). Unlike the aforementioned ependymoma variants, a significant proportion of clear cell ependymomas exhibit biologically aggressive behavior as well as histologic features of anaplasia (including endothelial proliferation, hypercellularity, and frequent mitoses), necessitating a WHO grade III designation.26 Additionally, this subtype will frequently be classified as the RELA fusion molecular variant based on further testing (see discussion in later section).63 Both clear cell and papillary variants

may be intermixed with foci of otherwise conventional or anaplastic ependymomas. Anaplastic Ependymoma (WHO Grade III) The histologic grading of ependymoma and what role such grading plays in clinical prognostication remain a contentious issue. In addition to the histologic features of conventional grade II ependymomas (circumscription, perivascular pseudorosettes, ependymal rosettes), the WHO 2016 puts forth high nuclear-to-cytoplasmic ratio and high mitotic count (e.g., >5/10 HPF or >10/10 HPF depending on series) as essential diagnostic features of anaplastic ependymoma.1 These features are often accompanied by hypercellularity, as well as widespread microvascular proliferation and/or necrosis of the palisading type1 (Fig. 8.5A–C). Although several large series utilized more specifically defined histologic criteria to define anaplasia in ependymomas, correlations between grade and prognosis remain tenuous at best.64–66 Compounding this issue of grading is the fact that in a sizable subset of ependymomas, one finds few to multiple small areas of hypercellularity containing numerous mitotic figures, sometimes with accompanying proliferative vasculature. 151

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Fig. 8.5  Histologic features of anaplastic ependymoma (WHO grade III) and unusual variant ependymoma patterns. (A) Hypercellular anaplastic ependymoma with numerous mitotic figures. (B) Anaplastic ependymoma showing abundant microvascular proliferation. (C) Anaplastic ependymoma with a focus of palisading necrosis. (D) Anaplastic ependymoma showing increased nuclear pleomorphism and mitotic activity. (E) Anaplastic ependymoma with evidence of a finger-like focus of microinvasion into adjacent CNS parenchyma. (F) Signet ring pattern. Ependymoma with abundant signet ring cells, wherein the nucleus is displaced to the periphery by a large clear vacuole. The latter likely represents large intracytoplasmic lumina.

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Fig. 8.5, cont’d  (G) Sclerotic pattern. Focus of dense fibrosis within an ependymoma. The atrophic epithelioid tumor cells are hard to recognize as glial. (H) Lipidized pattern. Ependymoma with extensive lipidization resembling foci of lipoma. Classic ependymal cytology with perivascular pseudorosettes is seen at the top of the image.

The threshold at which these zones of “focal anaplasia” become sufficient for WHO grade III designation has yet to be determined. Pleomorphic nuclei (Fig. 8.5D) may or may not be present; however, by definition, primitive or embryonal elements, with or without Homer Wright or ependymoblastic rosettes should not be present. Although all ependymomas display a predominantly solid growth pattern, foci of microinvasion into the adjacent brain parenchyma are more common in the anaplastic ependymomas (Fig. 8.5E). Given the inherent subjectivity of ependymoma grading noted, it is likely that molecular subgrouping of ependymomas will soon supplant histologic grading in providing relevant data for appropriate patient prognostication and treatment planning.

Other Patterns Many other morphologic patterns may be seen in ependymomas, including signet ring formation (Fig. 8.5F), likely representing enlarged intracytoplasmic lumina. This may prompt consideration of other entities, such as metastatic carcinoma, although classic features of ependymoma should be found in other portions of the tumor. Additionally, rare cases undergo extensive hyalinization or sclerosis, with entrapped tumor cells appearing small and epithelioid (Fig. 8.5G). This can similarly generate a differential diagnosis with other extensively collagenized tumors, such as astroblastoma and ganglioglioma. Regions of classic histology along with the appropriate immunoprofile and ultrastructural features confirm the diagnosis of ependymoma (see section Ancillary Diagnostic Studies later in chapter). Even rarer examples display extensive lipidization, such that portions of the tumor resemble lipoma (Fig. 8.5H). An exceptional occurrence is that of a malignant mesenchymal component arising within an ependymoma, the so-called “ependymosarcoma” (Fig. 8.6), essentially representing a gliosarcoma in which the precursor glioma is ependymoma rather than astrocytoma.67,68

Differential Diagnosis Ependymal tumors may be confused with a variety of CNS tumors. In general, conventional ependymomas can be effectively differentiated from the diffuse (infiltrative) gliomas by virtue of their solid growth pattern, which lacks significant intratumoral neurofilament positive axons (Fig. 8.7A). Ependymal canals and true rosettes are also helpful in this regard, although these are typically encountered only in the most well-differentiated examples (see Fig. 8.3C). Although perivascular

pseudorosettes are quite typical of ependymomas, a number of other tumors unfortunately may harbor similar structures. Glioblastomas sometimes feature surprisingly similar pseudorosettes, but grow in a much more infiltrative pattern. Pilocytic astrocytoma and pilomyxoid glioma may also resemble ependymomas in this regard, but ependymomas lack Rosenthal fibers and eosinophilic granular bodies typical of the former and the abundant myxoid microcystic background and typical SOX10 positivity of the latter.69 The perivascular processes found in the pseudorosettes of astroblastoma are characteristically shorter and wider than the delicate, long fibrillar processes in ependymomas. Perivascular pseudorosettes are a feature of angiocentric glioma; however, these tumors also show a longitudinal orientation of perivascular tumoral cells, subpial palisades, and infiltrative growth pattern; also, they are typically not contrast enhancing on radioimaging studies.70 Highly cellular anaplastic ependymomas may mimic embryonal tumor with multilayered rosettes (EMTR), though the latter represents an embryonal tumor containing primitive small blue cells, a characteristic C19MC amplification, and LIN28 expression by immunohistochemistry (see Chapter 12).71 Certain ependymoma variants may pose formidable diagnostic challenges. Tanycytic ependymomas, by virtue of their spindled fascicular growth pattern, may resemble schwannoma or pilocytic astrocytoma. Glial fibrillary acidic protein (GFAP) positivity is often extensive in both pilocytic astrocytomas and ependymomas, but is occasionally seen in schwannomas as well. Nonetheless, the typically diffuse intercellular pattern of collagen IV–positive basement membrane in schwannomas is not encountered in ependymomas. Dot-like positivity for epithelial membrane antigen (EMA) is typical of ependymoma but is not usually seen in pilocytic astrocytoma. Ultrastructural evidence of ependymal differentiation can also be extremely helpful in such cases.18,59 Clear cell ependymoma may closely mimic multiple primary CNS lesions containing clear cells (oligodendroglioma, neurocytic tumors, and hemangioblastoma) and metastatic clear cell carcinomas. Identification of perivascular pseudorosettes is the first clue to the diagnosis of clear cell ependymoma, whereas supportive immunohistochemical findings (especially dot-like positivity for EMA), EM features of ependymal differentiation, and molecular findings (RELA fusion or L1CAM immunostaining, lack of IDH1 mutation and/or 1p/19q deletion) help confirm the diagnosis.26,61 Papillary ependymoma may be confused with choroid plexus tumors, papillary meningiomas, papillary tumor of the pineal gland, or metastatic 153

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D Fig. 8.6  Ependymosarcoma occurring after many recurrences of a posterior fossa ependymoma. Postcontrast MR images (A, B) demonstrate invasion into the soft tissue of the scalp, as well as metastasis of the sarcomatous component to a cervical lymph node (B; arrow). Histopathology revealed foci of residual anaplastic ependymoma (C), as well as foci resembling fibrosarcoma (D).

B

carcinomas. Strong positivity for GFAP and lack of diffuse cytokeratin staining are characteristic of ependymoma, with EM confirmation not usually being necessary.5 Identification of a lobular architecture and cell clustering is helpful in separating subependymoma from other paucicellular gliomas, such as pilocytic astrocytoma. Lastly, myxopapillary ependymoma may be differentiated from potential diagnostic mimics such as chordoma, myxoid chondrosarcoma, and paraganglioma of the cauda equina region by virtue of its classic histopathology, immunohistochemical pattern (positive for vimentin, S-100, and GFAP; negative for cytokeratin, chromogranin, and synaptophysin), and characteristic ultrastructural finding of microtubular aggregates.72 Of note though, the myxopapillary ependymoma typically lacks the dot-like EMA pattern seen in other ependymoma variants.

154

Ancillary Diagnostic Studies

Immunohistochemistry With few exceptions, as noted later, the general immunohistochemical staining pattern shared by ependymal tumors is expression of S-100, GFAP, and vimentin5,73,74 (Fig. 8.7B). GFAP often highlights the perivascular pseudorosettes by staining the delicate cytoplasmic processes that radiate toward central blood vessels. Cytokeratin, OLIG2, and SOX10 positivity are typically negative or focal at best,69,75,76 whereas EMA often shows a characteristic punctate, dot-like pattern of cytoplasmic positivity; ring-like EMA staining is less frequently encountered5,26,73,75 (Fig. 8.7C). CD99 and D2-40 are also frequently positive, with variable membranous or dot-like staining, though neither is entirely specific.75,77 Stains for neuronal markers are typically negative, and lack of entrapped

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A

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Fig. 8.7  Immunohistochemical (A–C) and ultrastructural (D) features of ependymoma. (A) A neurofilament immunostain highlights the axons in the adjacent brain parenchyma. The lack of entrapped axons is consistent with a solid growth pattern. (B) The glial fibrillary acidic protein (GFAP) stain highlights elongated perivascular processes. (C) An epithelial membrane antigen (EMA) immunostain demonstrates a dot-like pattern of cytoplasmic positivity. (D) Electron microscopy. Zipper-like junctional complexes with desmosomes and intercellular aggregates of microvilli.

intratumoral neurofilament positive axons is especially helpful in demonstrating the solid nature of these tumors (Fig. 8.7A). However, it should also be recognized that neuronal differentiation has now been reported in rare ependymomas.78 In addition to GFAP, S-100, vimentin, and CD99, approximately 60% of myxopapillary ependymomas are positive for cyclooxygenase-2 (COX-2) (as compared with only 25% for other ependymoma subtypes).25,38,79 Occasional examples are immunopositive for p53, although this is nonspecific.80 Unlike other ependymomas, the myxopapillary variant is also usually EMA negative. Subependymomas are positive for GFAP and S-100, often with at least focal dot-like EMA staining; they may also be weakly positive for low-specificity neuronal markers such as neural cell adhesion molecule (NCAM) and neuron-specific enolase (NSE). The Ki-67 labeling index is lowest in subependymoma and myxopapillary ependymoma, with WHO grade II and III showing incrementally higher labeling indices.34,81 Electron Microscopy All ependymal tumors, including subependymoma and the listed variants, share similar ultrastructural characteristics of ependymal differentiation.

These include abundant intracellular intermediate filaments, long “zipper-like” intercellular junctional complexes including desmosomes, occasional cilia, and microvilli; the latter present both on cell surfaces and within microlumina56,57,59,82 (Fig. 8.7D). Myxopapillary ependymomas in addition exhibit interdigitating cell processes and microtubular aggregates bound by rough endoplasmic reticulum.37,83

Genetics Ependymomas as a group have no single unifying “genetic signature”; on the contrary, there is a rapidly expanding body of evidence that ependymomas represent multiple genetically distinct tumor subsets, not only relative to age of occurrence and location, but in terms of histologic grade and biologic potential.84,85 Comparative genomic hybridization studies have documented a number of chromosomal copy number alterations in ependymomas, including losses involving chromosomes 6q, 16, 17p, and 22 and gains of 1q, 5q, 7q, 9, and 15.86–88 Chromosome 22q loss is frequently observed in adult ependymomas and is strongly associated with a spinal location. Many of these spinal tumors harbor concomitant NF2 mutation, but this is not the case for intracranial ependymomas with 22q deletions.85,89,90 Additionally, chromosome 1q

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Practical Surgical Neuropathology gain represents a frequent finding in intracranial ependymomas from all age groups.91 This alteration, as well as 10q and 6q loss, has been associated with high-grade ependymomas.92–94 High-resolution molecular profiling platforms have been instrumental in rapidly expanding our understanding of genetic and epigenetic alterations involved in ependymoma oncogenesis, and likewise in identifying biologically distinct ependymoma subgroups. For instance, differing gene expression patterns have been demonstrated in ependymomas at specific sites; high expression levels of Notch are found in intracranial ependymomas whereas homeobox-containing genes are frequently expressed by ependymomas of extracranial sites.84 Activation of the Notch pathway and Tenascin-C expression have subsequently been shown to be associated with ependymoma progression, particularly in pediatric posterior fossa ependymomas.95 Overexpression of neuronal marker Neurofilament Light Polypeptide 70 (NEFL) is a frequent finding in pediatric supratentorial ependymomas and may correlate with prolonged progression-free survival.96 Supratentorial ependymomas can be divided into biologically distinct subgroups based on their genetic signatures. RELA fusion-positive ependymoma is a newly recognized entity in the 2016 WHO scheme.1 This genetically defined ependymoma variant accounts for the majority (approximately 70%) of pediatric supratentorial ependymomas, though it has been encountered in adults as well.97,98 The C11orf95–RELA fusion is by far the most commonly demonstrated alteration and is detectable by fluorescence in situ hybridization (FISH) assays utilizing break-apart probe sets around each of these genes. This oncogenic fusion drives aberrant activation of the NF-κB signaling pathway.63,97,98 These fusions are the result of chromothripsis, and rarely C11orf95 or RELA may fuse with other partners.98 RELA fusion positivity may be seen with a variety of histologic appearances and WHO grades. There does, however, appear to be a tendency for these tumors to exhibit branching capillaries (Fig. 8.8A) and clear cell morphology63; trisomy 19 is also typically present.63 L1CAM expression (Fig. 8.8B), detectable by immunohistochemistry, correlates with the presence of RELA fusion in supratentorial ependymomas.98 Recent data generated by one large multi-institutional study suggest that RELA fusion-positive ependymomas represent the most biologically aggressive of the supratentorial ependymal tumors; supratentorial subependymomas and supratentorial ependymomas with

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Yes-associated protein 1 (YAP1) fusions represented the other molecularly defined supratentorial subgroup in that study and had a better prognosis.99 There is clear evidence that posterior fossa ependymomas can similarly be divided into prognostically distinct groups, supportive data originating from several independent study cohorts. Group A posterior fossa (PFA) ependymomas are laterally situated tumors arising predominantly in infants and younger children, exhibiting a balanced genome and aggressive biologic behavior with frequent recurrences, metastases, and shortened survival. In contrast, Group B tumors (PFB) arise in older children and adults, tend to show more chromosomal instability/copy number alterations, and are associated with much better clinical outcomes compared to Group A tumors.9,100,101 From an epigenetic standpoint, PFA ependymomas exhibit a “CpG island methylator” or “CIMP” phenotype.102 Of particular interest, one recent multi-institutional study detected reduction of H3K27me3 in a significant proportion of pediatric posterior fossa ependymomas, with these tumors exhibiting striking clinical and biologic similarities to PFA ependymomas. H3K27me3 status may be reliably assayed by immunohistochemistry, and this study also provided strong evidence that loss of H3K27me3 expression may represent a useful surrogate marker of biologically aggressive pediatric PFA ependymomas.103 Lastly, spinal and supratentorial ependymomas have also been shown to harbor numerous hypermethylated genes, suggesting that epigenetic manipulation of gene expression may contribute to the tumorigenesis of other non-posterior fossa ependymomas as well.104 Myxopapillary ependymomas may show marked aneuploidy or polyploidy, often with gains of chromosomes 5, 7, 9, 16, and 18, or losses involving chromosomes 1 and 22.86,105,106 Pediatric MPEs may in fact harbor unique molecular signatures, with one study showing overexpression of homeobox B13 (HOXB13), NEFL, and PDGFRα at the gene expression and protein levels; this was not a feature of tested ependymomas of other sights and histologies in that study cohort.107 Systematic molecular characterization studies of large cohorts of subependymomas are lacking. Thus far, NF2 alterations have not been documented in subependymomas.6 One recent study found expression of HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin in subependymomas, suggesting possible future therapeutic targets.108

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Fig. 8.8  (A) RELA fusion-positive supratentorial ependymoma with multiple branching capillaries. (B) Immunohistochemical stain for L1CAM shows strong diffuse membrane positivity. 156

Ependymomas and Choroid Plexus Tumors

Treatment and Prognosis The extent of tumor excision has consistently been shown as one of the most reliable predictors of both progression-free and overall survival with regard to intracranial ependymomas in all age groups,5,64,109–115 and evidence indicates that demonstration of tumor microinvasion (see Fig. 8.5E) on the original resection specimen is an indicator of poor prognosis.116 Radiation therapy may prolong progression-free survival in those tumors that are incompletely excised113,117; preirradiation chemotherapy may be particularly efficacious in those children in which near-total excision of their intracranial ependymoma was accomplished.118 Relative to tumor location, pediatric supratentorial ependymomas tend to be associated with longer overall survival compared to pediatric posterior fossa ependymomas, although further molecular stratification should also be considered (see prior sections).119 In contradistinction, adult supratentorial ependymomas are associated with a significantly higher mortality rate then their infratentorial (posterior fossa and spinal) counterparts.109,112,120,121 Older age at diagnosis, larger tumor size, and high tumor grade are also associated with poor prognosis in adult intracranial ependymomas.112,121,122 Incomplete excision is strongly associated with shortened progression-free survival in spinal cord ependymomas, including myxopapillary ependymoma; adjuvant radiotherapy has been shown to provide survival benefit in cases with incomplete resection.123–127 Overall, children with ependymomas tend to fare far worse than adults, due in part to the much higher incidence of malignant histology and intracranial/posterior fossa localization, thus making complete resection technically challenging.128 Ependymomas arising within the first few years of life tend to be associated with particularly poor outcomes, in part due to difficulty in administering radiotherapy to these immature and developing brains.129 There is compelling evidence, however, that postoperative radiation therapy administered in the context of pediatric intracranial ependymomas may afford these patients significantly improved progression-free and overall survival rates compared to their nonradiated counterparts; this association apparently holds true even in patients less than 3 years old at the time of treatment.117,130 That being said, chemotherapy may also be beneficial in very young patients, with reduction in tumor volume and/or vascularity affording more complete subsequent surgical resection.129,131–134 Most first recurrences are local (i.e., at the site of the resection cavity). In children with recurrent intracranial ependymoma, complete surgical excision and to a lesser extent radiation of the relapsed lesion may provide some survival benefit.135,136 CSF dissemination is uncommon, but indicates poor prognosis. Extraneural metastases have been rarely encountered.137 Though many investigations have found histologic grading of ependymoma to be significantly correlated with overall or recurrencefree survival,64,91,109,111,113–115,125,128,129,138 several studies have not.66,116,134,139 An elevated Ki-67 proliferation index also tends to correlate well with WHO grade III status and with more aggressive biologic behavior in general.61,139–141 One study focused on ependymomas in adults found the vast majority were WHO grade I or II, worse outcomes being associated with anaplasia (WHO grade III), brain location, and Ki-67/MIB1 labeling indices greater than 10%.142 With respect to particular ependymoma variants, the clear cell ependymomas appear to constitute a more aggressive phenotype, often harboring histologic features coinciding with grade III status. Local recurrence is quite common, and these tumors have been shown to exhibit a capacity for transdural invasion into venous sinuses or extracranial metastasis into soft tissue and lymph nodes.26 In contrast, myxopapillary ependymomas are generally slow growing with a favorable overall survival. Despite their low-grade designation, almost half of all

patients experience local recurrence, irrespective of adequate excision; nonlocal recurrences have also been described.143,144 Tumor recurrence is particularly true of pediatric MPEs.145,146 Tumor encapsulation, allowing for complete excision, portends a lower recurrence rate, and adjuvant radiation therapy has been shown to aid in reducing recurrence; gross total resection, however, should be the primary goal of treatment as this tends to afford superior outcomes.1,147–149 Neuroaxis metastasis, though infrequent overall, may be seen with pediatric MPE, necessitating complete neuroaxis screening both at the time of diagnosis and during follow-up.7,150 Similar to other ependymoma subtypes, MPEs may overexpress EGFR; although EGFR overexpression may be a useful predictor of MPE relapse,151,152 this is not a consistent feature of other ependymal tumors.153,154 The sacral soft tissue variant of myxopapillary ependymoma is more frequent in children and though it tends to exhibit fairly indolent behavior, occasional extraneural metastases have been described.155,156 Lastly, the majority of subependymomas remain clinically silent through life, to be detected only incidentally on neuroimaging or at autopsy. Complete resection is generally curative, although rare late recurrences following subtotal resection have been reported. In contrast, subependymomas bearing other ependymomatous components tend to follow a clinical course akin to the higher grade portion of the tumor.6,34 As noted in the genetics section, a number of molecular “signatures” are proving prognostically significant in the realm of ependymal tumors. Gain of 1q and homozygous deletion of CDKN2A have both been linked with unfavorable prognosis.110,157,158 Telomerase activity has been demonstrated in a significant proportion of pediatric ependymomas and has been associated with shortened progression-free and overall survival.159,160 There is some evidence to support telomerase inhibition as a promising adjuvant therapy for telomerase-active pediatric ependymomas.159,161 Likewise, a number of microRNAs have been implicated as potential prognostic markers, as has expression of p53, Bcl-2, metalloproteinases MMP2 and 14, EZH2, PDGFRα, cyclin D1, nestin, nucleolin, claudin-5, and transcription factor EVI1, although additional testing is needed to confirm or refute these potential biomarkers.119,153,154,160,162–169 Lastly, various ependymoma subgroups have been defined by high-throughput genetic/epigenetic methods, and thus far the most unfavorable and biologically aggressive ependymomas appear to be those relegated to the posterior fossa Group A and supratentorial RELA fusion-positive groups, both of which predominate in the infant/pediatric age group.99

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Choroid Plexus Tumors Incidence and Demographics

Although choroid plexus tumors are uncommon in adulthood, they represent nearly 5% of childhood brain tumors and up to 20% of those arising within the first year of life.1 Accordingly, the peak incidence is within the first decade.170,171 Rare congenital and fetal examples have been described.172 Whereas choroid plexus papillomas (CPP) are approximately five times more frequent then choroid plexus carcinomas (CPC), overall, the vast majority of CPCs (>80%) arise in infants younger than 3 years of age, where they account for a third of all pediatric choroid plexus tumors. There is no particular gender predilection. Overall, CPCs tend to present at a significantly younger age than do CPPs,173 although multiple studies have also indicated that atypical CPPs arise in significantly younger patients than do CPPs.174,175 The vast majority of choroid plexus tumors are sporadic. In a small number of cases, CPPs are a component of Aicardi syndrome, with affected patients showing corpus callosum agenesis, chorioretinal abnormalities, and infantile spasms.176 CPCs occasionally arise in association with hereditary cancer predisposition syndromes, including the Li Fraumeni and rhabdoid predisposition syndrome (see Chapter 22), 157

Practical Surgical Neuropathology with germline mutations of TP53 and hSNF5/INI1/SMARCB1 genes, respectively.177–179

Localization and Clinical Manifestations Choroid plexus tumors typically arise within the lateral (50%), fourth (40%), or third (5%) ventricles. Of note, most lateral ventricular tumors present within the first two decades of life, whereas fourth-ventricle tumors have a more diverse age distribution.170 Rare sites of occurrence include the cerebellopontine angle or ectopic locations (intraparenchymal, suprasellar, spinal epidural region).180,181 Tumors may involve more than one ventricle simultaneously, and rare synchronous examples have been reported.182,183 Patients present with signs and symptoms related to increased intracranial pressure and hydrocephalus, due to excess CSF production by the tumor itself or obstruction of CSF pathways.180 During infancy, before the skull sutures have fused, the excess CSF production may result in an enlarging head. Both CPP and CPC have the potential to seed throughout the neuroaxis, though this is common in the latter and quite exceptional for the former.171,184

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Radiologic Features and Gross Pathology Choroid plexus tumors are characteristically solid, multilobated intraventricular masses that are isodense to hyperdense on CT; by MRI, they are isointense to gray matter on T1, hyperintense on T2, and show intense contrast enhancement (Fig. 8.9A). Flow voids and cystic areas are not uncommon. While CPPs are typically well marginated, CPCs tend to be large and have more irregular contours with frequent invasion of the surrounding parenchyma and associated edema185 (Fig. 8.9B). They likewise show variable calcification, hemorrhage, and necrosis. Leptomeningeal enhancement correlates with CSF dissemination of tumor. CPP samples are globular “cauliflower-like” friable, soft, and pink to red-brown masses, often with surface stippling (correlating with papillary microarchitecture); they sometimes exhibit intratumoral hemorrhages or calcification (Fig. 8.9C). Isolated examples are predominantly cystic.186 CPC is similar to CPP, though often punctuated by areas of hemorrhage and necrosis. In autopsy brains, CPPs are often adherent to the ventricular walls but otherwise well demarcated from the surrounding brain tissue. Conversely, CPCs frequently extend into periventricular brain parenchyma.170

B

Histopathology All choroid plexus tumors display histologic features of epithelial neoplasms, with grade depending on the degree of differentiation and malignancy (Table 8.2). CPPs (WHO grade I) represent the most differentiated of this group, and CPCs (WHO grade III) are frankly malignant. Atypical CPPs (aCPPs; WHO grade II) have features (and subsequently grade) intermediate between these two extremes, although they are more similar to the CPPs in their generally differentiated status. The histologic and cytologic features of these three tumor categories are presented herein.

Histologic Variants and Grading

Choroid Plexus Papilloma (WHO Grade I) CPPs are composed of numerous fibrovascular papillary projections covered by a single layer of cuboidal to columnar epithelium. Similar to native choroid plexus, the epithelial cells of CPPs may have either eosinophilic or clear cytoplasm187 (Fig. 8.10A and B). Unlike non-neoplastic choroid plexus, however (Fig. 8.10C), CPPs lack a cobblestone appearance that results from intercellular spaces and they display more cellular crowding and stratification, mildly elevated nuclear-to-cytoplasmic ratio, nuclear hyperchromasia and/or irregular nuclear profiles, and rare mitoses.170,171 Clear cytoplasmic vacuoles are also common 158

C Fig. 8.9  (A) Contrast-enhanced T1-weighted MRI showing a solid well-demarcated intraventricular choroid plexus papilloma (CPP) with intense enhancement. (B) Contrastenhanced T1-weighted MRI showing irregularly enhancing large lateral ventricular choroid plexus carcinoma with areas of necrosis, irregular margination, and surrounding edema. (C) CPP with classic cauliflower-like gross appearance.

Ependymomas and Choroid Plexus Tumors Table 8.2  Clinicopathologic and Imaging Findings of Choroid Plexus Tumors Tumor Type

Clinical Presentation

Neuroimaging

Histology

Ancillary Studies

Choroid plexus papilloma (CPP) (WHO grade I)

Hydrocephalus with signs/ symptoms of increased intracranial pressure

Solid, multilobated intraventricular mass, isodense to hyperdense on CT; by MRI, they are isointense on T1, hyperintense on T2, and show intense contrast enhancement; often contain cystic areas, flow voids

Fibrovascular papillary projections covered by a single layer of cuboidal to columnar epithelium

IHC—positive for vimentin, pancytokeratin, and transthyretin; variably positive for S-100 with focal GFAP; basement membrane staining for laminin; EMA- and CEA-negative EM—apical microvilli, cilia, and tight junctions, coated vesicles, membrane interdigitations, and cytoplasmic intermediate filaments; continuous basement membrane and fenestrated endothelium

Atypical CPP (WHO grade II)

Similar to CPP

Similar to CPP

CPPs with elevated mitotic activity, frequently with complex architecture

Similar to CPP

Choroid plexus carcinoma (CPC) (WHO grade III)

Similar to CPP though more rapid onset

Tend to be larger than CPP with more irregular contours, frequent invasion, and associated edema; variable calcification, hemorrhage, and necrosis

Solid hypercellular sheets of variably pleomorphic epithelioid cells with frequent mitoses; necrosis and invasion of surrounding tissue are frequent; cells with high N/C ratio or rhabdoid morphology may be seen

Similar IHC and EM findings to CPP; nuclei are positive for INI1 (i.e., retained), Ki-67 LI high, p53 positive

8

CEA, Carcinoembryonic antigen; CT, computed tomography; EM, electron microscopy; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; IHC, immunohistochemistry; LI, labeling index; MRI, magnetic resonance imaging; N/C, nuclear-to-cytoplasmic; WHO, World Health Organization.

(Fig. 8.10D). Cytologic preparations similarly contain well-formed papillary clusters, sheets or monolayers, and isolated single cuboidal to columnar cells with bland nuclei, dispersed chromatin, and moderate amounts of cytoplasm.188 Notable but uncommon histologic features include oncocytic change (Fig. 8.11), mucinous degeneration, melanin pigment, well-developed ependymal differentiation, neuropil-like islands, and osseous or cartilaginous metaplasia.189–191 Degenerative changes may include xanthomatous change, hyalinization, or calcification.189 Areas of necrosis, increased cellularity, loss of papillary architecture, and small foci of limited brain invasion may be encountered, although these are uncommon and should prompt a careful search for higher grade features (see sections on atypical CPP and CPC). Rare tumors in which the typical papillary architecture is replaced by gland-like or tubular arrangements have sometimes been referred to as choroid plexus (tubular) adenomas (Fig. 8.10F); evidence thus far indicates that in the absence of other worrisome features, these behave no differently from other CPPs and this pattern may be seen focally within otherwise typical CPPs. Therefore it remains unclear whether this is a distinct tumor type or simply a histologic pattern that may be encountered in some CPPs.192 A single pediatric posterior fossa tumor with synchronous CPP and ependymoma components has been reported.193 Atypical Choroid Plexus Papilloma (WHO Grade II) Clinicopathologic investigation of histologic features associated with an increased risk of recurrence in nonmalignant choroid plexus tumors has demonstrated that elevated mitotic activity (defined as two or more mitoses per 10 HPF) was the most significant determinant. Thus, CPPs with excessive mitotic activity are considered atypical, WHO grade II194 (see Fig. 8.10E and F). These tumors also frequently display complex architectural arrangements with cribriforming and anastomosing papillary formations. Additional histologic features often present in atypical CPPs include hypercellularity, nuclear pleomorphism, focal loss of papillary architecture or solid growth pattern (Fig. 8.10F), and necrosis. Choroid Plexus Carcinoma (WHO Grade III) Unlike CPPs, which generally look quite similar, CPCs are notable for their highly variable histology, often generating significant diagnostic confusion with a number of primary CNS and metastatic tumors.

CPCs show frank features of malignancy, often characterized by solid hypercellular sheets of variably pleomorphic epithelioid cells with frequent mitoses (Fig. 8.12A). Foci of papillary architecture may be retained in some CPCs (Fig. 8.12B), although they may be completely absent in others. Necrosis is common, and when surrounding brain parenchyma is sampled, extensive invasion may be seen. Tumor cells exhibiting rhabdoid morphology may occasionally be prominent, creating confusion with atypical teratoid/rhabdoid tumors (AT/RTs)187,195 (Fig. 8.12C). Nevertheless, one must approach such cases with great care, since some AT/RTs are intraventricular (see Differential Diagnosis section later). Likewise, some CPCs are composed predominantly of small primitive cells with a very high nuclear-to-cytoplasmic ratio, reminiscent of medulloblastomas and other embryonal neoplasms (Fig. 8.12D). Other uncommon histologic features similar to those listed earlier for CPPs (particularly melanin pigment and oncocytic morphology) may be rarely encountered.196 On cytologic preparations, CPCs demonstrate tight three-dimensional clusters and isolated anaplastic-appearing cells with prominent nuclear irregularities in the form of intranuclear pseudoinclusions, polylobation, coarse chromatin pattern, and micronucleoli.197 Cells with abundant cytoplasm, sometimes containing hyaline globules or vacuoles, may be encountered. Rare calcific deposits (psammomatous or dystrophic), necrosis, and abnormal mitoses are additional features.198

Differential Diagnosis Choroid plexus tumors need to be distinguished from a variety of low- and high-grade lesions. For instance, CPPs may closely resemble non-neoplastic choroid plexus. Any demonstrable mitotic or proliferative activity (MIB-1 or Ki-67 labeling), together with cytomorphologic and architectural features as noted earlier, would favor CPP.199 Additionally, non-neoplastic choroid plexus has a characteristic cobblestone appearance that is lacking in the CPP (see Fig. 8.10C). Papillary ependymoma and astroblastoma both exhibit a papillary architecture; however, CPP has laminin-positive basement membrane underlying strongly cytokeratinpositive epithelium and lacks the perivascular pseudorosettes and extensive GFAP staining typical of these other tumors. Similarly, CPC may resemble anaplastic ependymoma, and likewise can be differentiated from that tumor by virtue of its strong cytokeratin positivity, lack of 159

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Fig. 8.10  Histologic features of choroid plexus papilloma (CPP) (A–B, D), normal choroid plexus (C), and atypical CPP (E–F). (A, B) Fibrovascular papillary structures lined by bland cuboidal to columnar epithelial cells bearing eosinophilic to clear cytoplasm. (C) Unlike papillomas, normal choroid plexus epithelium displays intercellular spaces, imparting a cobblestonelike surface. (D) The epithelium in this CPP has prominent clear vacuoles. (E) Atypical CPP. Papilloma with elevated mitotic rate and architectural complexity. (F) Atypical CPP. Focal loss of papillary architecture with solid growth pattern and adenoma-like features.

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Fig. 8.11  Oncocytic choroid plexus papilloma with degenerative nuclear atypia. Note the increased granular-appearing eosinophilic cytoplasm (A), corresponding to mitochondria on an immunostain for antimitochondrial antigen (B).

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Fig. 8.12  Histologic features of choroid plexus carcinoma. (A) Choroid plexus carcinoma (CPC), showing hypercellular sheets of pleomorphic epithelioid cells with frequent mitoses. (B) CPC with pleomorphic epithelium covering papillary structures. (C) CPC cells with rhabdoid morphology. (D) CPC. Small primitive cells with high nuclear-to-cytoplasmic ratio, reminiscent of an embryonal neoplasm. 161

Practical Surgical Neuropathology significant fibrillarity and GFAP staining, a demonstrable though frequently fragmented basement membrane, and a lack of true rosettes and perivascular pseudorosettes.200 An E-cadherin-positive/NCAM-negative staining pattern may also help distinguish choroid plexus tumors from ependymomas, since the latter displays the opposite staining pattern; however, determination of the specificities of these staining patterns requires additional validation.201 Endolymphatic sac tumors are lowgrade carcinomas that often invade the petrous part of the temporal bone and may protrude into the cerebellopontine angle; they are nearly exclusively encountered in the setting of a von Hippel-Lindau (VHL) patient (see Chapter 22). These tumors closely resemble CPP from a histologic standpoint; although both may express GFAP and S-100, Kir7.1 and EAAT-1 expression is limited to choroid plexus tumors.202 Nevertheless, these tumors are usually easy to distinguish clinically and radiologically, given that neither petrous temporal bone involvement nor VHL as a predisposing tumor syndrome is encountered in CPC. Medulloepithelioma and embryonal carcinoma may sometimes mimic CPC, although the multilayered ribbons of primitive epithelioid-appearing cells in medulloepithelioma are typically negative for cytokeratin, and embryonal carcinomas are characteristically positive for placental alkaline phosphatase (PLAP), OCT 3/4, and CD30. As previously noted, CPCs may rarely contain variable cellular populations with rhabdoid morphology and a polyphenotypic immunoprofile, thus raising AT/RT as a diagnostic consideration. As CPCs are known to show deletions involving chromosome 22q, FISH analysis for determination of INI1 (22q11.2) gene copy numbers has minimal utility in this setting. Instead, retained nuclear staining with anti-INI1 (BAF-47) reliably differentiates CPC from AT/RT, the latter characteristically lacking appreciable staining with this antibody.203 Differentiating between choroid plexus tumors and metastatic carcinomas (papillary or otherwise) is a significant issue in the rare circumstance when CPCs arise in adults, often necessitating a battery of immunohistochemical stains for definitive classification. Transthyretin or S-100 expression is supportive evidence for choroid plexus neoplasia, although neither of these stains is terribly specific. GFAP positivity, often encountered focally in choroid plexus tumors, is likewise typically not encountered in metastatic carcinomas. However, most CPCs are negative or minimally positive for EMA, a marker that, while not terribly specific, is nevertheless strongly and extensively positive in

A

most carcinomas; in contrast, most CPCs are strongly vimentin positive, while systemic cancers are generally negative, with a few notable exceptions. Also, as covered in the following section, choroid plexus tumors frequently show a CK7+/CK20− pattern of positivity similar to that encountered in breast, ovarian, lung, and cholangiocarcinomas; all of the latter can be effectively ruled out by immunohistochemical means, because choroid plexus tumors will be negative for carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, Wilms tumor 1 (WT1), and thyroid transcription factor-1 (TTF-1).

Ancillary Diagnostic Studies

Immunohistochemistry CPPs consistently express pancytokeratin and vimentin, with the former displaying either diffuse (Fig. 8.13A) or dot-like (Fig. 8.13B) cytoplasmic immunoreactivity.187,200 Though variable patterns of positivity for CK7 and CK20 may be encountered, the most frequent are CK7+/CK20+ and CK+/CK20−, although this staining tends to be focal.189 Both EMA and CEA are usually negative, whereas up to 90% show some positivity for S-100 protein; these are nonspecific but helpful features in the distinction from most metastatic carcinomas.204,205 Staining for GFAP (Fig. 8.13C) may be detected at least focally in up to 50% of CPPs, and synaptophysin (Fig. 8.13D) is positive in some cases.204–206 Transthyretin is positive in the majority of CPPs, and staining for collagen IV or laminin is helpful in demonstrating the subepithelial layer of basement membrane in these tumors.187,207 CPCs similarly show immunopositivity for cytokeratin; however, S-100 and transthyretin are positive slightly less often (see Fig. 8.13E).187,207 Synaptophysin, GFAP, and carbohydrate antigen-19-9 (CA19-9) may all be focally expressed, while EMA and CEA staining is quite uncommon.208,209 Nuclear staining for INI1 is retained in CPCs, including those harboring cells with a rhabdoid morphology203 (Fig. 8.13F). Choroid plexus tumors have been found to express a variety of additional markers, including excitatory amino acid transporter-1 (EAAT1),202,210 Kir7.1,202 stanniocalcin-1,207 and E-cadherin.201 The MIB-1 (Ki-67) proliferative index is variable in CPCs, although it is typically high even in cases that otherwise appear well differentiated (see Fig. 8.13G). The majority of CPCs show nuclear positivity for p53 protein, although corresponding mutations of TP53 are quite uncommon.178,179,211,212

B

Fig. 8.13  Immunohistochemical (A–G) and ultrastructural (H) features of choroid plexus tumors. (A) Pancytokeratin shows widespread positivity. (B) Cytokeratin CAM 5.2 demonstrates a ball-like pattern of cytoplasmic positivity, characteristic of some choroid plexus tumors. 162

Ependymomas and Choroid Plexus Tumors

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D

E

F

G

H

Fig. 8.13, cont’d  (C) Focal glial fibrillary acidic protein expression in a choroid plexus papilloma. (D) Synaptophysin staining in many of the tumor cells. (E) Strong transthyretin expression was found in this poorly differentiated choroid plexus carcinoma. (F) Positive nuclear INI1 (BAF47) staining in a choroid plexus carcinoma. (G) A high Ki-67 labeling index was seen in this well-differentiated choroid plexus carcinoma. (H) Electron microscopy showing cells containing apical microvilli, cilia, and tight junctions separated from nearby capillaries by a continuous basement membrane in choroid plexus papilloma. 163

Practical Surgical Neuropathology Electron Microscopy The epithelial cells of CPP are typified by apical microvilli, cilia, tight intercellular junctions, coated vesicles, membrane interdigitations, and cytoplasmic intermediate filaments; these cells are separated from the fenestrated endothelium of nearby capillaries by continuous basement membrane213 (Fig. 8.13H). Similar ultrastructural features may be found (often with greater difficulty) in CPC.214

Genetics Whereas choroid plexus tumors are generally lacking any specific recurrent mutations, they are notable for larger chromosomal copy number alterations. CPPs are often hyperdiploid, with multiple gains involving chromosomes 5, 7, 8, 9, 12, 15, 17, 18, 20, and 21, as well as losses of chromosomes 10 and 22q.215–217 Hyperdiploidy is likewise frequent in atypical CPPs.217 Recurrent copy number gains of chromosomes 1, 2, 4, 12, and 20 and losses of chromosomes 5, 6, 16, 18, 19, and 22 occur in CPCs.218 In addition to focal chromosomal gains common to all choroid plexus tumors (chromosomes 14q21-q22, 7q22, and 9q21.12), focal alterations unique to CPCs and others shared by CPP and aCPP have been identified; the latter suggests that aCPPs represent immature variants of CPPs, whereas CPCs likely represent a genetically distinct group of tumors.217 Ruland et al’s study using molecular inversion probe single nucleotide polymorphism (MIP SNP) arrays indicates that CPCs with chromosomal losses of 9, 19p, and 22q are significantly more frequent in children under 3 years old, whereas gains on chromosomes 7, 8q, 14q, 19, and 21q are more common in older patients. Loss of 12q was associated with shorter survival in that study.218 The frequent overexpression and amplification of PDGF receptors in CPCs provide a potentially interesting target for novel therapies aimed at PDGF receptor signaling.219 Multiple studies have shed light onto transcription regulatory and epigenetic alterations that play a role in choroid plexus tumorigenesis and progression. For instance, gene expression profiling has identified a number of genes differentially expressed in CPP compared with nonneoplastic choroid plexus epithelium, including increased expression of transcription factor TWIST1.220 A novel cross-species genome-wide analysis has indicated several oncogenes that may be involved in the initiation and progression of CPC, including epigenome-regulating transcription factors TAF12 and NFYC, and RAD54L, which play key roles in DNA repair.221 Alternative lengthening of telomeres (ALT) may be encountered in nearly 25% of pediatric CPCs and is frequently associated with somatic TP53 mutations and ATRX point mutations, the latter leading to loss of expression by immunohistochemistry. Of interest, ALT appears to confer a prolonged overall survival in those children with TP53 mutant CPCs, and therefore, ALT analysis may contribute to risk stratification and targeted therapies to improve outcome for children with CPCs.222 Lastly, a study by Thomas et al. utilizing high-resolution methylation profiling analysis identified distinct epigenetic subgroups of choroid plexus tumors: pediatric low-risk tumors (mainly supratentorial CPP and aCPP), adult low-risk tumors (mainly infratentorial CPP and aCPP), and pediatric high-risk tumors (supratentorial CPP, aCPP, and CPC). Tumors in this pediatric high-risk methylation cluster were associated with a shorter progression-free and overall survival, with only a single tumor with progressive disease falling outside this methylation cluster.223

Treatment and Prognosis Prolonged recurrence-free and overall survival is typical for CPP, with 5-year survival rates reaching upward of 80% following complete surgical excision. CPCs are significantly more aggressive, with a tendency for metastatic dissemination and recurrence; survival rates are less than half those encountered for patients with CPPs.180 Not surprisingly, the 164

biologic behavior exhibited for atypical CPPs falls somewhere between these two extremes, but this category still tends to behave favorably in terms of survival, with the main increased risk being for local recurrence174 Surgical excision is the standard first line therapy for all choroid plexus tumors; together with histologic grade, extent of excision is a key determinant of patient progression-free and overall survival.224 Whereas CPCs that are amenable to complete surgical resection have a more favorable outcome with the addition of adjuvant chemotherapy or local radiotherapy, craniospinal irradiation may be necessary in those cases with subtotal resection or leptomeningeal dissemination (or both) at presentation.225,226 Extent of excision and metastatic status do not, however, appear to be significant prognostic factors for CPC arising in infancy (patients < 36 months old).227 Radiation therapy of these rapidly developing brains is typically avoided in this age group due to the high potential for significant neurocognitive impairment.228 In children with incompletely resected CPCs, neoadjuvant chemotherapy with ifosfamide, carboplatin, etoposide (ICE) may facilitate second-look surgery, often enabling complete or near-complete resection. Unfortunately, its usage also contributes to significant neurocognitive impairment in surviving patients.229 Radiotherapy should also be avoided in patients with CPC arising in the context of Li-Fraumeni syndrome.230 On the other hand, gross total resection is often curative for CPPs, allowing for a watchful waiting approach to follow-up in these patients.231 Patients with incompletely resected atypical CPPs or evidence of metastatic disease have been shown to respond favorably to multiagent chemotherapy.174 Surgery combined with multiagent chemotherapy has reportedly led to long-term survival in most aCPP and CPC patients in multiple studies.232,233 Though recurrence in the context of CPC portends an abysmal prognosis, this is not true for CPP.171 Finally, mitotic count of 2 or more per 10 HPF and elevated Ki-67 labeling index have been shown to correlate with increased risk of recurrence in CPP (i.e., atypical CPP),194 while chromosome 9p gain and 10q loss may indicate favorable survival for patients with CPCs.216 A number of genetic/epigenetic alterations in choroid plexus tumors have been recently uncovered in the research setting (see previous genetics section). As additional evidence accumulates supporting the usefulness of these molecular signatures in facilitating patient prognostication and/ or targeted treatment planning, it is likely that molecular testing will become an integral part of the routine pathologic workup/classification of choroid plexus tumors in the future.

Other Choroid Plexus Tumors Given the presence of mesenchymal, inflammatory, and meningothelial elements (tela choroidea) in the normal choroid plexus, a wide variety of other tumor masses of the choroid plexus are occasionally encountered in surgical neuropathology; these include meningioma, meningothelial hyperplasia, solitary fibrous tumor/hemangiopericytoma, inflammatory conditions, metastatic malignancies, and lymphoma. These topics are covered in the appropriate chapters elsewhere in the textbook. However, one additional entity is worth mentioning in this section: the xanthoma or xanthogranuloma of the choroid plexus (also called cholesterol granuloma of the choroid plexus). These lesions are typically encountered in the trigone of the lateral ventricles, most often presenting with bilateral disease. Subclinical examples of xanthomatous degeneration are common, whereas symptomatic cases are rare, most often coming to attention due to obstructive hydrocephalus. Radiologically, xanthogranulomas appear somewhat lobulated with heterogeneous signal characteristics due to variable contents of lipid and cholesterol, hemosiderin, fibrous tissue, and calcium throughout the mass (Fig. 8.14A). Grossly, they are similarly complex with variegated yellow, white, and red foci, often with areas of cystic degeneration.

Ependymomas and Choroid Plexus Tumors

8

A

B

C

Fig. 8.14  Choroid plexus xanthogranuloma. (A) Computed tomography showing a complex intraventricular mass in the right trigone, with heterogeneous signal characteristics. (B, C) Histology shows large aggregates of cholesterol clefts with surrounding foreign body reaction, foamy histiocytes, hemosiderin deposition, fibrous tissue, and calcifications. Residual choroid plexus is evident in the right upper portion of panel B.

Microscopically, they are often composed of large collections of cholesterol clefts, surrounded by foreign body giant cells, foamy histiocytes, hemosiderin-laden macrophages, fibrous tissue, and scattered calcifications (Fig. 8.14B and C); residual choroid plexus epithelium is often evident focally (Fig. 8.14B, upper right). Xanthogranulomas are benign and are thought to result from degeneration of the choroid plexus epithelium. Pure xanthomas of the choroid plexus are even rarer. Histologically, they are less complex, composed of foamy macrophages only. Xanthomas may be associated with hyperlipidemia or other systemic disorders. Suggested Readings Ellison D, Kocak M, Figarella-Branger D, et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed. 2011;10: 1–7. Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27:728–743. Parker M, Mohankumar KM, Punchihewa C, et al. C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature. 2014;506:451–455. Paulus W, Janisch W. Clinicopathologic correlations in epithelial choroid plexus neoplasms: a study of 52 cases. Acta Neuropathol (Berl). 1990;80:635–641. Reni M, Gatta G, Mazza E, et al. Ependymoma. Crit Rev Oncol Hematol. 2007;63:81–89. Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary ependymoma. A clinicopathologic and immunohistochemical study of 77 cases. Cancer. 1985;56:883–893. Wolff JE, Sajedi M, Brant R, et al. Choroid plexus tumours. Br J Cancer. 2002;87:1086–1091.

References 1. Lucchesi KM, Grant R, Kahle KT, et al. Primary spinal myxopapillary ependymoma in the pediatric population: a study from the Surveillance, Epidemiology, and End Results (SEER) database. J Neurooncol. 2016;130:133–140. 2. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131: 803–820. 3. Bailey P, Cushing H. Classification of the Tumors of the Glioma Group. Philadelphia: Lippincott; 1926. 4. Lehman NL. Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation? J Neuropathol Exp Neurol. 2008;67:177–188. 5. Teo C, Nakaji P, Symons P, et al. Ependymoma. Childs Nerv Syst. 2003;19:270–285. 6. Rushing EJ, Cooper PB, Quezado M, et al. Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol. 2007;85:297–305.

7. Fassett DR, Pingree J, Kestle JR. The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg. 2005;102:59–64. 8. Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary ependymoma. A clinicopathologic and immunohistochemical study of 77 cases. Cancer. 1985;56:883–893. 9. Witt H, Mack SC, Ryzhova M, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 2011;20:143–157. 10. Reni M, Gatta G, Mazza E, et al. Ependymoma. Crit Rev Oncol Hematol. 2007;63:81–89. 11. Van Gompel JJ, Koeller KK, Meyer FB, et al. Cortical ependymoma: an unusual epileptogenic lesion. J Neurosurg. 2011;114:1187–1194. 12. Nakamizo S, Sasayama T, Kondoh T, et al. Supratentorial pure cortical ependymoma. J Clin Neurosci. 2012;19:1453–1455. 13. Hiniker A, Lee HS, Chang S, et al. Cortical ependymoma with unusual histologic features. Clin Neuropathol. 2013;32:318–323. 14. Yang Y, Tian KB, Hao SY, et al. Primary intracranial extra-axial anaplastic ependymomas. World Neurosurg. 2016;90:704.e1–704.e9. 15. Spallone A, Marchione P, Belvisi D. Radiation-induced anaplastic ependymoma mimicking a skull base meningioma: a case report. Exp Ther Med. 2016;11:455–457. 16. Ma L, Xiao SY, Liu XS, et al. Intracranial extraaxial ependymoma in children: a rare case report and review of the literature. Neurol Sci. 2012;33:151–154. 17. Liu Z, Li J, Liu Z, et al. Supratentorial cortical ependymoma: case series and review of the literature. Neuropathol. 2014;34:243–252. 18. Boccardo M, Telera S, Vitali A. Tanycytic ependymoma of the spinal cord. Case report and review of the literature. Neurochirurgie. 2003;49:605–610. 19. Ragel BT, Osborn AG, Whang K, et al. Subependymomas: an analysis of clinical and imaging features. Neurosurg. 2006;58:881–890. 20. DiLuna ML, Levy GH, Sood S, et al. Primary myxopapillary ependymoma of the medulla: case report. Neurosurg. 2010;66:e1208–e1209. 21. Chakraborti S, Govindan A, Alapatt JP, et al. Primary myxopapillary ependymoma of the fourth ventricle with cartilaginous metaplasia: a case report and review of the literature. Brain Tumor Pathol. 2012;29:25–30. 22. Tseng YC, Hsu HL, Jung SM, et al. Primary intracranial myxopapillary ependymomas: report of two cases and review of the literature. Acta Radiol. 2004;45:344–347. 23. Barton S, Mirza M, Fielding J. A case of subcutaneous myxopapillary ependymoma presenting as a pilonidal sinus. Surgeon. 2004;2:292–293. 24. Tzerakis N, Georgakoulias N, Kontogeorgos G, et al. Intraparenchymal myxopapillary ependymoma: case report. Neurosurg. 2004;55:981. 25. Estrozi B, Queiroga E, Bacchi CE, et al. Myxopapillary ependymoma of the posterior mediastinum. Ann Diag Pathol. 2006;10:283–287. 26. Fouladi M, Helton K, Dalton J, et al. Clear cell ependymoma: a clinicopathologic and radiographic analysis of 10 patients. Cancer. 2003;98:2232–2244. 27. Tomek M, Jayajothi A, Brandner S, et al. Imaging features of spinal tanycytic ependymoma. Neuroradiol J. 2016;29:61–65.

165

Practical Surgical Neuropathology 28. Sun B, Wang C, Wang J, et al. MRI features of intramedullary spinal cord ependymomas. J Neuroimaging. 2003;13:346–351. 29. Chio JY, Chang KH, Yu IK, et al. Intracranial and spinal ependymomas: review of MR images in 61 patients. Korean J Radiol. 2002;3:219–228. 30. Furie DM, Provenzale JM. Supratentorial ependymomas and subependymomas: CT and MR appearance. J Comput Assist Tomogr. 1995;19:518–526. 31. Kahan H, Sklar EM, Post MJ, et al. MR characteristics of histopathologic subtypes of spinal ependymoma. AJNR Am J Neuroradiol. 1996;17:143–150. 32. Zhou S, Xiong J, Pan J, et al. Neuroradiological features of cervical and cervicothoracic intraspinal subependymomas: a study of five cases. Clin Radiol. 2016;71:499, e9–e15. 33. Silverstein JE, Lenchik L, Stanciu MG, et al. MRI of intracranial subependymomas. J Comput Assist Tomogr. 1995;19:264–267. 34. Prayson RA, Suh JH. Subependymomas: clinicopathologic study of 14 tumors, including comparative MIB-1 immunohistochemical analysis with other ependymal neoplasms. Arch Pathol Lab Med. 1999;123:306–309. 35. Bi Z, Ren X, Zhang J, et al. Clinical, radiological, and pathological features in 43 cases of intracranial subependymoma. J Neurosurg. 2015;122:49–60. 36. Inayama Y, Nishio Y, Ishii M, et al. Crush and imprint cytology of subependymoma: a case report. Acta Cytol. 2001;45:636–640. 37. Specht CS, Smith TW, DeGirolami U, et al. Myxopapillary ependymoma of the filum terminale. A light and electron microscopic study. Cancer. 1986;58:310–317. 38. Schittenhelm J, Becker R, Capper D, et al. The clinico-surgico-pathological spectrum of myxopapillary ependymomas: report of four unusual cases and review of the literature. Clin Neuropathol. 2008;27:21–28. 39. Awaya H, Kaneko M, Amatya VJ, et al. Myxopapillary ependymoma with anaplastic features. Pathol Int. 2003;53:700–703. 40. Zec N, De Girolami U, Schofield D, et al. Giant cell ependymoma of the filum terminale. A report of two cases. Am J Surg Pathol. 1996;20:1091–1101. 41. Manasa PL, Uppin MS, Sundaram C. Analysis of squash smear cytology of ependymomas. Acta Cytol. 2012;56:183–188. 42. Ernestus RI, Schroder R, Stutzer H, et al. Prognostic relevance of localization and grading in intracranial ependymomas of childhood. Childs Nerv Sys. 1996;12:522–526. 43. Coli A, Novello M, Massimi L, et al. Cartilage differentiation in ependymoma: histogenetic considerations on a new case. Childs Nerv Syst. 2014;30:1301–1305. 44. Wang X, Zhang S, Ye Y, et al. Ependymoma with cartilagenous metaplasia might have more aggressive behavior: a case report and literature review. Brain Tumor Pathol. 2012;29: 172–176. 45. Mridha AR, Sharma MC, Sarkar C, et al. Anaplastic ependymoma with cartilaginous and osseous metaplasia: report of a rare case and review of literature. J Neurooncol. 2007;82:75–80. 46. Gaur K, Batra VV, Gupta R, et al. Lipomatous ependymoma: report of a rare differentiation pattern with a comprehensive review of literature. Brain Tumor Pathol. 2016;33:209–215. 47. Sharma MC, Arora R, Lakhtakia R, et al. Ependymoma with extensive lipidization mimicking adipose tissue: a report of five cases. Pathol Oncol Res. 2000;6:136–140. 48. Gessi M, Marani C, Geddes J, et al. Ependymoma with neuropil-like islands: a case report with diagnostic and histogenetic implications. Acta Neuropathol (Berl). 2005;109:231–234. 49. Chan AC, Ho LC, Yip WW, et al. Pigmented ependymoma with lipofuscin and neuromelanin production. Arch Pathol Lab Med. 2003;127:872–875. 50. Vajtai I, Mucsi Z, Varga Z, et al. Signet-ring cell ependymoma: case report with implications for pathogenesis and differential diagnosis. Pathol Res Pract. 1999;195:853–858. 51. Vajtai I, von Gunten M, Fung C, et al. Oncocytic ependymoma: a new morphological variant of high-grade ependymal neoplasm composed of mitochondrion-rich epithelioid cells. Path Res Pract. 2011;207:49–54. 52. Shintaku M, Yoshida M, Ikarashi T, et al. Ependymoma with “granular cell” features: report of two cases. Neuropathol. 2012;32:654–664. 53. Gessi M, Kuchelmeister K, Lauriola L, et al. Rare histological variants in ependymomas: histopathological analysis of 13 cases. Virchows Archiv. 2011;459:423–429. 54. Bianchi E, Lejeune J, Sartenaer D, et al. Giant cell ependymoma of the thoracic spinal cord. Acta Neurol Belgica. 2012;112:71–75. 55. Li JY, Lopez JI, Powell SZ, et al. Giant cell ependymoma: report of three cases and review of the literature. Int J Clin Exp Pathol. 2012;5:458–462. 56. Kawano N, Ohba Y, Nagashima K. Eosinophilic inclusions in ependymoma represent microlumina: a light and electron microscopic study. Acta Neuropathol. 2000;99:214–218. 57. Kawano N, Yagishita S, Oka H, et al. Spinal tanycytic ependymoma. Acta Neuropathol. 2001;101:43–48. 58. Dvoracek MA, Kirby PA. Intraoperative diagnosis of tanycytic ependymoma: pitfalls and differential diagnosis. Diagn Cytopathol. 2001;24:289–292. 59. Langford LA, Barre GM. Tanycytic ependymoma. Ultrastruct Pathol. 1997;21:135–142. 60. Park SH, Park HR, Chi JG. Papillary ependymoma: its differential diagnosis from choroid plexus papilloma. J Korean Med Sci. 1996;11:415–421. 61. Min KW, Scheithauer BW. Clear cell ependymoma: a mimic of oligodendroglioma: clinicopathologic and ultrastructural considerations. Am J Surg Pathol. 1997;21:820–826. 62. Kawano N, Yada K, Yagishita S. Clear cell ependymoma. A histological variant with diagnostic implications. Pathol Anat Histopathol. 1989;415:467–472. 63. Figarella-Branger D, Lechapt-Zalcman E, Tabouret E, et al. Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling. Neuro Oncol. 2016;18:919–927.

166

64. Tihan T, Zhou T, Holmes E, et al. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol. 2008;21:165–177. 65. Figarella-Branger D, Civatte M, Bouvier-Labit C, et al. Prognostic factors in intracranial ependymomas in children. J Neurosurg. 2000;93:605–613. 66. Ellison D, Kocak M, Figarella-Branger D, et al. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed. 2011;10:1–7. 67. Vajtai I, Kuhlen D, Kappeler A, et al. Rapid spontaneous malignant progression of supratentorial tanycytic ependymoma with sarcomatous features—“ependymosarcoma”. Pathol Res Pract. 2010;206:493–498. 68. Rodriguez FJ, Scheithauer BW, Perry A, et al. Ependymal tumors with sarcomatous change (“ependymosarcoma”): a clinicopathologic and molecular cytogenetic study. Am J Surg Pathol. 2008;32:699–709. 69. Kleinschmidt-DeMasters BK, Donson AM, Richmond AM, et al. SOX10 distinguishes pilocytic and pilomyxoid astrocytomas from ependymomas but shows no differences in expression level in ependymomas from infants versus older children or among molecular subgroups. J Neuropathol Exp Neurol. 2016;75:295–298. 70. 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. 71. Spence T, Sin-Chan P, Picard D, et al. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol. 2014;128:291–303. 72. Coffin CM, Swanson PE, Wick MR, et al. An immunohistochemical comparison of chordoma with renal cell carcinoma, colorectal adenocarcinoma, and myxopapillary ependymoma: a potential diagnostic dilemma in the diminutive biopsy. Mod Pathol. 1993;6:531–538. 73. Hasselblatt M, Paulus W. Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas. Acta Neuropathol (Berl). 2003;106:385–388. 74. Mannoji H, Becker LE. Ependymal and choroid plexus tumors. Cytokeratin and GFAP expression. Cancer. 1988;61:1377–1385. 75. Svajdler M, Rychly B, Mezencev R, et al. SOX10 and Olig2 as negative markers for the diagnosis of ependymomas: an immunohistochemical study of 98 glial tumors. Histol Histopathol. 2016;31:95–102. 76. Otero JJ, Rowitch D, Vandenberg S. OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms. J Neurooncol. 2011;104:423–438. 77. Ishizawa K, Komori T, Shimada S, et al. Podoplanin is a potential marker for the diagnosis of ependymoma: a comparative study with epithelial membrane antigen (EMA). Clin Neuropathol. 2009;28:373–378. 78. Rodriguez FJ, Scheithauer BW, Robbins PD, et al. Ependymomas with neuronal differentiation: a morphologic and immunohistochemical spectrum. Acta Neuropathol. 2007;113:313–324. 79. Roma AA, Prayson RA. Expression of cyclo-oxygenase-2 in ependymal tumors. Neuropathol. 2006;26:422–428. 80. Prayson RA. Myxopapillary ependymoma: a clinicopathologic study of 14 cases including MIB-1 and p53 immunohistochemistry. Mod Pathol. 1997;10:304–310. 81. You H, Kim YI, Im SY, et al. Immunohistochemical study of central neurocytoma, subependymoma, and subependymal giant cell astrocytoma. J Neurooncol. 2005;74:1–8. 82. Mierau GW, Goin L. Perivascular elastic fibers: a diagnostic feature of ependymoma. Ultrastruct Pathol. 2007;31:251–255. 83. Ho KL. Microtubular aggregates within rough endoplasmic reticulum in myxopapillary ependymoma of the filum terminale. Arch Pathol Lab Med. 1990;114:956–960. 84. Palm T, Figarella-Branger D, Chapon F, et al. Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer. 2009;115:3955–3968. 85. Taylor MD, Poppleton H, Fuller CE, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–335. 86. Rousseau A, Idbaih A, Ducray F, et al. Specific chromosomal imbalances as detected by array CGH in ependymomas in association with tumor location, histological subtype and grade. J Neurooncol. 2010;97:353–364. 87. Olsen TK, Gorunova L, Meling TR, et al. Genomic characterization of ependymomas reveals 6q loss as the most common aberration. Oncol Rep. 2014;32:483–490. 88. Scheil S, Bruderlein S, Eicker M, et al. Low frequency of chromosomal inbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol. 2001;11:113–143. 89. Singh PK, Gutmann DH, Fuller CE, et al. Differential involvement of protein 4.1 family members DAL-1 and NF2 in intracranial and intraspinal ependymomas. Mod Pathol. 2002;15:526–531. 90. Lamszus K, Lachenmayer LK, Heinemann U, et al. Molecular genetic alterations on chromosomes 11 and 22 in ependymomas. Int J Cancer. 2001;91:803–808. 91. Rajeshwari M, Sharma MC, Kakkar A, et al. Evaluation of chromosome 1q gain in intracranial ependymomas. J Neurooncol. 2016;127:271–278. 92. Ward S, Harding B, Wilkins P, et al. Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridization in paediatric ependymoma. Genes Chromosomes Cancer. 2001;32:59–66. 93. Mendrzyk F, Korshunov A, Benner A, et al. Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res. 2006;12:2070–2079. 94. Dyer S, Prebble E, Davison V, et al. Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups. Am J Pathol. 2002;161:2133–2141.

Ependymomas and Choroid Plexus Tumors 95. Puget S, Grill J, Valent A, et al. Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol. 2009;27:1884–1892. 96. Andreiuolo F, Puget S, Peyre M, et al. Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol. 2010;12:1126–1134. 97. Pietsch T, Wohlers I, Goschzik T, et al. Supratentorial ependymomas of childhood carry C11orf95RELA fusions leading to pathological activation of the NF-kappaB signaling pathway. Acta Neuropathol. 2014;127:609–611. 98. Parker M, Mohankumar KM, Punchihewa C, et al. C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature. 2014;506:451–455. 99. Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27:728–743. 100. Wani K, Armstrong TS, Vera-Bolanos E, et al. A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol. 2012;123:727–738. 101. Hoffman LM, Donson AM, Nakachi I, et al. Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma. Acta Neuropathol. 2014;127:731–745. 102. Mack SC, Witt H, Piro RM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014;506:445–450. 103. Bayliss J, Mukherjee P, Lu C, et al. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med. 2016;8: 366ra161. 104. Rogers HA, Kilday JP, Mayne C, et al. Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death. Acta Neuropathol. 2012;123:711–725. 105. Tamiolakis D, Papadopoulos N, Venizelos I, et al. Loss of chromosome 1 in myxopapillary ependymoma suggests a region out of chromosome 22 as critical for tumour biology: a FISH analysis of four cases on touch imprint smears. Cytopathol. 2006;17:199–204. 106. Santi M, Quezado M, Ronchetti R, et al. Analysis of chromosome 7 in adult and pediatric ependymomas using chromogenic in situ hybridzation. J Neurooncol. 2005;72:25–28. 107. Barton VN, Donson AM, Kleinschmidt-DeMasters BK, et al. Unique molecular characteristics of pediatric myxopapillary ependymoma. Brain Pathol. 2010;20:560–570. 108. Kong LY, Wei J, Haider AS, et al. Therapeutic targets in subependymoma. J Neuroimmunol. 2014;277:168–175. 109. Amirian ES, Armstrong TS, Aldape K, et al. Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiol. 2012;39:116–124. 110. Godfraind C, Kaczmarska JM, Kocak M, et al. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol. 2012;124:247–257. 111. Phi JH, Wang KC, Park SH, et al. Pediatric infratentorial ependymoma: prognostic significance of anaplastic histology. J Neurooncol. 2012;106:619–626. 112. Vera-Bolanos E, Aldape K, Yuan Y, et al. Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients. Neuro Oncol. 2015;17:440–447. 113. Metellus P, Barrie M, Figarella-Branger D, et al. Multicentric French study on adult intracranial ependymomas: prognostic factors analysis and therapeutic considerations from a cohort of 152 patients. Brain. 2007;130:1338–1349. 114. Metellus P, Figarella-Branger D, Guyotat J, et al. Supratentorial ependymomas: prognostic factors and outcome analysis in a retrospective series of 46 adult patients. Cancer. 2008;113:175–185. 115. Kawabata Y, Takahashi JA, Arakawa Y, et al. Long-term outcome in patients harboring intracranial ependymoma. J Neurosurg. 2005;103:31–37. 116. Snuderl M, Chi SN, De Santis SM, et al. Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas. J Neuropathol Exp Neurol. 2008;67:911–920. 117. Pejavar S, Polley MY, Rosenberg-Wohl S, et al. Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. J Neurooncol. 2012;106:367–375. 118. Garvin JH, Selch MT, Holmes E, et al. Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group protocol 9942: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2012;59:1183–1189. 119. Virag J, Haberler C, Baksa G, et al. Region specific differences of claudin-5 expression in pediatric intracranial ependymomas: potential prognostic role in supratentorial cases. Pathol Oncol Res. 2016;23:245–252. 120. Amirian ES, Armstrong TS, Gilbert MR, et al. Predictors of survival among older adults with ependymoma. J Neurooncol. 2012;107:183–189. 121. Nuno M, Yu JJ, Varshneya K, et al. Treatment and survival of supratentorial and posterior fossa ependymomas in adults. J Clin Neurosci. 2016;28:24–30. 122. Hollon T, Nguyen V, Smith BW, et al. Supratentorial hemispheric ependymomas: an analysis of 109 adults for survival and prognostic factors. J Neurosurg. 2016;1–9. 123. Bostrom A, von Lehe M, Hartmann W, et al. Surgery for spinal cord ependymomas: outcome and prognostic factors. Neurosurg. 2011;68:302–308. 124. Keil VC, Schmitt AJ, Martin SC, et al. Optimising treatment strategies in spinal ependymoma based on 20 years of experience at a single centre. J Clin Neurosci. 2016;29:52–58. 125. Lin Y, Smith ZA, Wong AP, et al. Predictors of survival in patients with spinal ependymoma. Neurol Res. 2015;37:650–655. 126. Lin Y, Jea A, Melkonian SC, et al. Treatment of pediatric grade II spinal ependymomas: a population-based study. J Neurosurg Pediatr. 2015;15:243–249. 127. Oh MC, Ivan ME, Sun MZ, et al. Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas. Neuro Oncol. 2013;15:208–215.

128. Zawrocki A, Izycka-Swieszewska E, Papierz W, et al. Analysis of the prognostic significance of selected morphological and immunohistochemical markers in ependymomas, with literature review. Folia Neuropathol. 2011;49:94–102. 129. Shu HK, Sall WF, Maity A, et al. Childhood intracranial ependymoma: twenty-year experience from a single institution. Cancer. 2007;110:432–441. 130. Koshy M, Rich S, Merchant TE, et al. Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J Neurooncol. 2011;105:583–590. 131. Sung KW, Lim do H, Lee SH, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age. J Neurooncol. 2012;107:335–342. 132. Iwama J, Ogiwara H, Kiyotani C, et al. Neoadjuvant chemotherapy for brain tumors in infants and young children. J Neurosurg Pediatr. 2015;15:488–492. 133. Venkatramani R, Ji L, Lasky J, et al. Outcome of infants and young children with newly diagnosed ependymoma treated on the “Head Start” III prospective clinical trial. J Neurooncol. 2013;113:285–291. 134. Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol. 2007;8:696–705. 135. Zacharoulis S, Ashley S, Moreno L, et al. Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis. Childs Nerv Sys. 2010;26:905–911. 136. Bouffet E, Hawkins C, Ballourah W, et al. Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Rad Oncol Biol Physics. 2012;83:1541–1548. 137. Fischer C, Haque SS, Huse JT, et al. Extraneural ependymoma: distant bone, lung, liver, and lymph node metastases following bevacizumab. Pediatr Blood Cancer. 2013;60:143–145. 138. Korshunov A, Golanov A, Sycheva R, et al. The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer. 2003;100:1230–1237. 139. Zamecnik J, Snuderl M, Eckschlager T, et al. Pediatric intracranial ependymomas: prognostic relevance of histological, immunohistochemical, and flow cytometric factors. Mod Pathol. 2003;16:980–991. 140. Preusser M, Heinzl H, Gelpi E, et al. Ki78 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathol. 2008;53:39–47. 141. Suzuki S, Oka H, Kawano N, et al. Prognostic value of ki-67 (mib-1) and p53 in ependymomas. Brain Tumor Pathol. 2001;18:151–154. 142. Armstrong TS, Vera-Bolanos E, Bekele BN, et al. Adult ependymal tumors: prognosis and the M.D. Anderson Cancer Center experience. Neuro Oncol. 2010;12:862–870. 143. Weber DC, Wang Y, Miller R, et al. Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. Neuro Oncol. 2015;17:588–595. 144. Akyurek S, Chang EL, Yu TK, et al. Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center. J Neurooncol. 2006;80:177–183. 145. Stephen JH, Sievert AJ, Madsen PJ, et al. Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases. J Neurosurg. 2012;9:646–653. 146. Feldman WB, Clark AJ, Safaee M, et al. Tumor control after surgery for spinal myxopapillary ependymomas: distinct outcomes in adults versus children: a systematic review. J Neurosurg Spine. 2013;19:471–476. 147. Kukreja S, Ambekar S, Sharma M, et al. Outcome predictors in the management of spinal myxopapillary ependymoma: an integrative survival analysis. World Neurosurg. 2015;83:852–859. 148. Agbahiwe HC, Wharam M, Batra S, et al. Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation. Int J Rad Oncol Biol Physics. 2013;85:421–427. 149. Pedziqiatr K, Skowronska-Gardas A, Chojnacka M. Spinal cord ependymoma in children: results of postoperative radiotherapy. Radiother Oncol. 2013;106:181–185. 150. Bandopadhayay P, Silvera VM, Ciarlini PD, et al. Myxopapillary ependymomas in children: imaging, treatment and outcomes. J Neurooncol. 2016;126:165–174. 151. Verma A, Zhou H, Chin S, et al. EGFR as a predictor of relapse in myxopapillary ependymoma. Pediatr Blood Cancer. 2012;59:746–748. 152. Friedrich C, von Bueren AO, Kolevatova L, et al. Epidermal growth factor receptor overexpression is common and not correlated to gene copy number in ependymoma. Childs Nerv Syst. 2016;32:281–290. 153. Chen C, Chen L, Yao Y, et al. Nucleolin overexpression is associated with an unfavorable outcome for ependymoma: a multifactorial analysis of 176 patients. J Neurooncol. 2016;127:43–52. 154. Ailon T, Dunham C, Carret AS, et al. The role of resection alone in select children with intracranial ependymoma: the Canadian Pediatric Brain Tumour Consortium experience. Childs Nerv Syst. 2015;31:57–65. 155. Ilhan I, Berberoglu S, Kutluay L, et al. Subcutaneous sacrococcygeal myxopapillary ependymoma. Med Pediatr Oncol. 1998;30:81–84. 156. Cimino PJ, Agarwal A, Dehner LP. Myxopapillary ependymoma in children: a study of 11 cases and a comparison with the adult experience. Pediatr Blood Cancer. 2014;61:1969–1971. 157. Korshunov A, Witt H, Hielscher T, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol. 2010;28:3182–3190. 158. Kilday JP, Mitra B, Domerg C, et al. Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children’s Cancer Leukaemia Group (CCLG), Societe Francaise d’Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res. 2012;18:2001–2011.

8

167

Practical Surgical Neuropathology 159. Barszczyk M, Buczkowicz P, Castelo-Branco P, et al. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Acta Neuropathol. 2014;128:863–877. 160. Modena P, Buttarelli FR, Miceli R, et al. Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis. Neuro Oncol. 2012;14:1346–1356. 161. Wong VC, Morrison A, Tabori U, et al. Telomerase inhibition as a novel therapy for pediatric ependymoma. Brain Pathol. 2010;20:780–786. 162. Costa FF, Bischof JM, Vanin EF, et al. Identification of microRNAs as potential prognostic markers in ependymoma. PLoS ONE. 2011;6:e25114. 163. Braoudaki M, Lambrou GI, Giannikou K, et al. miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas. Tumour Biol. 2016;37:9887–9897. 164. Koos B, Bender S, Witt H, et al. The transcription factor evi-1 is overexpressed, promotes proliferation, and is prognostically unfavorable in infratentorial ependymomas. Clin Cancer Res. 2011;17:3631–3637. 165. Nambirajan A, Sharma MC, Gupta RK, et al. Study of stem cell marker nestin and its correlation with vascular endothelial growth factor and microvascular density in ependymomas. Neuropathol Appl Neurobiol. 2014;40:714–725. 166. Milde T, Hielscher T, Witt H, et al. Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol. 2012;22:848–860. 167. Moreno L, Popov S, Jury A, et al. Role of platelet derived growth factor receptor (PDGFR) over-expression and angiogensis in ependymoma. J Neurooncol. 2013;111:169–176. 168. Li AM, Dunham C, Tabori U, et al. EZH2 expression is a prognostic factor in childhood intracranial ependymoma: a Canadian Pediatric Brain Tumor Consortium study. Cancer. 2015;121:1499–1507. 169. de Andrade FG, Marie SK, Uno M, et al. Immunohistochemical expression of cyclin D1 is higher in supratentorial ependymomas and predicts relapses in gross total resection cases. Neuropathol. 2015;35:312–323. 170. Rickert CH, Paulus W. Tumors of the choroid plexus. Microsc Res Tech. 2001;52:104–111. 171. Wolff JE, Sajedi M, Brant R, et al. Choroid plexus tumours. Br J Cancer. 2002;87:1086–1091. 172. Raisanen J, Davis RL. Congenital brain tumors. Pathol. 1993;2:103–116. 173. Cannon DM, Mohindra P, Gondi V, et al. Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management. J Neurooncol. 2015;121:151–157. 174. Wrede B, Hasselblatt M, Peters O, et al. Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study. J Neurooncol. 2009;95:383–392. 175. Koh EJ, Wang KC, Phi JH, et al. Clinical outcome of pediatric choroid plexus tumors: retrospective analysis from a single institute. Childs Nerv Syst. 2014;30:217–225. 176. Frye RE, Polling JS, Ma LC. Choroid plexus papilloma expansion over 7 years in Aicardi syndrome. J Child Neurol. 2007;22:484–487. 177. Gozali AE, Britt B, Shane L, et al. Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children’s Hospital Los Angeles (CHLA) experience, 1991-2010. Pediatr Blood Cancer. 2012;58:905–909. 178. Krutilkova V, Trkova M, Fleitz J, et al. Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. Eur J Cancer. 2005;41:1597–1603. 179. Zakrzewska M, Wojcik I, Zakrzewski K, et al. Mutational analysis of hSNF5/INI1 and TP53 genes in choroid plexus carcinomas. Cancer Genet. 2005;156:179–182. 180. Menon G, Nair SN, Baldawa SS, et al. Choroid plexus tumors: an institutional series of 25 patients. Neurol India. 2010;58:429–435. 181. Pillai A, Rajeev K, Chandi S, et al. Intrinsic brainstem choroid plexus papilloma. Case report. J Neurosurg. 2004;100:1076–1078. 182. Scholsem M, Scholtes F, Robe PA, et al. Multifocal choroid plexus papilloma: a case report. Clin Neuropathol. 2012;31:430–434. 183. Karim A, Fowler M, McLaren B, et al. Concomitant choroid plexus papillomas involving the third and fourth ventricles: a case report and review of the literature. Clin Neurol Neurosurg. 2006;108:586–589. 184. Kaptanoglu E, Tun K, Celikmez RC, et al. Spinal drop metastasis of choroid plexus papilloma. J Clin Neurosci. 2007;14:381–383. 185. Taylor MB, Jackson RW, Hughes DG, et al. Magnetic resonance imaging in the diagnosis and management of choroid plexus carcinoma in children. Pediatr Radiol. 2001;31:624–630. 186. Miyagi Y, Natori Y, Suzuki SO, et al. Purely cystic form of choroid plexus papilloma with acute hydrocephalus in an infant. Case report. J Neurosurg. 2006;105:480–484. 187. Barreto AS, Vassallo J, Queiroz Lde S. Papillomas and carcinomas of the choroid plexus: histological and immunohistochemical studies and comparison with normal fetal choroid plexus. Arq Neuropsiquiatr. 2004;62:600–607. 188. Pant I, Chaturvedi S, Suri V, et al. Choroid plexus papilloma with cytologic differential diagnosis—a case report. J Cytol. 2007;24:89–91. 189. Ikota H, Tanaka Y, Tokoo H, et al. Clinicopathological and immunohistochemical study of 20 choroid plexus tumors: their histological diversity and the expression of markers useful for differentiation from metastatic cancer. Brain Tumor Pathol. 2011;28:215–221. 190. Hasselblatt M, Jeibmann A, Guerry M, et al. Choroid plexus papilloma with neuropil-like islands. Am J Surg Pathol. 2008;32:162–166. 191. Corcoran GM, Frazier SR, Prayson RA. Choroid plexus papilloma with osseous and adipose metaplasia. Ann Diagn Pathol. 2001;5:43–47. 192. Aquilina K, Nanra JS, Allcutt DA, et al. Choroid plexus adenoma: case report and review of the literature. Childs Nerv Syst. 2005;21:410–415. 193. Cai C, Stephens BH, Leonard JR, et al. Posterior fossa tumor with distinct choroid plexus papilloma and ependymoma components. Clin Neuropathol. 2015;34:132–135.

168

194. Jeibmann A, Hasselblatt M, Gerss J, et al. Prognostic implications of atypical histologic features in choroid plexus papilloma. J Neuropathol Exp Neurol. 2006;65:1069–1073. 195. Tena-Suck ML, Gomez-Amador JL, Ortiz-Plata A, et al. Rhabdoid choroid plexus carcinoma: a rare histological type. Arq Neuropsiquiatr. 2007;65:705–709. 196. Sav A, Scheithauer BW, Mazzola CA, et al. Oncocytic choroid plexus carcinoma: case report. Clin Neuropathol. 2010;29:14–20. 197. Kim K, Greenblatt SH, Robinson MG. Choroid plexus carcinoma. Report of a case with cytopathologic differential diagnosis. Acta Cytol. 1985;29:846–849. 198. Savage NM, Crosby JH, Reid-Nicholson MD. The cytologic findings in choroid plexus carcinoma: report of a case with differential diagnosis. Diagn Cytopathol. 2012;40:1–6. 199. D’Ambrosio AL, O’Toole JE, Connolly ES, et al. Villous hypertrophy versus choroid plexus papilloma: a case report demonstrating a diagnostic role for the proliferation index. Pediatr Neurosurg. 2003;39:91–96. 200. Ang LC, Taylor AR, Bergin D, et al. An immunohistochemical study of papillary tumors in the central nervous system. Cancer. 1990;65:2712–2719. 201. Figarella-Branger D, Lepidi H, Poncet C, et al. Differential expression of cell adhesion molecules (CAM), neural CAM and epithelial cadherin in ependymomas and choroid plexus tumors. Acta Neuropathol. 1995;89:248–257. 202. Schittenhelm J, Roser F, Tatagiba M, et al. Diagnostic value of EAAT-1 and Kir7.1 for distinguishing endolymphatic sac tumors from choroid plexus tumors. Am J Clin Pathol. 2012;138:85–89. 203. Judkins AR, Burger PC, Hamilton RL, et al. INI1 protein expression distinguishes atypical teratoid/ rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol. 2005;64:391–397. 204. Kato T, Fujita M, Sawamura Y, et al. Clinicopathological study of choroid plexus tumors: immunohistochemical features and evaluation of proliferative potential by PCNA and Ki-67 immunostaining. Noshuyo Byori. 1996;13:99–105. 205. Paulus W, Janisch W. Clinicopathologic correlations in epithelial choroid plexus neoplasms: a study of 52 cases. Acta Neuropathol (Berl). 1990;80:635–641. 206. Kepes JJ, Collins J. Choroid plexus epithelium (normal and neoplastic) expresses synaptophysin. A potentially useful aid in differentiating carcinoma of the choroid plexus from metastatic papillary carcinomas. J Neuropathol Exp Neurol. 1999;58:389–401. 207. Hasselblatt M, Bohm C, Tatenhorst L, et al. Identification of novel diagnostic markers for choroid plexus tumors. A microarray-based approach. Am J Surg Pathol. 2006;30:66–74. 208. Osada H, Mori K, Tamamoto T, et al. Choroid plexus carcinoma secreting carbohydrate antigen 19-9 in an adult. Neurol Med Chir (Tokyo). 2006;46:251–253. 209. Kohmura E, Maruno M, Sawada K, et al. Usefulness of synaptophysin immunohistochemistry in an adult case of choroid plexus carcinoma. Neurol Res. 2000;22:478–480. 210. Beschorner R, Schittenhelm J, Schimmel H, et al. Choroid plexus tumors differ from metastatic carcinomas by expression of the excitatory amino acid transporter-1. Human Pathol. 2006;37:854–860. 211. Jay V, Ho M, Chan F, et al. P53 expression in choroid plexus neoplasms: an immunohistochemical study. Arch Pathol Lab Med. 1996;120:1061–1065. 212. Lv SQ, Song YC, Xu JP, et al. A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma. Med Sci Monit. 2012;18:CS37–CS41. 213. Ghatak NR, McWhorter JM. Ultrastructural evidence for CSF production by a choroid plexus papilloma. J Neurosurg. 1976;45:409–415. 214. Felix I, Phudhichareonrat S, Halliday WC, et al. Choroid plexus tumors in children: immunohistochemical and scanning electron-microscopic features. Pediatr Neurosci. 1987;13:263–269. 215. Grill J, Avet-Loiseau H, Lellouch-Tubiana A, et al. Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas. Cancer Genet. 2002;136:121–125. 216. Rickert CH, Wiestler OD, Paulus W. Chromosomal imbalances in choroid plexus tumors. Am J Pathol. 2002;160:1105–1113. 217. Japp AS, Gessi M, Messing-Junger M, et al. High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors. J Neuropathol Exp Neurol. 2015;74:110–120. 218. Ruland V, Hartung S, Kordes U, et al. Choroid plexus carcinomas are characterized by complex chromosomal alterations related to patient age and prognosis. Genes Chromosomes Cancer. 2014;53:373–380. 219. Nupponen NN, Paulsson J, Jeibmann A, et al. Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas. Mod Pathol. 2008;21:265–271. 220. Hasselblatt M, Mertsch S, Koos B, et al. TWIST-1 is overexpressed in neoplastic choroid plexus epithelial cells and promotes proliferation and invasion. Cancer Res. 2009;69:2219–2223. 221. Tong Y, Merino D, Nimmervoll B, et al. Cross-species genomics identifies TAF12, NFYC, and RAD54L as choroid plexus carcinoma oncogenes. Cancer Cell. 2015;27:712–727. 222. Mangerel J, Price A, Castelo-Branco P, et al. Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors. Acta Neuropathol. 2014;128:853–862. 223. Thomas C, Sill M, Ruland V, et al. Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups. Neuro Oncol. 2016;18:790–796. 224. Bettegowda C, Adogwa O, Mehta V, et al. Treatment of choroid plexus tumors: a 20 year single institutional experience. J Neurosurg Pediatr. 2012;10:398–405. 225. Meyers SP, Khademian ZP, Chuang SH, et al. Choroid plexus carcinomas in children: MRI features and patient outcomes. Neuroradiol. 2004;46:770–780. 226. Wrede B, Liu P, Wolff JE. Chemotherapy improves the survival of patients with choroid plexus carcinoma: a meta-analysis of individual cases with choroid plexus tumors. J Neurooncol. 2007;85:345–351.

Ependymomas and Choroid Plexus Tumors 227. Lafay-Cousin L, Keene D, Carret AS, et al. Choroid plexus tumors in children less than 36 months: the Canadian Pediatric Brain Tumor Consortium (CPBTC) experience. Childs Nerv Syst. 2011;27:259–264. 228. Sun MZ, Oh MC, Ivan ME, et al. Current management of choroid plexus carcinomas. Neurosurg Rev. 2014;37:179–192, discussion 192. 229. Lafay-Cousin L, Mabbott DJ, Halliday W, et al. Use of ifosfamide, carboplatin, and etoposide chemotherapy in choroid plexus carcinoma. J Neurosurg Pediatr. 2010;5:615–621. 230. Bahar M, Kordes U, Tekautz T, et al. Radiation therapy for choroid plexus carcinoma patients with Li-Fraumeni syndrome: advantageous or detrimental? Anticancer Res. 2015;35:3013–3017.

231. Ogiwara H, Dipatri AJ Jr, Alden TD, et al. Choroid plexus tumors in pediatric patients. Br J Neurosurg. 2012;26:32–37. 232. Passariello A, Tufano M, Spennato P, et al. The role of chemotherapy and surgical removal in the treatment of choroid plexus carcinomas and atypical papillomas. Childs Nerv Syst. 2015;31:1079–1088. 233. Zaky W, Dhall G, Khatua S, et al. Choroid plexus carcinoma in children: the Head Start experience. Pediatr Blood Cancer. 2015;62:784–789.

8

169