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Ependymal Tumors César R. Lacruz 7.1 Introduction Ependymal tumors---ependymoma, subependymoma, and myxopapillary ependy-moma---represent a broad group of gliomas that manifests morphologic and ultra-structural evidence of ependymal differentiation. They account for 5% to 9% of all primary brain tum...

Ependymal Tumors César R. Lacruz 7.1 Introduction Ependymal tumors---ependymoma, subependymoma, and myxopapillary ependy-moma---represent a broad group of gliomas that manifests morphologic and ultra-structural evidence of ependymal differentiation. They account for 5% to 9% of all primary brain tumors in adults, 6% to 12% in children, and up to 30% in infants. Ependymal tumors are considered to originate from radial glial-like stem cells lin-ing the wall of the ventricles or the wall of the spinal canal, which is why they can occur along the entire neuroaxis. Because of advanced molecular testing techniques such as DNA methylation prof i ling, categorization of ependymomas has completely changed in the 2021 WHO classif i cation from being based on morphology to being based on location and molecular alteration into molecular groups across the supra-tentorial, posterior fossa, and spinal compartments. Two molecularly def i ned types of supratentorial ependymoma (with ZFTA or YAP1 fusion), two molecularly def i ned types of posterior fossa ependymoma (PFA and PFB), and a spinal ependymoma def i ned by the presence of MYCN amplif i ca-tion are now listed in this new classif i cation scheme. Also listed in the new WHO classif i cation are ependymomas def i ned by anatomic location but not by molecular alteration (e.g., supratentorial ependymoma, posterior fossa ependymoma). These designations can be used either when complete molecular classif i cation is not avail-able (NOS) or when tumors have been fully characterized but do not fi t within the established classif i cation system (NEC). C. R. Lacruz (\*) Complutense University School of Medicine, Madrid, Spain Synlab Pathology, Madrid, Spain © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. R. Lacruz (ed.), Central Nervous System Tumors, https://doi.org/10.1007/978-3-031-51078-6\_7 158 7.2 Ependymoma 7.2.1 Definition Ependymoma is a circumscribed glioma that focally demonstrates pseudorosettes or ependymal (true) rosettes and comprises uniform small cells with round to oval nuclei embedded in a fi brillary matrix (CNS WHO grade 2 or 3). 7.2.2 Localization and Clinical Manifestations There is a clear correlation among the locations of ependymomas and symptom-atology: Posterior fossa ependymomas mainly arise in the region of the fourth ventricle and may present with hydrocephalus, symptoms of increased intracra-nial pressure, and cerebellar ataxia. Supratentorial ependymomas are localized in the cerebral hemispheres (with or without an obvious connection with the ventricular system) and may present with seizures, focal neurologic def i cits, and symptoms of intracranial hypertension. Spinal cord ependymomas are intramed-ullary tumors that usually arise within cervical-thoracic segments and present with neck/back pain, numbness and paresthesia of the distal extremities, and atrophy of hand musculature. 7.2.3 Imaging and Gross Pathology The majority of all intracranial ependymomas (60%) are located in the posterior fossa and most often appear as well-circumscribed, variably enhancing, intra-ventricular masses that partially or completely fi ll the fourth ventricle. Intraparenchymal lesions are usually supratentorial (rarely they are found in the cerebellum), and generally they are large and variable in appearance, ranging from completely solid, enhancing masses to cysts with a mural nodule, or more heterogeneous masses. Spinal ependymomas are intramedullary, sausage-shaped lesions that commonly involve several contiguous spinal segments; ros-tral and caudal elongated cysts ("syringomyelia") are frequently encountered. Grossly, ependymomas tend to be well-def i ned, lobulated gray or tan-colored soft masses that often adjust themselves in form and size to their surroundings, which facilitate their complete resection. They may be partially cystic or con-tain areas of hemorrhage, necrosis, or calcif i cation. Tumors arising in the caudal fourth ventricle often fl ow through the foramina of Luschka and Magendie to grow into the cerebellopontine cistern surrounding the brainstem, as well as down through the foramen magnum---like a "tongue" of tumor---into the upper cervical spine (plastic ependymomas). This is a characteristic feature and can be seen on neuroimaging modalities. C. R. Lacruz 159 7.2.4 Molecular/Genetics The molecular characteristics of ependymomas, with different epidemiology and prognosis, are site-specif i c and form the basis of the 2021 WHO classif i cation scheme that consists of six distinct subgroups spread evenly among the supratento-rial, posterior fossa, and spinal compartments (Table 7.1). Table 7.1 Key characteristics of the six molecular subgroups of ependymoma Group Genetics WHO grade Age at presentation Outcome Supratentorial ependymomas ST-ZFTA ZFTA fusions, Chromothripsis, CDKN2A/2B loss 2/3 All age groups Intermediate ST-YAP1 YAP1 fusions 2/3 Infants/children Good Posterior fossa ependymomas PFA EZHIP mutations, H3 K27M mutations, 1q gain 2/3 Infants/children Poor PFB Chromosomal instability 2/3 Adolescents/adults Good Spinal ependymomas SP-EP NF2 mutations 2/3 Children/adults Good SP-MYCN MYCN-amplif i ed a Children/adults Poor PFA posterior fossa group A ependymoma; PFB posterior fossa group B ependymoma; SP-EP spinal ependymoma; SP-MYCN spinal ependymoma, MYCN-amplif i ed; ST-YAP1 supratentorial ependymoma, YAP-1 fused; ST-ZFTA supratentorial ependymoma, ZFTA fused; a no WHO grading of tumor 7 Ependymal Tumors Supratentorial ZFTA-Fused Ependymoma It is characterized by a gene fusion involving ZFTA, most commonly ZFTA::RELA fusion. ZFTA rearrangements are usually due to chromothripsis (massive chromosome fragmentation and abnormal reassembly) involving chromosome 11. In some cases, the homozygous deletion of CDKN2A/B is observed, which can have a negative impact on the prognosis. ZFTA fusion-positive ependymomas are more common, comprising 25--58% of all supratentorial ependymomas in adults and 66--84% in children. Supratentorial YAP1-Fused Ependymoma It is characterized by genomic fusion of the YAP1 gene with MAMLD1 (most cases) or other partner genes (e.g., YAP1::FAM118B). YAP1 fusion-positive ependymo-mas, which show more indolent behavior than ZFTA fusion-positive ependymomas, are rare and tend to occur primarily in young children. PFA Ependymoma It is characterized by loss of H3K27me3 due to overexpression of EZHIP or H3 p.K27M mutation. Tumors in this subtype have relatively low genomic instability; the most frequent alterations present are the gain of chromosome 1q (a poor prognos-tic indicator) and 9q. Additionally, PFA ependymoma exhibits a characteristic DNA methylation prof i le. PFA ependymomas occur mainly in infants, most have anaplas-tic features and have a signif i cantly worse prognosis than PFB ependymomas. 160 PFB Ependymoma In this tumor expression of nuclear histone H3K27me3 is retained, and several cyto-genetic changes involving entire chromosomes or chromosome arms have been detected such as 22q loss, monosomy 6, and monosomy 18. Additionally, PFB ependymoma shows a characteristic DNA methylation prof i le. PFB ependymomas occur manily in older children and adults, do not usually show features of anaplasia and have a better prognosis than PFA ependymomas. Spinal Ependymomas Spinal ependymomas have frequent loss of chromosome 22q (like PFB ependymo-mas) and mutations of NF2. Accordingly, patients with neurof i bromatosis type 2 develop spinal ependymomas (often multiple). Spinal ependymomas are asociated wit a favorable outcome in children and adults. MYCN-Amplified Spinal Ependymoma It is characterized by a high-level of MYCN amplif i cation and exhibits a DNA meth-ylation prof i le distinct from that of the other ependymal tumor types. MYCN- amplif i ed ependymoma is a rare (only 27 reported cases) aggressive tumor associated with poor progression-free and overal survival compared with that of other spinal ependymomas. 7.2.5 Histopathology and Grading Ependymoma grading is controversial and probably not as important as molecular features (see Table 7.1). Nonetheless, tumors can be given a grade of 2 or 3 based on histological features. Ependymoma, CNS WHO Grade 2 (Previously Classic Ependymoma) Generally, ependymomas are moderately cellular glial tumors with a circumscribed (e.g., no inf i ltrative) growth pattern. Key architectural features include perivascular pseudorosettes (radial formation of tumor cells around blood vessels) and true epen-dymal rosettes and canals (radial formation of cuboidal to prismatic tumor cells around a central rounded or elongated lumen, respectively). Although more specif i c than pseudorosettes, true rosettes and canals are seen in only a minority of cases. Cellularity of ependymomas comprises uniform small cells embedded in a fi brillary matrix that varies greatly from case to case and even regions within the same case. The nuclei are isomorphic, round to oval, and display abundant speckled chromatin (Fig. 7.1a--f). Geographic infarct-like zones of necrosis may occasionally be seen and do not inf l uence the prognosis. However, both palisading necrosis and micro-vascular proliferation are absent in these grade 2 tumors. C. R. Lacruz 161 a b c d e f Fig. 7.1 Ependymoma, CNS WHO grade 2. (a) Posterior fossa, cellular ependymoma with typi-cal nuclear-free spaces around vessels (perivascular pseudorosettes). (b) Larger pseudorosettes with tumor cells radially arranged around blood vessels with an intervening acellular zone. (c) Numerous true ependymal rosettes with periluminal cuboidal or columnar cells. (d) Ependymal canals with characteristic elongated lumen. (e) Uniform small cells embedded in a fi brillary matrix. \(f) Tumor cells have uniform, round to void nuclei with speckled chromatin and poorly def i ned fi brillary cytoplasm 7 Ependymal Tumors 162 a b c d Fig. 7.2 Ependymoma, CNS WHO grade 3. (a) Hypercellularity and high N/C ratio. (b) Nuclear overlapping and mitosis (arrow). (c) Microvascular proliferation typically characterized by multi-layered endothelial cells. (d) Carcinoma-like architecture and necrosis with abundant apop-totic bodies Ependymoma, CNS WHO Grade 3 (Previously Anaplastic Ependymoma) In addition to the histological features of conventional grade 2 ependymomas, the presence of hypercellularity with high nuclear to cytoplasmic ratio, increased mitotic count (e.g., \>5/10 HPF or \>10/10 HPF depending on series), widespread microvascular proliferation, and/or necrosis of the palisading type with abun-dant apoptotic bodies are diagnostic features of ependymoma grade 3 (Fig. 7.2a--d). Histological Patterns Several historically recognized histological patterns, including clear cell ependy-moma, papillary ependymoma, and tanycytic ependymoma, can be a prominent component of both classic and anaplastic ependymomas. However, these are no longer recognized as distinct subtypes. Clear cell ependymoma contains sheets of cells with clear, glycogen-rich cytoplasm (perinuclear halos), which is why it can mimic oligodendroglioma. The presence of thin branching "chicken-wire" capillar-ies may add to this diagnostic challenge (Fig. 7.3a). Papillary ependymoma shows C. R. Lacruz 163 a b c d Fig. 7.3 Ependymoma, histologic patterns. (a) Clear cell ependymoma contains sheets of cells with clear cytoplasm and well-def i ned plasma membrane, resembling oligodendroglioma. 7 Ependymal Tumors Perivascular anucleate zones can be subtle. (b) Papillary structures with gliof i brillary stroma char-acterize the papillary variant. (c) Pseudopapillary pattern featuring fi ngerlike projections lined by a single layer or multiple layers of cuboidal cells. (d) A fascicular pattern of elongated spindle cells with less conspicuous pseudorosettes characterizes the tanycytic variant a predominance of epithelial-like (cuboidal to columnar) cells lining papillae and fi ngerlike projections, which is why it may be confused with choroid plexus papil-loma. However, fi brovascular cores are not a feature (Fig. 7.3b, c). Tanycytic epen-dymoma is typif i ed by elongated spindle bipolar cells resembling the primitive radial glia-like tanycytes (from the Greek tanyos, meaning to stretch). With a pre-dominantly fascicular architecture together with the common absence of ependymal rosettes and pseudorosettes, tanycytic ependymoma may resemble pilocytic astro-cytoma and schwannoma (Fig. 7.3d). Other Patterns Rare ependymomas have been reported with extensive tumor cell vacuolation and signet ring formation, extensive hyalinization/sclerosis, lipomatous metaplasia, widespread pleomorphic giant cells, and melanotic differentiation (Fig. 7.4a--d). Also mixed subependymoma/ependymoma and myxopapillary ependymoma/epen-dymoma have been reported. Such combined tumors are graded on the basis of the ependymoma component. 164 a b c d Fig. 7.4 Ependymoma, other histologic patterns. (a) Ependymoma displaying numerous vacuoles and calcif i cations. (b) In this case, signet ring cells are predominant. (c) Ependymoma with promi-nent nuclear pleomorphism and giant cell formation. (d) This ependymoma shows ependymal (above) and melanocytic (below) components in combination 7.2.6 Cytology Ependymomas are cellular tumors that smear in fi brillar tissue fragments with dis-cohesive sheets of relatively small and uniform cells. Just as in histology, perivascu-lar pseudorosettes are responsible for the "arboreal" or "caterpillar" appearance seen in the smears of many cases. Not infrequently, smears can display glial and epithelial cellular properties in combination. Anaplastic (WHO grade 3) ependymo-mas show crowded tissue fragments with tumor cells displaying dark and irregular nuclei (Fig. 7.5a--d). 7.2.7 Immunophenotype Ependymomas typically express S100 protein, GFAP, and vimentin, whereas EMA often shows a characteristic dot-like perinuclear or ringlike pattern of cytoplasmic positivity (Fig. 7.6a--d). CD99, D2-40 (podoplanin), and CD56 (NCAM) are also frequently positive, though neither is entirely specif i c. On the other hand, OLIG2 expression is usually absent. C. R. Lacruz 165 a b c d Fig. 7.5 Ependymoma, cytologic features. (a) The characteristic branching "arboreal" appear-ance of pseudorosettes can be seen well in smears. Tumor cells remain tethered to the vessel wall by their glial tails. (b) High-magnif i cation view showing unevenly distributed glial cells in a fi bril-lary background. (c) In some cases, distinct dual glial and epithelial cell populations can be seen in the same preparation. (d) Nuclei in WHO grade 3 (anaplastic) ependymoma are larger and more clefted and grooved than in grade 2 (classic) ependymoma Molecular Groups and Surrogate IHC Supratentorial ependymoma, ZFTA::RELA fusion-positive: L1CAM expression (cytoplasmic), nuclear p65 (RELA) expression. Supratentorial ependymoma, YAP1 fusion-positive: there is not expression of L1CAM and tumor cell nuclei are nega-tive for p65 (RELA). PFA ependymoma: the loss of histone H3K27me3 can be evaluated by immunohistochemistry (loss of nuclear expression) allowing the diag-nosis of PFA; overexpression of EZHIP can also be identif i ed by immunohisto-chemical reaction. PFB ependymoma: retention of nuclear H3K27me3 expression but this fi nding is not specif i c. Spinal ependymoma, MYCN-amplif i ed: nuclear MYCN expression. Spinal ependymoma: MYCN expression is absent (Fig. 7.7a--f). 7 Ependymal Tumors 7.2.8 Differential Diagnosis Due to the many morphologic patterns of ependymoma, the differential diagnosis is long: 166 a b c d Fig. 7.6 Ependymoma, immunophenotype. (a--d) Immunohistochemistry shows many tumor cells expressing GFAP (a), and universal nuclear and cytoplasmic expression of S100 (b). Immunoreactivity for EMA is present in a variable number of tumor cells and usually manifests as paranuclear dot-like or ring structures (c), and/or along the luminal surface of true ependymal rosettes (d) Astrocytoma, IDH-mutant: Inf i ltrating (diffuse) pattern, no perivascular pseudoro-settes, no true rosettes, EMA (−), OLIG2 (+), IDH1 R132H (+). Pilocytic astrocytoma: Compact areas with Rosenthal fi bers, loose areas with eosin-ophilic granular bodies, OLIG2 (+), SOX10 (+). Pilomyxoid astrocytoma: Abundant myxoid background, SOX 2 (+), p16 (+). Astroblastoma, MN1-altered: Perivascular processes in pseudorosettes shorter and wider, extensive vascular hyalinization, MN1 gene rearrangements. Angiocentric glioma: Inf i ltrative growth pattern, longitudinal as well as radial ori-entation of perivascular cells, subpial vertical palisades. Embryonal tumor with multilayered rosettes vs anaplastic ependymoma: Primitive small blue cells, LIN28A (+), C19MC amplif i cation. Medulloblastoma vs anaplastic ependymoma: Neuroblastic (Homer Wright) rosettes, no true rosettes, synaptophysin diffusely (+). Oligodendroglioma vs clear cell pattern: Inf i ltrating (diffuse) pattern, neuronal sat-ellitosis, OLIG2 (+), IDH1 R132H (+), 1p/19q codeletion. C. R. Lacruz 167 a b c d e f Fig. 7.7 Ependymoma, molecular groups and surrogate IHC. (a--b) Supratentorial ependymoma, ZFTA fusion-positive: universal cytoplasmic expression of L1CAM (a), and nuclear immunoreac-tivity for p65 (encoded by RELA) (b). (c--d) PFA ependymoma: absence of nuclear expression of for H3K27me3 (c), and nuclear immunoreactivity for EZHIP (d). (e) PFB ependymoma: expres-sion of H3K27me3 is present in all tumor cells. (f) Spinal ependymoma, MYCN-amplif i ed: exten-sive nuclear immunoreactivity for MYCN Neurocytoma vs clear cell pattern: Cytologically monotonous, diffuse and strong synaptophysin (+), EMA (−), GFAP (−). 7 Ependymal Tumors Schwannoma vs tanycytic pattern: Almost always extra-axial, less intensely GFAP (+), SOX10 (+). 168 Choroid plexus tumors vs papillary pattern: Diffuse cytokeratin (+), no strong GFAP (+), KIR7.1 (+). 7.2.9 Treatment and Prognosis Complete surgical resection and a second-look surgery for resection of residual tumor are increasingly advocated. Posterior fossa tumors may cause hydrocephalus that require shunting. In addition to surgical intervention, postoperative radiother-apy is considered the standard of care for lowering risk of recurrence. Poor prognos-tic factors include a fourth ventricular location, grade 3 tumors (formerly known as anaplastic), and incomplete resection. Thus, generally, children have a worse prog-nosis (both fourth ventricular location and anaplastic variant are more common in children). Overall, the 5-year survival rate in children ranges from 50% to 75%. Molecular Subgroup Prognosis Three molecular subgroups, i.e., ZFTA fusion-positive supratentorial ependymoma, PFA ependymoma, and MYCN-amplif i ed spinal ependymoma, have the worst out-come. Homozygous deletion of CDKN2A and/or CDKN2B has been identif i ed as an independent predictor of dismal prognosis in a series of ependymomas with ZFTA::RELA fusions. 7.3 Myxopapillary Ependymoma 7.3.1 Definition and Epidemiology Myxopapillary ependymoma is a glial neoplasm characterized by the radial arrange-ment of epithelioid to spindle glial cells around vascularized myxoid stromal cores or rounded microcysts (CNS WHO grade 2). They represent 13% of all spinal epen-dymomas and are the most common tumors of the cauda equina region. Myxopapillary ependymomas occur at all ages but tend to have an earlier clinical presentation than other spinal ependymomas, with a mean age at presentation of 35 years. 7.3.2 Localization and Clinical Manifestations These tumors are located almost exclusively in the distal regions of the spinal cord (conus medullaris, fi lum terminale, and cauda equina) as intradural/extramedullary masses. Less frequently, tumors may arise in the upper levels of the spinal cord or may occur extradurally, arising in the sacrum or subcutaneous tissues around the sacro- coccyx. Clinically, they are associated with chronic low back, leg, or sacral pain, and it can be accompanied by sciatica, leg weakness, impotence, or sphincter dysfunction. C. R. Lacruz 169 7.3.3 Imaging and Gross Pathology On neuroimaging, myxopapillary ependymoma usually appear as a sharply circum-scribed, contrast-enhancing intradural spinal mass. Grossly, they are typically lobu-lated, oval, or sausage-shaped soft "bags" that may be invested by a fi brous pseudo capsule derived from the stroma of the fi lum. 7 Ependymal Tumors 7.3.4 Molecular/Genetics Recurrent gains of chromosome 16 and losses of chromosome 10 have been docu-mented. Myxopapillary ependymomas with a classic morphology are easily recog-nized, but they also have a unique DNA methylation prof i le that represents an ancillary method for unresolved lesions. 7.3.5 Histopathology Myxopapillary ependymoma characteristically shows a radial arrangement of cuboidal to elongated tumor cells around vascularized myxoid stromal cores or rounded microcysts (Fig. 7.8a). Tumor cells spindling and fascicular growth are common. The PAS and Alcian blue-positive myxoid material accumulate between tumor cells and blood vessels, being also collected in microcysts (Fig. 7.8b). Common secondary alterations include fi brosis, hemorrhage, and hemosiderin deposition. Rarely, examples termed "anaplastic myxopapillary ependymomas" manifest hypercellularity and reduced mucin in association with at least two of the following features: ≥ 2 mitosis/mm2, Ki-67 labeling index ≥10%, microvascular proliferation, and spontaneous (not induced) necrosis. 7.3.6 Cytology Smear preparations recapitulate the histologic fi ndings, containing aggregates of epithelioid to glial spindle cells arranged around vascularized-stromal cores and globules of metachromatic myxoid material (Fig. 7.8c, d). 7.3.7 Immunophenotype Positive stains: GFAP (Fig. 7.8e), S100 (50%), CD99, CD56 (NCAM), and variable EMA (Fig. 7.8f). Negative stains: OLIG2, NeuN, chromogranin A, IDH1 R132H, cytokeratins. 170 a b c d e f Fig. 7.8 Myxopapillary ependymoma. (a) Typical histology includes epithelioid cells arranged around hyalinized vascular core papillary structures and rounded mucinous microcysts. (b) Small collections of myxoid material are useful in the identif i cation of examples composed of epithelioid cells in conf l uent sheets. (c) Highly cellular smear preparation with slim columnar cells oriented toward fi bro-myxoid cores. (d) On smears, Diff-Quik stain highlights characteristic globules of metachromatic myxoid material. (e) Tumor cells surround mucinous or hyalinized vessels and strongly express GFAP. (f) Dot-like cytoplasmic EMA labeling is often focal C. R. Lacruz 171 7.3.8 Differential Diagnosis Because of its location and the presence of myxoid matrix, the differential diagnosis should be made with schwannoma, paraganglioma, and chordoma. 7.4.2 Localization and Clinical Manifestations The preferential location is attached to the wall of fourth (most commonly) or lat-eral ventricles, followed distantly by the third ventricle and central canal of the spinal cord. Subependymomas are usually asymptomatic and incidentally detected, 7 Ependymal Tumors Schwannoma: Antoni A and B tissue, Verocay bodies, no epithelial features, SOX 10 (+), GFAP (−) or focal. Cauda equina neuroendocrine tumor (paraganglioma): Acinar architecture (zell-ballen), no myxoid background, chromogranin A (+), GFAP (−). Chordoma: Physaliphorous cells, no glial cells, diffusely cytokeratin (+), brachyury (+), GFAP (−). 7.3.9 Staging Since myxopapillary ependymomas may exhibit leptomeningeal dissemination, craniospinal MRI and CSF cytology after initial surgery and diagnosis have been recommended. 7.3.10 Treatment and Prognosis Gross total resection may be curative, but incomplete removal may cause local or widespread dissemination. Radiotherapy improves progression-free survival. Tumors with anaplastic histology may carry an increased risk of aggressive behavior. 7.4 Subependymoma 7.4.1 Definition and Epidemiology Subependymomas are slow-growing, discrete gliomas characterized by the cluster-ing of uniform tumor cell nuclei in an abundant fi brillary matrix prone to microcys-tic change (CNS WHO grade 1). They occur more frequently (\~90%) in middle-age and elderly patients and represent approximately 8% of all ependymal tumors and \