Central Nervous System





Diffuse Astrocytic Tumors


Diffuse Astrocytomas of Each Grade are Now Divided Into One of Two Diagnostic Categories Based Upon the Isocitrate Dehydrogenase (IDH Gene Mutation Status (IDH Mutant or IDH Wildtype). if the Testing is Not Available or Cannot be Performed the Diagnosis is Specified as Diffuse Astrocytoma, Anaplastic Astrocytoma, or Glioblastoma, NOS (Not Otherwise Specified). The IDH Mutation May be Either in the IDH1 or IDH2 Genes. Most Low-Grade Diffuse Astrocytomas Have a Mutation in the IDH1 Gene, Most Commonly R132H


Clinical Features


Diffuse Astrocytomas, IDH Mutant, Wildtype, and Not Otherwise Specified





  • Commonly produce headaches, seizures, or focal neurologic deficits; symptoms related to the location of the tumor; they occur most frequently in cerebral hemisphere, most often in the frontal lobes. On MRI, low-grade and anaplastic astrocytomas show an ill-defined area of low signal on T1 with no contrast enhancement



  • Astrocytomas, IDH mutant, WHO grade II, occur in adults at mean age of 30 to 40 years and at a slightly older age when anaplastic astrocytoma, IDH mutant WHO grade III (between 35 and 45 years)



  • Both diffuse astrocytomas and anaplastic astrocytomas, IDH mutant or wildtype (WT), have an inherent tendency to progress to higher grades eventually transforming into glioblastoma (WHO grade IV). Glioblastomas, IDH WT occur commonly between ages 55 and 85 years with a mean of 62 years; these individuals present with a mass lesion that already shows features of high grade on MRI (areas of necrosis and ring-shaped enhancement) while glioblastomas IDH mutant occur at a mean of 45 years



  • Gliomatosis cerebri is a pattern of extensive involvement of the brain that may be evident on MRI. It shows diffuse enlargement of involved areas without a focal mass identifiable (T1 hypointensity, T2 hyperintensity); no enhancement



Diffuse Midline Glioma





  • Occurs mostly in children but can also occur in adults.



  • Predominates in midline, in brainstem, thalamus, spinal cord; less commonly cerebellum



  • MRI scans may show hemorrhage, necrosis, and contrast enhancement



Gross Pathology





  • Diffuse astrocytoma, WHO grade II; and anaplastic astrocytoma, WHO grade III; IDH mutant or WT have variable appearances ranging from subtle, barely visible lesion to large, soft, gelatinous, gray-white ill-defined infiltrative masses that blur the gray-white border and expand the cortex or white matter



  • Glioblastoma IDH mutant or WT: usually large, ill-defined, and centered in the white matter, often extending bilaterally and/or into the brainstem, with associated edema, hemorrhage, and necrosis




    • Extension across the corpus callosum is common: “butterfly glioma”




  • Giant cell glioblastomas and gliosarcoma may each be sharply circumscribed and firm owing to presence of connective tissue components



  • Diffuse midline glioma (H3k27M mutant): diffuse infiltration of parenchyma is typical with areas of necrosis and hemorrhage



Histopathology


See Figure 19.1 .




Figure 19.1


A, Low-grade astrocytoma. Cellular infiltrate of neoplastic astrocytes showing nuclear enlargement, nuclear membrane irregularity, and slight hyperchromasia. B, Anaplastic astrocytoma. Highly cellular tumor composed of neoplastic astrocytes with moderate nuclear pleomorphism, hyperchromatism, nuclear membrane irregularity, and mitoses. C, Glioblastoma (GBM). Notice the prominent area of necrosis with pseudopalisading. D, GBM. Neoplastic astrocytes surrounding endothelial proliferation (glial fibrillary acidic protein stain).


Astrocytoma IDH Mutant (WHO Grade II)





  • Hypercellular (relative to normal brain), infiltrative, ill-defined lesions typically centered in the white matter or less commonly the cerebral cortex



  • Neoplastic astrocytic nuclei vary from cigar shaped to oval with slight pleomorphism and hyperchromatism. They have fibrillary processes or scant not visible cytoplasmthat is not visible



  • Background microcysts may be present



  • Presence of a single mitosis should not prompt designation as an anaplastic astrocytoma



  • Sample size is important in this determination; a small sample with mitosis suggests an anaplastic designation, but a single mitosis in a large resection should not prompt a higher-grade diagnosis



Gemistocytic Astrocytoma IDM (WHO Grade II)





  • Neoplastic astrocytes have large cell bodies with abundant eosinophilic cytoplasm and short fibrillary processes and eccentric nuclei



  • Presence of at least 20% of gemistocytes is necessary for this designation



  • This subtype has a high tendency to progress to anaplastic astrocytoma



  • Mitotic figures are typically scant or absent



Anaplastic Astrocytomas IDH Mutant (WHO Grade III)





  • Tumor shows higher cellularity, increased nuclear pleomorphism, and hyperchromasia



  • Mitotic figures are present (see the previous discussion of mitoses in astrocytoma)



  • MIB-1 is elevated (5% to 10%) and glioblastomas (15% to 20%)



Glioblastoma IDH Mutant or Wildtype (WHO Grade IV)





  • Infiltrative, highly cellular tumor with a wide range of abnormal cytology



  • Cells with hyperchromatic, pleomorphic nuclei and ill-defined fibrillary cytoplasm are usually present



  • The following may also be seen: multinucleated cells, lipidized cells, granular cells, and epithelioid change



  • Numerous mitotic figures are always present



  • Rarely, metaplastic elements are present, including squamous or adenoid differentiation, bone, or cartilage (more common in gliosarcoma)



  • Required for diagnosis




    • Endothelial cell proliferation or areas of necrosis with or without pseudopalisading




Variants of Glioblastoma





  • Giant cell glioblastoma (WHO grade IV)




    • Large, bizarre cells with markedly pleomorphic nuclei and multinucleation



    • May have increased reticulin network and appear more circumscribed




  • Gliosarcoma (WHO grade IV)




    • Defined by the presence of a sarcomatous component in addition to a malignant astrocytic component in the neoplasm; molecular studies support a common origin of both cell types



    • Astrocytic component is high grade and may occasionally display adenoid or squamous metaplasia



    • Sarcomatous component most often shows histology suggesting fibrosarcoma




  • Epithelioid glioblastoma (WHO grade IV)




    • Cells characterized by circumscribed cytoplasm (epithelioid cells); occasionally rhabdoid cells are present




  • Small cell astrocytoma (WHO grade III or IV)




    • Monomorphous oval nuclei, mild nuclear hyperchromasia, occasional small nucleoli, scant cytoplasm, many mitoses



    • Endothelial proliferation or pseudopalisading necrosis may be present (if present, grade IV; if absent, grade III)



    • May exhibit architectural features causing confusion with oligodendroglioma, such as chicken-wire vasculature, clear halos, perineuronal satellitosis, and calcifications




  • Glioblastoma with primitive neuroectodermal component (WHO grade IV)




    • Presence of hypercellular nodules of cells with hyperchromatic carrot-shaped nuclei, high nuclear-to-cytoplasmic ratios, presence of abundant mitoses and karyorrhexis, and Homer Wright rosettes, within a glioblastoma; desmoplasia or large cell/anaplastic cytology may also be present




Diffuse Midline Glioma (H3 k27M Mutant)





  • Astrocytic morphology most often with small monomorphic cells, but occasionally pleomorphic nuclei



  • Most often with necrosis, endothelial proliferation, and mitoses



Special Stains and Immunohistochemistry





  • Diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, and variants




    • Glial fibrillary acidic protein (GFAP) positive in grades II and III; in glioblastoma less positive staining may be present



    • MIB-1 (Ki-67): labeling index is low in low-grade astrocytomas (<5%) and progressively higher with higher grades



    • IDH1 (R132H) immunohistochemistry may be extremely helpful in confirming presence of low-grade glioma in biopsy tissue in cases where distinction from reactive astrocytosis is difficult



    • Also helpful in distinguishing a diffuse astrocytoma from a pilocytic astrocytoma (PA) (PAs do not have IDH1 [R132H] mutation)



    • Positive for p53; may help distinguish a low-grade astrocytoma from reactive astrocytosis and from a PA



    • Cytokeratin: high-grade astrocytomas may show cross-reactivity to AE1/AE3 cytokeratin



    • Reticulin highlights mesenchymal and sarcomatous components in gliosarcoma and desmoplastic component in giant cell glioblastoma



    • Synaptophysin: often positive in glioblastoma with primitive neuroectodermal tumor (PNET) component in primitive cells; these foci are usually also GFAP and neuron-specific enolase (NSE) positive and have high MIB-1 labeling




  • Diffuse midline glioma




    • GFAP: variable



    • H3 K27M mutation specific antibody: positive



    • TP53: positive 50%



    • ATRX: positive 10%




Other Techniques for Diagnosis





  • Electron microscopy




    • Astrocytes show cytoplasmic intermediate filaments and cell processes; poorly formed cell junctions may be seen




  • Cytogenetics




    • Diffuse astrocytoma: if IDH1 R132H immunohistochemistry is not positive in a diffuse astrocytoma, gene sequencing of IDH1 and IDH2 genes may be indicated




      • Presence of mutation in IDH1 or IDH2 confers better prognosis and better response to treatment



      • ATRX gene mutations are also present in the majority of diffuse astrocytomas



      • TP53 mutation: in 59% of astrocytomas



      • O 6 -methylguanine methyltransferase (MGMT) promoter gene methylation: methylation decreases levels of MGMT protein resulting in increased response with temozolomide treatment; MGMT methylation also confers an improved response to other therapies that may be due to the molecular phenotype



      • Diffuse midline glioma




        • Three histone coding genes ( H3F3A, HIST1H3B, Hist1H3C ) have mutations at mutations K27 are found in this glioma, with gene H3F3A most frequently affected



        • No IDH1/IDH2 gene mutations






Differential Diagnosis


Metastasis (Metastatic Carcinoma or Metastatic Melanoma)





  • Metastatic carcinoma: cytokeratin and epithelial membrane antigen (EMA) positive



  • Metastatic melanoma: S-100, Melan-A, HMB-45, or other melanoma antibody typically positive



  • GFAP negative



Lymphoma





  • May show radiologic findings similar to those in GBM



  • Typically located in periventricular regions and multifocal



  • Angiocentric distribution



  • Leukocyte common antigen (LCA) positive; most are of B-cell lineage (CD20 positive)



Reactive Astrocytosis





  • Small cystlike spaces are not typically seen in reactive processes



  • Cellularity is not as high as in astrocytomas



  • Reactive astrocytes lack hyperchromatic and pleomorphic nuclei



  • More regular arrangement of cells



  • Absence of IDH1 or IDH2 gene mutations



Oligodendroglioma





  • Cells show cytologic features of oligodendrocytes, including perinuclear halos



  • Composed of uniform round cells with minimal cytologic atypia



  • Negative for GFAP



  • Both have IDH mutations, but only oligodendrogliomas have deletions of 1p/19q



Demyelinating Diseases





  • Characteristically have numerous foamy macrophages and inflammatory cells



  • Areas of demyelination and relative preservation of axons may be identified with myelin stains and neurofilament immunohistochemistry, respectively



Pearls





  • Diffuse astrocytoma IDH WT WHO grade II is a rarely diagnosed tumor. With this diagnosis, consideration should be given to additional genetic testing to allow consideration of other diagnoses such as: pilocytic astrocytomas, pleomorphic xanthoastrocytomas, or diffuse midline gliomas



  • Diffuse midline glioma was previously known as brainstem glioma and diffuse intrinsic pontine glioma



  • Diagnoses of oligoastrocytoma, NOS, or anaplastic oligoastrocytoma, NOS, may be made when an infiltrative diffuse glioma has cells with both astrocytic and oligodendroglial morphology but in which molecular testing could not be obtained could not be obtained or was inconclusive. Molecular analyses of oligoastrocytomas and anaplastic oligoastrocytomas have found that they fall into IDH mutant astrocytomas or anaplastic astrocytomas, IDH mutant and 1p/19q codeleted oligodendrogliomas, or anaplastic oligodendroglioma.





Selected References




  • Capper D., Zentgraf H., Balss J., et. al.: Monoclonal antibody specific for Idh1 R132H mutation. Acta Neuropathol 2009; 118: pp. 599-601.



  • Hawkins C., Ellison D.W., Sturm D.: Diffuse midline glioma, H3K27M-mutant.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 57-59.



  • Louis D.N., Suva M.L., Burger P.C., et. al.: Glioblastoma, IDH-wildtype.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 28-51.



  • Reifenberger G., Collins V.P., Hartmann C., et. al.: Oligoastrocytoma, NOS.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 75-77.



  • Solomon D.A., Wood M.D., Tihan T., et. al.: Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 2015; 26: pp. 569-580.



  • Venneti S., Santi M., Felicella M.M., et. al.: . Acta Neuropathol 2014; 128: pp. 743-753.



  • von Deimling A., Huse J.T., Yan H., et. al.: Diffuse astrocytoma, IDH-mutant.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 18-23.


Oligodendroglial Tumors


Oligodendroglioma, IDH-Mutant and 1p/19q-Codeleted, Anaplastic Oligodendroglioma, IDH-Mutant and 1p/19q-Codeleted (WHO Grades II To III)


Oligodendroglial neoplasms are now defined by the molecular signature of IDH mutation and presence of codeletion of 1p and 19q. With the publication of the new WHO manual in 2016, these have become integrated into the diagnosis


Clinical Features





  • Reported to represent between 12% and 20% of all infiltrating gliomas



  • Typically occurs in middle-aged adults between 35 and 50 years of age; there is a slight predominance in males



  • Patients present with a long history of progressively worsening neurologic symptoms



  • Commonly cause severe headache and seizures



  • CT and MRI show a well-defined mass, often with calcifications; presence of contrast enhancement suggests anaplastic morphology



Gross Pathology





  • Frontal lobe is the lobe most commonly involved; typically white-matter tumors; infiltration into the cortex is common, and infiltration into leptomeninges may be seen



  • Soft, ill-defined, gray-pink tumors, which often expand gray matter and blur gray-white matter junction



  • Mucoid degeneration with a gelatinous appearance may be seen



  • Cyst formation and focal intratumoral hemorrhage are common



Histopathology


Oligodendroglioma





  • Low to moderately cellular tumor composed of cells with round nuclei that are larger than normal oligodendrocytes and show atypia; nuclei are hyperchromatic and may appear lobate (cytologic features are well demonstrated with smear preparations) ( Figure 19.5A )



  • Formalin-fixed, paraffin-embedded tissue often causes the tumor cells to swell, resulting in an enlarged cell with well-defined cell membranes and clear cytoplasm; fried-egg appearance (not seen on smear preparations, frozen sections, or quickly fixed tissue)



  • Few glial fibrillary processes are seen



  • Two morphologic variants of oligodendroglial cells may also be present (especially in anaplastic tumors)




    • Minigemistocytes or microgemistocytes, exhibiting small pools of eosinophilic cytoplasm



    • Gliofibrillary oligodendrocytes, exhibiting paranuclear eosinophilic fibrils




  • A dense network of branching capillaries (chicken-wire appearance) is seen throughout the tumor



  • Mitotic activity is usually low



  • Microcalcifications and mucoid and microcystic degeneration are helpful diagnostic features



  • Focal hemorrhage is commonly seen



  • Cortex is often involved; perineuronal satellitosis, perivascular satellitosis, or subpial aggregation (secondary structures of Scherer) are often present



Anaplastic Oligodendroglioma





  • Same cytologic features described previously but with increased nuclear atypia and cellular pleomorphism while retaining round nuclear outlines



  • Increased cellularity is evident, but this finding is not sufficient for anaplastic designation (see Figure 19.5B )



  • Mitotic activity is marked (minimum of 6 mitoses/10 high power field [HPF])



  • Several studies have shown endothelial vascular proliferation to correlate with aggressive behavior and poor prognosis



  • Presence of geographic necrosis (with or without pseudopalisading) has also been found to correlate with aggressive behavior and poor prognosis but is not an independent prognostic factor in all studies



Special Stains and Immunohistochemistry





  • GFAP positive in reactive astrocytes, gliofibrillary oligodendrocytes, and minigemistocytes



  • Synaptophysin, Neu-N, and neurofilament negative except in rare specimens with foci of neurocytic differentiation



  • p53: weak to absent in low-grade tumors; may be present in high-grade tumors, especially after treatment



  • Cytokeratin negative



  • MIB-1: disease-free survival is significantly shorter in patients with a labeling index of more than 5% compared with patients with a labeling index of less than 5%



Other Techniques for Diagnosis





  • Cytogenetics




    • Losses of 1p and 19q are defining abnormality of oligodendrogliomas



    • Mutation in the IDH1 or IDH2 gene is also always present in oligodendroglioma



    • TP53 mutations are rare




Differential Diagnosis


Diffuse Astrocytoma





  • Tumor cells have greater nuclear irregularity and pleomorphism, no perinuclear halos, and fibrillary cytoplasm



  • GFAP positive



  • TP53 mutations; no losses of chromosomes 1p and 19q



Small Cell Variant of Anaplastic Astrocytoma and Glioblastoma





  • Cytologically monotonous, but oval, not round, nuclei



  • Numerous mitoses, pseudopalisading necrosis, vascular proliferation



  • GFAP positive cytoplasmic processes



  • No loss of chromosomes 1p and 19q or presence of IDH1 gene mutation



  • Amplification of EGFR and EGFRvIII , loss of chromosome 10q



Central Neurocytoma or Extraventricular Neurocytoma





  • Central neurocytoma is usually within the ventricle attached to the septum pellucidum




    • Well-circumscribed without infiltrative borders, neurocytic rosettes



    • Positive for synaptophysin



    • Lack of codeletions of chromosomes 1p and 19q




  • Extraventricular neurocytoma




    • Positive for synaptophysin



    • Deletions of 1p and/or 19q have been identified, but no IDH1/2 mutations are present




Dysembryoplastic Neuroepithelial Tumor





  • Usually found in younger individuals with a long history of seizures



  • Most are located in the temporal lobe



  • Histologically consists of a glioneuronal element, glial nodules, and cortical dysplasia



  • Distinction from an oligodendroglioma may be impossible on a fragmented specimen



Clear Cell Ependymoma





  • Usually affects younger individuals



  • Forms perivascular pseudorosettes consisting of cells with elongated, tapering processes and ependymal rosettes and canals



  • GFAP positive



  • Often anaplastic and exhibits noninfiltrative growth pattern



  • Lacks IDH mutation and codeletions of 1p/19q



Pilocytic Astrocytoma





  • Occurs in children usually



  • Cerebellar location, but also in hypothalamus, optic nerve, and brain stem



  • Elongated cells with prominent fibrillary cytoplasm, Rosenthal fibers, and eosinophilic granular bodies



  • GFAP positive



Pearls





  • Overall, patients have a survival time of 3 to 5 years for all oligodendrogliomas



  • Other factors associated with increased survival: younger age, frontal location, tumor size, complete surgical removal, and lack of enhancement



  • Most patients with anaplastic oligodendroglioma die of local recurrence; cerebrospinal fluid (CSF) dissemination or systemic metastases occur rarely





Selected References




  • Aldape K., Burger P.C., Perry A.: Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med 2007; 131: pp. 242-251.



  • Cairncross J.G., Ueki K., Zlatescu M.C., et. al.: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90: pp. 1473-1479.



  • Hartmann C., Meyer J., Balss J., et. al.: Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 2009; 118: pp. 469-474.



  • Reifenberger G., Collins V.P., Hartmann C., et. al.: Oligodendroglioma, IDH-mutant and 1p/19q codeleted and anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 60-74.


Other Astrocytic Tumors


Pilocytic Astrocytoma (WHO Grade I)


Clinical Features





  • Occurs predominantly in children and young adults; usually presents in the first two decades



  • Most common glioma in children



  • Most frequently occurs in the cerebellum; may be seen in the optic nerve, third ventricle, hypothalamus, brain stem, cerebral hemispheres, or thalamus



  • When arising in the brain stem, it is usually exophytic dorsally or extends into the cerebellopontine angle



  • Patients can present with either focal or nonlocalized neurologic deficits or symptoms of increased intracranial pressure; may present with seizures



  • MRI scans show a well-circumscribed contrast enhancing mass commonly associated with a cyst (multiple or solitary)



Gross Pathology





  • Typically well-circumscribed, soft, gray, discrete tumors



  • Cyst formation in about 50% of cases



Histopathology





  • Most commonly demonstrates a biphasic pattern consisting of pilocytic areas and microcystic components ( Figure 19.2A )




    • Loose, microcystic areas typically contain eosinophilic granular bodies or protein droplets



    • Pilocytic component shows elongated cells with densely packed fibrillary cytoplasm and Rosenthal fibers (tapered, eosinophilic, corkscrew-shaped hyaline structures); Rosenthal fibers are not always seen or necessary for diagnosis (see Figure 19.2B )




    Figure 19.2


    Pilocytic astrocytoma.

    A, Classic architecture of densely fibrillated areas alternating with microcystic areas. B, Diffuse pilocytic astrocytoma consisting only of densely packed elongated cells. Rosenthal fibers are also present.



  • A diffuse variant of PAs with a dense fibrillary component and lacking microcystic areas has been described and is associated with a good prognosis



  • Neoplastic astrocytes are usually piloid and have uniform nuclei with minimal pleomorphism



  • Multinucleated giant cells are commonly seen



  • Mitotic activity is rare; more frequently seen in tumors of infants



  • Endothelial proliferation and areas of hyalinization are common features



  • Focal areas of calcification may be seen, but necrosis is uncommon



  • Although grossly circumscribed, the tumor may have microscopic infiltration into adjacent brain tissue



  • Occasionally hypercellular tumors with increased pleomorphism and multinucleation (features associated with long-standing lesions) are seen



  • Pilomyxoid areas (see complete histologic description in the section on pilomyxoid astrocytomas [PMAs]) may be found in varying amounts in a PA; no prediction of tumor behavior is possible at present based on the quantity of these intermixed elements; given the possibility of aggressive behavior, a pilomyxoid component should be communicated to the clinician



Special Stains and Immunohistochemistry





  • GFAP positive



  • Synaptophysin positivity may be found



  • Negative for p53



  • MIB-1 labeling index ranges from 0% to 4% (mean 1%)



Other Techniques for Diagnosis





  • Electron microscopy: pilocytic astrocytes show abundant intermediate filaments; eosinophilic granular bodies contain intermediate filaments, osmiophilic granules, and myelin figures



  • Cytogenetics




    • Most PAs have KIAA1549-BRAF gene fusion (>70%), which is not present in low-grade diffuse astrocytomas and may be useful in distinguishing PAs from diffuse astrocytomas. This fusion is most frequently found in the cerebellar tumors but is seen in pilocytic tumors in all locations



    • Several other BRAF fusion have been identified in PAs. Additional molecular alterations (all affecting the MAPK pathway) found in PAs are: BRAF V600E, NF1 , FGFR1 fusion, FGFR1 mutation, NTRK1 fusion, KRAS mutation, RAF1 fusion




Differential Diagnosis


Diffuse Astrocytoma





  • Typically lack circumscription and contrast enhancement



  • Tissue infiltration and malignant behavior are much more common



  • Usually lacks biphasic pattern, Rosenthal fibers, and eosinophilic granular bodies



  • IDH mutation



Pilomyxoid Astrocytoma





  • May be difficult to exclude as focal areas of pilomyxoid morphology may be present in a PA



  • PMA typically do not have fibrillar areas, eosinophilic granular bodies, Rosenthal fibers, or calcifications; they do have a myxoid background, pseudorosette pattern, and monomorphic cells



Pleomorphic Xanthoastrocytoma





  • Lacks biphasic pattern



  • Typically more cellular and has increased nuclear pleomorphism



  • Xanthomatous cells are present that are not seen in PA



Ganglion Cell Tumors





  • Show clustered atypical neurons, which are immunohistochemically positive for neuronal markers



Hemangioblastoma





  • Also associated with cyst formation



  • Highly vascular with abundant reticulin formation



  • Contains foamy cells filled with lipid



Pearls





  • Important to distinguish pilocytic astrocytomas from fibrillary or diffuse astrocytomas because treatment and prognosis are different



  • Typically cured by complete resection; overall prognosis is excellent



  • Rare tumors have an aggressive clinical course, and transformation to glioblastoma has been reported





Selected References




  • Collins V.P., Jones D.T.W., Giannini C.: Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol 2015; 129: pp. 775-788.



  • Collins V.P., Tihan T., VandenBerg S.R., et. al.: Pilocytic astrocytoma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 80-88.



  • Korshunov A., Meyer J., Capper D., et. al.: Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118: pp. 401-405.



  • Reis G.F., Tihan T.: Practical molecular pathologic diagnosis of pilocytic astrocytomas. Surg Pathol Clin 2015; 8: pp. 63-71.


Pilomyxoid Astrocytoma (WHO Grade Not Assigned at Present)


Clinical Features





  • Closely related to PA but may have a more aggressive clinical course



  • Occurs predominantly in infants and young children (mean age, 18 months) and involves the chiasm and hypothalamus most often; it occasionally occurs in adults and the elderly



  • Reported in temporal lobe, thalamus, posterior fossa, and spinal cord



  • Symptoms may be nonlocalizing: failure to thrive, developmental delay, vomiting and feeding difficulties, generalized weakness, and altered levels of consciousness



  • Focal neurologic symptoms also occur: visual disturbances and endocrine dysfunction



  • Tendency to disseminate through CSF and to recur



  • MRI scans show hypointensity on T1-weighted and hyperintensity on T2-weighted images with homogeneous contrast enhancement



Gross Pathology





  • Myxoid ill-defined mass



Histopathology





  • Monomorphous, hypercellular, compact small bipolar cells set in a myxoid and fibrillary background



  • Angiocentric pattern of arrangement of cells suggestive of perivascular pseudorosettes is often evident



  • Limited peripheral parenchymal involvement



  • Rare nuclear pleomorphism



  • Usually lacks Rosenthal fibers and eosinophilic granular bodies



  • Mitotic figures may be present



  • Endothelial proliferation and necrosis reported in some cases



  • Tumors exhibiting features of both PMA and PA are reported and identified as intermediate lesions (see the section on PAs)



Special Stains and Immunohistochemistry





  • GFAP: diffuse positivity



  • Synaptophysin: positivity has been reported



  • Neuronal markers: negative



  • MIB-1 labeling index ranges from 2% to 20%



Other Techniques for Diagnosis





  • Cytogenetics: few studies that have been performed show KIAA1549-BRAF fusion as seen in PA



Differential Diagnosis


Pilocytic Astrocytoma





  • Occurs also in the chiasm and hypothalamus



  • Rosenthal fibers and eosinophilic granular bodies present



  • Biphasic architecture



Pearls





  • Reports suggest that pilomyxoid astrocytoma may be a variant of pilocytic astrocytoma



  • Pilomyxoid astrocytoma is locally aggressive with a tendency to recur (76%) and disseminate through the cerebrospinal fluid (14%); overall survival is 63 months





Selected References




  • Collins V.P., Tihan T., VandenBerg S.R., et. al.: Pilomyxoid astrocytoma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 88-89.



  • Johnson M.W., Eberhart C.G., Perry A., et. al.: Spectrum of pilomyxoid astrocytomas, intermediate pilomyxoid tumors. Am J Surg Pathol 2010; 34: pp. 1783-1791.



  • Kulac I., Tihan T.: Pilomyxoid astrocytomas: a short review. Brain Tumor Pathol 2019; 36: pp. 52-55.



  • Tihan T., Fisher P.G., Kepner J.L., et. al.: Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropath Exp Neurol 1999; 58: pp. 1061-1068.


Pleomorphic Xanthoastrocytoma (WHO Grade II) and Anaplastic Pleomorphic Xanthoastrocytoma (WHO Grade III)


Clinical Features





  • Rare astrocytic neoplasm usually found in children and young adults (66% are younger than 18 years)



  • Superficial location in the cerebral hemisphere (most frequently temporal lobe) often involving the meninges; rare involvement of the deep gray matter, cerebellum, spinal cord, sella, suprasellar region, and retina



  • Patients present typically with a long history of seizures and occasional headaches; seldom with focal neurologic signs



  • CT and MRI show a well-defined enhancing mass, adjacent to the meninges, that is solid or cystic with a mural nodule



Gross Pathology





  • Well-defined, cystic mass with a mural nodule or a solid mass



  • Often attached to the meninges; may spread along brain surface



Histopathology





  • Varied histologic pattern ranging from single or multinucleated giant cells to irregular spindle cells showing intracellular lipid accumulation (xanthomatous change) ( Figure 19.3 )




    Figure 19.3


    Pleomorphic xanthoastrocytoma.

    Infiltrate of neoplastic astrocytic cells with marked nuclear pleomorphism and xanthomatous changes. Eosinophilic granular bodies are present.



  • Reticulin network surrounding individual tumor cells; desmoplasia often present



  • Patchy lymphocytic infiltrates often seen



  • Variable degrees of vascular sclerosis



  • Eosinophilic granular bodies or protein droplets prominent



  • Neuronal differentiation may be present



  • Usually absent or inconspicuous mitotic activity and necrosis in Grade II



  • A diagnosis of anaplastic xanthoastrocytoma (WHO grade III) may be made when abundant mitoses are present. One study found that greater than equal to 5 or more mitoses/10 HPF was associated with poorer prognosis. Usually necrosis is also present. Endothelial proliferation is uncommon



Special Stains and Immunohistochemistry





  • GFAP, S-100 protein, and CD34 positive



  • Reticulin highlights fibrous network surrounding tumor cells



  • Synaptophysin and neurofilament variably positive



  • MIB-1 labeling index: less than 1% (unless anaplastic)



  • BRAF V600E mutation may be identified by immunohistochemistry



Other Techniques for Diagnosis





  • Electron microscopy: cells typically show abundant intermediate filaments, lysosomes, lipid droplets, basal lamina, and secondary lysosomes



  • Approximately 20% show ultrastructural features indicating neuronal differentiation: microtubules, dense core granules, and clear vesicles



  • Cytogenetic analyses: BRAF (V600E) mutations have been found in 50% to 78% of grade II pleomorphic xanthoastrocytomas and 47% of grade III anaplastic pleomorphic xanthoastrocytomas



Differential Diagnosis


Glioblastoma





  • Important distinction from pleomorphic xanthoastrocytoma because of poor prognosis associated with glioblastoma



  • Most lack reticulin investment and eosinophilic granular bodies



  • Usually not cystic with mural nodules; always a high mitotic index and endothelial proliferation or necrosis



Pilocytic Astrocytoma





  • Biphasic pattern is characteristic



  • Rosenthal fibers are commonly found



  • Usually less cellular and without xanthomatous changes



Ganglion Cell Tumors





  • Atypical neurons that are positive for neuronal markers (synaptophysin and neurofilament) are a defining feature



  • Usually lack xanthomatous changes



Pearls





  • Surgical resection is primary treatment with overall good prognosis, especially when gross total resection is possible in Grade II pleomorphic xanthoastrocytoma (PXA)



  • Hypothesized to arise from subpial astrocytes and often display neuronal differentiation





Selected References




  • Giannini C., Paulus W., Louis D.N., et. al.: Pleomorphic xanthoastrocytoma and anaplastic xanthoastrocytoma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 94-99.



  • Ida C.M., Rodriguez F.J., Burger P.B., et. al.: Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol 2015; 25: pp. 575-586.



  • Kepes J.J.: Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 1993; 3: pp. 269-274.



  • Schindler G., Capper D., Meyer J., et. al.: . Acta Neuropathol 2011; 121: pp. 397-405.


Subependymal Giant Cell Astrocytoma (WHO Grade I)


Clinical Features





  • Most common neoplastic process involving the brain in patients with tuberous sclerosis (TS)




    • TS is an autosomal dominant disorder with markedly variable penetrance and an incidence between 1 per 9000 and 1 per 10,000 births



    • Central nervous system (CNS) abnormalities include cortical hamartomas (tubers), subcortical glioneuronal hamartomas, subependymal glial nodules, subependymal giant cell astrocytoma (SEGA); other organs affected are skin, lung, retina, kidney, and heart



    • Neurologic symptoms in TS usually occur shortly after birth and include seizures and infantile spasms; cognitive disability and autism may become evident at older ages



    • Mutations in either of two genes, TSC1 (encoding hamartin) on chromosome 9 and TSC2 (encoding tuberin) on chromosome 16, are found in greater than 85% of patients with the TS complex




  • SEGA rarely occurs without association with TS




    • Occurs in 5% to 20% of persons with TS



    • Usually develops during childhood or adolescence



    • Clinical symptoms are usually secondary to obstructive hydrocephalus and occur when large SEGAs block CSF flow




Gross Pathology





  • Typically an exophytic, solid, fleshy, well-defined, tan mass arising in the wall of the lateral ventricle



Histopathology





  • Variable cellular morphology, including the following




    • Polygonal cells with abundant eosinophilic cytoplasm suggestive of gemistocytic astrocytes ( Figure 19.4 )




      Figure 19.4


      Subependymal giant cell astrocytoma.

      Infiltrate of astrocytic-appearing cells with abundant, frequently spindled eosinophilic cytoplasm. Prominent nucleoli are frequent.



      Figure 19.5


      A, Low-grade oligodendroglioma. Moderately cellular tumor composed of cells with round hyperchromatic nuclei and clear cytoplasm, giving the characteristic fried-egg appearance. B, Anaplastic oligodendroglioma. Notice the mitoses, high cellularity, nuclear enlargement, and hyperchromatism.



    • Spindle-shaped cells with fibrillary cytoplasm forming streams and bundles



    • Large pleomorphic cells with nuclei exhibiting prominent nucleoli, suggestive of neuronal differentiation (sometimes multinucleated)



    • Focal microcalcifications and scattered mast cells are common features



    • Ill-defined pseudorosette formation may be seen



    • Variable mitotic activity



    • Vascular proliferation and necrosis are uncommon



    • High-grade cytologic features do not appear to impose an adverse clinical course




Special Stains and Immunohistochemistry





  • GFAP, S-100 protein, synaptophysin, and neurofilament positive



  • Class III β-tubulin and neuropeptides (somatostatin and met-enkephalin) positive



  • MIB-1 (Ki-67): few positive cells (low proliferative index)



Other Techniques for Diagnosis





  • Cytogenetics: deletion mutations in TSC1 or TSC2 cause a constitutive up-regulation of mTOR complex 1 tumor suppressor complex, resulting in abnormal cellular proliferation



Differential Diagnosis


Gemistocytic Astrocytoma





  • May be considered because both lesions contain astrocytic cells with abundant pink glassy cytoplasm



  • Intraparenchymal tumor rather than an exophytic intraventricular mass



  • Typically shows an infiltrative architecture



  • No mast cell infiltrate and microcalcifications



Subependymal Glial Nodule





  • Considered to be a precursor to SEGA



  • More frequently calcified than SEGA



  • Usually asymptomatic; shows no growth on serial brain scans



  • Histologically identical to SEGA



Pearls





  • Debate still exists as to whether SEGAs can occur outside the setting of TS



  • Believed to be an astrocytic neoplasm; however, studies have shown that many tumors show a more glioneuronal phenotype



  • Tumors occasionally recur, but unlike gemistocytic astrocytoma, no malignant transformation has been shown, although local invasion has been reported



  • Approximately 50% of TS patients have a positive family history, suggesting a high rate of spontaneous mutation



  • Current standard treatment is surgical resection; studies have shown reduction in tumor size with administration of everolimus, an inhibitor of the mTOR complex 1





Selected References




  • Chan J.A., Zhang H., Roberts P.S., et. al.: Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004; 63: pp. 1236-1242.



  • Cotter J.A.: An update on the central nervous system manifestations of tuberous sclerosis complex. Acta Neuropathol 2020; 139: pp. 613-624.



  • Goh S., Butler W., Thiele E.A.: Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004; 63: pp. 1457-1461.



  • Krueger D.A., Care M.M., Holland K., et. al.: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: pp. 1801-1811.


Ependymal Tumors


Ependymoma (WHO Grade II), Anaplastic Ependymoma (WHO Grade III), Rela Fusion-Positive Ependymoma (WHO Grade II or III)


Clinical Features





  • Occur most commonly in children and young adults



  • Account for about 3% to 9% of all neuroepithelial tumors; most frequent neuroepithelial tumors of the spinal cord (50% to 60% of spinal gliomas)



  • Occur at any site along the ventricular system; most commonly in the posterior fossa, followed by the supratentorial compartment and then spinal cord



  • Most ependymomas in children occur in the brain and most that occur in adults are in the spinal cord



  • Newly defined ependymoma with C11orf95-RELA fusion is most common supratentorial ependymoma in children (approximately 70%). Patients most often present with symptoms of hydrocephalus, including nausea, vomiting, and headache; patients occasionally develop seizures



  • Posterior fossa tumors may cause visual disturbances or cerebellar ataxia



Gross Pathology





  • Soft gray-pink tumors that may be solid or cystic



  • Areas of hemorrhage or necrosis may be present



  • Typically protrude from the ventricular lining and fill the ventricular lumen; well demarcated, but may invade the adjacent brain parenchyma



Histopathology


See Figure 19.6 .




Figure 19.6


Ependymoma.

A, Low-power view shows a moderately cellular glial tumor with classic perivascular pseudorosettes. B, High-power view shows classic ependymal rosettes. Notice glial cells radially arranged to form a canal (phosphotungstic acid–hematoxylin stain). C, Myxopapillary ependymoma. Glial cells exhibiting perivascular arrangement with abundant interposed mucin deposition.


Ependymoma





  • Cellular tumors composed of monomorphic cells with round to oval hyperchromatic nuclei and long fibrillary cell processes



  • Perivascular pseudorosettes consisting of tumor cells radially arranged around blood vessels are prominent



  • True ependymal rosettes consisting of columnar cells radially arranged around a central lumen are less common than perivascular pseudorosettes



  • Calcification, as well as metaplastic cartilage or bone, may be seen



  • Areas of necrosis (with and without pseudopalisading) and endothelial proliferation may be seen in an otherwise low-grade appearing ependymoma



  • Histologic features distinguishing between grades II and III are unreliable (see below)



  • No RELA fusion-specific morphology described but will often have a branching vascular pattern or clear cell change



Ependymoma Variants





  • Papillary ependymoma (WHO grade II)




    • Extensive papillary formations




  • Clear cell ependymoma (WHO grade II)




    • Cells exhibit round nuclei and perinuclear halos



    • Anaplastic histologic features are often present



    • Occurs more frequently in supratentorial compartment than in infratentorial compartment




  • Tanycytic ependymoma (WHO grade II)




    • Occurs more commonly in spinal cord



    • Composed of elongated spindled glial cells forming fascicles



    • Ependymal rosettes often not present; perivascular pseudorosettes may be ill-defined




Anaplastic Ependymoma





  • Morphologic criteria that consistently correlate with prognosis are still debated and therapeutic decisions are not based on grading



  • Features commonly present in tumors designated as anaplastic are: (1) hypercellularity with nuclear hyperchromasia and pleomorphism; (2) abundant mitotic activity; (3) endothelial proliferation and/or necrosis with pseudopalisading are often present, but may also be seen in low-grade ependymomas



  • Perivascular pseudorosettes persist



Special Stains and Immunohistochemistry





  • GFAP: marked cytoplasmic immunoreactivity, especially prominent in the perivascular pseudorosettes



  • Cytokeratin: AE1/AE3 immunoreactivity present in most ependymomas; focal and variably strong positivity with other keratin antibodies



  • EMA: dotlike cytoplasmic immunoreactivity present in most neoplastic cells



  • CD99: diffuse and dotlike cytoplasmic immunoreactivity with accentuation at membrane surface



  • MIB-1 labeling index: more elevated in anaplastic ependymomas



  • L1CAM (CD171) immunoreactivity is associated with presence of RELA fusion gene (but is not specific)



Other Techniques for Diagnosis





  • Electron microscopy: cells show polarity with well-formed terminal bars; typically have surface microvilli, cilia, intercellular junctions (zonula adherens), and blepharoplasts



  • Cytogenetics:




    • An association between neurofibromatosis type 2 (NF2) and sporadic mutations in NF2 and spinal ependymomas is established



    • Gain of chromosome 1q is associated with poor prognosis in posterior fossa ependymomas



    • Homozygous deletion of CDKN2A/B is associated with poor prognosis in supratentorial ependymomas



    • Distinct molecular subgroups of ependymomas have been identified in each neuroanatomic compartment (supratentorial, posterior fossa, spinal canal)




      • In supratentorial compartment C11orf95-RELA or YAP1 fusions are found




        • May be identified by various methods; fluorescent in situ hybridization (FISH) may be used




      • In the posterior fossa two groups identified: EPN-A with few copy number alterations and EPN-B with gains/losses of whole chromosomes and chromosome arms



      • Spinal canal: ependymomas with gains/losses of whole chromosomes and chromosome arms identified





Differential Diagnosis


Metastatic Adenocarcinoma





  • Morphology more consistently epithelial



  • Cytokeratin positivity specific for site of origin; less likely positive in ependymoma



Fibrillary or Diffuse Astrocytoma





  • Poorly defined infiltrative tumor



  • Lacks rosette formation



  • EMA typically negative



  • Lower grade tumors are IDH1/2 mutated



Astroblastoma





  • Rare tumor



  • Located away from the ventricle



  • Shows marked and diffuse vascular sclerosis



  • Tumor cells have short, broad processes



  • Lacks true rosette formation



Choroid Plexus Papilloma or Carcinoma





  • Papillary architecture and no rosette formation ( Figure 19.7 )




    Figure 19.7


    Choroid plexus papilloma.

    Columnar epithelium overlying classic papillary architecture with central fibrovascular core.



  • Negative or only focally positive for GFAP



  • Carcinomas have a loose papillary architecture and consist of sheets of pleomorphic cells with a high mitotic rate; extensive necrosis is common



Oligodendroglioma





  • May be confused with clear cell ependymoma



  • Lacks fibrillary processes, perivascular pseudorosettes, and true rosettes



  • Has deletions of chromosomes 1p and 19q



Central Neurocytoma





  • Round cells with areas of neuropil



  • Synaptophysin positive



  • GFAP negative



Pearls





  • Recent research indicates that histologic grading of ependymomas into WHO grades II and III does not predict biological behavior and that molecular subgrouping more strongly correlates with behavior.





Selected References




  • Lester A., McDonald K.L.: Intracranial ependymomas: molecular insights and translation to treatment. Brain Pathol 2020; 30: pp. 3-12.



  • Pajtler K.W., Mack S.C., Ramaswamy V., et. al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 2017; 133: pp. 5-12.



  • Pajtler K.W., Witt H., Sill M., et. al.: Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Canc Cell 2015; 27: pp. 728-743.



  • Wu J., Armstrong T.S., Gilbert M.R.: Biology and management of ependymomas. Neuro Oncol 2016; 18: pp. 902-913.


Myxopapillary Ependymoma (WHO Grade I)


Clinical Features





  • Represents about 10% to 13% of all ependymomas



  • Typically presents in young adults at an average age of 36 years



  • Occurs more frequently in males (2.5:1)



  • Occurs almost exclusively in the conus-cauda-filum terminale region and rarely in the fourth or lateral ventricles or brain parenchyma



  • Also reported in subcutaneous tissue overlying the sacrococcyx and in the presacral and postsacral regions



  • Signs and symptoms include low back pain, sciatica, and focal neurologic deficits referable to the tumor location



Gross Pathology





  • Lobulated, circumscribed, soft gray tumors in the filum terminale or attached to nerve roots



Histopathology





  • Composed of papillae lined by monotonous elongated or columnar cells surrounding a central vascular core



  • Occasionally fascicular architecture is present



  • Abundant perivascular mucin pools and a fibrillary background



Special Stains and Immunohistochemistry





  • GFAP, vimentin, and S-100 protein positive



  • PAS and Alcian blue highlight perivascular mucin



  • Cytokeratin and EMA: each variably reported as positive and negative in literature



  • MIB-1: low (<2%)



Other Techniques for Diagnosis





  • Ultrastructural examination shows collagen-rich stroma, cells with basal lamina, and cellular interdigitation



  • Cytogenetics: polyploidy has been identified in myxopapillary ependymomas in the spinal canal



Differential Diagnosis


Metastatic Adenocarcinoma (Mucin Secreting)





  • Rarely involves the filum terminale



  • Consists of pleomorphic tumor cells with high mitotic rate



  • Hemorrhage and necrosis are typical



  • Strong cytokeratin positivity



Chordoma





  • Characterized by a lobular architecture with cords of epithelial and physaliphorous cells



  • Lacks papillary architecture and fibrillary background



  • GFAP negative; cytokeratin and brachyury positive



Schwannoma





  • Abundant reticulin



  • GFAP negative



Paraganglioma





  • Morphologic features of neuroendocrine differentiation



  • Immunoreactive for neuroendocrine markers



  • GFAP usually negative



Pearls





  • Typically slow-growing tumors with a favorable prognosis, but dissemination within neural axis is described



  • Recurrence or dissemination occurs more frequently in children and with incomplete resections; radiation treatment usually given in these settings



  • Tumors occurring in soft tissues have been associated with aggressive behavior and metastases





Selected References




  • McLendon R., Schiffer D., Rosenblum M.K., et. al.: Myxopapillary ependymoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds.2016.IARCLyonpp. 104-105.



  • Pajtler K.W., Witt H., Sill M., et. al.: Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Canc Cell 2015; 27: pp. 728-743.



  • Sonneland P.R.L., Scheithauer B.W., Onofrio B.M.: Myxopapillary ependymoma: a clinicopathologic and immunocytochemical study of 77 cases. Cancer 1985; 56: pp. 883-893.


Subependymoma (WHO Grade I)


Clinical Features





  • Most frequently found in adult males (male-to-female ratio, 4:1)



  • Most occur in the fourth (50% to 60%) or lateral (40% to 50%) ventricles; less commonly in the spinal cord



  • Many found incidentally at autopsy, but some cause symptoms, usually related to increased intracranial pressure due to obstruction of the ventricular system



  • Mean age at presentation of symptomatic tumors is 47 years



  • Symptoms related to mass effect may also be seen (focal neurologic signs, seizures)



  • MRI scans of symptomatic lesions show hypointense or isointense signals on T1 images, hyperintensity on T2 images, and heterogeneous contrast enhancement



Gross Pathology





  • Firm, tan-white, polypoid nodules of varying size



  • Arise from the lining of the ventricle or from the septum pellucidum and protrude in the ventricular lumen; usually well circumscribed



  • Focal hemorrhage, calcifications, and cystic changes may be present



Histopathology





  • Characterized by clusters of monomorphic tumor cells (resembling normal ependymal cells) in a dense fibrillary matrix of glial cell processes



  • Microcystic architecture is a common feature



  • Small blood vessel proliferation or focal hemorrhage may be seen within the tumor



  • Mitotic activity is rare to absent



  • Ependymal pseudorosettes may be seen but are not a typical finding; true rosettes are rare



  • Microcalcifications are common



  • Microcysts filled with basophilic amorphous material are common



Special Stains and Immunohistochemistry





  • GFAP positive, but may be variable in extent



  • S-100 protein diffusely positive



  • MIB-1: usually less than 1%



Other Techniques for Diagnosis





  • Ultrastructural examination shows surface microvilli, intercellular junctions, and cilia



  • Cytogenetics: three molecular groups have been defined, one in each neuroanatomic compartment (spinal canal, posterior fossa, and supratentorial)




    • Spinal canal subependymomas show chromosome 6q deletions while posterior fossa and supratentorial subependymomas show few to no copy number alterations




Differential Diagnosis


Ependymoma





  • Generally found in younger individuals



  • Usually symptomatic, producing hydrocephalus, visual disturbances, or cerebellar ataxia



  • More cellular and characterized by rosette and prominent pseudorosette formation



Pearls





  • For symptomatic lesions, surgical resection is the treatment of choice and is often curative



  • Tumors showing both ependymal and subependymal features are generally classified as ependymomas



  • Hypothesized to arise from subependymal glial cells (tanycytes) or astrocytes of the subependymal plate; may be a hamartomatous proliferation





Selected References




  • Jain A., Amin A.G., Jain P., et. al.: Subependymoma: clinical features and surgical outcomes. Neurol Res 2012; 34: pp. 677-684.



  • McLendon R., Schiffer D., Rosenblum M.K., et. al.: Myxopapillary ependymoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds.2016.IARCLyonpp. 102-103.


Other Neuroepithelial Tumors


Astroblastoma (No Assigned WHO Grade)


Clinical Features





  • Rare neoplasm occurring most frequently in children and young adults; uncommon in older adults; one study has noted a female predominance



  • Patients typically present with symptoms of mass effect; may have focal neurologic deficits, headache, or seizures



  • Usually located near or at the surface of the cerebral hemispheres; may arise in the corpus callosum, cerebellum, optic nerves, brain stem, or cauda equina



  • MRI shows a well-defined, contrast-enhancing mass with solid or cystic components; the solid component has a characteristic bubbly appearance and little associated T2 hyperintensity



Gross Pathology





  • Small cyst formation and focal necrosis may be seen, especially in larger tumors



Histopathology





  • Key feature is the astroblastic pseudorosette composed of broad, nontapering, nonfibrillar processes that radiate toward a central blood vessel



  • Depending on the tumor grade, cells may be monomorphic with inconspicuous nucleoli or show pleomorphic, hyperchromatic nuclei with obvious nucleoli



  • Marked perivascular hyalinization is characteristic and may coalesce to occupy extensive areas



  • Typically noninfiltrative interface with surrounding brain tissue



  • Low grade




    • Uniform distribution of perivascular pseudorosettes



    • Low mitotic activity (mean 1 mitosis/10 HPF)



    • Minimal cellular pleomorphism



    • No vascular proliferation or necrosis with pseudopalisading




  • High grade




    • Increased cellularity (focal or multifocal)



    • High mitotic rate (>5 mitoses/10 HPF)



    • Nuclear anaplasia



    • Endothelial proliferation and necrosis with pseudopalisading




Special Stains and Immunohistochemistry





  • GFAP, S-100, and vimentin: strong immunoreactivity



  • EMA: focal membranous immunoreactivity



  • Cytokeratin (low molecular weight): variable



  • MIB-1 index: low grade, 3%; high grade, greater than 10%



Other Techniques for Diagnosis





  • Electron microscopy: tumor cells contain abundant intermediate filaments and exhibit microvilli, poorly developed intercellular junctions, and rare cilia



  • Cytogenetics: No mutations in IDH1 or IDH2 genes. Recent molecular analyses have shown varied genetic abnormalities in tumors with astroblastoma morphology including BRAF V600E mutations, TP53 and TERT promoter mutations, CDKN2A/B homozygous deletions, and MN1 alterations



Differential Diagnosis


Ependymoma





  • Most are infratentorial and within or close to a ventricle



  • Lacks vascular hyalinization



  • Shows formation of true rosettes



  • Cells have elongated fibrillary processes and fibrillary background



Angiocentric Glioma





  • In contrast to astroblastoma, angiocentric gliomas are infiltrating lesions composed of piloid cells that exhibit circumferential arrangements of neoplastic cells around vessels in addition to radial arrangements (as seen in astroblastomas)



Papillary Meningioma





  • Contain distinct areas of meningothelial differentiation



  • Characteristically EMA positive



  • GFAP negative



Pearls





  • Discovery of varied genetic make-up of astroblastomas suggests that it may be a histologic pattern rather than a distinct brain entity. This may explain the difficulty in defining predictive histologic WHO grades





Selected References




  • Boisseau W., Euskirchen P., Mokhtari K., et. al.: Molecular profiling reclassifies adult astroblastoma into known and clinically distinct tumor entities with frequent mitogen-activated protein kinase pathway alterations. Oncologist 2019; 24: pp. 1584-1592.



  • Port J.D., Brat D.J., Burger P.C., et. al.: Astroblastoma: radiologic-pathologic correlation and distinction from ependymoma. Am J Neuroradiol 2002; 23: pp. 243-247.



  • Wood M.D., Tihan T., Perry A., et. al.: Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol 2018; 28: pp. 192-202.


Chordoid Glioma (WHO Grade II)


Clinical Features





  • Uncommon glioma arising in region of third ventricle



  • Mean age, 46 years; range, 12 to 70 years



  • Females affected more than males



  • Signs and symptoms usually secondary to obstructive hydrocephalus; reported symptoms include headache, weight loss, endocrine disturbances, autonomic disturbances, psychosis, and focal neurologic deficits



  • On MRI scan, well-circumscribed, usually anterior third ventricle, T1-isointense, and show diffuse homogeneous contrast enhancement



Gross Pathology





  • Well-circumscribed, fusiform, ovoid shape containing cysts; may be attached to the hypothalamus



Histopathology





  • Clusters of epithelioid cells and cords of spindle cells in a myxoid and mucinous background



  • Sparse to abundant lymphoplasmacytic infiltrates with Russell bodies



  • Rare mitotic figures, no necrosis, and endothelial proliferation



  • Does not infiltrate into surrounding brain, but Rosenthal fibers are present in adjacent reactive brain tissue



Special Stains and Immunohistochemistry





  • Periodic Acid Schiff (PAS) and Alcian blue positive background; mucin negative



  • Reticulin surrounds clusters of epithelioid cells



  • GFAP, CD34, and vimentin: strong diffuse immunoreactivity



  • TTF1 positive but variable in amount and intensity



  • EMA, cytokeratin, and s-100 variable positivity



  • MIB-1 labeling index: generally less than 2%



Other Techniques for Diagnosis





  • Electron microscopy: abundant intermediate filaments in cytoplasm, apical microvilli, abnormal cilia, focal basal lamina, and hemidesmosomes



  • Cytogenetics: No mutations in IDH1, IDH2, or BRAF genes have been found. A missense mutation in the PRKCA gene has recently been identified in approximately 30 cases



Differential Diagnosis


Chordoma





  • Limited cytokeratin immunoreactivity in chordoid glioma, compared with diffuse and strong reactivity in chordoma



  • Brachyury immunoreactive



  • Physaliferous cells characteristic



Chordoid Meningioma





  • Presence of whorls and psammoma bodies, nuclear pseudoinclusions



  • No immunoreactivity for GFAP; usually positive for EMA and progesterone receptor



  • Both may have inflammatory infiltrates



Pearls





  • Gross total resection is the optimal treatment, but adherence to hypothalamus may prevent complete resection and lead to significant morbidity and poor outcome



  • Cell of origin is hypothesized to be the tanycyte (glial progenitor cell with astrocytic and ependymal features) found in circumventricular organs (lamina terminalis in anterior third ventricular wall)



  • Metaplastic elements have been reported (chondroid)





Selected References




  • Bielle F., Villa C., Giry M., et. al.: Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis. Am J Surg Pathol 2015; 39: pp. 948-956.



  • Goode B., Mondal G., Hyun M., et. al.: A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 2018; 9: pp. 810.



  • Horbinski C., Dacic S., McLendon R.E., et. al.: Chordoid glioma: a case report and molecular characterization of five cases. Brain Pathol 2009; 19: pp. 439-448.



  • Rosenberg S., Simeonova I., Bielle F., et. al.: A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat Commun 2018; 9: pp. 2371.


Angiocentric Glioma (WHO Grade I)


Clinical Features





  • Slow-growing glioma



  • Reported in patients ranging in age from 2 to 70 years, but occurs most commonly in childhood and adolescence



  • Most present with seizures; longstanding history of seizures is common



  • Occurs most commonly in cerebral cortex



  • MRI of tumor shows a homogeneous not well-demarcated lesion of the cortex and white matter with focal extension to the ventricular surface; a peripheral rim of hyperintensity on T1-weighted images and hyperintensity on T2-weighted and fluid-attenuated inversion recovery images without enhancement are evident



Gross Pathology





  • Not yet described



Histopathology





  • Superficial cortical location with subpial accumulation



  • Infiltration of surrounding parenchyma



  • Monomorphous slender bipolar cells with angiocentricity



  • Circumferential (more common) or radial arrangements around vessels of all sizes



  • Occasional fascicular architecture



  • Rare mitoses; no necrosis or endothelial proliferation



  • Palmini and colleagues’ type 1 cortical dysplasia has been described adjacent to the tumors



Special Stains and Immunohistochemistry





  • GFAP: variable degrees of positivity, often around vessels



  • S-100 and vimentin positive



  • EMA surface and paranuclear dotlike positivity



  • Neu-N, chromogranin, and synaptophysin negative



  • MIB-1 index: 1% to 5%



Other Techniques for Diagnosis





  • Electron microscopy: perivascular cells contain cytoplasmic intermediate filaments and exhibit basement membrane; cell junctions, cilia, and microvilli are described, suggesting ependymal differentiation



  • Cytogenetics: IDH1 (R132H) mutation not present; recently MYB-QKI gene fusions have been described in angiocentric gliomas



Differential Diagnosis


Astrocytoma





  • Lacks monomorphic nuclear appearance of angiocentric glioma



  • No angiocentricity



Pilocytic Astrocytoma





  • Not infiltrative



  • EMA negative



Pilomyxoid Astrocytoma





  • Mucinous and myxoid background



  • Usual location in hypothalamus



  • Contrast enhancing



  • Occurs in very young patients



Ependymoma





  • Usually in or adjacent to a ventricle



  • Exhibits only radially arranged perivascular pseudorosettes and ependymal rosettes



  • Tumors containing patterns of angiocentric glioma and ependymoma have been reported so separation may be difficult



Astroblastoma





  • Radially arranged perivascular pseudorosettes with marked vessel sclerosis



Pearls





  • Excellent prognosis; gross total resection is usually curative with termination of seizures



  • Hypothesized to be of ependymal or radial glial cell origin





Selected References




  • Bandopadhayay P., Ramkissoon L.A., Jain P., et. al.: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 2016; 48: pp. 273-282.



  • Burger P.C., Jouvet A., Preusser M., et. al.: Angiocentric glioma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 110-120.



  • Wang M., Tihan T., Fojiani A.M., et. al.: Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropath Exp Neurol 2005; 64: pp. 875-881.


Neuronal and Glioneuronal Neoplasms


Gangliocytoma (WHO Grade I), Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (No WHO Grade), Dysplastic Cerebellar Gangliocytoma (WHO Grade I), Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I), Ganglioglioma (WHO Grade I and II), and Anaplastic Ganglioglioma (WHO Grade III)


Clinical Features





  • Gangliocytomas are WHO grade I; most gangliogliomas are WHO grade I; criteria for grade II gangliogliomas are not yet established and anaplastic gangliogliomas are uncommon (WHO grade III)




    • Low incidence (1.3% of all brain tumors), but the most common neoplasm in patients with chronic intractable focal epilepsy



    • Typically, supratentorial and usually involves the temporal lobe , but occur throughout the CNS



    • Most present in the first three decades; may be found in all ages



    • Often associated with a history of treatment-resistant epilepsy



    • CT and MRI usually show a solid or cystic mass; often with calcification and variable contrast enhancement




Multinodular Vacuolating Neuronal Tumor of the Cerebrum





  • Occurs most frequently in adults, located in cerebrum (most often temporal lobe)



  • Presents with seizures



  • MRI scan shows hyperintense nonenhancing nodular mass



  • No WHO grade assigned yet



Dysplastic Cerebellar Gangliocytoma (Lhermitte-Duclos Disease), WHO Grade I





  • Most often occurs in adults



  • Associated with Cowden syndrome



  • Not yet clear if it is neoplastic or hamartomatous



  • Clinical presentation is with cerebellar signs and symptoms, symptoms of obstructive hydrocephalus, or of mass effect



  • MRI scans demonstrate enlarged cerebellar folia



Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I)





  • Most occur before 2 years of age



  • Increasing head circumference, bulging fontanelles, lethargy



Gross Pathology





  • Gangliocytoma, ganglioglioma, and anaplastic ganglioglioma




    • Well-circumscribed gray granular mass that is variably solid and cystic; mural nodule within the cystic component is often seen



    • May extend into the leptomeninges and subarachnoid space



    • Extensive calcification, hemorrhage, or necrosis may be seen




  • Multinodular vacuolating neuronal tumor of the cerebrum




    • Discrete gray firm nodules in lower cortex and at gray/white matter junction




  • Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)




    • Single or multiple enlarged cerebellar folia




  • Desmoplastic infantile astrocytoma and ganglioglioma




    • Large cystic masses, superficially located, most often occurring in frontal and parietal lobes, may involve more than one lobe




Histopathology


Gangliocytoma





  • Composed entirely of neurons forming ill-defined groups, usually of low cellularity



  • Often exhibits cytologic atypia, including binucleation



Ganglioglioma and Anaplastic Ganglioglioma





  • Tumor composed of atypical ganglion cells as well as a neoplastic glial component ( Figure 19.8 )




    Figure 19.8


    Ganglioglioma.

    Mixed glial-neuronal neoplasm composed of neoplastic astrocytes intermixed with atypical clustered ganglion cells.



  • Neoplastic neurons are characterized by haphazard clustering, lack of orderly distribution, and, often, an abnormal location (in white matter)



  • Abnormal neurons may be small or large; often they are binucleated and have large nuclei and prominent nucleoli



  • Glial component is variably cellular and most commonly consists of a neoplastic astrocytic population; pilocytic morphology may be seen and oligodendroglial foci are rarely seen



  • Rosenthal fibers and eosinophilic granular bodies are often present



  • Atypical glial cells with large, bizarre, hyperchromatic nuclei with intranuclear cytoplasmic inclusions may be seen



  • Tumor cells may be in a reticulin-rich stroma



  • Foci of perivascular chronic inflammation is a common histologic feature



  • Microcalcifications are often present



  • Microcystic cavities may be present



  • Mitotic figures are rare



  • Anaplastic ganglioglioma (WHO grade III) shows increased glial cellularity; glial cells have pleomorphic hyperchromatic nuclei and increased mitoses are present and necrosis and endothelial proliferation may be present



Multinodular Vacuolating Neuronal Tumor of the Cerebrum





  • The tumor is composed of multiple nodules in the cortex, at gray/white matter junction, and/or subcortical white matter composed of cells resembling small neurons (amphophilic globose cytoplasm, vesicular nucleus containing a nucleolus), cytoplasmic and stromal vacuolation; no mitoses



Dysplastic Cerebellar Gangliocytoma (Lhermitte-Duclos Disease)





  • Molecular and granular cell layers of cerebellum are enlarged by variable sized dysplastic ganglion cells



  • Purkinje cells are decreased or lost



  • Mineralization may be present in the parenchyma



  • Subpial accumulations of ganglion cells may be seen



Desmoplastic Infantile Ganglioglioma and Astrocytoma, WHO Grade I





  • Dense fibrotic masses



  • Fibrous stroma with intermixed clusters or scattered astrocytes



  • Eosinophilic granular bodies and Rosenthal fibers



  • Ganglion cells and small neurocytic cells present in desmoplastic infantile ganglioglioma but may be sparse



Special Stains and Immunohistochemistry





  • Gangliocytoma, ganglioglioma, and anaplastic ganglioglioma




    • Reticulin-rich network often present (more in ganglioglioma, limited in gangliocytoma)



    • Variable positivity with synaptophysin, chromogranin, neurofilament, MAP2, and NSE in neuronal component



    • CD 34: positive in neurons in surrounding cortex frequent



    • GFAP: astrocytic component is positive



    • MIB-1: low index (<3%) in astrocytic component of typical ganglioglioma (grade I); elevated astrocytic component of anaplastic (grade III) gangliogliomas




  • Multinodular vacuolating neuronal tumor of the cerebrum




    • Cells are synaptophysin positive, MIB-1, GFAP, NeuN, and chromogranin negative




  • Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)




    • Dysplastic ganglion cells are synaptophysin positive




Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I)





  • Neuronal components positive with synaptophysin, NSE, and occasionally neurofilament



  • Astrocytic components positive with GFAP



  • Reticulin stain highlights desmoplastic component



Other Techniques for Diagnosis





  • Electron microscopy: neurons contain dense-core neurosecretory granules and occasionally exhibit synapses



  • Cytogenetic alterations and molecular alterations:




    • Gangliogliomas




      • Frequent gains of chromosome 7 and losses of chromosome 22



      • Mutation of BRAF (V600E) has been identified in 20% to 60% of ganglion cell component of gangliogliomas



      • No specific molecular abnormalities identified as yet in anaplastic gangliogliomas




    • Multinodular vacuolating neuronal tumor of the cerebrum




      • IDH1 , IDH2 , and BRAF (V600E) mutation negative




    • Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)




      • Adult-onset dysplastic cerebellar gangliocytoma is strongly associated with germline PTEN mutation but onset of disease in childhood is not





Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I)





  • Focal Recurrent Losses at 5q, 21q, and 10q



  • BRAF V600E mutation has been very rarely identified in desmoplastic infantile astrocytoma and ganglioglioma



Differential Diagnosis


Central Nervous System Ganglioneuroblastoma





  • Primitive Embryonal Cells are Intermixed with Dysplastic Ganglion Cells



Pilocytic Astrocytoma





  • Similar radiographic findings



  • Biphasic tumor consisting of pilocytic areas and a microcystic background



  • Lacks clusters of atypical neurons



Dysembryoplastic Neuroepithelial Tumor





  • Similar clinical picture to gangliocytoma and gangliogliomas



  • Composed of a multinodular architecture with a mucoid collagenous background



  • Neurons in dysembryoplastic neuroepithelial tumor (DNT) are typically normal; lacks clustering of pleomorphic neurons



Fibrillary or Diffuse Astrocytoma





  • Entrapped non-neoplastic neurons may suggest ganglioglioma



  • Tumor cells are negative for neuronal markers; positive for GFAP



  • MIB-1 index: higher in astrocytomas than gangliogliomas



  • IDH1/2 mutations usually present



Pleomorphic Xanthoastrocytoma





  • Pleomorphic, xanthomatous cells characterize the neoplasm



  • Exhibits both CD34 and GFAP positivity



  • Usually lacks a neuronal component



Pearls





  • Surgical resection for gangliocytoma and ganglioglioma is usually curative; no radiation or chemotherapy is needed; over 90% have a recurrence-free survival greater than 7 years



  • Eosinophilic granular bodies are evidence of chronicity and slow growth; they are not diagnostic of gangliogliomas and may be seen in pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and other low-grade astrocytomas



  • Malignant transformation of the glial cells is extremely rare (anaplastic ganglioglioma)



  • Ganglion cells may be difficult to appreciate on frozen section; patient age, radiographic findings, and clinical history are helpful



  • It remains unclear if multinodular and vacuolating neuronal tumor of the cerebrum is a neoplasm or a malformation; exhibits benign behavior





Selected References




  • Abel T.W., Baker S.J., Fraser M.M., et. al.: Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol 2005; 64: pp. 341-349.



  • Bianchi F., Tamburrini G., Massimi L., et. al.: Supratentorial tumors typical of the infantile age: desmoplastic infantile ganglioglioma (DIG) and astrocytoma (DIA). A review. Childs Nerv Syst 2016; 32: pp. 1833-1838.



  • Brat D., VandenBerg S., Figarella-Branger D., et. al.: Desmoplastic infantile astrocytoma and ganglioglioma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 144-146.



  • Chappe C., Padovani L., Scarvarda D., et. al.: Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol 2013; 23: pp. 574-583.



  • Choi E., Kim S.-I., Won J.-K., et. al.: Clinicopathological and molecular analysis of multinodular and vacuolating neuronal tumors of the cerebrum. Hum Pathol 2019; 86: pp. 203-212.



  • Horbinski C., Kofler J., Yeaney G., et. al.: Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol 2011; 21: pp. 564-574.



  • Huse J.T., Edgar M., Halliday J., et. al.: Multinodular and vacuolating neuronal tumors of the cerebrum: 10 cases of a distinctive seizure-associated lesion. Brain Pathol 2013; 23: pp. 515-524.



  • Pekmezci M., Villanueva-Meyer J.E., Goode B., et. al.: The genetic landscape of ganglioglioma. Acta Neuropathol Comm 2018; 6: pp. 47.



  • Pujadas E., Chen L., Rodriguez F.J.: Pathologic and molecular aspects of anaplasia in circumscribed gliomas and glioneuronal tumors. Brain Tumor Pathol 2019; 36: pp. 40-51.



  • Schindler G., Capper D., Meyer J., et. al.: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma, and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121: pp. 397-405.


Dysembryoplastic Neuroepithelial Tumor (WHO Grade I)


Clinical Features





  • Typically found in the first decade in the setting of drug-resistant epilepsy



  • Occurs most often in the mesial temporal lobe cortex; also reported in frontal, parietal, and occipital cortexes and selected infratentorial areas



Gross Pathology





  • May be well defined or poorly demarcated



  • Variable size; most measure a few centimeters



  • Gyral expansion with vague multinodular formation and mucoid viscous appearance



  • Small cyst formation often seen



  • Distortion of the overlying skull may be present



Histopathology





  • Cortical, multinodular, microcystic, mucoid tumor




    • Three classic histologic features




      • Glioneuronal element (“specific component”)




        • Oligodendroglial-like cells (OLC) form clusters and satellites around normal-appearing neurons floating in mucin-rich spaces ( Figure 19.9 )




          Figure 19.9


          Dysembryoplastic neuroepithelial tumor.

          Neurons floating in a mucoid matrix with oligodendroglial-like cells.



        • If only this element is present, it is called a “simple” DNT




      • Glial nodules




        • Aggregates of glial (variably astrocytic or oligodendroglial) cells




      • Cortical dysplasia (variably present)




    • Presence of the glioneuronal element and glial nodules is called a “complex” DNT




Special Stains and Immunohistochemistry





  • Synaptophysin, NSE, and Neu-N highlight neuronal component



  • GFAP stains astrocytic component



  • S-100, nestin, and CD34 protein stains oligodendroglial-like cells



  • Alcian blue highlights mucoid background (acid mucopolysaccharide)



  • MIB-1: usually low index, but up to 8% reported



Other Techniques for Diagnosis





  • Electron microscopy




    • OLC in the glial nodules or specific glial neuronal component have round or oval nuclei and scant cytoplasm with short processes



    • Cytoplasm contains mitochondria, free ribosomes, rough endoplasmic reticulum, and lysosomes



    • Occasional astrocytic (intermediate filaments) and neuronal differentiation (dense core granules) are seen




  • Cytogenetics: BRAF V600E mutation has been identified in 30% of DNT



Differential Diagnosis


Ganglioglioma





  • Dominant feature is bizarre, pleomorphic, or binucleate neurons



  • Shows a neoplastic glial component in addition to the abnormal neurons



  • Lacks multinodular architecture



  • Typically shows perivascular lymphoid infiltrate and may have abundant collagenous stroma



Oligodendroglioma





  • Lacks distinct multinodular architecture



  • No glioneuronal element



  • Difficult to distinguish from DNT in small biopsies



Pilocytic Astrocytoma





  • Composed of biphasic dense and loose piloid astrocytes without floating neurons or associated cortical dysplasia



Pearls





  • Histogenesis remains unknown; may be hamartomatous or a benign neoplasm



  • Surgical resection is reserved for patients with intractable seizures



  • Most patients remain seizure free and without tumor recurrence after resection



  • Recurrence and transformation to a higher-grade diffuse glioma are each uncommon but have been reported





Selected References




  • Chappe C., Padovani L., Scavarda D., et. al.: Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol 2013; 23: pp. 574-583.



  • Daumas-Duport C., Scheithauer B.W., Chodkiewicz J.P., et. al.: Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of 39 cases. Neurosurgery 1988; 23: pp. 545-556.



  • Thom M., Toma A., An S., et. al.: One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol 2011; 70: pp. 859-878.


Central and Extraventricular Neurocytoma (WHO Grade II), Cerebellar Liponeurocytoma (WHO Grade II)


Clinical Features





  • Incidence is 0.25% to 0.50% of all brain tumors



  • Typically occurs in young adults (ages 20 to 40 years)



  • Central neurocytoma: intraventricular tumors are usually found in the lateral or third ventricles, adjacent to the foramen of Monro




    • Central neurocytomas present with signs of increased intracranial pressure: headache, nausea, vomiting, seizures, visual disturbance, and papilledema



    • Extraventricular neurocytomas occur in parenchyma, away from the ventricular system; reported in cerebrum, cerebellum, deep gray matter, brain stem, spinal cord, pineal gland, and retina



    • Presentation of extraventricular neurocytomas is dependent on location of the tumor




  • Cerebellar liponeurocytoma




    • Rare low-grade (WHO grade II) neoplasm, usually occurring in cerebellar hemispheres composed of neurocytes with focal lipomatous differentiation



    • Mean age of occurrence, 50 years



    • CT and MRI characteristically show a heterogeneously contrast-enhancing, partially calcified intraventricular (or in extraventricular lesions, parenchymal) mass; cysts and calcification are common



    • MRI scans show an isointense or slightly hypointense mass on T1-weighted images and hyperintensity on T2-weighted images




Gross Pathology





  • Well-circumscribed, lobulated, soft, gray tumor



  • Typically, infiltration into the surrounding brain parenchyma is not seen



  • Often hemorrhagic, focally calcified, and cystic



Histopathology


Central Neurocytomas





  • Hypercellular tumor composed of diffuse sheets of monotonous uniform cells punctuated by anuclear areas composed of a fibrillar matrix, reminiscent of neuropil ( Figure 19.10 )




    Figure 19.10


    Central neurocytoma.

    The neoplasm is composed of a monotonous population of small round cells with a fine chromatin pattern and occasional nuclei-free islands suggesting neuropil.



  • Perivascular arrangement of cell processes resembling ependymal pseudorosettes may be seen



  • Delicate vascular stroma and microcalcifications are often present



  • Nuclei have regular outlines with salt and pepper chromatin and small inconspicuous nucleoli



  • Mitotic activity, endothelial proliferation, and necrosis are rare



  • Rare cases exhibit ganglion cells



Atypical Neurocytomas





  • Defined by elevation of MIB-1 index (>2%) with or without the presence of endothelial proliferation, necrosis, and increased cytologic atypia



Extraventricular Neurocytomas





  • Cytologically similar to central neurocytomas




    • Architectural pattern is more varied, such as clusters, ribbons, or rosettes, in addition to sheets



    • Higher degree of ganglionic differentiation and possibly glial differentiation




Cerebellar Liponeurocytoma





  • Composed of neurocytes, some showing lipidization



Special Stains and Immunohistochemistry





  • Synaptophysin: diffusely positive



  • NSE and Neu-N positive



  • Chromogranin and neurofilament usually negative



  • GFAP negative in central neurocytomas; variable in extraventricular neurocytomas



  • MIB-1 index: less than 2% in typical neurocytomas; more than 2% shortens recurrence-free survival



  • Cerebellar liponeurocytoma: in addition to neuronal markers, focal GFAP positivity is often present



Other Techniques for Diagnosis





  • Electron microscopy: membrane bound dense core neurosecretory granules, cytoplasmic microtubular arrays



  • Cytogenetic analyses: central neurocytomas have been shown to have trisomy 7, chromosome 17 deletion, and gains in 2p, 10q, 13q, and 18q; overexpression of IGF2, N-Myc, PTEN, and PDGF have also been reported




    • Extraventricular neurocytoma has been reported to have deletions of 1p and/or 19q but no deletions of IDH1/2.




Differential Diagnosis


Oligodendroglioma





  • Poorly circumscribed with an infiltrative border



  • Typically not located in the ventricle



  • Lacks salt-and-pepper nuclei, neuropil islands, and ganglion cell differentiation



  • Synaptophysin negative



Ependymoma (Especially Clear Cell Variant)





  • Cells have long fibrillary processes



  • Characteristically shows true rosettes



  • Typically protrudes from ventricular lining



  • GFAP positive and synaptophysin negative



Neuroblastoma (Primitive Neuroectodermal Tumor)





  • Hyperchromatic atypical cells with frequent mitoses



  • Lack of fine chromatin and neuropil islands



  • Intraparenchymal with tendency to seed neuraxis



  • Immunohistochemical profiles are the same



Pearls





  • Most are slow-growing tumors that are essentially cured by surgical resection; associated with an excellent prognosis



  • Recurrence and adverse outcomes are associated with subtotal resection and elevated MIB-1 proliferation index and elevated mitotic count (>2/10 HPF)





Selected References




  • Bonney P.A., Boettcher L.B., Krysiak R.S., et. al.: Histology and molecular aspects of central neurocytoma. Neurosurg Clin N Am 2015; 26: pp. 21-29.



  • Choudhari K., Kaliaperumal C., Jain A., et. al.: Central neurocytoma: a multi-disciplinary review. Br J Neurosurg 2009; 23: pp. 585-595.



  • Figarella-Branger D., Soylemezoglu F., Burger P.: Extraventricular neurocytoma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 159-160.



  • Kleihues P., Giangaspero F., Chimelli L., et. al.: Cerebellar liponeurocytoma.Louis D.N.Ohgaki H.Wiestler O.D. et. al.WHO Classification of Tumours of the Central Nervous System.2016.IARCLyon:pp. 161-163.



  • Lee S.J., Bui T.T., Chen C.H.J., et. al.: Central neurocytoma: a review of clinical management and histopathologic features. Brain Tumor Res Treat 2016; 4: pp. 49-57.



  • Vasiljevic A., Francois P., Loundow A.: Prognostic factors in central neurocytomas: a multicenter study of 71 cases. Am J Surg Pathol 2012; 36: pp. 220-227.


Papillary Glioneuronal Tumor (WHO Grade I)


Clinical Features





  • Usually low grade



  • Rare neoplasm; wide age range, from 4 to 75 years (mean age, 23 years)



  • Seizures, headaches, visual disturbances, language or gait disturbances, and mood changes have been reported as presenting symptoms



  • Occurs in cerebral parenchyma, most commonly in frontal and temporal lobes



  • MRI shows a well-circumscribed solid and cystic mass with contrast enhancement; may have a cyst with a mural nodule



Gross Pathology





  • Well-circumscribed solid and cystic mass, may have a mural nodule in a cyst



Histopathology





  • Architecturally composed of pseudopapillae and solid areas



  • Pseudopapillae exhibit pseudostratified, small cuboidal cells without atypia around hyalinized vessels



  • Solid areas contain mixtures of neurocytes and ganglion cells and cells intermediate between the two within a fibrillar or basophilic mucoid matrix



  • Rosenthal fibers, calcification, and old hemorrhage are seen



  • Mitoses are rare or absent



  • No endothelial proliferation or necrosis



Special Stains and Immunohistochemistry





  • GFAP, S100: cells of pseudopapillae positive



  • Synaptophysin, Neu-N, and neurofilament: cells from solid areas (neurocytes and ganglion cells) positive



  • Chromogranin and CD34: negative



  • MIB-1 index: range, 1% to 3%; reports of up to 26%



  • Epidermal growth factor receptor (EGFR) and IDH1 (R132H) immunohistochemistry: negative



  • p53: most often negative



Other Techniques for Diagnosis





  • Ultrastructural examination: pseudopapillae lining cells show astrocytic features with intermediate filaments; solid area cells show neuronal features such as microtubules, dense core, and clear vesicles and occasionally synaptic junctions



  • Cytogenetic analyses: fusion of SLC44A1-PRKCA identified by FISH in most reported cases




    • No codeletions of 1p or 19q or reports of IDH1 gene mutations




Differential Diagnosis


Papillary Ependymoma





  • Lacks solid component exhibiting neuronal elements



Papillary Meningioma





  • EMA positive



  • GFAP negative



  • Synaptophysin and Neu-N negative



Choroid Plexus Papilloma





  • Papillary formation not consistently GFAP positive



  • Lacks solid areas composed of neuronal elements



Metastatic Papillary Adenocarcinoma





  • Cytokeratin positive



  • GFAP, synaptophysin, and Neu-N negative



Astroblastoma





  • Lacks neuronal elements



Pearls





  • Good prognosis



  • Cases with atypical features (mitoses, endothelial proliferation, necrosis), elevated MIB-1 indices, and aggressive behavior have been reported





Selected References




  • Bourekas E.C., Bell S.D., Ladwig N.R., et. al.: Anaplastic papillary glioneuronal tumor with extraneural metastases. J Neuropathol Exp Neurol 2014; 73: pp. 474-475.



  • Komori T., Scheithauer B.W., Anthony D.C., et. al.: Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 1998; 22: pp. 1171-1183.



  • Pages M., Lacrois L., Tauziede-Espariat A., et. al.: Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion. Acta Neuropathol Commun 2015; 3: pp. 85.


Rosette-Forming Glioneuronal Tumor of The Fourth Ventricle (WHO Grade I)


Clinical Features





  • Rare neoplasm occurring at mean age of 32 years (range, 12 to 70 years)



  • Women affected more than men



  • Signs and symptoms secondary to obstructive hydrocephalus, headaches, ataxia, visual disturbances, and vertigo



  • MRI scan T1-weighted images show a heterogeneous (cystic or solid) isointense or hypointense lesion; it is hyperintense on T2-weighted images and usually shows focal contrast enhancement; calcifications may be seen on CT scan



  • Most often occur in the fourth ventricle, but they have been described in the spinal canal, pons, cerebellar vermis, and thalamus



Gross Pathology





  • Soft, gelatinous, well demarcated



Histopathology





  • Composed of neurocytic and glial cells



  • Neurocytic component exhibits small round nuclei and scant cytoplasm and forms perivascular pseudorosettes and Homer Wright rosettes, often accompanied by a microcystic, myxoid background; rarely, ganglion cells may be seen



  • Glial component exhibits piloid and spindle-shaped cells, may be more extensive than the neuronal component



  • Rosenthal fibers and eosinophilic granular bodies may be seen



  • Degenerative changes are often seen consisting of sclerotic vessels, collagen, calcifications, and hemosiderin-laden macrophages



  • Endothelial proliferation may be seen



  • Mitoses are rare



  • Well-defined tumor-parenchyma interface



Special Stains and Immunohistochemistry





  • Synaptophysin: positive granular staining of neurocytic component



  • NSE positive in neurocytic component



  • GFAP and S-100 positive in glial component



  • MIB-1 index: less than 3%



Other Techniques for Diagnosis





  • Electron microscopy: glial component has bundles of intermediate filaments; neurocytic component exhibits cells with small round nuclei, ribosomes, and rough endoplasmic reticulum; Golgi apparatus, sparse dense core granules, and microtubules in the rosette formations; occasional presynaptic specializations are seen



  • Cytogenetics: presence of PIK3CA and FGFR1 mutations and absence of KIAA1549-BRAF fusions, BRAF (V600E) mutation, codeletions of 1p/19q, or pathogenic mutations of IDH1/2



Differential Diagnosis


Pilocytic Astrocytoma





  • Usually occurs in younger individuals



  • Lacks neurocytic component and Homer Wright rosettes



  • Presence of KIAA1549-BRAF fusion



Central Neurocytoma





  • Does not have a biphasic appearance with the piloid astrocytic component alternating with the neurocytic component



Papillary Glioneuronal Neoplasm





  • More often occurs in cerebrum rather than fourth ventricle



  • Does not display Homer Wright rosettes



  • Exhibits pseudopapillary architecture formed by astrocytic cells



Ependymoma





  • Not biphasic (does not have the neurocytic component)



Medulloblastoma





  • Not biphasic (typically does not have the glial component) and is composed of primitive-appearing cells


Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Central Nervous System
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