Difference between revisions of "Ependymoma"

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'''Ependymoma''' is a [[neuropathology tumour]].   
'''Ependymoma''' is a [[neuropathology tumour]].   
* ''Myxopapillary ependymoma'' is dealt with separately in the [[myxopapillary ependymoma]] article.
* ''Subependymoma'' is dealt with separately in the [[Subependymoma]] article.


==General==  
==General==  
*Called the forgotten glial tumour.
*Called the forgotten glial tumour.
*Anatomic location and molecular data is essential for tumor diagnosis.


Epidemiology:<ref name=Ref_PBoD8_1334>{{Ref PBoD8|1334}}</ref>
Epidemiology:<ref name=Ref_PBoD8_1334>{{Ref PBoD8|1334}}</ref>
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*May be associated with [[neurofibromatosis type 2]].
*May be associated with [[neurofibromatosis type 2]].


There are five main ependymal tumors:<ref name=Ref_WHOCNS_74>{{Ref WHOCNS|74}}</ref>
#Ependymoma (not otherwise specified).
#*Other flavours:<ref>URL: [http://emedicine.medscape.com/article/1744030-overview http://emedicine.medscape.com/article/1744030-overview]. Accessed on: 17 January 2012.</ref>
#**Papillary ependymoma.
#**Clear cell ependymoma.
#**Tanycytic ependymoma.
#Ependymoma, RELA fusion-positive.<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref>
#*L1CAM +ve / Nuclear NFkappaB +ve.<ref>{{Cite journal  | last1 = Pietsch | first1 = T. | last2 = Wohlers | first2 = I. | last3 = Goschzik | first3 = T. | last4 = Dreschmann | first4 = V. | last5 = Denkhaus | first5 = D. | last6 = Dörner | first6 = E. | last7 = Rahmann | first7 = S. | last8 = Klein-Hitpass | first8 = L. | title = Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. | journal = Acta Neuropathol | volume = 127 | issue = 4 | pages = 609-11 | month = Apr | year = 2014 | doi = 10.1007/s00401-014-1264-4 | PMID = 24562983 }}</ref>
#*Majority of supratentorial ependymoma in children.
#Anaplastic ependymoma.
#[[Myxopapillary ependymoma]].
#*Classically at [[filum terminale]].
#[[Subependymoma]].
#*Typically seen in IVth ventricle.


The designation ''Cellular ependymoma'' is depreceated.
There are currently ten main ependymal tumors:<ref name=Ref_WHOCNS_74>{{Ref WHOCNS|74}}</ref>
#Supratentorial [[Subependymoma]]
#Supratentorial ependymoma, ZFTA-fusion positive
#Supratentorial ependymoma, YAP1-fusion positive
#Posterior fossa [[Subependymoma]]
#Posterior fossa ependymoma group A
#Posterior fossa ependymoma group B
#Spinal [[Subependymoma]]
#Spinal ependymoma
#Spinal ependymoma, MYCN-amplified
#[[Myxopapillary ependymoma]]
 
Ependymoma, NOS (not otherwise specified): Molecular analysis still missing.
Ependymoma, NEC (not elsewhere classfied): Tumor cannot assigned to any of the defined entities.
 
Note: Molecularly defined ependymomas can be still graded as CNS grade 2 or 3 depending on histological features.
 
*Depreceated terminologies:
**Papillary ependymoma.
**Clear cell ependymoma.
**Tanycytic ependymoma.
**Cellular ependymoma.
**Ependymoma, RELA fusion-positive.<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref><ref>{{Cite journal | last1 = Pietsch | first1 = T. | last2 = Wohlers | first2 = I. | last3 = Goschzik | first3 = T. | last4 = Dreschmann | first4 = V. | last5 = Denkhaus | first5 = D. | last6 = Dörner | first6 = E. | last7 = Rahmann | first7 = S. | last8 = Klein-Hitpass | first8 = L. | title = Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. | journal = Acta Neuropathol | volume = 127 | issue = 4 | pages = 609-11 | month = Apr | year = 2014 | doi = 10.1007/s00401-014-1264-4 | PMID = 24562983 }}</ref> This is now called Supratentorial ependymoma, ZFTA-fusion positive.
**Anaplastic ependymoma. This is now called CNS grade 3 ependymoma.


==Gross==
==Gross==
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*Ventricular location, but also within the spinal cord.
*Ventricular location, but also within the spinal cord.
*Dissemination possible.  
*Dissemination possible.  
*[[Myxopapillary ependymoma]] classically at [[filum terminale]].
*[[Subependymoma]] typically seen in IVth ventricle.
<gallery>
<gallery>
File:AFIP405711R-EPENDYMOMA.jpg | Radiology (AFIP)
File:AFIP405711R-EPENDYMOMA.jpg | Radiology (AFIP)
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==Microscopic==
==Microscopic==
===Classic ependymoma===
==="Classic" ependymoma===
*Come in two CNS WHO grades: 2 and 3.
*Usu. sharply demarcated from surrounding brain parenchyma.
Features:
Features:
*Cells have a "tadpole-like" morphology.
*Cells have a "tadpole-like" morphology.
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*Nuclear features monotonous, i.e. "boring".<ref>MUN. 6 Oct 2009.</ref>
*Nuclear features monotonous, i.e. "boring".<ref>MUN. 6 Oct 2009.</ref>
**There is little variation in size, shape and staining.
**There is little variation in size, shape and staining.
*Hyalinized vessels.
*Calcification.
*Rare cases with cartilagineous metaplasia.<ref>{{Cite journal  | last1 = Wang | first1 = X. | last2 = Zhang | first2 = S. | last3 = Ye | first3 = Y. | last4 = Chen | first4 = Y. | last5 = Liu | first5 = X. | title = Ependymoma with cartilaginous metaplasia might have more aggressive behavior: a case report and literature review. | journal = Brain Tumor Pathol | volume = 29 | issue = 3 | pages = 172-6 | month = Jul | year = 2012 | doi = 10.1007/s10014-011-0079-4 | PMID = 22228122 }}</ref>  
*Rare cases with cartilagineous metaplasia.<ref>{{Cite journal  | last1 = Wang | first1 = X. | last2 = Zhang | first2 = S. | last3 = Ye | first3 = Y. | last4 = Chen | first4 = Y. | last5 = Liu | first5 = X. | title = Ependymoma with cartilaginous metaplasia might have more aggressive behavior: a case report and literature review. | journal = Brain Tumor Pathol | volume = 29 | issue = 3 | pages = 172-6 | month = Jul | year = 2012 | doi = 10.1007/s10014-011-0079-4 | PMID = 22228122 }}</ref>  
*Branching capillaries usu. only in supratentorial ependymomas.
===Supratentorial ependymoma===
*Usu. connected to the ventricles.
*Mostly frontal or temporal lobe.
*Approx. 1/3 of all ependymal tumours (41% in children).
*Irregular CM enhancement.
*YAP1-fused tumors in children oft large at time of diagnosis.
*Cysts and/or calcification possible.
*Sharply demarcated from adjacent brain parenchyma.
*True ependymal rosettes are rare.
*Occasionally branching capillary vessels.
*Clear cell phenotypes more common than in other locations.
*Complete surgical resection is the best predictor.
*CSF spread in up to 15% of tumours.
===Posterior fossa ependymoma===
*Usu. 4th ventricle, less common in CPA.
*Most frequent in children.
*May contain tumour nodules with increased cell density.
*Micocysts, vascular hyalinization and calcification can be present.
*No morphologic differences between Group A and B tumours.
*Perivascular pseudorosettes almost always present.
*Rare papillary or tanicytic patterns.


DDx (classic ependymoma):
DDx (supratentorial and posterior fossa ependymoma):
*[[Subependymoma]].
*[[Subependymoma]].
*[[Glioblastoma]] (GBM).
*[[Glioblastoma]] (GBM).
*Gliomas with BCOR internal tandem duplication.
*[[Astroblastoma]], MN1-altered.
**Invasive border = GBM; circumscribed border of lesion = ependymoma.
**Invasive border = GBM; circumscribed border of lesion = ependymoma.
*[[Oligodendroglioma]] (Clear cell ependymoma))
*CNS embryonal tumour with BCOR internal tandem duplication.
===Spinal ependymoma===
*Isomorphic nuclei.
*Mitotic activity usu. very low.
*Calcification, hemorrhage, cystic and/or metaplastic changes may be seen.
*Most tumours show CNS grade 2 histology.
**CNS grade 3 tumours should be examined for MYCN amplification.
*Outcome usu. good, extent of resection is prognostic.
DDx (spinal ependymoma):
*[[Pilocytic astrocytoma]] (Tanycytic ependymoma)
*[[Pilocytic astrocytoma]] (Tanycytic ependymoma)
*[[Oligodendroglioma]] (Clear cell ependymoma))
*Diffuse midline glioma, H3 K27-altered
*Small cell glioblastoma (MYCN-amplified spinal ependymoma)


====Images====
===Images===
www:
www:
*[http://www.flickr.com/photos/ckrishnan/3862487821/in/photostream Ependymoma (flickr.com)].
*[http://www.flickr.com/photos/ckrishnan/3862487821/in/photostream Ependymoma (flickr.com)].
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File:EMA_ependymoma_periluminal.jpg | Periluminal EMA positivity in a ependymoma. (WC/jensflorian)
File:EMA_ependymoma_periluminal.jpg | Periluminal EMA positivity in a ependymoma. (WC/jensflorian)
File:Ependymoma_EMA.jpg | Dot-like EMA immunreactivity n a ependymoma. (WC/Marvin101)
File:Ependymoma_EMA.jpg | Dot-like EMA immunreactivity n a ependymoma. (WC/Marvin101)
File:Tanycytic ependymoma HE.jpg | Tanycytic ependymoma must not confused with [[pilocytic astrocytoma]]. (WC/jensflorian)
File:Tanycytic ependymoma HE.jpg | Tanycytic morphology in ependymoma must not confused with [[pilocytic astrocytoma]]. (WC/jensflorian)
File:Tanicytic_ependymoma_x10.jpg | Tanycytic ependymoma - low mag. (WC/jensflorian)
File:Tanicytic_ependymoma_x10.jpg | Tanycytic morphology in ependymoma - low mag. (WC/jensflorian)
File:Papillary_Ependymoma.jpg | Papillary ependymoma - low mag. (WC/jensflorian)
File:Papillary_Ependymoma.jpg | Papillary morphology in ependymoma - low mag. (WC/jensflorian)
File:Papillary_ependymoma_HE_x40.jpg | Papillary ependymoma - intermed. mag. (WC/jensflorian)
File:Papillary_ependymoma_HE_x40.jpg | Papillary morphology in ependymoma - intermed. mag. (WC/jensflorian)
File:Clear_cell_ependymoma_HE.jpg | Clear cell ependymoma may mimic [[oligodendroglioma]]. (WC/jensflorian)
File:Clear_cell_ependymoma_HE.jpg | Clear cell morphology in ependymoma may mimic [[oligodendroglioma]]. (WC/jensflorian)
File:HE_anaplastic_epedymomas_mitoses_pleomorphism.jpg | Brisk mitotic activity in a anaplastic ependymoma. (WC/jensflorian)
File:HE_anaplastic_epedymomas_mitoses_pleomorphism.jpg | Brisk mitotic activity in a anaplastic ependymoma. (WC/jensflorian)
File:Cartilaginous metaplasia ependymoma.jpg|Metaplastic transformation in an anaplastic ependymoma. (WC/jensflorian)
File:Cartilaginous metaplasia ependymoma.jpg|Metaplastic transformation in an anaplastic ependymoma. (WC/jensflorian)
File:Ependymoma_L1CAM_IHC.jpg | L1CAM immunohistochemistry indicates presence of C11orf-RELA fusion.
File:Ependymoma_L1CAM_IHC.jpg | L1CAM immunohistochemistry indicates presence of ZFTA-fusion.
File:Ependymoma_NFkappaB_IHC.jpg | Nuclear NFkappaB IHC indicates presence of C11orf-RELA fusion.
File:Ependymoma_NFkappaB_IHC.jpg | Nuclear NFkappaB IHC indicates presence of ZFTA-fusion.
</gallery>
</gallery>


===Grading===
===Grading===
Easy:
Easy:
*Subependymoma = WHO grade I.
*Subependymoma = CNS WHO grade 1.
*Myxopapillary ependymoma = WHO grade I.
*Myxopapillary ependymoma = CNS WHO grade 2.
Not-so-easy:
*Classic ependymoma = WHO grade II.
*Anaplastic ependymoma = WHO grade III.


Grade II vs. Grade III:
Not so easy:
All other ependymomas: WHO CNS Grade 2 vs. Grade 3 depends on:
*Cellular density.
*Cellular density.
*Mitoses.
*Mitoses (no clear cut-off).
*Necrosis.
*Necrosis (not prognostic).
*Microvascular proliferation.
*Microvascular proliferation.
*Poor interobserver reliability<ref>{{Cite journal  | last1 = Ellison | first1 = DW. | last2 = Kocak | first2 = M. | last3 = Figarella-Branger | first3 = D. | last4 = Felice | first4 = G. | last5 = Catherine | first5 = G. | last6 = Pietsch | first6 = T. | last7 = Frappaz | first7 = D. | last8 = Massimino | first8 = M. | last9 = Grill | first9 = J. | title = Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. | journal = J Negat Results Biomed | volume = 10 | issue =  | pages = 7 | month = May | year = 2011 | doi = 10.1186/1477-5751-10-7 | PMID = 21627842 }}</ref>
*Poor interobserver reliability<ref>{{Cite journal  | last1 = Ellison | first1 = DW. | last2 = Kocak | first2 = M. | last3 = Figarella-Branger | first3 = D. | last4 = Felice | first4 = G. | last5 = Catherine | first5 = G. | last6 = Pietsch | first6 = T. | last7 = Frappaz | first7 = D. | last8 = Massimino | first8 = M. | last9 = Grill | first9 = J. | title = Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. | journal = J Negat Results Biomed | volume = 10 | issue =  | pages = 7 | month = May | year = 2011 | doi = 10.1186/1477-5751-10-7 | PMID = 21627842 }}</ref>
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Notes:
Notes:
*Many tumours fall between grade II and grade III.  These are called "indeterminate" by many.
*Many tumours fall between grade 2 and grade 3.   
*Rare cases with sarcomatous or cartilaginous components.<ref>{{Cite journal  | last1 = Vajtai | first1 = I. | last2 = Kuhlen | first2 = D. | last3 = Kappeler | first3 = A. | last4 = Mariani | first4 = L. | last5 = Zimmermann | first5 = A. | last6 = Paulus | first6 = W. | title = Rapid spontaneous malignant progression of supratentorial tanycytic ependymoma with sarcomatous features - "Ependymosarcoma". | journal = Pathol Res Pract | volume = 206 | issue = 7 | pages = 493-8 | month = Jul | year = 2010 | doi = 10.1016/j.prp.2009.07.013 | PMID = 19853384 }}</ref><ref>{{Cite journal  | last1 = Boukas | first1 = A. | last2 = Joshi | first2 = A. | last3 = Jenkins | first3 = A. | last4 = Holliman | first4 = D. | title = Extensive cartilaginous metaplasia of recurrent posterior fossa ependymoma: case report and review of the literature. | journal = Pediatr Neurosurg | volume = 49 | issue = 2 | pages = 93-8 | month =  | year = 2013 | doi = 10.1159/000356931 | PMID = 24401698 }}</ref>
*Rare cases with sarcomatous or cartilaginous components.<ref>{{Cite journal  | last1 = Vajtai | first1 = I. | last2 = Kuhlen | first2 = D. | last3 = Kappeler | first3 = A. | last4 = Mariani | first4 = L. | last5 = Zimmermann | first5 = A. | last6 = Paulus | first6 = W. | title = Rapid spontaneous malignant progression of supratentorial tanycytic ependymoma with sarcomatous features - "Ependymosarcoma". | journal = Pathol Res Pract | volume = 206 | issue = 7 | pages = 493-8 | month = Jul | year = 2010 | doi = 10.1016/j.prp.2009.07.013 | PMID = 19853384 }}</ref><ref>{{Cite journal  | last1 = Boukas | first1 = A. | last2 = Joshi | first2 = A. | last3 = Jenkins | first3 = A. | last4 = Holliman | first4 = D. | title = Extensive cartilaginous metaplasia of recurrent posterior fossa ependymoma: case report and review of the literature. | journal = Pediatr Neurosurg | volume = 49 | issue = 2 | pages = 93-8 | month =  | year = 2013 | doi = 10.1159/000356931 | PMID = 24401698 }}</ref>


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*[[IDH-1]]-ve.
*[[IDH-1]]-ve.
*EMA (dots and rings).<ref>{{Cite journal  | last1 = Hasselblatt | first1 = M. | last2 = Paulus | first2 = W. | title = Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas. | journal = Acta Neuropathol | volume = 106 | issue = 4 | pages = 385-8 | month = Oct | year = 2003 | doi = 10.1007/s00401-003-0752-8 | PMID = 12898159 }}</ref>
*EMA (dots and rings).<ref>{{Cite journal  | last1 = Hasselblatt | first1 = M. | last2 = Paulus | first2 = W. | title = Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas. | journal = Acta Neuropathol | volume = 106 | issue = 4 | pages = 385-8 | month = Oct | year = 2003 | doi = 10.1007/s00401-003-0752-8 | PMID = 12898159 }}</ref>
**Widespread and strong EMA expression is indicative of YAP1-fused ependymoma.
*Olig2-ve.<ref>{{Cite journal  | last1 = Švajdler | first1 = M. | last2 = Rychlý | first2 = B. | last3 = Mezencev | first3 = R. | last4 = Fröhlichová | first4 = L. | last5 = Bednárová | first5 = A. | last6 = Pataky | first6 = F. | last7 = Daum | first7 = O. | title = SOX10 and Olig2 as negative markers for the diagnosis of ependymomas: An immunohistochemical study of 98 glial tumors. | journal = Histol Histopathol | volume = 31 | issue = 1 | pages = 95-102 | month = Jan | year = 2016 | doi = 10.14670/HH-11-654 | PMID = 26287936 }}</ref>
*Olig2-ve.<ref>{{Cite journal  | last1 = Švajdler | first1 = M. | last2 = Rychlý | first2 = B. | last3 = Mezencev | first3 = R. | last4 = Fröhlichová | first4 = L. | last5 = Bednárová | first5 = A. | last6 = Pataky | first6 = F. | last7 = Daum | first7 = O. | title = SOX10 and Olig2 as negative markers for the diagnosis of ependymomas: An immunohistochemical study of 98 glial tumors. | journal = Histol Histopathol | volume = 31 | issue = 1 | pages = 95-102 | month = Jan | year = 2016 | doi = 10.14670/HH-11-654 | PMID = 26287936 }}</ref>
*H3K27me in posterior fossa (loss indicates group A).<ref>{{Cite journal  | last1 = Panwalkar | first1 = P. | last2 = Clark | first2 = J. | last3 = Ramaswamy | first3 = V. | last4 = Hawes | first4 = D. | last5 = Yang | first5 = F. | last6 = Dunham | first6 = C. | last7 = Yip | first7 = S. | last8 = Hukin | first8 = J. | last9 = Sun | first9 = Y. | title = Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. | journal = Acta Neuropathol | volume =  | issue =  | pages =  | month = Jul | year = 2017 | doi = 10.1007/s00401-017-1752-4 | PMID = 28733933 }}</ref>
*H3K27me3 nuclear loss in Posterior fossa group A ependymoma (nuclear loss is diagnostic).<ref>{{Cite journal  | last1 = Panwalkar | first1 = P. | last2 = Clark | first2 = J. | last3 = Ramaswamy | first3 = V. | last4 = Hawes | first4 = D. | last5 = Yang | first5 = F. | last6 = Dunham | first6 = C. | last7 = Yip | first7 = S. | last8 = Hukin | first8 = J. | last9 = Sun | first9 = Y. | title = Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. | journal = Acta Neuropathol | volume =  | issue =  | pages =  | month = Jul | year = 2017 | doi = 10.1007/s00401-017-1752-4 | PMID = 28733933 }}</ref>
*L1CAM in supratentorial tumors (expression indicates RELA fusion).<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref>
*L1CAM in supratentorial tumors (expression indicates ZFTA fusion).<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref>
*p65 nuclear +ve in ZFTA-fused ependymoma.


==Molecular==
==Molecular==
'''Supratentorial Ependymoma'''
*SE, ZFTA-fusion positive: Adults and children (up to 80% of cases).<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref>
**ZFTA-RELA fusion most common alteration.
**Chromothripsis.
**EPHB2 amplifications  and CDKN2A deletions in a subset of these tumors<ref>{{Cite journal  | last1 = Philip-Hollingsworth | first1 = S. | last2 = Hollingsworth | first2 = RI. | last3 = Dazzo | first3 = FB. | title = Host-range related structural features of the acidic extracellular polysaccharides of Rhizobium trifolii and Rhizobium leguminosarum. | journal = J Biol Chem | volume = 264 | issue = 3 | pages = 1461-6 | month = Jan | year = 1989 | doi =  | PMID = 2912966 }}</ref>
*SE, YAP-fusion positive.
**Restricted to children (6-7% of all supratentorial ependymomas).
**YAP-MAMLD fusion most common alteration.
'''Posterior fossa Ependymoma'''
Two distinct molecular subgroups exist in the posterior fossa:<ref>{{Cite journal  | last1 = Witt | first1 = H. | last2 = Mack | first2 = SC. | last3 = Ryzhova | first3 = M. | last4 = Bender | first4 = S. | last5 = Sill | first5 = M. | last6 = Isserlin | first6 = R. | last7 = Benner | first7 = A. | last8 = Hielscher | first8 = T. | last9 = Milde | first9 = T. | title = Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. | journal = Cancer Cell | volume = 20 | issue = 2 | pages = 143-57 | month = Aug | year = 2011 | doi = 10.1016/j.ccr.2011.07.007 | PMID = 21840481 }}</ref>
Two distinct molecular subgroups exist in the posterior fossa:<ref>{{Cite journal  | last1 = Witt | first1 = H. | last2 = Mack | first2 = SC. | last3 = Ryzhova | first3 = M. | last4 = Bender | first4 = S. | last5 = Sill | first5 = M. | last6 = Isserlin | first6 = R. | last7 = Benner | first7 = A. | last8 = Hielscher | first8 = T. | last9 = Milde | first9 = T. | title = Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. | journal = Cancer Cell | volume = 20 | issue = 2 | pages = 143-57 | month = Aug | year = 2011 | doi = 10.1016/j.ccr.2011.07.007 | PMID = 21840481 }}</ref>
* Group A ependymomas:
* Group A ependymomas:
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**gene expression profiles similar to that of spinal cord ependymomas.
**gene expression profiles similar to that of spinal cord ependymomas.
**increased Chromosomal 1q gains. <ref>{{Cite journal  | last1 = Korshunov | first1 = A. | last2 = Witt | first2 = H. | last3 = Hielscher | first3 = T. | last4 = Benner | first4 = A. | last5 = Remke | first5 = M. | last6 = Ryzhova | first6 = M. | last7 = Milde | first7 = T. | last8 = Bender | first8 = S. | last9 = Wittmann | first9 = A. | title = Molecular staging of intracranial ependymoma in children and adults. | journal = J Clin Oncol | volume = 28 | issue = 19 | pages = 3182-90 | month = Jul | year = 2010 | doi = 10.1200/JCO.2009.27.3359 | PMID = 20516456 }}</ref>
**increased Chromosomal 1q gains. <ref>{{Cite journal  | last1 = Korshunov | first1 = A. | last2 = Witt | first2 = H. | last3 = Hielscher | first3 = T. | last4 = Benner | first4 = A. | last5 = Remke | first5 = M. | last6 = Ryzhova | first6 = M. | last7 = Milde | first7 = T. | last8 = Bender | first8 = S. | last9 = Wittmann | first9 = A. | title = Molecular staging of intracranial ependymoma in children and adults. | journal = J Clin Oncol | volume = 28 | issue = 19 | pages = 3182-90 | month = Jul | year = 2010 | doi = 10.1200/JCO.2009.27.3359 | PMID = 20516456 }}</ref>
Supratentorial ependymomas have also a distinct profile:
*70 % of these ependymomas have recurrent gene fusions involving RELA and C11orf95<ref>{{Cite journal  | last1 = Parker | first1 = M. | last2 = Mohankumar | first2 = KM. | last3 = Punchihewa | first3 = C. | last4 = Weinlich | first4 = R. | last5 = Dalton | first5 = JD. | last6 = Li | first6 = Y. | last7 = Lee | first7 = R. | last8 = Tatevossian | first8 = RG. | last9 = Phoenix | first9 = TN. | title = C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. | journal = Nature | volume = 506 | issue = 7489 | pages = 451-5 | month = Feb | year = 2014 | doi = 10.1038/nature13109 | PMID = 24553141 }}</ref>
*EPHB2 amplifications  and CDKN2A deletions in a subset of these tumors<ref>{{Cite journal  | last1 = Philip-Hollingsworth | first1 = S. | last2 = Hollingsworth | first2 = RI. | last3 = Dazzo | first3 = FB. | title = Host-range related structural features of the acidic extracellular polysaccharides of Rhizobium trifolii and Rhizobium leguminosarum. | journal = J Biol Chem | volume = 264 | issue = 3 | pages = 1461-6 | month = Jan | year = 1989 | doi =  | PMID = 2912966 }}</ref>
Note: Molecular subgroups have no treatment implications (at the moment).


==See also==
==See also==

Latest revision as of 13:20, 19 September 2022

Ependymoma
Diagnosis in short

Ependymoma grade II WHO. H&E stain
LM Perivascular pseudorosettes, ependymal rosettes
Subtypes Tanycytic, Clear cell, Papillary, Cellular
LM DDx Subependymoma, Glioblastoma, Pilocytic astrocytoma, Oligodendroglioma
IHC GFAP +ve
Prognosis intermediate to poor (WHO Grades II & III)


Ependymoma is a neuropathology tumour.

General

  • Called the forgotten glial tumour.
  • Anatomic location and molecular data is essential for tumor diagnosis.


Epidemiology:[1]

  • Usual site:
    • Adults: usually spinal cord.
    • Children: usually posterior fossa.
  • May be associated with neurofibromatosis type 2.


There are currently ten main ependymal tumors:[2]

  1. Supratentorial Subependymoma
  2. Supratentorial ependymoma, ZFTA-fusion positive
  3. Supratentorial ependymoma, YAP1-fusion positive
  4. Posterior fossa Subependymoma
  5. Posterior fossa ependymoma group A
  6. Posterior fossa ependymoma group B
  7. Spinal Subependymoma
  8. Spinal ependymoma
  9. Spinal ependymoma, MYCN-amplified
  10. Myxopapillary ependymoma

Ependymoma, NOS (not otherwise specified): Molecular analysis still missing. Ependymoma, NEC (not elsewhere classfied): Tumor cannot assigned to any of the defined entities.

Note: Molecularly defined ependymomas can be still graded as CNS grade 2 or 3 depending on histological features.

  • Depreceated terminologies:
    • Papillary ependymoma.
    • Clear cell ependymoma.
    • Tanycytic ependymoma.
    • Cellular ependymoma.
    • Ependymoma, RELA fusion-positive.[3][4] This is now called Supratentorial ependymoma, ZFTA-fusion positive.
    • Anaplastic ependymoma. This is now called CNS grade 3 ependymoma.

Gross

  • Radiology (AFIP)

  • Ependymoma in the fourth ventricle (AFIP)

  • Gross (AFIP)

Microscopic

"Classic" ependymoma

  • Come in two CNS WHO grades: 2 and 3.
  • Usu. sharply demarcated from surrounding brain parenchyma.

Features:

  • Cells have a "tadpole-like" morphology.
    • May also be described as ice cream cone-shaped.[5]
  • Rosettes = circular nuclear free zones/cells arranged in a pseudoglandular fashion; comes in two flavours in ependymoma:
    • Perivascular pseudorosettes = (tumour) cells arranged around a blood vessel; nuclei of cells distant from the blood vessel, i.e. rim of cytoplasm (from tumour cells) surround blood vessel (nucleus-free zone); more common than ependymal rosette... but less specific.
    • Ependymal rosette (AKA true ependymal rosette) = rosette has an empty space at the centre - key feature.
  • Nuclear features monotonous, i.e. "boring".[6]
    • There is little variation in size, shape and staining.
  • Hyalinized vessels.
  • Calcification.
  • Rare cases with cartilagineous metaplasia.[7]
  • Branching capillaries usu. only in supratentorial ependymomas.

Supratentorial ependymoma

  • Usu. connected to the ventricles.
  • Mostly frontal or temporal lobe.
  • Approx. 1/3 of all ependymal tumours (41% in children).
  • Irregular CM enhancement.
  • YAP1-fused tumors in children oft large at time of diagnosis.
  • Cysts and/or calcification possible.
  • Sharply demarcated from adjacent brain parenchyma.
  • True ependymal rosettes are rare.
  • Occasionally branching capillary vessels.
  • Clear cell phenotypes more common than in other locations.
  • Complete surgical resection is the best predictor.
  • CSF spread in up to 15% of tumours.

Posterior fossa ependymoma

  • Usu. 4th ventricle, less common in CPA.
  • Most frequent in children.
  • May contain tumour nodules with increased cell density.
  • Micocysts, vascular hyalinization and calcification can be present.
  • No morphologic differences between Group A and B tumours.
  • Perivascular pseudorosettes almost always present.
  • Rare papillary or tanicytic patterns.

DDx (supratentorial and posterior fossa ependymoma):

  • Subependymoma.
  • Glioblastoma (GBM).
  • Gliomas with BCOR internal tandem duplication.
  • Astroblastoma, MN1-altered.
    • Invasive border = GBM; circumscribed border of lesion = ependymoma.
  • Oligodendroglioma (Clear cell ependymoma))
  • CNS embryonal tumour with BCOR internal tandem duplication.

Spinal ependymoma

  • Isomorphic nuclei.
  • Mitotic activity usu. very low.
  • Calcification, hemorrhage, cystic and/or metaplastic changes may be seen.
  • Most tumours show CNS grade 2 histology.
    • CNS grade 3 tumours should be examined for MYCN amplification.
  • Outcome usu. good, extent of resection is prognostic.

DDx (spinal ependymoma):

  • Pilocytic astrocytoma (Tanycytic ependymoma)
  • Diffuse midline glioma, H3 K27-altered
  • Small cell glioblastoma (MYCN-amplified spinal ependymoma)

Images

www:

  • Ependymoma smear. (AFIP)

  • Perivascular pseudorosettes in a ependymoma. (AFIP)

  • Ependymoma - intermed. mag. (WC)

  • Ependymoma - low mag. (WC)

  • Ependymoma - high mag. (WC/Sbrandner)

  • True ependymal and pseudorosettes in a ependymoma. (WC/jensflorian)

  • Ependymal linings in a ependymoma. (WC/jensflorian)

  • GFAP IHC in a ependymoma. (WC/Sbrandner)

  • Periluminal EMA positivity in a ependymoma. (WC/jensflorian)

  • Dot-like EMA immunreactivity n a ependymoma. (WC/Marvin101)

  • Tanycytic morphology in ependymoma must not confused with pilocytic astrocytoma. (WC/jensflorian)

  • Tanycytic morphology in ependymoma - low mag. (WC/jensflorian)

  • Papillary morphology in ependymoma - low mag. (WC/jensflorian)

  • Papillary morphology in ependymoma - intermed. mag. (WC/jensflorian)

  • Clear cell morphology in ependymoma may mimic oligodendroglioma. (WC/jensflorian)

  • Brisk mitotic activity in a anaplastic ependymoma. (WC/jensflorian)

  • Metaplastic transformation in an anaplastic ependymoma. (WC/jensflorian)

  • L1CAM immunohistochemistry indicates presence of ZFTA-fusion.

  • Nuclear NFkappaB IHC indicates presence of ZFTA-fusion.

Grading

Easy:

  • Subependymoma = CNS WHO grade 1.
  • Myxopapillary ependymoma = CNS WHO grade 2.

Not so easy: All other ependymomas: WHO CNS Grade 2 vs. Grade 3 depends on:

  • Cellular density.
  • Mitoses (no clear cut-off).
  • Necrosis (not prognostic).
  • Microvascular proliferation.
  • Poor interobserver reliability[8]


Notes:

  • Many tumours fall between grade 2 and grade 3.
  • Rare cases with sarcomatous or cartilaginous components.[9][10]

IHC

  • Reticulin-ve.
  • GFAP+ve.
  • MIB1 (usu low).
  • IDH-1-ve.
  • EMA (dots and rings).[11]
    • Widespread and strong EMA expression is indicative of YAP1-fused ependymoma.
  • Olig2-ve.[12]
  • H3K27me3 nuclear loss in Posterior fossa group A ependymoma (nuclear loss is diagnostic).[13]
  • L1CAM in supratentorial tumors (expression indicates ZFTA fusion).[14]
  • p65 nuclear +ve in ZFTA-fused ependymoma.

Molecular

Supratentorial Ependymoma

  • SE, ZFTA-fusion positive: Adults and children (up to 80% of cases).[15]
    • ZFTA-RELA fusion most common alteration.
    • Chromothripsis.
    • EPHB2 amplifications and CDKN2A deletions in a subset of these tumors[16]
  • SE, YAP-fusion positive.
    • Restricted to children (6-7% of all supratentorial ependymomas).
    • YAP-MAMLD fusion most common alteration.

Posterior fossa Ependymoma Two distinct molecular subgroups exist in the posterior fossa:[17]

  • Group A ependymomas:
    • typically found in children.
    • laterally.
    • relatively unfavorable clinical outcome.
    • CpG island methylator phenotype.[18]
    • Loss of H3K27me.[19]
  • Group B ependymomas:
    • typically adults.
    • midline.
    • relatively favorable clinical outcomes.
    • gene expression profiles similar to that of spinal cord ependymomas.
    • increased Chromosomal 1q gains. [20]

See also

References

  1. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1334. ISBN 978-1416031215.
  2. ↑ The International Agency for Research on Cancer (Editors: Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.) (2007). Pathology and Genetics of Tumours of Tumors of the Central Nervous System (IARC WHO Classification of Tumours) (4th ed.). Lyon: World Health Organization. pp. 74. doi:10.1007/s00401-007-0243-4. ISBN 978-9283224303.
  3. ↑ Parker, M.; Mohankumar, KM.; Punchihewa, C.; Weinlich, R.; Dalton, JD.; Li, Y.; Lee, R.; Tatevossian, RG. et al. (Feb 2014). "C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.". Nature 506 (7489): 451-5. doi:10.1038/nature13109. PMID 24553141.
  4. ↑ Pietsch, T.; Wohlers, I.; Goschzik, T.; Dreschmann, V.; Denkhaus, D.; Dörner, E.; Rahmann, S.; Klein-Hitpass, L. (Apr 2014). "Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway.". Acta Neuropathol 127 (4): 609-11. doi:10.1007/s00401-014-1264-4. PMID 24562983.
  5. ↑ http://www.pathology.vcu.edu/WirSelfInst/tumor-2.html
  6. ↑ MUN. 6 Oct 2009.
  7. ↑ Wang, X.; Zhang, S.; Ye, Y.; Chen, Y.; Liu, X. (Jul 2012). "Ependymoma with cartilaginous metaplasia might have more aggressive behavior: a case report and literature review.". Brain Tumor Pathol 29 (3): 172-6. doi:10.1007/s10014-011-0079-4. PMID 22228122.
  8. ↑ Ellison, DW.; Kocak, M.; Figarella-Branger, D.; Felice, G.; Catherine, G.; Pietsch, T.; Frappaz, D.; Massimino, M. et al. (May 2011). "Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.". J Negat Results Biomed 10: 7. doi:10.1186/1477-5751-10-7. PMID 21627842.
  9. ↑ Vajtai, I.; Kuhlen, D.; Kappeler, A.; Mariani, L.; Zimmermann, A.; Paulus, W. (Jul 2010). "Rapid spontaneous malignant progression of supratentorial tanycytic ependymoma with sarcomatous features - "Ependymosarcoma".". Pathol Res Pract 206 (7): 493-8. doi:10.1016/j.prp.2009.07.013. PMID 19853384.
  10. ↑ Boukas, A.; Joshi, A.; Jenkins, A.; Holliman, D. (2013). "Extensive cartilaginous metaplasia of recurrent posterior fossa ependymoma: case report and review of the literature.". Pediatr Neurosurg 49 (2): 93-8. doi:10.1159/000356931. PMID 24401698.
  11. ↑ Hasselblatt, M.; Paulus, W. (Oct 2003). "Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas.". Acta Neuropathol 106 (4): 385-8. doi:10.1007/s00401-003-0752-8. PMID 12898159.
  12. ↑ Švajdler, M.; Rychlý, B.; Mezencev, R.; Fröhlichová, L.; Bednárová, A.; Pataky, F.; Daum, O. (Jan 2016). "SOX10 and Olig2 as negative markers for the diagnosis of ependymomas: An immunohistochemical study of 98 glial tumors.". Histol Histopathol 31 (1): 95-102. doi:10.14670/HH-11-654. PMID 26287936.
  13. ↑ Panwalkar, P.; Clark, J.; Ramaswamy, V.; Hawes, D.; Yang, F.; Dunham, C.; Yip, S.; Hukin, J. et al. (Jul 2017). "Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome.". Acta Neuropathol. doi:10.1007/s00401-017-1752-4. PMID 28733933.
  14. ↑ Parker, M.; Mohankumar, KM.; Punchihewa, C.; Weinlich, R.; Dalton, JD.; Li, Y.; Lee, R.; Tatevossian, RG. et al. (Feb 2014). "C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.". Nature 506 (7489): 451-5. doi:10.1038/nature13109. PMID 24553141.
  15. ↑ Parker, M.; Mohankumar, KM.; Punchihewa, C.; Weinlich, R.; Dalton, JD.; Li, Y.; Lee, R.; Tatevossian, RG. et al. (Feb 2014). "C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.". Nature 506 (7489): 451-5. doi:10.1038/nature13109. PMID 24553141.
  16. ↑ Philip-Hollingsworth, S.; Hollingsworth, RI.; Dazzo, FB. (Jan 1989). "Host-range related structural features of the acidic extracellular polysaccharides of Rhizobium trifolii and Rhizobium leguminosarum.". J Biol Chem 264 (3): 1461-6. PMID 2912966.
  17. ↑ Witt, H.; Mack, SC.; Ryzhova, M.; Bender, S.; Sill, M.; Isserlin, R.; Benner, A.; Hielscher, T. et al. (Aug 2011). "Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.". Cancer Cell 20 (2): 143-57. doi:10.1016/j.ccr.2011.07.007. PMID 21840481.
  18. ↑ Mack, SC.; Witt, H.; Piro, RM.; Gu, L.; Zuyderduyn, S.; Stütz, AM.; Wang, X.; Gallo, M. et al. (Feb 2014). "Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.". Nature 506 (7489): 445-50. doi:10.1038/nature13108. PMID 24553142.
  19. ↑ Panwalkar, P.; Clark, J.; Ramaswamy, V.; Hawes, D.; Yang, F.; Dunham, C.; Yip, S.; Hukin, J. et al. (Jul 2017). "Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome.". Acta Neuropathol. doi:10.1007/s00401-017-1752-4. PMID 28733933.
  20. ↑ Korshunov, A.; Witt, H.; Hielscher, T.; Benner, A.; Remke, M.; Ryzhova, M.; Milde, T.; Bender, S. et al. (Jul 2010). "Molecular staging of intracranial ependymoma in children and adults.". J Clin Oncol 28 (19): 3182-90. doi:10.1200/JCO.2009.27.3359. PMID 20516456.
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