Posterior Fossa A ependymoma

Posterior Fossa A ependymoma

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma1).


While supratentorial ependymomas are characterized by recurrent oncogenic fusions, infratentorial ependymomas can be classified by their epigenetic signatures into two main groups, pediatric-type (PFA) and adult-type (PFB) ependymomas


Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients 2).

H3K27me3 (me3) loss by immunohistochemistry (IHC) is a surrogate marker for PFA wherein its loss is attributed to overexpression of Cxorf67/EZH2 inhibitory protein (EZHIP), C17orf96, and ATRX loss. Nambirajan et al. aimed to subgroup posterior fossa ependymomas using me3 IHC and study correlations of the molecular subgroups with other histone-related proteins, 1q gain, Tenascin C, and outcome. IHC for me3, acetyl-H3K27, H3K27MATRXEZH2EZHIPC17orf96Tenascin C, and fluorescence in-situ hybridization for chromosome 1q25 locus were performed on an ambispective posterior fossa ependymomas cohort (2003-2019). H3K27M-mutant gliomas were included for comparison. Among 69 patients, PFA (me3 loss) constituted 64%. EZHIP overexpression and 1q gain were exclusive to PFA seen in 72% and 19%, respectively. Tenascin C was more frequently positive in PFA (p = 0.02). H3K27M expression and ATRX loss were noted in one case of PFA-EPN each. All H3K27M-mutant gliomas (n = 8) and PFA-EPN (n = 1) were EZHIP negative. C17orf96 and acetyl-H3K27 expression did not correlate with me3 loss. H3K27me3 is a robust surrogate for PF-EPN molecular subgrouping. EZHIP overexpression was exclusive to PFA EPNs and was characteristically absent in Diffuse midline glioma H3 K27M-mutants and the rare PFA harboring H3K27M mutations representing mutually exclusive pathways leading to me3 loss 3).

Ramaswamy and Taylor found that the strongest predictor of poor outcome in patients with posterior fossa ependymoma across the entire age spectrum was molecular subgroup PFA, which was reported in the paper entitled “Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis” in the Journal of Clinical Oncology. Patients with incompletely resected PFA tumors had a very poor outcome despite receiving adjuvant radiation therapy, whereas a substantial proportion of patients with PFB tumors can be cured with surgery alone 4).


A total of 72 Posterior fossa ependymomas cases were identified, 89% of which were PFA. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042) 5).

Effective treatment is limited to surgical resection and focal radiotherapy.


1)

Cavalli FMG, Hübner JM, Sharma T, Luu B, Sill M, Zapotocky M, Mack SC, Witt H, Lin T, Shih DJH, Ho B, Santi M, Emery L, Hukin J, Dunham C, McLendon RE, Lipp ES, Gururangan S, Grossbach A, French P, Kros JM, van Veelen MC, Rao AAN, Giannini C, Leary S, Jung S, Faria CC, Mora J, Schüller U, Alonso MM, Chan JA, Klekner A, Chambless LB, Hwang EI, Massimino M, Eberhart CG, Karajannis MA, Lu B, Liau LM, Zollo M, Ferrucci V, Carlotti C, Tirapelli DPC, Tabori U, Bouffet E, Ryzhova M, Ellison DW, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Pfister SM, Taylor MD, Aldape K, Pajtler KW, Kool M, Ramaswamy V. Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol. 2018 Aug;136(2):227-237. doi: 10.1007/s00401-018-1888-x. Epub 2018 Jul 17. PMID: 30019219; PMCID: PMC6373486.
2)

Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DT, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho YJ, von Deimling A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U, Guha A, Rutka JT, Lichter P, Korshunov A, Taylor MD, Pfister SM. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell. 2011 Aug 16;20(2):143-57. doi: 10.1016/j.ccr.2011.07.007. PMID: 21840481; PMCID: PMC4154494.
3)

Nambirajan A, Sharma A, Rajeshwari M, Boorgula MT, Doddamani R, Garg A, Suri V, Sarkar C, Sharma MC. EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations. Brain Tumor Pathol. 2020 Nov 1. doi: 10.1007/s10014-020-00385-9. Epub ahead of print. Erratum in: Brain Tumor Pathol. 2021 Jan 9;: PMID: 33130928.
4)

Ramaswamy V, Taylor MD. Treatment implications of posterior fossa ependymoma subgroups. Chin J Cancer. 2016 Nov 15;35(1):93. doi: 10.1186/s40880-016-0155-6. PMID: 27846874; PMCID: PMC5111181.
5)

Zapotocky M, Beera K, Adamski J, Laperierre N, Guger S, Janzen L, Lassaletta A, Figueiredo Nobre L, Bartels U, Tabori U, Hawkins C, Urbach S, Tsang DS, Dirks PB, Taylor MD, Bouffet E, Mabbott DJ, Ramaswamy V. Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer. 2019 Jun 1;125(11):1867-1876. doi: 10.1002/cncr.31995. Epub 2019 Feb 15. PMID: 30768777; PMCID: PMC6508980.

Brain metastases recurrence diagnosis

Brain metastases recurrence diagnosis

It is difficult to differentiate local brain metastases recurrence from radiation induced-changes in case of suspicious contrast enhancement. New advanced MRI techniques (perfusion and spectrometry) and Amino Acid Positron Emission tomography allow to be more accurate and could avoid a stereotactic biopsy for histological assessment, the only reliable but invasive method.

Whereas positron emission tomography (PET) with the widely used 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG) has low diagnostic accuracy after SRS, the use of radiolabelled amino acids or amino acid analogues such as L-methyl-11C-methionine (11C-MET) and O-(2-18F-Fluoroethyl)-L-Tyrosine (18F-FET) reaches sensitivity and specificity values in the range of 78 and 100 % rendering especially 18F-FET a highly reliable tracer in glioma imaging.


In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions 1).


Tran et al. performed a feasibility study to prospectively evaluate 11C methionine positron emission tomography and11C PBR28 positron emission tomography in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate tumor regrowth (TR) from radiation necrosis (RN).

Sequential imaging with dual tracers was well-tolerated. [11C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [11C]PBR28 was only accurate in 3/7 lesions. Tumor PBRTSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [11C]PBR28-PET.

Sequential use of PET tracers is safe and effective. [11C]Methionine was a reliable TR marker, but [11C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging 2).

The multimodal MRI has greatly contributed to refine the differential diagnosis between tumour recurrence and radionecrosis, which remains difficult. The FDG PET is helpful, in favour of the diagnosis of local tumour recurrence when a hypermetabolic lesion is found. Others tracers (such as carbon 11 or a fluoride isotope) deserve interest but are not available in all centres. Stereotactic biopsy should be discussed if any doubt remains 3).

An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. 4).


1)

Romagna A, Unterrainer M, Schmid-Tannwald C, Brendel M, Tonn JC, Nachbichler SB, Muacevic A, Bartenstein P, Kreth FW, Albert NL. Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties? Radiat Oncol. 2016 Oct 21;11(1):139. doi: 10.1186/s13014-016-0713-8. PMID: 27769279; PMCID: PMC5073742.
2)

Tran TT, Gallezot JD, Jilaveanu LB, Zito C, Turcu G, Lim K, Nabulsi N, Huang H, Huttner A, Kluger HM, Chiang VL, Carson R. [11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis. Mol Imaging. 2020 Jan-Dec;19:1536012120968669. doi: 10.1177/1536012120968669. PMID: 33147119.
3)

Patsouris A, Augereau P, Tanguy JY, Morel O, Menei P, Rousseau A, Paumier A. [Differentiation from local tumour recurrence and radionecrosis after stereotactic radiosurgery for treatment of brain metastasis.]. Cancer Radiother. 2014 Jan 13. pii: S1278-3218(13)00444-7. doi: 10.1016/j.canrad.2013.10.013. [Epub ahead of print] French. PubMed PMID: 24433952.
4)

Bette S, Gempt J, Wiestler B, Huber T, Specht H, Meyer B, Zimmer C, Kirschke JS, Boeckh-Behrens T. Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? Rofo. 2017 Jan;189(1):63-70. doi: 10.1055/s-0042-119686. PubMed PMID: 28002859.

Intracranial ganglioglioma

Intracranial ganglioglioma

Children and young patients are usually affected, and no gender predominance is recognised. It accounts for around 2% (from 0.4-3.8%) of all primary intracranial tumors, and up to 10% of primary cerebral tumors in children.

Because of their rarity, large-scale, population-based studies focusing on epidemiology and outcomes are lacking.

Ganglioglioma is a benign slow-growing neoplasm that most frequently occurs at the supratentorial region. Nevertheless, there are occasional reports of ganglioglioma occurring in thebrainstem and spinal cord.

see Cerebellar ganglioglioma.

see Intraventricular ganglioglioma

see Optic pathway ganglioglioma.

see Multifocal intracranial ganglioglioma

Molecular pathogenesis, risk factors for malignant progression, and their frequent association with drug-resistant focal seizures remain poorly understood. This contrasts recent progress in understanding the molecular-genetic basis and targeted treatment options in diffuse gliomas. The Neuropathology Task Force of the International League against Epilepsy examined available literature to identify common obstacles in diagnosis and research of LEAT. Analysis of 10 published tumour series from epilepsy surgery pointed to poor interrater agreement for the histopathology diagnosis. The Task Force tested this hypothesis using a web-based microscopy agreement study. In a series of 30 LEAT, 25 raters from 18 countries agreed in only 40% of cases. Highest discordance in microscopic diagnosis occurred between GG and DNT variants, when oligodendroglial-like cell patterns prevail, or ganglion cells were difficult to discriminate from pre-existing neurons. Suggesting new terminology or major histopathological criteria did not satisfactorily increase the yield of histopathology agreement in 4 consecutive trials. To this end, the Task Force applied the WHO 2016 strategy of integrating phenotype analysis with molecular-genetic data obtained from panel sequencing and 450k methylation arrays. This strategy was helpful to distinguish DNT from GG variants in all cases. The Task Force recommends, therefore, to further develop diagnostic panels for the integration of phenotype-genotype analysis in order to reliably classify the spectrum of LEAT, carefully characterize clinically meaningful entities and make better use of published literature 1).

The most common presentation is with temporal lobe epilepsy, presumably due to the temporal lobes being a favoured location.

Imaging findings mirror the various patterns of growth which these tumours may demonstrate and thus their appearance is very variable. Partially cystic mass with an enhancing mural nodule is seen in ~45% of cases. They may also simply present as a solid mass expanding the overlying gyrus. An infiltrating mass is uncommon and may reflect higher grade.

Findings are of a mass which is often non-specific. General features include:

iso- or hypodense

frequently calcified ~35%

bony remodelling or thinning can indicate the slow growing nature of the tumour

enhancement is seen in approximately 50% of cases (involving the solid non-calcified component)

Reported MR signal characteristics include:

T1 Solid component isointense to hypointense.

T1 C+ (Gd) solid component variable contrast enhancement

T2 hyperintense solid component variable signal in the cystic component depending on the amount of proteinaceous material or the presence of blood products peritumoural FLAIR/T2 oedema is distinctly uncommon

T2* (GE/SWI) calcified areas (common) will show blooming signal loss

Main differential diagnosis is that of other cortical tumours, with helpful distinguishing features including:

Dysembryoplastic neuroepithelial tumors (DNET)

contrast enhancement uncommon ‘bubbly appearance’ common

Pleomorphic xanthoastrocytoma (PXA)

contrast enhancement prominent dural tail sign is often seen

Oligodendroglioma

calcifications common

Desmoplastic infantile astrocytoma and ganglioglioma

young children dural involvement prominent large often multiple lesions

If in the spinal cord consider:

astrocytoma

ependymoma

The aim of a study was to evaluate whether ganglioglioma (GGL), dysembryoplastic neuroepithelial tumour (DNET) and FCD (focal cortical dysplasia) are distinguishable through diffusion tensor imaging. Additionally, it was investigated whether the diffusion measures differed in the perilesional (pNAWM) and in the contralateral normal appearing white matter (cNAWM). Six GGLs, eight DNETs and seven FCDs were included in this study. Quantitative diffusion measures, that is, axial, radial and mean diffusivity and fractional anisotropy, were determined in the lesion identified on isotropic T2 or FLAIR-weighted images and in pNAWM and cNAWM, respectively. DNET differed from FCD in mean diffusivity, and GGL from FCD in radial diffusivity. Both types of glioneuronal tumours were different from pNAWM in fractional anisotropy and radial diffusivity. For identifying the tumour edges, threshold values for tumour-free tissue were investigated with receiver operating characteristic analyses: tumour could be separated from pNAWM at a threshold ≤ 0.32 (fractional anisotropy) or ≥ 0.56 (radial diffusivity) *10-3 mm2/s (area under the curve 0.995 and 0.990 respectively). While diffusion parameters of FCDs differed from cNAWM (radial diffusivity (*10-3 mm/s2): 0.74 ± 0.19 vs. 0.43 ± 0.05; corrected p-value < 0.001), the pNAWM could not be differentiated from the FCD 2).

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma.

Gangliogliomas are WHO grade I tumours most frequently found in the temporal lobes (70%) 3) 4) but do occur anywhere in the central nervous system.

In a minority of cases (5%) these tumours show aggressive behaviour and histopathologic features and are then called anaplastic gangliogliomas (WHO grade III) 5) 6)

At this stage, no criteria for WHO II gangliogliomas have been established 7).

Gangliogliomas, as their name suggests, are composed of two cell populations:

ganglion cells (large mature neuronal elements): ganglio- neoplastic glial element: -glioma primarily astrocytic, although oligodendroglial or pilocytic astroctytoma components are also enountered 9 The proportion of each component varies widely, and it is the grade of the glial component that determines biological behaviour.

Dedifferentiation into high-grade tumours does occasionally occur, and it is usually the glial component (into a GBM). Only rarely is it the neuronal component (into a neuroblastoma).

They are closely related to both gangliocytomas (which contain only the mature neural ganglion cellular component) and ganglioneurocytoma (which also have small mature neoplastic neurones).

Neuronal origin is demonstrated by positivity to neuronal markers:

Synaptophysin: positive

Neurofilament protein: positive

MAP2: positive

Chromogranin-A: positive (usually negative in normal neurones)

CD34: positive in 70-80%

The glial component may also show cytoplasmic positivity for GFAP.

Ganglioglioma and pleomorphic xanthoastrocytoma were the histologic types with the strongest association with CD34 positivity with an odds ratio of 9.2 and 10.4, respectively, compared with dysembryoplastic neuroepithelial tumors in Low-Grade Epilepsy-Associated Tumors 8).

BRAFV600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma.

Gross total resection is achieved in the majority of cases.

Is the largest retrospective study of adult low-grade GGs up to date. Younger age, female gender, temporal lobe location, and GTR indicated better survival. Adjuvant RT and/or chemotherapy should not be considered after whatever surgery in adult patients with low-grade GGs, unless the malignant transformation has been confirmed 9)

In the surgical treatment of temporal lobe epilepsy with mesial temporal lobe tumor, whether to remove the hippocampus aiming for a better seizure outcome in addition to removing the tumor is a dilemma. Two pediatric cases treated successfully with tumor removal alone are presented.

The first case was an 11-year-old girl with a ganglioglioma in the left uncus, and the second case was a 9-year-old girl with a pleomorphic xanthoastrocytoma in the left parahippocampal gyrus. In both cases, the hippocampus was not invaded, merely compressed by the tumor. Tumor removal was performed under intraoperative electrocorticography (ECoG) monitoring. After tumor removal, abnormal discharges remained at the hippocampus and adjacent temporal cortices, but further surgical interventions were not performed. The seizures disappeared completely in both cases.

When we must decide whether to remove the hippocampus, the side of the lesion, the severity and chronicity of the seizures, and the presence of invasion to the hippocampus are the factors that should be considered. Abnormal discharges on ECoG at the hippocampus or adjacent cortices are one of the factors related to epileptogenicity, but it is simply a result of interictal irritation, and it is not an absolute indication for additional surgical intervention 10).

Gangliogliomas and ganglioneuromas are slow growing benign tumors.

In the largest retrospective study of adult low-grade GGs till 2020. Younger age, female gender, temporal lobe location, and GTR indicated better survival. Adjuvant RT and/or chemotherapy should not be considered after whatever surgery in adult patients with low-grade GGs, unless the malignant transformation has been confirmed 11)

Local resection is the treatment of choice and determines prognosis. In the brain, where a reasonable resection margin can be achieved, the prognosis is good, with recurrence-free survival reported to be 97% at 7.5-year follow-up 12).

In contrast, in the spinal cord where complete resection is often not possible without devastating deficits, local recurrence is very common.

Although the majority of patients have an excellent prognosis, infants and patients with brainstem tumors have worse survival rates.

Intracranial ganglioglioma case series.

Ganglioglioma case reports.


1)

Blümcke I, Coras R, Wefers AK, Capper D, Aronica E, Becker A, Honavar M, Stone TJ, Jacques TS, Miyata H, Mühlebner A, Pimentel J, Söylemezoğlu F, Thom M. Challenges in the histopathological classification of ganglioglioma and DNT: microscopic agreement studies and a preliminary genotype-phenotype analysis. Neuropathol Appl Neurobiol. 2018 Oct 16. doi: 10.1111/nan.12522. [Epub ahead of print] Review. PubMed PMID: 30326153.
2)

Rau A, Kellner E, Foit NA, Lützen N, Heiland DH, Schulze-Bonhage A, Reisert M, Kiselev VG, Prinz M, Urbach H, Mader I. Discrimination of epileptogenic lesions and perilesional white matter using diffusion tensor magnetic resonance imaging. Neuroradiol J. 2018 Nov 21:1971400918813991. doi: 10.1177/1971400918813991. [Epub ahead of print] PubMed PMID: 30461353.
3)

Rumboldt Z, Castillo M, Huang B et-al. Brain Imaging with MRI and CT. Cambridge University Press. (2012) ISBN:1139576399.
4) , 6) , 7) , 12)

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK “WHO Classification of Tumours of the Central Nervous System. 4th Edition Revised” ISBN: 9789283244929
5)

Song JY, Kim JH, Cho YH et-al. Treatment and outcomes for gangliogliomas: a single-center review of 16 patients. Brain Tumor Res Treat. 2014;2 (2): 49-55. doi:10.14791/btrt.2014.2.2.49
8)

Giulioni M, Marucci G, Cossu M, Tassi L, Bramerio M, Barba C, Buccoliero AM, Vornetti G, Zenesini C, Consales A, De Palma L, Villani F, Di Gennaro G, Vatti G, Zamponi N, Colicchio G, Marras CE. CD34 Expression in Low-Grade Epilepsy-Associated Tumors: Relationships with Clinicopathologic Features. World Neurosurg. 2018 Oct 9. pii: S1878-8750(18)32267-8. doi: 10.1016/j.wneu.2018.09.212. [Epub ahead of print] PubMed PMID: 30308344.
9) , 11)

Lin X, Huang R, Zhang P, Sun J, Dong G, Huang Y, Tian X. Low-grade gangliogliomas in adults: A population-based study. Cancer Med. 2020 Oct 27. doi: 10.1002/cam4.3577. Epub ahead of print. PMID: 33107220.
10)

Uda T, Kunihiro N, Nakajo K, Kuki I, Fukuoka M, Ohata K. Seizure freedom from temporal lobe epilepsy with mesial temporal lobe tumor by tumor removal alone without hippocampectomy despite remaining abnormal discharges on intraoperative electrocorticography: Report of two pediatric cases and reconsideration of the surgical strategy. Surg Neurol Int. 2018 Sep 10;9:181. doi: 10.4103/sni.sni_61_18. eCollection 2018. PubMed PMID: 30283714; PubMed Central PMCID: PMC6157038.
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