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.

May 2, Webinar Topic: Endoscopic Ant Fossa Meningioma Excision/ Intraventricular Tumor Management

IFNE/ WFNS Endoscopy Weekend Update 3
Topic: Endoscopic Ant Fossa Meningioma Excision/ Intraventricular Tumor Management

Time: May 2, 2020
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Pediatric posterior fossa tumor

Pediatric posterior fossa tumor

Epidemiology

Approximately half of pediatric central nervous system tumors are located in the posterior fossa.

Pilocytic astrocytomas (PAs), medulloblastomas (MBs), and ependymomas are the most common posterior fossa tumors.

High grade gliomas, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma of the fourth ventricle are less frequent.

Because of the different treatment options and variability in long-term outcome, an accurate and specific diagnosis is mandatory 1).

Classification

Diagnosis

Treatment

A developmental and anatomic approach to the posterior fossa tumors in children (together with diffusion imaging data) provides a reliable pre-surgical identification of the tumor and of its aggressiveness 2).

see Posterior fossa tumor treatment.

Complications

Outcome

Over the last decades, the mortality rate of children with posterior fossa tumors has gradually decreased. While survival has been the primary objective in most reports, quality of survival increasingly appears to be an important indicator of a successful outcome. Children with a PF tumor can sustain damage to the cerebellum and other brain structures from the tumor itself, concomitant hydrocephalus, the consequences of treatment (surgery, chemotherapy, radiotherapy), or a combination of these factors. Together, these contribute to long-term sequelae in physical functioning, neuropsychological late outcomes (including academic outcome, working memory, perception and estimation of time, and selective attention, long-term neuromotor speech deficits, and executive functioning). Long-term quality of life can also be affected by endocrinological complication or the occurrence of secondary tumors. A significant proportion of survivors of PF tumors require long-term special education services and have reduced rates of high school graduation and employment. Interventions to improve neuropsychological functioning in childhood PF tumor survivors include (1) pharmacological interventions (such as methylphenidate, modafinil, or donepezil), (2) cognitive remediation, and (3) home-based computerized cognitive training. In order to achieve the best possible outcome for survivors, and ultimately minimize long-term complications, new interventions must be developed to prevent and ameliorate the neuro-toxic effects experienced by these children 3).

Age at diagnosis and treatment factors are important variables that affect the outcomes of the survivors 4).

References

1)

Poretti A, Meoded A, Huisman TA. Neuroimaging of pediatric posterior fossa tumors including review of the literature. J Magn Reson Imaging 2012;35:32–47.
2)

Raybaud C, Ramaswamy V, Taylor MD, Laughlin S. Posterior fossa tumors in children: developmental anatomy and diagnostic imaging. Childs Nerv Syst. 2015 Oct;31(10):1661-76. doi: 10.1007/s00381-015-2834-z. Epub 2015 Sep 9. PubMed PMID: 26351220.
3)

Lassaletta A, Bouffet E, Mabbott D, Kulkarni AV. Functional and neuropsychological late outcomes in posterior fossa tumors in children. Childs Nerv Syst. 2015 Oct;31(10):1877-90. doi: 10.1007/s00381-015-2829-9. Epub 2015 Sep 9. PubMed PMID: 26351237.
4)

Hanzlik E, Woodrome SE, Abdel-Baki M, Geller TJ, Elbabaa SK. A systematic review of neuropsychological outcomes following posterior fossa tumor surgery in children. Childs Nerv Syst. 2015 Oct;31(10):1869-75. doi: 10.1007/s00381-015-2867-3. Epub 2015 Sep 9. PubMed PMID: 26351236.
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