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.

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.

Posterior fossa decompression for Chiari type 1 deformity

Posterior fossa decompression for Chiari type 1 deformity

Despite decades of experience and research, the etiology and management of Chiari type 1 deformity (CM-I) continue to raise more questions than answers. Controversy abounds in every aspect of management, including the indications, timing, and type of surgery, as well as clinical and radiographic outcomes.

A review of recent literature on the management of CM-I in pediatric patients was presented by Alexander et al., along with the experience in managing 1073 patients who were diagnosed with CM-I over the past two decades (1998-2018) at Children’s National Medical Center.

The general trend reveals an increase in the diagnosis of CM-I at younger ages with a significant proportion of these being incidental findings (0.5-3.6%) in asymptomatic patients as well as a rise in the number of patients undergoing Chiari posterior fossa decompression surgery (PFD). The type of surgical intervention varies widely. At there institution, 104 (37%) Chiari surgeries were bone-only PFD with/without outer leaf durectomy, whereas 177 (63%) were PFD with duraplasty. They did not find a significant difference in outcomes between the PFD and PFDD groups (p = 0.59). An analysis of failures revealed a significant difference between patients who underwent tonsillar coagulation versus those whose tonsils were not manipulated (p = 0.02).

While the optimal surgical intervention continues to remain elusive, there is a shift away from intradural techniques in favor of a simple, extradural approach (including dural delamination) in pediatric patients due to high rates of clinical and radiographic success, along with a lower complication rate. The efficacy, safety, and necessity of tonsillar manipulation continue to be heavily contested, as evidence increasingly supports the efficacy and safety of less tonsillar manipulation, including there own experience 1).


An accurate and reliable selection of patients based on clinical and neuroimaging findings is paramount for the success of neurosurgical treatment2).


The preferred treatment for Chiari type 1 deformity is foramen magnum decompression (FMD), and it is assumed to normalise ICP and craniospinal pressure dissociation.

Observations suggest that anatomical restoration of cerebrospinal fluid pathways by FMD does not lead to immediate normalisation of preoperatively altered pulsatile and static ICP in patients with CMI. This finding may explain persistent symptoms during the early period after FMD3).


A variety of surgical techniques for CM-I have been used, and there is a controversy whether to use posterior fossa decompression with duraplasty(PFDD) or posterior fossa decompression without duraplasty (PFD) in CM-I patients.

Chen et al., compared the clinical results and effectiveness of PFDD and PFD in adult patients with CM-I. The cases of 103 adult CM-I patients who underwent posterior fossa decompression with or without duraplasty from 2008 to 2014 were reviewed retrospectively. Patients were divided into 2 groups according to the surgical techniques: PFDD group (n = 70) and PFD group (n = 33). We compared the demographics, preoperative symptoms, radiographic characteristics, postoperative complications, and clinical outcomes between the PFD and PFDD patients. No statistically significant differences were found between the PFDD and PFD groups with regard to demographics, preoperative symptoms, radiographic characteristics, and clinical outcomes(P > 0.05); however, the postoperative complication aseptic meningitis occurred more frequently in the PFDD group than in the PFD group (P = 0.027). We also performed a literature review about the PFDD and PFD and made a summary of these preview studies. Our study suggests that both PFDD and PFD could achieve similar clinical outcomes for adult CM-I patients. The choice of surgical procedure should be based on the patient’s condition. PFDD may lead to a higher complication rate and autologous grafts seemed to perform better than nonautologous grafts for duraplasty 4).


The purpose of a study was to examine the utility of iMRI in determining when an adequate decompression had been performed.

Patients with symptomatic Chiari I malformations with imaging findings of obstruction of the CSF space at the foramen magnum, with or without syringomyelia, were considered candidates for surgery. All patients underwent complete T1, T2, and cine MRI studies in the supine position preoperatively as a baseline. After the patient was placed prone with the neck flexed in position for surgery, iMRI was performed. The patient then underwent a bone decompression of the foramen magnum and arch of C-1, and the MRI was repeated. If obstruction was still present, then in a stepwise fashion the patient underwent dural splitting, duraplasty, and coagulation of the tonsils, with an iMRI study performed after each step guiding the decision to proceed further.

Eighteen patients underwent PFD for Chiari I malformations between November 2011 and February 2013; 15 prone preincision iMRIs were performed. Fourteen of these patients (93%) demonstrated significant improvement of CSF flow through the foramen magnum dorsal to the tonsils with positioning only. This improvement was so notable that changes in CSF flow as a result of the bone decompression were difficult to discern.

The authors observed significant CSF flow changes when simply positioning the patient for surgery. These results put into question intraoperative flow assessments that suggest adequate decompression by PFD, whether by iMRI or intraoperative ultrasound. The use of intraoperative imaging during PFD for Chiari I malformation, whether by ultrasound or iMRI, is limited by CSF flow dynamics across the foramen magnum that change significantly when the patient is positioned for surgery 5).

Complications

References

1)

Alexander H, Tsering D, Myseros JS, Magge SN, Oluigbo C, Sanchez CE, Keating RF. Management of Chiari I malformations: a paradigm in evolution. Childs Nerv Syst. 2019 Jul 27. doi: 10.1007/s00381-019-04265-2. [Epub ahead of print] PubMed PMID: 31352576.
2)

Poretti A, Ashmawy R, Garzon-Muvdi T, Jallo GI, Huisman TA, Raybaud C. Chiari Type 1 Deformity in Children: Pathogenetic, Clinical, Neuroimaging, and Management Aspects. Neuropediatrics. 2016 Jun 23. [Epub ahead of print] PubMed PMID: 27337547.
3)

Frič R, Eide PK. Perioperative monitoring of pulsatile and static intracranial pressure in patients with Chiari malformation type 1 undergoing foramen magnum decompression. Acta Neurochir (Wien). 2016 Feb;158(2):341-7. doi: 10.1007/s00701-015-2669-0. Epub 2015 Dec 28. PubMed PMID: 26711284.
4)

Chen J, Li Y, Wang T, Gao J, Xu J, Lai R, Tan D. Comparison of posterior fossa decompression with and without duraplasty for the surgical treatment of Chiari malformation type I in adult patients: A retrospective analysis of 103 patients. Medicine (Baltimore). 2017 Jan;96(4):e5945. doi: 10.1097/MD.0000000000005945. PubMed PMID: 28121938.
5)

Bond AE, Jane JA Sr, Liu KC, Oldfield EH. Changes in cerebrospinal fluid flow assessed using intraoperative MRI during posterior fossa decompression for Chiari malformation. J Neurosurg. 2015 May;122(5):1068-75. doi: 10.3171/2015.1.JNS132712. Epub 2015 Feb 20. PubMed PMID: 25699415.
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