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.

Spinal Myxopapillary Ependymoma Epidemiology

Spinal Myxopapillary Ependymoma Epidemiology

The myxopapillary subtype of ependymomas (MPE) occurs mostly in the thoracolumbar region and is the most common form of ependymoma in the lumbar spine 1) 2) 3) 4).

In one study of 77 myxopapillary ependymomas 5). these tumors represented 27% of all spinal ependymomas and 90% of tumours in the conus medullaris 6) 7) 8) 9) 10) 11) 12).

Usually occurs in the adult population in the third and fourth decades of life and affect males more frequently than females 13) 14) 15).


Abdallah et al. retrospectively reviewed the medical records of 38 primary spinal myxopapillary ependymoma cases who underwent surgery at 2 neurosurgical centers spanning 16 years, from 2004 to 2019. All pediatric cases (patient age <18 years) who were diagnosed with MPE and re-presented with spinal seeding/drop metastases (SSM) were selected as the core sample for this study. Relevant literature was briefly reviewed.

Three pediatric MPE cases (2 females and 1 male) experienced SSM. The mean age at first presentation was 12.0 ± 1.0 years. The mean preoperative course was 2.9 ± 1.2 months. The predominant location was the lumbar spine in 2 tumors (both originated from filum terminale [FT]). Two tumors were located intradural intramedullary. Gross-total resection was achieved in 2 patients. No patient had neurofibromatosis type 2. No adjuvant treatment was given after the first surgery. The mean period between the first diagnosis and diagnosis of SSM was 44.0 ± 31.5 months. The location of SSM in all patients was the sacral spine (1 patient experienced distant metastasis in her brain besides her sacral metastasis). The mean follow-up was 68.3 ± 53.7 months.

They found a statistically significant relationship between SSM in pediatric MPEs and the intramedullary location, FT origin, and number of affected segments. Close clinical and radiological follow-up is essential for pediatric MPE patients. 16).

References

1) , 6) , 13)

Choi JY, Chang KH, Yu IK, et al. Intracranial and spinal ependymomas: Review of MR images in 61 patients. Korean J Radiol. 2002;3:219–228.
2) , 10)

Bavbek M, Altinors MN, Caner HH, Bilezikci B, Agildere M. Lumbar myxopapillary ependymoma mimicking neurofibroma. Spinal Cord. 2001;39:449–452.
3) , 11)

Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary ependymoma: A clinicopathologic and immunohistochemical study of 77 cases. Cancer. 1985;56:883–93.
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Celli P, Cervoni L, Cantore G. Ependymoma of the filum terminale: Treatment and prognostic factors in a series of 2 cases. Acta Neurochir. 1993;124:99–103.
5)

Sonneland PR, Scheithauer BW, Onofrio BM: Myxopapillary ependymoma: A clinicopathologic and immunocytochemical study of 77 cases. Cancer 56:883–893, 1985
7)

Sakai Y, Matsuyama Y, Katayama Y, et al. Spinal myxopapillary ependymoma: Neurological deterioration in patients treated with surgery. Spine. 2009;34:1619–1624.
8)

Wippold FJ, Smirniotopoulos JG, Moran CJ, Suojanen JN, Vollmer DG. MR imaging of myxopapillary ependymoma: Findings and value to determine extent of tumour and its relation to intraspinal structures. Am J Radiol. 1995;165:1263–67.
9)

Bagley CA, Wilson S, Kothbauer KF, Bookland MJ, Epstein F, Jallo GI. Long term outcomes following surgical resection of myxopapillary ependymomas. Neurosurg Rev. 2009;32:321–334.
14)

Volpp PB, Han K, Kagan AR, Tome M. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiation Oncology Biol Phys. 2007;69:1199–1204.
15)

Sun B, Wang C, Wang J, Liu A. MRI features of intramedullary spinal cord ependymomas. J Neuroimaging. 2003;13:346–351.
16)

Abdallah A. Spinal Seeding Metastasis of Myxopapillary Ependymoma: Report of Three Pediatric Patients and a Brief Literature Review [published online ahead of print, 2020 Aug 10]. Pediatr Neurosurg. 2020;1-14. doi:10.1159/000509061

Spinal myxopapillary ependymoma outcome

Spinal myxopapillary ependymoma outcome

Telomerase reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior 1).

Despite its benign biological nature, myxopapillary ependymoma (MPE) has a propensity to recur locally or distantly. Although variables influencing the prognosis, such as age, the extent of resection and radiotherapy, have been widely discussed, no definitive standard has been established.

Compared to other spinal tumors, many fewer histological markers have been elucidated to assist the determination of the prognosis.

Treatment failure of MPE occurred in approximately one-third of patients. The observed recurrence pattern of primary spinal MPE was mainly local, but a substantial number of patients failed nonlocally. Younger patients and those not treated initially with adjuvant RT or not undergoing gross total resection were significantly more likely to present with tumor recurrence/progression 2).

The 5-year survival rate of spinal ependymomas ranges from 57–100% 3) 4) 5) and 10–33% of patients will experience local invasion of the tumour or recurrence 6) 7).

Metastasis is rare in MPE but there have been several reported cases 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20).

References

1)

Deniel A, Marguet F, Beaussire L, Tobenas-Dujardin AC, Peillon C, Gambirasio MA, Veresezan O, Magne N, Di Fiore F, Laquerrière A, Sarafan-Vasseur N, Fontanilles M. TERTp mutation detection in plasma by droplet-digital PCR in spinal myxopapillary ependymoma with lung metastases. World Neurosurg. 2019 Jul 19. pii: S1878-8750(19)32017-0. doi: 10.1016/j.wneu.2019.07.111. [Epub ahead of print] PubMed PMID: 31330336.
2)

Weber DC, Wang Y, Miller R, Villà S, Zaucha R, Pica A, Poortmans P, Anacak Y, Ozygit G, Baumert B, Haller G, Preusser M, Li J. Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. Neuro Oncol. 2015 Apr;17(4):588-95. doi: 10.1093/neuonc/nou293. Epub 2014 Oct 9. PubMed PMID: 25301811; PubMed Central PMCID: PMC4483075.
3)

Volpp PB, Han K, Kagan AR, Tome M. Outcomes in treatment for intradural spinal cord ependymomas. Int J Radiation Oncology Biol Phys. 2007;69:1199–1204.
4) , 7)

Hanbali F, Fourney DR, Marmor E, et al. Spinal cord ependymoma: Radical surgical resection and outcome. Neurosurgery. 2002;51:1162–74.
5)

Asazuma T, Toyama Y, Suzuki N, et al. Ependymomas of the spinal cord and cauda equine: An analysis of 26 cases and a review of the literature. Spinal Cord. 1999;37:753–59.
6)

Bavbek M, Altinors MN, Caner HH, Bilezikci B, Agildere M. Lumbar myxopapillary ependymoma mimicking neurofibroma. Spinal Cord. 2001;39:449–452.
8)

Friedman DP, Hollander MD. Neuroradiology case of the day. Radiographics. 1998;18:794–98. [PubMed] 17. Patterson RH, Jr, Campbell WG, Jr, Parsons H. Ependymoma of the cauda equina with multiple visceral metastases. J Neurosurg. 1961;18:145–150.
9)

Agapitos E, Kavantzas N, Karaitianos J, Davaris P. Subcutaneous sacrococcygeal myxopapillary ependymoma: a case report. Archives d’anatomie et de cytologie pathologiques. 1995;43:157–159.
10)

Al Moutaery K, Aabed MY, Ojeda VJ. Cerebral and spinal cord myxopapillary ependymomas: a case report. Pathology. 1996;28:373–376.
11)

Helwig EB, Stern JB. Subcutaneous sacrococcygeal myxopapillary ependymoma: a clinicopathologic study of 32 cases. Am J Clin Pathol. 1994;81:156–161.
12)

Ilhan I, Berberoglu S, Kutluay L, Maden HA. Subcutaneous sacrococcygeal myxopapillary ependymoma. Medical and Pediatric Oncology. 1998;30:81–84.
13)

Kline MJ, Kays DW, Rojiani AM. Extradural myxopapillary ependymoma: report of two cases and review of the literature. Pediatric Pathology and Laboratory Medicine. 1996;6:813–822.
14)

Kramer GW, Rutten E, Sloof J. Subcutaneous sacrococcygeal ependymoma with inguinal lymph node metastasis. J Neurosurg. 1988;68:474–477.
15)

Pulitzer DR, Martin PC, Collins PC, et al. Subcutaneous sacrococcygeal (“myxopapillary”) ependymal rests. Am J Surgical Pathology. 1988;12:672–677.
16)

Woesler B, Moskopp D, Kuchelmeister K, et al. Intracranial metastasis of a spinal myxopapillary ependymoma. A case report. Neurosurgery Review. 1998;21:62–65.
17)

Graf M, Blaeker H, Otto HF. Extraneural metastasizing ependymoma of the spinal cord. Pathology Oncology Research. 1999;5:56–60.
18)

Mavroudis C, Townsend JJ, Wilson CB. A metastasizing ependymoma of the cauda equine: case report. J Neurosurg. 1977;47:771–775.
19)

Rubinstein LJ, Logan WJ. Extraneural metastases in ependymoma of the cauda equina. J Neurol Neurosurg Psychiatry. 1970;33:763–770.
20)

Rickert CH, Kedziora O, Gullotta F. Ependymoma of the cauda equine. Acta Neurochir. 1999;141:781–2.
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