Subependymal giant cell astrocytoma treatment

Subependymal giant cell astrocytoma treatment

The management of subependymal giant cell astrocytomas (SEGAs) has been traditionally represented by surgical treatment through an open craniotomic approach. Though open surgery still represents a major option in the management of this kind of tumors, the introduction of mTOR inhibitors in the clinical practice, technological advances in neuroendoscopy and the more recent use of Laser interstitial thermal therapy have significantly enlarged the range of available management opportunities.

A thorough review of the literature has been performed. Accordingly, current views in open surgical treatment, medical therapy, endoscopic tumor removal, and new trends (such as laser interstitial thermal therapy) are discussed.

The risk of significant neurological morbidity (5-50%) complicating open surgery has been for a long time representing a main drawback in the management of SEGAs. More recent series report a significant reduction of morbidity and mortality. The mTOR inhibitors have demonstrated efficacy in both warranting a tumor reduction by up to 60% of the tumor size and helping the control of seizures. However, the reported rate of side effects is as high as 30% and tumor recurrence is a documented occurrence at the time of mTOR inhibitor discontinuation. Endoscopic tumor removal has been more extensively considered an option due to the acquisition of new tools. Limits are still represented by tumor size (< 3 cm) and broad attachment of the tumor to the basal ganglia. Laser interstitial thermal therapy (LITT) is the more recently considered option. Though promising, only short follow-up is available so far, while data on medium- and long-term results of this treatment are completely lacking to date.

Surgical treatment remains a mainstay of the management of SEGAs. The indication for an open craniotomic approach should be balanced with an endoscopic tumor removal or LITT according to patient conditions, the presence or not of active hydrocephalus, and extension of the attachment of the tumor to the basal ganglia. The mTOR inhibitors do have a definite role both as primary and as adjuvant treatment, but consistent limitations are represented up to now by a not negligible rate of complications and the uncertainties related to the possibility of tumor recurrence once the medical treatment is discontinued 1).


Laviv et al.reported two cases of recurrent shunt malfunctions in adult TSC patients with protein-secreting SGCTs and describe the complexity of treating such patients with an emphasis on the role mTOR inhibitors may have in their management 2).


SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.


In a phase 1–2, open-label study in 28 patients with evidence of serial subependymal giant cell astrocytoma growth, the mTOR inhibitor everolimus (Afinitor, Novartis, East Hanover, NJ) was associated with a reduction in SEGA volume and improved quality of life 3).


Arroyo et al. present a seven-year-old boy with a large, symptomatic SEGA which was treated acutely with everolimus.

Everolimus treatment resulted in rapid reduction in tumor size, symptomatic improvement, and decrease in cerebrospinal fluid protein.

Everolimus can effectively reduce tumor size, decrease cerebrospinal fluid protein, and allow successful ventriculoperitoneal shunt placement without the need for surgical resection of a symptomatic SEGA 4).

References

1)

Frassanito P, Noya C, Tamburrini G. Current trends in the management of subependymal giant cell astrocytomas in tuberous sclerosis. Childs Nerv Syst. 2020 Sep 25. doi: 10.1007/s00381-020-04889-9. Epub ahead of print. PMID: 32978642.
2)

Laviv Y, Jackson S, Rappaport ZH. Persistent communicating hydrocephalus in adult tuberous sclerosis patients: a possible therapeutic role for everolimus. Acta Neurochir (Wien). 2015 Feb;157(2):241-5. doi: 10.1007/s00701-014-2309-0. Epub 2014 Dec 19. PubMed PMID: 25524658.
3)

Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801–1811
4)

Arroyo MS, Krueger DA, Broomall E, Stevenson CB, Franz DN. Acute Management of Symptomatic Subependymal Giant Cell Astrocytoma With Everolimus. Pediatr Neurol. 2017 Jul;72:81-85. doi: 10.1016/j.pediatrneurol.2017.04.008. Epub 2017 Apr 18. PubMed PMID: 28511812.

Atypical teratoid/rhabdoid tumor

Atypical teratoid/rhabdoid tumor

A malignant WHO grade IV embryonal tumor of the CNS comprised of poorly differentiated elements and rhabdoid cells and, by definition, includes inactivation of SMARCB1 (INI1) or (extremely rarely) SMARCA4 (BRG1). Histologically similar tumors lacking these molecular genetics should be classified as CNS embryonal tumors with rhabdoid features.

Many of these tumors were probably previously misdiagnosed as MDBs. Occurs primarily in infants and children (> 90% are < 5 years of age, with most age < 2 years). A minority are associated with primary renal rhabdoid tumor. The ratio of supratentorial to infratentorial AT/RTs is 4:3. Posterior fossa AT/RTs may occur in the cerebellar hemispheres, cerebellopontine angle (CPA) and brainstem. 33% have CSF spread at presentation. Althogh the prognosis is poor, not all AT/RTs have the same behavior, and at least 2 different molecular classes have been identified.


Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.

It was originally described a histological variant of Wilm’s tumor in 1978.


Atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In a study, Torchia et al., analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets.

They found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, they discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype 1).

Classification

AT/RT can occur anywhere in the central nervous system (CNS) including the spinal cord. About 60% will be in the posterior cranial fossa (particularly the cerebellum). One review estimated 52% posterior fossa, 39% sPNET (supratentorial primitive neuroectodermal tumors), 5% pineal, 2% spinal, and 2% multi-focal.

In the United States, three children per 1,000,000 or around 30 new AT/RT cases are diagnosed each year. AT/RT represents around 3% of pediatric cancers of the CNS.

Around 17% of all pediatric cancers involve the CNS; it is the most common childhood solid tumor.

see Adult sellar atypical teratoid rhabdoid tumor.

see Cerebellopontine angle atypical teratoid rhabdoid tumor.

Atypical Teratoid Rhabdoid Tumor of the Cauda Equina.

Atypical Teratoid Rhabdoid Tumor of the Conus Medullaris.

Pathology

Typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA 2).

Treatment

Atypical teratoid rhabdoid tumor treatment.

Outcome

Patient age at the time of diagnosis, supratentorial location of the mass and fewer complications with adjuvant treatments seem to be factors yielding good prognosis for AT/RT tumors. In agreement with the latest international protocols, multidisciplinary treatment is the ideal treatment, consisting of radiotherapy and chemotherapy after complete tumor resection 3).

Case series

Twenty-eight pediatric patients with CNS AT/RT who were treated with radiation therapy (RT) as part of multimodality treatment regimens at a single institution (1996-2015) were reviewed. Survival outcomes were analyzed in relation to possible prognostic factors.

The 28 patients analyzed were followed up for a median 48-month period. Median progression-free survival (PFS) was 11 months, and overall survival (OS) was 57 months. Patients < 3 years old had RT delayed for a longer period after surgery (p = 0.04), and the mean RT dose to tumor bed was lower (p < 0.01) than in patients ≥ 3 years old. In multivariate analysis, a higher primary tumor bed RT dose was identified as a favorable prognostic factor for both PFS (hazard ratio [HR] = 0.85 per gray, p < 0.01) and OS (HR = 0.92 per gray, p = 0.02). In addition, an interval between surgery and RT initiation > 2 months, with disease progression observed before RT, as compared with an interval ≤ 2 months without disease progression prior to RT, was associated with worse PFS (HR = 8.50, p < 0.01) and OS (HR = 5.27, p < 0.01).

Early and aggressive RT after surgery is critical for successful disease control in AT/RT patients. Conversely, a delay in RT until disease progression is observed that leads to unfavorable outcomes 4).


In a study, Torchia et al. analyzed 191 primary Atypical teratoid rhabdoid tumor ATRTs and 10 ATRT cell lines to define the genomics and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. They found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, they discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype 5).

References

1) , 5)

Torchia J, Golbourn B, Feng S, Ho KC, Sin-Chan P, Vasiljevic A, Norman JD, Guilhamon P, Garzia L, Agamez NR, Lu M, Chan TS, Picard D, de Antonellis P, Khuong-Quang DA, Planello AC, Zeller C, Barsyte-Lovejoy D, Lafay-Cousin L, Letourneau L, Bourgey M, Yu M, Gendoo DM, Dzamba M, Barszczyk M, Medina T, Riemenschneider AN, Morrissy AS, Ra YS, Ramaswamy V, Remke M, Dunham CP, Yip S, Ng HK, Lu JQ, Mehta V, Albrecht S, Pimentel J, Chan JA, Somers GR, Faria CC, Roque L, Fouladi M, Hoffman LM, Moore AS, Wang Y, Choi SA, Hansford JR, Catchpoole D, Birks DK, Foreman NK, Strother D, Klekner A, Bognár L, Garami M, Hauser P, Hortobágyi T, Wilson B, Hukin J, Carret AS, Van Meter TE, Hwang EI, Gajjar A, Chiou SH, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheinemann K, Fleming AJ, Johnston DL, Michaud J, Zelcer S, Hammond R, Afzal S, Ramsay DA, Sirachainan N, Hongeng S, Larbcharoensub N, Grundy RG, Lulla RR, Fangusaro JR, Druker H, Bartels U, Grant R, Malkin D, McGlade CJ, Nicolaides T, Tihan T, Phillips J, Majewski J, Montpetit A, Bourque G, Bader GD, Reddy AT, Gillespie GY, Warmuth-Metz M, Rutkowski S, Tabori U, Lupien M, Brudno M, Schüller U, Pietsch T, Judkins AR, Hawkins CE, Bouffet E, Kim SK, Dirks PB, Taylor MD, Erdreich-Epstein A, Arrowsmith CH, De Carvalho DD, Rutka JT, Jabado N, Huang A. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. Cancer Cell. 2016 Dec 12;30(6):891-908. doi: 10.1016/j.ccell.2016.11.003. PubMed PMID: 27960086.
2)

Jeong JY, Suh YL, Hong SW. Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report. Neuropathology. 2014 Aug;34(4):398-405. PubMed PMID: 25268025.
3)

Valencia-Moya A, González-García L, Ros-López B, Acha-García T, Weil-Lara B, Obando-Pacheco P, Arráez-Sánchez MÁ. Prognosis of atypical teratoid rhabdoid tumors (AT/RT) treated with multimodal therapy protocols. Report of our series. Neurocirugia (Astur). 2015 Apr 17. pii: S1130-1473(15)00020-2. doi: 10.1016/j.neucir.2015.01.003. [Epub ahead of print] PubMed PMID: 25900785.
4)

Yang WC, Yen HJ, Liang ML, Chen HH, Lee YY, Wong TT, Hu YW, Chen YW. Role of early and aggressive post-operative radiation therapy in improving outcome for pediatric central nervous system atypical teratoid/rhabdoid tumor. Childs Nerv Syst. 2019 Apr 13. doi: 10.1007/s00381-019-04126-y. [Epub ahead of print] PubMed PMID: 30982172.

Medulloblastoma classification

Medulloblastoma classification

The diagnosis of medulloblastoma incorporates the histologic and molecular subclassification of clinical medulloblastoma samples into wingless (WNT)-activated, sonic hedgehog (SHH)-activated, group 3 and group 4 subgroups. Accurate medulloblastoma subclassification has important prognostic and treatment implications.

Medulloblastoma, WNT-activated

Medulloblastoma, WNT-activated

Sonic hedgehog medulloblastoma

Sonic hedgehog medulloblastoma.

Medulloblastoma, SHH-activated, and TP53-mutant

Medulloblastoma, SHH-activated, and TP53-mutant.

Medulloblastoma, SHH-activated, and TP53-wildtype

Medulloblastoma, SHH-activated, and TP53-wildtype

Medulloblastoma, non-WNT/non-SSH

Medulloblastoma non-WNT/non-SSH

Group 3 medulloblastoma

Group 3 medulloblastoma

Group 4 medulloblastoma

Group 4 medulloblastoma

Histology

Medulloblastoma histologically defined:

Classic medulloblastoma

Desmoplastic nodular medulloblastoma

Medulloblastoma with extensive nodularity

Medulloblastoma, large cell/anaplastic

Medulloblastoma, NOS.

Localization

see Cerebellar medulloblastomas

see Cerebellopontine angle medulloblastoma

see Multifocal medulloblastoma.

Subgrouping

Immunohistochemistry (IHC)-based and nanoString-based subgrouping methodologies have been independently described as options for medulloblastoma subgrouping, however, they have not previously been directly compared. D’Arcy described the experience with nanoString-based subgrouping in a clinical setting and compare this with our IHC-based results. Study materials included FFPE tissue from 160 medulloblastomas. Clinical data and tumor histology were reviewed. Immunohistochemical-based subgrouping using β-catenin, filamin A and p53 antibodies and nanoString-based gene expression profiling was performed. The sensitivity and specificity of IHC-based subgrouping of WNT and SHH-activated medulloblastomas was 91.5% and 99.54%, respectively. Filamin A immunopositivity highly correlated with SHH/WNT-activated subgroups (sensitivity 100%, specificity 92.7%, p < 0.001). Nuclear β-catenin immunopositivity had a sensitivity of 76.2% and specificity of 99.23% for the detection of WNT-activated tumors. Approximately 23.8% of WNT cases would have been missed using an IHC-based subgrouping method alone. nanoString could confidently predict medulloblastoma subgroup in 93% of cases and could distinguish group 3/4 subgroups in 96.3% of cases. nanoString-based subgrouping allows for a more prognostically useful classification of clinical medulloblastoma samples 1).


Molecular subgrouping was performed by immunohistochemistry (IHC) for beta catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array.

IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation.

Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice 2).


The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon 3).

References

1)

D’Arcy CE, Nobre LF, Arnaldo A, Ramaswamy V, Taylor MD, Naz-Hazrati L, Hawkins CE. Immunohistochemical and nanoString-Based Subgrouping of Clinical Medulloblastoma Samples. J Neuropathol Exp Neurol. 2020 Jan 30. pii: nlaa005. doi: 10.1093/jnen/nlaa005. [Epub ahead of print] PubMed PMID: 32053195.
2)

Kaur K, Jha P, Pathak P, Suri V, Sharma MC, Garg A, Suri A, Sarkar C. Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres. J Neurooncol. 2019 May 18. doi: 10.1007/s11060-019-03187-y. [Epub ahead of print] PubMed PMID: 31104222.
3)

Mullarkey MP, Nehme G, Mohiuddin S, et al. Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases [published online ahead of print, 2020 Sep 3]. Pediatr Neurosurg. 2020;1-10. doi:10.1159/000509520
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