Pediatric Low-Grade Glioma Classification

Pediatric Low-Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes.

They constitute the largest, yet clinically and (molecular-) a histologically heterogeneous group of pediatric brain tumors of WHO grade I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest 1).

Pediatric low-grade gliomas were shown to be characterized by an array of distinct molecular aberrations. The cIMPACT-4 consensus proposed pediatric low-grade gliomas of the diffuse type to be characterized by distinct molecular changes rather than distinct histological features.

Fukuoka et al. described a small series of pediatric oligodendroglioma-like tumors with BRAF V600E mutations. Interestingly, they exhibited molecular changes usually associated with adult high-grade gliomas: chromosome instability, chromosome 7 gains, and chromosome 10 loss, but had an indolent natural history 2) 3).

Genetic abnormalities

Mobark et al. profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. THey detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, they identified a GOPCROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low-grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease-free. To the author’s knowledge, this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, they revealed the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG 4).


Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway.

This has led to PLGG clinical trials utilizing RAF– and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394.

Jain et al. report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, this study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions 5).

References

1)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.
2)

Yang RR, Li KK, Liu APY, Chen H, Chung NY, Chan AKY, Li F, Tat-Ming Chan D, Mao Y, Shi ZF, Ng HK. Low-grade BRAF V600E mutant oligodendroglioma-like tumors of children may show EGFR and MET amplification. Brain Pathol. 2020 Oct 8. doi: 10.1111/bpa.12904. Epub ahead of print. PMID: 33032379.
3)

Fukuoka K, Mamatjan Y, Ryall S, Komosa M, Bennett J, Zapotocky M, Keith J, Myrehaug S, Hazrati LN, Aldape K, Laperriere N, Bouffet E, Tabori U, Hawkins C. BRAF V600E mutant oligodendroglioma-like tumors with chromosomal instability in adolescents and young adults. Brain Pathol. 2020 May;30(3):515-523. doi: 10.1111/bpa.12799. Epub 2019 Nov 10. PMID: 31630459.
4)

Mobark NA, Alharbi M, Alhabeeb L, AlMubarak L, Alaljelaify R, AlSaeed M, Almutairi A, Alqubaishi F, Ahmad M, Al-Banyan A, Alotabi FE, Barakeh D, AlZahrani M, Al-Khalidi H, Ajlan A, Ramkissoon LA, Ramkissoon SH, Abedalthagafi M. Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia. PLoS One. 2020 Jan 29;15(1):e0228356. doi: 10.1371/journal.pone.0228356. eCollection 2020. PubMed PMID: 31995621.
5)

Jain P, Fierst TM, Han HJ, Smith TE, Vakil A, Storm PJ, Resnick AC, Waanders AJ. CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles. Oncogene. 2017 Aug 14. doi: 10.1038/onc.2017.276. [Epub ahead of print] PubMed PMID: 28806393.

Pediatric low-grade glioma treatment

Pediatric low grade glioma treatment

Low-grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, the second resection often is possible. Following incomplete resection, observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and/or radiologic progression are an indication of treatment with either chemo- or radiotherapyOverall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles, and details of which are summarized in the current guidelines. These represent the standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy, and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 1).


Within the multidisciplinary tumor board, all decisions concerning biopsy or resection at the time of diagnosis and progression must be carefully made weighing the potential risk of surgery vs. the therapeutic benefit of elucidating the histologic and molecular subtype of the tumor 2).

A treatment algorithm was compiled by members of the LGG working group of the SIOPE brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 3).

Since 2006 the German federal joint committee (G-BA, Gemeinsamer Bundesausschuss) has established that in line with all other pediatric hematological and oncological diseases – newly diagnosed low grade gliomas (LGG) patients must be treated within the current active society of pediatric oncology and hematology (Gesellschaft fuer paediatrische Onkologie und Haematologie, GPOH) trial or registry to ensure high quality standards of care and use of established referral systems 4).


Pediatric low grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multi-agent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560mg/m2 , four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% C.I. 57% – 76%), and 5-year PFS was 51% (95% C.I. 41% – 63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG 5).

Measures

Tumor measurement is important in unresectable pediatric low-grade gliomas (pLGGs) to determine either the need for treatment or assess response. Standard methods measure the product of the largest 2 lengths from transverse, anterior-posterior, and cranio-caudal dimensions (SM, cm). This single-institution study evaluated tumor volume measurements (VM, cm) in such pLGGs. Of 50 patients treated with chemotherapy for surgically inaccessible pLGG, 8 met the inclusion criteria of having 2 or more sequential MRI studies of T1-weighted Fast-Spoiled Gradient Recalled acquisition. SM and VM were performed by 2 independent neuroradiologists. Associations of measurement methods with defined therapeutic response criteria and patient clinical status were assessed. The mean tumor size at the first MRI scan was 20 cm and 398 cm according to SM and VM, respectively. VM results did not differ significantly from SM-derived spherical volume calculations (Pearson correlation, P<0.0001) with a high interrater reliability. Both methods were concordant in defining the tumor response according to the current criteria, although radiologic progressive disease was not associated with clinical status (SM: P=0.491, VM: P=0.208). In this limited experience, volumetric analysis of unresectable pLGGs did not seem superior to the standard linear measurements for defining tumor response 6).

References

1)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNS, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. Erratum in: Klin Padiatr. 2019 May;231(3):e2. PubMed PMID: 31108561.
2)

PackerRJ,Pfister S,BouffetEetal.Pediatric low-grade gliomas: implications of the biologic era. Neuro-oncology 2017; 19: 750–761
3) , 4)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.
5)

Dodgshun AJ, Maixner WJ, Heath JA, Sullivan MJ, Hansford JR. Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multi-agent chemotherapy. Int J Cancer. 2015 Aug 1. doi: 10.1002/ijc.29711. [Epub ahead of print] PubMed PMID: 26235348.
6)

Kilday JP, Branson H, Rockel C, Laughlin S, Mabbott D, Bouffet E, Bartels U. Tumor volumetric measurements in surgically inaccessible pediatric low-grade glioma. J Pediatr Hematol Oncol. 2015 Jan;37(1):e31-6. doi: 10.1097/MPH.0000000000000168. PubMed PMID: 25517914.

Low-grade glioma

Low-grade glioma

Low-grade gliomas (LGGs) are a diverse group of WHO grade I – WHO grade II of glial origin with pilocytic astrocytoma (PA) being the most frequent LGG diagnosis. It is now generally accepted that PA and most other LGGs are a single pathway disease of the MAPK signal transduction pathway 1).

Epidemiology

Classification

Risk Factors

The most frequent cancer predisposition syndromes in the LGG cohorts are Neurofibromatosis type 1 (NF1), with mostly pilocytic astrocytoma constituting around 10–20 % of LGG cases, and Tuberous Sclerosis Complex (TSC) with the characteristic subependymal giant cell astrocytoma (SEGA), constituting 1–2 % of LGG cases, respectively 2) 3)

Clinical features

Preoperative seizures could reflect intrinsic glioma properties 4).

Most patients experience epileptic seizures as a presenting symptom 5) 6) 7) 8) and cause medically-intractable seizure.

see Incidental low grade glioma.

The results of a genomic analysis suggest that low FOXO4 expression is a significant risk factor for epileptic seizures in patients with LGGs and is associated with the seizure outcome. FOXO4 may be a potential therapeutic target for tumor-associated epilepsy 9).


In patients with low-grade glioma (LGG), language deficits are usually only found and investigated after surgery. Deficits may be present before surgery but to date, studies have yielded varying results regarding the extent of this problem and in what language domains deficits may occur.

Twenty-three patients were tested using a comprehensive test battery that consisted of standard aphasia tests and tests of lexical retrieval and high-level language functions. The patients were also asked whether they had noticed any change in their use of language or ability to communicate. The test scores were compared to a matched reference group and to clinical norms. The presumed LGG group performed significantly worse than the reference group on two tests of lexical retrieval. Since five patients after surgery were discovered to have a high-grade glioma, a separate analysis excluding them were performed. These analyses revealed comparable results; however one test of word fluency was no longer significant. Individually, the majority exhibited normal or nearly normal language ability and only a few reported subjective changes in language or ability to communicate. This study shows that patients who have been diagnosed with LGG generally show mild or no language deficits on either objective or subjective assessment 10).

Diagnosis

Treatment

Outcome

Case series

References

1)

Jones DT, Gronych J, Lichter P et al. MAPK pathway activation in pilocytic astrocytoma. Cellular and molecular life sciences : CMLS 2012; 69: 1799–1811
2)

HernaizDrieverP,vonHornsteinS,PietschTetal.Naturalhistoryand management of low-grade glioma in NF-1 children. Journal of neuro-oncology 2010; 100: 199–207
3)

RandleSC.TuberousSclerosisComplex:AReview.Pediatricannals 2017; 46: e166–e171
4)

Smits A, Duffau H. Seizures and the natural history of World Health Organization grade II gliomas: a review. Neurosurgery. 2011;68:1326–1333.
5)

Liigant A, Haldre S, Oun A, et al. Seizure disorders in patients with brain tumors. Eur Neurol. 2001;45:46–51.
6)

Lynam LM, Lyons MK, Drazkowski JF, et al. Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review. Clin Neurol Neurosurg. 2007;109:634–638.
7)

Rosati A, Tomassini A, Pollo B, et al. Epilepsy in cerebral glioma: timing of appearance and histological correlations. J Neurooncol. 2009;93:395–400.
8)

Rudà R, Trevisan E, Soffietti R. Epilepsy and brain tumors. Curr Opin Oncol. 2010;22:611–620.
9)

Wang Y, Tang K, Zhao J, Liu L, Feng J. FOXO4 expression is associated with the occurrence and outcome of seizures: An RNA-sequencing analysis of low-grade gliomas. Seizure. 2017 Sep 21;52:41-45. doi: 10.1016/j.seizure.2017.09.012. [Epub ahead of print] PubMed PMID: 28963932.
10)

Antonsson M, Longoni F, Jakola A, Tisell M, Thordstein M, Hartelius L. Pre-operative language ability in patients with presumed low-grade glioma. J Neurooncol. 2017 Dec 1. doi: 10.1007/s11060-017-2699-y. [Epub ahead of print] PubMed PMID: 29196925.
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