Glioma outcome

Glioma outcome

In order to set up a reliable prediction system for the tumor grade and glioma outcome, Li et al. clarified the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. Li et al. found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, they utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expressions of ANXA2 and GPC1 tended to have a higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential “combination biomarker” for predicting the prognosis of glioma patients 1).

see Glioma Quality of Life.


The ability to resume professional activities following brain tumor surgery is an important patient-oriented outcome parameter. Senft et al. found that the majority of patients with gliomas were able to return to work following surgical and adjuvant treatment. Preservation of neurological function is of utmost relevance for individual patients quality of life 2)


Patients with IDH and TERTp glioma mutations have the best prognosis, and only IDH mutation patients and only TERTp mutation patients have the worst prognosis. Moreover, the molecular classification of gliomas by mutations of IDH and TERTp is not suitable for pediatric patients 3).

Also the O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival.


Infiltrative gliomas invade the brain, relentlessly recur, transform into higher-grade gliomas, and are invariably lethal 4) 5) 6). , mostly due to the poor glioblastoma outcome (Grade IV glioma).

Gliomas are considered incurable due to recurrence as demonstrated in a series of five patients who underwent hemispherectomies in 1928 7).

The prognosis improves as the amount of glioma removed increases 8) 9) 10) 11) 12).

Older age (>40 years), high pathological grade, invasion of the corpus callosum and high levels of Ki67 expression were risk factors associated with the intracranial dissemination of gliomas 13).


1)

Li X, Nie S, Lv Z, Ma L, Song Y, Hu Z, Hu X, Liu Z, Zhou G, Dai Z, Song T, Liu J, Wang S. Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma. Cell Death Dis. 2021 Mar 12;12(3):261. doi: 10.1038/s41419-021-03547-5. PMID: 33712571.
2)

Senft C, Behrens M, Lortz I, Wenger K, Filipski K, Seifert V, Forster MT. The ability to return to work: a patient-centered outcome parameter following glioma surgery. J Neurooncol. 2020 Sep 22. doi: 10.1007/s11060-020-03609-2. Epub ahead of print. PMID: 32960402.
3)

Qu CX, Ji HM, Shi XC, Bi H, Zhai LQ, Han DW. Characteristics of the isocitrate dehydrogenase gene and telomerase reverse transcriptase promoter mutations in gliomas in Chinese patients. Brain Behav. 2020 Mar 8:e01583. doi: 10.1002/brb3.1583. [Epub ahead of print] PubMed PMID: 32146731.
4)

DeAngelis LM (2001) Brain tumors. N Engl J Med 344:114–123.
5)

Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507.
6)

Behin A, Hoang-Xuan K, Carpentier AF, et al.(2003) Primary brain tumours in adults. Lancet 361:323–331.
7)

Dandy WE. Removal of right cerebral hemisphere for certain tumors with hemiplegia: preliminary report. JAMA. 1928;90:823–825.
8)

Chan-Seng E, Moritz-Gasser S, Duffau H. Awake mapping for low-grade gliomas involving the left sagittal stratum: Anatomofunctional and surgical considerations. J Neurosurg. 2014;120:1069–1077. doi: 10.3171/2014.1.JNS132015.
9)

Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62:753–764. doi: 10.1227/01.neu.0000318159.21731.cf.
10)

Han SJ, Sughrue ME. The rise and fall of ‘biopsy and radiate’: A history of surgical nihilism in glioma treatment. Neurosurg Clin N Am. 2012;23:207–214. doi: 10.1016/j.nec.2012.02.002.
11)

Giussani C, Roux FE, Ojemann J, Sganzerla EP, Pirillo D, Papagno C. Is preoperative functional magnetic resonance imaging reliable for language areas mapping in brain tumor surgery? Review of language functional magnetic resonance imaging and direct cortical stimulation correlation studies. Neurosurgery. 2010;66:113–120. doi: 10.1227/01.NEU.0000360392.15450.C9.
12)

Choi BD, Mehta AI, Batich KA, Friedman AH, Sampson JH. The use of motor mapping to aid resection of eloquent gliomas. Neurosurg Clin N Am. 2012;23:215–225. doi: 10.1016/j.nec.2012.01.013.
13)

Cai X, Qin JJ, Hao SY, Li H, Zeng C, Sun SJ, Yu LB, Gao ZX, Xie J. Clinical characteristics associated with the intracranial dissemination of gliomas. Clin Neurol Neurosurg. 2018 Feb 1;166:141-146. doi: 10.1016/j.clineuro.2018.01.038. [Epub ahead of print] PubMed PMID: 29427894.

Tectal glioma

Tectal gliomas fall under the grouping of childhood midbrain gliomas and unlike the other tumours in that group they are typically low grade astrocytomas with good prognosis.

Tectal plate gliomas are encountered in children and adolescents.

A male predilection has sometimes been reported although this is by no means certain.

An association with neurofibromatosis type I (NF1) has been reported 1).

Their expansion within the brainstem causes narrowing the aqueduct of Sylvius and causing obstructive hydrocephalus with presentation usually secondary to headache.

Additional symptoms may include gaze palsy, due to compression of the medial longitudinal fasciculus leading to an upgaze palsy, diplopia or Parinaud syndrome, although these are uncommon.

The vast majority of lesions are low grade astrocytoma, although occasionally other glial series tumours are encountered in the tectal region including ependymoma, ganglioglioma and primitive neuroectodermal tumours (PNET).

see Tectal ganglioglioma.

Since many of these are not biopsied, meaningful statistical analysis is not possible.

Diagnosis is based on initial suspicion fostered by the presentation of an obstructive hydrocephalus followed by physical exam which may potentially reveal indications of pyramidal tract dysfunction or cranial nerve palsies.

The superb sensitivity of MR and its multiplanar imaging capability permit unparalleled diagnostic accuracy in this region. The sagittal and axial planes are ideal for evaluating the tectum. CT remains important in the detection of acute hemorrhage and calcification. Grouping of abnormalities on the basis of anatomic boundaries (tectum, aqueduct, and quadrigeminal plate cistern) is useful in establishing the correct diagnosis 2).

CT

Typical CT finding is homogeneous expansion of tectal plate, isodense to grey matter with minimal enhancement on postcontrast images.

On CT it is not uncommon to find a central tectal calcification.


MRI studies reveal a characteristic well-circumscribed, isodense or hypodense mass on T1-weighted images, with hyperdensity on T2 imaging. Yet current radiological methods insufficiently distinguish tectal plate gliomas from brainstem tumors or gliomas in the neighboring structures, and a definitive diagnosis requires biopsy and histopathological analysis.

Typically the tumours demonstrate expansion of the tectal plate by a solid nodule of tissue.

T1: iso to slightly hypointense to grey matter

T2: hyperintense to grey matter

T1 C+ (Gd): usually no enhancement

With time the mass can develop small cystic spaces (sometimes associated with neurological deficits) or calcification.

Higher grade tumours tend to be larger and tend to enhance more vividly.

Tumors leading to occlusion of the aqueduct of Sylvius include those of pineal, thalamic, and tectal origins.

see Aqueductal tumor.

The differential diagnosis from germ cell tumor or pineal cyst is essential for treatment.

When the tectum is near-normal then the differential is largely limited to:

aqueductal stenosis

no mass lesion

a focal stenosis or web may be visible

With larger lesions, where the mass is not definitely arising from the tectal plate then the differential is essentially that of a pineal region mass and therefore includes:

pineal parenchymal tumours and germ cell tumours

pineal cyst

meningioma

cerebral metastasis

cavernous malformation

In patients with NF1 a hamartoma should also be considered. They tend to have some T1 hyperintensity.

Management is planned according to the degree of associated signs and symptoms, and may range from diligent observation and periodic screening for advancing tumor development, to cerebrospinal fluid shunting in an effort to resolve obstructive hydrocephalus, to radio- and chemotherapy. A wide range of minimally invasive approaches using endoscopy is available for the neurosurgeon, including endoscopic third ventriculostomy and endoscopic aqueductoplasty 3)

Tumors leading to occlusion of the sylvian aqueduct include those of pineal, thalamic, and tectal origins. These tumors cause obstructive hydrocephalus and thus necessitate a CSF diversion procedure such as an endoscopic third ventriculostomy (ETV), often coupled with an endoscopic biopsy (EBX).

As tectal plate gliomas are low grade and often very slow growing, shunting is often the only required intervention for long term survival. As surgical biopsy can have significant morbidity in this area, usually the diagnosis is made on imaging findings alone.

Imaging predictors of patients who will need further treatment include a size greater than 2.5 cm and presence of contrast enhancement.

In the minority of patients who progress, radiotherapy often leads to local control or even tumour regression.

Surgical excision is sometimes necessary.

Tectal plate gliomas showed indolent clinical courses, even after radiologic tumor progression. After the treatment of obstructive hydrocephalus, clinical and radiologic follow-up can be recommended for indolent tectal plate gliomas 4).


2015

Between October 2002 and May 2011, 11 patients with tectal gliomas were treated with Gamma Knife radiosurgery. Five patients had pilocytic astrocytomas and six nonpilocytic astrocytomas. Ten patients presented with hydrocephalus and underwent a CSF diversion procedure [7 V-P shunt and 3 endoscopic third ventriculostomy (ETV)]. The tumor volume ranged between 1.2-14.7 cc (median 4.5 cc). The prescription dose was 11-14 Gy (median 12 Gy).

Patients were followed for a median of 40 months (13-114 months). Tumor control after radiosurgery was seen in all cases. In 6/11 cases, the tumors eventually disappeared after treatment. Peritumoral edema developed in 5/11 cases at an onset of 3-6 months after treatment. Transient tumor swelling was observed in four cases. Four patients developed cysts after treatment. One of these cases required aspiration and eventually disappeared, one became smaller spontaneously, and two remained stable.

Gamma Knife radiosurgery is an effective and safe technique for treatment of tectal gliomas. Tumor shrinkage or disappearance after Gamma Knife radiosurgery may preclude the need for a shunt later on 5).


Dabscheck et al., conducted a retrospective review of all patients with tectal gliomas over a 22-year period at a single institution. Data extraction included sex, age at presentation of tectal glioma and age of presentation with seizures, magnetic resonance imaging (MRI) findings, seizure frequency and semiology, and EEG findings. They identified 79 patients, 66 of whom had adequate imaging and clinical data for further analysis. Eight patients (12.1%) had a history of seizures. Three patients had a clear symptomatic cause of seizures. Three patients were diagnosed with a tectal glioma as an incidental finding after a first seizure. One patient had a history of febrile convulsions. One patient had a generalized seizure 5 years after presenting with macrocephaly. Although the risk of seizure in children with known tectal glioma was relatively high, we did not identify specific clinical, radiologic, EEG, or MRI features that are predictive of increased risk. Thus, in children with tectal gliomas who have seizures, alternative causes for the seizures must be sought 6).


Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in this cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population 7).

2014

Forty-four patients with a mean age of 10.2 years who harbored tectal plate gliomas were included in the study. The mean clinical and radiological follow-up was 7.6 ± 3.3 years (median 7.9 years, range 1.5-14.7 years) and 6.5 ± 3.1 years (median 6.5 years, range 1.1-14.7 years), respectively. The most frequent intervention was CSF diversion (81.8% of patients) followed by biopsy (11.4%), radiotherapy (4.5%), chemotherapy (4.5%), and resection (2.3%). On MR imaging tectal plate gliomas most commonly showed T1-weighted isointensity (71.4%), T2-weighted hyperintensity (88.1%), and rarely enhanced (19%). The initial mean volume was 1.6 ± 2.2 cm(3) and it increased to 2.0 ± 4.4 cm(3) (p = 0.628) at the last follow-up. Frontal and occipital horn ratio (FOHR) and third ventricular width statistically decreased over time (p < 0.001 and p < 0.05, respectively).

The authors’ results support existing evidence that tectal plate gliomas frequently follow a benign clinical and radiographic course and rarely require any intervention beyond management of associated hydrocephalus 8).

2013

Twenty-two children were identified from a 15-year retrospective database of neuroendoscopic procedures performed at the authors’ institution, Children’s Hospital of Alabama, in patients with a minimum of 1 year of follow-up. Clinical outcomes, including the need for further CSF diversion and symptom resolution, were recorded. The frontal and occipital horn ratio (FOR) was measured on pre- and postoperative, 1-year, and last follow-up imaging studies.

In 17 (77%) of 22 children no additional procedure for CSF diversion was required. Of those in whom CSF diversion failed, 4 underwent successful repeat ETV and 1 required shunt replacement. Therefore, in 21 (96%) of 22 patients, CSF diversion was accomplished with ETV. Preoperative and postoperative imaging was available for 18 (82%) of 22 patients. The FOR decreased in 89% of children who underwent ETV. The FOR progressively decreased 1.7%, 11.2%, and 12.7% on the initial postoperative, 1-year, and last follow-up images, respectively. The mean radiological follow-up duration for 18 patients was 5.4 years. When ETV failed, the FOR increased at the time of failure in all patients. Failure occurred 1.6 years after initial ETV on average. The mean clinical follow-up period for all 22 patients was 5.3 years. In all cases clinical improvement was demonstrated at the last follow-up.

Endoscopic third ventriculostomy successfully treated hydrocephalus in the extended follow-up period of patients with TPGs. The most significant reduction in ventricular size was observed at the the 1-year followup, with only modest reduction thereafter 9).

2012

A 5-year-old boy who had tectal plate low grade glioma with obstructive hydrocephalus was managed with Codman programmable ventriculoperitoneal shunt. There was a spontaneous change in the opening pressure of the shunt valve leading to shunt malfunction. Routinely used household appliances produce a magnetic field strong enough to cause change in the setting of shunt valve pressure and may lead to valve malfunction 10).

2003

Tumors involving the tectal region constitute a distinct subgroup of brain stem gliomas with an indolent clinical course. Here, we present the clinical and neuroradiologic features of 9 children with tectal tumors. All patients presented with signs and symptoms of hydrocephalus and were managed with ventriculoperitoneal shunt insertion. MRI studies revealed focal hyperintense lesions on T2-weighted images without any contrast enhancement, and no evidence of progression was demonstrated in any patient. We also reviewed the published series of tectal gliomas in the literature to compare with our results. Based on these and other published series, it was concluded that intrinsic tectal gliomas of childhood with sizes less than 2 cm in diameter and without any tumor extension or contrast enhancement constitute a specific subgroup of tectal masses which rarely display invasive clinical behavior and should be managed conservatively. CSF diversion procedures and long-term yearly follow-up examinations with MRI scans are sufficient in these patients 11).

1999

A 10-year retrospective review has identified 11 consecutive children with tectal plate lesions. Headache, vomiting, a decline in school performance, tremor, and complex partial seizures were common presenting symptoms. All patients presented with signs and symptoms of hydrocephalus. Magnetic resonance (MR) imaging delineated an intra-axial mass lesion of the midbrain primarily localized to the tectal plate which uniformly was hyperintense on T2-weighted imaging and had a more variable appearance on T1-weighted imaging and rare enhancement with gadolinium. No patient underwent surgical resection, chemotherapy, or radiotherapy. Three of 11 patients (27%) showed evidence of progression in size or a new focus of enhancement on MR imaging, which was clinically asymptomatic. In this series, no patient with a tectal plate lesion less than 1.5 cm in maximal diameter and without gadolinium enhancement showed any evidence of clinical or radiological progression. Although intrinsic tectal lesions in children are clinically indolent and the initial management consists of CSF diversion, these lesions may eventually progress and still warrant long-term follow-up with serial MR imaging 12).

1998

A retrospective review was done of the medical records and imaging studies of 32 children (16 boys and 16 girls; mean age, 8 years) with tectal tumors. Eight children had CT, 11 had MR imaging, and 13 had both CT and MR studies. Findings from surgical and pathologic reports as well as from follow-up examinations (mean follow-up period, 5 years; range, 3.6 months to 17 years) were included in the review.

All patients had hydrocephalus and all but one required CSF diversion. The tectum was the center of the tumor in all cases and the majority of the tumors appeared isodense on CT scans, isointense on T1-weighted MR images, and hyperintense on T2-weighted images. Twenty patients required no further treatment. In this group, the mean maximum tumor diameter was 1.8 cm and enhancement occurred in two cases. At follow-up, 18 patients had stable tumor size, one had an increase in tumor size with cyst formation but no worsening of symptoms, and one had a decrease in tumor size. Twelve patients required further treatment (excision and/or radiotherapy) because of progression as indicated by either increased tumor size or worsening of symptoms. In this group, the mean maximum tumor diameter was 2.5 cm and contrast enhancement occurred in nine cases. Further follow-up in this group showed decreased tumor size in eight and stable residual tumor in three.

Tectal tumors in childhood have variable behavior. MR imaging assists in the clinical determination of which children need treatment beyond CSF diversion. Larger tumor size and enhancement are radiologic predictors of the need for further treatment 13).

1994

A series of 12 patients with tectal plate gliomas, is presented treated by direct surgery. Mean age was 19 years. All patients presented with signs of raised intracranial pressure and supratentorial hydrocephalus on CT scan. Diplopia was the most common local sign. CT scan and MR imaging showed 4 intrinsic, 6 exophytic, and 2 ventrally infiltrating tectal tumours. The histological diagnosis was low-grade astrocytoma in 7, high-grade astrocytoma in 2, oligodendroglioma in one, oligo-astrocytoma in one, and ependymoma in one case. The suboccipital supra- and transtentorial approach was used in every cases. Tumour resection was generous at the level of the superior colliculi, but on the contrary, resection was limited at the level of inferior colliculi due to the auditory risk. Tumour removal was total (macroscopically) in 9 cases and partial in 3 cases. There were 4 surgical complications and one death related to surgery. Parinaud’s syndrome was the most-common postoperative sequelae. Auditory hallucinations and the acoustic neglect syndrome were seen once. In three cases additional radiotherapy and chemotherapy were given once with severe sequelae. The treatment of tectal plate gliomas is controversial. The role of different therapeutic options remains open. We consider the tectal plate as a relatively safer territory for surgery than the ventral part of the midbrain. The brain stem auditory evoked potentials (BAEPs) and middle latency potentials (MLPs) monitoring can help to determine the appropriate limit of surgery 14).

see Tectal glioma case reports


1)

Dinçer A, Yener U, Özek MM. Hydrocephalus in patients with neurofibromatosis type 1: MR imaging findings and the outcome of endoscopic third ventriculostomy. AJNR Am J Neuroradiol. 2011 Apr;32(4):643-6. doi: 10.3174/ajnr.A2357. Epub 2011 Feb 17. PubMed PMID: 21330395.
2)

Friedman DP. Extrapineal abnormalities of the tectal region: MR imaging findings. AJR Am J Roentgenol. 1992 Oct;159(4):859-66. Review. PubMed PMID: 1529854.
3)

Igboechi C, Vaddiparti A, Sorenson EP, Rozzelle CJ, Tubbs RS, Loukas M. Tectal plate gliomas: a review. Childs Nerv Syst. 2013 Oct;29(10):1827-33. doi: 10.1007/s00381-013-2110-z. Epub 2013 Apr 24. Review. PubMed PMID: 23612874.
4)

Kim JW, Jung JH, Baek HJ, Kim SK, Jung TY. Case Reports of Tectal Plate Gliomas Showing Indolent Course. Brain Tumor Res Treat. 2020 Oct;8(2):109-112. doi: 10.14791/btrt.2020.8.e17. PMID: 33118343.
5)

El-Shehaby AM, Reda WA, Abdel Karim KM, Emad Eldin RM, Esene IN. Gamma Knife radiosurgery for low-grade tectal gliomas. Acta Neurochir (Wien). 2015 Feb;157(2):247-56. doi: 10.1007/s00701-014-2299-y. Epub 2014 Dec 16. PubMed PMID: 25510647.
6)

Dabscheck G, Prabhu SP, Manley PE, Goumnerova L, Ullrich NJ. Risk of seizures in children with tectal gliomas. Epilepsia. 2015 Sep;56(9):e139-42. doi: 10.1111/epi.13080. Epub 2015 Jul 21. PubMed PMID: 26193802.
7)

Gass D, Dewire M, Chow L, Rose SR, Lawson S, Stevenson C, Pai AL, Jones B, Sutton M, Lane A, Pruitt D, Fouladi M, Hummel TR. Pediatric tectal plate gliomas: a review of clinical outcomes, endocrinopathies, and neuropsychological sequelae. J Neurooncol. 2015 Mar;122(1):169-77. doi: 10.1007/s11060-014-1700-2. Epub 2015 Jan 13. PubMed PMID: 25582835.
8)

Griessenauer CJ, Rizk E, Miller JH, Hendrix P, Tubbs RS, Dias MS, Riemenschneider K, Chern JJ. Pediatric tectal plate gliomas: clinical and radiological progression, MR imaging characteristics, and management of hydrocephalus. J Neurosurg Pediatr. 2014 Jan;13(1):13-20. doi: 10.3171/2013.9.PEDS13347. Epub 2013 Nov 1. PubMed PMID: 24180680.
9)

Romeo A, Naftel RP, Griessenauer CJ, Reed GT, Martin R, Shannon CN, Grabb PA, Tubbs RS, Wellons JC 3rd. Long-term change in ventricular size following endoscopic third ventriculostomy for hydrocephalus due to tectal plate gliomas. J Neurosurg Pediatr. 2013 Jan;11(1):20-5. doi: 10.3171/2012.9.PEDS12243. Epub 2012 Nov 9. PubMed PMID: 23140213.
10)

Kataria R, Kumar V, Mehta VS. Programmable valve shunts: are they really better? Turk Neurosurg. 2012;22(2):237-8. doi: 10.5137/1019-5149.JTN.3011-10.1. PubMed PMID: 22437300.
11)

Dağlioğlu E, Cataltepe O, Akalan N. Tectal gliomas in children: the implications for natural history and management strategy. Pediatr Neurosurg. 2003 May;38(5):223-31. Review. PubMed PMID: 12686764.
12)

Grant GA, Avellino AM, Loeser JD, Ellenbogen RG, Berger MS, Roberts TS. Management of intrinsic gliomas of the tectal plate in children. A ten-year review. Pediatr Neurosurg. 1999 Oct;31(4):170-6. PubMed PMID: 10705925.
13)

Poussaint TY, Kowal JR, Barnes PD, Zurakowski D, Anthony DC, Goumnerova L, Tarbell NJ. Tectal tumors of childhood: clinical and imaging follow-up. AJNR Am J Neuroradiol. 1998 May;19(5):977-83. PubMed PMID: 9613524.
14)

Lapras C, Bognar L, Turjman F, Villanyi E, Mottolese C, Fischer C, Jouvet A, Guyotat J. Tectal plate gliomas. Part I: Microsurgery of the tectal plate gliomas. Acta Neurochir (Wien). 1994;126(2-4):76-83. PubMed PMID: 8042559.

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

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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.
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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.
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