Pediatric glioblastoma

Glioblastoma in children, when compared with adults, is relatively rare.

Despite this rarity, it is apparent from the limited number of publications that pediatric glioblastoma is quite distinct from their adult counterparts. The differences pertain to the molecular genetics, effectiveness of the adjuvant therapies, and possibly the prognosis after treatment. With a plethora of path-breaking translational research coming through in recent times, a host of new information is now available on pediatric glioblastomas that holds great promise as far as the future treatment options are concerned 1)

In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established.


Some anaplastic pleomorphic xanthoastrocytomas (PXA) were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, Nakamura et al., showed an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA 2).


Korshunov et al. investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease 3)

Treatment

Total resection and receiving chemotherapy adjuvant to radiation or chemoradiation (CRT) are most closely associated with improved progression free survival (PFS) and overall survival (OS). For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes 4).

Bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis 5).

Case reports

A rare case of primary pediatric glioblastoma multiforme in a 7-year-old girl with Turner’s syndrome is reported, and various aspects regarding clinical and pathophysiological issues have been discussed. Although Turner’s syndrome is not one of the congenital chromosomal abnormalities which demand routine CNS screening, neurological assessment may be of value in those with relevant clinical findings 6).

1)

Das KK, Kumar R. Pediatric Glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 15. Available from http://www.ncbi.nlm.nih.gov/books/NBK469983/ PubMed PMID: 29251872.
2)

Nakamura T, Fukuoka K, Nakano Y, Yamasaki K, Matsushita Y, Yamashita S, Ikeda J, Udaka N, Tanoshima R, Shiba N, Tateishi K, Yamanaka S, Yamamoto T, Hirato J, Ichimura K. Genome-wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma. Cancer Sci. 2019 Jan 4. doi: 10.1111/cas.13903. [Epub ahead of print] PubMed PMID: 30609203.
3)

Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA, Zheludkova O, Milde T, Witt O, Kulozik AE, Reifenberger G, Jabado N, Perry A, Lichter P, von Deimling A, Pfister SM, Jones DT. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015 Mar 10. [Epub ahead of print] PubMed PMID: 25752754.
4)

Walston S, Hamstra DA, Oh K, Woods G, Guiou M, Olshefski RS, Chakravarti A, Williams TM. A multi-institutional experience in pediatric high-grade glioma. Front Oncol. 2015 Feb 18;5:28. doi: 10.3389/fonc.2015.00028. eCollection 2015. PubMed PMID: 25741472; PubMed Central PMCID: PMC4332307.
5)

Umeda K, Shibata H, Saida S, Hiramatsu H, Arakawa Y, Mizowaki T, Nishiuchi R, Adachi S, Heike T, Watanabe K. Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma. Pediatr Int. 2015 Feb;57(1):169-71. doi: 10.1111/ped.12414. PubMed PMID: 25711258.
6)

Hanaei S, Habibi Z, Nejat F, Sayarifard F, Vasei M. Pediatric Glioblastoma Multiforme in Association with Turner’s Syndrome: A Case Report. Pediatr Neurosurg. 2015 Feb 25. [Epub ahead of print] PubMed PMID: 25720952.

Pediatric Chiari type 1 deformity

Epidemiology

Chiari type 1 deformity is commonly seen in pediatric neurology, neuroradiology, and neurosurgery and may have various clinical presentations depending on patient age. In addition, Chiari type 1 deformity is increasingly found by neuroimaging studies as an incidental finding in asymptomatic children 1).

Treatment

The ideal management in children regarding surgical and radiographic decision making is not clearly delineated.

Entezami et al., from the Department of Neurosurgery, AlbanyThomas Jefferson University, , Brown University, Providence, retrospectively reviewed a cohort of patients age 18 years and younger referred to a single neurosurgeon for CM1. Baseline MRIs of the spine were obtained. Non-operative patients had repeat imaging at 6-12 months. Patients who underwent an operation (decompression with/without duraplasty) had repeat imaging at 6 months.

One hundred and thirty-two patients with mean age of 10 years met inclusion criteria. All patients had post-operative symptomatic improvement.

They identified 26 patients with syrinx, 8 with scoliosis, 3 with hydrocephalus, and one had tethered cord. The average tonsillar descent was 8.1 mm in the non-operative group and 11.9 mm in the operative group. Ninety-five patients were managed conservatively (72%). Thirty-seven were offered surgery (28%), and 33 patients underwent intervention; 21 with duraplasty (64%) and 12 without (36%).

Pediatric patients with CM1 require both clinical and radiographic follow-up. Duraplasty may be performed if decompression fails to relieve symptomatology, but is not always needed. CM1 continues to present a challenge in surgical decision making. Adhering to a treatment paradigm may help alleviate difficult decision-making 2).

Chiari malformation Type I (CM-I) related to syndromic craniosynostosis in pediatric patients has been well-studied. The surgical management consists of cranial vault remodeling with or without posterior fossa decompression.

Outcome

Efforts to guide preoperative counseling and improve outcomes research are impeded by reliance on small, single-center studies.

Approximately 1 in 8 pediatric CM-I patients experienced a surgical complication, whereas medical complications were rare. Although complex chronic conditions (CCC) were common in pediatric CM-I patients, only hydrocephalus was independently associated with increased risk of surgical events. These results may inform patient counseling and guide future research efforts 3).

CM-I in children is not a radiologically static entity but rather is a dynamic one. Radiological changes were seen throughout the 7 years of follow-up. A reduction in tonsillar herniation was substantially more common than an increase. Radiological changes did not correlate with neurological examination finding changes, symptom development, or the need for future surgery. Follow-up imaging of asymptomatic children with CM-I did not alter treatment for any patient. It would be reasonable to follow these children with clinical examinations but without regular surveillance MRI 4).

Outcome assessment for the management of Chiari malformation type 1 is difficult because of the lack of a reliable and specific surgical outcome assessment scale. Such a scale could reliably correlate postoperative outcomes with preoperative symptoms.

Outcome is poor in approximately 3 in 10 patients 5).

The degree of tonsillar herniation has not been a reliable predictor of either symptom severity 6) or surgical outcome 7).

Arnautovic et al. identified 145 operative series of patients with CM-I, primarily from the United States and Europe, and divided patient ages into 1 of 3 categories: adult (> 18 years of age; 27% of the cases), pediatric (≤ 18 years of age; 30%), or unknown (43%). Most series (76%) were published in the previous 21 years. The median number of patients in the series was 31. The mean duration of the studies was 10 years, and the mean follow-up time was 43 months. The peak ages of presentation in the pediatric studies were 8 years, followed by 9 years, and in the adult series, 41 years, followed by 46 years. The incidence of syringomyelia was 65%. Most of the studies (99%) reported the use of posterior fossa/foramen magnum decompression. In 92%, the dura was opened, and in 65% of these cases, the arachnoid was opened and dissected; tonsillar resection was performed in 27% of these patients. Postoperatively, syringomyelia improved or resolved in 78% of the patients. Most series (80%) reported postoperative neurological outcomes as follows: 75% improved, 17% showed no change, and 9% experienced worsening. Postoperative headaches improved or resolved in 81% of the patients, with a statistical difference in favor of the pediatric series. Postoperative complications were reported for 41% of the series, most commonly with CSF leak, pseudomeningocele, aseptic meningitis, wound infection, meningitis, and neurological deficit, with a mean complication rate of 4.5%. Complications were reported for 37% of pediatric, 20% of adult, and 43% of combined series. Mortality was reported for 11% of the series. No difference in mortality rates was seen between the pediatric and adult series 8).

Case reports

A 16-year-old boy who admitted with symptoms related to CM-I. With careful examination and further genetic investigations, a diagnosis of Crouzon syndrome was made, of which the patient and his family was unaware before. The patient underwent surgery for posterior fossa decompression and followed-up for Crouzon’s syndrome.

This is the only case report indicating a late adolescent diagnosis of Crouzon syndrome through clinical symptoms of an associated CM-I 9).

References

1)

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.
2)

Entezami P, Gooch MR, Poggi J, Perloff E, Dupin M, Adamo MA. Current management of pediatric chiari type 1 malformations. Clin Neurol Neurosurg. 2018 Dec 10;176:122-126. doi: 10.1016/j.clineuro.2018.12.007. [Epub ahead of print] PubMed PMID: 30557765.
3)

Greenberg JK, Olsen MA, Yarbrough CK, Ladner TR, Shannon CN, Piccirillo JF, Anderson RC, Wellons JC 3rd, Smyth MD, Park TS, Limbrick DD Jr. Chiari malformation Type I surgery in pediatric patients. Part 2: complications and the influence of comorbid disease in California, Florida, and New York. J Neurosurg Pediatr. 2016 May;17(5):525-32. doi: 10.3171/2015.10.PEDS15369. Epub 2016 Jan 22. PubMed PMID: 26799408.
4)

Whitson WJ, Lane JR, Bauer DF, Durham SR. A prospective natural history study of nonoperatively managed Chiari I malformation: does follow-up MRI surveillance alter surgical decision making? J Neurosurg Pediatr. 2015 Aug;16(2):159-66. doi: 10.3171/2014.12.PEDS14301. Epub 2015 May 1. PubMed PMID: 25932776.
5)

Aliaga L, Hekman KE, Yassari R, Straus D, Luther G, Chen J, Sampat A, Frim D. A novel scoring system for assessing Chiari malformation type I treatment outcomes. Neurosurgery. 2012 Mar;70(3):656-64; discussion 664-5. doi: 10.1227/NEU.0b013e31823200a6. PubMed PMID: 21849925.
6)

Khan AA, Bhatti SN, Khan G, et al. Clinical and radiological findings in Arnold Chiari malformation. J Ayub Med Coll Abbottabad. 2010;22(2):75-78.
7)

NoudelR,GomisP,SotoaresG,etal.Posteriorfossavolumeincreaseaftersurgery for Chiari malformation type I: a quantitative assessment using magnetic resonance imaging and correlations with the treatment response. J Neurosurg. 2011;115(3): 647-658.
8)

Arnautovic A, Splavski B, Boop FA, Arnautovic KI. Pediatric and adult Chiari malformation Type I surgical series 1965-2013: a review of demographics, operative treatment, and outcomes. J Neurosurg Pediatr. 2015 Feb;15(2):161-77. doi: 10.3171/2014.10.PEDS14295. Epub 2014 Dec 5. PubMed PMID: 25479580.
9)

Canpolat A, Akçakaya MO, Altunrende E, Ozlü HM, Duman H, Ton T, Akdemir O. Chiari Type I malformation yielded to the diagnosis of Crouzon syndrome. J Neurosci Rural Pract. 2014 Jan;5(1):81-3. doi: 10.4103/0976-3147.127885. PubMed PMID: 24741262.

UpToDate: Pediatric intracranial tumor

Pediatric intracranial tumor

Epidemiology

Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood.

The location of brain tumors in very young children differs from the posterior fossa predominance of older children. This is especially true in the first 6– 12 months of life, where supratentorial location is signicantly more common.

Approximately 20% of pediatric intracranial tumors arise from the thalamus or brainstem, with an incidence rate of 5% and 15%, respectively.

Medulloblastoma is the most common malignant pediatric intracranial tumor.

Diffuse intrinsic pontine glioma account for 10% to 25% of pediatric intracranial tumor.

Diagnosis

Bächli et al., from the Heidelberg University Hospital, Germany, report a single-institutional collection of pediatric brain tumor cases that underwent a refinement or a change of diagnosis after completion of molecular diagnostics that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric central nervous system tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospectiveand not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway 1).

Treatment

Malignant brain tumors represent a true therapeutic challenge in neurooncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group.

The pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications.

At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors.

Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors.

Different approaches have been explored: * Prolonged postoperative chemotherapy and delayed irradiation as designed in the POG (Pediatric Oncology Group). * Postoperative chemotherapy without irradiation in the SFOP (Société Française d’Oncologie Pédiatrique) and in the GPO (German Pediatric Oncology) studies. *

The role of high-dose chemotherapy with autologous stem cells transplantation was explored in different ways: High-dose chemotherapy given in all patients as proposed in the Head Start protocol. High-dose chemotherapy given in relapsing patients as salvage treatment in the French strategy. In the earliest trials, the same therapy was applied to all histological types of malignant brain tumors and whatever the initial extension of the disease. This attitude was justified by the complexity of the classification of all brain tumors that has evolved over the past few decades leading to discrepancy between the diagnosis of different pathologists for a same tumor specimen. Furthermore, it has become increasingly obvious that the biology of brain tumors in very young children is different from that seen in older children. However, in the analysis of these trials an effort was made to give the results for each histological groups, according to the WHO classification and after a central review of the tumor specimens. All these collected data have brought to an increased knowledge of infantile malignant brain tumors in terms of diagnosis, prognostic factors and response to chemotherapy. Furthermore a large effort was made to study long term side effects as endocrinopathies, cognitive deficits, cosmetic alterations and finally quality of life in long term survivors. Prospective study of sequelae can bring information on the impact of the different factors as hydrocephalus, location of the tumor, surgical complications, chemotherapy toxicity and irradiation modalities. With these informations it is now possible to design therapeutic trials devoted to each histological types, adapted to pronostic factors and more accurate treatment to decrease long term sequelae 2).

Complications

Case series

1)

Bächli H, Ecker J, van Tilburg C, Sturm D, Selt F, Sahm F, Koelsche C, Grund K, Sutter C, Pietsch T, Witt H, Herold-Mende C, von Deimling A, Jones D, Pfister S, Witt O, Milde T. Molecular Diagnostics in Pediatric Brain Tumors: Impact on Diagnosis and Clinical Decision-Making – A Selected Case Series. Klin Padiatr. 2018 Jul 11. doi: 10.1055/a-0637-9653. [Epub ahead of print] PubMed PMID: 29996150.
2)

Kalifa C, Grill J. The therapy of infantile malignant brain tumors: current status? J Neurooncol. 2005 Dec;75(3):279-85. Review. PubMed PMID: 16195802.
WhatsApp WhatsApp us
%d bloggers like this: