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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 3  |  Page : 127-132

Pediatric diffuse intrinsic pontine gliomas

1 University of Cartagena, Cartagena, Colombia
2 Department of Neurosurgery, Narayan Medical College Hospital, Nellore, Andhra Pradesh, India
3 Department of Neurosurgery, Asenjo Neurosurgical Institute, Santiago, Chile

Date of Submission25-Dec-2018
Date of Decision12-Feb-2019
Date of Acceptance21-Aug-2019
Date of Web Publication26-Sep-2019

Correspondence Address:
Dr. Luis Rafael Moscote-Salazar
University of Cartagena, Cartagena
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_50_18

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Historically, brainstem gliomas have been one of the most difficult types of neoplasms to treat. They comprise 10%–20% of pediatric tumors of the central nervous system. The average age of diagnosis is 7–9 years, without a predilection for gender. The advent of magnetic resonance imaging and radiotherapy has significantly aided in the diagnosis and treatment of brainstem gliomas.

Keywords: Brain, brainstem tumors, diffuse brainstem gliomas, diffuse intrinsic pontine gliomas, neuro-oncology, pediatric gliomas, pediatric neurosurgery

How to cite this article:
Padilla-Zambrano HS, Garcia-Ballestas E, Agrawal A, Paez-Nova M, Pacheco-Hernandez AI, Moscote-Salazar LR. Pediatric diffuse intrinsic pontine gliomas. Glioma 2019;2:127-32

How to cite this URL:
Padilla-Zambrano HS, Garcia-Ballestas E, Agrawal A, Paez-Nova M, Pacheco-Hernandez AI, Moscote-Salazar LR. Pediatric diffuse intrinsic pontine gliomas. Glioma [serial online] 2019 [cited 2023 Mar 22];2:127-32. Available from: http://www.jglioma.com/text.asp?2019/2/3/127/267919

  Introduction Top

Stem-cell tumors are one subset of malignant neoplasms within the group of brain tumors in the pediatric population.[1],[2],[3],[4],[5] They represent about 12% of brain masses in this age group. Approximately 80% of infratentorial neoplasms are diffuse intrinsic pontine gliomas (DIPG).[4] The unresectability of this type of tumor leads these patients to undergo treatment without histological confirmation.[6],[7] It is known that radiotherapy plays a crucial role in the treatment of patients suffering from this type of neoplasms, extending survival and improving their quality of life over a period of time.[6],[7] Some studies and retrospective analyses have suggested a role for chemotherapy, although with very limited results.[2],[4],[7],[8] With chemoradiotherapy, reduction of this type of tumors has been demonstrated, but they tend to recur in a short period of time.[8],[9],[10],[11] These neoplasms have worse survival rates than any other type of tumor of the central nervous system.[12],[13] This review article seeks to describe the pathophysiologic, clinical, diagnostic, imaging, and treatment characteristics of DIPG.

  Epidemiology Top

DIPG is a low-prevalence, aggressive, and high-grade neoplasm that affects the pediatric population. It is considered one of the leading causes of death in children with brain tumors, and corresponds to 70%–80% of all infratentorial tumors in children and 15% of all brain tumors. It has an approximate incidence of 2 per 1,000,000.[1],[2],[3],[4],[5] DIPG originates in the brainstem at the bridge level in most children.[6],[7] This neoplasm, because of its infiltrating nature and location, is not a candidate for surgical resection. During the last 30 years of studies of the disease, no improvements in patient survival have been found.[2],[4],[7],[8], [10,],[11],[14],[15] The average age at the time of diagnosis is 7 years, with an equal prevalence in males and females, and 50% of patients survive <1 year after diagnosis.[5],[6],[7],[12],[13]

  Pathology Top

In general, gliomas are classified based on the location and appearance of the lesion. They can be located in the mesencephalic tectum, pontine tegmentum, or bulbous or cervicomedullary junction, and can be of intrinsic or exophytic appearance.[16] In magnetic resonance imaging (MRI), DIPG is characterized as a large, hypertrophic, expandable intra-axial mass in the brainstem, hyperintense on T2-weighted images (T2WIs) and in fluid-attenuated inversion recovery, and hypo/iso-intense on T1-weighted images (T1WIs).[9],[15],[16],[17] It has unsharp borders because of its diffuse and infiltrating nature, which does not allow it to be clearly differentiated from healthy tissue,[16],[18] making it difficult to measure the size of the mass.[19] This mass can spread rostrally to compromise the mesencephalon and laterally to compromise the cerebral peduncles and, rarely, extend caudally to compromise the bulb, although it is usual to demarcate the pontobulbar body to diagnose this tumor, except in late stages.[6],[15],[16],[20],[21],[22],[23],[24] In many studies, it is reported that involvement of >50%–70% of the axial diameter of the pons is a diagnostic imaging criterion.[5],[6],[10],[18],[25],[26],[27],[28],[29] This diffuse enlargement of the pons can compromise the surrounding structures such as the basilar artery by enveloping it, submerging it, or displacing it completely or partially [6],[9],[17],[18],[23],[25],[27],[28],[30],[31],[32] because it is common to characterize it exophytically toward the prepontine cistern or sometimes dorsally to the fourth ventricle,[6] causing hydrocephalus that may require shunting.[6] Its exophytic component is very easy to be confused with a low-grade glioma.[17],[31],[33]

Other characteristics of the lesion comprise intratumoral punctate hemorrhages, edema, and cystic necrosis that influence survival in an important way.[6],[25] It is relatively common to find lesions with contrast enhancement,[16] which indicate leptomeningeal dissemination at the time of diagnosis [16],[17] that can require spinal MRI if symptoms of dissemination are present.[6],[9] It is important to distinguish radiologically DIPGs from primitive neuroectodermal tumors (PNETs) in postmortem studies of patients diagnosed radiologically with DIPG, 22% of cases were actually PNETs.[16]

  Genetic Characteristics Top

From genetic analyses carried out with samples taken from autopsies and rarely from biopsies, three subgroups of pediatric DIPG have been identified, which are very similar to the mesenchymal, proliferative, and proneural groups.[7] Other additional subgroups have been applied to this tumor, such as N-myc proto-oncogene, Hedgehog, and platelet-derived growth factor receptor A.[7] In addition, mutations in histone H3.3 and H3.1 and activin A receptor, type I (ACVR1), have ended by characterizing the subgroups in DIPG.[7] In relation to mutations in histones, it has been found that in approximately 78% of tumor samples, there was a mutation in H3F3A (K27M) that codes for H3.3 or codes for H3.1 in H1ST1H3B. The mutation in K27M has been associated with worse prognosis. In addition, ACVR1 mutations have been identified in 32% of the patients, activating the signals of transforming growth factor-beta, which leads to an increase in gene transcription; fusions of the genes of neurotropin receptors (NTRK1, K2, or K3) are in 47% of the samples studied.[6],[8],[10],[11],[12],[34]

Other mutations associated with DIPG include those of the P53 and signaling pathways of the receptor tyrosine kinase Ras/phosphatidylinositol 3-kinase, as well as mutations of the platelet-derived growth factor receptor alpha.[11] The lack of clarity in models on the cellularity of the tumor, mainly induced by its precursor cells, has made its understanding difficult. However, a type of cells immunopositive for nestin and vimentin has recently been identified that is present in the ventral protuberance and is part of postnatal development. Given the frequency of the appearance of these cells at the average age at which the disease is diagnosed, it is speculated that they could be anatomically and temporally be related to the incidence of DIPG. Similarly, it has been discovered that about half of these cells have been confirmed with the presence of the olig2 transcription factor. Recently, it was demonstrated that olig2 and NG2 in oligodendrocytes, possibly involved in the asymmetric cell division of the glioma, were both involved in the proliferation of altered cells that constitute the neoplasia.[6]

H3K27 mutations

The dysregulation of H3K27 methylation was added to the classification of tumors of the nervous system of the World Health Organization for the histological diagnosis of DIPG.[35] Although the mechanism by which this alteration leads to cancer remains poorly understood, it is known that the enhancer of zeste homolog 2 protein is responsible for the repression of certain genes by methylation (including H3K27 methylation). This leads to cell growth, and the mutation of H3K27 leads to deregulation of this protective mechanism and finally to cancer.[36]

  Clinical Manifestations Top

DIPGs have a short duration of clinical presentation of symptoms at onset with progressive worsening.[37] The classic presentation includes a triad of neurological signs in which there is involvement of the long tracts; cranial nerves, usually VI or VII abnormalities; and cerebellar ataxia and cerebellar signs for no more than 1 month.[10],[15],[16],[24] Children suffer from pain, fatigue, depression, nausea, vomiting, and seizures.[31] It is possible for children to exhibit changes in mood and irritability, increased intracranial pressure secondary to obstructive hydrocephalus resulting from enlarged protrusion, or gelastic seizures.[22],[38]

  Diagnosis Top

The diagnosis is made by clinical examination and imaging. Because of the anatomical location of DIPG and the relatively poor performance, it was thought that biopsy should be avoided and that could only be justified in cases with an atypical presentation. The clinical diagnosis of gliomas is based on the presence of two thirds of the neurological anomalies in a period of <6 months.[17],[22],[39] The first stereotactic biopsies of brainstem gliomas guided by computed tomography (CT) were documented in 1985 by Coffey and Lunsford.[20] In the last decade, the implementation of stereotactic biopsy has shown that apart from being a completely safe procedure, it also makes it possible to specify the diagnosis through the study of biomarkers and extended molecular detection, thus avoiding confusion with other pontine pathologies.[15],[40]

  Imaging Top

MRI is appropriate for confirming the presence of a DIPG.[23] Although it is not 100% specific, MRI is a key technique in DIPG diagnosis because it is minimally invasive and safe. Furthermore, more than any other result, its findings can be pathognomonic for DIPG.[2],[12],[17],[23],[33],[39],[41] In 85% of cases, the imaging confirms the clinical diagnosis and the other 15% are other diagnoses with a clinical presentation similar to that of DIPG. When this neoplasm was first described, its diagnosis was made during surgery. It was with the advent of CT that the diagnosis of DIPG acquired greater precision. In the years before MRI, the current imprecise CT scan [33],[42] showed a lesion hypodense or isodense to white matter without the presence of calcifications.[6] Until recently, the inability to distinguish between tumor and nontumoral lesions was a limitation in the use of MRI.[43],[44] However, the incursion of contrast media allowed a clear distinction between the two,[9] and the technique evolved to such an extent that diagnostic accuracy was optimized by knowledge of the metabolic profile of the tumor, as will be seen later.

Postcontrast imaging

Experience with contrast media has shown that DIPG is a lesion that does not enhance,[16],[18] except in the presence of necrosis, which displays as a “ring-shaped” enhancement. This lack of enhancement is another factor that negatively influences the prognosis.[23],[25] Some have reported that contrast enhancement occurs only in a few cases with heterogeneous patterns,[9],[15],[19],[21],[22],[23],[24],[28],[30] while others deny that there are characteristic patterns.[45] Still others have reported that there is a clear uptake of contrast but in differing degrees [6],[29],[46] and that the degree of contrast enhancement is inversely proportional to survival.[3] For some time, it was accepted that it did not have the most relevance; however, recently, the question of whether the degree of enhancement heterogeneity had this property was answered positively. It has also been found that heterogeneity is a marker of some tumor-related conditions such as the presence of other tumors, cysts, necrosis, or edema.[25] Until recently, the correlation between neuroimaging and clinical findings was controversial; with the incursion of novel magnetic resonance techniques, there were answers for these conflicts. The first step in this evolutionary process of understanding the tumor by means of the images took place in the recognition of the T2WI as the most accurate modality to determine the degree of heterogeneity more than any other sequences.[3]

Mono- and multi-voxel spectroscopy

Mono- and multi-voxel spectroscopy, in addition to helping to differentiate primary tumor from a metastasis or injury caused by radiation (associated with the apparent diffusion coefficient [shown below]), evaluates the metabolic profile of DIPG by means of its variety of focus on the protons of the brain.[9],[15] Proton spectrometry allows the measurement of choline, creatine, citrate, N-acetyl-aspartate, lactate, citrate, and some lipids in the brain. Choline is an indicator of membrane turnover, which is increased in tumors. Creatine is related to certain cellular energy pathways, which decreases in the presence of tumors. N-acetyl-aspartate is a marker of the integrity of nerve cells, which decreases in the presence of tumors. Lactates together with citrate are hypoxia markers, highly present in the tumor. Lipids are elevated in tumors. A graphical display of the concentrations of the aforementioned substances can offer clues as to whether an area interrogated with a region of interest represents tumor or some other process. The ratio of choline: N-acetyl-aspartate and choline: creatine can differentiate tumor grade and can give a rough estimate of the response to treatment and, thus, predict survival.[6],[9],[12],[19],[22],[23]

Diffusion tensor imaging

Diffusion tensor imaging (DTI) is another innovative technique that follows water diffusion along white matter tracts to quantify the commitment of the bundles (mainly of the previous transverse pontine fibers, medial lemniscus, and corticospinal) by these tumors.[22],[29] Fractional anisotropy is a parameter used in the diffusion expander that describes the extent of diffusion anisotropy for water through nerve fibers. Tumors reduce the anisotropy of water (the speed with which water diffuses between the beams), a product of the infiltration and destruction of the white matter against the diffusion of the tumor.[9],[16] The diffusion expander also provides a value called apparent diffusion coefficient that facilitates a better understanding of the pathophysiologic compromise, conferring the ability to differentiate a DIPG or some other injury such as radiation artifacts or other tumors.[3],[9],[25],[29] It is important to highlight that in diseases of fulminating progression, paradoxically, there are opposite results regarding the diffusion of water.[9] The results obtained by this technique make it possible to differentiate the destruction produced by demyelinating diseases, in which the beams are truncated, whereas in DIPG, they are displaced.[23] Through the findings of low fractional anisotropy and high apparent diffusion coefficient, it has been determined that DIPG is a hypocellular tumor with extensive edema.[29] This technique still has limitations in tumors of the posterior fossa because of structures that produce interference in this region.[23]

Magnetic resonance perfusion

Magnetic resonance perfusion is a technique that quantifies the volume and flow of blood to a particular region of interest. Thus, the most perfused areas related to common brain tissue are equivalent to tumor tissue, the magnitude of which determines whether it is a high- or low-grade lesion. Accordingly, an estimate of the prognosis and response to treatment is obtained in conjunction with spectroscopy.[19],[23] This technique also identifies areas of the tumor that have developed anaplasia (important negative prognostic factor) and rules out that any doubtful image is due to an image device, confirming the presence of the tumor.[23] The high perfusion areas coincide with those restricted in the DTI.

Positron emission tomography

Positron emission tomography is a technique that evaluates the pathophysiologic profile of the tumor because of the use of a glucose analog (2-deoxy-2-[fluorine-18]fluoro-D-glucose), which differs from the rest of the nervous parenchyma.[23] Studies of patients with this tumor have reported an inverse relationship between glucose utilization and good prognosis and survival.[17],[19],[23] Glucose utilization also provides an estimate of the degree of the neoplastic lesion,[41] which may be used to illustrate the drug uptake capabilities of tumors with heterogeneous physiology.[1]

Understanding MRI techniques allows a better understanding of the clinicopathological correlation.[3],[45] Although DIPG is generally hyperintense on T2WIs, its heterogeneous character has also been recognized. Hyperintense zones, known as areas of ring enhancement, have been well described as nonnecrotic regions of the tumor, with low cellularity, early angiogenesis, and poor vascularization. This pattern of contrast uptake is caused by the rupture of the blood–brain barrier by erosion of the bed product of the tumor or leakage imperfection of the neovascular bed and extravasation of the contrast agent and simultaneous edema.[3],[25] This contrast pattern is characteristic of high-grade lesions, but its absence does not indicate low grade.[46] The hypointense foci are explained by a high cellularity, contrast enhancement on T1WIs, restricted diffusion, high apparent diffusion coefficient, and a large cerebral blood volume (increased perfusion). These T2-hypointense foci, present in 10% of the patients diagnosed with DIPG, revealed anaplasia,[6] and therefore, poorer prognosis. Of great interest is a form of uptake of late contrast visualized in T1, during the postcontrast phase, known as “occult enhancement.”[46] This consists of a prolonged permanence of the contrast by the vascular compartment of this region. It is associated with a somewhat higher cerebral blood volume and is a clear indicator of intratumoral angiogenesis in response to hypoxia. It does not indicate a defect in the blood–brain barrier, but its simplest explanation lies in the fact that the clearance of the contrast is prolonged in these new and dense networks of vessels.[3],[25],[46] This pattern has been recognized in DIPGs and also appears in glioblastoma multiforme. Its presence has been associated with a worse prognosis in both diagnoses.[46]

  Controversies in Diagnosis Top

Some authors assert that MRI is insufficient for the diagnosis of DIPG, and there has been considerable controversy about the use of other techniques because MRI may produce false positives.[25] It has been demonstrated more recently that biopsy is relatively of low risk, and sometimes an imaging diagnosis of DIPG can be refuted via biopsy as a less aggressive glioma or a PNET.[43] These authors take as reference the fact that MRI provides diagnostic images valuably equivalent to the biopsy, although clinical and neuroimaging data are insufficient for complete understanding of the tumor.[21] Numerous studies have already shown that biopsy results did not alter the treatment decision, so biopsy has been reserved for atypical neuroimaging results.[6],[16],[18],[20],[24],[28],[37],[40],[42],[44],[47],[48] There are pathologies that mimic the appearance of DIPG, such as PNET and gangliogliomas.[15] Therefore, atypia criteria have been proposed, such as the presence of a mass in peripontine areas with mesencephalon enhancement, bulb or peduncles, and a dorsal exophytic component (which are usually operable and end up being less aggressive lesions).[20] Among other reasons for biopsy, there was one that exposed the precarious understanding of the biology of the tumor to continue research work, so it was allowed to resort to biopsy if it was a research context.[20],[37],[46] In recent years, the implementation of stereotactic biopsy has improved the results through the incursion of neuronavigation and stereotactic neuroimaging techniques. Anatomical changes during surgery are anticipated with the combination of neuronavigation, intraoperative MRI, and intraoperative neurophysiological monitoring. These techniques constantly evaluate the state of the afferent and efferent nerve pathways by means of evoked potentials and continuous scanning and updating of the images to reach the tumor in a more precise way. In a study on 127 patients, the implementation of these techniques resulted in a safer and more precise resection, minimizing postoperative sequelae.[4]

  Management Top

In DIPG therapy, fractional focal radiotherapy has been the only effective therapeutic tool. Sessions are administered for 6 weeks with a total dose of 54–60 Gy that has shown good, but brief, clinical response and neurological improvements in about 70% of children undergoing this procedure.[24],[39] Symptoms in these patients are relieved by glucocorticoid therapy until the completion of radiotherapy sessions.[22] The results of chemotherapy have been poor because of the inability of drugs to adequately penetrate the blood–brain barrier. As a result, only 1% of the drug administered can reach the tumor.[3],[5],[12],[14],[15],[31],[33] The administration of enhanced convection chemotherapy is not affected by the blood–brain barrier; chemotherapeutic agents are released into the tumor itself through catheters surgically fixed in the tumor lesion. However, determining the optimal site for catheter placement in this technique remains a challenge for surgeons, and is still under investigation.[3],[6] Because of the anatomical location of these types of tumor and their generalized presentation in vital brainstem structures, they are not susceptible to surgical resection.[3],[19],[27],[41]

Adjuvant therapies for the treatment of gliomas have been proposed, including small molecules directed to tumor proliferation, apoptosis, cell cycle, angiogenesis, and DNA repair, but none of these has been successful.[13],[41] The scarcity of DIPG tissue is being reversed by the increased rates of image-guided stereotactic biopsy.[6],[8],[13],[21]

  Assessing Response to Treatment Top

There is a study method to predict the pattern of drug delivery and the effect of the treatment, called the “modular approach.” This consists of taking “building blocks” based on the clones of densely packed tumor cells, areas of angiogenesis, necrosis, and edema and applying different MRI techniques. The gradual changes in the images predict the response of the tumor to treatment.[3],[25] Several studies have concluded that MRI, and sometimes CT, can predict the response to chemotherapy.[19],[39] The method of measuring the response to treatment consists of taking the widest possible lengths of any two-dimensional cut of the T2 signal and applying the RECIST criteria,[28] as follows:[1],[30],[32],[38]

  1. Complete response: Pons returns to normal size and there is no sign of injury
  2. Partial response: Reduction >50% of the sum of the products of two perpendicular diameters of the tumor
  3. Stable disease: Intermediate stage between partial response and progressive disease
  4. Progressive disease: Increase >25% of the sum of two perpendicular diameters of the tumor.

  Outcomes Top

The prognosis of these tumors has remained poor in recent decades. Besides representing a therapeutic challenge, the worldwide survival of the gliomas has remained between 9 and 12 months.[6],[14],[28],[41] In addition, therapy with cytotoxic and targeted chemotherapeutics has been attempted and shown no clinical benefit because of inadequate tumor penetration by the drug.[1],[14] Children diagnosed with DIPG have survival probabilities <90% after 2 years of diagnosis.[3],[11],[20],[34] The only treatment that has shown clinical and radiographic responses is radiotherapy, in which approximately 70% of children have shown neurological improvement that was short in duration.[15]

  Conclusion Top

DIPGs account for about 80% of brainstem tumors. They are generally characterized by diffuse infiltration that symmetrically expands the anatomical structure of the affected site. As a subgroup of central nervous system gliomas, DIPGs have the worst prognosis. Patients evaluated with typical findings of this type of tumor are not routinely biopsied; their classification is based on the clinical picture and MRI. Its treatment is based largely on radiotherapy, which achieves a survival of 8–10 months.

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