Diffuse intrinsic pontine glioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Rithish Nimmagadda,MBBS.[2]

INTRODUCTION

The biologic nature of brainstem gliomas varies widely; these tumors might be low-grade and require minimal therapy, or they can be swiftly deadly even with vigorous therapy. The location of the tumor within the brainstem, the length of the clinical symptoms, and, increasingly, the mutational profile all affect the prognosis and course of treatment. Histologically, these tumors are often glioblastomas (WHO grade 4) or astrocytomas (WHO grade 3; anaplastic). However, the prognosis is not better for individuals whose biopsy revealed WHO grade 2 malignancies.High grade nonpontine gliomas, which are treated similarly to diffuse intrinsic pontine gliomas, make up around 10 to 20 percent of all nonpontine gliomas.

EPIDEMIOLOGY

About one-third of all pediatric high-grade gliomas and 10 to 20 percent of all pediatric central nervous system cancers are brainstem (midbrain, pons, and medulla oblongata) gliomas. Compared to adults, children are more likely to have brainstem gliomas. For instance, about 300 pediatric cases and 100 adult cases are recorded annually in the United States. Five to nine years old is the median age for diagnosis in children, with a slight female sex preponderance.

Pathophysiology

Diffuse intrinsic pontine gliomas are almost always high-grade astrocytomas when biopsied, while up to 25% may show low grade on traditional histologic characteristics. The majority of the tumors also develop quickly. Significantly, in diffuse intrinsic pontine gliomas, histopathologic grade is not correlated with prognosis; in fact, even low-grade diffuse pontine lesions behave aggressively and have a prognosis that is comparable to that of high-grade tumors.Seldom have pons glial tumors spread to distant locations at the time of diagnosis. Rather, they usually go down well-established fiber networks, particularly into the cerebellum and thalamus. Although spinal seeding is uncommon, it might be seen as the illness progresses.

MOLECULAR LEVEL-

1.Nearly 80 percent of diffuse intrinsic pontine gliomas contain mutually exclusive mutations in either HIST3H1B, one of many genes encoding histone H3.1, or H3F3A, one of two genes expressing the histone H3.3 variation. These mutations appear to be present in all tumor cells. Both mutations change the binding of mutant histone H3 to polycomb repressive complex 2 (PRC2), a crucial developmental regulator of gene expression, by substituting methionine for lysine 27 (H3 K27M).

2.Platelet-derived growth factor receptor (PDGFR) A and c-Met protein overexpression and amplification appear to be key molecular steps in the transition of cells to a malignant phenotype, more frequently observed in tumors with the H3.3 mutation. About 15% of diffuse intrinsic pontine gliomas have activating mutations in phosphatidylinositol 3-kinase (PI3K).

3.Pediatric diffuse intrinsic pontine gliomas are exceedingly unusual to have mutations in isocitrate dehydrogenase type 1 (IDH1) or type 2 (IDH2), which characterizes a significant fraction of adult grade 2 and 3 diffuse gliomas. On the other hand, up to 25% of adult brainstem gliomas may have IDH1/2 mutations, the majority of which are non-R132H variations. These mutations are linked to a better prognosis and may benefit from adjuvant chemotherapy in addition to radiation therapy.

CLINICAL FEATURES

Depending on the location of tumour the clinical features change accordingly.There are very few pathognomonic features pertaining to there syndrome .

-In more than 50% of cases, there are ataxia, cranial nerve palsies, and long tract symptoms including hemiparesis. Although III, IV, IX, and X may also be impacted, cranial nerves VI and VII are most frequently afflicted.

-Less than 10% of patients had hydrocephalus with high intracranial pressure (ICP) upon presentation.

-While little punctate hemorrhages might be observed in a large number of instances, significant intratumoral hemorrhage can be present in around 6% of patients at the time of diagnosis.

Usually manifesting within three months, diffuse intrinsic pontine gliomas have longer-lasting symptoms than focal brainstem gliomas. For brainstem tumors, the length of symptoms in relation to traditional radiography findings is a significant prognostic factor. Individuals who have had their symptoms for more than six months at the time of diagnosis often do considerably better than those who have had them for less time.

Diagnosis

IMAGING

Imaging tests are the gold standard for brainstem tumor identification and classification. MRIs and, less commonly, computed tomography (CT) are the most commonly used imaging techniques.Diffuse intrinsic pontine gliomas have a typical appearance on CT scans with hypodense to isodense appearance and variable contrast enhancement. Calcium is rarely identified within the tumor. MRI is superior to CT for defining these lesions. On MRI, diffuse pontine lesions are expansile, typically hypointense on T1- and hyperintense on T2-weighted images

High-grade tumors usually spread to nearby regions, such as the midbrain or medulla. Typically, axial development is seen through the cerebellar peduncles and into the cerebellum; malignancies enlarge the pons rather than moving it. They often surround the basilar artery and include exophytic components into the prepontine cistern. The tumors seem to respect the pontomedullary border on sagittal imaging.

The tumors' internal contrast enhancement might vary, sometimes ring-enhancing with centrally located necrosis. When ring-enhancing lesions seem well-circumscribed on MRI, this does not always mean the lesion is lower grade or has a more benign clinical history; this is sometimes not verified at the time of surgery or autopsy. There is hardly any contrast enhancement for diffuse pontine lesions. Diffuse uniform enhancement tumors are generally linked with longer symptoms, are more likely to be low grade tumors, and may present with a better prognosis.While MRI has become the standard method of evaluation of diffuse intrinsic pontine gliomas, the heterogeneous signal characteristics of these lesions and interobserver variability make serial assessment difficult

Differential Diagnosis

The most prevalent causes of nonneoplastic lesions in the brainstem include vascular malformations, encephalitis, uncommon parasite cysts, demyelinating illnesses (e.g., multiple sclerosis), and hamartomas in individuals with neurofibromatosis. There have also been isolated reports of adult extracranial carcinoma metastases in the pons.

Treatment

Treatment for a patient with a diffuse intrinsic pontine glioma consists of targeted tumor-specific interventions (chemotherapy, radiation treatment, and surgery) in addition to managing peritumoral edema. It is recommended that individuals take part in clinical trials, especially as the molecular pathophysiology of these cancers becomes clearer and targeted medicines start to be tested in humans.

Glucocorticoids: Giving patients with high-grade brainstem tumors glucocorticoids (such as dexamethasone) is a crucial first step in their therapy. Often a major factor in symptoms, peripheral edema can quickly reduce with steroid treatment. Steroids do not cure the underlying issue, but they can enhance clinical outcomes, which can have a significant impact on patients with short life expectancies and their quality of life.Regrettably, a considerable number of individuals necessitate extended dexamethasone treatment, leading to noteworthy problems associated with steroids. A monoclonal antibody called bevacizumab that blocks vascular endothelial growth factor (VEGF) has occasionally been used to control peritumoral edema without the negative effects of glucocorticoids.

Surgery: Outside of official clinical trials, surgery is generally not advised for children with a clinical diagnosis of diffuse brainstem glioma unless the clinical or imaging picture is unusual [54]. Routine biopsy is not able to detect people with lesions that are not high-grade astrocytomas because of the morbidity associated with surgery in this expressive region of the brain and the sampling error associated with biopsies.

A biopsy is more likely to be beneficial for adults. In this situation, as with IDH-mutant gliomas, establishing the tissue diagnosis may help prognostication and guide therapy. Furthermore, in investigations conducted both before and after the availability of MRI, up to 30 percent of biopsied patients had a diagnosis other than astrocytoma (such as lymphoma, ependymoma, or infection)

Radiation Therapy: The only treatment that seems to change the clinical course of diffuse intrinsic pontine gliomas is radiation therapy. None of the modifications—dosage escalation, modified fractionation, and radiosensitization—have shown to be more successful than radiation treatment administered normally, despite several studies.

Treatment areas for radiation therapy are usually limited to the volume of the tumor plus 1 to 2 cm of surrounding brainstem tissue. 1.8 Gy is the typical therapy dosage, administered five days a week, for a total dose of 54–59.4 Gy. Individuals experiencing severe symptoms might need to start radiation therapy right once.

Radiation treatment can cause a significant amount of tumor shrinking, but the effects are usually temporary, and patients cannot be cured with this method.

Chemotherapy:Children with diffuse intrinsic pontine gliomas have not responded well to chemotherapy. Many therapeutic approaches have been attempted in adults and children, including single chemotherapy drugs, multiple combination regimens, and high-dose therapy with stem cell rescue, but none have shown any conclusive benefits. While most adult patients with high-grade gliomas now receive temozolomide as part of their standard therapy, testing in conjunction with radiation for recently diagnosed diffuse intrinsic pontine gliomas has not shown any improvement in activity when compared to radiation alone, and it is linked to a higher risk of toxicity and side effects.

Prognosis

The prognosis of diffuse intrinsic pontine glioma is poor, with a median overall survival of 10 to 11 months. Five-year survival is less than 3 percent, and many long-term survivors have evidence of moderate or severe cognitive impairment, likely as a consequence of radiation therapy