What is DIPG (Diffuse Intrinsic Pontine Glioma)?
DIPG is a highly aggressive, infiltrative brainstem tumor occurring primarily in children aged 5-9 years, characterized by expansile pontine lesions with approximately 80% harboring the H3 K27M mutation, and carrying a universally fatal prognosis with median survival of only 8-12 months despite treatment. 1, 2
Classification and Molecular Definition
DIPG is now classified under the broader category of Diffuse Midline Glioma (DMG), H3 K27-altered, WHO grade IV, reflecting updated nomenclature in the WHO CNS5 classification. 1 This change encompasses not only H3 K27M mutations but also other mechanisms causing loss of H3 K27 trimethylation, such as EZHIP protein overexpression. 1
Key Molecular Features
The H3 K27M mutation (occurring in either H3F3A or HIST1H3B/C genes) is the defining molecular alteration, found in approximately 80% of DIPGs and nearly half of other midline gliomas. 1
This mutation interferes with EZH2/PRC2 methyltransferase activity, resulting in global hypomethylation and derepression of PRC2 target genes, which drives the aggressive biological behavior independent of histologic appearance. 1
Diagnosis requires demonstration of the H3 K27M mutation via either direct sequencing or immunohistochemistry using mutant-specific antibodies that show diffuse nuclear positivity, while H3K27me3 antibody shows loss of nuclear staining. 1
Epidemiology and Demographics
Peak incidence occurs in children aged 5-9 years (0.56 per 100,000 population), though DIPG can occur in adolescents and young adults, with 21% of cases occurring in patients ≥10 years of age. 1, 3
Males have higher mortality rates despite diagnosis being more common in females. 1
Five-year survival rates remain below 20% despite combined modality therapy with surgery, radiation, and systemic treatment. 1
Clinical Presentation
DIPG presents with rapid symptom onset over weeks to months, not years, which is critical for distinguishing it from benign conditions. 2
Neurological Manifestations
94% of children have abnormal neurological findings at diagnosis, with 60% presenting with papilledema. 2
Multiple cranial nerve deficits are expected, including abducens nerve palsy (causing diplopia), facial nerve weakness, dysphagia, and dysarthria. 2
Long tract signs are common, manifesting as ataxia, gait disturbance, abnormal reflexes, and altered sensation. 2
Signs of increased intracranial pressure include headaches, nausea, vomiting, and blurred vision. 2
Radiographic Characteristics
Classically, DIPGs present as expansile pontine lesions with locoregional infiltration, though imaging findings are heterogeneous. 1
Variable Imaging Features
Intratumor contrast enhancement, hemorrhage, and necrosis may be present. 1
Gliomatosis-like diffuse parenchymal involvement can occur. 1
Leptomeningeal and/or intraventricular spread may be observed. 1
Histologic Heterogeneity
The histologic appearance is widely variable, ranging from bland hypocellular infiltrative astrocytoma to highly pleomorphic glioma with glioblastoma features. 1 Critically, it is the K27M signature—not the histologic appearance—that most closely associates with aggressive biological behavior. 1
Important Diagnostic Caveat
Not all infiltrative gliomas arising in the midline qualify for K27M-DMG diagnosis—the defining H3 K27M mutation must be demonstrated. 1 Midline gliomas lacking this mutation should be worked up following standard infiltrative glioma algorithms with histomorphologic classification and grading. 1
Prognosis
DIPG remains universally fatal with a devastating median survival of 8-12 months from diagnosis, with only 59.2% of patients surviving 1 year and fewer than 5% reaching 5 years. 2, 3 Long-term survivors (≥24 months) are more likely to be older at presentation and have longer symptom duration before diagnosis. 3
Risk Factors
Exposure to high-dose ionizing radiation is linked to pediatric brain malignancies, with estimated latency of 7-9 years between exposure and tumor development. 1
Inherited cancer predisposition syndromes including neurofibromatosis type 1, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency (CMMRD) increase susceptibility. 1
Critical Diagnostic Approach
Immediate brain MRI with contrast is mandatory when DIPG is suspected to exclude other intracranial pathology. 2 Complete cranial nerve examination and comprehensive ophthalmological evaluation are required to fully characterize the extent of neurological involvement. 2