Spinal cord diffuse midline glioma, H3 K27M-mutant

A 26-year-old female was admitted with a 5-month history of progressive weakness of the left inferior limb, recently with numbness of both extremities and urinary incontinence. Upon examination, there was spastic paraparesis of the left inferior limb (G2) and right inferior limb (G4), with hyperreflexia and Babinski sign bilaterally.

Dorso-lumbar computed tomography (CT) was reported as normal, with no evident osteoarticular changes associated with spinal cord compression (figures 1a, 1b). However, the assessment of intrinsic disease of the spinal cord on CT is often difficult; therefore, magnetic resonance imaging (MRI) was performed, showing an extensive fusiform lesion expanding the spinal cord and occupying most of the vertebral canal, with ill-defined borders, from the level of C5-C6 to the plane of D6. It demonstrated hyperintensity on T2 (figure 2a), hypointensity on T1 (figure 2b) and hyperintensity on STIR (figure 2c). There was a small (infracentimetric) left parasagittal component, on the level of D4-D5, that showed faint enhancement after gadolinium administration (figures 3a, 3b). There were no signs of acute or chronic haemorrhage, or intralesional or perilesional cysts. There was no bone remodelling or extension to the lateral foramina.

Eventually, biopsy established the diagnosis of diffuse midline glioma, H3 K27M-mutant.

Background

Diffuse midline glioma, H3K27M-mt, is a rare and aggressive tumour classified as WHO grade 4, regardless of histological features [1]. It was renamed to “diffuse midline glioma, H3K27-altered” in the 2021 WHO Classification of Tumours of the CNS to integrate recent findings that other molecular changes also result in H3K27 alterations [2]. Most cases display astrocytic morphology, while a small percentage contain oligodendroglial-like features with high histological grades [2].

Clinical perspective

H3K27-alteration is more common in younger groups, although the exact incidence in adults is unknown [1]. Symptoms are unspecific and vary according to the location and mass effect of the glioma, including cranial nerve palsies, raised intracranial pressure, cerebellar signs (pons/brainstem), limb weakness, paraesthesia, and pain (spinal cord).

Imaging perspective

Typically, it manifests as an infiltrating lesion in the pons, although it can be found in other midline structures such as the thalamus or spinal cord; less common locations include the corpus callosum, hypothalamus, pineal gland, and tectum [3]. Although location in the midline should raise suspicion for this entity, signal characteristics are nonspecific, showing hypointensity on T1w and hypersignal on T2w imaging, which may be heterogeneous. ADC and perfusion values can be helpful (may show reduction and increase, respectively) [3]; however, their applicability is still limited in the spinal cord. Contrast enhancement varies from nonenhancing to irregular peripheral enhancement and central necrotic foci [4]. Importantly, the degree of tumour enhancement is often less than expected for a high-grade tumour, which may hinder the distinction from a low-grade adult-type glioma [3]. Final diagnosis was reached after biopsy, with identification of K27M-mutation.

Outcome

Diffuse midline glioma (H3K27M-mt) has a very poor prognosis, with a 2-year survival rate of up to 10% [4]. These lesions exhibit more aggressive features in the paediatric population owing to their distinct molecular patterns [5]. The role of surgery is primarily for diagnosis, which requires biopsy [1]. Despite therapeutic advances in chemoradiotherapy and targeted therapy regimens, there has been no substantial survival improvement in patients with H3K27M mutations in recent years [5, 6].

Take Home Message/ Teaching Points

Progressive bilateral inferior limb weakness, sensory changes and sphincter incontinence should prompt MRI assessment to exclude intrinsic lesions of the spinal cord.

H3K27-altered glioma should be considered when there is a diffuse midline lesion, especially in the pons and thalamus, but also in the spinal cord.

Imaging is crucial to guide the surgery/biopsy.

Tumour enhancement varies greatly, and the lack of it should not discourage the diagnosis.