P Seetahal-Maraj1; S Harewood1, R Banfield2, P St Louis1
1Department of Neurosurgery, San Fernando General Hospital, San Fernando
2Department of Radiology, San Fernando General, Hospital, Trinidad and Tobago, West Indies
Corresponding Author
Dr Panduranga Seetahal-Maraj
San Fernando General Hospital
Paradise Pastures, Independence Avenue, San Fernando
Email: [email protected]
DOI:
DOAJ: 38f5774fe66848449eef568dc43ffed1
Copyright: This is an open-access article under the terms of the Creative Commons Attribution License which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.
©2022 The Authors. Caribbean Medical Journal published by Trinidad & Tobago Medical Association.
ABSTRACT
The H3 K27M – altered is a recognized subtype of diffuse midline gliomas. These brain tumours primarily occur in children, but cases have been documented in young adults. They are World Health Organization Grade IV tumours, with median survival of 12 months. There is a poor response to chemoradiotherapy, and molecular testing is required for an accurate diagnosis.
We report on a young female with a diffuse midline tumour, who succumbed to her illness after a period of seven months. Diagnostic challenges ensued due to the unavailability of molecular analysis locally, and the diagnosis was made post-mortem. This case aims to promote awareness of this pathology, and the need to increase local histopathological services.
INTRODUCTION
Diffuse midline gliomas (DMG) are a subset of central nervous system (CNS) tumours that are predominantly diagnosed in the pediatric population.1 Their midline location and diffuse infiltrative growth pattern risks significant morbidity with biopsy.2 The H3 K27M – altered is a recognized subtype of DMG, with several documented cases in adults.3 They are WHO Grade IV tumours, with an average life expectancy of 7 –12 months.1,4 At this time, the true incidence in adults is unknown, due to the rarity of this mutation, along with the need for specific diagnostic immunostaining.1 There is a poor response to chemoradiotherapy, and molecular testing is required for an accurate diagnosis.2 Molecular testing for H3 K27M-altered is currently not available in Trinidad and Tobago, nor is there a fellowship-trained neuropathologist. We report on a case of this rarely encountered tumour and the challenges faced in making an accurate diagnosis.
CASE DESCRIPTION
A 28-year-old female presented to the emergency department with a one-month history of memory loss, confusion, speech hesitancy and right upper limb weakness. There was no associated headaches, fever, visual disturbances, seizures, nausea or vomiting. The remainder of the medical history was unremarkable.
On examination, her Glasgow Coma Scale (GCS) score was 13/15 (E3 M6 V4). Her pupils were 3mm bilaterally and reactive to light and accommodation. All cranial nerves had intact function. Sensory examination was normal. On motor examination, increased tone was noted in the right upper and lower limbs. Power was graded as 3/5 in the right upper and lower limbs, but 5/5 on the left. Hyperreflexia was present in all limbs, with an upgoing right plantar reflex. No clonus was elicited. Blood investigations were unremarkable and the patient proceeded to have imaging studies.
A CT scan of the brain (Figure 1) showed bilateral hypodense thalamic masses which did not enhance post-contrast administration. Significant white matter oedema was noted in the left cerebral hemisphere, involving the left lentiform nucleus and insula cortex. The lateral ventricles were dilated and there was surrounding periventricular hypodensity, suggestive of trans-ependymal seepage of cerebrospinal fluid (CSF). A preliminary diagnosis of obstructive hydrocephalus secondary to a primary glioma was made, potentially a diffuse midline glioma. CT scans of the chest, abdomen and pelvis did not reveal any other lesions.
The patient’s relatives were counselled regarding the need for urgent treatment of the obstructive hydrocephalus. She was started on steroids to address the oedema, and a ventriculoperitoneal shunt was inserted. Postoperative neurological improvement was noted, with her GCS improving to 15/15 and power now graded as 4/5 in the right upper and lower extremities. One week later she experienced a focal seizure of the right upper extremity, and was started on anticonvulsant therapy. MRI of the brain was done, and revealed T1 hypointense, T2 hyperintense lesions of the thalami, with no uptake post-gadolinium administration. These findings were consistent with a diffuse midline glioma. The patient and her family were advised on stereotactic biopsy, but they declined further procedures.
This patient was re-admitted five months later with a generalized tonic-clonic seizure. On examination, she had a right hemiplegia with right gaze preference, impaired upward gaze and nystagmus. Repeat imaging was done, revealing marked progression of her midline brain tumour noted. (Figure 1) Stereotactic biopsy was again recommended, however the procedure was declined by the patient’s family. The patient experienced a progressive decline in her clinical condition, with subsequent demise.
Post-mortem examination revealed that the brain was grossly oedematous. (Figure 2) There was haemorrhagic necrosis within the brain stem. Sections revealed a hyperaemic tumour, 8 cm in greatest dimension, originating within the left thalamic region, and extension into the left cerebral hemisphere. Extensive surrounding inflammatory changes were noted. The cerebellum was unremarkable. Her histologic slides were subsequently submitted for neuropathology review at a foreign institution, which suggested a diagnosis of Diffuse Midline Glioma, H3 K27M-altered.
Figure 1 – A: Non-contrast axial CT brain showing white matter oedema, lateral ventricular dilatation, and bilateral thalamicasses; B: Contrast axial CT brain showing lack of contrast uptake of the thalamic masses; C: Dilatation of temporal horns; D: T2 FLAIR axial MRI showing hyperintense signal in the thalami, left lentiform nucleus and left insula cortex. E: Axial CT brain with contrast, showing disease progression at 5 months. F: T2 FLAIR axial MRI at 5 months, showing decompressed ventricles and extension of the hyperintensities into the surrounding cortex.
Figure 2: A: Coronal section through both cerebral hemispheres showing a well-circumscribed nodule with hyperaemia in the left paraventricular region B: Axial section of the brainstem and cerebellum showing necrosis and haemorrhage within the brainstem. C: H&E low power: hypercellular spindle lesions. D: H&E high power, with moderate cytological atypia. E: GFAP showing diffuse strong positivity. F: CD34 with focal positivity, highlighting vascularity. G: upregulation of smooth muscle actin, in keeping with high grade glioma
DISCUSSION
The WHO updated its classification of CNS tumours in 2021 to utilize both histopathological and molecular characteristics, facilitating an integrated diagnosis of these lesions. In particular, isocitrate dehydrogenase (IDH) 1/2 gene mutations, 1p19q co-deletion, EZHIP protein overexpression and histone H3 variants have revamped the way in which diffuse gliomas are diagnosed.3
Diffuse gliomas are not the typical solid tumour, as compared to carcinomas or sarcomas. They are composed of infiltrating cells of variable densities, and have the propensity to spread far from the originating point, and completely replace the brain parenchyma.5
H3 K27M-altered
DMG H3 K27M-altered is primarily known as a midline glial tumour of children and young adults. It is typically seen in the thalamus, pons, hypothalamus, cerebellum and spinal cord.5-7 This entity replaces the term diffuse intrinsic pontine glioma, after the 2016 WHO CNS tumour classification update. The term ‘mutant’ has been replaced with ‘altered’ in the subsequent 2021 WHO CNS tumour classification update, implying further mechanisms may be involved in the pathological process, aside from those previously described.3 It is regarded as a grade IV tumour, and therefore has one of the worst prognoses of all brain tumours.
Molecular analysis
Molecular profiling of brain tumours not only improves diagnostic accuracy, but allows for predictive prognosis, and enables target identification. Currently, three main groups of adult DMG can be identified – 1p19q codeletion (best prognosis), IDH mutant without 1p19q codeletion (intermediate prognosis) and IDH wild-type without 1p19q codeletion (worst prognosis).6 Mutations in the histone H3 gene are seen in a subset of the IDH wild-type gliomas, and directly impact gene transcription and DNA methylation. This leads to a highly aggressive tumour with a poor therapeutic response.8 Median survival ranges from 10 – 19.7 months, and 2-year survival less than 10% even with surgery and chemoradiotherapy.
Emerging therapeutic options for DMG H3 K27M-altered
Surgical intervention is typically reserved for biopsy or debulking, as DMGs occur in eloquent tissue, and maximal resection is usually not possible. While extent of resection usually correlates with survival (for example, in glioblastoma), it has not been found to improve survival in DMG with H3 K27M-altered.9
Piunti et al examined the relationship between the H3 K27M-mutation and bromodomain proteins. It was concluded that JQ1 bromodomain inhibitor carries dual properties in the fight against H3 K27M-altered DMG tumour cells.10 This may provide potential therapeutic targets in humans. Research into chimeric antigen-receptor T-cells and drugs modifying the histone epigenome may provide future solutions.2
Alternative diagnostic methods
Huang et al described the use of ‘liquid biopsies’ (CSF) to detect the presence of H3 K27M-altered, by sequencing the DNA obtained after centrifugation.8 This avoids the need for biopsy of midline structures and the associated risks.
Challenges faced in low-resource settings
Several hurdles are faced in the diagnosis and management of these patients. The updating of the integrated molecular and histological diagnostic WHO (2021) classification of CNS tumors highlights the need for ready access to molecular testing, specific immunostaining and neuropathological review.1 Without these resources, we are unable to accurately diagnose these tumors in the local setting. Consequently, targeted treatment modalities to allow improved survival cannot then be deployed.
This lack of resources may include (but not be limited to) stereotactic biopsy of deep seated brain tumours, fellowship-trained neuropathologists, immunohistochemistry, and the exorbitant cost of sending specimens abroad for molecular testing.
Clinical trials in brain tumour patients are limited locally, and some of the population may be culturally averse to participating in these trials, even if available. Adding to the dilemma is the fact that local patients commonly refuse treatment/biopsy of brain tumours (as in the index case). This is a loco-regional hurdle, whereby the true incidence, treatment and outcomes in patients with these tumours cannot be adequately determined.
Raising awareness of this pathology, along with the development of a robust brain tumour registry, may therefore positively influence the diagnostic accuracy of these patients and approach the true incidence of this disorder within our unique cultural community.
CONCLUSION
Despite the uncommon occurrence of DMG H3 K27M-altered, its occurrence in children and young adults, diagnostic challenges, poor prognosis and difficulty in treatment underlines the importance of understanding its molecular biology. Without local access to the appropriate tools, afflicted patients are unable to be accurately diagnosed and possibly treated. Development of a centralized referral lab (even if regional), for molecular testing would provide a solution to this dilemma. An effort to procure dedicated neuropathologists will be of even greater value in the neuropathological assessment of these uncommon brain tumours.
Ethical Approval statement – Not Applicable
Conflict of Interest statement – Not Applicable
Informed Consent statement – Informed consent was given to us by the patient’s family, for use of all images and reporting of the case
Funding statement – Not Applicable
REFERENCES
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- Huang TY, Piunti A, Lulla RR, Qi J, Horbinski CM, Tomita T, et al. Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma. Acta Neuropathol Commun. 2017;5(1):28.
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