Brain tumours are the second most common malignancies seen in children and adults. According to 2016 WHO classification, DMG’s are grade IV tumours [19] and are highly aggressive. These tumours harbour K27M mutation in genes called H1 SI1H3B/C and H3F3A, which are responsible for coding mutant histone protein H3.1 and H3.3. Literature suggests that these tumours occur primarily in children but few cases would occur in adults too. [20] Current study suggests that the incidence of these tumours was high (58.6%) in adults compared to paediatric population (41.4%) with males population being 65.5% and females 34.5%.Previous studies showed more than 50% tumours were located in thalamus, followed by cerebellum (≥ 30%), brainstem (20–25%) and spinal cord (5–10%)[21] which was similar to the findings in our study showing 56%, 20.7%, 27.6% respectively and 6.9% in cervical spine where as 10.3% in dorsal spine. Symptoms related to DMG depend on the tumour location which included double vision, problem with swallowing, spasticity in limbs, hemiparesis, loss of balance etc. [22, 23] In our study we found 41.4% cases with hemiparesis, 17.2% with spasticity in limbs & cerebellar symptoms, 17.2% without any deficit, 13.8% with cranial nerve involvement with affected vision,10.3% with paraparesis, sensory and hearing loss, speech disturbance and nystagmus. Usually, DMG in MRI appears as a mass spreading in the middle area of the brain. [24] In our study MRI findings were noted in all the cases and 62.1% cases presented with T1 Hypo intensity and T2 hyper intensity while 13.7% had T1 iso and T2 iso intensities and 3.4% cases presented with T2 hypo intensity.
Some studies reported that most of the cases had heterogeneous enhancement on contrast MRI. [25, 26] Our study revealed, higher number of cases had heterogeneous enhancement (31%) followed by no or poor enhancement (25%), peripheral enhancement (14%) and homogenous enhancement (7%).
However, diagnosing diffuse midline gliomas by imaging alone is not possible as these tumours resemble Glioblastomas and other high-grade brain cancers.
Haihui Jiang et al. in 2020 studied H3 K27M mutation in diffuse midline glioma and compared the molecular as well as clinical and radiological association between pediatric and adult age groups.[28] In our study, we found that maximally opted procedure was subtotal resection followed by gross total resection, partial resection and biopsy. In our study in 28% cases Gross total excision, 3% case Near total excision, 21% Sub total excision, 10% cases decompression,10% cases Stereotactic Biopsy and in 38% cases Open biopsy was performed.
In the same study patients who had hydrocephalus, VP shunt was placed prior to the resection. [28] In our study, we placed shunt/ reservoir in 34% of the total cases who had hydrocephalus. In a study by JiaXu Lim et al. found that the H3K27M positive DMG lesion was moderately vascular. [29] In contrary, our study found 66% significant vascularity and 17% cases showed mild vascularity.
David. Solomon et al observed K27 Mutation positive gliomas in older adults till 65 years. [30] In his case series of 47 DMGs, histone H3-K27M mutation was discrepant with IDH1-R132H mutation as well as EGFR implication, seldom co occurred with BRAF-V600E mutation and was seen with p53 overexpression, loss of ATRX and monosomy 10. [31] Enomoto et al., and Karisa et al., found 8.69% and 8.3% ATRX loss respectively in contrast to our observation of 45% ATRX loss and approx 55% patients presented ATRX retention. [32, 33] In one case report of diffuse midline glioma of H3K27M-mutation around 15% of tumour cells and IDH sequencing were devoid of mutation similar to our study where 21% patients didn’t show mutation.
Haihui Jiang and his colleagues studied the outcome by comparing the molecular and radiological features as well as the prognosis of DMG based on preoperative MR images. [28] During RT simultaneous temozolomide (TMZ) in accordance with CT (stupp protocol) was given at a dose of 75mg/m2/d. On molecular level a high Ki-67 index of 17/27(63.6%) was observed in paediatric patients and only 14/37(37.8%) in adults. The study hence concluded that the children with H3K27M mutant DMG show distinct clinical, radiographic, and molecular characteristics as well as dismal prognosis. Radiotherapy is an important regimen that could significantly prolong the survival of patients with DMG. [28]
Kenneth J. Cohen et al. in 2017 studied Diffuse intrinsic Pontine Glioma (DIPG) and found that response to radiotherapy was poor in H3K27 wild variant. It was good in H3.1 K27M mutant with significant overall survival duration which was in concurrence to present study with 27.6% cases showing improvement. [34]
Toshiyuki Enomoto et al. stated, H3K27M mutant has a stronger association with prognosis than histological grade in the midline gliomas. Compare to children, adult DMG cases had survival time much longer. [21] In their study, paediatric patients had a median survival of 7–11 months, compared to 2–4 months in our study, significantly lower than the adult population i.e.,7–16 months. Mean survival duration of males and more than 6 months disease duration cases was high as compared to females and less than 6 months disease duration cases respectively in our study.
Toshiyuki and his colleagues examined adult midline glioma that developed in thalamus, brain stem or spinal cord with H3K27M mutation had poor prognosis which was similar to present study. [21]
Elena V. Daoud et al., found that the patients with shunt placement had survival duration of 22.8 months while in our study (1.5–2.5 months; p = 0.02) as compared to without shunt / reservoir placed (7-16months). [35] Post-operative outcome in our study, 17% cases were improved post operatively and 83% cases didn’t show significant improvement. 59% cases showed immediate post operative complications like GCS drop, need of mechanical ventilation, hemiparesis, and seizures. 34% cases had no complications and 7% had delayed post operative complications like generalised weakness & headache. Ki67 index among these patients was significantly low in those who were improved post operatively compared to no improvement. On 6 months follow-up 72% cases died and 20.7% cases were alive. They further confirmed 171 cases with mild types of IDH1 and IDH2, H3K27M mutation with poor prognosis in paediatric cases, whereas it showed good prognosis in older age group supporting that the mutation may have an age dependent effect. [21] Our study also showed similar kind of results.