Prevalence of BRAF V600 in primary gliomas: a systematic review

Aims Glioma is a fatal disease that causes significant years of life lost to an individual. Mutations in the driver gene BRAF, such as the V600 alteration, may contribute to gliomagenesis in adults and children through abnormal signaling causing uncontrolled cell proliferation. The use of BRAF-inhibitor drugs including Vemurafenib and Dabrafenib have shown a favorable response in 48% and 50% of melanoma patients with BRAF V600 mutations respectively. BRAF inhibitors and MEK inhibitors have shown efficacy in certain paediatric gliomas in the recurrent setting. Despite the potential benefit of BRAF inhibitors, the prevalence of BRAF V600 within primary gliomas is not fully discovered. Some studies identify the prevalence to be over 50%, while others find the prevalence to be around 1%. We performed a comprehensive systematic review to determine the prevalence of BRAF V600 within the adult and paediatric glioma population in different diagnostic groups. Method A systematic literature search was performed using Ovid MEDLINE and Embase from genesis to the 22nd October 2020. Studies were not restricted by language. Studies were eligible if patients were histologically diagnosed according to WHO guidelines as a primary glioma evaluating the prevalence of BRAF V600 and included ≥ 10 primary glioma patients. The review protocol was registered in PROSPERO (CRD42019127704). Search results were managed using Endnote. Two independent reviewers assessed the eligibility of the publications using Rayyan, conflicts were evaluated by a third reviewer. Included articles were extracted by one reviewer and confirmed by a second reviewer. Risk of bias assessments were conducted using Hoy et al’s risk of bias tool. Results were synthesized using “metaprop” in R. The meta-analysis was carried out in R which produced forest plots. Results Our cohort included 182 studies with a total of 13669 adult and paediatric glioma patients classified diagnostically according to WHO guidelines. Among 48 glioma entities, BRAF V600 was identified most commonly in epithelioid glioblastoma with a prevalence of 69% (95% confidence interval (CI): 45-89%), followed by pleomorphic xanthoastrocytoma with a prevalence of 56% (95% CI: 48-64%), anaplastic pleomorphic xanthoastrocytoma with a prevalence of 38% (95% CI: 23-54%), ganglioglioma with a prevalence of 40% (95% CI: 33-46%), and anaplastic ganglioglioma with a prevalence of 46% (95% CI: 18-76%). Other glioma entities were found to have a prevalence of BRAF V600, these include astroblastoma (24%), desmoplastic infantile astrocytoma (16%), subependymal giant cell astrocytoma (8%), dysembryoplastic neuroepithelial tumour (3%), diffuse astrocytoma (3%), and pilocytic astrocytoma (3%). Conclusion To our knowledge, this is the largest systematic review examining the prevalence of BRAF V600 in adult and paediatric glioma classified according to diagnostic WHO criteria. However, there were some limitations in this review. The sample sizes of some studies were very small, and the method of mutational analysis for BRAF V600 varied between papers. We found BRAF V600 in a significant prevalence of epithelioid glioblastoma, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma, and anaplastic ganglioglioma. Of interest, BRAF V600 mutation was found in a lower prevalence of astroblastoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, dysembryoplastic neuroepithelial tumour, diffuse astrocytoma, and pilocytic astrocytoma. Consideration of assessment of BRAF V600 mutation may enable further treatment options with BRAF and/or MEK inhibitors in these particular diagnostic entities.

LGG-36. DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIG) WITH A PPP1CB-ALK FUSION IN A 6-YEAR-OLD GIRL

Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are benign glioneuronal tumors that typically occur in infants, involve the superficial cerebral cortex, and have an excellent prognosis. DIA/DIG are a distinct molecular entity based on DNA methylation profiling. BRAF600 mutations are frequently reported in DIG/DIA. A recent comprehensive genetic analysis of infantile hemispheric gliomas identified 2 unique groups: group 1 harbored alterations in the receptor tyrosine kinase (RTK) genes ALK, ROS1, NTRK, and MET and group 2 harbored alterations in the RAS/MAPK pathway. We report a case of a 6.5-year-old girl who presented with seizures and right homonymous hemianopia. MRI of her brain demonstrated a large cystic/solid left hemispheric mass with remodelling of the overlying skull, consistent with a long-standing process. She underwent a gross total resection (GTR) and pathology demonstrated a DIG with a PPP1CB-ALK gene fusion (exon 5 to exon 20) identified by RNA sequencing. She remains disease free 12 months following GTR. A literature review identified 4 reported cases of pediatric brain tumors with PPP1CB-ALK gene fusions including: a 3-month-old with a hemispheric high-grade glioma which recurred 4 years later and pathology showed mature ganglioglioma, with both tumors showing the identical PPP1CB-ALK gene fusion; a 10-month-old infant with a hemispheric low-grade glioma; an infant with a “congenital” hemispheric high-grade glioma; and a child with an astrocytoma with no further clinical data. PPP1CB-ALK gene fusion appears to be a rare oncogenic driver in gliomas of infancy, including DIG.

Desmoplastic Infantile Astrocytoma and Desmoplastic Infantile Ganglioglioma – not so infantile anymore

DIA and DIG are rare, infantile, supratentorial neoplasms that usually occur in children before 2years of age and are exceedingly rare in older age groups. They appear as hypodense, cystic masseswith solid components showing dural attachment on neuroimaging. They are characterized byreticulin-rich spindle cell stroma containing connective tissue due to meningeal involvement,microscopically. These tumors have potential for misdiagnosis because they contain varyingproportions of neoplastic glial, neuronal and poorly differentiated cells, which causes them to have a“small round blue cell tumor” like appearance, though they have a good prognosis if correctlydiagnosed. The current study report two cases diagnosed at our institution that had very latepresentation with varying complaints which challenged the normally believed dictum of these tumorsbeing entirely infantile.

Novel suprasellar location of desmoplastic infantile astrocytoma and ganglioglioma: a single institution’s experience

OBJECTIVEThe aim of this study was to describe the clinical presentation, imaging appearance, and differential outcomes based on tumor location in 7 patients with desmoplastic infantile astrocytoma and desmoplastic infantile gangliogliomas (DIA/DIG).METHODSData of 7 patients with histopathology-proven DIA/DIGs and preoperative imaging were retrospectively reviewed, and age, sex, clinical presentation, imaging characteristics, tumor location, surgical procedure, postoperative morbidity, and overall mortality were recorded.RESULTSTwo subgroups of patients with DIA/DIGs were found to exist based on whether their tumor was located in the cerebral hemispheres or suprasellar region. Nearly all patients presented with rapidly enlarging head circumference regardless of tumor location. However, ocular abnormalities, including nystagmus and preference for downward gaze, were specific for patients with suprasellar disease. These patients experienced significant postoperative complications and had poor long-term outcomes. In contrast, patients with hemispheric tumors underwent more extensive resection than patients with suprasellar tumors, had uneventful postoperative courses, and had no documented long-term comorbidities.CONCLUSIONSPostoperative course and long-term outcome for patients with DIA/DIGs were correlated to the anatomical location and radiographic appearance of their tumor at presentation, despite having histologically and molecularly indistinguishable, WHO grade I tumors.