Spinal Low-grade Gliomas Research Articles

The impact of adjuvant radiotherapy on overall survival in spinal low-grade gliomas: a propensity score-matched analysis.

Spinal low-grade gliomas (sLGGs) are a group of tumors that arise from glial cells in the spinal cord. Current evidence supporting the use of adjuvant radiotherapy for the management of sLGG is lacking. We hence aimed to compare overall survival rates in patients receiving surgery alone with those receiving surgery with adjuvant radiotherapy. The NCDB, a large, nationwide, US-based cancer registry was used. Relevant cases were identified using the following ICD-O-3 histological codes: 9382, 9384, 9400, 9410, 9411, 9420, 9421, 9424, 9425, and 9450, along with the ICD-O-3 topographical codes for spinal meninges (C70.1) and spinal cord (C72.0), excluding spinal ependymomas. Overall survival was the primary outcome. Propensity score matching 1:1 was used to balance the cohorts prior to Kaplan-Meier survival analysis. A total of 552 patients were included in the study, with 440 in the surgery alone group and 156 in the surgery with adjuvant radiotherapy group. Patients in the surgery with adjuvant radiotherapy group were significantly older (median age 40.0 vs. 24.0 years, p < 0.001), and exhibited higher proportions of WHO grade 2 tumors (p < 0.001). Adjuvant chemotherapy was more frequently administered in the surgery with adjuvant radiotherapy group (23% vs. 7%, p < 0.001). Overall, adjuvant radiotherapy was not associated with improved survival, with a significantly higher mortality in the radiotherapy group before propensity score matching (p < 0.0001). After matching, the difference in overall survival was no longer significant (p = 0.11). This study found no significant overall survival benefit associated with the use of adjuvant radiotherapy for spinal low-grade gliomas (sLGG). Although patients who received adjuvant radiotherapy initially demonstrated higher mortality rates, this difference was largely due to confounding factors such as more advanced disease in this group.

Thoracic low grade glial neoplasm with concurrent H3 K27M and PTPN11 mutations

We present the case of a 41-year-old man who developed worsening mid-thoracic back pain and imaging revealed a well-circumscribed intramedullary tumor in the thoracic spinal cord. Subtotal resection was performed, and histopathological analysis showed a cytologically bland, minimally proliferative glial neoplasm. Sequencing revealed H3 K27M and an activating PTPN11 mutation. Serial imaging revealed slow tumor regrowth over a three year period which prompted a second resection. The recurrent tumor displayed a similar low grade-appearing histology and harbored the same H3 K27M and PTPN11 mutations as the primary. While the prognostic importance of isolated H3 K27M in spinal gliomas is well-known, the combination of these two mutations in spinal low grade glioma has not been previously reported. Importantly, PTPN11 is a component of the MAPK signaling pathway. Thus, as building evidence shows that low grade-appearing gliomas harboring H3 K27M mutations along with BRAF or FGFR1 mutations have a relatively more favorable course compared to isolated H3 K27M-mutant midline gliomas, the present case provides new evidence for the prognostic importance of activating mutations in other components of the MAPK signaling pathway. This case further highlights the importance of clinico-radio-pathologic correlation when incorporating evolving genetic data into the integrated diagnosis of rare neuroepithelial tumors.

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.

Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce. We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36). Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment. The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.

LGG-34. CLINICAL AND MOLECULAR CHARACTERIZATION OF A MULTI-INSTITUTIONAL COHORT OF PEDIATRIC SPINAL CORD LOW-GRADE GLIOMAS

BACKGROUNDThe MAPK/ERK pathway is involved in cell growth and proliferation, and mutations in the BRAF paralog of this pathway have made it an oncogene of interest in pediatric cancer. Previous studies have identified that BRAF mutations as well as BRAF-KIAA1549 fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic aberrations in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG.METHODSWe analyzed 46 spinal LGGs from children age 1–25 years from two institutions, Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids) for the presence of BRAF fusions or mutations. Data was correlated with clinical information. A 67 gene panel additionally screened for other possible genetic abnormalities of interest in the patient cohort from CHCO. In the Sick Kids cohort, BRAFV600E was tested for by ddPCR and IHC while BRAF fusions where detected by FISH, RT-PCR or Nanostring platform.RESULTSOf the 31 patient samples who underwent fusion analysis, 13 (42%) harbored the BRAF-KIAA1549 fusion. Overall survival (OS) for patients confirmed positive for BRAF-KIAA1549 was 100% compared to 76% for fusion negative patients. Other mutations of interest were also identified in this patient cohort including BRAFV600E, STK11, PTPN11, H3F3A, APC, TP53, PIK3CA (polymorphism), FGFR1, and CDKN2A deletion.CONCLUSION BRAF-KIAA1549 was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and trends towards longer OS although not statistically significant.

LGG-19. SPINAL LOW-GRADE GLIOMAS IN CANADIAN CHILDREN: A MULTI-CENTRE RETROSPECTIVE REVIEW

PURPOSEPrimary spinal low-grade gliomas (LGGs) are rare, can be difficult to treat, and can result in significant morbidity. The management of pediatric spinal LGGs remains controversial.METHODSA national multi-centre retrospective review of spinal LGGs diagnosed in children less than 18 years of age between 1990–2015 was undertaken to examine the clinical features, pathological subtypes, and treatment outcomes.RESULTSForty-three patients from five institutions were included. The median age of diagnosis was 5.2 years. All patients were symptomatic at diagnosis. Forty-four percent of patients were diagnosed at least 6 months after symptoms developed. Two patients had metastatic disease at diagnosis. The most common histology was pilocytic astrocytoma (48.8%). Molecular information was available for 15/43 patients: 6 patients had BRAF fusions and 4 patients had BRAF V600E mutations. Gross-total resection was achievable in only 6 patients. Twenty-seven patients were treated with surgery-only and the others received chemotherapy and/or focal radiation. Eleven patients were irradiated. No patients were registered in clinical trials for first-line therapy. Twenty-three patients experienced relapse or progression. Patients were followed for a median of 8.3 years (range, 0.5–20.4 years). Five-year progression-free survival (PFS) and overall survival (OS) rates were 48.3% (95% CI, 32.3% to 62.5%) and 89.7% (95% CI, 74.6% to 96.1%) respectively.CONCLUSIONThere is significant heterogeneity in surgical outcomes and treatment modalities of pediatric spinal LGGs. The PFS and OS rates remain suboptimal, likely due to tumor location. The low clinical trial enrollment rate highlights the paucity of available trials for spinal LGGs.

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas.

BackgroundThe mitogen-activated protein kinases/extracelluar signal-regulated kinases pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549–BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG.MethodsWe retrospectively analyzed 46 spinal gliomas from patients aged 1–25 years from Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (SickKids). CHCO utilized a 67-gene panel that assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At SickKids, BRAFV600E was assessed by droplet digital polymerase chain reaction and immunohistochemistry. BRAF fusions were detected by fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or NanoString platform. Data were correlated with clinical information.ResultsOf 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549–BRAF. All 13 (100%) patients with confirmed KIAA1549–BRAF survived the entirety of the study period (median [interquartile range] follow-up time: 47 months [27–85 months]) and 15 (83.3%) fusion-negative patients survived (follow-up time: 37.5 months [19.8–69.5 months]). Other mutations of interest were also identified in this patient cohort including BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion.Conclusion KIAA1549–BRAF was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549–BRAF negative patients, although this was not statistically significant.

Evaluating pediatric spinal low-grade gliomas: a 30-year retrospective analysis.

Most pediatric spinal tumors are low-grade gliomas (LGGs). Characterization of these tumors has been difficult given their heterogeneity and rare incidence. The objective was to characterize such tumors diagnosed at our institution. Spinal tumors diagnosed in our pediatric patients between 1984 and 2014 were reviewed retrospectively. Demographics, presentation, pathology, imaging, management, and sequelae were examined. Forty patients had spinal LGG tumors, 24 (62%) of which were pilocytic astrocytomas. The most common initial presentations were pain (n = 15), partial extremity paralysis (n = 13), and ataxia (n = 11), with the diagnosis frequently delayed by months (median = 5.9 months, range 4 days-6.2 years). Twenty-nine patients had some tumor resection, and 8 required adjuvant therapy with chemotherapy (n = 4) or radiation (n = 4) post-resection. Ten other patients received only biopsy for histologic diagnosis, who were treated with chemotherapy (n = 4) or radiation (n = 5) post biopsy. Tumor progression was noted in 16 patients (2 after gross-total resection; 10, partial resection; and 4, biopsy). During the evaluation period, 3 patients died secondary to tumor progression. BRAF status could have shortened progression-free survival: patients with BRAFV600E mutations (n = 3) all experienced progression within 10 months. Long-term sequelae of the disease/treatment were mostly residual neurologic deficits (paresthesia, paralysis), chemotherapy-induced hearing loss, and scoliosis. Spinal LGG is a rare entity with significant long-term effects. Although surgery is the most common initial treatment option, more in-depth analysis of molecular biomarkers may improve stratification and prognostication.

Leptomeningeal dissemination of low-grade intramedullary gliomas: About one case and review

Leptomeningeal (LM) dissemination arises rarely in patients with low-grade gliomas. Few cases of LM dissemination of spinal cord low-grade gliomas have been reported in children. Here, we report a case of an intramedullary spinal cord low-grade glioma occurring in an adult presenting by LM dissemination. A 57-year-old man presented with a history of headaches and visual acuity deterioration. Neurological examination revealed mental confusion, decreasing left limb strength and left positive Babinski sign. Lumbar puncture showed low CSF glucose, high CSF protein and no tumor cells. Spinal MRI revealed an intramedullary spinal lesion with a diffuse leptomeningeal enhancement. A spinal meningeal biopsy showed arachnoiditis with isolated atypical cells which were cytokeratin immunopositive. A differential diagnosis was proposed between arachnoiditis close to an infectious process or close to meningeal carcinomatosis. An intramedullary biopsy was programmed but the patient died 1 month after biopsy. The post-mortem examination showed thickened leptomeninges and an ill-circumscribed intramedullary grey lesion. Histological examination revealed a low-grade glial neoplasm composed of monomorphous spindle “piloid” cells with diffuse dissemination to leptomeninges. Glial fibrillary acidic protein immunostaining showed scattered immunoreactive cells. Clinical and pathological features of this case are unusual. Pathogenesis and prognosis of low-grade gliomas with LM dissemination are poorly understood. This case, like cases occurring in children, cannot easily be classified in the present WHO system of classification of CNS tumors. Spinal low-grade gliomas with LM dissemination may represent a possible distinctive clinico-pathological entity.