Julie H. Harreld

Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups

BackgroundGangliogliomas are low-grade glioneuronal tumors of the central nervous system and the commonest cause of chronic intractable epilepsy. Most gangliogliomas (>70%) arise in the temporal lobe, and infratentorial tumors account for less than 10%. Posterior fossa gangliogliomas can have the features of a classic supratentorial tumor or a pilocytic astrocytoma with focal gangliocytic differentiation, and this observation led to the hypothesis tested in this study - gangliogliomas of the posterior fossa and spinal cord consist of two morphologic types that can be distinguished by specific genetic alterations.ResultsHistological review of 27 pediatric gangliogliomas from the posterior fossa and spinal cord indicated that they could be readily placed into two groups: classic gangliogliomas (group I; n = 16) and tumors that appeared largely as a pilocytic astrocytoma, but with foci of gangliocytic differentiation (group II; n = 11). Detailed radiological review, which was blind to morphologic assignment, identified a triad of features, hemorrhage, midline location, and the presence of cysts or necrosis, that distinguished the two morphological groups with a sensitivity of 91% and specificity of 100%. Molecular genetic analysis revealed BRAF duplication and a KIAA1549-BRAF fusion gene in 82% of group II tumors, but in none of the group I tumors, and a BRAF:p.V600E mutation in 43% of group I tumors, but in none of the group II tumors.ConclusionsOur study provides support for a classification that would divide infratentorial gangliogliomas into two categories, (classic) gangliogliomas and pilocytic astrocytomas with gangliocytic differentiation, which have distinct morphological, radiological, and molecular characteristics.

Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

MR imaging evaluation of inferior olivary nuclei: comparison of postoperative subjects with and without posterior fossa syndrome.

BACKGROUND AND PURPOSE: Posterior fossa syndrome is a severe postoperative complication occurring in up to 29% of children undergoing posterior fossa tumor resection; it is most likely caused by bilateral damage to the proximal efferent cerebellar pathways, whose fibers contribute to the Guillain-Mollaret triangle. When the triangle is disrupted, hypertrophic olivary degeneration develops. We hypothesized that MR imaging patterns of inferior olivary nucleus changes reflect patterns of damage to the proximal efferent cerebellar pathways and show association with clinical findings, in particular the presence or absence of posterior fossa syndrome. MATERIALS AND METHODS: We performed blinded, randomized longitudinal MR imaging analyses of the inferior olivary nuclei of 12 children with and 12 without posterior fossa syndrome after surgery for midline intraventricular tumor in the posterior fossa. The Fisher exact test was performed to investigate the association between posterior fossa syndrome and hypertrophic olivary degeneration on MR imaging. The sensitivity and specificity of MR imaging findings of bilateral hypertrophic olivary degeneration for posterior fossa syndrome were measured. RESULTS: Of the 12 patients with posterior fossa syndrome, 9 had bilateral inferior olivary nucleus abnormalities. The 12 patients without posterior fossa syndrome had either unilateral or no inferior olivary nucleus abnormalities. The association of posterior fossa syndrome and hypertrophic olivary degeneration was statistically significant (P < .0001). CONCLUSIONS: Hypertrophic olivary degeneration may be a surrogate imaging indicator for damage to the contralateral proximal efferent cerebellar pathway. In the appropriate clinical setting, bilateral hypertrophic olivary degeneration may be a sensitive and specific indicator of posterior fossa syndrome.

Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination

arms 1p and 19q were examined by interphase fluorescence in situ hybridization (iFISH). The presence of KIAA1549BRAF fusion transcripts was also tested by reverse transcription polymerase chain reaction (RT-PCR). We collected relevant clinical information and follow-up radiologic studies to characterize the tumors’ clinical behavior and tendency for leptomeningeal dissemination. DLGNT presents most commonly in children and young adults [6]. Similarly, among the five patients in our series, four were children (5–14 years old) and one was a young adult (20 years old). There was no apparent gender predilection, although female patients were older in our series. Pre-operative imaging was not available for one child. While diffuse leptomeningeal enhancement was not identified by MRI in any of the five cases, extensive intramedullary involvement across multiple segments was typical (Supplemental Figure). Except for one distal thoracic tumor spanning three segments, all tumors spanned ≥7 segments, with holospinal involvement from obex to conus in two cases. All four pre-operatively imaged tumors appeared central within the cord, filling and expanding the central canal (Fig. 1). All were multicystic, with peripheral variably solid or nodular enhancement. This mixed solid/cystic appearance, with T1 hypointensity and T2 hyperintensity, matches the imaging characteristics of DLGNT with a spinal cord mass [3, 6, 8–10]. None of the five patients had documented leptomeningeal metastasis during follow-up (2 months – 7.5 years). Tumor cells in DLGNT have a characteristic oligodendrocyte-like morphology and express OLIG2. The expression of GFAP or synaptophysin is more variable. Signs of neurocytic or ganglion cell differentiation are present in 10–20% of cases [6, 10]. Neuropil-like hypocellular zones and glial foci that resemble a pilocytic astrocytoma are sometimes seen [10]. Mimicking DLGNT, the five spinal Concurrent KIAA1549-BRAF fusion and chromosome 1p deletion with or without concomitant chromosome 19q loss are recurrent molecular alterations in the diffuse leptomeningeal glioneuronal tumor (DLGNT) [6, 7, 10], in which widespread leptomeningeal dissemination is a diagnostic feature [1, 6, 10]. We have reviewed five spinal cord tumors (Table 1) that show the morphologic and molecular genetic characteristics of DLGNT, but in which radiographically apparent leptomeningeal dissemination was not identified at presentation. At the initial review, we sought to understand the relationship between these tumors and DLGNT by undertaking immunohistochemical analyses with a panel of neural markers: GFAP, OLIG2, and synaptophysin, and with antibodies to the BRAF V600E, histone H3.1/H3.3 K27 M, and IDH1 R132H mutant proteins. Duplication of chromosome 7q34 (a surrogate marker for the presence of KIAA1549-BRAF fusion) and deletion of chromosome

Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease.

Massively calcified low‐grade glioma – a rare and distinctive entity

Microscopic dystrophic calcification is a common finding in diverse pathologies of the central nervous system (CNS), including tumours. However, dense widespread macroscopic calcification within tumours is rare and described as case reports in the literature, most often in association with low-grade gliomas (LGGs) [1–6]. With institutional review board approval, we reviewed the clinical features, radiology and histopathology of four extensively calcified paediatric LGGs, supplementing our review with targeted molecular analysis of relevance to LGGs. Patients’ ages ranged from 4 to 16 years at presentation, and the male : female ratio was 1:3. Presenting symptoms included headache, dysaesthesia and epilepsy, and the duration of symptoms ranged from 5 weeks to 4 years. Three tumours were located in the cerebrum, and one was thalamic. Three LGGs were well circumscribed with minimal surrounding oedema (Figure 1); one demonstrated significant oedema. All were densely calcified. Contrast enhancement, when evaluated, was heterogeneous. All tumours were totally resected. Post-operatively, three patients were asymptomatic, but one patient presenting with a temporal lobe tumour developed migraine and depression. Microscopy of all four tumours revealed non-infiltrative LGGs with dispersed densely calcified concretions (Figure 2). The architecture of the tumours and their cytology were idiosyncratic, characteristic of neither pilocytic astrocytoma nor diffuse glioma. Mildly atypical cells at low density and with a subtle astrocytic morphology produced a sheet-like pattern between deposits of calcification. One tumour was composed of cells with either an oligodendroglial or an astrocytic phenotype. Perivascular collections of lymphocytes, eosinophilic granular bodies and Rosenthal fibres were also noted in this case, but the tumour contained neither piloid cells nor ganglion cells. A delicate branching vasculature of fine capillaries characterized many areas in all tumours, and hyalinized vessels were present in one case. High-grade features including mitotic activity, microvascular proliferation and necrosis were not identified. In all cases, many tumour cells demonstrated immunoreactivities for glial fibrillary acidic protein (GFAP) and S-100, but there was no immunoreactivity for synaptophysin. Neurofilament protein (NFP)-immunopositive axon twigs were variably present between tumour

Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma

Background Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). Methods Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. Results At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. Conclusions Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Relative ADC and Location Differ between Posterior Fossa Pilocytic Astrocytomas with and without Gangliocytic Differentiation

BACKGROUND AND PURPOSE: Pilocytic astrocytomas, the most common posterior fossa tumors in children, are characterized by KIAA1549-BRAF fusions and shows excellent 5-year survival rates. Pilocytic astrocytoma with gangliocytic differentiation, a recently defined pilocytic astrocytoma variant that includes glial and neuronal elements similar to a ganglioglioma, may be distinguished from a classic ganglioglioma by molecular, radiologic, and histopathologic features. This study investigated whether imaging could distinguish posterior fossa pilocytic astrocytoma with and without gangliocytic differentiation. MATERIALS AND METHODS: Preoperative MRIs (± CTs) of 41 children (age range, 7 months to 15 years; mean age, 7.3 ± 3.7 years; 58.5% male) with pilocytic astrocytoma with gangliocytic differentiation (n = 7) or pilocytic astrocytoma (n = 34) were evaluated; differences in tumor location, morphology, and minimum relative ADC between tumor types were compared (Wilcoxon rank sum test, Fisher exact test). Histopathology and BRAF fusion/mutation status were reviewed. Associations of progression-free survival with diagnosis, imaging features, and BRAF status were examined by Cox proportional hazards models. RESULTS: Pilocytic astrocytoma with gangliocytic differentiation appeared similar to pilocytic astrocytoma but had lower minimum relative ADC (mean, 1.01 ± 0.17 compared with 2.01 ± 0.38 for pilocytic astrocytoma; P = .0005) and was more commonly located within midline structures (P = .0034). BRAF status was similar for both groups. Non-total resection (hazard ratio, 52.64; P = .0002), pilocytic astrocytoma with gangliocytic differentiation diagnosis (hazard ratio, 4.66; P = .0104), and midline involvement (hazard ratio, 3.32; P = .0433) were associated with shorter progression-free survival. CONCLUSIONS: Minimum relative ADC and tumor location may be useful adjuncts to histopathology in differentiating pilocytic astrocytoma with gangliocytic differentiation from pilocytic astrocytoma. Shorter progression-free survival in pilocytic astrocytoma with gangliocytic differentiation is likely due to a propensity for involvement of midline structures and poor resectability.

Imaging Children with CNS Tumors

Though many pediatric brain tumors are diagnosed by head computed tomography (CT) performed for emergent indications such as vomiting, ataxia, or altered mental status, CT, even with intravenous contrast, is insufficient for tumor characterization or metastasis detection. CT also carries a low risk of radiation-induced secondary cancers; this risk increases with cumulative dose without a threshold effect (Miglioretti et al. 2013). Furthermore, the eye lens, which may be exposed to radiation with head CT, is sensitive to radiation-induced cataract formation at doses as low as 0.5 Sv (Fish et al. 2011). Magnetic resonance imaging (MRI) offers far superior tissue contrast without radiation, and is therefore the gold-standard for diagnosis of central nervous system (CNS) tumors and metastases. As technology advances, MRI becomes increasingly important in diagnosing metastasis, since it detects leptomeningeal metastatic disease in up to 50% of those with false-negative cerebrospinal fluid (CSF) examination and better correlates with survival than CSF results (Maroldi et al. 2005; Terterov et al. 2010; Pang et al. 2008). MRI is particularly important in children with ependymomas, in whom CSF may be negative despite the presence of extensive leptomeningeal involvement (Poltinnikov and Merchant 2006). It is therefore critical to optimize imaging for initial diagnosis and for detection of postsurgical resection residual tumor and leptomeningeal metastasis.

Isolated Optic Nerve Glioma in Children With and Without Neurofibromatosis: Retrospective Characterization and Analysis of Outcomes

Isolated optic nerve glioma is a rare tumor with no consensus for the best therapeutic approach. Therefore, tumor control and preservation of visual function remain a challenge. In this retrospective study, we describe our experience over 30 years in a single-institutional cohort of children with isolated optic nerve glioma, focusing on treatments and visual outcomes. Seventeen children were followed for a median period of 8 years (range, 2-22 years). Diagnosis was based on typical neuroradiologic findings, and 3 patients had histologic confirmation of their tumors. In our study, conservative management preserved the vision of most patients with neurofibromatosis type 1 (NF1). NF1-related optic nerve gliomas were less often treated but were associated with a lower probability of progression and with occasional spontaneous regression. Sporadic tumors more frequently exhibited aggressive clinical behavior with a higher propensity for posterior extension, often requiring surgical intervention.