Brett J. Theeler

Moving toward molecular classification of diffuse gliomas in adults

Diffuse gliomas are a heterogenous group of neoplasms traditionally classified as grades II to IV based on histologic features, and with prognosis determined mainly by histologic grade and pretreatment clinical factors. Our understanding of the molecular basis of glioma initiation, tumor progression, and treatment failure is rapidly evolving. A molecular profile of diffuse gliomas is emerging. Studies evaluating gene expression and DNA methylation profile have found multiple glioma subtypes and an association between subtype and survival. The recent discovery of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma has provided reproducible prognostic biomarkers and novel therapeutic targets. Glioblastomas that exhibit CpG island hypermethylator phenotype, proneural gene expression, or IDH1 mutation identify a subset of patients with markedly improved prognosis. Accumulated evidence supports the stratification of both low-grade and anaplastic diffuse gliomas into prognostic groups using 1p/19q codeletion and IDH mutation status. A classification scheme incorporating clinical, pathologic, and molecular information may facilitate improved prognostication for patients treated in the clinic, the development of more effective clinical trials, and rational testing of targeted therapeutics.

Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor

Rosette-forming glioneuronal tumor (RGNT) is a recentlydescribed CNS neoplasm generally involving posteriormidline structures with frequent extension in the fourthventricle [5]. With only one case of postoperative recur-rence reported to date [8], RGNT is considered to havefavorable outcome and the current standard of care issurgical excision without adjuvant therapy. To date, nomolecular alterations have been reported for this tumor.Alterations in the PI3K/AKT pathway are frequent in manycancers [11] and have been reported in CNS tumors [1, 2,6, 7]. Here, we report the identification of frequent PIK3CAmutations in a series of RGNTs reviewed at our institution.We searched our medical record database and identifiedeight cases of RGNT. The mean age at diagnosis was26 years (range 15–50) and the male:female ratio was 1:1.Clinical data was available for seven patients, with amedian follow-up time of 5 years (range 1–13) (Table 1).Two patients had late recurrences despite gross totalresection. The first had a recurrence at 9 years and hasremained stable 1 year after repeat resection. The secondhad a recurrence at 4 years with sacral and intraventriculardissemination and has been stable 2 years after 12 cycles oftemozolomide and cis-retinoic acid. The remaining patientswere recurrence-free at last follow-up.All eight cases showed classic histologic features ofRGNT including rosette-forming oligodendroglia-likecells, localized synaptophysin immunoreactivity withinrosettes, and fibrillary glial background (Fig. 1a, b). Theidentification of two cases with recurrence in a relativelysmall series of patients was unexpected and prompted us totest these tumors for known oncogenic mutations. Archivedformalin-fixed paraffin-embedded tumor tissue, onlyavailable for four of eight cases, was submitted for massspectrometry array mutation profiling (MassARRAY sys-tem, Sequenom, San Diego, CA) with a panel covering 86single nucleotide variant (SNV) hotspots in 14 genes:AKT1 (3), AKT2 (2), AKT3 (2), BRAF (10), EGFR (1),GNAQ (3), GNAS (2), IDH1 (3), IDH2 (3), KRAS (9), MET(11), NRAS (7), PI3KCA (29, in exons 1, 4, 6, 7, 9, 18, and20) and RET (1). Sequenom

Low rate of R132H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas

Diffuse gliomas not only are more frequent in the cerebral hemispheres but also occur in the brainstem, cerebellum, and spinal cord. In adult populations, 5 % or less localize to the infratentorium [6, 14]. Primary tumors of the spinal cord are uncommon and only 2.5 % are diffuse gliomas [6]. In the brainstem, many gliomas are diagnosed solely by radiology and even when a biopsy is obtained it tends to be of minute size, rendering interpretations challenging. Accurate diagnostic ancillary studies on such specimens would therefore be valuable.

High-Grade Gliomas

Opinion statementHigh-grade gliomas (HGGs) should be treated with maximal, safe surgical resection followed by 57–60xa0Gy of partial-field external beam or intensity-modulated radiotherapy to a 2xa0cm margin surrounding the resection cavity. The standard of care for newly diagnosed glioblastoma includes concurrent temozolomide (TMZ) during radiotherapy and adjuvant TMZ for six or more cycles. The optimal role of chemotherapy in anaplastic gliomas is unresolved. Carefully selected patients with anaplastic gliomas can be treated with combination chemotherapy (procarbazine, lomustine, vincristine; PCV) or TMZ as initial therapy after surgical resection, adjuvant therapy after radiotherapy, or at recurrence in patients with anaplastic glioma. Patients with recurrent glioblastoma can be treated with intravenous bevacizumab or dose-intense regimens of TMZ, but selection of optimal candidates for either therapy is unresolved. Other currently available targeted biologic agents are not part of routine management of patients with HGGs. Combination therapeutic trials of antiangiogenic and other targeted agents are ongoing in patients with HGGs. The way forward for patients with HGGs will involve treatments targeting the molecular abnormalities that are important to tumor initiation and growth. All patients with HGGs should be evaluated for clinical trial eligibility at diagnosis and upon recurrence.

Teaching NeuroImage: Isolated intracranial Rosai-Dorfman disease mimicking a meningioma

A 56-year-old woman presented with involuntary left arm and leg movements. MRI with gadolinium revealed a heterogeneously enhancing, extra-axial mass at the right frontoparietal convexity, causing mass effect, vasogenic edema, and dural thickening (figure). Intraoperatively the mass was noted to invade nearby cortex, sulci, and the superior sagittal sinus. Meningioma was suspected. Pathology revealed a lymphohistiocytic infiltrate with histiocytes positive …