Kakkar Aanchal, Majumdar Atreye, Pathak Pankaj, Kumar Anupam, Kumari Kalpana, Tripathi Manjari, Sharma Mehar C, Suri Vaishali, Tandon Vivek, Chandra Sarat P, Sarkar Chitra
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
Neurol India. 2017 Sep-Oct;65(5):1076-1082. doi: 10.4103/neuroindia.NI_207_17.
Gangliogliomas (GGs) are slow-growing glioneuronal tumors seen in children and young adults. They are associated with intractable epilepsy, and have recently been found to harbor BRAF (B- rapidly accelerated fibrosarcoma) gene mutations. However, the mammalian target of rapamycin (mTOR) signaling pathway, downstream of BRAF, has not been evaluated extensively in GGs.
GG cases were retrieved, clinical data obtained, and histopathological features reviewed. Sequencing for BRAF V600E mutation, analysis of BRAF copy number by quantitative real-time polymerase chain reaction, and immunohistochemistry for mTOR pathway markers p-S6 and p-4EBP1 were performed.
Sixty-four cases of GG were identified (0.9% of central nervous system tumors). Of these, 28 had sufficient tumor tissue for further evaluation. Mixed glial and neuronal morphology was the commonest (64%) type. Focal cortical dysplasia was identified in the adjacent cortex (6 cases). BRAF V600E mutation was identified in 30% of GGs; BRAF copy number gain was observed in 50% of them. p-S6 and p-4EBP1 immunopositivity was seen in 57% cases each. Thus, mTOR pathway activation was seen in 81% cases, and was independent of BRAF alterations. 87% patients had Engel grade I outcome, while 13% had Engel grade II outcome. Both the Engel grade II cases analyzed showed BRAF V600E mutation.
BRAF V600E mutation is frequent in GGs, as is BRAF gain; the former may serve as a target for personalized therapy in patients with residual tumors, necessitating its assessment in routine pathology reporting of these tumors. Evidence of mTOR pathway activation highlights similarities in the pathogenetic mechanisms underlying GG and focal cortical dysplasia, and suggests that mTOR inhibitors may be of utility in GG patients with persistent seizures after surgery.
节细胞胶质瘤（GGs）是儿童和青年中可见的生长缓慢的神经胶质神经元肿瘤。它们与难治性癫痫相关，并且最近发现含有BRAF（B-快速进展性纤维肉瘤）基因突变。然而，BRAF下游的哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在GGs中尚未得到广泛评估。
检索GG病例，获取临床数据，并复习组织病理学特征。进行BRAF V600E突变测序、通过定量实时聚合酶链反应分析BRAF拷贝数以及对mTOR通路标志物p-S6和p-4EBP1进行免疫组织化学检测。
共鉴定出64例GG（占中枢神经系统肿瘤的0.9%）。其中，28例有足够的肿瘤组织进行进一步评估。混合性胶质和神经元形态是最常见的类型（64%）。在相邻皮质中发现局灶性皮质发育异常（6例）。30%的GGs中鉴定出BRAF V600E突变；其中50%观察到BRAF拷贝数增加。p-S6和p-4EBP1免疫阳性分别见于57%的病例。因此，81%的病例中可见mTOR通路激活，且与BRAF改变无关。87%的患者Engel分级为I级，而13%为Engel分级II级。分析的2例Engel分级II级病例均显示BRAF V600E突变。
BRAF V600E突变在GGs中很常见，BRAF增加也很常见；前者可作为残留肿瘤患者个性化治疗的靶点，因此有必要在这些肿瘤的常规病理报告中进行评估。mTOR通路激活的证据突出了GG和局灶性皮质发育异常潜在发病机制的相似性，并表明mTOR抑制剂可能对术后仍有癫痫发作的GG患者有用。
