脑海绵状血管畸形的临床、基因组和组织病理学多样性。
Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations.
作者信息
Ren Jian, Wang Daochao, Wang Leiming, Jiang Chendan, Tian An, Cui Ziwei, Ren Yeqing, Bian Lisong, Zeng Gao, Meng Guolu, Shan Yongzhi, Liang Jiantao, Xiao Xinru, Tang Jie, Wei Yukui, He Chuan, Sun Liyong, Ma Yongjie, Yu Jiaxing, Li Guilin, Ye Ming, Hu Peng, Li Jingwei, Li Ye, Niu Lijian, Li Qianwen, Ling Feng, Burkhardt Jan-Karl, Zhang Hongqi, Hong Tao
机构信息
Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological Disorders, No. 45 Changchun Street, Xicheng District, 100053, Beijing, China.
Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China.
出版信息
Acta Neuropathol Commun. 2025 Feb 5;13(1):23. doi: 10.1186/s40478-025-01940-1.
Cerebral cavernous malformations (CCMs) are hemorrhagic vascular disorders with varied clinical and radiological presentations, occurring sporadically due to MAP3K3 or PIK3CA mutations or through inherited germline mutations of CCM genes. This study aimed to clarify the clinical, genetic, and pathological features of CCMs using a multicenter cohort across three Chinese centers. We analyzed 290 surgical specimens from symptomatic CCM patients, utilizing whole-exome sequencing, droplet digital PCR, and targeted panel sequencing, alongside immunohistology to examine genotypic and phenotypic differences. Among 290 cases, 201 had somatic MAP3K3, PIK3CA, or germline CCM mutations, each associated with distinct clinical parameters: hemorrhage risk (P < 0.001), lesion size (P = 0.019), non-hemorrhagic epilepsy (P < 0.001), Zabramski classifications (P < 0.001), developmental venous anomaly presence (P < 0.001), and MRI-detected edema (P < 0.001). PIK3CA mutations showed a higher hemorrhage risk than MAP3K3 and combined MAP3K3 & PIK3CA mutations (P < 0.001). Within PIK3CA mutations, the p.H1047R variant correlated with higher bleeding risk than p.E545K (P = 0.007). For non-hemorrhagic epilepsy, patients with single MAP3K3 mutations or combined MAP3K3 & PIK3CA mutations were at greater risk than those with PIK3CA mutations alone. Histopathologically, lesions with PIK3CA mutations displayed cyst walls, pS6-positive dilated capillaries, and fresh blood cells, while MAP3K3 and double mutation lesions exhibited classic CCM pathology with SMA-positive and KLF4-positive vessels, collagen, and calcification. PIK3CA lesions had fewer KLF4-positive cells than double mutations lesions (P < 0.001), and EndMT (SMA-positive) cells compared to double mutation lesions (P < 0.05) and MAP3K3 mutations (P < 0.001), with more pS6 compared to MAP3K3 mutations (P < 0.05). This study underscores the diverse clinical, genomic, and histopathological characteristics in CCMs, suggesting potential predictive markers based on mutation subtypes and MRI features.
脑海绵状血管畸形（CCMs）是一种出血性血管疾病，具有多样的临床和影像学表现，可因MAP3K3或PIK3CA突变而散发性发生，或通过CCM基因的遗传性种系突变发生。本研究旨在利用来自中国三个中心的多中心队列，阐明CCMs的临床、遗传和病理特征。我们分析了290例有症状的CCM患者的手术标本，采用全外显子组测序、液滴数字PCR和靶向测序板测序，并结合免疫组织学检查基因型和表型差异。在290例病例中，201例有体细胞MAP3K3、PIK3CA或种系CCM突变，每种突变都与不同的临床参数相关：出血风险（P < 0.001）、病变大小（P = 0.019）、非出血性癫痫（P < 0.001）、Zabramski分类（P < 0.001）、发育性静脉异常的存在（P < 0.001）和MRI检测到水肿（P < 0.001）。PIK3CA突变显示出比MAP3K3以及MAP3K3和PIK3CA联合突变更高的出血风险（P < 0.001）。在PIK3CA突变中，p.H1047R变体比p.E545K具有更高的出血风险（P = 0.007）。对于非出血性癫痫，单一MAP3K3突变或MAP3K3和PIK3CA联合突变的患者比仅PIK3CA突变的患者风险更高。组织病理学上，PIK3CA突变的病变显示囊肿壁、pS6阳性扩张毛细血管和新鲜血细胞，而MAP3K3和双突变病变表现出典型的CCM病理，有SMA阳性和KLF4阳性血管、胶原蛋白和钙化。PIK3CA病变的KLF4阳性细胞比双突变病变少（P < 0.001），与双突变病变相比，EndMT（SMA阳性）细胞较少（P < 0.05），与MAP3K3突变相比也较少（P < 0.001），与MAP3K3突变相比，pS6更多（P < 0.05）。本研究强调了CCMs中多样的临床、基因组和组织病理学特征，提示基于突变亚型和MRI特征的潜在预测标志物。
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