H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and EGFR-mutant. H3F3B, another gene encoding histone H3.3 in addition to H3F3A, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of H3F3B-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with H3F3B-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic H3F3B p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that H3F3B-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. PPM1D and NF1 were frequently mutated in H3F3B-mutant DMGs. Survival analysis showed that H3F3B-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, H3F3B mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between H3F3B-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.

OBJECTIVES:We aimed to investigate the clinicopathologic features of and genetic changes in Sturge-Weber syndrome (SWS) in patients with refractory epilepsy.METHODS:Clinical data were retrospectively analyzed. H&E and immunohistochemistry were performed to assess pathologic changes. Targeted amplicon sequencing was applied to investigate the somatic GNAQ (c.548G>A) mutation. The potential predictors of seizure outcomes were estimated by univariate and multivariate statistical analyses.RESULTS:Forty-eight patients with SWS and refractory epilepsy were enrolled. According to the imaging data and pathologic examination, ipsilateral hippocampal sclerosis (HS), calcification of leptomeningeal arteries, and focal cortical dysplasia were found in 14 (29.2%), 31 (64.6%), and 37 (77.1%) patients, respectively. A high frequency of GNAQ alteration was detected in both cerebral cortex (57.7%) and ipsilateral hippocampus (50.0%) from patients with SWS. During follow-up, 43 of 48 patients (85.4%) had achieved seizure control (Engel class I). Statistically, HS signs on imaging were found to be independent predictors of unfavorable seizure outcomes (P = .015).CONCLUSIONS:Calcification of leptomeningeal arteries, focal cortical dysplasia, and GNAQ alteration are common features in SWS pathology. Patients with refractory epilepsy caused by SWS can achieve satisfactory seizure control after surgery, but seizure control was compromised in patients with comorbid HS.

OBJECTIVE:Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI). METHODS:This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis. RESULTS:We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis. INTERPRETATION:The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203.

Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850 K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1 A, 2 A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., glial scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 mapped explicitly to biological pathways related to neurodegeneration, biogenesis of the extracellular matrix (ECM) components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.

目的 探讨脉络丛癌(CPC)的临床病理及免疫组化特征.方法 收集首都医科大学宣武医院诊断的CPC共10例,总结临床病例资料、组织学以及免疫组化特征,并进行文献复习.结果 10例CPC发病部位以脑室居多,侧脑室及四脑室总占比60％;其次散发在枕叶、顶叶、脑干及鞍区,占比40％.年龄0.7～14岁,中位年龄为3.0岁;男性4例,女性5例;均有不同程度的中枢神经系统疾病表现,常见为嗜睡、哭闹、头痛及脑积水等症状.影像学表现为孤立性实性肿物,镜下符合2021版CNS WHO CPC诊断标准.免疫组化表型中EMA均表现为灶状阳性,GFAP、CK、CK7和CK20均有各自比例的阳性值和阳性结果,Ki-67增殖指数为15％～50％,INI-1未见缺失.特异性较强的两个指标:Kir7.1细胞膜及细胞质表达,阳性细胞数为80％,其中1例阳性细胞数低于50％;TTR在细胞质中表达,阳性细胞数为60％.结论 CPC是一种罕见的、生长迅速的、好发于婴幼儿的恶性肿瘤,EMA、GFAP、CK、CK7及CK20表达有一定的规律,Kir7.1和TTR诊断CPC特异性较强,鉴别诊断婴幼儿中枢神经系统恶性肿瘤具有一定的临床价值.

The characteristics of H3.3 G34-mutant gliomas in adults have yet to be specifically described. Thirty adults with H3.3 G34-mutant diffuse gliomas were retrospectively reviewed for clinical and pathologic information. Molecular profiling using next-generation sequencing was performed in 29 of the 30 H3.3 G34-mutant patients with 1 patient lacking available tumor samples, as well as 82 IDH/H3 wild-type adult diffuse glioma patients. The age at diagnosis of H3.3 G34-mutant diffuse gliomas was significantly younger than IDH/H3 wild-type gliomas (24 vs. 57 y, P <0.001). Overall, 19 of the 30 patients were diagnosed of glioblastoma with the primitive neuronal component, and 8 were glioblastoma. The molecular profiling analysis revealed higher frequencies of Olig-2 loss of expression, TP53 mutation, ATRX mutation, PDGFRA mutation, and MGMT promoter methylation ( P <0.05) in H3.3 G34-mutant gliomas than IDH/H3 wild-type gliomas. No TERT promoter mutation and only 1 case of EGFR amplification were detected in the H3.3 G34-mutant cohort, the frequencies of which were significantly higher in the IDH/H3 wild-type cohort. A dismal prognosis was observed in H3.3 G34-mutant patients comparing to IDH/H3 wild-type cohort (overall survival: 14 vs. 22 mo; P =0.026). Univariate and multivariate analyses showed that the extent of resection and TP53 mutation were independently affecting prognosis. The distinct pathologic and molecular features of H3.3 G34-mutant diffuse gliomas in adult patients demonstrated the clinical importance of detecting H3.3 G34R/V mutations. The dismal prognosis of this rare high-grade glioma disease we reported here would further promote the investigation of dedicated therapeutic strategies.

目的 探讨大脑淋巴瘤病(lymphomatosis cerebri,LC)的临床病理学特点,以期为临床诊治提供思路.方法 选取2020年1月至2022年1月首都医科大学宣武医院确诊的LC患者4例,对其临床资料、影像学及病理学特点进行回顾性分析.结果 4例患者中男3例,女1例,年龄49～63岁,平均59岁.临床表现为进行性进展的认知功能障碍、行为改变和行走不稳等,影像学检查均表现为大脑弥漫性及多发性病变,以白质受累为主,CT呈低密度影,T1WI等或低信号,T2WI及FLAIR高信号,无明显强化.3例为立体定向穿刺活检标本,1例为开颅手术切除标本.组织学诊断均为弥漫性大B细胞淋巴瘤,结合临床及影像学表现,符合原发性中枢神经系统淋巴瘤、LC.结论 LC为累及中枢神经系统的弥漫性病变,以白质受累为主,亚急性或快速进展的认知功能障碍为其显著临床特征,涉及的鉴别诊断复杂多样,立体定向穿刺活检为获得确定诊断提供了可能性,尽早明确病理诊断是确保临床进行精准治疗的关键.

Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient’s status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy.

目的 探讨筛状神经上皮肿瘤的临床病理特征与鉴别诊断.方法 回顾性分析1例筛状神经上皮肿瘤患者的临床病理特征、免疫组织化学染色及分子病理学特征,并复习相关文献.结果 患者男性,11个月时出现恶心、呕吐,头颅CT提示第四脑室占位性病变,行第四脑室肿瘤部分切除术,术后11个月肿瘤复发,MRI见第四脑室不规则巨大囊实性混合肿块,再次行第四脑室及脑干病损切除术.镜下见肿瘤细胞成筛状、腺管状及乳头状浸润性生长,局灶伴坏死.免疫组化染色显示肿瘤细胞CK、EMA弥漫阳性,SMARCB1表达缺失,E-cadherin阴性,二代测序检测证实SMARCB1基因7号外显子杂合性缺失,诊断:筛状神经上皮肿瘤.结论 筛状神经上皮肿瘤是一种SMARCB1缺失的非横纹肌样罕见肿瘤,具有独特的神经病理学和临床特征,需要与脉络丛癌、不典型畸胎样/横纹肌样瘤鉴别.

BACKGROUND:Meningeal carcinomatosis is mainly associated with breast cancer, lung cancer, and melanoma. However, meningeal carcinomatosis secondary to a neurenteric cyst with malignant features is extremely rare.CASE PRESENTATION:We report the case of a 35-year-old woman who was admitted to the hospital with a 10-month history of headache, 6-month history of diplopia, 4-month history of hearing loss, and 1-month history of back pain, suggesting a diagnosis of chronic meningitis. Notably, enhanced brain and spinal cord magnetic resonance imaging (MRI) revealed extensive lesions with enhancement signals in the pia mater of the pons and cervical, thoracic, and lumbar spinal cord. The cerebral spinal fluid profile showed that pressure was significantly elevated, with a slight increase in leukocytes that mostly comprised mononuclear cells and decreased glucose concentration. Cytology evaluation showed a small cluster of atypical nuclei, which were suspected to be tumor cells arising from the epithelium. However, no primary tumor was found through comprehensive body and skin screening. After a histopathological biopsy of subarachnoid meninx of the thoracic spinal canal, the cause of meningeal carcinomatosis of this patient was determined as neurenteric cysts with malignant features, which is extremely rare.CONCLUSION:This is the first case to ever report neurenteric cysts as a cause of leptomeningeal carcinomatosis and the first ever report of neurenteric cysts presenting as leptomeningeal carcinomatosis without typical cyst visible on brain MRI. This extremely rare case provided a novel view on the pathogenesis of meningeal carcinomatosis and clinical presentation of neurenteric cysts, highlighting the value of meningeal biopsy in chronic meningitis of unknown causes.

目的 探讨脂肪神经细胞瘤的临床病理学特征、诊断及鉴别诊断要点.方法 选取2011年6月至2020年3月首都医科大学宣武医院病理科和福建医科大学附属第一医院病理科诊断的脂肪神经细胞瘤9例,回顾性分析患者的临床资料、影像学特征、病理学特点、免疫表型及预后.结果 9例患者中,男4例,女5例,年龄5～63岁,首发症状为头痛、头晕伴恶心呕吐8例,行走不稳1例.影像学显示,7例病灶位于小脑半球,1例病灶位于侧脑室,均为单发肿块;另有1例病灶位于侧脑室和延髓,为多发性病变.组织学表现由小而一致的神经元和脂肪样细胞组成.1例肿瘤细胞具有异型性,局部核分裂象易见,诊断为WHO 2～3级;2例肿瘤细胞异型性明显,可见血管内皮细胞增生及小灶状坏死,呈非典型脂肪神经细胞瘤形态,诊断为WHO 3级.免疫组化结果显示,9例肿瘤细胞均弥漫表达CD56、突触素(Syn)和神经元特异性烯醇化酶(neuron specific enolase,NSE),8例肿瘤细胞局灶表达巢蛋白(Nestin),5例肿瘤细胞局灶或弥漫表达胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP),2例肿瘤细胞局灶表达S-100蛋白,3例个别肿瘤细胞少突胶质细胞系转录因子-2(Olig-2)阳性;肿瘤细胞均不表达神经元核抗原(NeuN)、神经丝(neurofilament,NF)和上皮细胞膜抗原(epithelial membrane antigen,EMA).6例Ki-67增殖指数较低,为1％～4％,3例肿瘤细胞生长活跃的区域及呈非典型脂肪神经细胞瘤结构,Ki-67增殖指数为5％～20％.7例随访6～54个月,2例术后复发.结论 脂肪神经细胞瘤是一种罕见的中枢神经系统肿瘤,好发于小脑半球,确诊需结合组织病理学特点和免疫组化结果,需与中枢神经细胞瘤、脑室外神经细胞瘤及少突胶质细胞瘤鉴别.首要治疗方式为手术切除,患者预后良好.

随着神经影像学技术和神经外科技术尤其是外科手术机器人的发展和应用，立体定向活检手术逐渐成为神经系统疑难病例精确诊断的有力手段。病理科将接收越来越多的活检小标本，并面对各种各样的非肿瘤性病变以及处于早期的病变。病理医师如何迎接挑战，突破瓶颈？该文从神经病理基本病变的识别，紧密结合临床、影像及实验室检查以及密切关注分子生物学新进展三方面介绍作者在神经病理诊断实践中的体会。

Objective:To analyze the clinicopathological and molecular features and prognostic implications of adult isocitrate dehydrogenase wild type (IDH-wt) diffuse gliomas.Methods:A total of 87 cases of adult IDH-wt diffuse gliomas from 2016 to 2020 in Xuanwu Hospital of Capital Medical University were retrospectively collected. The clinicopathological characteristics and prognosis were analyzed. Molecular characteristics were also analyzed using Sanger sequencing and next generation sequencing.Results:There were 53 males and 34 females, aged from 19 to 78 years (mean 53 years). Histopathologically, there were 63 (72.4%) glioblastomas, 16 (18.4%) anaplastic astrocytomas, six (6.9%) diffuse astrocytomas, and one (1.1%) each of anaplastic oligodendrocytoma, and anaplastic oligodendroglioma. Common molecular genetic changes in IDH-wt gliomas included TERT promoter mutation which was found in 60 cases (69.0%); MGMT promoter methylation in 43 cases (49.4%); EGFR mutation in 38 cases (43.7%); PTEN mutation in 35 cases (40.2%) and TP53 mutation in 32 cases (36.8%). In addition, PDGFRA mutation was detected in 17 cases (19.5%), CDK4 amplification in 15 cases (17.2%) and MDM2 amplification in 11 cases (12.6%). In IDH-wt diffuse gliomas, there was no significant difference in the overall survival between TERT promoter, EGFR, PTEN, TP53, PDGFRA, CDK4, MDM2 mutations and the wild-type, since these gene mutations could co-occur in any case ( P>0.05). Also there was no significant difference in the overall survival between the WHO grade Ⅱ/Ⅲ gliomas and glioblastoma patients with these gene mutations ( P>0.05). Conclusions:TERT promoter, EGFR, PTEN, TP53, PDGFRA, CDK4 and MDM2 gene mutations are common molecular genetic changes in adult IDH-wt gliomas, and are associated with poor prognosis. It is suggested that these genes are potentially useful for predicting the prognosis and should be tested in adult IDH-wt gliomas.

Primary tumors of the spinal cord are rare, accounting for 3–6% of tumors in the central nervous system, particularly in children. KIAA1549-BRAF fusion is more common in pilocytic astrocytoma (PA) and IDH1 R132H mutation is rare in infratentorial tumors. Here, we report a 10-year-old male patient who presented with weakness in lower limbs that progressed to difficulty walking. Magnetic resonance imaging (MRI) revealed an intramedullary solid-cystic lesion from the medulla oblongata to the thoracic spin 4 level, with the expansion of the spinal cord. The lesion exhibited patchy enhancement at C4-T1, indicating a tentative diagnosis of astrocytoma. The patient underwent resection of the lesion in the spinal canal from the cervical 6 level to the thoracic 2 level. Histopathology confirmed diagnosis of astrocytoma, WHO grade 2. Genetic analysis showed both IDH1 R132H mutation and KIAA1549-BRAF fusion. Therefore, our integrated diagnosis was astrocytoma, IDH mutation, WHO grade 2. Its molecular analyses include IDH1 R132H mutation and KIAA1549-BRAF fusion. After the operation, the patient did not receive chemo- or radiotherapy, and underwent an aggressive rehabilitation regiment. Follow up 10 months later, symptoms improved. To our best knowledge, this is the first case of concomitant IDH mutation and BRAF fusion in pediatric spinal cord astrocytoma.

We present a rare case of an ETMR with co-occurrence of DICER1 and H3 K27M mutations.

Objective: To analyze the clinicopathological characteristics, diagnosis and prognosis of meningioangiomatosis (MA), and to investige the possible origion of spindle cells. Methods: Seventeen cases of MA were collected at Xuanwu Hospital of Capital Medical University and the First Affiliated Hospital of Fujian Medical University, from June 2012 to March 2020. The clinical manifestations, radiologic, histopathologic, immunohistochemical features and patients' outcome were analyzed. The presumed origin of spindle cells was evaluated by immunohistochemical staining. Results: Of the 17 patients, 9 were males and 8 were females. The age ranged from 3 to 56 years old. Thirteen patients presented with seizure as the initial symptom. The lesions were solitary and located in the cerebral cortex. Histopathologically, there were proliferation of small blood vessels and perivascular spindle cells in the cerebral cortex. The spindle cells had no obvious atypia, mitoses and necrosis. Four cases were combined with transitional meningioma. Immunohistochemically, the proliferative perivascular spindle cells were positive for vimentin in all cases, and focally positive for EMA and SSTR2. Ki-67 proliferation index was low. Neurofibrillary tangles were demonstrated by AT8. All 17 patients received surgical treatment and were followed up for one to 93 months. None had seizure attacks or tumor recurrence. Conclusions: MA is a rare slow-growing intracranial lesion, and the perivascular spindle cells could be derived from meningothelial cells, and MA is often associated with degeneration of the cerebral cortex and meningioma. The patients have good prognosis after surgical treatment.

Objective:To investigate the clinicopathological features, diagnosis and prognosis of diffuse leptomeningeal glioneuronal tumor (DLGNT).Methods:Five cases of DLGNT diagnosed from January 2016 to January 2020 were collected from Xuanwu Hospital, Capital Medical University. The clinical features, histopathologic characteristics, immunohistochemical and molecular genetic findings and prognosis were analyzed and the relevant literature was reviewed.Results:The five patients (two males and three females) were aged 2 to 52 years (median 11 years), and had history of increased intracranial pressure (headache and vomiting) or limb weakness. Three of them were younger than 16 years of age. The imaging studies showed diffuse intracranial and intraspinal nodular leptomeningeal thickening and enhancement, with or without parenchymal involvement. At times there were associated small cyst-like lesions. Imaging interpretations were inflammatory lesions in three cases and space occupying lesions in two. Microscopically, in three cases the tumors showed low to moderate cellularity, consisting of relatively monomorphous oligodendrocyte-like cells arranged in small nests or diffusely distribution. No mitosis and necrosis were observed. In two cases there were increased cellularity with a diffuse honeycomb pattern. The tumor showed mild to moderate polymorphism with hyperchromatic nuclei. Mitosis, endothelial vascular proliferation and glomeruloid vessels were seen. Necrosis was absent. The tumor cells in all five cases were positive for synaptophysin,Olig2 and negative for IDH1 and H3 K27M. GFAP was focally positive in four cases and only one case expressed NeuN partly. The Ki-67 labeling index was 1%-35%. BRAF fusion was detected in four cases. Genetic analysis showed solitary 1p deletion in two cases (2/5), while all cases were negative for 1p/19q co-deletion (0/5). The five patients were followed up for 13 to 28 months (median 15 month). One patient died after 27 months. There was no evidence of tumor progression in the remaining four patients.Conclusions:DLGNT is rare and easily confused with other central nervous system tumors and inflammatory lesions. Therefore, the diagnosis of DLGNT should be made based on comprehensive information including imaging, morphologic and corresponding immunohistochemical examinations and molecular genetics to avoid misdiagnosis and delay in management.