中枢神经系统血管母细胞瘤家系及基因学研究

目的探讨家族性中枢神经系统血管母细胞瘤(hemangioblastoma,HB)的临床特点及Von Hippel-Lin-dau(VHL)基因突变情况。方法对一个家族性中枢神经系统血管母细胞瘤所有成员进行临床资料收集及分析,绘制系谱图;并对家系成员进行VHL基因测序。结果该家系有5例患病,其中3例患者均行手术治疗,2例患者因该病死亡。VHL基因检测未发现VHL基因突变。结论早期发现及治疗能降低HB的危害,发现家族性HB应对家系成员进行普查,并行VHL基因检测,确诊为VHL病的患者需终生随访,以便及时处理复发或新发病灶。     

Genetic study of a large Chinese kindred with von Hippel-Lindau disease

Background Von HippeI-Lindau (VHL) disease is a heraditary cancer syndrome caused by germline mutations of the VHL tumor on the suppressor gene. This study was to show the clinical characteristics of a large Chinese kindred with yon HippeI-Lindau disease and to evaluate the role of the genetic test of VHL disease in the diagnosis of VHL disease and clinical screening of members of the VHL disease family.Methods DNA extracted from peripheral blood was amplified by PCR to three exons of the VHL gene in 27 members of a large kindred with VHL disease. PCR products were directly sequenced. The involvements of multi-organs in the kindred with VHL disease were confirmed by history taking and radiography.Results Of 47 members in the four generations of the kindred, 18 members were diagnosed as having VHL desease. Clinical manifestations of 18 patients included: central nervous system (CNS)hemangioblastoma (5), renal cell carcinoma and CNS hemangioblastoma (3), renal cell carcinoma and retinal angioma (3), renal cell carcinoma and multiple pancreatic cysts (1), renal cell carcinoma and retinal angioma and multiple pancreatic cysts (2), renal cell carcinoma and CNS hemangioblastomas and multiple pancreatic cysts (1), and multiple pancreatic cysts and multiple renal cysts (1), multiple pancreatic cysts (2). The common lesions of the 18 patients were renal cell carcinoma (55.6%), CNS hemangioblastoma (50.0%), retinal angioma (27.8%), and multiple pancreatic cysts (38.9%). Among the 27 members who volunteered for genetic analysis, 15 members including 9 affected family patients and 2 asymptomatic patients and 4 carriers, who are still alive, presented a codon 78 from Asn to Ser change at nucleotide 446 (A→G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic patients were initially diagnosed by genetic testing and subsequently confirmed radiologically and surgically. Members without gene mutation had no clinical evidence of VHL disease.Conclusions The large Chinese kindred with VHL disease was classified as type I . The main characteristics in the kindred were higher incidence of renal cell carcinoma and lower incidence of retinal angioma. Genetic test plays an important role in early detecting asymptomatic patients and the carriers in clinical screening of members of the families with VHL disease. It is also important to prevent the transmission of VHL disease to their offsprings in the kindred.     

Molecular basis of von Hippel-Lindau syndrome in Chinese patients

Background  Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families.

Methods  Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA).

Results  The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM_000551.2: c.463+1G>T, was novel. The other seven VHL mutations, c.233A>G [p.Asn78Ser], c.239G>T [p.Ser80Ile], c.319C>G [p.Arg107Gly], c.481C>T [p.Arg161X], c.482G>A [p.Arg161Gln], c.499C>T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation.

Conclusions  Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families. 

     

结合临床特征探讨腹部超声在诊断Von-Hippel-Lindau综合征中的作用

目的 分析Von-Hippel-Lindau(VHL)综合征的临床特征,探讨腹部超声在诊断VHL综合征中的作用。方法 回顾性分析1994年1月至2017年12月在北京协和医院收治的35例VHL综合征患者的临床资料,包括首诊年龄、症状、体征、受累脏器、手术次数、检查方法等,分析腹部超声对诊断VHL综合征的作用。 结果 35例患者中,嗜铬细胞瘤(14例)及神经系统血管母细胞瘤(13例)为常见的首发肿瘤,神经系统血管母细胞瘤(21例)、嗜铬细胞瘤(19例)、肾癌(17例)及胰腺占位(15例)为常见的肿瘤。主要手术原因为神经系统血管母细胞瘤(22例次)、嗜铬细胞瘤(23例次)及肾癌(13例次)。33例患者腹部脏器受累,20例(60.6%)首次被腹部超声发现,其中6例为健康体检时发现。行肾上腺超声33次,27次诊断准确。行胰腺超声16次,13次诊断准确。行肾脏超声19次,8次诊断准确。结论 当超声发现肾脏、肾上腺、胰腺等部位的多发肿瘤时,超声医师要仔细询问家族史和神经系统疾病史,考虑VHL综合征的可能性。当临床提示存在VHL综合征时,超声能够发现及诊断腹部肿瘤,同时可以用于长期随访观察肿瘤的变化。超声是VHL综合征腹部疾病筛查和随诊的重要手段。     

VHL基因研究与中枢神经系统血管网状细胞瘤

希佩尔-林道病(Von Hippel-Lindau,VHL)是一种常染色体显性遗传病,以发生中枢神经系统和其他内脏器官多系统肿瘤为特征。VHL基因是重要的肿瘤抑制基因,VHL基因突变导致VHL蛋白及pVHL-ElonginC-Elongin B-Cul2复合物形成障碍,引起形成富血管肿瘤重要步骤的缺氧诱导因子功能障碍,导致肿瘤发生。发生中枢神经系统血管网状细胞瘤是VHL病中的常见事件。     

Screening for von Hippel-Lindau disease by DNA polymorphism analysis.

OBJECTIVE--Von Hippel-Lindau (VHL) disease is a rare, inherited multisystem neoplastic disorder. There is no biochemical test available to distinguish VHL disease gene carriers from their healthy siblings. We evaluated DNA polymorphism analysis as a method for identifying disease gene carriers. DESIGN--Prospective comparison of the results of DNA analysis with a comprehensive clinical screening examination. SETTING--The Clinical Center of the National Institutes of Health. PATIENTS--Blood was collected from 182 members of 16 families with VHL disease. Forty-eight asymptomatic individuals, at risk of developing this hereditary illness (with an affected parent or sibling), were examined for occult disease at the Clinical Center of the National Institutes of Health and tested by DNA polymorphism analysis. RESULTS--DNA polymorphism analysis predicted nine disease gene carriers and 33 individuals with the wild-type (normal) allele among the 48 individuals at risk of developing VHL disease; the test was not informative in six individuals. All nine individuals predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 individuals predicted to carry the wild-type allele. CONCLUSIONS--DNA polymorphism analysis can identify individuals likely to carry the VHL disease gene among asymptomatic members of disease families. This technique serves to focus attention on those individuals who require periodic medical examination and may help to alleviate the morbidity and mortality associated with this disease.     

老年肿瘤患者合并术后认知功能障碍的影响因素及诊断防治策略

术后认知功能障碍(POCD)是患者在全身麻醉和手术后出现的中枢神经系统损害.老年肿瘤患者由于肿瘤本身原因、年龄、合并多种内科疾病等因素,在全身麻醉后更容易发生POCD.本文综合评述了老年肿瘤患者术后并发POCD的常见诱因、病理生理改变、临床表现、诊断要点、治疗及预防等.     

儿童原发性中枢神经系统肿瘤763例临床分析

目的对儿童原发性中枢神经系统肿瘤的发病情况作分析调查。方法回顾性分析763例18岁以下儿童原发性中枢神经系统肿瘤病例的年龄和性别的分布情况与肿瘤的发生部位、病理学类型和分级。结果763例患儿的平均年龄为12．7岁,男女比例为1．56：1。其中颅内肿瘤占93．4％（713／763）,脊髓肿瘤占6．6％（50／763）。颅内肿瘤中,相对于幕下肿瘤（30．5％,233／763）来说,以幕上（包括松果体一四叠体区）的肿瘤（62．4％,476／763）为主。本组病例中,经病理学诊断患儿为688例,经临床诊断患儿35例。其中最常见的5种肿瘤分别为：星形细胞肿瘤（25．7％,177／688）．颅咽管瘤（12．8％,88／688）,髓母细胞瘤（9．3％,64／688）,生殖细胞肿瘤（8．9％,61／688）,垂体瘤（7．5％,52／688）。结论儿童原发性中枢神经系统肿瘤的发病具有其特殊性,对其诊断与治疗有指导性。因此,根据儿童的特点处理原发性神经系统肿瘤,能够在尽可能保留神经系统功能的情况下．综合治疗病灶。     

VHL病并发双侧肾癌1例报告及文献复习

VHL病是一种家族性常染色体显性遗传性肿瘤病,病变可累及多个器官、表现多样,包括中枢神经系统血管母细胞瘤、内脏肿瘤和内脏多发囊肿等。对本病的了解将有助于对本病的及时诊断,避免误诊和漏诊该病。本文将报道1例并发双侧肾癌的VHL患者并结合文献阐述VHL病的临床特点、诊断方法以及治疗。     

超微超顺磁性氧化铁在中枢神经系统疾病磁共振影像诊断中的应用

超微超顺磁性氧化铁(USPIO)作为磁共振对比剂具有血浆半衰期长、能够特异性结合巨噬细胞两个重要特性。相对于目前临床普遍使用的钆螯合物对比剂,USPIO对部分中枢神经系统疾病的诊断具有一些独特的优势,但仍有待进一步的临床研究确证。本文就近年来USPIO在部分中枢神经系统疾病磁共振影像诊断中的应用研究进展作一综述。     

Neurologic manifestations of von Hippel-Lindau disease

John A. Butman, MD, PhD; W. Marston Linehan, MD; Russell R. Lonser, MD

JAMA. 2008;300(11):1334-1342.

von Hippel-Lindau disease (VHL) is an autosomal-dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. Patients with VHL are predisposed to develop lesions of the central nervous system and viscera. Central nervous system lesions include hemangioblastomas (the most common tumor in VHL) and endolymphatic sac tumors (ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas, and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in patients with VHL. Recent molecular biologic investigations into these VHL-associated central nervous system lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different.

     

病例式教学在中枢神经系统肿瘤病理教学中的应用

目的：探讨在中枢神经系统肿瘤病理的教学中应用病例式教学模式的意义.方法：选取北京市神经外科研究所神经病理室存档神经系统肿瘤病例160例,其中常见多发肿瘤100例;疑难肿瘤25例;误诊病例5例;WHO新分类的神经系统肿瘤10例;考核病例20例.结果：通过考核病例检验,年轻医师及进修医师诊断正确率达到95％以上.结论：在神经系统肿瘤教学中,应用病例式教学法有助于学生从临床、影像、病理三方面加深对病变的了解,有助于提高学生的临床工作能力及诊断水平.     

磁共振波谱在脑肿瘤诊断和治疗中的应用

磁共振波谱(MRS)是一种新兴的无创性体内观察组织代谢的方法，在脑肿瘤的基础和临床研究中具有重要价值。作者重点综述MRS在脑肿瘤诊断和鉴别诊断、治疗决策和疗效评价以及鉴别肿瘤复发与放射治疗后坏死方面的新进展。     

中枢神经细胞瘤的临床病理特点和治疗

目的中枢神经细胞瘤(CNC)是一种分化程度较高的良性神经系统肿瘤,好发于青壮年,本文报道3例中枢神经细胞瘤,结合文献探讨中枢神经细胞瘤的临床病理特点和治疗.方法回顾性分析2002年9月～2004年2月我科收治的3例中枢神经细胞瘤,结合文献进行探讨.结果 2例位于侧脑室,1例位于透明膈;组织学特点为:肿瘤由密集和均匀一致的少突胶质细胞样小圆细胞及成片的无核纤细原纤维岛间质组成.未见异型增生及坏死.免疫组化2例突触素(Syn)阳性,1例突触素(Syn)可疑阳性,3例胶质纤维酸性蛋白(GFAP)阴性.3例均行显微镜下全切或大部分切除,术后行放射治疗.随访至今均未复发.结论中枢神经细胞瘤是好发于脑室内的分化好的神经元性肿瘤,病理形态易误诊为少突胶质细胞瘤、室管膜瘤和神经母细胞瘤.免疫组化检查Syn和GFAP在中枢神经细胞瘤的诊断和鉴别诊断中起重要作用.外科手术和术后放疗是常规的治疗手段,预后良好.     

颅内原发性中枢神经系统淋巴瘤的MRI诊断

目的探讨颅内原定性中枢神经系统淋巴瘸（Primary Central Nervous System Lymphoma．PCNSL）的MRI特征及病理学表现,以提高对该病的诊断准确性。方法回顾性分析经病理证实的15例颅内的PCNSL的MRI特征,所有病例均行MR平扫加增强扫描。结果10例为单发,5例多发。肿瘤多呈类圆形、浅分叶状或无固定的形态：MRI平扫T1WI上呈等或稍低信号,T2WI呈稍低、等或稍高信号：1例可见大片状长T1长T2囊变坏死区。增强扫描病灶多明显均匀强化,呈团块状、结节状、片絮状或无固定的形状,边缘不规整：1例呈环形强化,内部囊变坏死区无强化。5例可见“缺口征”、“脐凹征”,1例见“尖角征”．结论颅内PCNSL的MRI表现具有一定的特征性,仔细分析可提高其诊断准确性。     

Hereditary non-polyposis colorectal cancer (HNPCC): new germline mutation (190-191 del AA) in the human MLH1 gene and review of clinical guidelines for surveillance of affected families

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common genetic diseases comprising at least 5-6% of all colorectal cancers. It is characterized by early onset and mostly right-sided tumors (proximal to the splenic flexure). Molecular analyses are useful methods for diagnosis in index patients and for the detection of risk persons in affected families. A 37-year-old female patient whose family history fulfilled the criteria for hereditary non-polyposis colorectal cancer (HNPCC) was studied using PCR and DNA sequencing for the detection of mutations in the mismatch repair genes hMSH2 and hMLH1. Additionally, literature was reviewed (MEDLINE research until 2000) concerning clinical guidelines for surveillance in HNPCC families. A new deletion of two adenosine nucleotides (190-191 del AA) at codon 64 in exon 2 of the hMLH1 gene was found. The frameshift led to a stop codon at amino acid position 75. This mutation is considered to be disease causing in the development of the colorectal cancer of this family. Six publications with detailed recommendations for the surveillance of risk persons were found in the literature. Following their guidelines, colonoscopy is recommended from 20-30 years on for members of a family who fulfills either the Amsterdam criteria or the Bethesda criteria in combination with a detection of microsatellite instability. Female risk persons should be investigated gynecologically, including a transvaginal ultrasound examination, from 25-35 years on for the early detection of endometrial or ovarian cancer. Recommendations for gastroscopy, abdominal ultrasound examination and urine analysis are not given in all publications. Genetic counseling is recommended from 18 years on for all members of affected families.     

CT联合MRI在中枢神经脱髓鞘疾病诊断中的价值分析

目的分析CT、MRI在中枢神经脱髓鞘疾病诊断中的临床价值。方法回顾性分析我院20例拟诊断为中枢神经脱髓鞘疾病患者的临床资料,所有患者均接受CT或(和)MRI检查,并行手术治疗。以手术病理结果为金标准,评价CT、MRI诊断中枢神经脱髓鞘疾病灵敏度、特异度、阳(阴)性预测值和Kappa值,并比较两种成像学方法的影像表现。结果 CT诊断中枢神经脱髓鞘疾病的灵敏度为0.667,特异度为0.500,准确度为0.636,阳性预测值为0.857,阴性预测值为0.250,Kappa值为0.120,CT与手术结果的一致性较差;MRI诊断中枢神经脱髓鞘疾病的灵敏度为0.909,特异度为0.500,准确度为0.846,阳性预测值为0.909,阴性预测值为0.500,Kappa值为0.409,CT与手术结果的一致性一般;CT诊断异常率为63.64%,MRI诊断异常率为84.62%;CT平扫示轻度水肿与占位效应,难以与中枢神经系统肿瘤相鉴别,MRI病变周围水肿较CT显示更为清晰。结论 CT、MRI可对中枢神经脱髓鞘疾病进行有效诊断,且MRI诊断效果优于CT,但对于非典型病例,其影像学表现不具有特征性,应结合临床、病程、病理、实验室检查等多方面进行鉴别。     

中枢神经系统孤立性纤维瘤的MRI特征及鉴别诊断

目的探讨中枢神经系统孤立性纤维瘤(SFT)MRI表现特征,提高对该病的正确诊断及鉴别诊断水平。方法收集8例经手术病理证实的SFT,其中6例为颅内SFT、2例为椎管内SFT,分析其部位、形态大小、信号特点及邻近脑膜和骨质改变等。结果 6例颅内SFT位于幕上,2例椎管内SFT位于颈段和胸段的硬膜下。肿瘤在T1WI多呈等或稍低信号,T2WI多呈稍高信号,内可见短T2信号和流空血管影,所有病灶增强扫描后均呈明显强化。1例颅内STF可见"脑膜尾征",2例椎管内SFT未见"脊膜尾征",2例颅内SFT邻近骨质受压变薄。6例颅内SFT在DWI上分别呈稍低信号、等信号和稍高信号。结论 MRI对中枢神经系统SFT的诊断及鉴别诊断具有一定的价值。     

颅内血管母细胞瘤的临床分析

目的:探讨不同类型颅内血管母细胞瘤头颅CT、MRI影像特征以及临床特点。方法:采用回顾方法对102例经手术和病理证实的脑血管母细胞瘤进行临床、影像学分析及手术疗效总结。结果:囊腔结节型脑血管母细胞瘤典型表现为囊腔大、结节小及结节显著异常强化;实质性脑血管母细胞瘤信号强度在T2W2明显增高,增强后显著强化。瘤内或瘤周可见血管流空信号。102例手术119次,切瘤126枚,肿瘤全切除114枚,治愈率81.4%,合并VHL术后复发率60.0%(6/10)明显高于散发性5.4%(5/92)。结论:CT和MRI是诊断脑血管母细胞瘤的有效方法,尤其是多轴位成像及增强扫描可避免肿瘤及壁结节漏诊。合并VHL病及多灶病变较散发性脑血管母细胞瘤易复发,易产生新病灶且预后差,应终身随访和定期影像学检查,以便发现新病灶。     

神经系统黑色素瘤7例临床分析

目的 探讨神经系统黑色素瘤的诊断和治疗。方法 分析自1978年至2003年收治的7例神经系统黑色素瘤的临床表现、外科治疗和预后情况。结果 4例体表有黑色素痣,其余临床表现无特异性。6例患者均全部切除病灶。病理检查确诊转移性黑色素瘤6例,原发性黑色素瘤1例。对4例患者随访,3例患者术后3～11个月复发,其中1例行二次手术,4例均在术后3～14个月死亡。结论 神经系统黑色素瘤发病率低,术前误诊率高,治疗以手术切除为主,结合立体定向放射外科治疗。本病预后差。