汤武装 张丽 张晓雷 胡秀秀

脑膜癌病25例临床分析

汤武装 张丽 张晓雷 胡秀秀

目的 探讨脑膜癌病的临床特点和诊断依据。 方法 对25例确诊为脑膜癌病患者的临床资料及脑脊液细胞学资料进行回顾性分析。结果 25例脑膜癌病患者中, 临床表现为头痛24例, 恶心、呕吐21例, 脑膜刺激征阳性20例, 视乳头水肿12例, 意识障碍6例, 四肢无力6例, 视力减退5例,癫痫发作5例, 精神症状5例, 听力障碍3例, 头晕3例, 发热2例, 颈痛1例；20例患者头颅CT/MRI均未见脑膜异常, 5例行头颅MRI增强扫描可见2例脑膜强化, 1例脑皮质肿胀, 1例脑积水, 1例小脑蚓部左侧可疑结节；腰椎穿刺脑脊液压力升高12例, 蛋白升高16例, 糖、氯降低14例, 23例患者行脑脊液细胞学检查均发现异型细胞, 17例患者行脑脊液免疫组化染色均发现转移癌；17例患者经临床及病理学确定其原发肿瘤, 来源于肺癌10例(其中1例肺癌合并前颊黏膜鳞癌)、胃癌3例、贲门癌2、乳腺癌1例、可疑卵巢癌1例, 8例来源未明。结论 脑膜癌病为恶性肿瘤颅内转移的特殊形式, 临床表现复杂, 缺乏特异性, 早期以颅内压升高为主；头颅MRI增强扫描对脑膜癌病诊断有一定指导意义；脑脊液细胞学检查结合免疫组化染色是脑膜癌病确诊的主要依据。

脑膜癌病；脑脊液细胞学；免疫细胞组化；MRI增强扫描

脑膜癌病(meningeal carcinomatosis, MC)亦称癌性脑膜炎,是指脑和脊髓的软膜内转移性肿瘤细胞弥漫播散或呈多数的局灶性浸润, 临床表现脑、颅神经和脊髓受损的症状, 为中枢神经系统转移癌的一种特殊分布类型, 在实体肿瘤患者中发生率约为5%［1］。该病起病隐匿, 临床表现及影像学检查均缺乏特异性, 易于误诊和漏诊。以往认为MC很少见, 近年来随着临床认识水平的提高, 以及癌症患者生存期的延长,使得MC的发病率也呈明显上升趋势。本文对南京脑科医院近年来收治的25例脑膜癌病患者临床资料进行回顾性分析如下。

1 临床资料

1.1 一般资料 收集2006年11月～2011年5月南京医科大学附属脑科医院神经内科住院的, 经脑脊液细胞学确诊的脑膜癌病患者25例, 其中男11例, 女14例；年龄32～64岁,平均 (52±7.72)岁, 其中＞50岁15例(60%)；病程3～300 d,平均(41.5±8.1)d。7例患者既往有明确的恶性肿瘤病史, 包括胃癌3例, 贲门癌、肺癌、前颊黏膜鳞癌、乳腺癌各1例。

1.2 临床表现与体征 起病形式多为亚急性(18例病程≤30 d)或慢性起病, 病情进展较快, 首发症状为头痛24例(96%), 恶心、呕吐21例(84%), 头晕3例(12%), 发热2例(8%)。临床有意识障碍6例(24%), 四肢无力6例(24%), 视力减退5例(20%), 癫痫发作5例(20%), 精神症状5例(20%), 听力障碍3例(12%), 头昏1例(4%), 颈痛1例(4%)；脑膜刺激征阳性20例(80%)、可疑阳性1例(4%), 视乳头水肿12例(48%)。

1.3 影像学检查 20例患者头颅CT和(或)头颅MRI平扫均未发现脑膜异常信号, 仅5例为多发性腔隙性脑梗死, 2例右额叶异常信号, 1例枕大池囊肿, 1例脱髓鞘脑病, 1例第五、第六脑室形成, 余10例未见明显异常；5例行头颅MRI增强扫描, 其中2例脑膜强化, 1例脑皮质肿胀, 1例脑积水伴右颞叶软化, 1例小脑蚓部左侧可疑结节；4例行头颅静脉血管成像(MRV)检查, 均未见异常。

1.4 脑脊液检查 25例患者均行腰椎穿刺脑脊液(cerebrospinal fluid, CSF) 检查, CSF压力≥200 mmH2O 13例(52%), 正常10例, 2例未测压。CSF白细胞升高［(10～70)×106/L］ 8例(32%)；蛋白含量增高16例(64%), 正常8例, 降低1例；糖及氯化物降低14例(56%), 正常11例(44%)。细胞学检查发现异型细胞23例(92%), 其中17例行CSF细胞免疫组化染色均发现转移癌。

1.5 原发肿瘤来源 根据病史、临床表现及相关病理学检查等寻找原发肿瘤来源, 本组25例MC患者中, 有17例患者(68%)找到原发肿瘤, 来源于肺癌10例(其中1例合并前颊黏膜鳞癌)、胃癌3例、贲门癌2例、乳腺癌1例、可疑卵巢癌1例；8例患者未查明原发肿瘤, 其中7例血清CEA明显升高, 3例血清CA199明显升高。

2 讨论

脑膜癌病是指原发病灶的癌细胞选择性浸润软脑膜、脑和脊髓蛛网膜下腔, 并随血管周围间隙侵入脑皮质引起的一系列临床综合征。肿瘤细胞通过血行转移或淋巴转移种植播散, 脑膜转移的原发恶性肿瘤可来自中枢神经系统, 也可来源于中枢神经系统以外。前者多见于室管膜癌、弥漫性脑膜胶质瘤［2］、中枢神经系统淋巴瘤［3］等。后者以肺癌、胃肠道癌、乳腺癌、黑色素瘤最常见［4,5］。报道指出仍有大约20%～40%的脑膜癌病原发病灶不明［6］。本组患者均为神经系统以外的恶性肿瘤转移, 以肺癌最为多见, 占40%, 其次为消化道肿瘤,占20%, 乳腺癌占5%, 基本符合转移规律, 本组25例脑膜癌病患者8例来源未明(32%), 结果与既往研究［6］基本相符。

脑膜癌病病理上为肿瘤细胞广泛浸润软脑膜, 颅底神经根和腰骶神经根也是易受累部位。因此脑膜癌病主要有脑部症状、颅神经症状、脊神经症状等三组表现。肿瘤细胞转移到脑膜后引发局部炎性反应, 影响到CSF的循环及颅内压力改变, 因此头痛、恶心呕吐、脑膜刺激征是患者最常见的表现［7］。颅高压或脑膜转移性病灶刺激皮质可能导致痫性发作；过高的颅内压可以抑制皮质功能, 造成精神症状及或意识障碍等。随着癌细胞沿软脑膜或脑脊膜的扩散, 侵犯颅神经和脊神经根而出现相应的临床表现。本组25例患者中24例有头痛, 21例出现恶心呕吐, 6例存在意识障碍, 癫痫发作5例,精神症状5例, 头晕3例, 脑膜刺激征阳性者20例, 可疑阳性1例, 视乳头水肿12例。即几乎所有病例均以脑部症状起病, 且以颅内压升高为突出表现。本组5例视力减退, 听力障碍3例, 以第Ⅱ、Ⅸ对颅神经受累为主；1例颈痛为脊神经根受累表现。

影像学检查对脑膜癌病诊断帮助有限, 头颅CT/MRI平扫阳性率不高, 且定性困难［8］, 头颅MRI增强扫描可提高阳性率。国外报道［9］经脑脊液细胞学病理证实的脑膜癌病患者中, 2/3头颅MRI增强有阳性发现。本组患者头颅CT或MRI平扫均未发现脑膜异常信号；5例头颅MRI增强扫描仅2例有脑膜强化, 另外3例分别表现为脑皮质肿胀、脑积水伴右颞叶软化及小脑蚓部左侧可疑结节。脑膜强化是由于肿瘤炎性反应, 脑膜内层血管高度扩张, 使血管通透性增加所致, 所以肿瘤转移早期时脑膜可以不强化。对脑膜癌病的早期诊断CT或MR平扫价值不高, 头颅MR增强扫描对诊断有一定的辅助作用。

脑脊液细胞学检查对脑膜癌病的诊断非常重要, 是主要的确诊依据。CSF细胞学检查发现肿瘤细胞是确诊脑膜癌病的金标准, 其敏感性为75%～90%, 特异性为100%［10］。本组25例患者CSF细胞学检查发现23例有异型细胞, 敏感性92%, 与文献报道［10］一致。常规及生化检查可见白细胞轻～中度增加, 蛋白升高16例(64%), 糖及氯化物降低14例(56%),这是由于癌细胞浸润破坏了血脑屏障导致CSF生成吸收障碍, 以及肿瘤代谢消耗所致。

CSF细胞学检查中的常规迈-格-姬(MGG)染色只能从形态学角度观察细胞, 对细胞的定性有很大局限性, 有时难以与慢性脑膜炎时出现的变性细胞鉴别, 而肿瘤细胞变性时也会失去其恶性的特性而难以辩认。免疫组化染色可明确细胞组织学性质, 补充单一细胞学检查的不足, 通过免疫组化染色与脑脊液细胞学检查结合可检出脑脊液细胞学检查阴性的病例, 明显提高了对癌细胞的检出率［12］。本组17例患者行CSF细胞免疫组化染色检查, 结果全部呈现典型染色,因此CSF细胞免疫组化染色检查与细胞学检查结合可提高脑膜癌病的诊断敏感性, 减少脑膜癌病的漏诊率。

本文为临床资料的回顾性分析, 样本量少, 存在一定的局限性。总之, 对中老年患者, 特别是有肿瘤病史者, 不明原因的颅内压升高, 定性困难的脑膜炎及临床表现多样而缺乏特异性的患者, 且头颅CT或MRI检查无明显异常者, 要考虑有脑膜癌病的可能。应尽早行反复的CSF细胞学检查,有条件的联合脑脊液免疫组织化学染色, 必要时行头颅MRI增强扫描, 并在此基础上进一步寻找原发灶, 做到早诊断早治疗, 避免漏诊和误诊。

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Clinical analysis of 25 cases of meningeal carcinomatosis

TANG Wu-zhuang,ZHANGli, ZHANG Xiao-lei,et al.
Department of Neurology, Yixing People’s Hospital Aftiliated to Jiangsu Universily,Yixing 214200, China

Objective To investigate the clinical features and diagnostic evidence of meningeal carcinomatosis (MC).Methods The clinical data and cerebrospinal fluid(CSF) cytology data of 25 cases diagnosed as meningeal carcinomatosis were retrospectively reviewed.Results In 25 patients of MC, there were 11 men and 14 women and the mean age was (52±7.72) years old.24 cases of patients with headache, 21 cases of patients with nausea and vomiting, meningeal irritation sign was positive in 20 cases, papilledema were found in 12 cases, disturbance of consciousness were found in 6 cases, four limbs weakness were found in 6 cases, vision loss were found in 5 cases, seizures were found in 5 cases, psychiatric symptoms were found in 5 cases, hearing-impaired were found in 3 cases, dizziness were found in 3 cases, fever were found in 2 cases, neck pain were found in 1 case.No meningeal enhancement were found in cranial CT and (or) cranial MRI scan among 20 patients, 5 patients underwent cranial MRI enhanced scan showed 2 cases of meningeal enhancement, 1 case of swelling of the cerebral cortex, 1 case of hydrocephalus and 1 case of the left cerebellar vermis suspicious nodules.CSF pressure increases in 12 cases, 16 cases of protein increase, and 14 cases of sugar and chlorine decrease.23 patients with CSF cytology were found atypical cells, and 17 patients with CSF immunohistochemical staining were found metastatic cancer.Primary tumor source of 17 patients were found by the clinical and pathological, 10 cases were diagnosed with lung cancer (from which 1 case was mergered former buccal mucosa squamous cell carcinoma), 3 cases were diagnosed with gastric cancer, 2 cases were diagnosed with cardia cancer, 1 case of breast cancer, 1 case of suspicious ovarian cancer, and 8 cases of unknown source.Conclusion MC is a special form of malignant brain metastases, clinical manifestations are complex but lack of specificity.The main manifestations are increased intracranial pressure in early stage.Cranial MRI enhanced scan may provide some referential value for the diagnosis of MC.CSF cytology combined with immunohistochemical staining is the main method to diagnose MC.

Meningeal carcinomatosis；Cerebrospinal fluid cytology；Immunohistochemical staining；MRI enhancement scanning

214200 江苏大学附属宜兴市人民医院神经内科(汤武装)；南京医科大学附属脑科医院老年神经科(张丽 张晓雷胡秀秀)

胡秀秀, E-mail：xxh198312@sina.com