[Auxiliary Diagnostic Value of Tumor Markers in the Cerebrospinal Fluid and Blood for Leptomeningeal Metastasis from Non-small Cell Lung Cancer]

Background: Leptomeningeal metastasis (LM) is one of the most common causes of death in patients with advanced non-small cell lung cancer (NSCLC), which is defined as malignant cells spreading to meninges and cerebrospinal fluid (CSF). Therefore, early diagnosis and timely treatment are essential. CSF cytology is the gold standard for LM diagnosis, however, it has a low sensitivity for diagnosis and can't be used to evaluate the treatment effect. The aim of this study was to assess the clinical value of serum and CSF tumor markers (TM) in the diagnosis and treatment of NSCLC patients with LM.

Methods: Nineteen patients with NSCLC-LM and 27 patients with nonmalignant neurological diseases (NMNDs) were included. We tested the levels and positive rates of carbohydrate antigen (CEA), carbohydrate antigen-125 (CA125), cytokeratin 19 fragments (CYFRA21-1) and neurone specific enolase (NSE) in CSF and serum, compared the sensitivity and specificity in the diagnosis of LM between different groups, and analyzed the correlation of detection between serum and CSF. Finally, we measured serum and CSF TM dynamically in 2 patients with NSCLC developing LM in an attempt to correlate these with the treatment response of extracranial and intracranial, respectively.

Results: The levels and positive rates of TM in CSF and serum in LM group were higher than those in NMNDs (P<0.05). In LM group, the levels of CEA, CYFRA21-1 and CEA were significantly higher in CSF than that in the serum (P<0.05), whereas, there was no statistical significance in positive rates of TM between CSF and serum (P>0.05). In CSF, CYFRA21-1 has the highest sensitivity (88.2%) and CEA has the best specificity (92.3%) to distinguish patients between LM and NMNDs. For combined detection of CEA, CA125, CYFRA 21-1 and NSE in CSF, when at least CEA or NSE was positive in patients with LM, the sensitivity and negative predictive value were 100.0%, and the specificity was 74.1%. When both CYFRA21-1 and NSE were positive, the specificity and positive predictive value were 100.0%, and the sensitivity was 78.9%. Furthermore, subgroup analysis showed that the detection rates of TM in CSF cytology positive population was higher than that in typical abnormalities magnetic resonance imaging population, but there was no statistical difference (P>0.05). The detection of TM between serum and CSF in LM patients had no significant correlation. Moreover, biochemical properties of CSF from ventricle and lumbar puncture are similar, therefore evaluating the levels of TM in serum and CSF dynamically can be used to assess the extracranial and intracranial treatment effect, respectively.

Conclusions: Our study demonstrates that Serum and CSF TM can work as an auxiliary clinical diagnostic tool, which has a potential value in early diagnosis of NSCLC patients with LM. Serial measurement of TM may play an important role in the clinical management of NSCLC patients with LM, which is worthy of further promotion and clinical application.

【中文题目：血清及脑脊液肿瘤标志物在非小细胞肺癌软脑膜转移辅助诊治中的价值】 【中文摘要：背景与目的 软脑膜转移（leptomeningeal metastasis, LM）是指恶性肿瘤细胞浸润软脑膜，并在脑脊液（cerebrospinal fluid, CSF）中播散，预后极差，是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者致死的重要原因之一，因此早期的诊断和及时的治疗具有重要意义，CSF细胞学是LM诊断的金标准，但常常伴随着检测敏感性低、无法评估疗效等问题。本文旨在探讨血清及CSF中肿瘤标志物（tumor markers, TM）在NSCLC伴LM患者诊治的临床价值。方法 选取NSCLC伴LM患者19例，另选同期27例神经系统良性肿瘤（nonmalignant neurological diseases, NMNDs）患者作为对照组。观察比较两组患者血清和CSF中癌胚抗原（carbohydrate antigen, CEA）、糖类抗原125（carbohydrate antigen-125, CA125）、细胞角蛋白19片断抗原（cytokeratin 19 fragments, CYFRA21-1）和神经元烯醇化酶（neurone specific enolase, NSE）检测水平和检出阳性率，比较不同组TM的敏感性和特异性，并分析血清与CSF中TM检出情况相关性，最后动态监测2例LM患者血清和CSF中TM水平，分别评估颅外和颅内治疗疗效。结果 LM组CSF和血清中TM水平和检出阳性率均高于对照组（P<0.05），同时LM组CSF中CEA、CYFRA21-1、NSE水平高于血清，差异有统计学意义（P<0.05）。CSF中TM检出阳性率与血清差异不具有统计学意义（P>0.05）。CSF中CYFRA21-1敏感性最高（88.2%），CEA特异性最好（92.3%），联合指标中CEA或NSE任一项超过临界值则敏感性和阴性预测值为100%，特异性为74.1%。CYFRA21-1和NSE同时超过临界值时特异性和阳性预测值为100%，敏感性为78.9%。亚组分析显示，CSF细胞学阳性人群TM检出阳性率超过有磁共振成像（magnetic resonance imaging, MRI）异常的人群，但不具有统计学差异（P>0.05）。LM组血清与CSF中TM检出阳性率不一致。另外，脑室中CSF与腰穿中CSF具有相同的生化性质，动态监测血清和CSF中TM浓度，可分别评估颅外和颅内病灶的疗效。结论 血清和CSF中TM为NSCLC伴LM患者增加了一个早期辅助诊断指标，动态监测可评估治疗疗效，值得临床推广应用。】 【中文关键词：肺肿瘤；软脑膜转移；脑脊液；肿瘤标志物；诊断】.

Keywords: Cerebrospinal fluid; Diagnosis; Leptomeningeal metastasis; Lung neoplasms; Tumor markers.