BACKGROUND Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical manifestation, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease. Here we evaluate the CSF circulating tumor DNA (ctDNA) in the diagnosis of MC. METHODS A total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF ctDNA extraction and cancer-associated gene mutations detection by next-generation sequencing (NGS) at the same time. RESULTS The most frequent primary tumor in this study was lung cancer (26/35, 74%), followed by gastric cancer (2/35, 6%), breast cancer (2/35, 6%), prostatic cancer (1/35, 3%), parotid gland carcinoma (1/35, 3%) and lymphoma (1/35, 3%) while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty-five CSF samples (25/35; 71%) were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100%) were revealed having detectable ctDNA in which cancer-associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast-enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 63%) were consistent with MC. The sensitivity of the neuroimaging was 88% (95% confidence intervals [95% CI], 75 to 100) (p = 22/25) and 63% (95% CI, 47 to 79) (p = 22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71% (95% CI, 56 to 86) (n = 25/35) compared to that of CSF ctDNA. CONCLUSIONS This study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. We find cancer-associated gene mutations in ctDNA from CSF of patients with MC at 100% of our cohort, and utilizing CSF ctDNA as liquid biopsy technology based on the detection of cancer-associated gene mutations may give additional information to diagnose MC with negative CSF cytology and/or negative neuroimaging findings.

中文翻译：

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通过下一代测序评估脑脊液ctDNA检测在脑膜癌的诊断中的作用。

背景技术脑膜癌变（MC）是脑转移的最严重形式，并导致明显的发病率和死亡率。目前，根据临床表现，脑脊液（CSF）阳性细胞学检查和/或神经影像学特征可常规确诊MC。但是，脑脊液细胞学检查和神经影像学检查结果的阴性率通常会导致无法从实际患有该病的患者中诊断出MC。在这里，我们评估脑脊液循环肿瘤DNA（ctDNA）在MC的诊断中。方法从35例MC患者中收集35份CSF样本，同时进行CSF细胞学检查，CSF ctDNA提取和下一代测序（NGS）检测与癌症相关的基因突变。结果本研究中最常见的原发肿瘤是肺癌（26 / 35，74％），其次是胃癌（2/35，6％），乳腺癌（2/35，6％），前列腺癌（1/35，3％），腮腺癌（1/35，3％）和淋巴瘤（1 / 35，3％），尽管使用了各种检查方法，但其余2例患者中均未发现原发肿瘤。在CSF细胞学检查中发现了25份CSF样品（25/35; 71％），而所有35份CSF样品（35/35; 100％）都被发现具有可检测的ctDNA，其中检测到与癌症相关的基因突变。研究中的所有35名MC患者均接受了对比增强的脑部MRI和/或CT检查，其中22例神经影像学特征（22/35； 63％）与MC一致。相比之下，神经影像学的敏感性为88％（95％置信区间[95％CI]，为75至100）（p = 22/25）和63％（95％CI，47至79）（p = 22/35）分别对应于CSF细胞学和CSF ctDNA。与CSF ctDNA相比，CSF细胞学检查的敏感性为71％（95％CI，56至86）（n = 25/35）。结论这项研究表明，CSF ctDNA的敏感性要高于CSF细胞学和神经影像学检查结果。我们在100％的队列研究中发现了MC患者的CSF ctDNA中与癌症相关的基因突变，基于CSF ctDNA作为液体活检技术的基础上检测到与癌症相关的基因突变可能为诊断CSF阴性的MC提供更多信息细胞学检查和/或神经影像学检查阴性。