Division of Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston.
Cancer Center, Massachusetts General Hospital, Boston.
JAMA Netw Open. 2021 Aug 2;4(8):e2120040. doi: 10.1001/jamanetworkopen.2021.20040.
Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions.
To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis.
DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018.
The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection.
In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients.
This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.
脑膜疾病（LMD）是癌症的一种破坏性并发症，由于脑脊液（CSF）细胞学评估的敏感性低，目前是基准诊断方法，因此经常被误诊。提高诊断敏感性可能会导致治疗决策的改善。
评估脑脊液游离 DNA（cfDNA）分析是否比细胞学分析更能准确诊断 LMD。
设计、地点和参与者：这项在 2 家大型三级医疗中心的神经肿瘤科诊所进行的诊断性研究评估了从 2015 年至 2018 年期间 30 名疑似或确诊 LMD 患者的 CSF 样本中进行基因组测序，以识别肿瘤衍生的 cfDNA。从相同的 CSF 样本中进行了细胞学分析，并比较了这两种测试的结果。这项研究包括 2 个患者群体：22 名细胞学证实的 LMD 患者无实质肿瘤紧贴其 CSF，8 名有实质脑转移瘤而无 LMD 证据的患者。如果先前的 CSF 细胞学分析阳性提示存在恶性细胞，则认为存在 LMD。分析于 2015 年至 2018 年进行。
主要结局是 cfDNA 分析的诊断准确性，定义为正确诊断的测试次数与总测试次数之比。在数据收集之前就形成了假设。
共有 30 名患者（23 名女性[77%]；中位年龄 51 岁[范围，28-81 岁]）参与了这项研究，主要表现为转移性实体恶性肿瘤。对于以前通过细胞学分析诊断为 LMD 且无实质肿瘤紧贴 CSF 的 48 份随访样本，cfDNA 结果在评估 45 份（94%；95%CI，83%-99%）的 LMD 中是准确的，而细胞学分析在 36 份（75%；95%CI，60%-86%）中是准确的，差异有统计学意义（P=0.02）。在 43 份 LMD 阳性样本中，CSF cfDNA 分析对 40 份样本（93%；95%CI，81%-99%）的 LMD 敏感，而细胞学分析对 31 份样本（72%；95%CI，56%-85%）的 LMD 敏感，差异有统计学意义（P=0.02）。对于 3 名实质脑转移瘤紧贴 CSF 且无 LMD 可疑的患者，细胞学检查均未发现 LMD 阳性，而 cfDNA 检查均为阳性。
这项诊断性研究发现，cfDNA CSF 检测比细胞学评估的敏感性和准确性均有所提高，除了紧贴 CSF 的实质肿瘤外，这表明诊断 LMD 的能力有所提高。考虑将 CSF cfDNA 分析纳入临床护理是合理的。
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