Evaluating the cerebrospinal fluid ctDNA detection by next-generation sequencing in the diagnosis of meningeal Carcinomatosis

Abstract

BackgroundMeningeal 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.MethodsA 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.ResultsThe 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.ConclusionsThis 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.

Evaluating Infectious, Neoplastic, Immunological, and Degenerative Diseases of the Central Nervous System with Cerebrospinal Fluid-Based Next-Generation Sequencing

“…In addition, CSF liquid biopsy does not suffer from the inherent problems of tissue biopsy that commonly hamper subsequent molecular analysis, such as inadequacy and formalin fixation, and could depict intra-tumor heterogeneity more comprehensively, especially when compared to small biopsies [ 62 , 63 , 66 , 193 ]. Likewise, it exhibits higher sensitivity to detect leptomeningeal metastases than imaging or CSF cytology [ 62 , 95 – 98 ]. Evidence suggests that CSF liquid biopsy should be favored over its plasma counterpart when evaluating a CNS tumor, either primary or metastatic, as it shows a higher concentration of ctDNA and a higher mutation detection rate, and it depicts the CNS lesion molecular profile more accurately, especially when dealing with brain metastases.…”

“…Diagnosis and follow-up of metastatic CNS lesions are typically performed with neuroimaging and CSF cytology; however, the latter suffer from low sensitivity [ 93 , 94 ]. NGS was found to outweigh the diagnostic performance of imaging and cytology in terms of sensitivity for the detection of brain metastases [ 62 , 95 – 98 ]. It was also able to detect targetable mutations in metastatic lung (e.g., EGFR , ALK , or ROS1 ) [ 62 , 96 , 97 , 99 – 102 ], melanoma [ 95 – 97 ], and breast cancer [ 96 ], also identify mechanisms of acquired resistance to therapy, such as the EGFR T790M mutation [ 96 , 103 – 106 ].…”

Leptomeningeal Carcinomatosis: A Clinical Dilemma in Neuroendocrine Neoplasms

“…Interestingly, new approaches have been introduced recently to improve the diagnostic accuracy of CSF. Circulating tumor DNA (ctDNA) might be promising but is not ubiquitously accessible [ 33 , 34 ]. Our patient collective also reflects the difficulty of accurately diagnosing LC.…”

ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

“…However, up to 20% of patients with positive clinical and radiographic signs presented false-negative CSF cytology [ 72 , 73 ]. Several studies have shown that ctDNA can be detected in the CSF of patients with negative cytology analysis [ 20 , 27 , 32 , 74 ]. Cytology has limited sensitivity, and the analysis of ctDNA can complement the diagnosis of leptomeningeal metastases.…”