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

Yue Zhao,Jun-Zhao Cui,Yue-Li Zou,Xiao-Su Guo,Jun-Ying He,Hui Bu,Li Guo

doi:10.1186/s12883-019-1554-5

Yue Zhao, Jun-Zhao Cui + Show 5 more

Open Access

https://doi.org/10.1186/s12883-019-1554-5

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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.

Highlights

Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality
The presence of neoplastic cells in the cerebrospinal fluid (CSF) is the most useful finding to confirm the diagnosis and CSF cytology remains the gold diagnostic standard, but 25–30% of suspected clinical cases with MC diagnosed based on clinical picture and neuroimaging findings will not be confirmed by this method [3, 4]
The positive rate of CSF cytology for neoplastic cells will increase with the number of punctures, the false negative rate is still high, due to the similarity between tumor cells and ependymal cells, contamination by blood brought about by multiple punctures, difficulty of the distinction lymphoma cells caused by viral infections of central nervous system (CNS), few tumor cells in the collected specimen and inadequate preparation of the sample [5]

Summary

Introduction

Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. The diagnosis of MC is routinely confirmed on the basis of clinical manifestation, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging features. Meningeal carcinomatosis (MC), called neoplastic meningitis (NM) is the most severe form of brain metastasis and causes significant morbidity and mortality [1]. MC is to be missed in diagnosis and misdiagnosed because of diverse clinical manifestations and the lack of sensitive and specific diagnostic tools, which has presented difficulties for early treatment of patients with MC [2]. The diagnosis of MC is routinely confirmed on the basis of clinical signs and symptoms, cerebrospinal fluid (CSF) cytology, and/or neuroimaging (contrast-enhanced brain MRI and/or CT) findings [2]. It is important to evaluate an alternative method for diagnosis of MC especially for cases with persistently negative CSF cytology and/or persistently negative neuroimaging results

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