Abstract
BackgroundCytology remains the gold standard for the detection of malignant cells in ascites. However, its sensitivity is limited. The aim of this study was to evaluate DNA methylation biomarkers for the differential diagnosis of benign (ascites in patients without malignancy), malignant (ascites in cancer patients directly caused by malignancy), and paramalignant (ascites in cancer patients caused by comorbidities but not by malignancy) ascites.MethodsA cohort of 283 patients (134 cancer patients, 149 patients with benign diseases) presenting with ascites was prospectively enrolled. Ascites was evaluated by means of cytopathological investigation and DNA methylation of SHOX2 and SEPT9 in the cell-free and cellular fraction. DNA methylation in bisulfite-converted DNA was determined using quantitative methylation specific real-time PCR. Cytopathological and DNA methylation results were evaluated with regard to diagnosis and overall survival (OS).ResultsPatients with positive DNA methylation had a poor overall survival compared to methylation-negative patients (hazard ratio: HR = 1.97, p = 0.001). In multivariate survival analysis, DNA methylation was an independent prognostic parameter (p = 0.003) together with age (HR = 1.03, p < 0.001) and the presence of malignant disease (HR = 1.87, p < 0.001).The combination of methylation with cytopathological analyses led to a 42 % increase in the detection rate of malignant ascites, resulting in 37 % positively diagnosed cancer patients and a specificity of 97 %. Among cancer patients, patients with DNA methylation-positive ascites showed an adverse clinical course (HR = 1.63, p = 0.039).ConclusionsDNA methylation testing adds diagnostic and prognostic information and might constitute an effective ancillary method for the differential diagnosis of malignant, paramalignant, and benign ascites.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0192-7) contains supplementary material, which is available to authorized users.
Highlights
Cytology remains the gold standard for the detection of malignant cells in ascites
An earlier study in which stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was determined in the cellular fraction of pleural effusions revealed an elevated SHOX2 background methylation—even in patients without malignancies—while SEPT9 methylation was solely found in cancer patients [22]
The cutoff previously established on pleural effusion (10 % SHOX2 DNA methylation) was applied to the ascites samples analyzed in this study
Summary
Cytology remains the gold standard for the detection of malignant cells in ascites. Ascites is defined as the pathological accumulation of fluid in the peritoneal cavity. It is the most frequent complication in patients with compensated cirrhosis with about 50 % of the patients developing ascites in a. Ascites can be caused by malignant neoplasia, heart failure, tuberculosis, and pancreatitis [2]. Depending on the volume of the ascites, abdominal girth and body weight increases. Runyon et al reported that malignancies account for 10 % of ascites [4]. The pathophysiologic mechanism of the development of malignant ascites is complex. An impaired lymphatic drainage combined with increased vascular permeability leads to the accumulation of protein and
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