Body cavity fluids accumulating in progressive malignancies are potential subjects
of regular clinical testing for cancer-related features. Besides the cellular component,
the supernatant of the fluid proved to gain diagnostic impact as the cell-free DNA
(cfDNA) fraction ideally reflects general molecular features of the related tumorous
process, e.g. in lung carcinoma. Thus, malignant pleural effusions can be used for
lung cancer genetic profiling and this might remain the only source for testing in
critical cases. The cfDNA concentration of the pleural effusion depends on many factors
in both benign and malignant conditions. Further to direct pleural metastatic spread,
the redirection of tissue lymphatic circulation, tumor angiogenesis, inflammatory
processes and other variables may contribute to or enhance the enrichment of the effusion
tumor DNA from the earliest stages of carcinogenesis. Our review addresses the traffic
of cfDNA in the pleural space and the diagnostic utility of effusion cfDNA from the
perspective of the complex pleural pathophysiology.