Pleural fluid pro-cathepsin D was significantly higher in patients diagnosed with MPE and can be used to discriminate between MPE and BPE. In addition, a cut-off level for pleural fluid pro-cathepsin D of 0.5960 pg/ml was predictive of MPE in patients with exudative pleural effusion with moderate sensitivity and specificity.
Pleural fluid cytology is usually used for diagnosing MPE; however, its diagnostic yield was only about 50% in previous reports [5, 12]. Furthermore, even when the cytology results are negative, a thoracoscopic pleural biopsy is not feasible in most patients with an advanced stage of cancer. Thus, various biomarkers have been investigated, and pro-cathepsin D is one of the potential candidates for diagnosing MPE. Pro-cathepsin D, which is a proform of lysosomal aspartic peptidase cathepsin D, was overexpressed in breast cancer, lung cancer, and hepatocellular carcinoma [9, 11, 13, 14]. In agreement with previous reports, our study showed that pro-cathepsin D was significantly higher in patients with MPE than those with BPE. The reason why we chose pro-cathepsin D rather than cathepsin D as a potential diagnostic marker was that previous studies have suggested that mature cathepsin D participates in intracellular protein catabolism, hormone and antigen processing, and the apoptotic pathway, which also occur in non-neoplastic cells [15, 16]. On the other hand, the proform pro-cathepsin D was correlated with enhanced proliferation and neoplastic transformation [17, 18]. Thus, we aimed to investigate the diagnostic role of pro-cathepsin D in MPE. This study showed the correlation of serum and pleural fluid pro-cathepsin D and its diagnostic performance in MPE with moderate sensitivity and specificity.
Regarding underlying mechanisms of pro-cathepsin D, previous studies suggested that they are involved in multiple stages of tumour progression including proliferation, invasion, metastasis, angiogenesis, and apoptosis [19, 20]. From this perspective, pro-cathepsin D might be used as a prognostic marker as well as a diagnostic marker. Though this study could not demonstrate the association of pro-cathepsin D level and patient prognosis due to its small sample size, Y.-J. Qi and colleagues suggested its role as a candidate biomarker associated with hepatocellular carcinoma development and progression . Future study with a larger study population is needed to establish its role as a prognostic marker, which will provide invaluable information to clinicians and patients.
There are several potential limitations to our study. First, this study is retrospective and investigated a small number of patients. Second, we could not provide sufficient evidence to replace previous diagnostic methods with pleural fluid pro-cathepsin D. Third, laboratory facilities are necessary to measure pleural fluid pro-cathepsin D, which limits its application to other institutions. Fourth, patients with MPE were enrolled only when cancer cells were observed on cytology, although malignant cells may not be visualized on cytology in the real world.
In conclusion, our study suggests that pleural fluid pro-cathepsin D could be a potential novel biomarker to discriminate between MPE and BPE. In addition, a cut-off level for pleural fluid pro-cathepsin D of 0.5960 pg/ml was predictive of MPE in patients with exudative pleural effusion with moderate sensitivity and specificity.