Pleural fluid pro-cathepsin D was significantly higher in patients with MPE than in those with BPE. The diagnostic sensitivity and NPV for MPE at the pro-cathepsin D cut-off >0.596 pg/mL were 81% and 89%, respectively. Thus, pleural fluid pro-cathepsin D may be useful in discriminating MPE from BPE.
Pleural fluid cytology is usually used for diagnosing MPE; however, its diagnostic yield was only about 50% in previous reports [5, 15]. 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, 16, 17]. 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 [18, 19]. On the other hand, the proform pro-cathepsin D was correlated with enhanced proliferation and neoplastic transformation [20, 21]. Thus, we aimed to investigate the diagnostic role of pro-cathepsin D in discriminating MPE from BPE. This study showed the correlation of serum and pleural fluid pro-cathepsin D and its diagnostic performance in MPE with moderate sensitivity and specificity.
According to our results, pro-cathepsin D alone may not be sufficient to discriminate MPE from BPE. However, pleural fluid pro-cathepsin D can potentially be added to other diagnostic methods for rule-in or rule-out purposes in patients with suspected MPE. Because 0.596 pg/mL of pleural fluid pro-cathepsin D revealed an NPV of 88.9%, a clinically meaningful application of pleural fluid pro-cathepsin D in ruling out MPE is suggested . In contrast, pro-cathepsin D values of 1.017 pg/mL in pleural fluid and 0.711 pg/mL in plasma could serve as cut-off values to achieve 100% specificity in MPE diagnosis. These cut-off values of pro-cathepsin D may be advantageous for ruling in the patients with suspected MPE who require extensive study in order to make a histologic diagnosis.
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 [23, 24]. 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, given the nature of the retrospective study design, the optimal sample size could not be determined before the research was conducted. Second, the small sample size may limit the statistical significance of the study. However, it may not be feasible to enroll a predetermined and sufficient number of patients with MPE at a single center, since this is a relatively rare disease entity to encounter in daily practice. Thus, despite the imperfect design of this study, it may still be meaningful in terms of suggesting a novel biomarker for diagnosing pleural effusions. Third, laboratory facilities are necessary to measure pleural fluid pro-cathepsin D, which limits its application to other institutions. Fourth, considering that preclinical studies have also shown pro-cathepsin D overexpression in breast cancer and hepatocellular carcinoma [9, 11, 16, 17], it was postulated that pleural pro-cathepsin D may serve as a potential biomarker for diagnosing MPE. However, its diagnostic role should be interpreted with caution because most of the MPE in this study originated from lung cancer.