Pleural biomarkers in diagnostics of malignant pleural effusion: a narrative review

Abstract

Although cytology and pleural biopsy of pleural effusion (PE) are the gold standards for diagnosing malignant pleural effusion (MPE), these tools' diagnostic accuracy is plagued by some limitations such as low sensitivity, considerable inter-observer variation and invasiveness. The assessment of PE biomarkers may hence be seen as an objective and non-invasive diagnostic alternative in MPE diagnostics. In this review, we summarize the characteristics and diagnostic accuracy of available PE biomarkers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), carbohydrate antigens 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3), a fragment of cytokeratin 19 (CYFRA 21-1), chitinase-like proteins (CLPs), vascular endothelial growth factor (VEGF) and its soluble receptor, endostatin, calprotectin, cancer ratio, homocysteine, apolipoprotein E (Apo-E), B7 family members, matrix metalloproteinase (MMPs) and tissue-specific inhibitors of metalloproteinases (TIMPs), reactive oxygen species modulator 1 (Romo1), tumor-associated macrophages (TAMs) and monocytes, epigenetic markers (e.g., cell-free microRNA and mRNA). We summarized the evidence from systematic review and meta-analysis for traditional tumor markers' diagnostic accuracy. According to the currently available evidence, we conclude that the traditional tumor markers have high specificity (around 0.90) but low sensitivity (around 0.50). The diagnostic accuracy of novel tumor markers needs to be validated by further studies. None of these tumor biomarkers would have sufficient diagnostic accuracy to confirm or exclude MPE when used alone. A multi-biomarker strategy, also encompassing the use of artificial intelligence algorithms, may be a valuable perspective for improving the diagnostic accuracy of MPE.

Development and Validation of a Scoring System for Early Diagnosis of Malignant Pleural Effusion Based on a Nomogram

“…Also, other tumor markers have been reported to be useful in lung cancer (such as CYFRA 21-1, NSE, or CR), which were not evaluated in this study. In addition, novel biomarkers, such as serum interleukin-27 (IL-27), gas chromatography-mass spectrometry (GC-MS) metabolomics, and serum reactive oxygen species modulator 1 (ROMO1), have been proposed as potential indexes for diagnosing lung cancer-associated MPE, but only a few were routinely detected in clinical practice (18,(37)(38)(39).…”

“…The utility of biomarkers in the diagnosis of MPE has been studied extensively ( 16 , 18 ). Nonetheless, which biomarkers are the key to determining the diagnosis of MPE are yet controversial.…”

“…Thus, developing a method to accurately differentiate MPE from BPE at the earliest is highly desirable. The utility of biomarkers in the diagnosis of MPE has been studied extensively (16,18). Nonetheless, which biomarkers are the key to determining the diagnosis of MPE are yet controversial.…”

“…Several biomarkers have been investigated for the identification of MPE and BPE in previous studies, such as adenosine deaminase (ADA), carcinoembryonic antigen (CEA), and lactate dehydrogenase (LDH) (16)(17)(18). However, no single marker from blood or PE could obtain both high sensitivity and specificity.…”

CEA and ADA in Pleural Fluid for Differential Malignant Pleural Effusion and Tuberculous Pleural Effusion

“…The diagnosis of malignant pleural effusion is based on pleural effusion cytology and pleural biopsy as the gold standard. But there are disadvantages such as low sensitivity, invasiveness, and heavy reliance on the diagnostic experience of pathologists [4] . While the Mycobacterium tuberculosis culture technique, as the gold standard for the diagnosis of tuberculous pleural effusion, suffers from a low positivity rate and long culture time.…”