MicroRNA expression in pleural fluid as a diagnostic biomarker of malignant pleural effusion: promise, pragmatism, and the path forward

Cancer is the most common cause of exudative pleural effusions. Approximately 25% of pleural effusions that undergo diagnostic thoracentesis are due to neoplasia, with lung cancer being the primary tumor that metastasizes most frequently to the pleura (1,2). The main method for diagnosing malignant pleural effusion (MPE) is cytological analysis of pleural fluid (PF), which detects malignant cells in approximately 55% of cases (3,4). Consequently, at least 45% of MPEs result in false-negative cytology, with this rate increasing to 75% in squamous cell carcinoma and mesothelioma (4,5). In addition, cytomorphological differentiation between adenocarcinoma, mesothelioma, and reactive mesothelial cells is difficult and requires the application of immunocytochemical panels on cell-block specimens (6,7). In cases where suspicion remains despite negative PF cytological results, invasive procedures such as pleural biopsy are warranted. Furthermore, some researchers consider pleural tissue samples crucial for the molecular characterization of MPEs, which may influence the recommendation for targeted therapies (8). However, the feasibility of conducting invasive procedures, particularly local anesthetic thoracoscopy, is contingent upon the patient’s overall condition and the availability of resources at each hospital (9,10).

Obtaining a noninvasive diagnosis of MPE with false-negative PF cytology is challenging for clinicians (11). In one study, the combination of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in PF, adopting cut-off points with 100% specificity, identified only 40% of cytology-negative MPE cases (12). Another study showed that the measurement of epithelial cell adhesion molecule (EpCAM) in PF cell lysates yielded 75% sensitivity and 100% specificity for labelling adenocarcinomatous effusions (13). Approximately one-third of biopsy-proven cytology-negative MPEs displayed EpCAM levels above the discriminating threshold (98 pg/g total lysate protein). Nevertheless, the limitation of these and other biomarkers is that they do not prevent the need for cytohistological confirmation of malignancy. Immunohistochemical markers can be used on cell blocks derived from PF or pleural biopsy specimens to determine the origin of the primary tumor invading the pleura, differentiate mesothelioma from adenocarcinoma, and distinguish malignant from reactive mesothelial proliferation (7). Unfortunately, formalin fixation and paraffin embedding of PF cell blocks or pleural biopsy specimens negatively impact liquid biopsy by causing chemical modifications and fragmentation of nucleic acids, which reduces the quality and yield of analyzable deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) for molecular assays (14). Consequently, fresh or unfixed PF (e.g., supernatant) is preferred for molecular analyses (15,16).

Liquid biopsy of pleural effusion involves the molecular analysis of tumor-derived nucleic acids, primarily cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA), directly from the acellular supernatant of PF, eliminating the need for invasive tissue sampling. This method facilitates the detection of tumor-specific genetic and epigenetic alterations, including mutations, copy number variations, and methylation patterns. Such information is crucial for guiding the diagnosis, prognosis, and therapeutic decision-making in malignancies associated with pleural effusions. One study demonstrated that PF supernatant was superior to plasma for detecting cfDNA and that the PF-to-plasma cfDNA ratio coupled with the cfDNA fragment length profile distinguished benign from malignant effusions, even when the latter had a false-negative cytology (17).

In addition to cfDNA, numerous other nucleic acids are found in biofluids, such as circulating cell-free RNA (cfRNA). This includes both coding [messenger RNA (mRNA)] and non-coding RNA (ncRNA) species. Non-coding RNAs comprise all RNA molecules that do not encode proteins and are frequently dysregulated in cancer and detectable in PF (18). They account for more than 98% of the human genome. However, only a small proportion of ncRNAs have been studied, suggesting that the ncRNA family may contain many clinically relevant biomarkers that are still unexplored. The broad category of ncRNAs includes microRNAs (miRNAs), long non-coding RNA (lncRNAs), and other small RNAs. miRNAs (typically 19–25 nucleotides long) are the most predominant and abundant ncRNA species. They regulate gene expression post-transcriptionally and are highly stable in PF and exosomes, resisting degradation by RNases and harsh storage conditions.

miRNAs can be measured in different PF compartments, specifically in the cell-free supernatant and exosomes (extracellular vesicles of 50–100 nm secreted from cells). Exosomal miRNAs are of particular interest because exosomes protect their RNA cargo from degradation, resulting in enhanced stability and preservation of miRNAs during sample processing and storage (19). Various techniques are available for measuring miRNAs in PF, applicable to both cell-free PF supernatants and exosome fractions. The selection of the appropriate method is contingent upon the study phase (discovery versus validation), sample volume, and number of miRNAs to be analyzed. All methodologies require prior extraction of total RNA from the supernatants or extracellular vesicles, followed by specific protocols for miRNA quantification. Next-generation sequencing (NGS), microarray profiling, high-throughput quantitative polymerase chain reaction (qPCR) arrays (e.g., TaqMan OpenArray), and NanoString technologies are the most useful tools for RNA discovery (20-22). These platforms enable the simultaneous screening of hundreds of miRNAs to identify differentially expressed candidates between malignant and benign effusions. In contrast, the main validation methods for miRNA analysis in PF samples are quantitative reverse transcription PCR (qRT-PCR), digital droplet PCR (ddPCR), and, less frequently, northern blotting and fluorescence in situ hybridization (FISH). These techniques confirm the presence, size, and localization of specific miRNAs identified during the discovery phase.

qRT-PCR is widely regarded as the gold standard for routine quantification of specific miRNAs because of its exceptional sensitivity, specificity, cost-effectiveness, and compatibility with standard laboratory equipment and workflow. Nevertheless, certain technical limitations exist, such as the potential presence of inhibitors in PF, which may affect qRT-PCR performance and result in false negatives or an underestimation of miRNA levels in the sample. Moreover, quantification by qRT-PCR requires normalization to the stable endogenous controls. A study identified U6 small nuclear RNA (U6 snRNA) and miR-192 as suitable stable reference genes for the relative quantification of miRNAs in PF (23). Finally, the absence of standardized protocols for sample collection, processing, RNA extraction, normalization, and assay platforms introduces variability and limits reproducibility across laboratories and studies. It is considered that 10 mL of PF is sufficient for ancillary molecular studies, including miRNA analysis (24). Lower volumes may require adjustments, such as pre-amplification, particularly for low-abundance targets or less sensitive platforms. Most published studies have used between 0.5 and 5 mL of PF. ddPCR is the most sensitive and specific method for the absolute quantification of miRNAs in PF, outperforming qRT-PCR (25). Moreover, ddPCR does not require standard curves or endogenous controls, which is advantageous for fluids in which normalization is challenging (26). However, ddPCR requires specialized equipment and is more labor-intensive and costly than qRT-PCR.

Several studies have calculated the diagnostic accuracy of different miRNAs in PF for differentiating between malignant and benign pleural effusions (19,21,22,27-37) (Table 1). Others have reported a differential expression of miRNAs between malignant and benign PFs without offering measures of diagnostic accuracy (23,38-41). Finally, some studies have explored the prognostic value of certain miRNAs (42-45). There is no consensus on the specific miRNAs with the highest diagnostic efficacy. However, certain miRNAs, such as miR-21, miR-24, miR-141, miR-182, miR-200, and miR-210, have been replicated in several studies (22,27,30-33,35,36). Overall, research efforts focused on assessing the diagnostic potential of miRNAs in PF samples have encountered several limitations. Sample size requirements differ substantially between the discovery and validation phases of miRNA biomarker studies of MPEs. Although the discovery phase typically uses a small sample size (20–40 PF samples) to identify candidates with differential expression (19,21,22,28,32,33,35-37), the validation phase requires a substantially larger sample size to provide adequate statistical power. This means including at least 80–100 independent PF samples, which is not always the case (Table 1). An appropriate sample size must be paired with etiological diversity to avoid overestimating biomarker performance due to selection bias or limited disease representation. Regrettably, most studies restrict the etiological spectrum of MPEs to lung cancer (21,27-30,32,34,35) and, in certain instances, benign effusions to heart failure (19,22) or tuberculosis (35). Published studies evaluating individual miRNAs in PF for malignancy report area under the curve (AUC) values between 0.61 and 0.98, although only values ≥0.85 may indicate sufficient accuracy for clinical use. In addition to a high AUC, a test is considered accurate and clinically actionable if it has a high specificity (≥90%). This can sometimes only be achieved when several miRNAs are combined with each other (19,22,29-31,33,35,36) or with other biomarkers such as CEA (28,29,37). The lack of absolute specificity for miRNAs implies that some benign effusions may yield positive results, which can lead to unnecessary procedures, patient harm, and mismanagement. This highlights the importance of integrating miRNA testing with clinical judgment and other diagnostic methods, avoiding sole reliance on positive miRNA results for the diagnosis of malignancy.

Importantly, patients with pleural effusions who benefit most from miRNA-based diagnostic testing are those with an unclear etiology, where standard cytology is inconclusive. Only a few studies have addressed the potential of miRNA measurements to substantially improve the diagnostic yield in cytology-negative MPEs (22,36,37,44). Watabe et al. identified elevated miR-21 expression in extracellular vesicles derived from pleural lavage fluid in patients diagnosed with lung cancer who exhibited negative PF cytology (44). In a study conducted by Zhu et al., 61 (85%) of the 72 MPE samples that were initially missed during cytological examination were successfully identified using a three-miRNA signature (miR-21, miR-29c, and miR-182) in the PF (36). Finally, in a recent study, the abundance of three miRNAs (miR-141-3p, miR-203a-3p, and miR-200c-3p) correctly classified all MPEs with false-negative cytological examination results (22).

A recent study by Zhao et al. published in Translational Lung Cancer Research explored the diagnostic utility of exosomal miR-182-5p in labeling MPEs (37). This research addresses a critical clinical need: the establishment of a reliable, minimally invasive biomarker that can aid in the early and accurate diagnosis of MPE. Through the application of NGS, the authors identified miR-182-5p as being significantly upregulated in MPE samples. This finding was subsequently validated in a larger cohort, revealing that miR-182-5p alone demonstrated acceptable diagnostic performance with an AUC of approximately 0.80. Notably, when combined with CEA, the diagnostic performance improved substantially, achieving an AUC of 0.91. This suggests that a multi-marker strategy may offer superior diagnostic accuracy compared with the use of individual biomarkers.

A significant strength of this study lies in its comprehensive and unbiased approach. By employing NGS, the authors ensured that candidate miRNA identification was not restricted by prior hypotheses. Additionally, the study cohort included a diverse spectrum of benign etiologies, such as tuberculosis, parapneumonic effusion, and congestive heart failure, making the findings more generalizable than those of previous studies, which were limited to a single etiology. The methodological rigor is also noteworthy; the authors used two different internal references, Caenorhabditis elegans miR-39 (cel-miR-39) and U6 snRNA, to quantify miRNA expression, thereby highlighting how normalization choices can influence diagnostic performance. Furthermore, the integration of bioinformatics analyses enriched the study by suggesting possible biological roles for the identified miRNAs, opening avenues for mechanistic investigations of MPE pathogenesis.

However, certain limitations temper enthusiasm for immediate clinical translation. The initial NGS phase involved a small sample size of only 20 participants, which may have limited the robustness of miRNA profiling. Although the validation cohort was larger, it was still derived from a single center, raising questions regarding the generalizability of the findings. Another practical limitation is that miR-182-5p was undetectable in approximately 21% of cases, indicating technical challenges in exosome isolation and miRNA quantification that must be addressed before these assays can be standardized for routine clinical use. The influence of internal reference selection on diagnostic accuracy further underscores the absence of consensus on exosomal miRNA normalization, an issue that continues to hinder reproducibility across studies. Moreover, the retrospective use of stored PF samples raises questions regarding the stability of exosomal miRNAs over time, suggesting that future investigations should prioritize prospective designs using fresh specimens.

Clinically, although miR-182-5p alone does not meet the threshold for a standalone diagnostic marker, its combination with CEA shows promise. However, whether this incremental improvement translates into meaningful clinical utility remains to be demonstrated. Future research should focus on validating these findings in larger, multicenter cohorts, refining exosomal miRNA quantification protocols, and developing robust multi-marker panels that combine both miRNAs and protein biomarkers, such as CEA and/or CA 15-3. Additionally, a deeper investigation into the functional role of miR-182-5p in pleural metastasis and tumor microenvironment interactions may yield insights with both diagnostic and therapeutic implications.

In summary, Zhao et al. have taken a commendable step forward in the search for effective liquid biopsy tools in thoracic oncology. Their findings position exosomal miR-182-5p as a promising, although not yet definitive, biomarker for MPE. Continued methodological refinement and external validation are essential to determine whether this biomarker can be integrated into clinical workflows, either as a companion to existing diagnostics or as part of an emerging multi-analyte strategy for the management of pleural effusion.

The detection of miRNAs in PF represents the intersection of translational promise and clinical pragmatism. As biomarkers, miRNAs offer the alluring potential of noninvasive, rapid, and mechanistically informative diagnostics for pleural malignancies. However, this promise must be tempered by a pragmatic understanding of the current barriers to implementation, including heterogeneity in analytical platforms, lack of normalization consensus, and limited reproducibility across different clinical settings. Moving forward, the field must prioritize collaborative efforts toward standardization, validation in real-world cohorts, and integration into established diagnostic workflows. Only by aligning scientific innovation with methodological rigor can we fulfill the promise of PF miRNA detection and translate it into meaningful advances in patient care.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article did not undergo external peer review.

Funding: This study was supported by funding from the Instituto de Salud Carlos III (grant No. PI23/00926), Diputació de Lleida (grant No. PP10721), Sociedad Española de Neumología y Cirugía Torácica (grant No. 1273-2022) and Agència de Gestió d’Ajuts Universitaris i de Recerca (grant No. 2021 SGR 00781).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-844/coif). Both authors report that this study was supported by funding from the Instituto de Salud Carlos III (grant No. PI23/00926), Diputació de Lleida (grant No. PP10721), Sociedad Española de Neumología y Cirugía Torácica (grant No. 1273-2022) and Agència de Gestió d’Ajuts Universitaris i de Recerca (grant No. 2021 SGR 00781). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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