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. 2025 Jun 11;11(3):503–517. doi: 10.1007/s41030-025-00301-6

A Diagnostic Approach to Malignant Pleural Mesothelioma

Avinash Aujayeb 1,✉, Philippe Astoul 2
PMCID: PMC12373620  PMID: 40498282

Abstract

In this concise article, we give a current overview of the practical approach to diagnosing pleural mesothelioma (PM). PM is a rare, incurable, aggressive cancer almost exclusively related to previous asbestos exposure. We begin by outlining the general approach to pleural malignancy. The focus then shifts to pleural mesothelioma (PM), with discussions on cytological analyses, a direct-to-thoracoscopy approach, specialist services, and future directions. This narrative review aims to provide an updated, practical overview of current and emerging diagnostic strategies.

keywords: Pleural mesothelioma, Thoracoscopy, Pleural malignancy, Malignant pleural effusion, Cytology

Key Summary Points

Pleural mesothelioma (PM) is an aggressive cancer typically linked to previous asbestos exposure.
Diagnosis relies on a high index of suspicion and often requires direct thoracoscopic biopsies with pleural fluid management.
Histopathological confirmation is crucial for prognostication.
Serum and pleural biomarkers might have a role to play in the future.
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Introduction

Mesothelioma is an aggressive, incurable cancer that can affect any part of the body but is typically confined to the pleura or the peritoneal surfaces. Pleural mesothelioma (PM) is almost exclusively linked with asbestos exposure, although this association (and other causative agents) is debated further in this article [1–3].

Asbestos is a naturally occurring mineral that forms as long, thin fibrous crystals. The several types are chrysotile ('white asbestos'), actinolite, amosite ('brown asbestos'), anthophyllite, crocidolite ('blue asbestos'), and tremolite. They are all carcinogenic. There is often a lag period between exposure and disease presentation, which can vary from a few years to a few decades. High-risk occupations include heating engineers, boiler repair technicians, and shipyard workers, just to cite a few examples. There are also a considerable number of cases occurring in those who shared households with exposed workers. The use of asbestos has been banned in several countries, but unregulated use in Asia and Africa is increasing and will cause mesothelioma for decades to come [4–6]. Huang et al. suggest that globally, the age-standardized incidence rate of PM was about 0.30 per 100,000 people in 2020, with Northern Europe and Australasia showing the highest incidence rates, while the Caribbean and Africa had the lowest rates [6].

This article aims to summarise the diagnostic approach to PM—this would not be possible without first describing how the patients might present, the radiological and interventional investigations, the pathological landscape, and finally how an exemplar service should be configured. Peritoneal mesothelioma and the oncological treatment landscape will not be addressed in this review. The review is based on the expert opinion of the authors, who are both experienced pleural physicians. We also expand on future directions in PM diagnostics.

Patient Characteristics

Real-world data of patients with PM come from large registries such as Surveillance, Epidemiology, and End Results (SEER) Program from the United States or prospective observational trials such as “A prospective obServational cohort Study collecting data on dEmographics, Symptoms and biomarkerS (ASSESS-Meso),” which is only based in the United Kingdom (UK) [7, 8]. Patients are normally predominantly male and in their sixth or seventh decade in life. Presenting symptoms, which can comprise breathlessness, cough, fatigue, weight loss, and sweating can be vague and associated with several respiratory conditions. However, the presence of chest pain is worrisome, and should be taken seriously—pain usually means invasion of the parietal pleural layer. All nociceptive nerve fibres are on the parietal pleura with relative sparing of the visceral lining [9]. The most common clinical presentation will be a unilateral pleural effusion (the next most common presentation will be a pleural mass), which will be most likely right-sided. This is due to the relatively greater surface area of the right pleural cavity and perhaps the straighter right main bronchus (allowing for more inhalation of asbestos fibres) when compared to the left pleural cavity and the left main bronchus. The mechanism behind the development of the pleural effusion is complex and beyond the scope of this article, but in a nutshell is due to the increased secretory effects of the developing malignancy as well as the decreased resorptive capacity of the lymphatic system in the parietal pleura [10].

Radiological Investigations

Initial investigative steps are radiological. A chest radiograph or X-ray will detect pleural effusions (a volume of approximately 200–250 ml will be detected on plain radiographs) as well as masses (Figs. 1 and 2). Following on from simple radiographs, computed tomography (CT) with contrast in the venous phase is the imaging modality of choice and can detect very small effusions and characterise pleural abnormalities. Leung’s criteria, first established in 1990, suggest a diagnosis of pleural malignancy [11, 12]. Any of the four features of pleural thickening is suggestive of malignant pleural disease. Leung’s criteria are (1) circumferential pleural thickening, (2) nodular pleural thickening, (3) parietal pleural thickening greater than 1 cm, and (4) mediastinal pleural involvement.

Leung’s criteria were derived from 53 patients. The specificities of the criteria labelled 1–4 above were 100%, 94%, 94%, and 88%, with corresponding sensitivities of 41%, 51%, 36%, and 56%, respectively, with an overall sensitivity of 72% and specificity of 83% if one or more of those criteria were present. These findings have been replicated over time [13].

Thoracic ultrasound (TUS) is crucial for the safety of any pleural interventions, which usually follow on from the CT scans. TUS can also show nodularity, both diaphragmatic and visceral, which again increase the probability of malignancy, as shown in Fig. 1.

Fig. 1.

Fig. 1

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Thoracic ultrasound (TUS) of a pleural effusion with a diaphragmatic nodule with diaphragmatic thickening (indicated by the star)

Magnetic resonance imaging also has very high sensitivity for malignancy but outside clinical trials, its use is not widespread [14]. Positron emission tomography (PET) scans can be used to highlight areas of pleural thickening but again is not routinely used and care must be taken that previous areas of pleurodesis can mimic malignancy on this imaging [15, 16]. These aspects are discussed in greater detail later on.

Staging of PM follows the tumour, node and metastasis (TNM) classification set out by the International Association for the Study of Lung Cancer (IASLC) for malignant pleural mesothelioma (MPM). The current TNM classification is on its ninth version and it is beyond the scope of this paper to summarise how the classification is reached. CT images are used as that imaging modality is easily accessible worldwide. Only the T component of the classification is changing from the eighth to the ninth version [17–20].

Diagnostic Procedures

The approach to a unilateral pleural effusion is the same in all suspected pleural malignancies. If it is safe to do so, a unilateral pleural effusion can be aspirated to allow for biochemical and cytological characterization, as well as to relieve breathlessness. No intervention for pleural fluid should be performed without the prior use of thoracic ultrasound (TUS) [21]. The appearances of pleural, visceral and diaphragmatic thickening and nodularity further increase the suspicion of pleural malignancy as explained above. Pleural effusions due to PM are typically exudative by Light’s criteria, and can have low pH and glucose levels, those being markers of the high metabolic activity in the malignant pleural effusion. The optimal volume of pleural fluid for cytological analysis seems to be 50 ml, and a cell block should be prepared.

However, Arnold et al. have shown that pleural fluid cytology can be very high in patients with suspected breast or ovarian cancers, but that the yield in patients with PM can be less than 6% (Fig. 2, reproduced from Arnold et al.) [22]. Thus, in patients with suspected PM, a biopsy to obtain tissue is normally required. Sundaralingam et al. have shown, in a multicentre retrospective UK-based study, that the most effective methods for obtaining tissue to enable molecular analysis are image-guided biopsy (CT or ultrasound) or local anaesthetic (medical) thoracoscopy (LAT) [23]. Cancerous deposits do not affect the pleural homogenously, causing characteristic skip lesions, so blind biopsies in suspected pleural malignancy are not advocated [24].

Fig. 2.

Fig. 2

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Diagnostic sensitivity of pleural fluid cytology

What type of biopsy is offered to the patient will depend on local resource availability, as well as the requirement for fluid control, as radiological image-guided biopsies do not offer that, and the patient would invariably have to undergo another procedure. Ultrasound-guided (USS) biopsy offers the advantages of being feasible in a clinical setting by respiratory practitioners and avoiding the use of ionising radiation. USS-guided biopsy has a diagnostic yield of 84% in meta-analyses [25]. There is currently a feasibility study being conducted in the UK looking at combining procedures (biopsy and an indwelling pleural catheter [IPC]) if there is a target that can be identified for a USS-guided biopsy. It also seems that the accelerated pathway is acceptable to patients [26]. CT-guided biopsy is usually performed by radiologists and uses ionising radiation—it has an even higher diagnostic yield than USS-guided biopsy at 93% [25].

However, LAT offers a multi-modality approach of total fluid drainage (there is no risk of re-expansion pulmonary oedema due to the equalization of pleural and atmospheric pressures during the procedure), biopsy of directly visualised malignant deposits and fluid control via either talc pleurodesis or insertion of an IPC. LAT is a very safe procedure with low complication rates overall and can be performed by respiratory physicians [27]. It has a very high sensitivity for pleural malignancy. In cases of suspected PM, should resources allow, a direct-to-LAT approach is advocated with multi-site deep biopsies incorporating fat and muscle tissue to allow full tumour characterization. Tsim et al. found that negative pleural fluid cytology is very likely in those with asbestos exposure, and in those patients, LAT should be the first diagnostic step [28]. LAT practice is very variable all over the world, with some centres having a length of stay of 3 days or more, and others offering day-case LAT with IPC insertion and same-day discharge [29].

Should LAT not be available, the favoured option would be video-assisted thoracoscopy (VATS), which is performed by cardiothoracic surgeons. VATS differs from LAT—the former is usually done under general anaesthetic and with two ports and the latter is done under deep sedation with one port. Additional procedures, such as adhesiolysis, can also be performed at VATS. There are no studies comparing LAT and VATS directly, but LAT is generally perceived as the more appropriate procedure for patients with suspected pleural malignancies, as they are usually frailer, and less tolerant of a general anaesthetic [30]. Diagnostic yields of LAT and VATS are similar, often above 95%. The benefits of LAT are less pain, shorter procedure times and reduced length of stay if performed as a day-case procedure. However, VATS techniques are evolving over time, and now so-called ‘awake VATS’ can be performed, as well as day-case procedures for carefully selected patients. Recent guidance suggests that LAT is a very safe procedure with very low mortality and less than 2% of major complications such as bleeding or subcutaneous emphysema [12]. Complication rate from VATS approaches 10% [30]. The favoured approach of the authors is to go for LAT in all new patients, whilst referring for VATS those patients with non-diagnostic biopsies or who might require additional procedures such as adhesiolysis.

Histopathological Approach

As described above, pleural fluid or tissue samples are used for the evaluation of suspected PM cases. Recently, guidelines for pathologic diagnosis were published from the International Mesothelioma Interest Group (iMiG) [31]. PM is still divided into epithelioid, biphasic, and sarcomatoid variants, but suggested the term mesothelioma instead of malignant mesothelioma. If tumour cells are shed into pleural fluid, cytological analysis can be helpful—the fluid is typically highly cellular, with clear nuclear atypia, big tissue clusters, and multinucleated cells. Typical markers which would favour a diagnosis of pleural mesothelioma are described in Fig. 3, which is reproduced from the iMiG position statement.

Fig. 3.

Fig. 3

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Characteristic markers for the diagnosis of PM. WTI1 Wilms tumor-1, D2-40 podoplanin, HEG 1 "Heart of Glass" homolog 1, CEA carcinoembryonic antigen, TTF 1 thyroid transcription factor-1, BG 8 blood group 8, MOC-31 anti-epithelial-related antigen mouse monoclonal primary antibody, Ber-EP4 Ep-CAM/epithelial-specific antigen.

(© 2010 College of American Pathologists- permission to reuse the image is granted, as the source is acknowledged)

However, with cytology, stromal invasion cannot be assessed, nor can subtyping or grading. Cytology also cannot help in cases of sarcomatoid mesothelioma, as those tumours do not shed cancer cells [32]. Hence, there is a need for biopsies.

Histology is therefore crucial in the diagnosis of PM. Epithelioid mesotheliomas usually show up as polygonal, oval, and cuboidal cells; sarcomatoid mesotheliomas have spindle cells and biphasic mesotheliomas have features of both. Immunohistochemistry is crucial to the final diagnosis [33]. Figure 4 below shows the common markers that will be positive. Figures 4, 5, and 6 show typical features of epithelioid, sarcomatoid, and biphasic mesotheliomas. Further tests can be used, including the so-called ancillary tests, which detect specific mesothelioma-associated genetic mutations. The breast cancer gene 1(BRCA1)-associated protein-1 (BAP-1) is a tumour-suppressor gene, and germline or somatic pathogenic variants are associated with multiple tumours, including PM. A meta-analysis of 1824 patients, of which 1016 had PM, showed an overall pooled sensitivity of 0.56 (95% CI: 0.50–0.62) but a specificity of 1.00 (95% CI: 0.95–1.00) for BAP1 loss, making BAP1 loss a reliable tool for ‘rule in’ of PM. The most common genetic mutation in PM is homozygous deletion of the 9p21 locus, where deletion affects a group of genes, such as p16 (also known as cyclin-dependent kinase inhibitor (CDKN)-2A), CDKN2B, and methylthioadenosine phosphorylase (MTAP). P16 deletion can be detected using fluorescence in situ hybridization (FISH), but has low sensitivity for PM detection (0.53) (95% CI: 0.35–0.70). However, when used together, BAP1 loss and p16 deletion increase diagnostic sensitivity (combined sensitivity 0.76 (95% CI: 0.62–0.88) [34]. A proposed diagnostic algorithm is shown in Fig. 7, reproduced from Chapel et al. [34].

Fig. 4.

Fig. 4

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Epithelioid pleural mesothelioma (PM)

Fig. 5.

Fig. 5

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Desmoplastic pleural mesothelioma (PM)

Fig. 6.

Fig. 6

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Sarcomatoid pleural mesothelioma (PM)

Fig. 7.

Fig. 7

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Proposed diagnostic algorithm for pleural mesothelioma (PM)

Service Setup

Patients with suspected pleural malignancies are best served in a pleural clinic. The last decade or so has seen an increase in such clinics being delivered with ready access to TUS, procedure rooms and physician expertise. For example, in one of the author’s centres (Northumbria Healthcare NHS Foundation Trust in the North East of England), a new patient appointment is 45 min which allows for a full history, examination, any required procedures and eventually communicating the cancer diagnosis. The National Health Service (NHS) in England remunerates each trust per new patient who has their first procedure in the outpatient setting via the Best Practice Tariff, thus offering incentives for full outpatient management of these patients [35]. Support from Mesothelioma Clinical Specialist Nurses (MCSNs) is crucial in the patient pathway and is well established in some centres [1]. Whilst RESPECT-Meso did not show a benefit for those patients who were assigned specialist palliative care, the study had a number of limitations, including a high failure rate of screening and exclusion of patients who had started systemic anti-cancer treatment as well as those with World Health Organisation performance statuses of 2 [36]. Further studies, albeit non-randomised have shown the benefits of MCSNs in being a point of contact for the patients, coordinating care, providing psychological and nutritional support and enabling trial recruitment [37, 38]. As mentioned above, the British Thoracic Society guidance is quite clear on the role of MCSNs [1]. Services must have a way of accessing the various biopsy modalities described in the previous sections. As alluded to earlier, we also feel that the 45-min appointment is optimal for the communication of the cancer diagnosis. There is clear published guidance on this [35, 38].

Services should also have access to a specialist mesothelioma multidisciplinary team meeting comprising respiratory physicians, oncologists, surgeons, pathologists, palliative care physicians, MCSNs, and research practitioners. These team meetings are proven to streamline patient care, improve recruitment into research trials, and improve mortality [39–41].

The Known Unknowns: Potential for New Clinical Approaches

Role of Magnetic Resonance Imaging (MRI) and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)

MRI is not routinely used in the assessment of pleural lesions, but it can have diagnostic value in specific cases, as thoracic wall and diaphragmatic infiltrations can be important prognostic factors [42]. Moreover, it can be useful in the setting of preoperative work-up and also for restaging after neoadjuvant systemic treatment [43]. Consensus panel technical recommendations for the use of MRI in patients with mesothelioma have been drawn through the International Mesothelioma Interest Group (IMIG) in 2022 [44]. For a morphologic assessment, T1-weighted and T2-weighted sequences are usually performed with T1 post-contrast sequences for better detection of pleural lesions. Functional sequences such as diffusion weighting imaging (DWI), associated with the evaluation of apparent diffusion coefficient (ADC) maps, are now introduced in chest MRI protocols to differentiate benign from malignant disease [45]. DWI showed utility in differentiating between different MPM histological subtypes with a good correlation between ADC values and the three different histologic subtypes [46]. It is superior to CT in demonstrating infiltration of the thoracic wall/endothoracic fascia and diaphragmatic invasion (69% vs. 46% and 82% vs. 55%, respectively) [43]. This suggests a potential role in the preoperative evaluation of patients with pleural malignancies, as well as in assessing diaphragmatic abnormalities or diagnosing soft tissue lesions due to the contrast it provides for such lesions. MRI can also be used in patients allergic to contrast agents. The limitations of thoracic MRI include reduced accessibility, high cost, longer image acquisition time, and artifacts caused by respiratory and cardiac movements) [45].

The use of FDG-PET in diagnosing PM remains a topic of debate, with no clear agreement on its routine application for assessing pleural lesions. One of the reasons is its limited accessibility and high cost [46]. PM lesions also generally show higher FDG uptake compared to benign conditions due to increased metabolic activity. However, the pleura may also demonstrate elevated FDG uptake in response to inflammation, infection, or previous talc pleurodesis, leading to the possibility of false-positive results [9]. Additionally, pleural tumours with lower metabolic activity might appear negative on FDG-PET, causing false-negative outcomes. The effectiveness of FDG-PET can vary when evaluating pleural thickening, with or without pleural effusion. FDG-PET is valuable in distinguishing malignant from benign pleural lesions, offering a sensitivity of 95% and specificity of 82%, as well as for assessing pleural abnormalities in patients with known cancers, where it has a sensitivity of 86% and specificity of 80%. However, studies have shown that FDG-PET is not reliable for differentiating malignant from benign pleural effusions, with a sensitivity of 81% and specificity of 74% [48]. Despite these mixed findings, there is general agreement that FDG-PET offers both functional and morphological insights into pleural lesions, providing more detailed information than CT scans. It aids not only in diagnosing metastasis but also in accurately staging the disease, particularly in T staging [49]. Moreover, FDG-PET can guide pleural biopsy by identifying areas with higher FDG uptake or help monitor treatment responses [50].

Pleural and Serum Mesothelin Levels

Mesothelin (MSLN), a glycoprotein overexpressed in PM and other solid tumors, has emerged as a promising biomarker and therapeutic target [51]. MSLN plays a role in tumor adhesion, metastasis, and chemoresistance, interacting with mucin 16 (MUC16) to promote cancer progression. MSLN’s overexpression has led to its exploration as a biomarker for diagnosis, prognosis, and treatment response monitoring [52]. Soluble mesothelin-related peptide (SMRP), derived from MSLN shedding, is detectable in serum and pleural fluid, making it a potential diagnostic tool. However, SMRP lacks sensitivity and has limited utility in early detection. Several studies have investigated MSLN’s prognostic value, but results remain inconclusive. While some suggest high MSLN expression correlates with worse survival, others indicate a neutral or even protective role. MSLN-targeted therapies have gained traction, including monoclonal antibodies, antibody–drug conjugates (ADCs), immunotoxins, cancer vaccines, and chimeric antigen receptor (CAR) T cell therapy [53]. Amatuximab (MORAb-009), a chimeric monoclonal antibody targeting MSLN, showed promising disease control rates but failed to demonstrate significant survival benefits in phase II trials. ADCs such as anetumab ravtansine, BMS-986148, and BAY2287411 aim to selectively deliver cytotoxic agents to MSLN-positive tumors. Among them, anetumab ravtansine demonstrated activity in preclinical models but failed to outperform vinorelbine in phase II trials. Immunotoxins like SS1P and LMB-100 utilize bacterial toxins to induce tumour cell death. While early studies showed some clinical responses, challenges such as immunogenicity and off-target toxicities hindered their success. Vaccination strategies, including the Listeria monocytogenes-based CRS-207, seek to enhance anti-MSLN immune responses. CRS-207 showed limited efficacy in MPM, leading to the discontinuation of clinical trials. CAR T cell therapy has emerged as a novel approach, with several trials investigating MSLN-targeted CAR T constructs. Early-phase studies demonstrated safety and feasibility, with some patients achieving stable disease or partial responses. Strategies such as locoregional administration and combination with immune checkpoint inhibitors are being explored to enhance CAR T cell efficacy. Despite these advances, no MSLN-targeted therapy has yet achieved FDA approval for MPM. The complexity of MPM’s tumour microenvironment, immunosuppressive factors, and interpatient heterogeneity present significant challenges. Future research aims to refine MSLN-targeting strategies, improve patient selection criteria, and combine immunotherapies for better outcomes. In conclusion, MSLN represents a compelling target for MPM diagnosis and treatment. While various MSLN-directed therapies have shown promise, their clinical efficacy remains limited [54]. Ongoing research and novel combination approaches hold potential for improving outcomes for patients with MPM.

Breath Tests

Although research has been conducted on various tissue and blood biomarkers (such as mesothelin, osteopontin, fibulin-3, HMGB1 protein, aquaporin 1, microRNAs, and proteomics-based markers), there remains a significant gap in understanding how these non-invasive biomarkers can detect early metabolic and inflammatory changes in individuals exposed to asbestos and suffering from PM. To aid in distinguishing patients with PM from healthy individuals, the analysis of exhaled breath has been explored as a potential non-invasive diagnostic tool [55]. In line with several cancers, including PM, the identification of volatile organic compounds (VOCs) linked to tumour metabolism has shown promising results for screening and diagnosis. Recent research using xenografts has demonstrated the ability to capture, analyse, and separate VOC signatures from xenografts and controls, helping to differentiate PM histological subtypes [56]. However, studies on exhaled breath biomarkers for PM are still in their early stages. Despite this, breath analysis holds potential for the future due to its non-invasive nature and the ability to detect a variety of biomarkers that reflect human metabolism. It is important, though, to interpret VOC profiles with caution, as the respiratory system is exposed to numerous external substances, and the elimination of endogenous VOCs can be influenced by factors such as physiological conditions, smoking, and medications. Thus, further prospective studies employing standardized methods and adhering to the latest guidelines are needed, with validation on larger populations to address the challenges of ‘breathomics’ [57, 58].

Novel Biopsy Techniques

As described above, LAT is the method of choice for the diagnosis of PM in the presence of a pleural effusion, although so-called ‘dry thoracoscopy’ in the absence of a pleural effusion has been described [59–61]. Technical difficulties during the procedure (lack of lung deflation due to adhesions, poor visibility of parietal pleura due to loculations, lack of deep biopsies due to bleeding for example) or just inadequate biopsies at an incorrectly identified area of the parietal pleura might well lead to histopathological samples not showing malignancy—the so-called ‘non-specific pleuritis’ [62]. In those with high clinical suspicion for pleural malignancy, a repeat biopsy is often required, which might well be via a VATS. Various techniques have been proposed to enable that the right area is biopsied. Fluorescence thoracoscopy with 5-aminolaevulinic acid (5-ALA), in addition to white light thoracoscopy, has been shown to be feasible and have increased diagnostic yield [63]. Patients need to ingest a weight-dependent amount of 5-ALA before undergoing thoracoscopy. Another method that has been tried is probe-based confocal laser endomicroscopy (pCLE). This allows live imaging of cellular structures and various single-centre studies have confirmed feasibility and safety; uptake, however, is not widespread, probably due to the upfront costs of the equipment and lack of training regarding the interpretation of findings during pCLE [64, 65]. Another method of confirming the right biopsy would be to have rapid on-site evaluation (ROSE) techniques available, but this relies on the presence of a cytopathologist or other staff having adequate training [66]. As such, the use of ROSE is not widespread, and its use in mesothelioma is debatable, as a diagnosis of PM often requires examination of the deep visceral layers for invasion and immunohistochemistry, as described above.

Conclusions

This narrative article provides an updated practical approach to pleural mesothelioma (PM), detailing current and emerging diagnostic methods, histopathological techniques, and service setup—all essential for delivering patient-centred care. It also highlights several future developments that warrant further research and evaluation.

Author Contributions

Avinash Aujayeb conceived the idea of the article. Avinash Aujayeb and Philippe Astoul both wrote the article and revised the manuscript for content.

Funding

No funding or sponsorship was received for this study or publication of this article.

Declarations

Conflict of Interest

Avinash Aujayeb is an Editorial Board member of Pulmonary Therapy. Avinash Aujayeb was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Philippe Astoul has no conflicts of interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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