Year 2024 - Diagnosis of malignant pleural mesothelioma: updates and open questions
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FOREWORD
Diseases of the pleura are among the world's fastest-growing health concerns, affecting about one million people a year and often correlated with a dismal prognosis. One of these pleural pathologies is malignant pleural mesothelioma (MPM), a neoplastic disease mainly caused by exposure to asbestos that is still to this day a diagnostic challenge. A timely diagnosis is crucial in determining the most appropriate treatment approach for the patient, but the choice of diagnostic methods depends on the operator's experience and local facilities, as well as on the performance of each diagnostic procedure. Since the analysis of pleural fluid cytology is not enough to diagnose MPM, histopathological and morphological features obtained by tissue biopsies are critical. In addition, the quality of biopsy specimens is of crucial importance and often requires a high level of expertise.
Because adequate tissue biopsy is paramount, medical or video-assisted thoracoscopy (MT or VATS) is deemed to be the most suitable approach. Indeed, MT is the diagnostic gold standard for malignant pleural diseases. In addition, this medical-surgical approach may allow diagnostic and therapeutic procedures: it affords the possibility of video-assisted biopsies, allows high volumes of pleural fluid to be drained and sterile calibrated talcum powder to be administered in order to perform pleurodesis, allows the placement of pleural catheters, and may soon be the proper approach for potential intrapleural therapy.
In this context, dedicated diagnostic routes remain a crucial necessity, especially for quick and correct diagnosis of PM.
Finally, multidisciplinary assessment should always be carried out in order to direct the patient to the best personalized diagnostic and therapeutic path. Currently, the diagnosis of MPM remains an unsolved problem despite multidisciplinary team (MDT) meetings, mainly due to the lack of a standardized diagnostic work-up. This review aims to provide an overview of diagnostic procedures in order to propose a clear strategy.
EPIDEMIOLOGY AND PATHOGENESIS
The pleura is a serious surface and is the most common location of mesothelioma, although the pericardium, peritoneum, and tunica vaginalis can also be affected [6].
Pleural mesothelioma is strongly linked to asbestos exposure. It is more common in men, usually due to occupational exposure. However, there is an increasing trend among women, while asbestos is less frequently a cause of disease, as recently reported [7,8]. Therefore, despite asbestos being banned in Western countries, MPM is still a therapeutic challenge notwithstanding advances in research.
The molecular pathogenesis of PM is multifactorial, driven by mechanisms more or less related to asbestos [9]. Asbestos fibers are hydrated mineral silicates divided into two groups: serpentine (curly fibers, “white” asbestos) and amphibole (amosite and crocidolite, needle-like fibers, “brown” and “blue” asbestos, respectively). All fiber types are carcinogenic, but crocidolite appears to be the most aggressive causative agent, according to the International Agency for Research on Cancer (IARC) [10], but the risk of developing PM is also related to the length and heaviness of exposure, in spite of recent results from animal studies [11,12,13,14]. After being inhaled and migrating into the pleura, the fibers create a pro-inflammatory environment and cause oxidative and mechanical damage to cells and DNA damage through macrophages and species reactive to oxygen and nitrogen (ROS/RNS) [15].
Non-asbestos-related MPM can be caused by non-asbestos mineral fibers and nonmineral agents. Eryonite and fluoroedenite, mineral fibers with properties nearly similar to those of asbestos, have shown to be carcinogenic in case of environmental exposure [16,17]. As far as nonmineral sources are concerned, radiation has been linked to the development of MPM either as a result of therapeutic exposure, which in this case usually occurs in irradiated tissue, or as a result of occupational exposure [18].
The association between MPM and Simian Virus 40 (SV40) in humans is a controversial issue. SV40 is a polyomavirus with oncogenic potential that can both induce mesenchymal cell transformation in vitro and the onset of MPM in laboratory animals. SV40 antibodies and Tag expression in serum samples from PM patients were significantly higher than in healthy patients, suggesting an association. This, however, does not represent evidence that SV40 is responsible for tumor onset [19]. SV40 can act as an exogenous agent that increases the basal level of spontaneous mutations and lowers the threshold for tumor development [20]. Recent studies aiming at an association between PM and SV40 in the crocidolite-contaminated area suggested that the onset of MPM was not related to the SV40 infection and that crocidolite exposure was the main cause [21,22].
In addition to environmental exposure, despite the low frequency of protein-altering mutations [23] and limiting the potential for targeted molecular therapy, the genetic profile of MPM revealed common gene deletion or loss mutations and germline alterations in CDKN2A, BRCA1, BRCA2, and XPC that have been shown to be linked to disease development [24,25]. Among these mutations, somatic or inherited alterations in the tumor suppressor gene BRCA1-associated protein 1 (BAP1), which produces deubiquitinase enzymes that control apoptosis, cell advancement, growth inhibition, chromatin remodeling, and DNA repair response, play an important role in MPM development [26]. According to recent studies, BAP1 depletion is a strong predictor of cancer in mesothelioma differentiation and predicts better survival for patients undergoing chemotherapy [9,27,28].
PRESENTATION
Symptoms
Symptoms vary with the type of malignant mesothelioma.
Pleural mesothelioma is the most frequent form, and symptomatology depends mainly on the presence of pleural effusions. In particular, PM patients with pleural effusion may manifest cough, dyspnea, and chest pain. Chest pain may occur even in the absence of effusion, due to invasion of the chest wall. As the disease progresses further, changes may also occur due to compression of mediastinal organs, such as the airways, digestive tract, or large vessels. As a result, symptoms such as difficulty in swallowing, dysphagia, dysphonia, and edema of the neck and face may occur.
In addition to this specific symptomatology related to anatomical changes caused by pleural effusion, often associated with pathologic pleural thickening, the patient may also complain of non-pathognomonic and nonspecific symptoms such as a general state of discomfort, worsening asthenia, muscle weakness, and weight loss.
The symptoms of peritoneal mesothelioma are often nonspecific and include weight loss, cachexia, malaise, and asthenia. Conversely, more specific symptoms related to abdominal anatomical changes due to ascites are characterized by abdominal pain, nausea and vomiting, and fever. In these cases, intestinal obstruction, blood clotting abnormalities, anemia, and fever may occur.
Radiological Characteristics
The first radiological approach for MPM is usually a chest X-ray. Because of the larger pleural surface of the right hemithorax, asbestos fibers have a greater preference for the right pleural surface, and right-sided disease is usual (1.6 to 1 ratio) [29]. As explained above, a unilateral pleural effusion is a common finding (malignant tumors of the pleura are associated with pleural effusions in up to 94% of cases), and masses can also be found [30]. The next step involves performing a computed tomography (CT) scan with venous contrast. Peak contrast in MPM occurs after four and a half minutes, so delayed venous-phase imaging is necessary. Leung's criteria, first described in 1994, have stood the test of time: circumferential pleural thickening, nodular pleural thickening, parietal pleural thickening greater than 1 centimeter, and mediastinal pleural involvement have specificity of 94%, 94%, 88%, and 100% and sensitivity of 51%, 36%, 56%, and 41%, respectively [31].
However, about 40% of CT scans can be reported as being benign in spite of an underlying malignant diagnosis, and nearly 50% of patients with PM can have a benign CT report without a referral to specialized chest radiology [32]. The percentage is even lower with CT pulmonary angiography (27%). With specialist reporting, the referred sensitivity and specificity can be much higher [33].
At the time of the procedure on pleural fluid (discussed later), sonography is currently mandatory. The sonographic features of MPM are similar to those of any malignant disease: nodular pleural thickening of more than 1 centimeter and diaphragmatic modularity have high specificity (95-100%) but poor sensitivity (40%) [34].
Other imaging methods have been studied. Positron emission tomography (PET) can help assess distant disease, but MPM has relatively low metabolic activity. Therefore, patients with early-stage disease may have a false-negative PET scan, and patients with previous pleurodesis or concurrent inflammatory conditions such as rheumatoid arthritis may have false-positive scans [35,36]. A previous meta-analysis concluded that PET CT should not be recommended to differentiate between malignant and benign effusions [37]. The value of PET CT in the obtainment of biopsies will be discussed later.
Magnetic resonance imaging (MRI) has shown great promise in clinical trials. MRI is very good for soft tissue characterization and is better than CT for the assessment of chest wall and diaphragm invasion. However, its use is not widespread because of the associated costs and implications for service delivery. The sensitivity of MRI can be as high as 92% in selected patients [38].
DIAGNOSIS
Diagnostic evaluation - Pleural effusion survey and tissue biopsies
As explained above, most malignant tumors of the pleura show up as a pleural effusion.
With chest sonography, it is possible to identify the pleural effusion and take a sample (a pleural sampling) if it is safe to do so. If needed, up to one liter of fluid can be removed at the same time to relieve dyspnea (therapeutic aspiration).
Analysis of the pleural fluid should then determine whether it is an exudate or transudate according to Light's criteria (pleural fluid is considered an exudate if the pleural fluid protein/serum fluid protein ratio is > 0.5, pleural fluid lactate dehydrogenase (LDH)/serum fluid lactate dehydrogenase ratio > 0.6, or pleural fluid LDH > 2/3 of the upper limit of normal serum LDH). Malignant tumors are often associated with exudative effusions, although up to 10% of transudative effusions may be malignant.
In addition to biochemical analysis, cytological evaluation of the fluid is relevant. As with any test, pre-test probability is important. Previous research has shown that cytology is useful in less than 6% of PM cases, but sensitivity can reach 95% in patients with ovarian or breast cancer [39].
Therefore, many clinics recommend a direct biopsy approach in patients with a high clinical suspicion of mesothelioma, as suggested by the updated British Thoracic Society 2023 guidelines on pleural disease [40]. Pleural fluid cytology cannot determine the extent of tumor invasion, although it does support visceral involvement of the pleura [41,42].
There are three methods for obtaining a biopsy: echo-guided, CT scan or local anesthesia thoracoscopy (LAT). To obtain an effective molecular profile, tissue in the form of a pleural biopsy is required. Sundaralingam et al. demonstrated that the highest yield for molecular marker analysis was obtained with LAT procedures (95%). CT- and sonography-guided biopsies yielded 86% and 77%, respectively (p = 0.004) [43]. LAT is the preferred option for the diagnosis of MPM, with diagnostic yields often reported as greater than 95% and very low complication rates. It offers a therapeutic (all associated pleural fluid can be drained to relieve symptoms), diagnostic (areas of pleural malignancy can be biopsied under direct vision), and preventive (talc pleurodesis via poudrage with or without insertion of an indwelling pleural catheter) option. The various techniques related to the LAT procedure fall outside the scope of this article but are well described elsewhere [44]. However, patients must be adequately fit to undergo LAT, and if LAT is not feasible and an obvious radiologic target is present, such as easily visible parietal nodules, image-guided biopsies can be performed. While CT-guided biopsies are the sole responsibility of radiologists, sonographic biopsies are increasingly performed by respiratory physicians with good results [45,46].
PET-CT has been used previously to detect pleural tissue that is metabolically active, in spite of the limitations mentioned above [47]. The recent TARGET study showed that PET-CT is not useful for guiding new pleural biopsies in those patients who have undergone a previous nondiagnostic biopsy, so it appears that PET has no important role in mesothelioma diagnosis [48]. It is only recommended in patients to clarify signs of distant disease [30].
Molecular and genetic markers
The MPM molecular landscape is characterized by heterogeneity in the inactivation of tumor suppressors and activation of specific targets that could be a focus for new personalized therapies.
Potential molecular targets of MPM reflect alterations involving genes that play a role in cell cycle regulation.
Of these, homozygous deletion of 9p21 can be detected in MPM in 50-75% of cases [49], and this genetic alteration may involve cyclin-dependent kinase inhibitor 2A (CDKN2A) and methylthioadenosine phosphorylase (MTAP).
Other molecular markers include genes that code for receptor tyrosine kinases. Among these, the epidermal growth factor receptor (EGFR), known to be involved in the proliferation and regulation of cell growth and the angiogenesis process, is often overexpressed in MPM (approximately 40-90%) [50,51]. For this reason, many studies have been directed at the application of EGFR inhibitors in MPM, but have failed to show a significant clinical benefit [52,53,54,55]. There are probably multiple reasons for the poor efficacy of these drugs. Indeed, despite overexpression, mutations or amplification of EGFR are very rare in PM. In addition, there may be concurrent genetic and molecular alterations that trigger resistance mechanisms [56].
The TAM receptors (Tyro3, Axl, and Mer) [57], usually expressed in solid tumors and among them in PM, are another family of tyrosine kinases receptors. Proteins of the TAM family have been shown to play an important role in tumor development and progression, metastasis, and alteration of the microenvironment, often resulting in drug resistance [58,59]. Other genetic alterations could be a target for PM, such as changes in genes involved in the Hippo signaling pathway [60,61,62]. In particular, the suppressor gene of the neurofibromatosis type 2 (NF2) tumor is frequently detected in PM as somatically mutated [63]. In PM, alterations in this gene can be found in about 50 percent, such as nonsense or missense mutations, gene rearrangements, and deletions with loss of heterozygosity resulting in bi-allelic loss of function [64].
The NF2 gene codes for the Merlin protein, which plays a crucial role in cell proliferation and survival, cell signaling pathways, and the balance between oncosuppressors and oncogenes [65,66,67,68]. The components of the Hippo pathway have tumor suppressive activity and are represented by LATS1/2 (large tumor suppressor kinase 1/2), MST1/2 (mammalian STE20-like protein kinase, (SAV1) Salvador homolog 1, and (MOB1) kinase activator 1A/BPM has been shown to be related to dysregulation of the Hippo pathway, involving YAP/TAZ oncoproteins and LATS1/2 tumor suppressors, through activation of specific mechanisms: initiation, progression, metastasis, and drug resistance [60]. Activation of YAP and TAZ leads to the regulation of transcriptionally useful genes, such as TEAD1-4 [61,62].
In close association with Hippo-dependent processes, the PI3K pathway is often activated in MPM and has been shown to be involved in cancer cell survival and proliferation [69]. MPM can also be characterized by molecular and genetic alterations involving enzymes that are related to cellular metabolism. Of these, ASS1 (argininosuccinate synthetase1) is a precursor enzyme for several molecules involved in tumorigenesis and is often (in about 45-65%) downregulated in nonepithelioid MPM [70,71]. Another enzyme involved in metabolism is glutamine, a substrate used in redox homeostasis, the Krebs cycle, and nucleic acid synthesis. The YAP1/TEAD pathway affects glutamine signaling. [72]. Of the surface targets, mesothelin is one of the most studied cancer-associated antigens overexpressed on the PM cell membrane, which appears to be involved in tumor development, metastasis, and drug resistance [73,74,75,76,77,78,79,80,81,82]. The soluble form of mesothelin stems from cell membrane release promoted by proteases [83]. Healthy mesothelial cells in the pleura, pericardium, and peritoneum poorly express mesothelin; this emphasizes how this molecule can be considered an ideal biomarker for designing targeted therapy [84,85]. Regarding possible surface targets for PM patients, another ideal antigen for targeted treatments is the oncophytic glycoprotein 5T4, given its high expression in mesothelioma cell lines [86]. PM can also be characterized by germline and acquired mutations in genes involved in the DNA damage response. Indeed, genes involved in DNA repair pathways are often found in PM. Of these genes, BRCA1-BAP1 (breast cancer gene 1-associated protein 1) is the most common in PM (about 60%) [81,87,88]. EZH2 (enhancer zeste homolog 2) is an oncogenic enzyme that regulates gene expression in carcinogenesis and is required for lung mesothelial differentiation [89,90]. Furthermore, several studies suggest that an altered DNA repair system affects PM pathogenesis by leaving uncorrected genomic alterations [91]. Given the role of BRCA1 in PM and the involvement of BAP1 and BRCA1 in the DNA damage response, these genetic alterations could be used as biomarkers, using, for example, PARP inhibitors (PARPi) [92].
The comprehensive characterization of PM phenotypes and the pathogenetic mechanisms that shape their development and evolution are still unclear. Recent multi-omics analyses aim at identifying ideal markers based on genetic and molecular alterations. The integration of anatomopathologic analyses in combination with the definition of biomolecular and genetic features may provide a more accurate picture of the disease and new therapeutic approaches [93].
New potential diagnostic tests (Breath Test, etc.)
Several markers of PM have been studied (or are being studied in large-scale mesothelioma studies such as ASSESS-Meso and Meso-Origins). First, pleural and serum mesothelin (or Soluble Mesothelin Related Peptides [SMRP]) levels. Previous studies have shown that more than 80% of PM cells can express mesothelin, but the overall sensitivity and specificity of serum mesothelin levels are 0.61 and 0.8, respectively [94]. SMRPs were studied in the SWAMP study. A decrease in SMRPs between baseline and 8 weeks after chemotherapy would suggest a stable disease burden, at least based on contemporary imaging. Lower SMRP levels at the end of the treatment are also associated with better survival [95]. Additional prospective studies examining SMRPs, such as a sub-study of ASSESS-meso, are currently being finalized and will be reported soon. Pleural fluid mesothelin, which is secreted directly from mesothelial cells into the pleural fluid, has also been studied [96,97]. Pleural mesothelin levels are increased as shown by Pass but so far they have not been shown to be a reliable marker of disease. Other markers such as fibulin-3, osteopontin, megakaryocyte enhancing factor (MPF), and hyaluronic acid (HA) have been studied but never prospectively and none of them are recommended for routine use [98].
There has been interest in volatile organic compounds (VoCs) from exhaled breath for many years. VoCs have previously been shown to discriminate between patients with PM and patients with high asbestos exposure, as well as patients with benign asbestos lung disease [99]. More recent refinements of the process have suggested that some VoCs might have 100% sensitivity and specificity, but only 7 patients with PM have been studied [100]. Large-scale validation of these breath tests is needed in areas of high and low prevalence.
Liquid biopsy
In the oncology arena, liquid biopsy is increasingly applied for early identification of at-risk individuals, diagnosis, treatment monitoring, disease progression, and prognosis. However, the innovations that have been attained in this field have not been translated into the clinical practice of patients with PM and promising non-invasive markers [101,102,103]. In this context, several markers have been analyzed and research efforts have been undertaken to identify an ideal, non-invasive, and effective biomarker to follow patients with MP
Of these, several studies have focused on their possible applicability in clinical practice: Proteins such as mesothelin [104,105,106,107,108,109,110], osteopontin [105,111,112], fibulin-3 (FBLN3) [109,110,113], high-mobility group box 1 (HMGB1) [114,115, 116], CD138 [117], angiogenic factors [118,119], microRNAs [120,121], circulating tumor DNA (ctDNA) [122,123,124], circulating tumor cells (CTCs) [125,126], exosomes [127].
Nevertheless, although there are many candidate biomarkers, only mesothelin has received the approval of the Federal Drug Agency, although it has low diagnostic sensitivity. OPN is an indicator of the duration of asbestos exposure and has a potential prognostic role, but it lacks specificity for MPM.
Proteomic approaches have also been applied to define predictive prognostic signatures, but these results are still in the research phase [128,129,130]. The analysis of epigenetic features could also lead to breakthrough approaches for PM pathology. However, these findings require additional validation and confirmation on large sample sizes [131].
As yet, despite exciting prospects, the use of circulating biomarkers and liquid biopsies in current practice for the management of pleural mesotheliomas is not clearly defined [132,133].
Artificial intelligence
Artificial intelligence (AI) has been investigated for the diagnosis of various pathological conditions. Indeed, the application of AI to MPM patients could have great potential in making diagnosis easier [134]. In this context, researchers have analyzed clinical, radiological, and biological variables of MPM patients to come up with innovative diagnostic methods using artificial intelligence techniques.
Latif and colleagues used databases of MPM patients to mine MPM-related symptoms and identify risk factors for this malignancy as early as possible. The authors of this research believe that artificial intelligence and data analysis of MPM patients could be useful not only for early diagnosis, but also for the management of comorbidities of patients affected by this disease [135]. Other research has been conducted to determine the best possible system for early identification of individuals at risk of developing MPM and patients with a worse prognosis. In this field, algorithms based on artificial intelligence have been applied to develop experimental models that define specific risk and prognostic factors for this disease [136]. Likewise, some scientists have furthered the study of MPM risk variables by including characteristics of both patients and healthy subjects in the analyses so as to have larger databases [137].
Several machine learning algorithms were also applied for early detection of MPM patients. The techniques used in this research were resampling, adaptive synthetic (ADASYN) sampling and minority synthetic oversampling technique (SMOTE) [138].
A useful methodology for predicting the survival of MPM patients from specific images was also devised: the MesoNet [139].
The ability to identify early individuals at risk of developing cancer is one of the most significant frontiers in medicine. Hence, artificial technologies can contribute to the development of AI models for early detection, treatment monitoring, and prognosis definition.
Specifically, AI could offer a quick, effective and non-invasive method for diagnosing patients with MPM. However, artificial technology is not yet applicable in clinical practice due to some limitations and shortcomings as well as the complexity of the healthcare field. Optimizing learning processes and improving data classification will result in improvements in the field of AI applied to medicine, to complement current diagnostic methods.
STAGING AND HISTOLOGICAL CLASSIFICATION
Staging
The eighth revision of the TNM, carried out by the experts of the IASLC (International Association for the Study of Lung Cancer) Mesothelioma Staging Project, was achieved by analyzing huge amounts of data from MPM patients (>3500) [140,141,142]. The stage of the disease is of critical importance in defining the most appropriate course of treatment for the patient. More specifically, it can point toward therapeutic interventions aimed at prolonging survival and improving outcomes rather than palliative treatments alone.
Out of the non-invasive staging techniques, CT represents the first approach both for the definition of active anticlastic treatment for patients who can benefit from such treatment and for ineligible patients who will be referred to palliative care. Indeed, in these cases, CT may be useful during the planning of palliative thoracoscopy with possible talc pleurodesis [141].
PET-CT can be used to perform lymph node staging and to detect rare distant metastases, although the results of this diagnostic technique can often be controversial due to the occurrence of false positives [143,144,145].
MRIs are not usually done for MPM except to analyze the most peripheral areas (the apices, subclavicular vessels, diaphragmatic areas, etc.), which are useful in defining the resectability of the disease [146]. Although the metastasis rate of MPM is very rare, MRIs can be performed to identify brain metastases more sensitively than CTs; however, they are not superior in detecting lymph node metastases or visceral pleural tumors [147]. In clinical practice, the application of MRIs remains limited, as CTs or PET-CTs are preferred; MRI-based staging approaches are currently applied for research purposes only [148]. Of the invasive techniques, mediastinoscopy can be applied as a procedure to analyze mediastinal lymph nodes [149,150].
Bronchoscopy with EBUS is another technique routinely used for lymph node staging of thoracic tumors and is also sometimes applied for MPM [151,152].
EUS is used very rarely to study suspicious lymph nodes on radiologic evaluation in patients with MPM [153]. Of the other invasive staging techniques, thoracoscopy and laparoscopy may be applied, although this is rarely done and only to identify stage IV patients not diagnosed by PET-CTs[154].
Histological Classification
Suitable tissue specimens are required in order to diagnose MPM, which remains purely histological, based on specific and validated pathologic classifications defined by experts worldwide [155,156,157,158]. Pleural effusion is one of the most common presentations of MPM. Therefore, cytology is the first diagnostic technique to be carried out. In these cases, cytologic procedures make it possible to distinguish between benign and malignant pleurisy [159]. However, even after obtaining the cytologic diagnosis, tissue confirmation remains crucial. In fact, the sensitivity of cytologic diagnosis is about 30-75%, similar to that obtained from fine-needle biopsies and certainly lower than that of pleural biopsies [160,161]. However, if the patient is not susceptible to biopsy (poor performance status, comorbidities, concomitant medications...), the diagnosis can be ascertained based on cytology alone [39,157].
In most cases, a conclusive diagnosis derived from biopsy material in the proper quantity and quality is necessary to allow conclusive characterization [162]. In addition, the quality of the specimen can affect the accuracy of histologic classification and subtyping.
Macroscopic analysis is critical in the diagnostic process of MPM, in view of the fact that the topographical features of the tumor are crucial for pathologic staging, as well as the fact that mesothelioma varies over the course of the natural history of the tumor.
Differentiation between different types of MPM and pleural metastases from other primary neoplasms (lung, breast, etc.) is obtained by applying immunohistochemical analysis and specific sets of antibodies. In addition to this, claudin 4 has recently been studied, which would seem to be very useful in the differential diagnosis between MPM and adenocarcinoma [157]. Cytokeratin remains a very useful marker for defining sarcomatoid MPM [159].
MPM can be categorized into three main histological subtypes: epithelioid, sarcomatoid, and biphasic. It is also used as a prognostic and predictive factor for specific therapy. However, comprehensive implementations of this coding have been introduced due to the 2021 WHO classification of pleural tumors [163,164]. In particular, several studies have explored the importance of different cytologic features, architectural patterns, and stromal characteristics as useful prognostic factors in identifying patients who are candidates for multimodal treatment [165].
Another factor linked to prognosis is grading; in fact, specific morphologic features, such as mitotic count, nuclear atypia, and necrosis, could be used for risk stratification and the definition of more personalized therapies [166,167,168].
The current classification systems for MPM have, therefore, been updated to include specific features such as architectural pattern definition, stromal and cytological features, and biological and molecular features in pathological analysis [164].
The 2021 WHO classification of pleural tumors features major changes compared with previous classifications. In more detail, these are the most crucial changes: the renaming of WDPM (well-differentiated papillary mesothelioma) to WDPMT (well-differentiated papillary mesothelial tumor) [169], the recognition of mesothelioma in situ as a defined disease entity [161,170,171,172], the addition of architectural, cytological, and stromal features of the three well-known histologic classifications (epithelioid, sarcomatoid, and biphasic) to the 2021 classification because of their prognostic role and the introduction of nuclear grading for diffuse epithelioid mesothelioma.
CONCLUSIONS
This literature review provides an overview of the diagnostic pathway for malignant pleural mesothelioma.
The main constraint of this review is that it is in fact a review of the author's opinions and practice. However, we believe it is informative and practical for the general public.
Future work should focus on the widespread application of innovative molecular diagnostic tests, rigorous staging, the clinical use of MRIs, the effective use of non-endoscopic pleural biopsies, and the appropriate use of AI.
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