Pleural mesothelioma | Medicina Clínica (English Edition)

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BAP1: proteína 1 asociada a BRCA1; CEA: carcinoembryonic antigen («antígeno carcinoembrionario»); FISH: Fluorescent In Situ Hybridization («hibridación fluorescente in situ»); IHC: inmunohistoquímica; MTAP: metiltioadenosina fosforilasa; TTF-1: Thyroid Transcription Factor-1 («factor de transcripción tiroidea 1»); WT-1: Wilms tumor-1. aLa determinación de CDKN2A por técnica FISH es más cara y consume más tiempo que la tinción inmunohistoquímica para MTAP." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Manuel Porcel" "autores" => array:1 [ 0 => array:2 [ "nombre" => "José Manuel" "apellidos" => "Porcel" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020622004028" "doi" => "10.1016/j.medcle.2022.08.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004028?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775322001774?idApp=UINPBA00004N" "url" => "/00257753/0000015900000005/v1_202208310516/S0025775322001774/v1_202208310516/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S238702062200403X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2022.04.010" "estado" => "S300" "fechaPublicacion" => "2022-09-09" "aid" => "5992" "copyright" => "Elsevier España, S.L.U." 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Chest X-ray shows circumferential pleural thickening (A), which is confirmed by computed tomography (B), where an associated pleural effusion is also seen (C)." ] ] ] "textoCompleto" => "IntroductionIn the European Union, a disease is defined as rare when it affects no more than one person in 2000. Consequently, pleural mesothelioma (PM) is considered a rare disease in Europe, with a prevalence of 3.1 cases per 100,000 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> According to GLOBOCAN (Global Cancer Observatory), a subsidiary of the World Health Organisation, 30,870 new cases of mesothelioma were diagnosed worldwide in 2020 (44.2% in Europe and 31.5% in Asia) and 26,278 people died of the disease.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The age-adjusted incidence rate was 0.30/100,000 and the mortality rate was 0.25/100,000. The tumour predominantly affects males (70%). In that same year, 586 new cases of mesothelioma were identified in Spain, 504 individuals died, and the estimated prevalence of the disease for the last 5 years was 1.58/100,000.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> More than 90% of mesotheliomas originate in the pleura and 5–6% in the peritoneum, with mesotheliomas of the pericardium or the tunica vaginalis being very rare.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> This review will briefly address the etiopathogenic, clinical, prognostic, and therapeutic aspects of diffuse PM.EtiopathogenesisInhalation of asbestos fibres suspended in the air is considered the main etiopathogenic mechanism of PM. Approximately 80% of these patients have a history of direct or indirect exposure to asbestos.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> However, only about 10% of exposed individuals will end up developing a PM, after a latency period of about 40 years (range: 20–50) from exposure.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> There is a linear relationship between the amount of exposure and the risk of disease.The word asbestos is etymologically derived from Greek and means "inextinguishable or incombustible", denoting that this mineral does not deteriorate even when subjected to fire or other agents. “Amiantos”, the source word for asbestos in many languages, also derives from the Greek and means "undefiled", referring to the fact that this silicate presents in the form of white fibres. Asbestos comprises 6 fibrous metasilicates, including white (chrysotile), blue (crocidolite) and brown (amosite) asbestos. Chrysotile is the most used in construction and the least toxic, amosite (the second most used) is used in thermal insulation, and crocidolite is the most toxic of the 3 and is used in the manufacture of fibre cement pipes or covers (uralite) and fireproof material. Chrysotile is the only representative of the so-called serpentine fibres (because of their curved shape), while the rest of the asbestos fibres are amphibole (straight or elongated and highly biopersistent).The list of jobs that may carry a risk of exposure to asbestos is extensive, since it has been widely used in the iron and steel, automobile, naval, aeronautical, chemical, textile, and construction industries. Exposure to asbestos can be not only occupational, but also domestic or "para-occupational" (e.g., washing of work clothes) and environmental (e.g., demolition or deterioration of buildings, proximity to asbestos factories or mines, living or working in asbestos-containing buildings, erosion of naturally occurring asbestos). The term natural occurring asbestos refers to the presence of asbestos fibres (e.g., tremolite) or asbestiform minerals (e.g., erionite, vermiculite, fluoro-edenite) in soil and rocks in certain geographical areas, which may be released by climate erosion or human activities or inadvertently used for the construction of buildings, representing a major source of environmental exposure.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The occupational exposure is more common in men with PM, while domestic or environmental exposure affects men and women equally. Many cases of PM considered idiopathic or spontaneous are likely to be unrecognised cases of asbestos exposure.As of July 2019, 67 countries had developed laws prohibiting the use of asbestos.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> However, it is not yet banned in China, India, Russia, or the USA, among others. In Spain, a ban on the manufacture, marketing or installation of products containing asbestos was introduced in 2002. Russia and Kazakhstan are the largest producers of asbestos in the world, with a total of 790,000 and 210,000 metric tons in 2020, respectively.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> On the other hand, Asia and the Middle East were the regions with the highest consumption of this material (1.18 million metric tons) in 2019.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The precise carcinogenic mechanisms of asbestos are not fully understood. The amphiboles reach the alveolus and are phagocytosed by macrophages. Such phagocytosis may be inefficient, activating a series of inflammatory responses (reactive oxygen species, proinflammatory cytokines) and creating a mutagenic microenvironment around mesothelial cells.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Mutations in the BRCA-1 associated protein 1 (BAP1) gene, located on the short arm of chromosome 3, are particularly important as they prevent apoptosis of mesothelial cells and favour the accumulation of additional mutations (e.g. in the genes cyclin-dependent kinase inhibitor 2A [CDKN2A], neurofibromatosis type 2 [NF2], TP53, SET domain containing 2 [SETD2]), and SET domain bifurcated 1 [SETDB1]), favouring their malignant transformation. The loss or inactivation of the BAP1 gene, present in around 60% of PMs,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> justifies tumour development by the tumour suppressor effect of the protein it encodes, whose anti-ubiquitination activity regulates processes such as DNA repair, cell cycle, apoptosis, chromatin structuring and cell proliferation.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Other common genetic alterations in PM also involve tumour suppressor genes: the CDKN2A gene, which encodes p16 and p14 proteins; the NF2 gene encoding the merlin protein; the TP53 gene encoding the p53 protein; and the SETD2 and SETDB1 genes encoding a histone methyltransferase protein of the same name. In fact, germline BAP1 mutations are associated with a syndrome of autosomal dominant inheritance cancers in humans, including mesothelioma (mostly of epithelioid lineage), uveal melanoma, cutaneous melanoma, renal cell carcinoma and, less commonly, basal cell carcinoma and atypical Spitz tumour.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Familial PMs accounted, however, for only 0.5% of 560 PMs in a Spanish multicentre series.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Exposure to ionising radiation in supradiaphragmatic fields (e.g., lymphoma survivors who underwent radiotherapy) is also a risk factor for the development of PM.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Finally, carbon nanotubes have physicochemical characteristics (shape, size, biopersistence) similar to asbestos fibres. Their potential biomedical applications are wide-ranging and include the delivery of anti-tumour drugs or radiotracers in imaging tests. In experimental animals, they induce PM through signalling pathways common to asbestos tumorigenesis, and therefore future monitoring of their effects in humans is required.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>DiagnosisThe mean age of onset of PM is approximately 70 years and the main symptoms are dyspnoea (∽65%), chest pain (∽50%), weight loss (∽40%) and cough (∽20%).<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a> About 3% of PMs develop before the age of 45,<a class="elsevierStyleCrossRef" href="#bib0095">19</a> and it appears that this subgroup of patients has differential features both clinically (similar gender distribution, lower history of asbestos exposure and higher prior radiotherapy) and genetically (lower prevalence of CDKN2A deletion) compared to older patients.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> The most common finding on chest X-ray is a unilateral pleural effusion (PE), with or without associated pleural thickening (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Dyspnoea is explained by PE or tumour infiltration of the lung, while chest pain is often related to soft tissue invasion (chest wall, mediastinum) or neuropathic involvement. The disease should be highly suspected in subjects with a history of occupational exposure to asbestos or suggestive radiological data (e.g., pleural plaques).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Imaging techniques: stagingImaging tests strengthen the clinical suspicion of PM and are essential for tumour staging (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and decide if it is potentially resectable.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> All subjects should have a contrast-enhanced computed tomography (CT) of the chest and upper abdomen, with extension to the abdominopelvic area if the diagnosis is confirmed. To optimize visualization of the pleural membranes, images should be acquired in the venous phase, 1–4min after contrast administration.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> The most characteristic radiological data is the presence of a circumferential pleural thickening (30–55%) together with an ipsilateral PE (90%)<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The former is significantly less common in malignant metastatic PEs (10–19%). Mediastinal, diaphragmatic, and fissural pleural thickening are also more common in PM than in metastatic PE.<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> The visualization of pleural “asbestos” plaques is variable (20–65%).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Positron emission tomography (PET) combined with CT (PET-CT) is useful for detecting nodal and extrathoracic disease in potentially operable patients. It should be indicated before any pleurodesis attempt since the inflammation caused by the sclerosing agent would give rise to false positives. On the other hand, a negative PET-CT (maximum standardized uptake value or SUV<2,5) has been described in around 10% of PM cases, especially in early stages of the tumour and in elderly people.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> In addition to pre-surgical staging, PET-CT may help to identify the ideal site for pleural biopsy (area with increased SUV) in cases of diffuse pleural thickening.Since the distinction between resectable (T3) and unresectable (T4) tumours is critical, contrast-enhanced MRI is an appropriate test in seemingly surgical patients when the aim is to establish possible tumour invasion of the chest wall, endothoracic fascia, diaphragm or mediastinal vessels, for which CT is inaccurate.Occasionally, when the diagnosis of extension is uncertain and the patient is a surgical candidate, invasive techniques such as endobronchial or endoscopic ultrasonography, mediastinoscopy, contralateral thoracoscopy, or laparoscopy may be required.Cytohistological studiesThere are 3 histological types of diffuse PM: epithelioid (∽60−70%), sarcomatoid (∽10%) and biphasic or mixed (∽20−30%)<a class="elsevierStyleCrossRefs" href="#bib0090">18,26</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). However, in some series the percentage of unspecified histologies can reach 40−50% of all cases.<a class="elsevierStyleCrossRefs" href="#bib0070">14,27</a> The definitive diagnosis of PM requires cytohistological confirmation. The various scientific societies are unanimous in recommending pleural biopsy as the diagnostic method of choice, preferably thoracoscopically-assisted.<a class="elsevierStyleCrossRefs" href="#bib0140">28–33</a> However, a cytological study of the pleural fluid should always be the first step, as it may sometimes be diagnostic of epithelioid PM, but not of the sarcomatoid variant where cells rarely exfoliate into the pleural space. At least 40−50ml of pleural fluid should be tested and both Papanicolaou- or Giemsa-stained smears and haematoxylin-eosin-stained paraffin-embedded cell blocks should be examined in the laboratory, as they are complementary tests.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> Immunohistochemical studies are performed on the cell block specimens. In a recent meta-analysis that included 1347 cases of PM, the sensitivity of pleural fluid cytology to identify this tumour was only 28.9%.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Therefore, if PM is suspected and a first cytological study is negative, a pleural biopsy should be carried out directly without the need to repeat a second diagnostic thoracocentesis (a common action in metastatic PE).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Ultrasound or CT-guided pleural biopsies represent a minimally invasive procedure that is particularly useful when there are areas of pleural thickening, as well as a good alternative when thoracoscopy is not possible due to the physical condition of the patient or the unavailability of such a technique. Outside of these circumstances, thoracoscopy with sedation, using rigid or semi-rigid instruments through a single port of entry, allows pleural tissue to be obtained under direct visualization. Biopsies should be deep and ideally come from 3 different areas.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> Demonstration of subpleural fat invasion and sufficient sample for immunohistochemical studies are key elements for a diagnosis of certainty. Some studies show that around 20% of epithelioid PM diagnosed by biopsy are reclassified as biphasic PM in the surgically resected specimen.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In part, this fact could be explained by intratumoral heterogeneity.With the material available, be it a cell block of pleural fluid or a biopsy, the pathologist must sequentially answer 2 questions: 1) are the cells observed of mesothelial (MP or reactive mesothelium) or epithelial (carcinoma) origin, and 2) if the cells are mesothelial, are they malignant in nature or reactive to a benign condition? (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Regarding the first question, the diagnosis of PM (epithelioid) requires the combination of at least 2 positive immunohistochemical markers of mesothelium (e.g., calretinin, WT-1, D2-40) and 2 negative markers of carcinoma (e.g., claudin 4, TTF-1, CEA).<a class="elsevierStyleCrossRefs" href="#bib0170">34,37</a> The antibodies selected must have >80% of sensitivity and specificity (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Sarcomatoid PMs usually stain with broad-spectrum cytokeratins, unlike sarcomas. Once the mesothelial cell differentiation is confirmed, the distinction between MP and reactive mesothelial proliferation is established with 3 markers: BAP1, methylthioadenosine phosphorylase (MTAP), and CDKN2A (p16). The first 2 are assessed by immunohistochemistry and the third by Fluorescent In Situ Hybridization (FISH). Characteristically, PM has a complete (or partial) loss of nuclear BAP1 and cytoplasmic MTAP expression (negative staining), as well as a homozygous deletion of CDKN2A.<a class="elsevierStyleCrossRefs" href="#bib0190">38,39</a> A meta-analysis including 1824 patients (1016 with mesothelioma, predominantly pleural) showed a sensitivity of BAP1 immunostaining of histological and cytological specimens of 74% for the epithelioid variety, 50% for the biphasic variety and 7% for the sarcomatoid variety; an overall weighted sensitivity of 56%, specificity of 100%, positive likelihood ratio of 549 and negative likelihood ratio of 0.44 were reported.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Regarding sarcomatoid PMs, CDKN2A is more sensitive (70–80%) than BAP1.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> More recently, another meta-analysis evaluated the diagnostic efficacy of these markers on cytological specimens (cell blocks and/or smears) from 5324 patients with PM.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> The respective sensitivities and specificities described were: BAP1, 65% and 99%; MTAP, 47% and 99%; CDKN2A, 62% and 100%; and the combination of BAP1 and CDKN2A, 83% and 100%.<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Finally, in recent years numerous studies have been published on the potential usefulness of certain diagnostic biomarkers of PM in blood and pleural fluid, such as mesothelin, fibulin 3 or high mobility group box 1 proteins (HMGB1).<a class="elsevierStyleCrossRef" href="#bib0210">42</a> The most studied has been mesothelin, a membrane glycoprotein usually measured by immunoassay techniques (ELISA). In a recent meta-analysis, the area under the curve (AUC) of mesothelin in plasma was 0.86 and 0.83 in pleural fluid.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Another meta-analysis reported an overall sensitivity of 73% and a specificity of 90% for pleural fluid mesothelin.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Its detection is not common in clinical practice, and, in any case, it does not avoid the need to demonstrate the existence of PM by histological criteria. A potential utility of mesothelin could be the monitoring of treatment in patients with epithelioid PM and normal renal function.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>PrognosisSurvival at 1, 3 and 5 years of 9458 patients with PM from the English CAS (Cancer Analysis System) registry was 38, 16 and 8%, respectively<a class="elsevierStyleCrossRef" href="#bib0135">27</a>; data very similar to those offered by the SEER (Surveillance, Epidemiology, and End Results program) database of the National Cancer Institute in the USA on 2138 cases (39.4, 11.8 and 3.8%, respectively)<a class="elsevierStyleCrossRef" href="#bib0215">43</a> and other large series.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> The overall median survival of the CAS cohort was 8.3 months and that of the SEER cohort was 9 months. Survival is negatively influenced by sarcomatoid histology, advanced stages (N2 or M1), and palliative care treatment only. Thus, in the CAS cohort, the median overall survival of patients with epithelioid, biphasic, unspecified, and sarcomatoid histologies was 13.3; 8.3; 5.8 and 4.3 months, respectively.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Subjects treated with surgery lived a median of 17 months, those who received systemic cancer treatment, with or without radiotherapy, 14 months, and those who received only palliative care or radiotherapy alone 4.6 months.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>A validated prognostic model is that described by Brims et al.,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> which categorises patients into 4 groups with different survival, depending on the existence of weight loss, performance status, haemoglobin and albumin levels, and histological type of tumour.TreatmentPM is nowadays an incurable disease. Symptomatic PE and pain control are priority objectives. The application of other therapeutic measures must take into account factors such as stage, histology, age, performance status and patient preferences. The disease may be unsuspectedly widespread. Thus, in a necropsy study of 318 patients with PM, it was found that 88% had extrapleural dissemination and 55% extrathoracic, with the most common sites of metastatic spread being lymph nodes (53%), pericardium (45%), contralateral lung (36%), liver (32%), peritoneum (24%), bone (14%), and myocardium (13%).<a class="elsevierStyleCrossRef" href="#bib0230">46</a>Palliative treatmentThe pain of the PM patient often has a mixed nociceptive and neuropathic component. A combination of non-opioid (paracetamol, non-steroidal anti-inflammatory drugs), opioid (tramadol, morphine) and neuropathic pain (gabapentin, pregabalin) drugs may be required. Local analgesic radiotherapy is occasionally indicated (total dose of 20−40Gy) or interventional techniques such as percutaneous cervical cordotomy or intercostal nerve blocks.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> Nutritional and psychological support should be part of palliative care.The management of dyspnoea secondary to PE is the key to improving the patient's quality of life. In patients with very poor performance status in whom death is expected within days or a few weeks, therapeutic thoracocentesis is an appropriate measure.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> It consists of draining as much pleural fluid as possible, discontinuing the procedure when no more fluid is aspirated or when symptoms develop, such as chest tightness, pain or persistent cough. For the rest of the patients, the definitive control of the pleural space can be carried out indistinctly through the insertion of an indwelling pleural catheter (IPC)<a class="elsevierStyleCrossRef" href="#bib0245">49</a> or a chemical talc pleurodesis.<a class="elsevierStyleCrossRefs" href="#bib0250">50,51</a> Talc (4g) is administered as a powder through a thoracoscope (talc poudrage) or dissolved in physiological saline (talc slurry) through a chest catheter or the IPC itself. Pleurodesis would be contraindicated in cases of non-expandable lung, a situation that is observed in a third of PM cases.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> As it is difficult to predict the existence of a non-expandable lung, IPC is used in many centres as the first line of therapy. When the tumour is discovered during thoracoscopy, the most pragmatic approach would be to spray talc after the biopsy and place an IPC at the same time. Thus, if the lung fails to expand, IPC can establish PE control. The IPC is a fenestrated silicone tube (15.5French) that is placed on an outpatient basis and allows home treatment of PE. Through its connection to a vacuum bottle, regular drainage (e.g., 3 times a week or when the patient has symptoms) prevents symptomatic fluid re-accumulation. In about half of the cases, spontaneous pleurodesis occurs, leading to definitive removal of the IPC.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> If early removal is important to the patient, intensive daily emptying of the pleural fluid may be chosen (e.g., for 10 days) and, if the lung expands, subsequent instillation of talc slurry.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>SurgerySurgery has a very limited role in PM since it will always be incomplete due to the multifocal nature of the disease. It can only be considered in highly selected patients with epithelioid or biphasic PM in stages I-IIIA, good performance status and cardiorespiratory capacity. In addition, it should be performed by experienced surgeons and in the context of a clinical trial or multimodal therapy (e.g., 4 courses of chemotherapy with neoadjuvant or adjuvant cisplatin-pemetrexed and/or adjuvant radiotherapy).<a class="elsevierStyleCrossRef" href="#bib0160">32</a> If indicated, the goal is complete macroscopic resection of all visible or palpable tumour through a single port of entry. If, during surgery, this objective proves not to be feasible (20−40% of cases), the surgical procedure should be discontinued. Possible surgical modalities are pleurectomy/decortication, in its simple and extended variants, and extrapleural pneumonectomy. Pleurectomy/decortication consists of complete removal of the pleura (visceral and parietal) and of all visible tumour, with the possibility of adding resection of the pericardium and hemidiaphragm (extended and generally preferred form). In extrapleural pneumonectomy, the lung is removed in addition to the pleura, pericardium and hemidiaphragm, but this is not recommended given its high morbidity and mortality.<a class="elsevierStyleCrossRefs" href="#bib0145">29,54</a>RadiotherapyThe role of radiotherapy in the context of multimodal treatment is controversial since it does not improve survival and can cause significant toxicity in neighbouring organs. Intensity-modulated radiotherapy has a better safety profile, but the existing studies are scarce. The use of prophylactic radiotherapy on instrumentation tracts used for diagnosis or treatment of the disease had been recommended for decades to reduce the risk of subcutaneous metastases. This action is currently discouraged by all scientific guidelines.<a class="elsevierStyleCrossRefs" href="#bib0140">28–33</a> A recent meta-analysis of 5 randomized studies involving 737 patients showed that prophylactic irradiation reduces the risk of procedure tract metastases (odds ratio 0.55), at the expense of some degree of skin toxicity.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> However, survival and the course of the disease remain unchanged, so it seems more appropriate to irradiate only patients who have developed this complication.Systemic therapyCurrently, the standard systemic treatment in the subject with unresectable PM and an ECOG performance scale (Eastern Cooperative Oncology Group) of 0–2 comprises 3 possible regimens<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The first and most conventional is combination chemotherapy of cisplatin (or carboplatin) and pemetrexed every 3 weeks for 4–6 courses, with folic acid and vitamin B12 supplementation to reduce pemetrexed toxicity. Maintenance therapy with gemcitabine could be considered, although the evidence is weak, and it is not routinely recommended.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> A second regimen would be the combination of cisplatin (or carboplatin), pemetrexed, and bevacizumab (antiangiogenic) every 3 weeks for a maximum of 6 courses, followed by maintenance with bevacizumab every 3 weeks until disease progression. Finally, a third regimen involves immunotherapy with nivolumab administered every 3 weeks together with ipilimumab every 6 weeks until disease progression, onset of toxicity or a maximum period of 2 years. This dual immunotherapy regimen requires the patient to have an ECOG scale of 0−1. It can be used in any histological type of PM, regardless of programmed death ligand 1 (PD-L1) expression, although it would be particularly recommended in biphasic or sarcomatoid PM. In contrast, given that immunotherapy may take longer to achieve an antitumor effect, in patients with voluminous epithelial PM it might be preferable to use one of the first 2 regimens described.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> In any case, any of these 3 first-line therapeutic options should be prescribed without delay once the diagnosis is established, before any functional deterioration of the patient (ECOG≥3) could contraindicate them. These first-line treatments offer overall survivals of around 18 months. Systemic treatment of PM is a very dynamic field, and we may soon see new first-line options such as the combination of chemotherapy and immunotherapy, with or without antiangiogenic drugs.<a class="elsevierStyleCrossRef" href="#bib0280">56</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>There is more uncertainty about second-line treatments, although single (nivolumab or ipilimumab) or dual immunotherapy is encouraged in patients who have not previously received it.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33,56</a> As mentioned, PE-L1 expression is not a criterion for selecting patients who can be treated with immune checkpoint inhibitors. Other options would be retreatment with cisplatin-pemetrexed or pemetrexed alone or, if confirmed in new trials, the combination of gemcitabine and ramucirumab (a monoclonal antibody that binds to vascular endothelial growth factor receptor-2).<a class="elsevierStyleCrossRefs" href="#bib0160">32,56</a>The evaluation of the response to treatment in the context of a clinical trial is based on the information offered by chest CT. The definition of complete response, partial response, progressive disease and stable disease must follow the RECIST criteria (Response Evaluation Criteria in Solid Tumors) modified for PM.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> However, with the growing use of immunotherapy, these criteria should be reviewed.Future perspectivesThe use of liquid biopsy in non-blood samples such as pleural fluid could favour a minimally invasive diagnosis of PM in the future.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) techniques and other biotechnological advances may help design gene therapies for this disease.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> More randomized clinical trials with a sufficient number of patients are needed to discover new therapeutic approaches in PM, a disease with an ominous prognosis whose management has not started to change until very recently with the advent of immunotherapy. To explore whether positron emission tomography is a useful marker to select patients who may benefit from immunotherapy, the potential use of intrapleural immunotherapy and of molecular and cell therapies (dendritic cell vaccines, chimeric antigen receptor T-cell therapies) are just some of the challenges that translational research on PM holds for us.<a class="elsevierStyleCrossRefs" href="#bib0280">56,60</a>FundingNo funding has been received.Conflict of interestsThe author declares no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1765266" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1552223" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1765265" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1552224" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Etiopathogenesis" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Diagnosis" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Imaging techniques: staging" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Cytohistological studies" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Prognosis" ] 8 => array:3 [ "identificador" => "sec0035" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Palliative treatment" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Surgery" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Radiotherapy" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Systemic therapy" ] ] ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Future perspectives" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-02-06" "fechaAceptado" => "2022-03-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1552223" "palabras" => array:6 [ 0 => "Mesothelioma" 1 => "Malignant pleural effusion" 2 => "Asbestos" 3 => "BRCA-1 associated protein 1" 4 => "Indwelling catheters" 5 => "Immunotherapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1552224" "palabras" => array:6 [ 0 => "Mesotelioma" 1 => "Derrame pleural maligno" 2 => "Asbesto" 3 => "Proteína 1 asociada a BRCA1" 4 => "Catéter permanente" 5 => "Inmunoterapia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The diagnosis of diffuse pleural mesothelioma requires in most cases a pleural biopsy, performed either under imaging guidance (ultrasound or CT) or thoracoscopy. Loss of BAP1 or MTAP expression (immunohistochemistry) and homozygous deletion of CDKN2A (fluorescence in situ hybridization) are the basic molecular markers for the diagnosis of mesothelioma. The histologic type and patient’s performance status are the most important prognostic factors. Pleural effusion can be managed by the insertion of tunneled pleural catheters, either as a stand-alone measure (e.g., patients not amenable to multimodality therapy who have been diagnosed by pleural fluid cytology or image-guided biopsy) or combined with the administration of aerosolized talc during a diagnostic thoracoscopy. Immunotherapy is one of the front-line approaches in inoperable patients, particularly in biphasic or sarcomatous histologic varieties." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El diagnóstico de mesotelioma pleural difuso requiere en la mayoría de los casos una biopsia pleural, realizada bajo control de imagen (ecografía o tomografía computarizada) o mediante toracoscopia. La pérdida de expresión de BAP1 o de MTAP (inmunohistoquímica) y la deleción homocigota de CDKN2A (hibridación fluorescente in situ) constituyen los marcadores moleculares básicos para el diagnóstico de mesotelioma. El tipo histológico y el estado funcional del paciente son los factores pronósticos más importantes. El control del derrame pleural se puede realizar a través de la inserción de catéteres pleurales tunelizados, bien como medida aislada (p. ej. pacientes no susceptibles de terapia multimodal que se han diagnosticado por citología del líquido pleural o biopsia guiada por imagen) o combinada con la administración de talco aerosolizado durante una toracoscopia diagnóstica. La inmunoterapia constituye una de las primeras líneas de tratamiento en pacientes inoperables, particularmente en las variedades histológicas bifásicas o sarcomatosas." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1276 "Ancho" => 2508 "Tamanyo" => 312256 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0040" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pleural mesothelioma. Chest X-ray shows circumferential pleural thickening (A), which is confirmed by computed tomography (B), where an associated pleural effusion is also seen (C)." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1758 "Ancho" => 2917 "Tamanyo" => 271837 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0045" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for cellular atypia in fluid samples or pleural biopsy. BAP1: BRCA1-associated protein 1; CEA: carcinoembryonic antigen; FISH: Fluorescent In Situ Hybridization; IHC: immunohistochemistry; MTAP: methylthioadenosine phosphorylase; TTF-1: Thyroid Transcription Factor-1; WT-1: Wilms tumor-1. aCDKN2A determination by FISH is more expensive and time consuming than immunohistochemical staining for MTAP." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1625 "Ancho" => 2500 "Tamanyo" => 190343 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Simplified diagnostic and therapeutic algorithm for pleural mesothelioma. IPC: indwelling pleural catheter; PE: pleural effusion; ECOG: Eastern Cooperative Oncology Group; PM: pleural mesothelioma; US: ultrasonography; CT: computed tomography." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0055" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T-Primary tumour</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor limited to the ipsilateral parietal and/or visceral pleura \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor that affects the ipsilateral pleura (parietal or visceral) together with: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Diaphragm muscle involvement, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Invasion of the underlying lung parenchyma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor that affects the ipsilateral pleura (parietal or visceral) together with: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Invasion of the endothoracic fascia, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Extension to the mediastinal fat, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Solitary and completely resectable tumour focus extended to soft tissues of the chest wall, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Non-transmural involvement of the pericardium \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T4<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor that affects the ipsilateral pleura (parietal or visceral) together with: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Diffuse extension or multifocal tumour masses in the chest wall, with or without rib destruction, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Transdiaphragmatic spread of tumour to the peritoneum, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Tumor spread to the contralateral pleura, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Tumor extension to mediastinal organs<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a>, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Tumor spread to the spine<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a>, or \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">* Extension to the inner surface of the pericardium, with or without pericardial effusion, or tumour involvement of the myocardium \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N-Lymph nodes</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No regional lymph node metastases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metastases in ipsilateral bronchopulmonary, hilar, or mediastinal lymph nodes<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N2<a class="elsevierStyleCrossRef" href="#tblfn0030">f</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metastases in contralateral mediastinal lymph nodes, or ipsilateral or contralateral supraclavicular lymph nodes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M-Metastasis</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No distant metastasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Distant metastasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Staging</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T1 N0 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T2–T3 N0 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T1–T2 N1 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IIIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T3 N1 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IIIB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T1–T3 N2 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T4 N0–N2 M0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Any T, any N, M1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "T3 implies locally advanced but potentially resectable tumour." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "T4 implies locally advanced but technically unresectable tumour." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Oesophagus, trachea, great vessels, heart." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Vertebrae, intervertebral foramen, spinal cord or brachial plexus." ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "Includes internal mammary, subcarinal, paratracheal, aortopulmonary, paraesophageal, diaphragmatic, pericardial fat, or intercostal lymph nodes." ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "N2 implies contraindication for debulking surgery." ] ] ] "descripcion" => array:1 [ "en" => "TNM staging of pleural mesothelioma (8th ed. International Association for the Study of Lung Cancer)." ] ] 4 => array:9 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Fortin et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0060" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "PE: pleural effusion." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign and preinvasive mesothelial tumours</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adenomatoid tumour \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Focal proliferation without multifocal or diffuse spread in the pleura \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well-differentiated papillary mesothelial tumour \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare tumour. Papillary formation covered with a single layer of mesothelial cells, without stromal invasion. It occurs as a nodule or arborescent mass in the visceral or parietal pleura, together with recurrent PE. Absence of mesothelioma molecular data<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mesothelioma in situ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">It manifests as recurrent or persistent PE, without evidence of tumour on imaging tests or thoracoscopic examination. Pleural fluid cytology may be indistinguishable from epithelioid mesothelioma. There should be no histological data of tumour invasion in the biopsy, but there should be molecular markers of mesothelioma<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a>. It can progress to invasive mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mesothelioma</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Localized mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Solitary localized pleural mass, without invasion outside the margins of the tumour and with histology of diffuse mesothelioma. Rare (1% of mesotheliomas) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diffuse mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diffuse pleural thickening with invasion of adjacent structures (adipose tissue, musculoskeletal, lung). Three histological varieties (epithelioid, sarcomatoid, biphasic) and characteristic molecular data<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelioid mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The architectural pattern<a class="elsevierStyleCrossRef" href="#tblfn0040">b</a>, certain cytological and stromal data, and nuclear grading (atypia, mitoses, presence or absence of necrosis) have prognostic significance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sarcomatoid mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Desmoplastic mesothelioma is a variant of sarcomatoid mesothelioma characterized by dense collagen fibres separated by malignant mesothelial cells arranged in a storiform pattern. These features should be present in>50% of the tumour obtained from surgical resections<a class="elsevierStyleCrossRef" href="#tblfn0045">c</a>; in small biopsy specimens should only be indicated if desmoplastic features are present \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biphasic mesothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There must be a minimum of 10% of both epithelioid and sarcomatoid components in surgical specimens<a class="elsevierStyleCrossRef" href="#tblfn0045">c</a>, but any percentage is acceptable in small biopsies or cytology \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "Loss of expression of BAP1 or MTAP by immunohistochemistry, homozygous deletion of CKN2A by fluorescent hybridization in situ, BAP1 or CKN2A mutations by next generation sequencing." ] 1 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "b" "nota" => "The pleomorphic and transitional patterns have a similar prognosis to sarcomatoid and biphasic mesotheliomas, respectively." ] 2 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "c" "nota" => "Extended pleurectomy/decortication or extrapleural pneumonectomy." ] ] ] "descripcion" => array:1 [ "en" => "Classification of mesothelial tumours according to WHO (5th ed. 2021)." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0065" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "BAP1: BRCA1-associated protein 1; CEA: carcinoembryonic antigen ; CK: cytokeratin; EpCAM: epithelial cell adhesion molecule; IMP-3, insulin-like growth factor 2 mRNA-binding protein 3; MTAP: methylthioadenosine phosphorylase; TTF-1: Thyroid Transcription Factor-1; WT-1: Wilms tumor-1." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Markers to confirm mesothelial origin<a class="elsevierStyleCrossRef" href="#tblfn0050">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Carcinoma markers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Markers to differentiate benign from malignant mesothelial proliferations \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Calretinin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Claudine 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BAP1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wilms tumor-1 (WT-1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TTF-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MTAP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D2-40 (podoplanin)<a class="elsevierStyleCrossRef" href="#tblfn0055">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CEA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IMP-3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CK 5/6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EpCAM (Ber-EP4 or MOC-31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Desmin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B72.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p40/p63<a class="elsevierStyleCrossRef" href="#tblfn0060">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0050" "etiqueta" => "a" "nota" => "There is immunoreactivity in both benign and malignant mesothelial cells." ] 1 => array:3 [ "identificador" => "tblfn0055" "etiqueta" => "b" "nota" => "It is the most sensitive marker in sarcomatoid mesothelioma." ] 2 => array:3 [ "identificador" => "tblfn0060" "etiqueta" => "c" "nota" => "Squamous cell carcinoma marker." ] ] ] "descripcion" => array:1 [ "en" => "Immunohistochemical markers commonly used in the differential diagnosis of mesothelioma." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Orphanet Report Series. 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Pleural mesothelioma

Mesotelioma pleural

José Manuel Porcel

Unidad de Medicina Pleural, Servicio de Medicina Interna, Hospital Universitari Arnau de Vilanova, IRBLleida, Universitat de Lleida, Lleida, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In the European Union&#44; a disease is defined as rare when it affects no more than one person in 2000&#46; Consequently&#44; pleural mesothelioma &#40;PM&#41; is considered a rare disease in Europe&#44; with a prevalence of 3&#46;1 cases per 100&#44;000 inhabitants&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> According to GLOBOCAN <span class="elsevierStyleItalic">&#40;Global Cancer Observatory&#41;</span>&#44; a subsidiary of the World Health Organisation&#44; 30&#44;870 new cases of mesothelioma were diagnosed worldwide in 2020 &#40;44&#46;2&#37; in Europe and 31&#46;5&#37; in Asia&#41; and 26&#44;278 people died of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The age-adjusted incidence rate was 0&#46;30&#47;100&#44;000 and the mortality rate was 0&#46;25&#47;100&#44;000&#46; The tumour predominantly affects males &#40;70&#37;&#41;&#46; In that same year&#44; 586 new cases of mesothelioma were identified in Spain&#44; 504 individuals died&#44; and the estimated prevalence of the disease for the last 5 years was 1&#46;58&#47;100&#44;000&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> More than 90&#37; of mesotheliomas originate in the pleura and 5&#8211;6&#37; in the peritoneum&#44; with mesotheliomas of the pericardium or the tunica vaginalis being very rare&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> This review will briefly address the etiopathogenic&#44; clinical&#44; prognostic&#44; and therapeutic aspects of diffuse PM&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Etiopathogenesis</span><p id="par0010" class="elsevierStylePara elsevierViewall">Inhalation of asbestos fibres suspended in the air is considered the main etiopathogenic mechanism of PM&#46; Approximately 80&#37; of these patients have a history of direct or indirect exposure to asbestos&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However&#44; only about 10&#37; of exposed individuals will end up developing a PM&#44; after a latency period of about 40 years &#40;range&#58; 20&#8211;50&#41; from exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> There is a linear relationship between the amount of exposure and the risk of disease&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The word asbestos is etymologically derived from Greek and means &#34;inextinguishable or incombustible&#34;&#44; denoting that this mineral does not deteriorate even when subjected to fire or other agents&#46; &#8220;Amiantos&#8221;&#44; the source word for asbestos in many languages&#44; also derives from the Greek and means &#34;undefiled&#34;&#44; referring to the fact that this silicate presents in the form of white fibres&#46; Asbestos comprises 6 fibrous metasilicates&#44; including white &#40;chrysotile&#41;&#44; blue &#40;crocidolite&#41; and brown &#40;amosite&#41; asbestos&#46; Chrysotile is the most used in construction and the least toxic&#44; amosite &#40;the second most used&#41; is used in thermal insulation&#44; and crocidolite is the most toxic of the 3 and is used in the manufacture of fibre cement pipes or covers &#40;uralite&#41; and fireproof material&#46; Chrysotile is the only representative of the so-called serpentine fibres &#40;because of their curved shape&#41;&#44; while the rest of the asbestos fibres are amphibole &#40;straight or elongated and highly biopersistent&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The list of jobs that may carry a risk of exposure to asbestos is extensive&#44; since it has been widely used in the iron and steel&#44; automobile&#44; naval&#44; aeronautical&#44; chemical&#44; textile&#44; and construction industries&#46; Exposure to asbestos can be not only occupational&#44; but also domestic or &#34;para-occupational&#34; &#40;e&#46;g&#46;&#44; washing of work clothes&#41; and environmental &#40;e&#46;g&#46;&#44; demolition or deterioration of buildings&#44; proximity to asbestos factories or mines&#44; living or working in asbestos-containing buildings&#44; erosion of naturally occurring asbestos&#41;&#46; The term natural occurring asbestos refers to the presence of asbestos fibres &#40;e&#46;g&#46;&#44; tremolite&#41; or asbestiform minerals &#40;e&#46;g&#46;&#44; erionite&#44; vermiculite&#44; fluoro-edenite&#41; in soil and rocks in certain geographical areas&#44; which may be released by climate erosion or human activities or inadvertently used for the construction of buildings&#44; representing a major source of environmental exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The occupational exposure is more common in men with PM&#44; while domestic or environmental exposure affects men and women equally&#46; Many cases of PM considered idiopathic or spontaneous are likely to be unrecognised cases of asbestos exposure&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">As of July 2019&#44; 67 countries had developed laws prohibiting the use of asbestos&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> However&#44; it is not yet banned in China&#44; India&#44; Russia&#44; or the USA&#44; among others&#46; In Spain&#44; a ban on the manufacture&#44; marketing or installation of products containing asbestos was introduced in 2002&#46; Russia and Kazakhstan are the largest producers of asbestos in the world&#44; with a total of 790&#44;000 and 210&#44;000 metric tons in 2020&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> On the other hand&#44; Asia and the Middle East were the regions with the highest consumption of this material &#40;1&#46;18 million metric tons&#41; in 2019&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The precise carcinogenic mechanisms of asbestos are not fully understood&#46; The amphiboles reach the alveolus and are phagocytosed by macrophages&#46; Such phagocytosis may be inefficient&#44; activating a series of inflammatory responses &#40;reactive oxygen species&#44; proinflammatory cytokines&#41; and creating a mutagenic microenvironment around mesothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Mutations in the BRCA-1 associated protein 1 &#40;BAP1&#41; gene&#44; located on the short arm of chromosome 3&#44; are particularly important as they prevent apoptosis of mesothelial cells and favour the accumulation of additional mutations &#40;e&#46;g&#46; in the genes <span class="elsevierStyleItalic">cyclin-dependent kinase inhibitor 2A</span> &#91;CDKN2A&#93;&#44; <span class="elsevierStyleItalic">neurofibromatosis type 2</span> &#91;NF2&#93;&#44; TP53&#44; <span class="elsevierStyleItalic">SET domain containing 2</span> &#91;SETD2&#93;&#41;&#44; and <span class="elsevierStyleItalic">SET domain bifurcated 1</span> &#91;SETDB1&#93;&#41;&#44; favouring their malignant transformation&#46; The loss or inactivation of the BAP1 gene&#44; present in around 60&#37; of PMs&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> justifies tumour development by the tumour suppressor effect of the protein it encodes&#44; whose anti-ubiquitination activity regulates processes such as DNA repair&#44; cell cycle&#44; apoptosis&#44; chromatin structuring and cell proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Other common genetic alterations in PM also involve tumour suppressor genes&#58; the CDKN2A gene&#44; which encodes p16 and p14 proteins&#59; the NF2 gene encoding the merlin protein&#59; the TP53 gene encoding the p53 protein&#59; and the SETD2 and SETDB1 genes encoding a histone methyltransferase protein of the same name&#46; In fact&#44; germline BAP1 mutations are associated with a syndrome of autosomal dominant inheritance cancers in humans&#44; including mesothelioma &#40;mostly of epithelioid lineage&#41;&#44; uveal melanoma&#44; cutaneous melanoma&#44; renal cell carcinoma and&#44; less commonly&#44; basal cell carcinoma and atypical Spitz tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Familial PMs accounted&#44; however&#44; for only 0&#46;5&#37; of 560 PMs in a Spanish multicentre series&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Exposure to ionising radiation in supradiaphragmatic fields &#40;e&#46;g&#46;&#44; lymphoma survivors who underwent radiotherapy&#41; is also a risk factor for the development of PM&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Finally&#44; carbon nanotubes have physicochemical characteristics &#40;shape&#44; size&#44; biopersistence&#41; similar to asbestos fibres&#46; Their potential biomedical applications are wide-ranging and include the delivery of anti-tumour drugs or radiotracers in imaging tests&#46; In experimental animals&#44; they induce PM through signalling pathways common to asbestos tumorigenesis&#44; and therefore future monitoring of their effects in humans is required&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis</span><p id="par0040" class="elsevierStylePara elsevierViewall">The mean age of onset of PM is approximately 70 years and the main symptoms are dyspnoea &#40;&#8765;65&#37;&#41;&#44; chest pain &#40;&#8765;50&#37;&#41;&#44; weight loss &#40;&#8765;40&#37;&#41; and cough &#40;&#8765;20&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> About 3&#37; of PMs develop before the age of 45&#44;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and it appears that this subgroup of patients has differential features both clinically &#40;similar gender distribution&#44; lower history of asbestos exposure and higher prior radiotherapy&#41; and genetically &#40;lower prevalence of CDKN2A deletion&#41; compared to older patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The most common finding on chest X-ray is a unilateral pleural effusion &#40;PE&#41;&#44; with or without associated pleural thickening &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Dyspnoea is explained by PE or tumour infiltration of the lung&#44; while chest pain is often related to soft tissue invasion &#40;chest wall&#44; mediastinum&#41; or neuropathic involvement&#46; The disease should be highly suspected in subjects with a history of occupational exposure to asbestos or suggestive radiological data &#40;e&#46;g&#46;&#44; pleural plaques&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Imaging techniques&#58; staging</span><p id="par0045" class="elsevierStylePara elsevierViewall">Imaging tests strengthen the clinical suspicion of PM and are essential for tumour staging &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and decide if it is potentially resectable&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> All subjects should have a contrast-enhanced computed tomography &#40;CT&#41; of the chest and upper abdomen&#44; with extension to the abdominopelvic area if the diagnosis is confirmed&#46; To optimize visualization of the pleural membranes&#44; images should be acquired in the venous phase&#44; 1&#8211;4<span class="elsevierStyleHsp" style=""></span>min after contrast administration&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The most characteristic radiological data is the presence of a circumferential pleural thickening &#40;30&#8211;55&#37;&#41; together with an ipsilateral PE &#40;90&#37;&#41;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The former is significantly less common in malignant metastatic PEs &#40;10&#8211;19&#37;&#41;&#46; Mediastinal&#44; diaphragmatic&#44; and fissural pleural thickening are also more common in PM than in metastatic PE&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> The visualization of pleural &#8220;asbestos&#8221; plaques is variable &#40;20&#8211;65&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Positron emission tomography</span> &#40;PET&#41; combined with CT &#40;PET-CT&#41; is useful for detecting nodal and extrathoracic disease in potentially operable patients&#46; It should be indicated before any pleurodesis attempt since the inflammation caused by the sclerosing agent would give rise to false positives&#46; On the other hand&#44; a negative PET-CT &#40;maximum standardized uptake value or SUV<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>2&#44;5&#41; has been described in around 10&#37; of PM cases&#44; especially in early stages of the tumour and in elderly people&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In addition to pre-surgical staging&#44; PET-CT may help to identify the ideal site for pleural biopsy &#40;area with increased SUV&#41; in cases of diffuse pleural thickening&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Since the distinction between resectable &#40;T3&#41; and unresectable &#40;T4&#41; tumours is critical&#44; contrast-enhanced MRI is an appropriate test in seemingly surgical patients when the aim is to establish possible tumour invasion of the chest wall&#44; endothoracic fascia&#44; diaphragm or mediastinal vessels&#44; for which CT is inaccurate&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Occasionally&#44; when the diagnosis of extension is uncertain and the patient is a surgical candidate&#44; invasive techniques such as endobronchial or endoscopic ultrasonography&#44; mediastinoscopy&#44; contralateral thoracoscopy&#44; or laparoscopy may be required&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Cytohistological studies</span><p id="par0065" class="elsevierStylePara elsevierViewall">There are 3 histological types of diffuse PM&#58; epithelioid &#40;&#8765;60&#8722;70&#37;&#41;&#44; sarcomatoid &#40;&#8765;10&#37;&#41; and biphasic or mixed &#40;&#8765;20&#8722;30&#37;&#41;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;26</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; However&#44; in some series the percentage of unspecified histologies can reach 40&#8722;50&#37; of all cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;27</span></a> The definitive diagnosis of PM requires cytohistological confirmation&#46; The various scientific societies are unanimous in recommending pleural biopsy as the diagnostic method of choice&#44; preferably thoracoscopically-assisted&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;33</span></a> However&#44; a cytological study of the pleural fluid should always be the first step&#44; as it may sometimes be diagnostic of epithelioid PM&#44; but not of the sarcomatoid variant where cells rarely exfoliate into the pleural space&#46; At least 40&#8722;50<span class="elsevierStyleHsp" style=""></span>ml of pleural fluid should be tested and both Papanicolaou- or Giemsa-stained smears and haematoxylin-eosin-stained paraffin-embedded cell blocks should be examined in the laboratory&#44; as they are complementary tests&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Immunohistochemical studies are performed on the cell block specimens&#46; In a recent meta-analysis that included 1347 cases of PM&#44; the sensitivity of pleural fluid cytology to identify this tumour was only 28&#46;9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Therefore&#44; if PM is suspected and a first cytological study is negative&#44; a pleural biopsy should be carried out directly without the need to repeat a second diagnostic thoracocentesis &#40;a common action in metastatic PE&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Ultrasound or CT-guided pleural biopsies represent a minimally invasive procedure that is particularly useful when there are areas of pleural thickening&#44; as well as a good alternative when thoracoscopy is not possible due to the physical condition of the patient or the unavailability of such a technique&#46; Outside of these circumstances&#44; thoracoscopy with sedation&#44; using rigid or semi-rigid instruments through a single port of entry&#44; allows pleural tissue to be obtained under direct visualization&#46; Biopsies should be deep and ideally come from 3 different areas&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Demonstration of subpleural fat invasion and sufficient sample for immunohistochemical studies are key elements for a diagnosis of certainty&#46; Some studies show that around 20&#37; of epithelioid PM diagnosed by biopsy are reclassified as biphasic PM in the surgically resected specimen&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In part&#44; this fact could be explained by intratumoral heterogeneity&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">With the material available&#44; be it a cell block of pleural fluid or a biopsy&#44; the pathologist must sequentially answer 2 questions&#58; 1&#41; are the cells observed of mesothelial &#40;MP or reactive mesothelium&#41; or epithelial &#40;carcinoma&#41; origin&#44; and 2&#41; if the cells are mesothelial&#44; are they malignant in nature or reactive to a benign condition&#63; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Regarding the first question&#44; the diagnosis of PM &#40;epithelioid&#41; requires the combination of at least 2 positive immunohistochemical markers of mesothelium &#40;e&#46;g&#46;&#44; calretinin&#44; WT-1&#44; D2-40&#41; and 2 negative markers of carcinoma &#40;e&#46;g&#46;&#44; claudin 4&#44; TTF-1&#44; CEA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;37</span></a> The antibodies selected must have <span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>80&#37; of sensitivity and specificity &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Sarcomatoid PMs usually stain with broad-spectrum cytokeratins&#44; unlike sarcomas&#46; Once the mesothelial cell differentiation is confirmed&#44; the distinction between MP and reactive mesothelial proliferation is established with 3 markers&#58; BAP1&#44; methylthioadenosine phosphorylase &#40;MTAP&#41;&#44; and CDKN2A &#40;p16&#41;&#46; The first 2 are assessed by immunohistochemistry and the third by <span class="elsevierStyleItalic">Fluorescent</span> In Situ <span class="elsevierStyleItalic">Hybridization</span> &#40;FISH&#41;&#46; Characteristically&#44; PM has a complete &#40;or partial&#41; loss of nuclear BAP1 and cytoplasmic MTAP expression &#40;negative staining&#41;&#44; as well as a homozygous deletion of CDKN2A&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39</span></a> A meta-analysis including 1824 patients &#40;1016 with mesothelioma&#44; predominantly pleural&#41; showed a sensitivity of BAP1 immunostaining of histological and cytological specimens of 74&#37; for the epithelioid variety&#44; 50&#37; for the biphasic variety and 7&#37; for the sarcomatoid variety&#59; an overall weighted sensitivity of 56&#37;&#44; specificity of 100&#37;&#44; positive <span class="elsevierStyleItalic">likelihood ratio</span> of 549 and negative <span class="elsevierStyleItalic">likelihood ratio</span> of 0&#46;44 were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Regarding sarcomatoid PMs&#44; CDKN2A is more sensitive &#40;70&#8211;80&#37;&#41; than BAP1&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> More recently&#44; another meta-analysis evaluated the diagnostic efficacy of these markers on cytological specimens &#40;cell blocks and&#47;or smears&#41; from 5324 patients with PM&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The respective sensitivities and specificities described were&#58; BAP1&#44; 65&#37; and 99&#37;&#59; MTAP&#44; 47&#37; and 99&#37;&#59; CDKN2A&#44; 62&#37; and 100&#37;&#59; and the combination of BAP1 and CDKN2A&#44; 83&#37; and 100&#37;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Finally&#44; in recent years numerous studies have been published on the potential usefulness of certain diagnostic biomarkers of PM in blood and pleural fluid&#44; such as mesothelin&#44; fibulin 3 or high mobility group box 1 proteins &#40;HMGB1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> The most studied has been mesothelin&#44; a membrane glycoprotein usually measured by immunoassay techniques &#40;ELISA&#41;&#46; In a recent meta-analysis&#44; the area under the curve &#40;AUC&#41; of mesothelin in plasma was 0&#46;86 and 0&#46;83 in pleural fluid&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Another meta-analysis reported an overall sensitivity of 73&#37; and a specificity of 90&#37; for pleural fluid mesothelin&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Its detection is not common in clinical practice&#44; and&#44; in any case&#44; it does not avoid the need to demonstrate the existence of PM by histological criteria&#46; A potential utility of mesothelin could be the monitoring of treatment in patients with epithelioid PM and normal renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prognosis</span><p id="par0085" class="elsevierStylePara elsevierViewall">Survival at 1&#44; 3 and 5 years of 9458 patients with PM from the English CAS <span class="elsevierStyleItalic">&#40;Cancer Analysis System&#41;</span> registry was 38&#44; 16 and 8&#37;&#44; respectively<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#59; data very similar to those offered by the SEER <span class="elsevierStyleItalic">&#40;Surveillance&#44; Epidemiology&#44; and End Results program&#41; database</span> of the <span class="elsevierStyleItalic">National Cancer Institute</span> in the USA on 2138 cases &#40;39&#46;4&#44; 11&#46;8 and 3&#46;8&#37;&#44; respectively&#41;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> and other large series&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> The overall median survival of the CAS cohort was 8&#46;3 months and that of the SEER cohort was 9 months&#46; Survival is negatively influenced by sarcomatoid histology&#44; advanced stages &#40;N2 or M1&#41;&#44; and palliative care treatment only&#46; Thus&#44; in the CAS cohort&#44; the median overall survival of patients with epithelioid&#44; biphasic&#44; unspecified&#44; and sarcomatoid histologies was 13&#46;3&#59; 8&#46;3&#59; 5&#46;8 and 4&#46;3 months&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Subjects treated with surgery lived a median of 17 months&#44; those who received systemic cancer treatment&#44; with or without radiotherapy&#44; 14 months&#44; and those who received only palliative care or radiotherapy alone 4&#46;6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">A validated prognostic model is that described by Brims et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> which categorises patients into 4 groups with different survival&#44; depending on the existence of weight loss&#44; performance status&#44; haemoglobin and albumin levels&#44; and histological type of tumour&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0095" class="elsevierStylePara elsevierViewall">PM is nowadays an incurable disease&#46; Symptomatic PE and pain control are priority objectives&#46; The application of other therapeutic measures must take into account factors such as stage&#44; histology&#44; age&#44; performance status and patient preferences&#46; The disease may be unsuspectedly widespread&#46; Thus&#44; in a necropsy study of 318 patients with PM&#44; it was found that 88&#37; had extrapleural dissemination and 55&#37; extrathoracic&#44; with the most common sites of metastatic spread being lymph nodes &#40;53&#37;&#41;&#44; pericardium &#40;45&#37;&#41;&#44; contralateral lung &#40;36&#37;&#41;&#44; liver &#40;32&#37;&#41;&#44; peritoneum &#40;24&#37;&#41;&#44; bone &#40;14&#37;&#41;&#44; and myocardium &#40;13&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Palliative treatment</span><p id="par0100" class="elsevierStylePara elsevierViewall">The pain of the PM patient often has a mixed nociceptive and neuropathic component&#46; A combination of non-opioid &#40;paracetamol&#44; non-steroidal anti-inflammatory drugs&#41;&#44; opioid &#40;tramadol&#44; morphine&#41; and neuropathic pain &#40;gabapentin&#44; pregabalin&#41; drugs may be required&#46; Local analgesic radiotherapy is occasionally indicated &#40;total dose of 20&#8722;40<span class="elsevierStyleHsp" style=""></span>Gy&#41; or interventional techniques such as percutaneous cervical cordotomy or intercostal nerve blocks&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Nutritional and psychological support should be part of palliative care&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The management of dyspnoea secondary to PE is the key to improving the patient&#39;s quality of life&#46; In patients with very poor performance status in whom death is expected within days or a few weeks&#44; therapeutic thoracocentesis is an appropriate measure&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> It consists of draining as much pleural fluid as possible&#44; discontinuing the procedure when no more fluid is aspirated or when symptoms develop&#44; such as chest tightness&#44; pain or persistent cough&#46; For the rest of the patients&#44; the definitive control of the pleural space can be carried out indistinctly through the insertion of an indwelling pleural catheter &#40;IPC&#41;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> or a chemical talc pleurodesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> Talc &#40;4<span class="elsevierStyleHsp" style=""></span>g&#41; is administered as a powder through a thoracoscope &#40;talc <span class="elsevierStyleItalic">poudrage&#41; or</span> dissolved in physiological saline &#40;talc <span class="elsevierStyleItalic">slurry</span>&#41; through a chest catheter or the IPC itself&#46; Pleurodesis would be contraindicated in cases of non-expandable lung&#44; a situation that is observed in a third of PM cases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> As it is difficult to predict the existence of a non-expandable lung&#44; IPC is used in many centres as the first line of therapy&#46; When the tumour is discovered during thoracoscopy&#44; the most pragmatic approach would be to spray talc after the biopsy and place an IPC at the same time&#46; Thus&#44; if the lung fails to expand&#44; IPC can establish PE control&#46; The IPC is a fenestrated silicone tube &#40;15&#46;5<span class="elsevierStyleHsp" style=""></span>French&#41; that is placed on an outpatient basis and allows home treatment of PE&#46; Through its connection to a vacuum bottle&#44; regular drainage &#40;e&#46;g&#46;&#44; 3 times a week or when the patient has symptoms&#41; prevents symptomatic fluid re-accumulation&#46; In about half of the cases&#44; spontaneous pleurodesis occurs&#44; leading to definitive removal of the IPC&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> If early removal is important to the patient&#44; intensive daily emptying of the pleural fluid may be chosen &#40;e&#46;g&#46;&#44; for 10 days&#41; and&#44; if the lung expands&#44; subsequent instillation of talc <span class="elsevierStyleItalic">slurry</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Surgery</span><p id="par0110" class="elsevierStylePara elsevierViewall">Surgery has a very limited role in PM since it will always be incomplete due to the multifocal nature of the disease&#46; It can only be considered in highly selected patients with epithelioid or biphasic PM in stages I-IIIA&#44; good performance status and cardiorespiratory capacity&#46; In addition&#44; it should be performed by experienced surgeons and in the context of a clinical trial or multimodal therapy &#40;e&#46;g&#46;&#44; 4 courses of chemotherapy with neoadjuvant or adjuvant cisplatin-pemetrexed and&#47;or adjuvant radiotherapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> If indicated&#44; the goal is complete macroscopic resection of all visible or palpable tumour through a single port of entry&#46; If&#44; during surgery&#44; this objective proves not to be feasible &#40;20&#8722;40&#37; of cases&#41;&#44; the surgical procedure should be discontinued&#46; Possible surgical modalities are pleurectomy&#47;decortication&#44; in its simple and extended variants&#44; and extrapleural pneumonectomy&#46; Pleurectomy&#47;decortication consists of complete removal of the pleura &#40;visceral and parietal&#41; and of all visible tumour&#44; with the possibility of adding resection of the pericardium and hemidiaphragm &#40;extended and generally preferred form&#41;&#46; In extrapleural pneumonectomy&#44; the lung is removed in addition to the pleura&#44; pericardium and hemidiaphragm&#44; but this is not recommended given its high morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;54</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Radiotherapy</span><p id="par0115" class="elsevierStylePara elsevierViewall">The role of radiotherapy in the context of multimodal treatment is controversial since it does not improve survival and can cause significant toxicity in neighbouring organs&#46; Intensity-modulated radiotherapy has a better safety profile&#44; but the existing studies are scarce&#46; The use of prophylactic radiotherapy on instrumentation tracts used for diagnosis or treatment of the disease had been recommended for decades to reduce the risk of subcutaneous metastases&#46; This action is currently discouraged by all scientific guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;33</span></a> A recent meta-analysis of 5 randomized studies involving 737 patients showed that prophylactic irradiation reduces the risk of procedure tract metastases &#40;<span class="elsevierStyleItalic">odds ratio</span> 0&#46;55&#41;&#44; at the expense of some degree of skin toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> However&#44; survival and the course of the disease remain unchanged&#44; so it seems more appropriate to irradiate only patients who have developed this complication&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Systemic therapy</span><p id="par0120" class="elsevierStylePara elsevierViewall">Currently&#44; the standard systemic treatment in the subject with unresectable PM and an ECOG performance scale <span class="elsevierStyleItalic">&#40;Eastern Cooperative Oncology Group&#41;</span> of 0&#8211;2 comprises 3 possible regimens<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The first and most conventional is combination chemotherapy of cisplatin &#40;or carboplatin&#41; and pemetrexed every 3 weeks for 4&#8211;6 courses&#44; with folic acid and vitamin B12 supplementation to reduce pemetrexed toxicity&#46; Maintenance therapy with gemcitabine could be considered&#44; although the evidence is weak&#44; and it is not routinely recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> A second regimen would be the combination of cisplatin &#40;or carboplatin&#41;&#44; pemetrexed&#44; and bevacizumab &#40;antiangiogenic&#41; every 3 weeks for a maximum of 6 courses&#44; followed by maintenance with bevacizumab every 3 weeks until disease progression&#46; Finally&#44; a third regimen involves immunotherapy with nivolumab administered every 3 weeks together with ipilimumab every 6 weeks until disease progression&#44; onset of toxicity or a maximum period of 2 years&#46; This dual immunotherapy regimen requires the patient to have an ECOG scale of 0&#8722;1&#46; It can be used in any histological type of PM&#44; regardless of programmed death ligand 1 &#40;PD-L1&#41; expression&#44; although it would be particularly recommended in biphasic or sarcomatoid PM&#46; In contrast&#44; given that immunotherapy may take longer to achieve an antitumor effect&#44; in patients with voluminous epithelial PM it might be preferable to use one of the first 2 regimens described&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> In any case&#44; any of these 3 first-line therapeutic options should be prescribed without delay once the diagnosis is established&#44; before any functional deterioration of the patient &#40;ECOG<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3&#41; could contraindicate them&#46; These first-line treatments offer overall survivals of around 18 months&#46; Systemic treatment of PM is a very dynamic field&#44; and we may soon see new first-line options such as the combination of chemotherapy and immunotherapy&#44; with or without antiangiogenic drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">There is more uncertainty about second-line treatments&#44; although single &#40;nivolumab or ipilimumab&#41; or dual immunotherapy is encouraged in patients who have not previously received it&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33&#44;56</span></a> As mentioned&#44; PE-L1 expression is not a criterion for selecting patients who can be treated with immune checkpoint inhibitors&#46; Other options would be retreatment with cisplatin-pemetrexed or pemetrexed alone or&#44; if confirmed in new trials&#44; the combination of gemcitabine and ramucirumab &#40;a monoclonal antibody that binds to vascular endothelial growth factor receptor-2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;56</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The evaluation of the response to treatment in the context of a clinical trial is based on the information offered by chest CT&#46; The definition of complete response&#44; partial response&#44; progressive disease and stable disease must follow the RECIST criteria <span class="elsevierStyleItalic">&#40;Response Evaluation Criteria in Solid Tumors&#41;</span> modified for PM&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> However&#44; with the growing use of immunotherapy&#44; these criteria should be reviewed&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Future perspectives</span><p id="par0135" class="elsevierStylePara elsevierViewall">The use of liquid biopsy in non-blood samples such as pleural fluid could favour a minimally invasive diagnosis of PM in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> CRISPR &#40;Clustered Regularly Interspaced Short Palindromic Repeat&#41; techniques and other biotechnological advances may help design gene therapies for this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> More randomized clinical trials with a sufficient number of patients are needed to discover new therapeutic approaches in PM&#44; a disease with an ominous prognosis whose management has not started to change until very recently with the advent of immunotherapy&#46; To explore whether positron emission tomography is a useful marker to select patients who may benefit from immunotherapy&#44; the potential use of intrapleural immunotherapy and of molecular and cell therapies &#40;dendritic cell vaccines&#44; chimeric antigen receptor T-cell therapies&#41; are just some of the challenges that translational research on PM holds for us&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;60</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">No funding has been received&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The author declares no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">The diagnosis of diffuse pleural mesothelioma requires in most cases a pleural biopsy&#44; performed either under imaging guidance &#40;ultrasound or CT&#41; or thoracoscopy&#46; Loss of BAP1 or MTAP expression &#40;immunohistochemistry&#41; and homozygous deletion of CDKN2A &#40;fluorescence in situ hybridization&#41; are the basic molecular markers for the diagnosis of mesothelioma&#46; The histologic type and patient&#8217;s performance status are the most important prognostic factors&#46; Pleural effusion can be managed by the insertion of tunneled pleural catheters&#44; either as a stand-alone measure &#40;e&#46;g&#46;&#44; patients not amenable to multimodality therapy who have been diagnosed by pleural fluid cytology or image-guided biopsy&#41; or combined with the administration of aerosolized talc during a diagnostic thoracoscopy&#46; Immunotherapy is one of the front-line approaches in inoperable patients&#44; particularly in biphasic or sarcomatous histologic varieties&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">El diagn&#243;stico de mesotelioma pleural difuso requiere en la mayor&#237;a de los casos una biopsia pleural&#44; realizada bajo control de imagen &#40;ecograf&#237;a o tomograf&#237;a computarizada&#41; o mediante toracoscopia&#46; La p&#233;rdida de expresi&#243;n de BAP1 o de MTAP &#40;inmunohistoqu&#237;mica&#41; y la deleci&#243;n homocigota de CDKN2A &#40;hibridaci&#243;n fluorescente <span class="elsevierStyleItalic">in situ</span>&#41; constituyen los marcadores moleculares b&#225;sicos para el diagn&#243;stico de mesotelioma&#46; El tipo histol&#243;gico y el estado funcional del paciente son los factores pron&#243;sticos m&#225;s importantes&#46; El control del derrame pleural se puede realizar a trav&#233;s de la inserci&#243;n de cat&#233;teres pleurales tunelizados&#44; bien como medida aislada &#40;p&#46; ej&#46; pacientes no susceptibles de terapia multimodal que se han diagnosticado por citolog&#237;a del l&#237;quido pleural o biopsia guiada por imagen&#41; o combinada con la administraci&#243;n de talco aerosolizado durante una toracoscopia diagn&#243;stica&#46; La inmunoterapia constituye una de las primeras l&#237;neas de tratamiento en pacientes inoperables&#44; particularmente en las variedades histol&#243;gicas bif&#225;sicas o sarcomatosas&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pleural mesothelioma&#46; Chest X-ray shows circumferential pleural thickening &#40;A&#41;&#44; which is confirmed by computed tomography &#40;B&#41;&#44; where an associated pleural effusion is also seen &#40;C&#41;&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for cellular atypia in fluid samples or pleural biopsy&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">BAP1&#58; BRCA1-associated protein 1&#59; CEA&#58; <span class="elsevierStyleItalic">carcinoembryonic antigen</span>&#59; FISH&#58; <span class="elsevierStyleItalic">Fluorescent</span> In Situ <span class="elsevierStyleItalic">Hybridization</span>&#59; IHC&#58; immunohistochemistry&#59; MTAP&#58; methylthioadenosine phosphorylase&#59; TTF-1&#58; <span class="elsevierStyleItalic">Thyroid</span> Transcription Factor-1&#59; WT-1&#58; <span class="elsevierStyleItalic">Wilms tumor-1</span>&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>CDKN2A determination by FISH is more expensive and time consuming than immunohistochemical staining for MTAP&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">T-Primary tumour</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>T1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Tumor limited to the ipsilateral parietal and&#47;or visceral pleura&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>T2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Tumor that affects the ipsilateral pleura &#40;parietal or visceral&#41; together with&#58;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#42; Diaphragm muscle involvement&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#42; Invasion of the underlying lung parenchyma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>T3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor that affects the ipsilateral pleura &#40;parietal or visceral&#41; together with&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#42; Invasion of the endothoracic fascia&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Extension to the mediastinal fat&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Solitary and completely resectable tumour focus extended to soft tissues of the chest wall&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Non-transmural involvement of the pericardium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>T4<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor that affects the ipsilateral pleura &#40;parietal or visceral&#41; together with&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Diffuse extension or multifocal tumour masses in the chest wall&#44; with or without rib destruction&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Transdiaphragmatic spread of tumour to the peritoneum&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Tumor spread to the contralateral pleura&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Tumor extension to mediastinal organs<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Tumor spread to the spine<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&#44; or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#42; Extension to the inner surface of the pericardium&#44; with or without pericardial effusion&#44; or tumour involvement of the myocardium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N-Lymph nodes</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>N0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No regional lymph node metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>N1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metastases in ipsilateral bronchopulmonary&#44; hilar&#44; or mediastinal lymph nodes<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>N2<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metastases in contralateral mediastinal lymph nodes&#44; or ipsilateral or contralateral supraclavicular lymph nodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">M-Metastasis</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No distant metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Distant metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staging</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T1 N0 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T2&#8211;T3 N0 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T1&#8211;T2 N1 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IIIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T3 N1 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IIIB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T1&#8211;T3 N2 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T4 N0&#8211;N2 M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any T&#44; any N&#44; M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:6 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">T3 implies locally advanced but potentially resectable tumour&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">T4 implies locally advanced but technically unresectable tumour&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Oesophagus&#44; trachea&#44; great vessels&#44; heart&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Vertebrae&#44; intervertebral foramen&#44; spinal cord or brachial plexus&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Includes internal mammary&#44; subcarinal&#44; paratracheal&#44; aortopulmonary&#44; paraesophageal&#44; diaphragmatic&#44; pericardial fat&#44; or intercostal lymph nodes&#46;</p>"
            ]
            5 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "f"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">N2 implies contraindication for debulking surgery&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">TNM staging of pleural mesothelioma &#40;8th ed&#46; <span class="elsevierStyleItalic">International Association for the Study of Lung Cancer</span>&#41;&#46;</p>"
        ]
      ]
      4 => array:9 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Source&#58; Fortin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0060"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PE&#58; pleural effusion&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign and preinvasive mesothelial tumours</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Adenomatoid tumour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Focal proliferation without multifocal or diffuse spread in the pleura&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Well-differentiated papillary mesothelial tumour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare tumour&#46; Papillary formation covered with a single layer of mesothelial cells&#44; without stromal invasion&#46; It occurs as a nodule or arborescent mass in the visceral or parietal pleura&#44; together with recurrent PE&#46; Absence of mesothelioma molecular data<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mesothelioma in situ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">It manifests as recurrent or persistent PE&#44; without evidence of tumour on imaging tests or thoracoscopic examination&#46; Pleural fluid cytology may be indistinguishable from epithelioid mesothelioma&#46; There should be no histological data of tumour invasion in the biopsy&#44; but there should be molecular markers of mesothelioma<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&#46; It can progress to invasive mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mesothelioma</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Localized mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Solitary localized pleural mass&#44; without invasion outside the margins of the tumour and with histology of diffuse mesothelioma&#46; Rare &#40;1&#37; of mesotheliomas&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diffuse mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diffuse pleural thickening with invasion of adjacent structures &#40;adipose tissue&#44; musculoskeletal&#44; lung&#41;&#46; Three histological varieties &#40;epithelioid&#44; sarcomatoid&#44; biphasic&#41; and characteristic molecular data<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Epithelioid mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The architectural pattern<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a>&#44; certain cytological and stromal data&#44; and nuclear grading &#40;atypia&#44; mitoses&#44; presence or absence of necrosis&#41; have prognostic significance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sarcomatoid mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Desmoplastic mesothelioma is a variant of sarcomatoid mesothelioma characterized by dense collagen fibres separated by malignant mesothelial cells arranged in a storiform pattern&#46; These features should be present in<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; of the tumour obtained from surgical resections<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">c</span></a>&#59; in small biopsy specimens should only be indicated if desmoplastic features are present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Biphasic mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">There must be a minimum of 10&#37; of both epithelioid and sarcomatoid components in surgical specimens<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">c</span></a>&#44; but any percentage is acceptable in small biopsies or cytology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Loss of expression of BAP1 or MTAP by immunohistochemistry&#44; homozygous deletion of CKN2A by fluorescent hybridization in situ&#44; BAP1 or CKN2A mutations by next generation sequencing&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">The pleomorphic and transitional patterns have a similar prognosis to sarcomatoid and biphasic mesotheliomas&#44; respectively&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Extended pleurectomy&#47;decortication or extrapleural pneumonectomy&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Classification of mesothelial tumours according to WHO &#40;5th ed&#46; 2021&#41;&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0065"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">BAP1&#58; BRCA1-associated protein 1&#59; CEA&#58; <span class="elsevierStyleItalic">carcinoembryonic antigen</span> &#59; CK&#58; cytokeratin&#59; EpCAM&#58; epithelial cell adhesion molecule&#59; IMP-3&#44; insulin-like growth factor 2 mRNA-binding protein 3&#59; MTAP&#58; methylthioadenosine phosphorylase&#59; TTF-1&#58; <span class="elsevierStyleItalic">Thyroid</span> Transcription Factor-1&#59; WT-1&#58; <span class="elsevierStyleItalic">Wilms tumor-1</span>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Markers to confirm mesothelial origin<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Carcinoma markers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Markers to differentiate benign from malignant mesothelial proliferations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Calretinin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Claudine 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BAP1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Wilms tumor-1</span> &#40;WT-1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TTF-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MTAP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D2-40 &#40;podoplanin&#41;<a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CEA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IMP-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK 5&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EpCAM &#40;Ber-EP4 or MOC-31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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