Diagnosis and Treatment of Malignant Pleural Mesothelioma

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A. Infiltración masiva de la pleura parietal por mesotelioma maligno de tipo epitelioide. B. Infiltración difusa de la pleura parietal y visceral por mesotelioma maligno de tipo epitelioide. C. Nódulos «perlados» en afectación masiva de la pleura parietal por mesotelioma de tipo epitelioide. D. Placas pleurales y masas de mesotelioma de tipo sarcomatoso en la pleura parietal." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco Rodríguez Panadero" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Francisco" "apellidos" => "Rodríguez Panadero" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1579212915000415" "doi" => "10.1016/j.arbr.2015.02.009" "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/S1579212915000415?idApp=UINPBA00003Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289614002270?idApp=UINPBA00003Z" "url" => "/03002896/0000005100000004/v2_201503280455/S0300289614002270/v2_201503280455/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S1579212914003814" "issn" => "15792129" "doi" => "10.1016/j.arbr.2014.12.006" "estado" => "S300" "fechaPublicacion" => "2015-04-01" "aid" => "993" "copyright" => "SEPAR" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Bronconeumol. 2015;51:185-92" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3888 "formatos" => array:3 [ "EPUB" => 151 "HTML" => 2936 "PDF" => 801 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Indications for Active Case Searches and Intravenous Alpha-1 Antitrypsin Treatment for Patients With Alpha-1 Antitrypsin Deficiency Chronic Pulmonary Obstructive Disease: An Update" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "185" "paginaFinal" => "192" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización sobre indicaciones de búsqueda activa de casos y tratamiento con alfa-1 antitripsina por vía intravenosa en pacientes con enfermedad pulmonar obstructiva crónica asociada a déficit de alfa-1 antitripsina" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Taken from Vidal et al.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1426 "Ancho" => 2483 "Tamanyo" => 137024 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for AAT deficiency (AATD)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco Casas, Ignacio Blanco, María Teresa Martínez, Ana Bustamante, Marc Miravitlles, Sergio Cadenas, José M. 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Carlos III, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diagnóstico y tratamiento del mesotelioma pleural maligno" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1999 "Ancho" => 2658 "Tamanyo" => 482937 ] ] "descripcion" => array:1 [ "en" => "Various thoracoscopic images of malignant pleural mesothelioma. (A) Massive epithelioid malignant mesothelioma invasion of the parietal pleural. (B) Diffuse epithelioid malignant mesothelioma infiltration of parietal and visceral pleura. (C) “String of pearls” nodes in massive epithelioid invasion of the parietal pleural. (D) Pleural plaques and sarcomatous mesothelioma masses in the parietal pleura." ] ] ] "textoCompleto" => "IntroductionMesothelioma is a tumor derived from the mesothelium, the mesoderm cell layer that lines the embryonic coelom (body cavity). This tissue subsequently develops into the pleura, pericardium, peritoneum and the testicular tunica vaginalis. Because of its mesodermal origin, the mesothelium can potentially develop an epitheloid component and a sarcomatous component. Since the 1950s, mesothelioma has been associated with asbestos,<a class="elsevierStyleCrossRef" href="#bib0500">1</a> particularly blue asbestos (crocidolite) and white asbestos (cristolite). It has also been associated with erionite, a natural soil contaminant that occurs in several regions throughout the world, but especially in Cappadocia (Turkey), where a very high incidence of mesothelioma has been recorded, although this may also be due to a certain genetic susceptibility.<a class="elsevierStyleCrossRef" href="#bib0505">2</a> Approximately 80% of cases of mesothelioma show a cause-effect relationship with workplace exposure to asbestos in a wide spectrum of professions,<a class="elsevierStyleCrossRef" href="#bib0510">3</a> but the possibility of environmental exposure must also be considered. This generally originates from local mines or factories handling this mineral, or contamination from the clothes of asbestos workers.<a class="elsevierStyleCrossRef" href="#bib0515">4</a> A dose–response relationship between accumulated asbestos exposure (high levels of exposure, duration of exposure or both) and malignant mesothelioma has been shown, and there is no threshold below which the risk of contracting the disease can be ruled out.<a class="elsevierStyleCrossRefs" href="#bib0520">5–7</a> Mesothelioma can develop in any of the above-mentioned mesodermal structures, but the most common presentation (over 90% of cases) is pleural. Nevertheless, the incidence of the disease is relatively low, ranging from 7 cases per million inhabitants/year in Japan to 40 per million/year in Australia, mainly in line with asbestos exposure rates in previous decades.<a class="elsevierStyleCrossRef" href="#bib0535">8</a> In Europe, incidence is approximately 20 cases per million/year, but this rate varies widely between countries, and is also related to asbestos exposure in the past. The latency period between exposure and manifestation of the disease is long–generally around 40 years, while outlying values (up to 75 years in the series of Bianchi et al.) vary greatly<a class="elsevierStyleCrossRef" href="#bib0540">9</a>–suggesting that the worldwide incidence may still be expected to rise. Based on asbestos exposure figures, the incidence of mesothelioma in Europe is expected to peak in around 2020, and will vary widely between countries.<a class="elsevierStyleCrossRef" href="#bib0545">10</a>For this review article, a PubMed search (<a href="http://www.ncbi.nlm.nih.gov/pubmed">http://www.ncbi.nlm.nih.gov/pubmed</a>), updated 18 March 2014, was performed, combining the terms malignant + pleural + mesothelioma. A total of 4670 articles, including 736 reviews, were found. The most relevant articles selected as the basis for this review of malignant pleural mesothelioma were detailed prospective studies in large series, evidence-based clinical guidelines and some papers on very specific areas, such as biomarkers or innovative techniques with outlooks on the future.Diagnosis of Malignant Pleural MesotheliomaThe initial clinical presentation of mesothelioma may be dyspnea, generally associated with developing pleural effusion. Pleural pain, not clearly related with breath movements, is also a common manifestation. Weight loss and other symptoms are rare in the early stages, but as the condition advances, marked hemithorax retraction is often observed and pain becomes particularly intense and persistent.Imaging Techniques in the Diagnosis of MesotheliomaAlthough chest X-ray is the first step in diagnosis, and can provide information on the presence of effusion, diffuse pleural thickening or masses, computed tomography (CT), preferably with contrast medium, is essential for the proper evaluation of the patient and for determining the diagnostic procedure: diffuse pleural thickening with prominent lymph nodes suggests mesothelioma, particularly in patients with a history of exposure to asbestos of any type.<a class="elsevierStyleCrossRef" href="#bib0550">11</a> However, CT has poor sensitivity for the evaluation of mediastinal node involvement or contralateral or peritoneal lung pleural involvement. Positron emission tomography (PET) is much more useful for studying these regions and the possibility of distant metastases, particularly if it is combined with CT (PET-CT).<a class="elsevierStyleCrossRef" href="#bib0555">12</a> PET-CT is particularly useful for pre-surgery staging of malignant pleural mesothelioma, for evaluating treatment response, and for detecting possible relapse.<a class="elsevierStyleCrossRef" href="#bib0560">13</a> However, its sensitivity and specificity for detecting N2 disease in mesothelioma is low,<a class="elsevierStyleCrossRef" href="#bib0565">14</a> and false negatives may be found in tuberculous pleurisy,<a class="elsevierStyleCrossRef" href="#bib0570">15</a> empyema<a class="elsevierStyleCrossRef" href="#bib0575">16</a> or in patients with a history of previous pleurodesis.<a class="elsevierStyleCrossRef" href="#bib0580">17</a>Magnetic resonance imaging (MRI) provides greater contrast than CT for defining tumor chest wall invasion, but it cannot reliably detect metastatic disease.<a class="elsevierStyleCrossRef" href="#bib0585">18</a>Pleural Fluid StudiesThoracocentesis can provide data suggestive of mesothelioma, but rarely diagnostic: high levels of hyaluronic acid (>100000ng/ml) are highly indicative of malignant pleural mesothelioma.<a class="elsevierStyleCrossRef" href="#bib0590">19</a> Elevated hyaluronic acid also has good prognostic values, with higher levels being associated with better survival.<a class="elsevierStyleCrossRef" href="#bib0595">20</a>Adenosine deaminase (ADA) levels may be raised in mesothelioma patients,<a class="elsevierStyleCrossRef" href="#bib0600">21</a> but before they are labeled as ADA false positives, it should be remembered that malignant mesothelioma may sometimes coexist with tuberculous pleurisy, so a culture for Mycobacterium tuberculosis is recommended in these cases.<a class="elsevierStyleCrossRef" href="#bib0605">22</a>Pleural fluid cytology may reveal mesothelioma, but it is often difficult to distinguish between benign and malignant mesothelial hyperplasia.<a class="elsevierStyleCrossRef" href="#bib0610">23</a> This test is also unable to determine the invasive character of the tumor, currently considered an essential feature for a definitive diagnosis).<a class="elsevierStyleCrossRef" href="#bib0615">24</a> However, in some exceptional cases, cytology may be combined with imaging techniques for the evaluation of extrapleural invasion.<a class="elsevierStyleCrossRef" href="#bib0620">25</a> Immunocytochemical and immunohistochemical techniques are also essential for differentiating between mesothelioma and metastatic adenocarcinoma in the pleura,<a class="elsevierStyleCrossRef" href="#bib0625">26</a> and require biopsy tissue or paraffin-embedded preparation of the cell button after centrifugation of a sufficient volume of pleural fluid (>100ml). A diagnosis of mesothelioma can be reliably made when all the following conditions are found: atypical mesothelial proliferation in the pleural fluid + cell block immunohistochemistry consistent with mesothelioma + diffuse pleural thickening with nodularity + absence of any intra- or extrapulmonary mass suggestive of another primary tumor.<a class="elsevierStyleCrossRef" href="#bib0630">27</a> However, a diagnosis of malignant mesothelioma generally has legal implications. Therefore, when surgery is proposed an attempt should always be made to obtain sufficient tissue specimens for more accurate tumor typing.<a class="elsevierStyleCrossRef" href="#bib0635">28</a>Histological Diagnosis of Malignant Pleural MesotheliomaThe classic types of malignant pleural mesothelioma are epithelioid, sarcomatous and biphasic, but there are also rare subtypes, such as desmoplastic mesothelioma (that may be confused with benign fibrous pleuritic), small cell mesothelioma and lymphohistiocytoid mesothelioma (that may be confused with lymphoma). Immunohistochemical evaluation is essential for identifying these types. However, no single marker has 100% sensitivity and specificity for mesothelioma, so various monoclonal antibody panels must be determined, of which at least 2 must be positive for mesothelioma. In the epithelioid subtype, these should be preferably calretinin (particularly useful if the nucleus, in addition to the cytoplasma, is stained), Wilms’ tumor antigen 1 (WT-1) or epithelial membrane antigen (EMA) or wide-spectrum, low molecular weight cytokeratins, such as CK5 OR CK6, and 2 negative markers, such as Ber-EP4 (membrane marker) and thyroid transcription factor 1 (TTF-1, nuclear marker). Carcinoembryonic antigen (CEA) is very useful for distinguishing metastatic carcinoma, particularly of pulmonary origin, from mesothelioma (in which it is practically always negative), and if mesothelioma is suspected in a woman, endoplasmic reticulum (ER) expression should also be investigated: this never occurs in mesothelioma but is a common feature of metastatic breast tumors<a class="elsevierStyleCrossRef" href="#bib0635">28</a> (see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). When the tumor contains a sarcomatous component, it often needs to be distinguished from metastases, such as squamous cell lung cancer or transitional cell carcinoma. Although some antibodies used for epithelioid mesothelioma are equally valid for sarcomatous types, some others are often needed for firm evidence, such as p63 and MOC 31 (see <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Pleural Biopsy and Thoracoscopy in the Diagnosis of MestheliomaBlind pleural needle biospy (without real-time imaging techniques) yields unsatisfactory results in the diagnosis of mesothelioma, not only due to lack of control when selecting the exact sampling point, but also due to the small size of such samples. In case of diffuse nodular pleural thickening, needle biopsy yield may improve considerably if it is performed with the aid of CT<a class="elsevierStyleCrossRefs" href="#bib0640">29,30</a> or real-time ultrasound.<a class="elsevierStyleCrossRef" href="#bib0650">31</a> In 1 study, a diagnostic yield of 75% was achieved in cases in which biopsies were >10mm, falling to only 8% if specimens were smaller.<a class="elsevierStyleCrossRef" href="#bib0655">32</a> This finding clearly supports the use of thoracoscopy in the diagnosis of malignant pleural mesothelioma. Thoracoscopy (or pleuroscopy) can be performed with local anesthesia and intravenous analgesia/sedation.<a class="elsevierStyleCrossRef" href="#bib0660">33</a> In our hospital, we have used this technique to diagnose more than 80 pleural mesotheliomas<a class="elsevierStyleCrossRef" href="#bib0665">34</a> (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Video-assisted thoracoscopic surgery (VATS) improves tumor staging, particularly in the mediastinal region, and can be used for pleurectomy/decortication, although more resources, including general anesthesia and tracheal intubation, will be required.<a class="elsevierStyleCrossRef" href="#bib0670">35</a> The yield from pleuroscopy, also known as “medical thoracoscopy”, is suboptimal in mesothelioma with sarcomatous component,<a class="elsevierStyleCrossRef" href="#bib0675">36</a> and for this subtype, more representative samples can be obtained with VATS or mini-thoracotomy.<a class="elsevierStyleCrossRef" href="#bib0680">37</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Early Diagnosis of Malignant Pleural MesotheliomaDespite a clearly defined risk population (individuals exposed to some form of asbestos), one of the major challenges we face is the lack of tools for making a sufficiently early diagnosis to allow radical treatment of the disease. This can only be achieved with biomarkers that can detect disease before the development of effusion or diffuse pleural thickening, along with sufficiently sensitive and specific imaging techniques.Biomarkers in the Diagnosis of Malignant MesotheliomaThe biomarker generating the most interest in recent years is soluble mesothelin. This protein is closely correlated with tumor size and progression in epithelioid mesothelioma (although it tends to be negative in sarcomatous type).<a class="elsevierStyleCrossRef" href="#bib0685">38</a> However, values are affected by renal function, and one of the major problems is the identification of the right cutoff point for distinguishing between benign and malignant pleural involvement.<a class="elsevierStyleCrossRef" href="#bib0690">39</a> In any case, it seems that pleural fluid mesothelin levels are more useful than serum levels, and this greatly limits the value of this biomarker in the early diagnosis of subjects with a history of asbestos exposure but no pleural effusion. If screening suggests a low probability of mesothelioma, low mesothelin levels may help to rule out the disease, while high levels would justify the use of more invasive techniques in the case of suspected mesothelioma.<a class="elsevierStyleCrossRefs" href="#bib0695">40–42</a> In all events, mesothelin appears to be more useful for monitoring treatment than for the differential diagnosis of pleural effusion.<a class="elsevierStyleCrossRef" href="#bib0710">43</a>Efforts to overcome the problems of mesothelin and other markers include a recent study of the ability of fibulin-3 to distinguish between healthy subjects with a history of asbestos exposure and mesothelioma patients, and even between mesothelioma and other malignant or benign diseases of the pleura. Thus, Pass et al. found that fibulin in plasma had 96.7% sensitivity and 95.5% specificity at a cutoff point of 52.8ng/ml. When patients with relatively early stage mesothelioma were compared with individuals exposed to asbestos but with no evidence of disease, sensitivity and sensitivity of a cutoff point of 46ng/ml of fibulin-3 were 100% and 94.1%, respectively.<a class="elsevierStyleCrossRef" href="#bib0715">44</a> These excellent results still need proper external validation, and it must be remembered that sample extraction and processing techniques may significantly affect the results: in the case of fibulin, determination in plasma (before activation of the coagulation process) is much more reliable than in serum, due, as with other markers, to thrombin-fibulin interactions.<a class="elsevierStyleCrossRef" href="#bib0720">45</a>In recent years, gene expression in mesothelioma has been the object of intensive research,<a class="elsevierStyleCrossRef" href="#bib0725">46</a> and the expression of certain proteins has been targeted, including aquaporin-1, associated with selective water transport through the membrane and with cell proliferation.<a class="elsevierStyleCrossRef" href="#bib0730">47</a> Of special interest is the work on micro-RNA (miRNA) in mesothelioma. These are short, non-protein coding RNAs (17–22 nucleotides) that regulate gene expression and play an important role in oncogenesis.<a class="elsevierStyleCrossRef" href="#bib0735">48</a> They have high tissue specificity for detecting the origin of a tumor and also for distinguishing mesothelioma from other metastatic pleural tumors.<a class="elsevierStyleCrossRef" href="#bib0740">49</a> Consequently, miRNA detection in peripheral blood may become an excellent marker for mesothelioma in the near future.<a class="elsevierStyleCrossRef" href="#bib0745">50</a>Treatment of Malignant Pleural MesotheliomaPleural mesothelioma generally responds poorly to chemotherapy and radiotherapy and surgery is rarely curative, because the tumor is usually diagnosed too late. For this reason, it is essential to carefully evaluate the patient before selecting the best treatment modality. If radical treatment is being considered, lung and cardiac function, other comorbidity factors, and the physical and psychological status of the patient must be assessed. Choice of one or other of the various available options is dictated by the clinical situation and tumor extension (TNM) determined by imaging techniques. However, none of the currently available imaging techniques is precise enough to determine the “T” and “N” components in malignant pleural mesothelioma, and post-surgical staging often widely exceeds pre-surgical findings.<a class="elsevierStyleCrossRef" href="#bib0750">51</a> Until more robust TNM staging can be defined, the system established by theUnion Internationale contre le Cancer (UICC) should be used<a class="elsevierStyleCrossRef" href="#bib0755">52</a> (see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Surgical Treatment of Malignant Pleural MesotheliomaThe main objective of surgery is the gross resection of all malignant growth. The assumption is that this leads to longer survival and that patients who have gross evidence of remaining tumor will have poorer survival.<a class="elsevierStyleCrossRef" href="#bib0760">53</a> However, accumulated evidence suggests that full resection (macro- and microscopic) of mesothelioma is impossible, irrespective of the surgical technique used. Therefore, it is accepted that surgery is aimed at local disease control, elimination of pleural effusion, release of lung trapped by the tumor, improvement of ventilation/perfusion disorders and relief of pain from chest wall invasion.<a class="elsevierStyleCrossRef" href="#bib0765">54</a> All these considerations are particularly applicable to epithelioid mesothelioma, since the sarcomatous or biphasic types have a worse prognosis, and as such, are poorer candidates for any type of surgery.<a class="elsevierStyleCrossRef" href="#bib0750">51</a>Extrapleural PneumonectomyExtrapleural pneumonectomy involves resection of the lung and the parietal pleura, and is usually completed with ipsilateral resection of the pericardium and diaphragm, in addition to systematic dissection of the mediastinal lymphatic chains. Perioperative mortality is around 5% in highly experienced hospitals. However, morbidity is high and includes cardiac and respiratory complications, of particular relevance in the unipulmonary situation encountered after extrapleural pneumonectomy (EPP). Other complications include bronchopleural fistula, empyema and bleeding.<a class="elsevierStyleCrossRefs" href="#bib0770">55,56</a> In any event, this intervention commonly involves persistent residual gross and microscopic disease, so it should be planned within the context of multimodal therapy, based on the combined use of surgery, chemotherapy and radiation therapy.<a class="elsevierStyleCrossRef" href="#bib0780">57</a> Hyperthermia, combined with chemotherapy, or local photodynamic therapy have occasionally been used.<a class="elsevierStyleCrossRef" href="#bib0785">58</a> Many multimodal treatment protocols recommend chemotherapy as pre-surgery induction treatment (neoadjuvant chemotherapy), with radiation therapy administered to the affected hemothorax after resection.<a class="elsevierStyleCrossRef" href="#bib0790">59</a> Nevertheless, the most recent guidelines recommend avoiding surgery if progressive disease is observed after neoadjuvant chemotherapy; besides, EEP is only recommended in the context of controlled clinical trials performed by specialized teams of investigators.<a class="elsevierStyleCrossRefs" href="#bib0630">27,28</a>Pleurectomy/DecorticationAlthough pleurectomy/decortication, aimed primarily at releasing the lung and the chest wall from constriction caused by the tumor, is associated with a higher risk of local relapse than EEP, it involves fewer complications.<a class="elsevierStyleCrossRef" href="#bib0795">60</a> The best candidates for this type of surgery are patients with gross diffuse tumors in the parietal wall, but only focal sites in the viscera.<a class="elsevierStyleCrossRef" href="#bib0765">54</a> The procedure can be performed using VATS, with the advantage of minimizing morbidity associated with thoracotomy<a class="elsevierStyleCrossRef" href="#bib0800">61</a> and the possibility of performing pleurodesis during the same intervention, if resection cannot be completed.EEP constitutes a more radical approach, but in recent years its advantages over pleurectomy/decortication have been questioned.<a class="elsevierStyleCrossRefs" href="#bib0805">62,63</a> No superiority was observed for either technique in a recent randomized study performed in the United Kingdom (the Mesothelioma and Radical Surgery [MARS] study).<a class="elsevierStyleCrossRef" href="#bib0815">64</a> Nevertheless, the MARS study has been severely criticized, due to significant deviations from the original protocol design and the number of patients finally included in one of the study groups.<a class="elsevierStyleCrossRef" href="#bib0820">65</a> In any case, although some groups with extensive experience in both techniques find it unacceptable to forgo resection of grossly visible tumor (giving a poorer prognosis),<a class="elsevierStyleCrossRef" href="#bib0765">54</a> the idea of resecting the greatest tumor volume possible, while preserving the underlying lung and combining surgery with chemotherapy and radiation therapy in multimodal treatment, is gaining ground.<a class="elsevierStyleCrossRef" href="#bib0825">66</a>Radiation Therapy in Malignant MesotheliomaRadical radiation therapy administered to the whole hemithorax is seriously limited by the risk of damaging critical organs, such as the lung, liver, heart, bone marrow and esophagus, although these negative effects are being palliated by optimized application techniques.<a class="elsevierStyleCrossRef" href="#bib0830">67</a> However, there is no convincing evidence that this alone prolongs survival in mesothelioma.<a class="elsevierStyleCrossRef" href="#bib0835">68</a> On the other hand, palliative radiation therapy plays an important role in the control of pain from chest wall infiltration.<a class="elsevierStyleCrossRefs" href="#bib0840">69,70</a> The classic recommendation has been to administer prophylactic radiation therapy to avoid tumor seeding in the thoracoscopy or thoracotomy scars,<a class="elsevierStyleCrossRefs" href="#bib0850">71,72</a> but this practice is not supported by available evidence, and is no longer advised.<a class="elsevierStyleCrossRefs" href="#bib0630">27,28</a>Chemotherapy, Immunotherapy and Other Tailored TreatmentsRecent clinical guidelines advise against delaying the administration of chemotherapy, which must be considered before the patient's functional status begins to deteriorate.<a class="elsevierStyleCrossRefs" href="#bib0630">27,28</a> The combination of various agents, including pemetrexed and platinum compounds, generally produces better results than monotherapy.<a class="elsevierStyleCrossRefs" href="#bib0860">73,74</a> Current trends in research are oriented toward new therapeutic targets focused on controlling angiogenesis and apoptotic pathways via specific ligands, such as platelet derived growth factor (PDGF, that is quite often expressed in the mesothelioma and associated with poorer survival) and mesothelin (expressed only in the epithelioid subtype), among others.<a class="elsevierStyleCrossRefs" href="#bib0870">75,76</a> Immunotherapy is another aspect of multimodal therapy that can be effective in the treatment of mesothelioma, since this tumor uses regulatory T-cells (Tregs) and M2 macrophages to escape the immune system. New therapeutic strategies combining cytoreductive surgery, chemotherapy, immunotherapy and radiation therapy may lead to better disease control.<a class="elsevierStyleCrossRef" href="#bib0880">77</a> There is a wide spectrum of possible approaches for achieving notably synergic antitumor effects, from passive immunotherapy (using cytokines or specific antibodies) to immune response modulation using dendritic cells or others.<a class="elsevierStyleCrossRefs" href="#bib0885">78–80</a>PleurodesisControl of pleural effusion is a priority in most patients with malignant pleural mesothelioma, and a good option for this is talc pleurodesis. However, in our experience, pleurodesis tends to fail more often in this tumor than in others, possibly due to difficulties in achieving re-expansion of the lung that has been trapped by the tumor.<a class="elsevierStyleCrossRef" href="#bib0900">81</a> Previous studies by our group show that the extension of the tumor in the pleural cavity has a negative effect on pleurodesis.<a class="elsevierStyleCrossRef" href="#bib0905">82</a> It seems likely, then, that other biological factors, unidentified to date, are also involved. According to recent in vitro experiments carried out by our group, malignant mesothelial cells are more resistant to the action of talc than other cell lines, as observed in both the modulation/blocking of angiogenesis and in cell proliferation (unpublished data).When pleurodesis fails, or is considered unfeasible due to massive lung entrapment by the tumor, the best option is to place a tunneled pleural catheter for drainage of pleural fluid at home. This procedure also induces spontaneous pleurodesis in a considerable number of cases.<a class="elsevierStyleCrossRefs" href="#bib0910">83–86</a>It is important to remember that previous pleurodesis does not rule out the need for surgical resection of mesothelioma, whether by EEP or pleurectomy/decortication.<a class="elsevierStyleCrossRef" href="#bib0765">54</a>Future OutlookMolecular biology and nanotechnology are coming together in the newly emerging concept of “theranostics”, the aim of which is to combine diagnosis and treatment in the same procedure with the use of drugs that specifically target each malignancy subtype. If the right ligands were found, they could be used in PET or single photon emission computed tomography (SPECT) for the early diagnosis of mesothelioma.<a class="elsevierStyleCrossRefs" href="#bib0930">87–89</a> Highly sensitive probes combined with biofluorescent techniques that can detect tumors in animal models have been developed.<a class="elsevierStyleCrossRefs" href="#bib0945">90,91</a> Techniques based on labeled antibodies or nanoparticles with nuclear magnetic resonance are available,<a class="elsevierStyleCrossRefs" href="#bib0955">92,93</a> and the prospect of eventually using these in humans is good. Until such time, however, it seems more realistic to concentrate on the search for markers that are detectable in peripheral blood and sufficiently sensitive and specific for the diagnosis of malignant mesothelioma. Along with imaging techniques, the most promising field appears to be comprehensive screening for early mesothelioma markers using proteomics. This can simultaneously analyze the profiles of large numbers of proteins (over 1000), in panels configured to achieve the greatest diagnostic sensitivity and specificity.<a class="elsevierStyleCrossRefs" href="#bib0965">94,95</a> As explained above, miRNA detection in peripheral blood is another emerging field in the hunt for a sufficiently early diagnostic test for mesothelioma.Gene therapy has often been proposed in mesothelioma to compensate for the poor results of immune therapy in locally advanced disease. To this end, different strategies, such as “suicide genes” (which make the tumor sensitive to certain drugs), administration of tumor suppressor genes, or the transfer of immunomodulatory genes to the pleural space have been proposed.<a class="elsevierStyleCrossRefs" href="#bib0975">96–99</a> Results in the clinic are rather disheartening to date due to vector-related problems and relative inefficiency in controlling large tumor masses. However, gene therapy is most likely to be incorporated into the multimodal strategy, and when combined with nanotechnology techniques it will contribute very significantly to the improvement of treatment of malignant pleural mesothelioma in the future.FundingPart of the funding of the research performed by our group in this article, was funded by Project PI-0358-2010, of the Health Council of the Government of Andalusia.Conflict of InterestsThe author states that he has no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres468858" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec491507" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres468859" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec491508" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Diagnosis of Malignant Pleural Mesothelioma" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Imaging Techniques in the Diagnosis of Mesothelioma" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Pleural Fluid Studies" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Histological Diagnosis of Malignant Pleural Mesothelioma" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Pleural Biopsy and Thoracoscopy in the Diagnosis of Mesthelioma" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Early Diagnosis of Malignant Pleural Mesothelioma" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Biomarkers in the Diagnosis of Malignant Mesothelioma" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Treatment of Malignant Pleural Mesothelioma" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Surgical Treatment of Malignant Pleural Mesothelioma" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Extrapleural Pneumonectomy" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Pleurectomy/Decortication" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Radiation Therapy in Malignant Mesothelioma" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Chemotherapy, Immunotherapy and Other Tailored Treatments" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Pleurodesis" ] ] ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Future Outlook" ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of Interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-04-06" "fechaAceptado" => "2014-06-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec491507" "palabras" => array:4 [ 0 => "Malignant pleural mesothelioma" 1 => "Biomarkers" 2 => "Malignant pleural effusion" 3 => "Thoracoscopy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec491508" "palabras" => array:4 [ 0 => "Mesotelioma pleural maligno" 1 => "Biomarcadores" 2 => "Derrame pleural maligno" 3 => "Toracoscopia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "There are three major challenges in the diagnosis of malignant pleural mesothelioma: mesothelioma must be distinguished from benign mesothelial hyperplasia; malignant mesothelioma (and its subtypes) must be distinguished from metastatic carcinoma; and invasion of structures adjacent to the pleura must be demonstrated. The basis for clarifying the first two aspects is determination of a panel of monoclonal antibodies with appropriate immunohistochemical evaluation performed by highly qualified experts. Clarification of the third aspect requires sufficiently abundant, deep biopsy material, for which thoracoscopy is the technique of choice. Video-assisted needle biopsy with real-time imaging can be of great assistance when there is diffuse nodal thickening and scant or absent effusion. Given the difficulties of reaching an early diagnosis, cure is not generally achieved with radical surgery (pleuropneumonectomy), so liberation of the tumor mass with pleurectomy/decortication combined with chemo- or radiation therapy (multimodal treatment) has been gaining followers in recent years. In cases in which surgery is not feasible, chemotherapy (a combination of pemetrexed and platinum-derived compounds, in most cases) with pleurodesis or a tunneled pleural drainage catheter, if control of pleural effusion is required, can be considered. Radiation therapy is reserved for treatment of pain associated with infiltration of the chest wall or any other neighboring structure. In any case, comprehensive support treatment for pain control in specialist units is essential: this acquires particular significance in this type of malignancy." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El diagnóstico del mesotelioma pleural maligno presenta 3 importantes retos: es necesario distinguir entre hiperplasia mesotelial benigna y mesotelioma, entre mesotelioma maligno (con subtipos) y carcinoma metastásico, y también se requiere demostrar la invasión de estructuras vecinas a la pleura. Para aclarar los 2 primeros aspectos hay que basarse en un panel de anticuerpos monoclonales con adecuado estudio inmunohistoquímico–realizado por manos muy expertas–y para el tercero hay que apoyarse en biopsias suficientemente amplias y profundas, y la toracoscopia es la técnica de elección. La biopsia con aguja guiada con técnicas de imagen en tiempo real puede ser de gran ayuda cuando existe marcado engrosamiento nodular difuso y derrame pequeño o ausente. Dadas las dificultades de un diagnóstico precoz, es infrecuente que se consiga un tratamiento curativo mediante cirugía radical (pleuroneumonectomía), por lo que en los últimos años está ganando adeptos la liberación de masa tumoral mediante pleurectomía/decorticación, con asociación de quimio y radioterapia a las técnicas quirúrgicas (terapia multimodal). En los casos en que la cirugía no es factible se plantea la quimioterapia (combinando pemetrexed y compuestos de platino en la mayoría de los casos), con pleurodesis o colocación de un catéter pleural tunelizado si se requiere el control del derrame pleural, y se reserva la radioterapia para el tratamiento del dolor asociado a infiltración de la pared torácica o cualquier otra estructura vecina. En todo caso, es esencial un completo tratamiento de soporte para el control del dolor (que adquiere particular protagonismo en esta neoplasia) en unidades especializadas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Rodríguez Panadero F. Diagnóstico y tratamiento del mesotelioma pleural maligno. Arch Bronconeumol. 2015;51:177–184." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1999 "Ancho" => 2658 "Tamanyo" => 482937 ] ] "descripcion" => array:1 [ "en" => "Various thoracoscopic images of malignant pleural mesothelioma. (A) Massive epithelioid malignant mesothelioma invasion of the parietal pleural. (B) Diffuse epithelioid malignant mesothelioma infiltration of parietal and visceral pleura. (C) “String of pearls” nodes in massive epithelioid invasion of the parietal pleural. (D) Pleural plaques and sarcomatous mesothelioma masses in the parietal pleura." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "CEA: carcinoembryonic antigen; EMA: epithelial membrane antigen; ER: endoplasmic reticulum marker; TTF-1: thyroid transcription factor-1; WT-1: Wilms tumor antigen 1.Source: Adapted from Scherpereel et al.<a class="elsevierStyleCrossRef" href="#bib0635">28</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibody \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Epithelioid mesothelioma \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenocarcinoma \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Calretinin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Essential \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (nucleus and cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">± (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">WT-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (nuclear) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(lung) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (membrane) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CK5/CK6 keratins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Monoclonal CEA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ber-EP4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">± (membrane) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (membrane) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TTF-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (nucleus, lung) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">B72.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (cytoplasm, lung) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ER \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (nucleus, breast) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab726046.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immunohistochemical Markers for Differentiating Epithelioid Mesothelioma From Other Metastatic Pleural Tumors." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "p63: p53 homolog, but more useful for differential diagnosis; WT-1: Wilms tumor antigen 1.Source: Adapted from Scherpereel et al.<a class="elsevierStyleCrossRef" href="#bib0635">28</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibody \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sarcomatous mesothelioma \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Squamous cell or transitional cell carcinoma \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Calretinin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (nucleus and cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">WT-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (nucleus) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CK5/CK6 keratins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">p63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (nucleus) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ber-EP4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">± (membrane) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (cytoplasm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">MOC 31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Useful \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">± (membrane) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ (membrane) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab726044.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immunohistochemical Markers for Differentiating Sarcomatous Mesothelioma From Squamous Cell or Transitional Cell Carcinoma." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Adapted from Van Meerbeeck et al.<a class="elsevierStyleCrossRef" href="#bib0755">52</a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Stage \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tumor extension \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unilateral parietal pleural involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T1a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parietal pleural involvement with or without mediastinal pleural or diaphragmatic pleural involvement, but with no visceral pleural involvement. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parietal pleural involvement with focal visceral pleural involvement. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unilateral parietal or visceral involvement with invasion of underlying lung or diaphragmatic muscle \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unilateral involvement of any pleural area, with invasion of at least one of the following structures: endothoracic fascia, mediastinal fat, soft tissue of chest wall (focal) or nontransmural invasion of the pericardium \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">T4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Involvement of any pleural zone with invasion of at least one of the following structures: internal surface of the pericardium (with or without effusion), peritoneum, mediastinal structures, contralateral pleura, spine, diffuse invasion of the chest wall (with or without rib destruction) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">N0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No lymph node involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">N1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ipsilateral bronchopulmonary or hilar lymph node involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">N2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ipsilateral mediastinal lymph node involvement, including the ipsilateral internal mammary and/or peridiaphragmatic nodes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">N3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Contralateral mediastinal, contralateral internal mammary and/or contralateral supraclavicular lymph node involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">M0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No extrathoracic metastases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">M1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extrathoracic, hematogenous or non-regional lymph node metastases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Stage I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T1aN0 (1A); T1bN0 (1B) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Stage II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T2N0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Stage III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Any T3, N1 or N2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Stage IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Any T4, N3 or M1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab726045.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Malignant Pleural Mesothelioma TNM Staging." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:99 [ 0 => array:3 [ "identificador" => "bib0500" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Ind Med" "fecha" => "1960" "volumen" => "17" "paginaInicial" => "260" "paginaFinal" => 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Review

Diagnosis and Treatment of Malignant Pleural Mesothelioma

Diagnóstico y tratamiento del mesotelioma pleural maligno

Francisco Rodríguez Panaderoa,b

a Instituto de Biomedicina de Sevilla (IBiS), Unidad Médico-Quirúrgica de Enfermedades Respiratorias (UMQER), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Sevilla, Spain

b CIBER de Enfermedades Respiratorias (CIBERES), I.S. Carlos III, Madrid, Spain

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and there is no threshold below which the risk of contracting the disease can be ruled out&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">5&#8211;7</span></a> Mesothelioma can develop in any of the above-mentioned mesodermal structures&#44; but the most common presentation &#40;over 90&#37; of cases&#41; is pleural&#46; Nevertheless&#44; the incidence of the disease is relatively low&#44; ranging from 7 cases per million inhabitants&#47;year in Japan to 40 per million&#47;year in Australia&#44; mainly in line with asbestos exposure rates in previous decades&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">8</span></a> In Europe&#44; incidence is approximately 20 cases per million&#47;year&#44; but this rate varies widely between countries&#44; and is also related to asbestos exposure in the past&#46; The latency period between exposure and manifestation of the disease is long&#8211;generally around 40 years&#44; while outlying values &#40;up to 75 years in the series of Bianchi et al&#46;&#41; vary greatly<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">9</span></a>&#8211;suggesting that the worldwide incidence may still be expected to rise&#46; Based on asbestos exposure figures&#44; the incidence of mesothelioma in Europe is expected to peak in around 2020&#44; and will vary widely between countries&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">For this review article&#44; a PubMed search &#40;<a href="http://www.ncbi.nlm.nih.gov/pubmed">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed</a>&#41;&#44; updated 18 March 2014&#44; was performed&#44; combining the terms <span class="elsevierStyleItalic">malignant &#43; pleural &#43; mesothelioma</span>&#46; A total of 4670 articles&#44; including 736 reviews&#44; were found&#46; The most relevant articles selected as the basis for this review of malignant pleural mesothelioma were detailed prospective studies in large series&#44; evidence-based clinical guidelines and some papers on very specific areas&#44; such as biomarkers or innovative techniques with outlooks on the future&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of Malignant Pleural Mesothelioma</span><p id="par0015" class="elsevierStylePara elsevierViewall">The initial clinical presentation of mesothelioma may be dyspnea&#44; generally associated with developing pleural effusion&#46; Pleural pain&#44; not clearly related with breath movements&#44; is also a common manifestation&#46; Weight loss and other symptoms are rare in the early stages&#44; but as the condition advances&#44; marked hemithorax retraction is often observed and pain becomes particularly intense and persistent&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Imaging Techniques in the Diagnosis of Mesothelioma</span><p id="par0020" class="elsevierStylePara elsevierViewall">Although chest X-ray is the first step in diagnosis&#44; and can provide information on the presence of effusion&#44; diffuse pleural thickening or masses&#44; computed tomography &#40;CT&#41;&#44; preferably with contrast medium&#44; is essential for the proper evaluation of the patient and for determining the diagnostic procedure&#58; diffuse pleural thickening with prominent lymph nodes suggests mesothelioma&#44; particularly in patients with a history of exposure to asbestos of any type&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">11</span></a> However&#44; CT has poor sensitivity for the evaluation of mediastinal node involvement or contralateral or peritoneal lung pleural involvement&#46; Positron emission tomography &#40;PET&#41; is much more useful for studying these regions and the possibility of distant metastases&#44; particularly if it is combined with CT &#40;PET-CT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">12</span></a> PET-CT is particularly useful for pre-surgery staging of malignant pleural mesothelioma&#44; for evaluating treatment response&#44; and for detecting possible relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">13</span></a> However&#44; its sensitivity and specificity for detecting N2 disease in mesothelioma is low&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">14</span></a> and false negatives may be found in tuberculous pleurisy&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">15</span></a> empyema<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">16</span></a> or in patients with a history of previous pleurodesis&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">17</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Magnetic resonance imaging &#40;MRI&#41; provides greater contrast than CT for defining tumor chest wall invasion&#44; but it cannot reliably detect metastatic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pleural Fluid Studies</span><p id="par0030" class="elsevierStylePara elsevierViewall">Thoracocentesis can provide data suggestive of mesothelioma&#44; but rarely diagnostic&#58; high levels of hyaluronic acid &#40;&#62;100<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#41; are highly indicative of malignant pleural mesothelioma&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">19</span></a> Elevated hyaluronic acid also has good prognostic values&#44; with higher levels being associated with better survival&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Adenosine deaminase &#40;ADA&#41; levels may be raised in mesothelioma patients&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">21</span></a> but before they are labeled as ADA false positives&#44; it should be remembered that malignant mesothelioma may sometimes coexist with tuberculous pleurisy&#44; so a culture for <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> is recommended in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">22</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Pleural fluid cytology may reveal mesothelioma&#44; but it is often difficult to distinguish between benign and malignant mesothelial hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">23</span></a> This test is also unable to determine the invasive character of the tumor&#44; currently considered an essential feature for a definitive diagnosis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">24</span></a> However&#44; in some exceptional cases&#44; cytology may be combined with imaging techniques for the evaluation of extrapleural invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">25</span></a> Immunocytochemical and immunohistochemical techniques are also essential for differentiating between mesothelioma and metastatic adenocarcinoma in the pleura&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">26</span></a> and require biopsy tissue or paraffin-embedded preparation of the cell button after centrifugation of a sufficient volume of pleural fluid &#40;&#62;100<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46; A diagnosis of mesothelioma can be reliably made when all the following conditions are found&#58; atypical mesothelial proliferation in the pleural fluid &#43; cell block immunohistochemistry consistent with mesothelioma &#43; diffuse pleural thickening with nodularity &#43; absence of any intra- or extrapulmonary mass suggestive of another primary tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">27</span></a> However&#44; a diagnosis of malignant mesothelioma generally has legal implications&#46; Therefore&#44; when surgery is proposed an attempt should always be made to obtain sufficient tissue specimens for more accurate tumor typing&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Histological Diagnosis of Malignant Pleural Mesothelioma</span><p id="par0045" class="elsevierStylePara elsevierViewall">The classic types of malignant pleural mesothelioma are epithelioid&#44; sarcomatous and biphasic&#44; but there are also rare subtypes&#44; such as desmoplastic mesothelioma &#40;that may be confused with benign fibrous pleuritic&#41;&#44; small cell mesothelioma and lymphohistiocytoid mesothelioma &#40;that may be confused with lymphoma&#41;&#46; Immunohistochemical evaluation is essential for identifying these types&#46; However&#44; no single marker has 100&#37; sensitivity and specificity for mesothelioma&#44; so various monoclonal antibody panels must be determined&#44; of which at least 2 must be positive for mesothelioma&#46; In the epithelioid subtype&#44; these should be preferably calretinin &#40;particularly useful if the nucleus&#44; in addition to the cytoplasma&#44; is stained&#41;&#44; Wilms&#8217; tumor antigen 1 &#40;WT-1&#41; or epithelial membrane antigen &#40;EMA&#41; or wide-spectrum&#44; low molecular weight cytokeratins&#44; such as CK5 OR CK6&#44; and 2 negative markers&#44; such as Ber-EP4 &#40;membrane marker&#41; and thyroid transcription factor 1 &#40;TTF-1&#44; nuclear marker&#41;&#46; Carcinoembryonic antigen &#40;CEA&#41; is very useful for distinguishing metastatic carcinoma&#44; particularly of pulmonary origin&#44; from mesothelioma &#40;in which it is practically always negative&#41;&#44; and if mesothelioma is suspected in a woman&#44; endoplasmic reticulum &#40;ER&#41; expression should also be investigated&#58; this never occurs in mesothelioma but is a common feature of metastatic breast tumors<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; When the tumor contains a sarcomatous component&#44; it often needs to be distinguished from metastases&#44; such as squamous cell lung cancer or transitional cell carcinoma&#46; Although some antibodies used for epithelioid mesothelioma are equally valid for sarcomatous types&#44; some others are often needed for firm evidence&#44; such as p63 and MOC 31 &#40;see <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pleural Biopsy and Thoracoscopy in the Diagnosis of Mesthelioma</span><p id="par0050" class="elsevierStylePara elsevierViewall">Blind pleural needle biospy &#40;without real-time imaging techniques&#41; yields unsatisfactory results in the diagnosis of mesothelioma&#44; not only due to lack of control when selecting the exact sampling point&#44; but also due to the small size of such samples&#46; In case of diffuse nodular pleural thickening&#44; needle biopsy yield may improve considerably if it is performed with the aid of CT<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">29&#44;30</span></a> or real-time ultrasound&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">31</span></a> In 1 study&#44; a diagnostic yield of 75&#37; was achieved in cases in which biopsies were &#62;10<span class="elsevierStyleHsp" style=""></span>mm&#44; falling to only 8&#37; if specimens were smaller&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">32</span></a> This finding clearly supports the use of thoracoscopy in the diagnosis of malignant pleural mesothelioma&#46; Thoracoscopy &#40;or pleuroscopy&#41; can be performed with local anesthesia and intravenous analgesia&#47;sedation&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">33</span></a> In our hospital&#44; we have used this technique to diagnose more than 80 pleural mesotheliomas<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">34</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Video-assisted thoracoscopic surgery &#40;VATS&#41; improves tumor staging&#44; particularly in the mediastinal region&#44; and can be used for pleurectomy&#47;decortication&#44; although more resources&#44; including general anesthesia and tracheal intubation&#44; will be required&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">35</span></a> The yield from pleuroscopy&#44; also known as &#8220;medical thoracoscopy&#8221;&#44; is suboptimal in mesothelioma with sarcomatous component&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">36</span></a> and for this subtype&#44; more representative samples can be obtained with VATS or mini-thoracotomy&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">37</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Early Diagnosis of Malignant Pleural Mesothelioma</span><p id="par0055" class="elsevierStylePara elsevierViewall">Despite a clearly defined risk population &#40;individuals exposed to some form of asbestos&#41;&#44; one of the major challenges we face is the lack of tools for making a sufficiently early diagnosis to allow radical treatment of the disease&#46; This can only be achieved with biomarkers that can detect disease before the development of effusion or diffuse pleural thickening&#44; along with sufficiently sensitive and specific imaging techniques&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Biomarkers in the Diagnosis of Malignant Mesothelioma</span><p id="par0060" class="elsevierStylePara elsevierViewall">The biomarker generating the most interest in recent years is soluble mesothelin&#46; This protein is closely correlated with tumor size and progression in epithelioid mesothelioma &#40;although it tends to be negative in sarcomatous type&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">38</span></a> However&#44; values are affected by renal function&#44; and one of the major problems is the identification of the right cutoff point for distinguishing between benign and malignant pleural involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">39</span></a> In any case&#44; it seems that pleural fluid mesothelin levels are more useful than serum levels&#44; and this greatly limits the value of this biomarker in the early diagnosis of subjects with a history of asbestos exposure but no pleural effusion&#46; If screening suggests a low probability of mesothelioma&#44; low mesothelin levels may help to rule out the disease&#44; while high levels would justify the use of more invasive techniques in the case of suspected mesothelioma&#46;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">40&#8211;42</span></a> In all events&#44; mesothelin appears to be more useful for monitoring treatment than for the differential diagnosis of pleural effusion&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">43</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Efforts to overcome the problems of mesothelin and other markers include a recent study of the ability of fibulin-3 to distinguish between healthy subjects with a history of asbestos exposure and mesothelioma patients&#44; and even between mesothelioma and other malignant or benign diseases of the pleura&#46; Thus&#44; Pass et al&#46; found that fibulin in plasma had 96&#46;7&#37; sensitivity and 95&#46;5&#37; specificity at a cutoff point of 52&#46;8<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; When patients with relatively early stage mesothelioma were compared with individuals exposed to asbestos but with no evidence of disease&#44; sensitivity and sensitivity of a cutoff point of 46<span class="elsevierStyleHsp" style=""></span>ng&#47;ml of fibulin-3 were 100&#37; and 94&#46;1&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">44</span></a> These excellent results still need proper external validation&#44; and it must be remembered that sample extraction and processing techniques may significantly affect the results&#58; in the case of fibulin&#44; determination in plasma &#40;before activation of the coagulation process&#41; is much more reliable than in serum&#44; due&#44; as with other markers&#44; to thrombin-fibulin interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">45</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In recent years&#44; gene expression in mesothelioma has been the object of intensive research&#44;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">46</span></a> and the expression of certain proteins has been targeted&#44; including aquaporin-1&#44; associated with selective water transport through the membrane and with cell proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">47</span></a> Of special interest is the work on micro-RNA &#40;miRNA&#41; in mesothelioma&#46; These are short&#44; non-protein coding RNAs &#40;17&#8211;22 nucleotides&#41; that regulate gene expression and play an important role in oncogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">48</span></a> They have high tissue specificity for detecting the origin of a tumor and also for distinguishing mesothelioma from other metastatic pleural tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">49</span></a> Consequently&#44; miRNA detection in peripheral blood may become an excellent marker for mesothelioma in the near future&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">50</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment of Malignant Pleural Mesothelioma</span><p id="par0075" class="elsevierStylePara elsevierViewall">Pleural mesothelioma generally responds poorly to chemotherapy and radiotherapy and surgery is rarely curative&#44; because the tumor is usually diagnosed too late&#46; For this reason&#44; it is essential to carefully evaluate the patient before selecting the best treatment modality&#46; If radical treatment is being considered&#44; lung and cardiac function&#44; other comorbidity factors&#44; and the physical and psychological status of the patient must be assessed&#46; Choice of one or other of the various available options is dictated by the clinical situation and tumor extension &#40;TNM&#41; determined by imaging techniques&#46; However&#44; none of the currently available imaging techniques is precise enough to determine the &#8220;T&#8221; and &#8220;N&#8221; components in malignant pleural mesothelioma&#44; and post-surgical staging often widely exceeds pre-surgical findings&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">51</span></a> Until more robust TNM staging can be defined&#44; the system established by the</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Union Internationale contre le Cancer</span> &#40;UICC&#41; should be used<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">52</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Surgical Treatment of Malignant Pleural Mesothelioma</span><p id="par0085" class="elsevierStylePara elsevierViewall">The main objective of surgery is the gross resection of all malignant growth&#46; The assumption is that this leads to longer survival and that patients who have gross evidence of remaining tumor will have poorer survival&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">53</span></a> However&#44; accumulated evidence suggests that full resection &#40;macro- and microscopic&#41; of mesothelioma is impossible&#44; irrespective of the surgical technique used&#46; Therefore&#44; it is accepted that surgery is aimed at local disease control&#44; elimination of pleural effusion&#44; release of lung trapped by the tumor&#44; improvement of ventilation&#47;perfusion disorders and relief of pain from chest wall invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">54</span></a> All these considerations are particularly applicable to epithelioid mesothelioma&#44; since the sarcomatous or biphasic types have a worse prognosis&#44; and as such&#44; are poorer candidates for any type of surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Extrapleural Pneumonectomy</span><p id="par0090" class="elsevierStylePara elsevierViewall">Extrapleural pneumonectomy involves resection of the lung and the parietal pleura&#44; and is usually completed with ipsilateral resection of the pericardium and diaphragm&#44; in addition to systematic dissection of the mediastinal lymphatic chains&#46; Perioperative mortality is around 5&#37; in highly experienced hospitals&#46; However&#44; morbidity is high and includes cardiac and respiratory complications&#44; of particular relevance in the unipulmonary situation encountered after extrapleural pneumonectomy &#40;EPP&#41;&#46; Other complications include bronchopleural fistula&#44; empyema and bleeding&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">55&#44;56</span></a> In any event&#44; this intervention commonly involves persistent residual gross and microscopic disease&#44; so it should be planned within the context of multimodal therapy&#44; based on the combined use of surgery&#44; chemotherapy and radiation therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">57</span></a> Hyperthermia&#44; combined with chemotherapy&#44; or local photodynamic therapy have occasionally been used&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">58</span></a> Many multimodal treatment protocols recommend chemotherapy as pre-surgery induction treatment &#40;neoadjuvant chemotherapy&#41;&#44; with radiation therapy administered to the affected hemothorax after resection&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">59</span></a> Nevertheless&#44; the most recent guidelines recommend avoiding surgery if progressive disease is observed after neoadjuvant chemotherapy&#59; besides&#44; EEP is only recommended in the context of controlled clinical trials performed by specialized teams of investigators&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">27&#44;28</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pleurectomy&#47;Decortication</span><p id="par0095" class="elsevierStylePara elsevierViewall">Although pleurectomy&#47;decortication&#44; aimed primarily at releasing the lung and the chest wall from constriction caused by the tumor&#44; is associated with a higher risk of local relapse than EEP&#44; it involves fewer complications&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">60</span></a> The best candidates for this type of surgery are patients with gross diffuse tumors in the parietal wall&#44; but only focal sites in the viscera&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">54</span></a> The procedure can be performed using VATS&#44; with the advantage of minimizing morbidity associated with thoracotomy<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">61</span></a> and the possibility of performing pleurodesis during the same intervention&#44; if resection cannot be completed&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">EEP constitutes a more radical approach&#44; but in recent years its advantages over pleurectomy&#47;decortication have been questioned&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">62&#44;63</span></a> No superiority was observed for either technique in a recent randomized study performed in the United Kingdom &#40;the Mesothelioma and Radical Surgery &#91;MARS&#93; study&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">64</span></a> Nevertheless&#44; the MARS study has been severely criticized&#44; due to significant deviations from the original protocol design and the number of patients finally included in one of the study groups&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">65</span></a> In any case&#44; although some groups with extensive experience in both techniques find it unacceptable to forgo resection of grossly visible tumor &#40;giving a poorer prognosis&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">54</span></a> the idea of resecting the greatest tumor volume possible&#44; while preserving the underlying lung and combining surgery with chemotherapy and radiation therapy in multimodal treatment&#44; is gaining ground&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">66</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Radiation Therapy in Malignant Mesothelioma</span><p id="par0105" class="elsevierStylePara elsevierViewall">Radical radiation therapy administered to the whole hemithorax is seriously limited by the risk of damaging critical organs&#44; such as the lung&#44; liver&#44; heart&#44; bone marrow and esophagus&#44; although these negative effects are being palliated by optimized application techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">67</span></a> However&#44; there is no convincing evidence that this alone prolongs survival in mesothelioma&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">68</span></a> On the other hand&#44; palliative radiation therapy plays an important role in the control of pain from chest wall infiltration&#46;<a class="elsevierStyleCrossRefs" href="#bib0840"><span class="elsevierStyleSup">69&#44;70</span></a> The classic recommendation has been to administer prophylactic radiation therapy to avoid tumor seeding in the thoracoscopy or thoracotomy scars&#44;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">71&#44;72</span></a> but this practice is not supported by available evidence&#44; and is no longer advised&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">27&#44;28</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Chemotherapy&#44; Immunotherapy and Other Tailored Treatments</span><p id="par0110" class="elsevierStylePara elsevierViewall">Recent clinical guidelines advise against delaying the administration of chemotherapy&#44; which must be considered before the patient&#39;s functional status begins to deteriorate&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">27&#44;28</span></a> The combination of various agents&#44; including pemetrexed and platinum compounds&#44; generally produces better results than monotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0860"><span class="elsevierStyleSup">73&#44;74</span></a> Current trends in research are oriented toward new therapeutic targets focused on controlling angiogenesis and apoptotic pathways <span class="elsevierStyleItalic">via</span> specific ligands&#44; such as platelet derived growth factor &#40;PDGF&#44; that is quite often expressed in the mesothelioma and associated with poorer survival&#41; and mesothelin &#40;expressed only in the epithelioid subtype&#41;&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">75&#44;76</span></a> Immunotherapy is another aspect of multimodal therapy that can be effective in the treatment of mesothelioma&#44; since this tumor uses regulatory T-cells &#40;Tregs&#41; and M2 macrophages to escape the immune system&#46; New therapeutic strategies combining cytoreductive surgery&#44; chemotherapy&#44; immunotherapy and radiation therapy may lead to better disease control&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">77</span></a> There is a wide spectrum of possible approaches for achieving notably synergic antitumor effects&#44; from passive immunotherapy &#40;using cytokines or specific antibodies&#41; to immune response modulation using dendritic cells or others&#46;<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">78&#8211;80</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Pleurodesis</span><p id="par0115" class="elsevierStylePara elsevierViewall">Control of pleural effusion is a priority in most patients with malignant pleural mesothelioma&#44; and a good option for this is talc pleurodesis&#46; However&#44; in our experience&#44; pleurodesis tends to fail more often in this tumor than in others&#44; possibly due to difficulties in achieving re-expansion of the lung that has been trapped by the tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">81</span></a> Previous studies by our group show that the extension of the tumor in the pleural cavity has a negative effect on pleurodesis&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">82</span></a> It seems likely&#44; then&#44; that other biological factors&#44; unidentified to date&#44; are also involved&#46; According to recent <span class="elsevierStyleItalic">in vitro</span> experiments carried out by our group&#44; malignant mesothelial cells are more resistant to the action of talc than other cell lines&#44; as observed in both the modulation&#47;blocking of angiogenesis and in cell proliferation &#40;unpublished data&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">When pleurodesis fails&#44; or is considered unfeasible due to massive lung entrapment by the tumor&#44; the best option is to place a tunneled pleural catheter for drainage of pleural fluid at home&#46; This procedure also induces spontaneous pleurodesis in a considerable number of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0910"><span class="elsevierStyleSup">83&#8211;86</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">It is important to remember that previous pleurodesis does not rule out the need for surgical resection of mesothelioma&#44; whether by EEP or pleurectomy&#47;decortication&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">54</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Future Outlook</span><p id="par0130" class="elsevierStylePara elsevierViewall">Molecular biology and nanotechnology are coming together in the newly emerging concept of &#8220;theranostics&#8221;&#44; the aim of which is to combine diagnosis and treatment in the same procedure with the use of drugs that specifically target each malignancy subtype&#46; If the right ligands were found&#44; they could be used in PET or single photon emission computed tomography &#40;SPECT&#41; for the early diagnosis of mesothelioma&#46;<a class="elsevierStyleCrossRefs" href="#bib0930"><span class="elsevierStyleSup">87&#8211;89</span></a> Highly sensitive probes combined with biofluorescent techniques that can detect tumors in animal models have been developed&#46;<a class="elsevierStyleCrossRefs" href="#bib0945"><span class="elsevierStyleSup">90&#44;91</span></a> Techniques based on labeled antibodies or nanoparticles with nuclear magnetic resonance are available&#44;<a class="elsevierStyleCrossRefs" href="#bib0955"><span class="elsevierStyleSup">92&#44;93</span></a> and the prospect of eventually using these in humans is good&#46; Until such time&#44; however&#44; it seems more realistic to concentrate on the search for markers that are detectable in peripheral blood and sufficiently sensitive and specific for the diagnosis of malignant mesothelioma&#46; Along with imaging techniques&#44; the most promising field appears to be comprehensive screening for early mesothelioma markers using proteomics&#46; This can simultaneously analyze the profiles of large numbers of proteins &#40;over 1000&#41;&#44; in panels configured to achieve the greatest diagnostic sensitivity and specificity&#46;<a class="elsevierStyleCrossRefs" href="#bib0965"><span class="elsevierStyleSup">94&#44;95</span></a> As explained above&#44; miRNA detection in peripheral blood is another emerging field in the hunt for a sufficiently early diagnostic test for mesothelioma&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Gene therapy has often been proposed in mesothelioma to compensate for the poor results of immune therapy in locally advanced disease&#46; To this end&#44; different strategies&#44; such as &#8220;suicide genes&#8221; &#40;which make the tumor sensitive to certain drugs&#41;&#44; administration of tumor suppressor genes&#44; or the transfer of immunomodulatory genes to the pleural space have been proposed&#46;<a class="elsevierStyleCrossRefs" href="#bib0975"><span class="elsevierStyleSup">96&#8211;99</span></a> Results in the clinic are rather disheartening to date due to vector-related problems and relative inefficiency in controlling large tumor masses&#46; However&#44; gene therapy is most likely to be incorporated into the multimodal strategy&#44; and when combined with nanotechnology techniques it will contribute very significantly to the improvement of treatment of malignant pleural mesothelioma in the future&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">Part of the funding of the research performed by our group in this article&#44; was funded by Project <span class="elsevierStyleGrantNumber" refid="gs1">PI-0358-2010</span>&#44; of the <span class="elsevierStyleGrantSponsor" id="gs1">Health Council of the Government of Andalusia</span>&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of Interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The author states that he has no conflict of interests&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Diagnosis of Malignant Pleural Mesothelioma"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Imaging Techniques in the Diagnosis of Mesothelioma"
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              "identificador" => "sec0020"
              "titulo" => "Pleural Fluid Studies"
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              "identificador" => "sec0025"
              "titulo" => "Histological Diagnosis of Malignant Pleural Mesothelioma"
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              "titulo" => "Pleural Biopsy and Thoracoscopy in the Diagnosis of Mesthelioma"
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              "identificador" => "sec0035"
              "titulo" => "Early Diagnosis of Malignant Pleural Mesothelioma"
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              "titulo" => "Biomarkers in the Diagnosis of Malignant Mesothelioma"
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          "titulo" => "Treatment of Malignant Pleural Mesothelioma"
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              "identificador" => "sec0050"
              "titulo" => "Surgical Treatment of Malignant Pleural Mesothelioma"
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              "identificador" => "sec0055"
              "titulo" => "Extrapleural Pneumonectomy"
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              "titulo" => "Pleurectomy&#47;Decortication"
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              "identificador" => "sec0065"
              "titulo" => "Radiation Therapy in Malignant Mesothelioma"
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              "titulo" => "Chemotherapy&#44; Immunotherapy and Other Tailored Treatments"
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              "titulo" => "Pleurodesis"
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          "titulo" => "Future Outlook"
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    "fechaRecibido" => "2014-04-06"
    "fechaAceptado" => "2014-06-10"
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            0 => "Malignant pleural mesothelioma"
            1 => "Biomarkers"
            2 => "Malignant pleural effusion"
            3 => "Thoracoscopy"
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            0 => "Mesotelioma pleural maligno"
            1 => "Biomarcadores"
            2 => "Derrame pleural maligno"
            3 => "Toracoscopia"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are three major challenges in the diagnosis of malignant pleural mesothelioma&#58; mesothelioma must be distinguished from benign mesothelial hyperplasia&#59; malignant mesothelioma &#40;and its subtypes&#41; must be distinguished from metastatic carcinoma&#59; and invasion of structures adjacent to the pleura must be demonstrated&#46; The basis for clarifying the first two aspects is determination of a panel of monoclonal antibodies with appropriate immunohistochemical evaluation performed by highly qualified experts&#46; Clarification of the third aspect requires sufficiently abundant&#44; deep biopsy material&#44; for which thoracoscopy is the technique of choice&#46; Video-assisted needle biopsy with real-time imaging can be of great assistance when there is diffuse nodal thickening and scant or absent effusion&#46; Given the difficulties of reaching an early diagnosis&#44; cure is not generally achieved with radical surgery &#40;pleuropneumonectomy&#41;&#44; so liberation of the tumor mass with pleurectomy&#47;decortication combined with chemo- or radiation therapy &#40;multimodal treatment&#41; has been gaining followers in recent years&#46; In cases in which surgery is not feasible&#44; chemotherapy &#40;a combination of pemetrexed and platinum-derived compounds&#44; in most cases&#41; with pleurodesis or a tunneled pleural drainage catheter&#44; if control of pleural effusion is required&#44; can be considered&#46; Radiation therapy is reserved for treatment of pain associated with infiltration of the chest wall or any other neighboring structure&#46; In any case&#44; comprehensive support treatment for pain control in specialist units is essential&#58; this acquires particular significance in this type of malignancy&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El diagn&#243;stico del mesotelioma pleural maligno presenta 3 importantes retos&#58; es necesario distinguir entre hiperplasia mesotelial benigna y mesotelioma&#44; entre mesotelioma maligno &#40;con subtipos&#41; y carcinoma metast&#225;sico&#44; y tambi&#233;n se requiere demostrar la invasi&#243;n de estructuras vecinas a la pleura&#46; Para aclarar los 2 primeros aspectos hay que basarse en un panel de anticuerpos monoclonales con adecuado estudio inmunohistoqu&#237;mico&#8211;realizado por manos muy expertas&#8211;y para el tercero hay que apoyarse en biopsias suficientemente amplias y profundas&#44; y la toracoscopia es la t&#233;cnica de elecci&#243;n&#46; La biopsia con aguja guiada con t&#233;cnicas de imagen en tiempo real puede ser de gran ayuda cuando existe marcado engrosamiento nodular difuso y derrame peque&#241;o o ausente&#46; Dadas las dificultades de un diagn&#243;stico precoz&#44; es infrecuente que se consiga un tratamiento curativo mediante cirug&#237;a radical &#40;pleuroneumonectom&#237;a&#41;&#44; por lo que en los &#250;ltimos a&#241;os est&#225; ganando adeptos la liberaci&#243;n de masa tumoral mediante pleurectom&#237;a&#47;decorticaci&#243;n&#44; con asociaci&#243;n de quimio y radioterapia a las t&#233;cnicas quir&#250;rgicas &#40;terapia multimodal&#41;&#46; En los casos en que la cirug&#237;a no es factible se plantea la quimioterapia &#40;combinando pemetrexed y compuestos de platino en la mayor&#237;a de los casos&#41;&#44; con pleurodesis o colocaci&#243;n de un cat&#233;ter pleural tunelizado si se requiere el control del derrame pleural&#44; y se reserva la radioterapia para el tratamiento del dolor asociado a infiltraci&#243;n de la pared tor&#225;cica o cualquier otra estructura vecina&#46; En todo caso&#44; es esencial un completo tratamiento de soporte para el control del dolor &#40;que adquiere particular protagonismo en esta neoplasia&#41; en unidades especializadas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez Panadero F&#46; Diagn&#243;stico y tratamiento del mesotelioma pleural maligno&#46; Arch Bronconeumol&#46; 2015&#59;51&#58;177&#8211;184&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Various thoracoscopic images of malignant pleural mesothelioma&#46; &#40;A&#41; Massive epithelioid malignant mesothelioma invasion of the parietal pleural&#46; &#40;B&#41; Diffuse epithelioid malignant mesothelioma infiltration of parietal and visceral pleura&#46; &#40;C&#41; &#8220;String of pearls&#8221; nodes in massive epithelioid invasion of the parietal pleural&#46; &#40;D&#41; Pleural plaques and sarcomatous mesothelioma masses in the parietal pleura&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">CEA&#58; carcinoembryonic antigen&#59; EMA&#58; epithelial membrane antigen&#59; ER&#58; endoplasmic reticulum marker&#59; TTF-1&#58; thyroid transcription factor-1&#59; WT-1&#58; Wilms tumor antigen 1&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Adapted from Scherpereel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a></p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Epithelioid mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Calretinin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Essential&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;nucleus and cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#177; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">WT-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;nuclear&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;lung&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">EMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CK5&#47;CK6 keratins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Monoclonal CEA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Ber-EP4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#177; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">TTF-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;nucleus&#44; lung&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">B72&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;cytoplasm&#44; lung&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;nucleus&#44; breast&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemical Markers for Differentiating Epithelioid Mesothelioma From Other Metastatic Pleural Tumors&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">p63&#58; p53 homolog&#44; but more useful for differential diagnosis&#59; WT-1&#58; Wilms tumor antigen 1&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Adapted from Scherpereel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sarcomatous mesothelioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Squamous cell or transitional cell carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Calretinin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;nucleus and cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">WT-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;nucleus&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CK5&#47;CK6 keratins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">p63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;nucleus&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Ber-EP4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#177; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;cytoplasm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">MOC 31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Useful&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#177; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43; &#40;membrane&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemical Markers for Differentiating Sarcomatous Mesothelioma From Squamous Cell or Transitional Cell Carcinoma&#46;</p>"
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        "etiqueta" => "Table 3"
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        "fuente" => "Source&#58; Adapted from Van Meerbeeck et al&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">52</span></a>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tumor extension&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">T1a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">T2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unilateral parietal or visceral involvement with invasion of underlying lung or diaphragmatic muscle&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">T4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Involvement of any pleural zone with invasion of at least one of the following structures&#58; internal surface of the pericardium &#40;with or without effusion&#41;&#44; peritoneum&#44; mediastinal structures&#44; contralateral pleura&#44; spine&#44; diffuse invasion of the chest wall &#40;with or without rib destruction&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">N0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No lymph node involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">N1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ipsilateral bronchopulmonary or hilar lymph node involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">N2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ipsilateral mediastinal lymph node involvement&#44; including the ipsilateral internal mammary and&#47;or peridiaphragmatic nodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">N3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Contralateral mediastinal&#44; contralateral internal mammary and&#47;or contralateral supraclavicular lymph node involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No extrathoracic metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Extrathoracic&#44; hematogenous or non-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" title="table-entry  " align="left" valign="top">Stage I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T1aN0 &#40;1A&#41;&#59; T1bN0 &#40;1B&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Stage II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T2N0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Stage III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Any T3&#44; N1 or N2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Stage IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Any T4&#44; N3 or M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Malignant Pleural Mesothelioma TNM Staging&#46;</p>"
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      "titulo" => "References"
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                  "contribucion" => array:1 [
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2015.02.009

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2024 November	11	8	19
2024 October	125	30	155
2024 September	116	21	137
2024 August	141	63	204
2024 July	102	25	127
2024 June	83	30	113
2024 May	158	36	194
2024 April	66	23	89
2024 March	60	29	89
2024 February	47	23	70
2023 March	24	4	28
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2022 December	103	50	153
2022 November	136	57	193
2022 October	106	39	145
2022 September	112	60	172
2022 August	122	55	177
2022 July	78	57	135
2022 June	88	71	159
2022 May	80	54	134
2022 April	92	79	171
2022 March	118	51	169
2022 February	126	53	179
2022 January	132	46	178
2021 December	112	74	186
2021 November	117	52	169
2021 October	197	61	258
2021 September	94	67	161
2021 August	96	45	141
2021 July	86	38	124
2021 June	144	67	211
2021 May	135	51	186
2021 April	321	155	476
2021 March	181	65	246
2021 February	141	44	185
2021 January	151	55	206
2020 December	109	44	153
2020 November	107	43	150
2020 October	90	46	136
2020 September	115	38	153
2020 August	81	36	117
2020 July	90	46	136
2020 June	106	30	136
2020 May	153	42	195
2020 April	165	56	221
2020 March	140	28	168
2020 February	130	47	177
2020 January	112	48	160
2019 December	167	50	217
2019 November	123	50	173
2019 October	115	41	156
2019 September	177	47	224
2019 August	96	45	141
2019 July	130	49	179
2019 June	902	47	949
2019 May	181	56	237
2019 April	352	77	429
2019 March	226	61	287
2019 February	160	41	201
2019 January	934	59	993
2018 December	151	62	213
2018 November	267	72	339
2018 October	501	57	558
2018 September	216	59	275
2018 May	79	6	85
2018 April	145	61	206
2018 March	134	54	188
2018 February	90	47	137
2018 January	147	48	195
2017 December	102	45	147
2017 November	94	57	151
2017 October	98	82	180
2017 September	99	108	207
2017 August	114	78	192
2017 July	91	48	139
2017 June	104	68	172
2017 May	109	66	175
2017 April	102	62	164
2017 March	123	50	173
2017 February	78	23	101
2017 January	71	33	104
2016 December	95	24	119
2016 November	129	32	161
2016 October	141	53	194
2016 September	186	36	222
2016 August	135	26	161
2016 July	66	50	116
2016 March	2	0	2
2016 February	1	0	1
2015 December	3	0	3
2015 October	65	2	67
2015 September	77	21	98
2015 August	88	27	115
2015 July	43	19	62
2015 May	1	2	3
2015 April	2	3	5

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