Although 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.11 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).12 PET-CT is particularly useful for pre-surgery staging of malignant pleural mesothelioma, for evaluating treatment response, and for detecting possible relapse.13 However, its sensitivity and specificity for detecting N2 disease in mesothelioma is low,14 and false negatives may be found in tuberculous pleurisy,15 empyema16 or in patients with a history of previous pleurodesis.17

Magnetic resonance imaging (MRI) provides greater contrast than CT for defining tumor chest wall invasion, but it cannot reliably detect metastatic disease.18

Thoracocentesis can provide data suggestive of mesothelioma, but rarely diagnostic: high levels of hyaluronic acid (>100000ng/ml) are highly indicative of malignant pleural mesothelioma.19 Elevated hyaluronic acid also has good prognostic values, with higher levels being associated with better survival.20

Adenosine deaminase (ADA) levels may be raised in mesothelioma patients,21 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.22

Pleural fluid cytology may reveal mesothelioma, but it is often difficult to distinguish between benign and malignant mesothelial hyperplasia.23 This test is also unable to determine the invasive character of the tumor, currently considered an essential feature for a definitive diagnosis).24 However, in some exceptional cases, cytology may be combined with imaging techniques for the evaluation of extrapleural invasion.25 Immunocytochemical and immunohistochemical techniques are also essential for differentiating between mesothelioma and metastatic adenocarcinoma in the pleura,26 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.27 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.28

The 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 tumors28 (see Table 1). 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 Table 2).

Blind 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 CT29,30 or real-time ultrasound.31 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.32 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.33 In our hospital, we have used this technique to diagnose more than 80 pleural mesotheliomas34 (see Fig. 1). 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.35 The yield from pleuroscopy, also known as “medical thoracoscopy”, is suboptimal in mesothelioma with sarcomatous component,36 and for this subtype, more representative samples can be obtained with VATS or mini-thoracotomy.37

Fig. 1.

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.

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Despite 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.

The 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).38 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.39 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.40–42 In all events, mesothelin appears to be more useful for monitoring treatment than for the differential diagnosis of pleural effusion.43

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.44 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.45

In recent years, gene expression in mesothelioma has been the object of intensive research,46 and the expression of certain proteins has been targeted, including aquaporin-1, associated with selective water transport through the membrane and with cell proliferation.47 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.48 They have high tissue specificity for detecting the origin of a tumor and also for distinguishing mesothelioma from other metastatic pleural tumors.49 Consequently, miRNA detection in peripheral blood may become an excellent marker for mesothelioma in the near future.50

The 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.53 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.54 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.51

Extrapleural 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.55,56 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.57 Hyperthermia, combined with chemotherapy, or local photodynamic therapy have occasionally been used.58 Many multimodal treatment protocols recommend chemotherapy as pre-surgery induction treatment (neoadjuvant chemotherapy), with radiation therapy administered to the affected hemothorax after resection.59 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.27,28

Although 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.60 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.54 The procedure can be performed using VATS, with the advantage of minimizing morbidity associated with thoracotomy61 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.62,63 No superiority was observed for either technique in a recent randomized study performed in the United Kingdom (the Mesothelioma and Radical Surgery [MARS] study).64 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.65 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),54 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.66

Radical 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.67 However, there is no convincing evidence that this alone prolongs survival in mesothelioma.68 On the other hand, palliative radiation therapy plays an important role in the control of pain from chest wall infiltration.69,70 The classic recommendation has been to administer prophylactic radiation therapy to avoid tumor seeding in the thoracoscopy or thoracotomy scars,71,72 but this practice is not supported by available evidence, and is no longer advised.27,28

Recent clinical guidelines advise against delaying the administration of chemotherapy, which must be considered before the patient's functional status begins to deteriorate.27,28 The combination of various agents, including pemetrexed and platinum compounds, generally produces better results than monotherapy.73,74 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.75,76 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.77 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.78–80

Control 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.81 Previous studies by our group show that the extension of the tumor in the pleural cavity has a negative effect on pleurodesis.82 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.83–86

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.54