DIAGNOSTIC AND THERAPEUTIC ASPECTS IN MALIGNANT Pleural mesothelioma
The diagnosis of mesothelioma requires a distinction between benign and malignant mesothelial involvement, and between malignant mesothelioma and metastatic carcinoma. For this, immunohistochemical techniques performed on large biopsies are necessary. Thoracoscopy is the technique of choice, although needle biopsy using real-time imaging techniques can be very useful if there is marked nodular thickening. Radical surgery (pleuropneumonectomy) is unlikely to be truly curative, so reduction of tumor mass by pleurectomy/decortication is gaining popularity, with the combination of chemotherapy and radiotherapy to surgery (multimodal therapy). When resection is not feasible, chemotherapy is considered, with pleurodesis or placement of a tunneled pleural catheter if control of the pleural effusion is required and radiation therapy is reserved to treat chest wall infiltration. Complete pain control (which takes on a particular role in this neoplasm) in specialized units is also essential.
Diagnosis of malignant pleural mesothelioma requires making the distinction between benign mesothelial hyperplasia and true mesothelioma, and between malignant mesothelioma and metastatic pleural adenocarcinoma. This involves immunohisto-chemical techniques applied on large biopsy specimens, and thoracoscopy is the best choice for obtaining them. A real-time image-guided needle biopsy can also be very helpful in presence of marked nodular pleural thickening. Radical surgery (ie, extrapleural pneumonectomy) is unlikely to cure completely the patient, and cytoreduction surgery with preservation of the underlying lung (pleurectomy/decortication), with the addition of chemo and radiation therapy (muiltimodal treatment), is gaining adepts in the last few years. When surgery is not feasible at all, early chemotherapy -with pleurodesis or placement of an indwelling pleural catheter (to control the effusion if necessary) – is advisable. Radiation therapy should be reserved to treat chest wall infiltration in those cases, and complete control of pain in specialized units is also essential in those patients.
Mesothelioma was a rare tumor of the pleura until the first half of the 20th century and the uncertainty about its origin and histological characteristics meant that for years it was included in a group of tumors called “Endotheliomas” (whose origin was thought to be that resided in the endothelium of small vessels), and its mesodermal origin was later established. Since the 1950s, its association with asbestos 1 has been known , particularly in its forms of “ blue asbestos ” (or crocidolite) and “ white asbestos ” ( chrysotile ), and its relationship with exposure is also well known. to erionite, which is a natural soil pollutant in various regions of the world, particularly in the Cappadocia region (Turkey), where a very high incidence of this tumor is observed, probably also associated with a certain genetic susceptibility 2 . In approximately 80% of mesothelioma cases, there is a clear cause-effect relationship with occupational exposure to asbestos, with a wide spectrum of professions involved 3 . Possible environmental exposure must also be taken into account, generally due to proximity to mines or factories where the mineral is handled or due to contamination through the clothing of asbestos workers 4. A dose-response relationship has been demonstrated between cumulative exposure to asbestos (high levels of exposure, duration of exposure, or both) and malignant mesothelioma, and there is no threshold below which the risk of contracting the disease is ruled out 5 , 6 , 7 . Mesothelioma can appear in any of the structures of embryonic mesodermal origin (pleura, pericardium, peritoneum, “tunica vaginalis” and others) but the most frequent presentation -in more than 90% of cases- is pleural. However, its incidence is relatively low, ranging from seven cases per million inhabitants/year in Japan to 40 in Australia, depending mainly on the exposure to asbestos that has occurred in past decades in those countries.8 . In Europe, the incidence is estimated at 20 cases per million / year, with notable variation between countries (also in relation to the history of exposure to asbestos in the past), but in any case a global increase is expected, based on the long period latency between exposure and manifestation of the disease, which is around 40 years, with a wide margin between extreme values (up to 75 years in the series by Bianchi et al.) 9 . Based on the consumption of asbestos, it has been estimated that the peak of maximum incidence of mesothelioma will be registered around the year 2020 in Europe, with marked differences between countries 10 .
DIAGNOSIS OF MALIGNANT PLEURAL MESOTHELIOMA
The initial symptoms of mesothelioma are usually of little clinical relevance, with the appearance of imprecise and persistent chest pain with little relation to respiratory movements. On occasions, dyspnea may occur, generally related to the presence of pleural effusion, and in early clinical stages, weight loss or any other symptoms are rare; Later, marked retraction of the hemithorax usually appears, and the pain acquires special intensity and persistence.
Imaging techniques for the diagnosis of pleural mesothelioma
First of all, chest radiography can provide us with information on the presence of diffuse pleural effusion and thickening or masses, but computed tomography (CT) – preferably with contrast – is essential for choosing the diagnostic steps to follow: thickening and diffuse pleural mesothelioma suggests nodular prominences, especially in a patient with a history of previous exposure to asbestos in all its forms 11 . On the other hand, it has been suggested that the estimation of tumor volume by CT may be important for making therapeutic decisions 12 . The nuclear magnetic resonance(NMR) provides a better contrast than CT for defining the invasion of the chest wall, but can not reliably detect the presence of metastatic disease in other parts 13 . On the other hand, CT is not very sensitive to assess a possible mediastinal lymph node involvement – which has a relevant prognostic value 14 , 15 – or the existence of contralateral or peritoneal pleural involvement. To investigate these aspects – and the presence of possible distant metastases – positron emission tomography ( PET ) is much more useful , especially when combined with CT (PET-CT) 16. PET-CT plays an important role in the preoperative staging of malignant pleural mesothelioma with a view to prognosis, 17 , 18 in the assessment of response to treatment and in the detection of possible recurrences, 19 but its sensitivity is relatively low for detecting disease N2 in this disease 20 . On the other hand, false positives of PET can be seen in tuberculous pleurisy 21 , empyema 22 or in patients with a history of previous pleurodesis 23 . In any case, the combination of several techniques can provide valuable information to establish the prognosis and the best therapeutic strategy 24 .
Study of pleural fluid in mesothelioma
Thoracentesis can provide some suggestive -but rarely diagnostic- data of mesothelioma: high levels of hyaluronic acid ( > 100,000 ng / ml) are highly suggestive of malignant pleural mesothelioma 25 , and a marked prognostic value is also attributed to this parameter, of Thus, a high hyaluronic acid is associated with better survival 26 .
Elevated LDH values in pleural fluid have been correlated with a worse prognosis, 27 with 500 U / L as cut-off point, but pH and glucose in pleural fluid seem to be more relevant : Low pH and glucose have been associated with shorter survival in carcinomatous pleural effusions 28 , 29 , 30 , 31 and also have prognostic value in mesotheliomas. It is important to note that pleural pH and glucose are significantly lower in mesotheliomas than in metastatic carcinomas, as can be seen in our series of malignant pleural effusions submitted to thoracoscopy (see Table 1 ).
Table 1 . Comparison between mesotheliomas and metastatic pleural carcinomas in our series of patients with malignant pleural effusion who underwent thoracoscopy.
|MESOTHELIOMAS (N = 87)||NO MESOTHELIOMAS (N = 499)||P value|
|Age (years)||63.3 ± 1.2 (*) (37-86)||60.2 ± 0.6 (16-90)||NS|
|Gender (M / F)||68/19||224/275||< 0.001|
|Hemithorax occupation (%)||60% (5-133)||62% (5-140)||NS|
|Pleural fluid volume|
|extracted by thoracoscopy (mL)||1973 ± 128 (0-5200)||1689 ± 50 (0-6000)||0.03|
|pleural fluid pH||7.28 ± 0.02 (Median = 7.29)||7.32 ± 0.01 (Median = 7.35)||0.012|
|Glucose in pleural L. (mg / dL)||54.2 ± 4.6 (Median = 57.5)||86.6 ± 2.6 (Median = 85)||< 0.001|
|LDH in L. pleural||958 ± 162||968 ± 80||NS|
|Pl. Parietal involvement (0-3) (**)||2.4 ± 0.1||2.1 ± 0.1||< 0.001|
|Visceral Pl. Involvement (0-3) (**)||1.7 ± 0.1||1.6 ± 0.1||NS|
|Tumor involvement in the pleural cavity (0-9) (**)||6 ± 0.2||5.2 ± 0.1||< 0.001|
|Survival after thoracoscopy (months)||11.4 ± 1.5 (Median = 9.3) (0.3-41.1)||9.9 ± 1.1 (Median = 3.7) (0.3-124)||NS|
(*) Data are presented as mean ± standard error of the mean.
(**) The quantification of tumor involvement was carried out following the methodology previously described by our Group (reference 30).
Adenosine deaminase (ADA) levels may be elevated in patients with mesothelioma 32 , but -before labeling them as false positives of the ADA- it must be taken into account that malignant mesothelioma and tuberculous pleurisy can sometimes coexist, and therefore it is recommended culture for M. tuberculosis in these cases 33 .
The cytology of pleural fluid may suggest the presence of mesothelioma, but often poses problems between mesothelial hyperplasia benign and malignant 34 and is also unable to demonstrate the invasiveness of the tumor (which is currently considered an essential feature for definitive diagnosis) 35 . However, in most cases they can be combined cytology and imaging techniques to evaluate the invasion Extrapleural 36 . On the other hand, immunocyte / histochemical techniques are always necessary to establish the distinction between mesothelioma and metastatic adenocarcinoma in the pleura 37This requires tissue obtained by biopsy, or cell blocks prepared by inclusion of the cell button in paraffin after centrifugation of a sufficient volume of pleural fluid ( > 100 ml). The combination of all the following assumptions can provide the diagnosis of mesothelioma with sufficient reliability: atypical mesothelial proliferation in the pleural fluid + immunohistochemical studies compatible with mesothelioma in cell blocks + diffuse pleural thickening with nodulations + absence of masses in the lung or any other organ that suggest another primary tumor 38. However , and especially the legal implications involved in the diagnosis of malignant mesothelioma in most cases and also when surgery poses, try to always get large tissue samples to establish more securely the tumor 39 .
Histological aspects of malignant pleural mesothelioma
Epithelioid , sarcomatous, and biphasic types are distinguished in malignant pleural mesothelioma, but there are also rare subtypes, such as desmoplastic mesothelioma (which can be confused with benign fibrous pleurisy), small cell mesothelioma, and lymphohistiocytoid mesothelioma(which could be confused with a lymphoma), and immunohistochemical studies are key to distinguish between them. However, there is no marker with 100% sensitivity and specificity for mesothelioma and therefore it is essential to go to different panels of monoclonal antibodies, including at least two positive markers for mesothelioma, in the epithelioid subtype, calretinin would be preferable (particularly useful if it stains nucleus, in addition to the cytoplasm), WT-1, (Wilms tumor antigen 1) or EMA (epithelial membrane antigen) or broad-spectrum, low-molecular-weight cytokeratins , such as CK5 or CK6 – and two negative markers, such as Ber-EP4 (membrane marker) and TTF-1 ( thyroid transcription factor 1, nuclear marker). CEA ( carcinoembryonic antigen ) is very useful to distinguish metastatic carcinoma -especially of pulmonary origin- from mesothelioma (in which it is practically always negative), and in case of suspected mesothelioma in women it is convenient to also test the expression of ER ( endoplasmic reticulum ), which never appears in mesothelioma and does appear in metastatic breast tumors (see Table 2 ). When the tumor has a sarcomatous component, it is often necessary to distinguish it from metastatic tumors, such as squamous cell lung or transitional cell carcinoma. Although some of the antibodies used for epithelial mesothelioma are useful here, you often have to rely on different ones, such as p63 and MOC 31 (SeeTable 3 ).
Table 2 . Markers to differentiate epithelioid mesothelioma from other metastatic pleural tumors with immunohistochemical techniques
|Antibody||Diagnostic value||Epithelioid mesothelioma||Adenocarcinoma|
|Mesothelioma||Calretinin||Essential||+++ (nucleus and cytoplasm)||+/- (cytoplasm)|
|WT-1||Useful||++ (nuclear)||– (Lung)|
|EMA||Useful||++ (membrane)||+++ (cytoplasm)|
|CK5 / CK6 Keratins||Useful||++ (cytoplasm)||–|
|Adenocarcinoma||Monoclonal CEA||Very useful||–||++ (cytoplasm)|
|Ber-EP4||Very useful||+/- (membrane)||+++ (membrane)|
|TTF-1||Very useful||–||++ (nucleus, lung)|
|B72.3||Very useful||–||+++ (cytoplasm, lung)|
|Breast cancer||ER||Very useful||–||++ (nucleus, breast)|
(WT-1 = Wilms tumor antigen 1, EMA = Epithelial membrane antigen, CEA = Carcinoembryonic antigen, TTF-1 = Thyroid transcription factor-1, ER = Endoplasmic reticulum marker). (Adapted from Scherpereel et al, reference 39) (See text).
Table 3 . Markers to differentiate sarcomatoid mesothelioma from other metastatic pleural tumors using immunohistochemical techniques
|Antibody||Diagnostic value||Sarcomatoid mesothelioma||Adenocarcinoma|
|Mesothelioma||Calretinin||Useful||+++ (nucleus and cytoplasm)||+ (cytoplasm)|
|CK5 / CK6 Keratins||Not useful||++ (cytoplasm)||+++ (cytoplasm)|
|Squamous cell carcinoma||p63||Very useful||–||+++ (core)|
|Ber-EP4||Very useful||+/- (membrane)||+++ (cytoplasm)|
|MOC 31||Useful||+/- (membrane)||+++ (membrane)|
(WT-1 = Wilms tumor antigen 1) (Adapted from Scherpereel et al, reference 39) (See text).
Performance of pleural needle biopsy and thoracoscopy in the diagnosis of mesothelioma
The “blind” pleural biopsy (without the use of real-time imaging techniques) is unsatisfactory for the diagnosis of mesothelioma, not only due to the lack of control regarding the exact point from which the samples are obtained, but also due to the small size of these 40 . When there is diffuse nodular pleural thickening, the performance of needle biopsy can be considerably improved if performed with the help of CT 41 , 42 or real-time ultrasound 43 . Thoracoscopy (or pleuroscopy ) is much more cost-effective because it allows the collection of more and larger samples, it can be performed under local anesthesia and intravenous analgesia / sedation 44, and we have diagnosed more than 80 pleural mesotheliomas with this method 45 . VATS ( “video-assisted thoracoscopic surgery” ) allows better staging of the tumor (especially in the mediastinal area) and even pleurectomy / decortication in selected cases, but requires more resources, including general anesthesia and tracheal intubation 46 . The performance of pleuroscopy (also called “medical thoracoscopy”) is suboptimal in mesothelioma with a sarcomatous component 47 , and therefore it is preferable to obtain more representative samples by VATS or mini-thoracotomy 48 .
Early diagnosis in malignant pleural mesothelioma
One of the main challenges we face in mesothelioma lies in the fact that, although we have identified the population at risk (individuals exposed in one way or another to asbestos), we lack the tools to achieve a sufficiently early diagnosis that allows apply radical treatment. This implies the need for biomarkers capable of detecting the disease before effusion or diffuse pleural thickening develops, and for now there are also no imaging techniques with sufficient sensitivity and specificity to achieve this objective.
Study of biomarkers in malignant pleural mesothelioma
The biomarker that has received the most attention in recent years is soluble mesothelin , which is closely correlated with tumor size and progression in epithelioid mesothelioma (non-sarcomatous, in which it is usually negative) 49 . However, their values are influenced by renal function, and one of its biggest problems lies in the choice of a suitable cutting point to distinguish between benign and malignant pleural involvement 50. In any case, it seems clear that mesothelin levels are more useful in pleural fluid than in serum, and this greatly limits its value for early diagnosis in subjects with a history of asbestos exposure but who do not present with pleural effusion. Given a low pre-test probability of suffering from mesothelioma, low levels of mesothelin can help to rule it out, while high levels reinforce the use of more invasive diagnostic techniques in a patient with suspected mesothelioma 51 , 52 , 53 . In any case, it seems that mesothelin is more useful for monitoring treatment than for differential diagnosis in pleural effusions 54 .
Trying to overcome the problems of mesothelin and other markers, it has been recently published that fibulin-3 is able to distinguish between healthy people with a history of exposure to asbestos and patients with mesothelioma, and even between mesothelioma and other malignant or benign processes of pleura 55. These excellent initial results have not been revalidated by another study recently carried out in Australia – a country with a high prevalence of mesothelioma – and in which mesothelin and fibulin-3 values were compared in the same plasma and pleural fluid samples. In this study, a better diagnostic performance of mesothelin over fibulin-3 was confirmed, which did show a good predictive value of survival when its values were high in the pleural fluid of patients with mesothelioma, especially in the sarcomatous or mixed 56 .
THERAPEUTIC PERSPECTIVES OF MALIGNANT PLEURAL MESOTHELIOMA
Mesothelioma tends to have a poor response to chemotherapy and radiotherapy, and surgery is rarely curative, because the tumor is generally diagnosed too late, and therefore the careful evaluation of each patient before choosing the best treatment is especially important. If radical surgery is being considered, it is critical to assess lung and heart function, the presence of other comorbidity factors, and the physical and psychological state of the patient. The choice between the different therapeutic options is dictated by the clinical situation and the tumor extension studies (TNM) using imaging techniques. However, none of the currently available techniques is accurate enough to ensure the “T” and “N” in malignant pleural mesothelioma.57 . Until a more robust TNM staging is achieved, it is advisable to follow that established by the UICC (“ Union Internationale contre le Cancer ”) 58 (see Table 4 ).
Table 4 . TNM staging of malignant pleural mesothelioma
|T1||Unilateral infiltration of the parietal pleura|
|T1a||Infiltration of the parietal pleura, with or without involvement of the mediastinal or diaphragmatic pleura, but without visible involvement of the visceral pleura|
|T1b||Infiltration of the parietal pleura and focal involvement of the visceral|
|T2||Unilateral infiltration of the parietal or visceral pleura, with invasion of the underlying lung or diaphragm muscle|
|T3||Unilateral involvement of any area of the pleura and invasion of at least one of the following structures: endothoracic fascia, mediastinal fat, soft tissue of the chest wall (focal), or non-transmural invasion of the pericardium|
|T4||Involvement of any area of the pleura and with invasion of at least one of the following structures: internal face of the pericardium (with or without effusion), peritoneum, mediastinal structures, contralateral pleura, spine, diffuse invasion of the chest wall (with or without without costal destruction)|
|N0||No node involvement|
|N1||Ipsilateral bronchopulmonary or hilar lymph node involvement|
|N2||Ipsilateral involvement of mediastinal nodes, from the a. internal mammary and / or peridiaphragmatic|
|N3||Contralateral involvement of any of the mediastinal and / or internal mammary and / or supraclavicular lymph node stations|
|M0||Absence of extrathoracic metastases|
|M1||Extrathoracic, hematogenous, or non-regional node metastases|
|STADIUM I||T1aN0 (1A); T1bN0 (1B)|
|STAGE III||Any T3, N1 or N2|
|STAGE IV||Any T4, N3 or M1|
(Adapted from van Meerbeeck et al, reference 58).
The principal goal of surgery is resected macroscopically throughout the tumor, thereby assuming better survival is obtained, and patients in which residues are macroscopically visible tumor survival is less 59 . However, the currently accumulated evidence suggests that it is not possible to achieve a complete resection (macro and microscopic) in malignant pleural mesothelioma, regardless of the surgical technique that is applied and for this reason it is accepted today that the surgery is basically oriented to local control the disease, eliminate the pleural effusion, free the lung trapped by the tumor, improve ventilation / perfusion disorders and alleviate pain caused by invasion of the chest wall 60. All these considerations apply especially to epithelioid type mesothelioma, since the sarcomatous or biphasic component has a worse prognosis and is consequently a worse candidate for any type of surgery 57 .
It involves en bloc resection of the lung and parietal pleura, and is usually completed with pericardial and diaphragm resection on that side, in addition to systematic dissection of the mediastinal ganglion chains. Although perioperative mortality is around 5% in centers with extensive experience, it has high morbidity, including cardiac and respiratory complications (which may acquire special relevance due to the one-lung situation in which the patient remains after this intervention), bronchopleural fistula, empyema and bleeding, among others 61 , 62 . In any case, and due to the usual persistence of macro or microscopic tumor residues, this intervention must be considered within the framework of multimodal therapy, which is supported by the combined use of surgery, chemotherapy and radiotherapy 63 . Occasionally hyperthermia – combined with chemotherapy – or local photodynamic therapy 64 has also been used . In many protocols multimodal therapy chemotherapy given as induction therapy before surgery (neoadjuvant chemotherapy), and after resection radiation is applied on the affected hemithorax 65 . However, the most recent clinical guidelines recommend ruling out surgery if progress of the disease is observed after neoadjuvant chemotherapy and, in any case, recommend that extrapleural pneumonectomy be performed only in the context of well-controlled clinical trials and by groups specialized in this technique 38, 39 .
Pleurectomy / decortication
Although it is associated with a greater risk of local recurrence than pleuropneumonectomy, it presents fewer complications than that 66 , and is mainly aimed at freeing the lung and the chest wall from the constriction caused by the tumor. Patients with macroscopic diffuse presence of tumor in the parietal pleura, but only focal in the visceral, are the best candidates for this type of surgery. It can be performed using VATS , which has the advantage of minimizing the morbidity associated with thoracotomy 67 , 68 and pleurodesis can be done in the same act if complete resection is not feasible.
Although extrapleural pneumectomy is a more radical approach, its advantages over pleurectomy / decortication have been widely questioned in recent years 69 , 70 and in a recent randomized study in the United Kingdom (MARS study, “ Mesothelioma and Radical Surgery ”) The superiority of one over the other was not demonstrated 71 . On the other hand, the MARS study has been harshly criticized for the significant deviations that occurred from the protocol initially proposed and for the number of patients who were eventually included in each of the study branches 72. In any case, and although for some groups with extensive experience in both techniques it is considered inappropriate to leave macroscopically visible remains of the tumor (which leads to a worse prognosis), the idea of resecting the largest possible volume of the tumor while preserving the tumor is gaining adherents. underlying lung and in any case combining surgery with chemotherapy and radiotherapy, within the framework of trimodal therapy 73 .
Radiation therapy in malignant pleural mesothelioma
Radical radiotherapy applied to an entire hemithorax is seriously limited by the risk of damaging critical organs such as the lung, liver, heart, spinal cord and esophagus, and to alleviate this, application techniques are being optimized 74 , although there is no convincing evidence that alone prolongs the survival of patients with mesothelioma 75 . On the other hand, palliative radiotherapy plays an important role in controlling pain caused by infiltration of the chest wall 76 , 77 . Classically, prophylactic radiotherapy has been recommended to avoid tumor seeding in thoracoscopy or thoracotomy scars 78 , 79but this practice is not supported by the available evidence and is currently discouraged 38 , 39 .
Chemotherapy, immunotherapy and other personalized therapies
Recent clinical guidelines recommend not delaying the administration of chemotherapy and it should be taken into consideration before functional deterioration of the patient appears 38 , 39 . The combination of several agents (including pemetrexed and platinum compounds) generally produces better results than monotherapy 80 , 81 . The current trend is aimed at investigating new therapeutic targets focused on controlling angiogenesis and apoptotic pathways through specific ligands, including PDGF (“ platelet derived growth factor ”, which is overexpressed quite frequently in mesothelioma and is associated with worse survival) and mesothelin(which is expressed only in the epithelial subtype) among others 82 , 83 . Also within multimodal therapy, immunotherapy can play an important role in the treatment of mesothelioma, because this tumor is capable of evading the immune system through T-regulatory cells ( Treg ) and M2 macrophages. For this reason, new therapeutic strategies that combine surgical cytoreduction, chemotherapy, immunotherapy and radiotherapy could achieve better control of the disease 84. From passive immunotherapy (using specific cytokines or antibodies) to modulation of the immune response by dendritic cells or others, there is a wide spectrum of possibilities to achieve markedly synergistic antitumor effects 85 , 86 , 87 .
Control of pleural effusion is a priority in most patients with pleural tumors, including mesothelioma and talc pleurodesis may be a good option. However, in our experience, more pleurodesis failures tend to occur in this tumor than in others (see Table 5 ) and there are possible explanations for this:-
Difficulty adequately re-expanding the lung, cloistered by the tumor 88 . Thus, previous studies by our Group show that the extension of the tumor in the pleural cavity has a negative influence on pleurodesis 89 . The degree of involvement of the visceral pleura -which implies greater difficulty for lung re-expansion- is related in our series of malignant pleural effusions with the result of pleurodesis (see Table 5 ) and we observed a close correlation between this involvement and the pH of the pleural fluid (r = -0.402, p < 0.001), so that a low pH makes it more likely that the visceral pleura is diffusely affected.-
In addition to mechanical factors, it is likely that other biological factors not well known to date also influence pleurodesis. For several decades, low pH in pleural fluid has been associated with a worse prognosis in mesotheliomas 90 -and also in other tumors- and with a worse response to any pleurodesis attempt 91 , although the biological mechanisms involved are not clear. In recent years, much attention has been paid to the regulation of intra and extracellular pH in tumors, especially in the most aggressive 92 , 93 , 94 and it seems that an acid extracellular pH (which is closely related to a context of tissue hypoxia) 95it facilitates tumor aggressiveness through hypoxia-inducible factor-1 (HIF-1), whose over-expression triggers a series of suppressive mechanisms of apoptosis in tumor cells 96 . The aquaporin-1 seems to be involved in regulation of this process 97 and are already proposed some initiatives based on these new therapeutic targets 98 .-
On the other hand, and according to recent experiments carried out ” in vitro ” by our Group, malignant mesothelial cells are more resistant to the action of talc than other cell lines, and this is evidenced both in the modulation / blocking of angiogenesis and in cell proliferation (unpublished data).
Table 5 . Differences Between Mesotheliomas and Metastatic Pleural Carcinomas in Our Series of Patients With Malignant Pleural Effusion Undergoing Thoracoscopy and Talc Pleurodesis
|Result of pleurodesis (*)||B||M||Partial||B||M||Partial|
|Age (years)||63.8 ± 1.5||63.5 ± 3.7||63.4 ± 3.7||60.3 ± 0.8||61.1 ± 1.9||58.3 ± 1.8|
|Hemithorax occupation (%)||60 ± 5||66 ± 9||58 ± 7||60 ± 2||68 ± 6||69 ± 4|
|Pleural fluid vol. (ML)||2234||1974||1945||1767||1794||1798|
|± 176||± 217||± 310||± 66||± 80||± 141|
|Pleural pH (**)||7.30 ± 0.02||7.22 ± 0.03||7.26 ± 0.05||7.35 ± 0.01||7.22 ± 0.02||7.30 ± 0.02|
|Glucose L.pl. (mg / dL) (**)||63 ± 7||37 ± 7||44 ± 12||93 ± 3||63 ± 8||75 ± 6|
|LDH||981 ± 184||1227 ± 574||868 ± 254||676 ± 52||2376 ± 696||901 ± 159|
|Pl. Parietal involvement (0-3)||2.4 ± 0.1||2.5 ± 0.2||2.4 ± 0.2||2.1 ± 0.1||2.2 ± 0.1||2.2 ± 0.1|
|Visceral Pl involvement (0-3) (***)||1.6 ± 0.1||1.9 ± 0.1||2.2 ± 0.1||1.5 ± 0.1||1.9 ± 0.1||1.7 ± 0.1|
|Survival||10.5 ± 2.3||11.4 ± 2.3||13.8 ± 3.1||12.4 ± 1.7||11.9 ± 5.8||8.4 ± 1.7|
(*) Pleurodesis results: B (good) = Control of the pleural effusion during the entire follow-up of the patients, M (bad) = Recurrence of the pleural effusion at any time during the follow-up, requiring repeated evacuations. Partial = Recurrence of the pleural effusion at any time during the follow-up of the patients, but with a volume lower than that which existed prior to pleurodesis and without requiring evacuation. The pleurodesis results were significantly worse in mesotheliomas than in metastatic pleural carcinomas.
(**) The pH and pleural glucose were significantly higher in cases with effective pleurodesis (B), both in mesotheliomas and in metastatic carcinomas.
(***) The involvement of the visceral pleura was significantly less in the cases with a good pleurodesis result in both groups of tumors.
When pleurodesis fails, or if it is considered unlikely due to the presence of a lung massively trapped by the tumor, the best option is the insertion of a tunnelled pleural catheter , which allows the home evacuation of pleural fluid and induces spontaneous pleurodesis in a considerable proportion of cases 99 , 100 , 101 , 102 .
It is important to note that the performance of previous pleurodesis does not preclude surgical resection in the case of mesothelioma, regardless of the technique used (extrapleural pneumonectomy or pleurectomy / decortication) 60 .
CONCLUSIONS AND FUTURE PERSPECTIVES
From what has been explained so far, it is clear that the diagnosis of malignant pleural mesothelioma is generally made too late to be able to apply a curative treatment, since in the vast majority of cases the surgery does not manage to eliminate all the tumor tissue and on the other hand part of the tumor is not very sensitive to chemo and radiotherapy. Therefore, there is a need to develop more sensitive and specific imaging techniques and biomarkers than those available up to now, and it is also necessary to optimize the therapeutic options, with the ultimate goal of completely eliminating the tumor in all its locations.
At the present time, it seems that the most realistic thing would be to search for detectable markers in peripheral blood -especially in people with a history of occupational or environmental exposure to asbestos- and who have adequate sensitivity and specificity to detect malignant mesothelioma early. Within this line, the most promising field of research is oriented – together with the development of better imaging techniques – to the exhaustive search for markers using proteomic techniques , which simultaneously analyze the profiles of a large number of proteins (more than 1000) and they will allow the preparation of panels configured to achieve the maximum diagnostic sensitivity and specificity 103 , 104 .
In recent years, intensive work has been done on gene expression studies in mesothelioma 105 , and considerable emphasis is placed on the expression of certain proteins such as aquaporin-1 , which is related to the selective transport of water through the membrane and to cell proliferation 106 , 107 , 108 , and the study of micro-RNAs (miRNAs) in mesothelioma also stands out. MiRNAs are short RNAs (17 to 22 nucleotides) that do not encode proteins, which regulate gene expression and play an important role in oncogenesis 109. They have high tissue specificity to detect the origin of a tumor and to distinguish mesothelioma other metastatic tumors of the pleura 110 . On the other hand, the detection of miRNAs in peripheral blood could make them excellent markers of mesothelioma in the near future 111 .
In many cases, the use of gene therapy in mesothelioma has been considered to compensate for the limited efficacy of immunotherapy when the tumor is locally very advanced. To do this, different strategies are used, such as the use of “suicide genes” (which transfer to the tumor the ability to become sensitive to certain drugs), the administration of oncosuppressive genes or the transfer of immunomodulatory genes to the pleural space 112 , 113 , 114 , 115. Although its clinical application has so far obtained rather disappointing results, largely due to problems related to the vectors used and their relative inefficiency in controlling a large tumor mass, it is very likely that the inclusion of gene therapy in the multimodal strategy and its combination nanotechnology-based techniques contribute very significantly to improve the treatment prospects for malignant pleural mesothelioma in the future. Combining molecular biology and nanotechnology techniques, the concept of “ theranostics”, Which aims to combine diagnosis and treatment in the same procedure through the use of drugs specifically directed to each neoplasm phenotype. If the right ligands could be found, they could be applied for the early diagnosis of mesothelioma using PET or SPECT ( single photon emission computed tomography ) 116 , 117 , 118 . Probes combined with highly sensitive biofluorescent techniques have already been developed that are capable of detecting tumors in animal models 119 , 120 , and there are also techniques based on labeled antibodies, combined or not with nanoparticles, for use with nuclear magnetic resonance 121, 122 . All this presents a stimulating horizon for its application in humans in the not too distant future.
The author declares no conflicts of interest in relation to this article.
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