Malignant Pleural Mesothelioma Epidemiology, Pathogenesis, Molecular Biology and Clinical Presentation

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EPIDEMIOLOGY

Malignant pleural mesothelioma (MPM) is uncommon neoplasm with aggressive behavior, originating from the mesothelial cells the pleura. It is commonly associated with asbestos exposure (Opitz, 2014).

According to the epidemiological studies, there are 14 200 new reported cases of MPM all over the world each year. The death was responsible for over 92 000 deaths from 1994 to 2008 (Delgermaa et al., 2011, Park et al., 2011).

The disease has more male predominance that can be attributed to more occupational hazards of asbestos. MPM can occur at any age, but generally, the risk raises with age. The peak incidence appears to be in the 5th and 6th decades (Scherpereel et al., 2010, Delgermaa et al., 2011).

Several reports showed a strong relation between mesothelioma incidence in any country and the consumption of asbestos in the past decades. Even in the same country, the areas with high mesothelioma incidence are mostly the locations with heavy asbestos use (Bianchi and Bianchi, 2012).

Malignant pleural mesothelioma is a considerable health problem worldwide. Data is showing a rising incidence in the industrialized countries including Europe, Japan, and Australia, and falling in the United States because of the asbestos ban since 1960. The peak is expected to be around 2020 (Delgermaa et al., 2011, Scherpereel et al., 2010).

The situation is more serious in the developing countries, where the use of asbestos increases exponentially. Thus a dramatic increase is expected (Burki, 2010).

The global burden of MPM is mostly higher than mortality registries suggest due to different reasons including the difficulty in diagnosing MPM, unreported cases especially in developing countries,  inaccurate death certification and inaccurate death certification, and absence of specific codes for MPM in the International Classification of Diseases (ICD) until 1994. (Robinson, 2012, Bianchi and Bianchi, 2012).

In Egypt, MPM is mainly attributed to asbestos exposure. Epidemiological data prove that mesothelioma incidence is rising markedly. The number of individuals (635 cases) diagnosed in the first four years of the third-millennium from 2000 to 2003 at the National Cancer Institute (NCI) and Abbassia Chest Hospital, Cairo was higher than  the number of cases diagnosed in the previous 11 years at NCI, Cairo by four times (Gaafar and Eldin, 2005).

In a retrospective study from Cairo University Hospitals and National Cancer Institute, 584 patients diagnosed as MPM between 1998 to 2007. The male/female ratio was 1.35/1. 13.9% of patients had occupational exposure to asbestos. Resident plays a main role in two regions, Helwan and Shoubra (27.3% and 20.6% respectively), while in Upper and Lower Egypt the level was 12.7% and 17.5% respectively (Akl et al., 2010).

Retrospective data from Ain Shams Clinical Oncology department showed the presence of 304 patients between January 2003 and December. The mean age was 52.1 years. The majority of patients (62.5%) a past history of occupational asbestos exposure or came from endemic place as Shoubra El Kheima, Helwan, and El Hawamdia  (Adel et al., 2011).

Forty cases of mesothelioma between 2003 and 2007 had been reported in the Gharbiah Population-based Cancer Registry (GPCR). Most of them were males (25 cases) (Curado et al., 2007).

In the published data from the National Cancer Registry Program (NCRP) in 2014 (covering: Damietta, Minya, and Aswan, the total number of mesothelioma cases were 161 in 2013 and 174 in 2015. The number of the new cases is expected to reach 456 by the end of 2050 (Ibrahim et al., 2014).

Risk factors

Exposure to asbestos represents the primary risk factor; approximately 80% of MPM cases have a history of asbestos exposure. Other possible risk factors are erionite, carbon nanoparticles prior exposure to radiation, the simian virus 40 (SV-40), and genetic predisposition (Ettinger et al., 2016).

1)    Asbestos:

In 1960, Wagner and his colleagues showed first evidence between the development of mesothelioma and asbestos in people living or working in the asbestos mine area in South Africa (Wagner et al., 1960).

The World Health Organization (WHO) and the International Agency for Research on Cancer (IARC), listed all types of asbestos as class I carcinogens, and the leading cause of mesothelioma (Røe and Stella, 2015).

Asbestos exposure is related to work and is considered among the occupational diseases. Mesothelioma has been found in individuals growing up near natural asbestos resources or in areas where asbestos was used for industry.  Also, there is an increasing incidence among housewives and family members of asbestos workers (Geltner et al., 2016).

Although short or low-level asbestos exposures have been linked to the development of mesothelioma, the risk of MPM development demonstrates dose dependence. The disease is characterized by long latency period between asbestos exposure and the onset of symptoms up to 40 years, and 99 % of cases show a latency of more than 15 years (Bianchi and Bianchi, 2007, Robinson, 2012).

Industries using asbestos started in Egypt in 1948 by Sigwart El–Maasara Company in in Shobra El-Khaymah and Helwan districts, which manufacture both cement pipes and corrugated roofing panels reinforced with asbestos. After that, another 14 asbestos factories appeared, the most famous is the Ora Misr firm in the 10th of Ramadan city (50 km east of Cairo) uses asbestos in the production process and the Helwan factory. Populations living in these areas have proved to be exposed to higher environmental asbestos counts and at greater risk to develop MPM (Akl et al., 2010, Awad, 2011).

Although the Egyptian government banned asbestos in 2004, asbestos is still used in Egypt in the production of insulation boards, water pipes, and fire-resistant clothing (Madkour et al., 2009, Awad, 2011).

2)    Erionite:

Erionite is a non-asbestos fibrous mineral that can be found naturally in the volcanic tuffs, or soil in certain parts of the world as Turkey, Iran, Western United States and Mexico (Ilgren et al., 2014).

The relationship between erionite and development of MPM began with the discovery of a high incidence of MPM in particular Turkish villages, which could not be attributed to asbestos exposure (Baris et al., 1978).

Several studies on rodents and humans have confirmed the potent carcinogenicity of erionite, which has been listed as a group I human carcinogen by the IARC working group (Carbone et al., 2011).

3)    Carbon nanotubes:

Carbon nanotubes (CNTs) may be used in a wide range of applications in modern technology. As they have similarities to asbestos fibers regarding shape and size, this may raise the question of their safety for human health. Laboratory studies showed the ability of these particles to produce mesothelioma-like changes in susceptible strains of mice following intraperitoneal administration (Donaldson et al., 2013).

4)    Radiation:

Ionizing radiation may be a risk factor for the development of mesothelioma, with a long latent period between the initial exposure and the diagnosis of the second malignancy (Moolgavkar et al., 2017).

Large retrospective studies, utilizing data from the US Surveillance, Epidemiology, and End Results program (SEER), showed an increased risk of MPM in patients receiving radiotherapy for primary malignancies as Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer, and breast cancer (Neugut et al., 1997, Travis et al., 2005, Tward et al., 2006).

Other sources of radiation exposure as exposure to external radiation at nuclear facilities have been linked to the development of MPM (Gibb et al., 2013).

5)    Viral oncogenes:

Simian virus 40 (SV40) is a polyomavirus of monkey origin with double-stranded DNA. The transmission to humans resulted from the SV40 contaminated polio vaccines between 1955-1963. The virus has been identified in several tumors including MPM (Cleaver et al., 2013).

The virus DNA was detected in 20 out of 40 fresh tumor tissues from 40 MPM Egyptian patients presenting at NCI, Cairo. Thirty-one cases had a history of asbestos exposure; 18 of them were SV40 positive (Zekri et al., 2007).

6)    BRCA1-Associated Protein 1 (BAP 1)

BRCA1-Associated Protein 1 (BAP 1) is a tumor suppressor gene located at 3p21 and one of the most commonly somatically lost or mutated genes in around 40- 60% of MPM cases. The rate of BAP1 mutation in Egyptian MPM is 38.5% according to recently published study on 120 patients treated at NCI, Cairo  (Cigognetti et al., 2015, El Bastawisy et al., 2017).

The BAP1 germline mutations increase the susceptibility to asbestos-induced MPM and are characteristic of a heritable cancer predisposing syndrome with affected individuals developing tumors such as MPM, uveal and cutaneous melanoma (Sneddon and Creaney, 2016).

Pathogenesis

It is not completely understood how asbestos can induce MPM. After inhalation of asbestos fibers, they migrate to the pleura resulting in pleural irritation and a repeated cycles of tissue damage (Bibby et al., 2016).

Asbestos fibers can disturb the cell division and produce aneuploidy and structural chromosomal abnormalities. They release reactive oxygen species, causing oxidative stress and cellular damage, provoking DNA alterations. Oxidative stress occurs through catalysis of radical reactions by iron in the asbestos fibers and the release of reactive oxygen species by phagocytizing macrophages and neutrophils, activated by asbestos (Szulkin, 2014).

As a result of asbestos exposure, mesothelial cells release inflammatory cytokines and growth factors as tumor necrosis factor-α, interleukin-1β, transforming growth factor-β and platelet-derived growth factor providing a favorable tumor microenvironment (Bibby et al., 2016).

The released tumor necrosis factor-α activates nuclear factor-κB, leading to mesothelial cell survival, while the increased interleukin-6 (IL-6) secretion results in the expression of vascular endothelial growth factor (VEGF), which sustains new blood vessel formation. Also, the exposed mesothelial cells release that high-mobility group box 1 (HMGB 1) protein, promoting an inflammatory response. All the changes facilitate the malignant transformation of mesothelial cells as well as their future growth (Yang et al., 2010, Chen and Pace, 2012).

Although both asbestos and erionite share the same mechanisms of toxicity and carcinogenesis, erionite is assumed to be more carcinogenic than asbestos. It can induce the transformation of human mesothelial cells. The release of HMGB1 after erionite exposure is an important initiator of the chronic inflammation with the release of IL-1β and TNF-α. Also, erionite activates the nod-like receptor-family protein 3 (NLRP3) inflammasome, which releases IL-1β, IL-6, IL-8, and VEGF, and this is accompanied by the activation of an autocrine feedback loop modulated via the IL-1 receptor (Carbone and Yang, 2012).

Simian monkey virus 40 (SV40) has two oncoproteins, a large tumor antigen (TAg) and small tumor antigen (tAg). In infected mesothelial cells, asbestos stimulates the epidermal growth factor receptor (EGFR), which results in activation of the transcription factor AP1. SV40 results in the early onset of telomerase activity, which causes immortalization. T Ag binds to the cellular p53 and retinoblastoma (RB) family proteins, and inhibit their activity. Asbestos appears to raise the SV40-mediated transformation of human mesothelial cells, indicating that asbestos and SV40 might be co-carcinogens. TheSV40 infection causes other changes, including inhibition of protein phosphatase 2A (PP2A) and the tumor suppressor gene RASSF1A, and activation of NOTCH-1, the MET oncogene, as well as the insulin-like growth factor 1 (Gaudino et al., 2014, Tognon et al., 2016).

MOLECULAR BIOLOGY

Several studies show that BRCA1-associated protein-1(40%–60%), tumor protein 53 (TP53) (57%), cyclin-dependent kinase inhibitor 2A (CDKN2A) (45%–75%), and Neurofibromatosis Type 2 (NF2) (14%–50%) are frequently abnormal in pleural mesothelioma (Kato et al., 2016).

The BAP1 gene is a member of the tumor suppressor genes family that is located on chromosome 3p21.3 and encodes the protein BAP1, which plays an essential role in the ubiquitin-proteasome pathway in histone deubiquitination, regulation of cell cycle progression, modulation of chromatin, gene transcription, and DNA repair (Assis and Isoldi, 2014).

The protein P53 is considered as the guardian of the DNA and is encoded by the TP53. This protein plays a crucial role in the cellular response to DNA damage (Frezza and Martins, 2012).

Mutations in the CDKN2A locus, which encodes the tumor suppressors p16(INK4A) and p14(ARF) result in alterations in the p53 and retinoblastoma pathways (Bueno et al., 2016).

The NF2 gene encodes for the Merlin protein that is associated with the inhibition of several mitogenic signaling pathways (Petrilli and Fernández-Valle, 2016).

The phosphatase and tensin homolog protein (PTEN) is encoded by the PTEN gene encoded by the PTEN, which is an anti-oncogene located on chromosome 10q23. PTEN is known to regulate the AKT pathway negatively; thus, the loss of PTEN expression increases AKT pathway activation leading to an uncontrolled cell growth (Agarwal et al., 2013).

The PI3K/AKT/mTOR pathway is altered in MPM and plays a crucial role in cell proliferation, survival, and motility in many cancers. In 62% of MPM cell lines, AKT activation was reported (Zhou et al., 2014).

Other pathways are dysregulated in MPM. The receptor tyrosine kinases (RTKs) stimulate cell proliferation, survival, differentiation, and cell cycle control. The overexpression of the epidermal growth factor receptor (EGFR) plays a vital role in the progression of several cancers (Fasano et al., 2014).

The vascular endothelial growth factor receptors (VEGF) stimulates angiogenesis, and its role in the malignancy is well established. High levels of VEGF in MPM have been demonstrated, being associated with a worse patient survival (Harada et al., 2017).

Mutations in TP53 and RB are not a common event in MM; however, alterations in p16INK4a/p14ARF are frequent. The p16INK4a and p14ARF have effects on the pRb and p53 pathways. The p16INK4a inhibits the cyclin dependent kinases (CDks), preventing the inactivation of pRb; on the other hand, the p14ARF promotes degradation of murine double minute 2 (MDM2, leading then to the stabilization of p53 (de Assis et al., 2014).

The BCL-2 family of genes has a critical role in the apoptosis process. There are several proteins, which are divided into proapoptotic and antiapoptotic proteins. Apoptosis inversely accompanies BCL-2 expression; however, this protein is not frequently expressed in MPM. High levels of BCL-XL are a common event in MPM; however, downregulation of BCL-XL increases apoptosis and the cytostatic effects of chemotherapy. (Varin et al., 2010).

The hippo pathway regulates cell proliferation, growth, differentiation, and death, and it has been involved in the development of MPM (Miyanaga et al., 2015).

The Wnt pathway plays an essential role in the determination of cell fate, proliferation, polarity, and cell death during embryonic development. The Wnt signaling pathway has been reported in MPM (Fox et al., 2013).

CLINICAL PRESENTATION

Patients usually present with a triad of pleural effusion, dyspnea, and chest wall pain in 60% of cases (Patel and Dowell, 2016).

The duration from onset of symptoms and diagnosis is around 2–3 months, but gradual and vague symptoms may hold up diagnosis up to 3–6 months or more. However, symptoms may present for an even longer time until a diagnosis is established, leading in some cases to long latency periods (Roden and Lee, 2015).

Dyspnea may result from the accumulation of pleural fluid or lung encasement by the tumor, which causes decreased chest wall expansion (van Meerbeeck et al., 2011).

Chest pain is a common symptom and may be due to the effusion or the tumor. It is usually dull and sometimes described as a “dragging” sensation. Pleuritic pain is less common but can occur in the presence of parietal pleural irritation. Chest pain worsens with the disease progresses, particularly if the infiltration of the chest wall occurs. Bony pain from rib invasion or neuropathic pain secondary to intercostal nerve involvement may also occur (Bibby et al., 2016).

Coughing is usually not a prominent symptom, but It is more frequent in patients presenting with a pleural effusion (Park et al., 2015).

Spread to the opposite pleural cavity and across the diaphragm is seen in 10%–20% of patients. Peritoneal involvement may appear as ascites or intestinal obstruction and results in significant morbidity. The onset of local symptoms typically leads to diagnostic evaluation. Late features include constitutional symptoms and hematogenous metastases to virtually any organ (Patel and Dowell, 2016).

The local expansion of MPM can lead to chest wall masses, that may invade into mediastinal structures, or pressure on large vessels, nerves, the esophagus, the trachea or airways resulting in unusual symptoms such as superior vena cava syndrome, hoarseness, Horner’s syndrome, diaphragmatic paralysis, or dysphagia. Invasion of the pericardium and the heart might lead to pericardial tamponade and arrhythmias (van Meerbeeck et al., 2011).

Several paraneoplastic syndromes have been described with MPM including hypercalcemia, hypoglycemia, autoimmune hemolytic anemia, hypercoagulable states, and disseminated intravascular coagulation (Mott, 2012).

STAGING

Historically, several MPM staging systems have been proposed and used, most initially developed from small single-institution databases and predominantly retrospective surgical series. The most practical and commonly used system is the tumor-node-metastasis system elaborated by the International Mesothelioma Interest Group (IMIG). This system currently adopted by the American Joint Committee on Cancer (Rusch, 1996, Edge and Compton, 2010).

To identify potential deficits in the MPM staging, the International Association for the study of lung cancer (IASLC) Staging and Prognostic Factors Committee (ISPC), in collaboration with IMIG, initiated an enormous multinational database in 2009 to revise the lung cancer staging system. Data were submitted on 3,101 patients from 15 centers on four continents, all of whom had some form of surgical management. Overall survival (OS) data  supported continued use of the original MPM staging classification but detected several important areas for improvement, in particular for the T and N components (Rusch et al., 2012).

Another database including 3519 patients diagnosed between 2000 and 2013 in 29 centers worldwide was developed to acquire more detailed TNM information to refine the staging system. (Pass et al., 2016).

Examination of the OS for T categories based on the current 7th edition staging classification showed a difference between all clinically staged categories except for T1a versus T1b and T3 versus T4. Pathological staging did not show a survival difference between adjacent categories except for T3 versus T4. Performance improved with the collapse of T1a and T1b into a single T1 category.  Consequently, a recommendation was made to all current T descriptors should be kept and to merge  T1a and T1b into a T1 category (Nowak, 2012).

Regarding the N categories (as in the 7th edition staging classification), there was no significant difference in OS between cN0, cN1, and cN2. For pathologically staged tumors, patients with pN0 tumors had a better OS in comparison to those withpN1 or pN2 tumors, but no OS difference was found between pN1 and pN2. Exploratory analyses found that tumors with both pN1 and pN2 nodal involvement had a poorer OS than those with pN2 only. Based on those finding, it was recommended to collapse N1 and N2 into a new N1 category and to rename the current N3 category as N2 (Rice et al., 2016).

There were about 84 cases out of 3,519 having distant metastasis (cM1).  cM1 cases had a poorer median OS in comparison to those with T4 or N3 (as in the 7th edition), leading to the inclusion of only cM1 in the stage IV group (Rusch et al., 2016a).

Thus, the optimal stage groupings for the 8th edition of staging classification were: stage IA (T1,N0,M0), stage IB (T2-3,N0,M0), stage II (T1-2,N1,M0), stage IIIA (T3,N1,M0), stage IIIB (T1-3,N2,M0 or any T4), and stage IV (any M1) (Amin and Edge, 2017).

DIAGNOSTIC WORKUP

Malignant mesothelioma is a challenging malignancy to diagnose. There is no evidence regarding the optimum sequencing of diagnostic tests. The usual sequence is to start with imaging studies to provide diagnostic and staging information. Further investigation of suspected MPM includes the sampling of pleural fluid for biochemical and cytological examination. Unfortunately, the cytological yield is low in MPM, and biopsies are usually required to confirm the diagnosis and identify the histological sub-type. Several biomarker tests have been evaluated with limited clinical value (Bibby et al., 2016).

•    Imaging

A.    Chest Radiographs

Radiological appearances of MPM are variable and can include pleural thickening, effusion, mass, complete hemithorax opacification or even a normal appearance in early cases. When the pleura is diffusely thickened in advanced cases, a rind of soft tissue often has a nodular or scalloped appearance can be obvious (Roden and Lee, 2015).

B.    Computed Tomography

Computed Tomography (CT) is essential in patients with MPM. CT features of pleural malignancy are the pleural enhancement, invasion of the chest wall, mediastinum or diaphragm, in addition to nodular or mediastinal pleural thickening and interlobar fissural nodularity, with a sensitivity and specificity of 68% and 78%, respectively (Hallifax et al., 2014).

Despite the overall benefits of CT scanning, it is less accurate when compared to other modalities for the staging of MPM. CT is particularly poor at assessing T4 stage where assessment of invasion through soft tissue such as diaphragm and chest wall is required. CT also performs poorly at lymph node staging, particularly when detecting involved N2 and N3 nodes (Truong et al., 2013).

C.    Magnetic Resonance Imaging

Magnetic Resonance Imaging enables differentiation of tumor from normal adjacent tissues by imaging in multiple planes using different pulse sequences. Thus, magnetic resonance imaging (MRI) may improve delineation of the tumor regarding the surrounding tissues, especially when surgical resections considered to be a part of the treatment plan (Truong et al., 2013, Baas et al., 2015).

Thoracic MRI is superior to CT in the accuracy of staging evaluation of two sites of local invasion: the endo thoracic fascia or single chest wall focus (69% vs. 46%) and the diaphragm (82% vs. 55%) (Heelan et al., 1999, Plathow et al., 2008).

Also, MRI can give functional information through the use of contrast agents, e.g. gadolinium, or techniques such as diffusion-weighted imaging-MRI or dynamic contrast enhancement-MRI. Combining functional data with standard imaging produces sensitivity and specificity rates >90% for differentiating malignant pleural disease from benign (Coolen et al., 2014).

D.    Positron emission tomography/computed tomography (PET CT)

Owing to the ability to provide both metabolic and morphologic information about a lesion, PET and PET/CT have raised as important complementary techniques for the assessment of pleural disease. It is more sensitive than CT in detecting nodal involvement and distant metastasis, and in differentiating tumor activity from benign disease. In comparison to CT, it both downstages some disease by excluding lesions potentially significant by CT, and upstages disease by detecting the tumor in sites not detected by CT (van Zandwijk et al., 2013, Piacibello, 2016).

The accuracy of PET/CT is more than chest CT, thoracic MR imaging, and PET alone for the staging of MPM. For stage II and stage III disease, the accuracy of PET/CT is 1.0, compared with 0.77 (stage II) and 0.75 (stage III) for CT, 0.86 (stage II) and 0.83 (stage III) for PET, and 0.8 (stage II) and 0.9 (stage III) for tho¬racic MR imaging (Plathow et al., 2008).

In patients scheduled to undergo radical surgical resection, a distinction between M0 and M1 tumors, or between T3 and T4 tumors, is critical in determining possible respectability  (Basu et al., 2011, Sharif et al., 2011).

The use of FDG-PET to identify metastatic disease or nodal metastases may upstage or downstage patients, leading to a change of management in between 20-38% of patients (Erasmus et al., 2005, Basu et al., 2011).

FDG-PET is more accurate in detecting distant occult metastases than anatomical imaging and identifies a higher number of mediastinal lymph node metastases than CT alone, with moderate specificity, although low sensitivity, in the detection of nodal disease (Erasmus et al., 2005, Pilling et al., 2010).

Also, it may help in differentiating the pathological subtype, the FDG affinity of epithelial type MPM is lower than sarcomatous and mixed-type histopathology (Terada et al., 2012).

As FDG uptake is a marker of metabolic activity, false negative results are possible in early disease or tumors with a low proliferation rate. Conversely, inflammatory disorders such as rheumatoid pleuritis and tuberculous pleurisy can produce false-positive results, as can prior pleurodesis. It is recommended that staging with 18F-FDG PET should be performed before the enforcement of pleurodesis (Bibby et al., 2016).

E.    Ultrasonography (US)

Ultrasonography is a portable and inexpensive imaging technique. In patients with pleural fluid and lesions adjacent to the pleura, it guides pleural interventions including thoracentesis, tube insertion, and needle biopsies (Koegelenberg and Diacon, 2013).

By using similar morphological criteria as those used in CT (pleural thickening >1 cm, pleural and diaphragmatic thickening >7 mm), US can differentiate malignant from benign pleural effusions with a sensitivity of 79% and specificity of 100%. (Qureshi et al., 2009).

•    Diagnostic procedures

No large prospective studies are comparing the optimal technique for obtaining a diagnostic specimen for MPM. Common methods include thoracentesis, closed pleural needle biopsy, and thoracoscopy either medical thoracoscopy (MT) or video thoracoscopic surgery (VATS)(Patel and Dowell, 2016).

A.    Image guided biopsy

Blind “closed needle” pleural biopsy has long been popular due to its relative inexpensiveness and practicality. In the last 15 years, blind pleural biopsy has been shown to have a poor diagnostic yield in malignancy and its use is diminishing (Dixon et al., 2015).

Image-guided biopsy performed under US or CT guidance allows focal pleural thickening or nodules as little as 5 to be biopsied accurately and safely. The choice between the two techniques depends on expertise, cost, and equipment. US-guided biopsy allows for real time visualization of the biopsy needle. The use of CT allows areas inaccessible to the US to be biopsied (e.g., behind ribs) (Dixon et al., 2015).

Current data suggest that CT-assisted and ultrasound- assisted closed pleural biopsies have high diagnostic yields ranging from 85 to 87% for all diagnoses, even as high as 94% in cases with pleural thickening, nodularity or pleural-based mass lesions (Koegelenberg and Diacon, 2013).

Pleural biopsies performed under the guidance of imaging techniques have low rates of complications, and major complications are not expected (Koegelenberg and Diacon, 2013).

B.    Thoracoscopy

Thoracoscopy is recommended when suspicion for mesothelioma is present and prior less invasive methodologies have failed to confirm the diagnosis. It allows adequate tissue sampling with a diagnostic yield of 90–95%, as well as management of the effusion with effective pleurodesis (Reinersman et al., 2016).

Both MT and VATS have acceptable safety profile with low mortality rates reported in the literature. Interventional pulmonologists perform MT, under moderate sedation with local anesthetics in a spontaneously breathing patient and generally outside the operating theatre and mostly requires one single port of entry to the thoracic cavity. VATS is performed by a surgeon under general anesthesia in an intubated patient in the operating theatre and requires at least three ports of entry to the thoracic cavity (Shojaee and Lee, 2015).

C.    Thoracotomy

Thoracotomy is rarely used as a diagnostic tool nowadays. It is mostly indicated for patients who cannot be diagnosed with other techniques and who can simultaneously undergo a surgical procedure for diagnosis and treatment at the same session (Metintas et al., 2016).

D.    Mediastinoscopy

Mediastinoscopy has the potential to detect mediastinal nodes in pleural diffuse malignant mesothelioma patients, its sensitivity and specificity have not been established in large prospective trials (Attanoos and Allen, 2013).

E.    Endobronchial ultrasound-guided fine needle biopsy

It can provide useful information: when imaging techniques give contradictory data for mediastinal lymph node involvement (Metintaş, 2015).

F.    Laparoscopy

Malignant pleural mesothelioma trans-diaphragmatic disease invasion and disease spread to the peritoneum are missed in up to 10% of cases by imaging modalities. Thus, before performing an aggressive cytoreductive surgery, some centers explore the peritoneum. If the peritoneum is evident by eye inspection, random biopsies and peritoneal was for cytology are performedx (Wald et al., 2016).

•    Pathological diagnosis

The pathological diagnosis of MPM can be problematic as (1) MPMs are a heterogeneous group of neoplasms (2) MPM have many variants (3) The pleura is a common site for metastasis, and pleural reactive changes may be confused with MPM (4) There are other rare benign and malignant pleural tumors (Baas et al., 2015).

A conclusive diagnosis of MPM needs a representative material regarding biopsy location (normal and abnormal pleura), depth (to assess fat and muscle tumor invasion), and quantity (enough material to allow immunohistochemical characterization). Thus, fine needle biopsies are not primarily recommended because they are associated with low sensitivity (Opitz, 2014).

A.    Gross morphology

In early stages, mesothelioma presents as multiple small nodules on the parietal and sometimes visceral pleura. With progression, the nodules become confluent with fusion of the visceral and parietal pleurae leading to encasement and contraction of the lung. The tumor may reach several centimeters in thickness and range from firm to gelatinous in consistency (Jindal, 2017).

B.    Histopathology

Most MPMs are identified or suspected on routine hematoxylin-eosin (H&E) staining. Histologically, it can show an epithelial morphology (epithelioid mesothelioma), a fibrous/spindle cell morphology (sarcomatoid mesothelioma), or a combination of both (biphasic mesothelioma) (Travis et al., 2015).

The epithelioid type represents 60% of cases and consists of polygonal cells that may look like reactive mesothelial cells. These tumors may exhibit multiple growth patterns, including solid, tubulopapillary and acinar. About 20% of mesotheliomas are sarcomatoid and typically consist of spindled cells. Less frequently, sarcomatoid mesotheliomas can be desmoplastic (less than 5%.) The remaining mesotheliomas are classified as biphasic and contain both epithelioid and sarcomatoid areas within the same tumor (Kumar et al., 2014).

Tumors with sarcomatoid morphology are quite resistant to therapy and have median survivals of 6 months from diagnosis. By contrast, mostly epithelioid tumors, especially well- differentiated variants, are associated with prolonged survivals of 1–2 years from diagnosis (Flores et al., 2008).

C.    Differential diagnosis

The differential diagnoses for epithelioid MPM includes adenocarcinomas; for sarcomatoid includes sarcomas and other spindle cell neoplasms, and for biphasic includes mixed or biphasic tumors such as synovial sarcoma and metastatic pleomorphic carcinoma of the lung. The desmoplastic type has a similar histology to fibrous pleuritis, and the differential diagnosis is challenging, particularly with a small biopsy specimen. Reactive mesothelial hyperplasia associated with pleuritis or other lung or pleural disease must be differentiated from early-stage epithelioid mesothelioma (Inai, 2008).

D.    Immunohistochemistry (IHC)

Immunohistochemistry (IHC) is the most helpful ancillary technique in integrating the diagnosis of MPM. However, no single marker has 100% sensitivity and specificity for mesothelioma, so various monoclonal antibody panels must be determined, of which at least two must be positive for mesothelioma. In the epithelioid subtype, these should be preferably calretinin (mostly useful if the nucleus, besides the cytoplasm, is stained), Wilms’ tumor antigen 1 (WT-1), epithelial membrane antigen (EMA) or wide-spectrum, low molecular weight cytokeratins as CK5 or CK6. Two negative markers for carcinoma are needed, such as Ber-EP4, thyroid transcription factor 1 (TTF-1), MOC-31, blood group 8 (BG8), carcinoembryonic antigen (monoclonal), and Napsin A (Husain et al., 2012).

For diagnosis of sarcomatoid MPM, IHC plays a limited role. Most of sarcomatoid MPM express pan‐cytokeratins, vimentin and even markers of smooth muscle differentiation (e.g., smooth muscle actin), but mesothelial markers often fail to recognize mesothelial differentiation of sarcomatoid MPM or rather show a weak and focal expression, only. The most useful markers for sarcomatoid MPM include D2‐40 and calretinin (Scherpereel et al., 2010, Novello et al., 2016).

Desmin, epithelial membrane antigen, p53, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and glucose transporter 1 (GLUT-1) markers can be used in the differential diagnosis of mesothelioma and reactive mesothelial cell proliferations, but their sensitivity and specificity are low. In mesothelial hyperplasia, EMA, p53, GLUT-1, and IMP3 usually stain negatively, while desmin often stains positively. The opposite occurs in the case of MPM  (fOviedo and Cagle, 2012).

More recently, several papers have proposed that lack of nuclear BAP1 immunostaining is a reliable marker to distinguish malignant mesothelial cells from benign mesothelial cells (Andrici et al., 2015, Cigognetti et al., 2015).

E.    Diagnosis in cytology

This remains a controversial subject. The reliability of an MPM diagnosis on effusion cytology is highly variable, (sensitivity ranging from 16‐73%) and is very much dependent upon cytologist experience (Walters and Maskell, 2011, Segal et al., 2013).

Recent evidence has indicated a cytopathological diagnosis of MPM can be reliable with 100% positive predictive value if carried out in conjunction with other ancillary techniques such as IHC, molecular biology, electron microscopy and analysis of soluble biomarkers but has lower sensitivity compared to histopathological diagnosis that remains as the gold-standard diagnostic tool (Segal et al., 2013).

F.    Fluorescence in situ hybridization

The investigation of p16/CDKN2A deletion using fluorescence in situ hybridization (FISH) for genetic analysis is useful in the differentiation of mesothelioma and benign reactive mesothelial proliferations. It is possible to explore (CDKN2A) p16 deletion through FISH (Wu et al., 2013).

G.    Electron microscopy

When IHC results are not useful in differentiating mesotheliomas from other malignancies, electron microscopy should be employed to make a definitive diagnosis. Mesothelial cells classically have long-branching microvilli, compared with the short nonbranching microvilli of carcinomas (Powers and Carbone, 2015).

•    Diagnostic biomarkers

Soluble mesothelin‐related peptide (SMRP), osteopontin and fibulin‐3 have so far been proposed as promising MPM markers in both serum and pleural effusion fluid. However, low sensitivity, specificity, and reproducibility characterize their clinical application, then requiring further validation before their use as diagnostic or screening tools (Novello et al., 2016).

A meta‐analysis of 28 publications including 7550 patients (1562 MPM and 5988 non‐MPM patients) confirmed that serum SMRP to have an overall sensitivity of 60% and a specificity of 81%. The same review also demonstrated that pleural fluid SMRP has an overall sensitivity of 75%, and specificity 76% (Cui et al., 2014).

The diagnostic sensitivity and specificity of osteopontin were 65% and 81%, respectively in a meta-analysis of six studies including a total of 360 MPM cases and 546 non-MPM cases (Hu et al., 2014).

A systematic review and meta-analysis about the diagnostic value of fibulin-3 for malignant pleural mesothelioma included eight studies and confirmed that the overall sensitivity and specificity of blood fibulin-3 were 87% and 89%, respectively. The sensitivity and specificity of pleural fluid fibulin-3 for MPM were 73% and 80%, respectively (Ren et al., 2016).

Carcinoembryonic antigen (CEA) is a negative marker and is not elevated in MPM. It may be helpful to rule out MPM if the cytological/histological analysis is inconclusive (van den Heuvel et al., 2008, Baas et al., 2015).

Prognosis

The prognosis of MPM is poor, with overall survival being about 9 to 17 months after diagnosis. Few patients can be cured. Most patients die from the local extension and respiratory failure. In some cases, tumor extension below the diaphragm may cause death from small intestinal obstruction. Death may also occur due to arrhythmias, heart failure, or stroke resulting from tumor invasion of the heart or pericardium (Smith, 2012).

•    Prognostic factors

Studying of the international association for the study of lung cancer (IASCLC) mesothelioma database suggests the prognostic importance of histology and stage. In this database, median survivals for those with epithelial, biphasic, and sarcomatoid histology were 19, 13, and 8 months, respectively. Based on staging, patients with stage I, II, III, and IV disease had median survivals of 20, 19, 16, and 11 months, respectively (Rusch et al., 2012).

Other poor prognostic features include poor performance status, age >75 years, elevated lactate dehydrogenase (LDH), and hematologic abnormalities (i.e., high white blood cell count, high neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios, low lymphocyte-to-monocyte ratio (LMR), low hemoglobin level, and high platelet count) (Wolf et al., 2010, Cihan et al., 2014, Yamagishi et al., 2015).

There is a controversy about the prognostic role of biomarkers. However High baseline SMRP and osteopontin serum levels may be correlated with poor overall survival. Other serum, tissue and molecular markers investigated in MPM fail to have any proven status in assessment of prognosis or stratification of patients in clinical trials (Arnold et al., 2017).

Several authors reported a prognostic role for PET CT, a high SUVmax was associated with shorter survival and a greater death risk than a low SUVmax, and can be used to stratify patients for survival and outcome by separating patients into good and poor prognostic groups. Additionally, recent evidence also supports other metabolic indices like metabolic (MTV) and total lesion glycolysis (TLG) in having even better prognostic implications than SUVmax (Kitajima et al., 2016).

•    Programmed death-ligand 1

There is some evidence that MPM is an immunogenic tumor that induces immune recognition, infiltration of immune cells and death mediated by autoimmunity. Additionally, MPM appears to be responsive to immunotherapy, and there are some cases of spontaneous regression reported suggesting an antitumor immune response (Pilling et al., 2007, Jackaman et al., 2009).

The programmed cell death (PD-1/PD-L1) pathway plays a critical role in to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity (Ohaegbulam et al., 2015).

Engagement of programmed cell death receptor 1 (PD-1), which is expressed on activated T cells, with its ligands programmed death-ligand 1 (PD-L1) and programmed death-ligand (PD-L2), limits T-cell effector functions. Tumors can bypass anti-tumor responses by overexpressing PD-L1 (Pardoll, 2012).

Programmed death-ligand 1 (PD-L1) is expressed in 20–40% of patients with malignant pleural mesothelioma and appears to be more common in non-epithelioid tumors. PD-L1-positive MPM seems to be associated with worse prognosis than is PD-L1-negative disease (median survival 4·8–5·0 months vs 14·5–16·3 months (Mansfield et al., 2014, Cedrés et al., 2015, Combaz-Lair et al., 2016, Thapa et al., 2017).

Researchers from Mayo clinic evaluated the expression of PD-L1 in 106 MPM patients using a mouse monoclonal anti-human PD-L1. Positive expression was defined as ≥5% positively-stained cells. 42 patients (40%) expressed PD-L1. All sarcomatoid mesotheliomas except one desmoplastic subtype expressed PD-L1. Median Survival was significantly decreased for patients with PD-L1 expression (5 months) compared to those whose tumors did not (14.5 months) (p<0.0001). In a multivariate model, PD-L1 expression and sarcomatoid mesothelioma remained significantly associated with worse survival [(p=0.04) and (p=0.03) respectively] (Mansfield et al., 2014).

In Spain, formalin-fixed, paraffin-embedded tissue of 119 MPM patients from two institutions was stained with rabbit monoclonal primary PD-L1 antibody (clone E1L3N). PD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012) (Cedrés et al., 2015).

The expression of PD-L1 in 68 French patients was assessed using E1L3N and SP142 clones in in tumor cells (TCs) and in tumor-infiltrating lymphocytes in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) a positivity threshold of 1%.  PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016) (Combaz-Lair et al., 2016).

A multicenter international study investigated PD-L1 expression among 329 patients using E1L3N. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with non-epithelioid histological subtype. Also, high PD-L1-positive expression correlated with worse prognosis (p < 0.001).

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