**4. Biological behavior**

recognized [7]. The recent decline in incidence is attributable to declining asbestos exposure, and this trend is expected to continue [2]. On the other hand, asbestos use in Western Europe remained high until 1980, and substantial quantities are still used in several European countries. Peto et al. suggested that for the period 1995–2029 the number of men dying from mesothelioma in Western Europe each year will almost double over the next 20 years, from 5,000 in 1998 to about 9,000 around 2018, and then decline, with a total of about a quarter of a million deaths over the next 35 years [8]. The highest risk will be suffered by men born around 1945–50, of whom about 1 in 150 will die of mesothelioma. These projections are based on the fit of a simple age and birth cohort model to male pleural cancer mortality from 1970 to 1989 for six countries (Britain, France, Germany, Italy, The Netherlands and Switzerland) which together account for three-quarters of the population of Western Europe [8]. According to Surveillance, Epidemiology and End Results (SEER) Program data, the incidence of malignant mesothelioma in the United States is estimated to be between 1-2/million in states with minimal exposure to mineral fibers and 10-15/million in states where large amounts of asbestos were used [9]. The latest data available show that malignant mesothelioma is responsible for approximately 3,000 deaths per year in the United States and an additional 5,000 deaths in Western Europe [10], [11]. The latency period, which is the interval between first exposure and the development of malignant mesothelioma, ranges from about 25 to 71 years and appears to be influenced by the amount of exposure, because workers in trades with higher amounts of exposure may experience shorter latencies compared to those exposed to lower amount of asbestos [11], [12]. It is of crucial importance for the Thoracic Surgeons to be fully informed about malignant pleural mesothelioma in order to reach the correct diagnosis and recommend

The main risk factor in developing malignant mesothelioma is asbestos exposure [13]. Asbestos refers collectively to a group of naturally occurring hydrated mineral silicate fibers that include two major forms: serpentine, represented by chrysotile (white asbestos); and the amphiboles, including crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite, actinolite and tremolite[13],[14].Crocidolitefibersareregardedasthemostoncogenictypeofasbestosbecause they are long and thin, and are believed to persist longer in the pleura, but the exact way in which asbestos induces the development of malignant mesothelioma is still not well understood [13], [14]. Inflammation appears to play a critical role as following asbestos exposure in vivo, recruit‐ ment of mononuclear phagocytes (which differentiate into macrophages that in turn phagocy‐ tize asbestos) was observed, resulting in the release of tumour necrosis factor-alpha (TNF-a) by the phagocytes and mesothelial cells [14]. Exposure to asbestos can also lead to the accumula‐ tion of DNA damage in mesothelial cells through interaction with reactive nitrogen and oxygen species,whichcoupledtotheactivationoftheNF-kBpathwaybyTNF-aperpetuatesthesurvival

Crocidolite asbestos is found only in South Africa and Western Australia but has been exported all over the world for various industrial uses [17]. Chrysotile accounts for 97% of worldwide

the appropriate treatment when dealing with it.

168 Principles and Practice of Cardiothoracic Surgery

of the DNA-damaged mesothelial cells [14–16].

**3. Epidemiology**

The right pleural cavity is more commonly involved than the left. In the early stages of the disease, the tumour often appears as multiple nodules on the surface of the visceral and parietal pleurae [1]. Occasionally, a localized pleural mass may develop but more often the nodules coalesce to form a sheet of tumour which surrounds the lung, extends along the fissures and may invade the underlying parenchyma [1]. Pericardial and diaphragmatic invasion are common. Bronchial invasion, usually by spread from the pleura near the hilum, is uncommon and may lead to diagnostic confusion if tumour is visible at bronchoscopy [26]. At post-mortem examination, distant metastases are common, occurring in about two-thirds of the cases with sarcomatoid type and one-third of the patients with the epithelioid and mixed types [26].

Diffuse malignant mesothelioma is divided into three main histological types: epithelioid which is most common, sarcomatoid and mixed or biphasic. The epithelial variety displays several patterns including tubulopapillary and glandular [1]. Histochemical and immunohis‐ tochemical stains assist in differentiating epithelioid mesothelioma from adenocarcinoma, the most common and difficult differential diagnosis [27].

A small number of localized serosal/subserosal neoplasms with histopathologic, histochemi‐ cal, immunohistochemical, and ultrastructural features identical to those of diffuse malignant mesothelioma have been described and given the designation ''localized malignant mesothe‐ lioma'' [28]. Crotty et al first described a series of 6 localized malignant mesotheliomas in 1994 [28]. Localized malignant mesotheliomas are extremely rare solitary circumscribed nodular tumors, attached either in a sessile or pedunculated manner to the surface of the pleura [29]. Most localized malignant mesotheliomas present as incidental findings or with nonspecific symptoms. Epithelial-type localized malignant mesotheliomas predominate, and very few tumors are purely sarcomatous [29]. However, as opposed to ordinary diffuse malignant mesotheliomas where epithelial forms have a better prognosis than sarcomatous forms and biphasic forms are intermediate, histologic subtype does not correlate with survival [29]. Tumor size also does not appear to affect the clinical course [28]. Because of the vastly different treatment and prognosis, it is crucial to separate localized malignant mesotheliomas from diffuse malignant mesotheliomas. Diffuse malignant mesotheliomas always show gross and/ or microscopic evidence of widespread tumor on the serosal surface, as individual tumor nodules, or as a rind around viscera or as tumor caking [29]. Recurrent spread of localized malignant mesothelioma in the manner of diffuse malignant mesothelioma has been reported [30]. The crucial feature of localized malignant mesothelioma is that many cases can apparently be cured by surgical excision [29]. Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.

instruments for screening and diagnosis are based on radiological tests, posing evident econom‐ icandradio-protectionistproblems[35].Anadequatescreeningprogramandsubsequentearlier detection might improve patient outcome [36]. Current guidelines on mesothelioma manage‐ ment do, however, not advocate the use of screening and recommend that the efficacy of any screeningtoolshouldbefurtherevaluatedinhigh-riskpopulations[37].Solublemesothelin(SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma [38], [39]. Mesothelin is a 40 kDa cell surface glycophosphatidylinositol- anchored protein expressed at a low level by normal mesothelial cells in the pleura, peritoneum, and pericardium. It is highly expressed in pancreatic cancer, ovarian cancer, mesotheliomas, and some other cancers [40]. Hollevoet et al. showed that the longitudinal behavior of SM and MPF in controls indicates that a biomarker-based screening approach can benefit from the incorporation of serial measure‐ ments and individual-specific screening rules, adjusted for age and glomerular filtration rate (GFR)intheirprospectivelongitudinalcohortstudyinasbestos-exposedindividuals[34].Largescale validation remains nevertheless mandatory to elucidate whether such an approach can

Recent Advances in Surgical Techniques for Multimodality Treatment of Malignant Pleural Mesothelioma

http://dx.doi.org/10.5772/53397

171

Other authors are evaluating different combination of biological indicators as screening and early diagnosis markers, such as plasma osteopontin (pOPN) and serum soluble mesothelinrelated peptides (SMRP) [35]. OPN is a glycoprotein overexpressed in several human neo‐ plasms such as lung, breast, and colon cancer [41]. OPN modulates cell-matrix interactions; high levels correlate with tumor invasion, progression, and metastasis [35]. Serum OPN (sOPN) levels in patients with malignant pleural mesothelioma have been reported to be higher than in healthy subjects [42], [43]. Cristaudo et al. showed for the first time that combined SMRP and pOPN measurements can increase both sensitivity and specificity, in diagnosis of epithelioid malignant pleural mesothelioma, in terms of combined risk index [35].

Biomarkers are also urgently needed for the selection of patients likely to benefit from multimodality therapy regimens while preventing aggressive but futile treatment interven‐ tions in ineligibles [37], [44]. Serum C-reactive protein (CRP) is known as a widely available routine marker for diagnosis and follow-up of patients affected by various inflammatory diseases [45]. Recently, a negative prognostic value has been assigned to elevated serum CRP levels in several malignant diseases including breast, ovarian, renal, and lung cancer [45–49]. The results of Ghanim et al. suggest that multimodality regimens including radical resection increase survival selectively in malignant pleural mesothelioma patients with normal pre‐

The last few years there is an increased focus on markers of resistance, which can be used to predict treatment efficacy and thereby guide treatment decisions. Cisplatin and carboplatin work by binding to the DNA forming adducts that lead to intra- or interstrand cross-links. The formation of these DNA cross-links inhibits the cell from replicating and drives it toward apoptosis. This proapoptotic signal can be counteracted by the cells' intrinsic ability to recognize and repair the DNA damage. Nucleotide excision repair is a highly conserved pathway that maintains DNA integrity by removing helix-distorting cross-links. This pathway seems to be a key element in mediating resistance toward platinum compounds. There are three important steps in this pathway. First, the DNA damage is recognized then excised, and

treatment serum CRP levels, in their retrospective multicenter analysis [50].

improve the early detection of mesothelioma [34].

#### **5. Clinical presentation**

The majority of cases occur in men, reflecting their greater frequency of occupational asbestos exposure. A careful occupational history should be taken when mesothelioma is suspected or confirmed [1]. Median age at presentation is in the seventh decade but the disease may occur at any age [31]. During the early stages of disease, dyspnea is the predominant symptom and is related to the presence of an effusion. When the effusion is drained, patients are asympto‐ matic [17], [32]. As the tumor grows, patients develop ill-defined, mild, but continuous chest discomfort. Dyspnea may actually improve during this phase of the disease because, with tumor growth, the pleural surfaces fuse and the effusion resolves [17], [33]. Only when the disease becomes locally advanced does the patient develop severe chest pain, which is related to tumor infiltration of the chest wall and intercostal nerves [17], [33]. This is accompanied by a sense of chest tightness and dyspnea caused by entrapment of the lung by tumor [17]. There may be anorexia, weight loss and general malaise. Profuse sweats, particularly at night, often occur [1]. In the final stages of disease, dyspnea and chest pain become severe and unremitting [17]. These symptoms are related to encasement of the chest wall, lung, and mediastinum, and are occasionally associated with mediastinal shift and compression of the contralateral lung [17], [32]. Subcutaneous nodules may develop, particularly at sites of previous pleural aspiration or biopsy [1]. Other late features may include superior vena caval obstruction, pericardial tamponade due to malignant effusion or pericardial constriction due to tumour invasion of the pericardium [1], [32]. The tumour may spread to the abdominal cavity causing ascites. Mesothelioma may metastasize widely to all areas including the contralateral pleura and lung, intra- and extra-thoracic lymph nodes, liver, bone and brain [1], [26].
