**6. The role of biomarkers in early detection of malignant pleural mesothelioma and in predicting patients' response after therapy and outcome**

Because of mesothelioma's nonspecific presenting symptoms, patients often suffer a substan‐ tial diagnostic delay, resulting in a more advanced disease at diagnosis [34]. At present, the only

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 improve the early detection of mesothelioma [34].

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

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].

**6. The role of biomarkers in early detection of malignant pleural mesothelioma and in predicting patients' response after therapy and**

Because of mesothelioma's nonspecific presenting symptoms, patients often suffer a substan‐ tial diagnostic delay, resulting in a more advanced disease at diagnosis [34]. At present, the only

biologic behavior, and far better prognosis.

**5. Clinical presentation**

170 Principles and Practice of Cardiothoracic Surgery

**outcome**

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

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 finally, the excised area is resynthesized. Excision repair cross-complementation group 1 enzyme (ERCC1) plays a rate-limiting step in this process by forming a complex with xero‐ derma pigmentosum complementation group F that excises the damaged DNA [51–54]. Two studies have recently addressed the possible predictive and prognostic role of ERCC1 in malignant pleural mesothelioma [51]. In an observational study by Righi et al., immunohis‐ tochemistry was used to detect ERCC1 in a cohort of 45 malignant pleural mesotheliomas treated with different platinum-based therapies (cisplatin-pemetrexed or carboplatin-peme‐ trexed in different regimens) [55]. In this series, there was no association between ERCC1 status and treatment response, but the authors did find high ERCC1 levels to be associated with a better prognosis regardless of the chemotherapy regimen used [51], [55]. Zucali et al. also used immunohistochemistry to detect ERCC1 in a retrospective cohort of 67 malignant pleural mesotheliomas treated with a combination of pemetrexed and carboplatin [56]. These authors found no association between ERCC1 protein status and clinical outcome in terms of disease control, progression-free survival and overall survival [51], [56]. The retrospective study of Zimling et al. in malignant pleural mesothelioma patients treated with cisplatin/vinorelbine suggests that low ERCC1 expression, evaluated by immunohistochemistry, may predict longer progression-free survival, a result that warrants further validation [51].

T1 T1a Tumour limited to the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. No

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

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

173

T1b Tumour involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura.

T2 Tumour involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral

T3 Describes locally advanced but potentially resectable tumour. Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral) with at least one of the following features:

Solitary completely resectable focus of tumour extending into the soft tissues of the chest wall

T4 Describes locally advanced technically unresectable tumour. Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral) with at least one of the following features: Diffuse extension or multifocal masses of tumour in the chest wall with or without associated rib destruction

Tumour extending through to the internal surface of the pericardium with or without a pericardial effusion,

N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal

N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral or contralateral

**Table 1.** New International Staging System for Malignant Pleural Mesothelioma (IMIG): TNM staging (Rusch VW).

Confluent visceral pleural tumour (including the fissures) or extension of tumour from visceral pleura into

involvement of the visceral pleura

Involvement of diaphragmatic muscle

the underlying pulmonary parenchyma

Involvement of the endothoracic fascia Extension into the mediastinal fat

Non-transmural involvement of the pericardium

Direct transdiaphragmatic extension of tumour to the peritoneum

N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes

Direct extension of tumour to the contralateral pleura Direct extension of tumour to one or more mediastinal organs

Direct extension of tumour into the spine

or tumour involving the myocardium

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastases

supraclavicular lymph nodes

MX Presence of distant metastases cannot be assessed

mammary nodes

M0 No distant metastasis M1 Distant metastasis present

N Lymph nodes

M Metastases

Scattered foci of tumour also involving the visceral pleura

pleura) with at least one of the following features:

### **7. Staging**

Because of the lack of a universally accepted staging system, the International Mesothelioma Interest Group (IMIG) developed an internationally accepted staging system that was based on the available data correlating clinical and pathologic extent of disease with outcome [57]. The IMIG staging system has become universally accepted and adopted by the UICC and the AJCC. [17] This is based upon a TNM (tumour, node, metastasis) system (Tables 1 and 2) [57]. Information regarding the degree of visceral and parietal pleural involvement often requires the use of diagnostic thoracoscopy by means of VATS (Video Assisted Thoracic Surgery). Chest CT may also be helpful.

Cervical mediastinoscopy as a pre-operative invasive mediastinal staging tool remains still a debating issue. The high rate of false negative results or the presence of disease in lymph nodes inaccessible by mediastinoscopy, are the main reasons for its limited role in the staging algorithm [58]. Pilling et al. suggested the use of cervical mediastinoscopy as a selection tool in order to identify the patients who would benefit most from extrapleural pneumonectomy as nodal size on CT is an unreliable marker of malignancy [59]. Lately, it has been proposed that cervical mediastinoscopy should be used as routine method of prognostic staging in all patients undergoing radical surgery for malignant pleural mesothelioma [60].

Positron emission tomography (PET) scan has a crucial role in thoracic oncology due to its impact on diagnosis, staging and prognosis [61]. PET is useful diagnostic tool to identify and stage malignant pleural mesothelioma and differentiate it from benign pleural disease. Its impact in the prediction of survival, determination of mortality risk and detection of metasta‐ ses and recurrent disease is considered valuable. However, the combination of PET-CT can produce superior diagnostic results than PET alone [62].

finally, the excised area is resynthesized. Excision repair cross-complementation group 1 enzyme (ERCC1) plays a rate-limiting step in this process by forming a complex with xero‐ derma pigmentosum complementation group F that excises the damaged DNA [51–54]. Two studies have recently addressed the possible predictive and prognostic role of ERCC1 in malignant pleural mesothelioma [51]. In an observational study by Righi et al., immunohis‐ tochemistry was used to detect ERCC1 in a cohort of 45 malignant pleural mesotheliomas treated with different platinum-based therapies (cisplatin-pemetrexed or carboplatin-peme‐ trexed in different regimens) [55]. In this series, there was no association between ERCC1 status and treatment response, but the authors did find high ERCC1 levels to be associated with a better prognosis regardless of the chemotherapy regimen used [51], [55]. Zucali et al. also used immunohistochemistry to detect ERCC1 in a retrospective cohort of 67 malignant pleural mesotheliomas treated with a combination of pemetrexed and carboplatin [56]. These authors found no association between ERCC1 protein status and clinical outcome in terms of disease control, progression-free survival and overall survival [51], [56]. The retrospective study of Zimling et al. in malignant pleural mesothelioma patients treated with cisplatin/vinorelbine suggests that low ERCC1 expression, evaluated by immunohistochemistry, may predict longer

Because of the lack of a universally accepted staging system, the International Mesothelioma Interest Group (IMIG) developed an internationally accepted staging system that was based on the available data correlating clinical and pathologic extent of disease with outcome [57]. The IMIG staging system has become universally accepted and adopted by the UICC and the AJCC. [17] This is based upon a TNM (tumour, node, metastasis) system (Tables 1 and 2) [57]. Information regarding the degree of visceral and parietal pleural involvement often requires the use of diagnostic thoracoscopy by means of VATS (Video Assisted Thoracic Surgery). Chest

Cervical mediastinoscopy as a pre-operative invasive mediastinal staging tool remains still a debating issue. The high rate of false negative results or the presence of disease in lymph nodes inaccessible by mediastinoscopy, are the main reasons for its limited role in the staging algorithm [58]. Pilling et al. suggested the use of cervical mediastinoscopy as a selection tool in order to identify the patients who would benefit most from extrapleural pneumonectomy as nodal size on CT is an unreliable marker of malignancy [59]. Lately, it has been proposed that cervical mediastinoscopy should be used as routine method of prognostic staging in all

Positron emission tomography (PET) scan has a crucial role in thoracic oncology due to its impact on diagnosis, staging and prognosis [61]. PET is useful diagnostic tool to identify and stage malignant pleural mesothelioma and differentiate it from benign pleural disease. Its impact in the prediction of survival, determination of mortality risk and detection of metasta‐ ses and recurrent disease is considered valuable. However, the combination of PET-CT can

patients undergoing radical surgery for malignant pleural mesothelioma [60].

produce superior diagnostic results than PET alone [62].

progression-free survival, a result that warrants further validation [51].

**7. Staging**

CT may also be helpful.

172 Principles and Practice of Cardiothoracic Surgery


**Table 1.** New International Staging System for Malignant Pleural Mesothelioma (IMIG): TNM staging (Rusch VW).


**•** Ejection fraction > 40%

**•** Extrapleural pneumonectomy

**•** Pleurectomy - Decortication

**9. Extrapleural pneumonectomy**

complete exclusion of macroscopic disease [66].

Therapy

tures' class [64], [67].

**•** Mean pulmonary artery pressure < 30 mmHg

The aim of surgical treatment is to achieve the maximum cytoreduction and radical resection of macroscopic lesions of the disease and includes the following approaches [65]:

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

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

175

**•** Pleurectomy - Decortication and Hyperthermic Pleural ChemoPerfusion / Photodynamic

The extrapleural pneumonectomy involves radical excision of the entire lung, en block with the parietal pleura, including the ipsilateral hemidiaphragm and pericardium and radical mediastinal lymph node dissection. The main goal of this surgical technique is to achieve

The surgical technique is usually applied with posterolateral thoracotomy. In case of previous incisions (probably for biopsy), all scars should be excluded in order to avoid spreading the disease. Entry into the thoracic cavity is usually made through the sixth intercostal space. To achieve good surgical field, the sixth rib may be excised or a second thoracotomy must be performed below in order to facilitate better resection and reconstruc‐ tion of the hemidiaphragm. After division of the intercostal space, an extrapleural plan is created separating the parietal pleura from endothoracic fascia, carefully, without enter‐ ing the pleural cavity. Usually we begin with blunt and sharp dissection caudal-tocephalad. Particular attention is required during the preparation of parietal pleura to the anatomical area of internal mammary vessels, azygos vein, aorta, esophagus, superior vena cava, inferior vena cava and mediastinum. The pericardium is opened and explored for possible metastases and eventually is resected. The hemidiaphragm is resected with very careful dissection from the peritoneum, without entering the peritoneal cavity. Then a complete mediastinal lymphadenectomy is carried out and ligation of major thoracic duct. Finally in order to complete pneumonectomy, pulmonary artery and veins as well as the main bronchus are ligated. The deficit of the pericardium is restored by placing bovine pericardium, while hemidiaphragm defect restored with synthetic mesh. Finally place a chest tube, followed by closure of the wound in accordance with the anatomical struc‐

The complications of this surgical procedure are represented in the table 3 below:

**Table 2.** New International Staging System for Malignant Pleural Mesothelioma (IMIG): Clinical staging (Rusch VW).
