Abstract
Mesothelioma is a rare, malignant tumor of the pleura (malignant pleural mesothelioma, MPM). It is a common disease, arising from the mesothelial cells lining the pleura (Cancer Control 13:255–263, 2006). Mesothelial cells form a monolayer (mesothelium) lining the serosal cavities (pleural, pericardial and peritoneal) and the organs contained within these cavities (Int J Biochem Cell Biol 36(1):9–16, 2004). Other, less common tumors of the pleura, include solitary fibrous tumor, adenomatoid tumor, calcifying fibrous pseudotumor, and pleural desmoid tumors (Chest 137(4):1005–1006, 2010). MPM is a resistant tumor in chemotherapy and radiotherapy, with rapid progression and results in a median survival time of 12 months (Rev Mal Respir 24:6S157–6S164, 2007). MPM extends into organs in the vicinity and disturbs functions of vital organs. It rarely metastasizes to distant organs, until it develops into a terminal stage (Lancet 366(9483):397–408, 2005). These metastases can cause compression of heart and great vessels (leads to cardiac tamponade), superior vena cava syndrome, bone and neuropathic pain and massive pleural effusion. MPM frequently penetrates into lung parenchyma causing progressive respiratory failure (Biomed Res Int, 2013). Mesothelioma can also arise in the peritoneum, the pericardium or the tunica vaginalis
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Keywords
- Mesothelial Cell
- Overall Response Rate
- Malignant Pleural Mesothelioma
- Solitary Fibrous Tumor
- Superior Vena Cava Syndrome
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1 Introduction
Mesothelioma is a rare, malignant tumor of the pleura (malignant pleural mesothelioma, MPM). It is a common disease, arising from the mesothelial cells lining the pleura [1]. Mesothelial cells form a monolayer (mesothelium) lining the serosal cavities (pleural, pericardial and peritoneal) and the organs contained within these cavities [2]. Other, less common tumors of the pleura, include solitary fibrous tumor, adenomatoid tumor, calcifying fibrous pseudotumor, and pleural desmoid tumors [3]. MPM is a resistant tumor in chemotherapy and radiotherapy, with rapid progression and results in a median survival time of 12 months [4]. MPM extends into organs in the vicinity and disturbs functions of vital organs. It rarely metastasizes to distant organs, until it develops into a terminal stage [5]. These metastases can cause compression of heart and great vessels (leads to cardiac tamponade), superior vena cava syndrome, bone and neuropathic pain and massive pleural effusion. MPM frequently penetrates into lung parenchyma causing progressive respiratory failure [6]. Mesothelioma can also arise in the peritoneum, the pericardium or the tunica vaginalis.
2 Epidemiology and Incidence
The most common cause of this tumor, is the occupational exposure to asbestos, in places such as mines, shipyards, cement factories etc [7]. Asbestos refers to six fibrous silicate minerals, found widely throughout the world and is divided into two categories: a serpentine form and a rodlike form.
There is a long time latency period between exposure to asbestos and development of MPM (10–30 years), so a long period of exposure to asbestos is required, in order to develop MPM. Asbestos fibers, cause chronic inflammation to the mesothelium, so this is the factor that leads to carcinogenesis, via tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Family members of patients with MPM, can develop this tumor in higher rates, due to secondary exposure to asbestos. Other agents that can lead to MPM formation, are mineral fibers (e.g. erionite), prior radiotherapy, thorium dioxide used for diagnostic purposes and simian virus 40 (SV-40) [8]. Nanosized particles of medical and industrial purposes could cause MPM formation [6]. Mutations of BRCA-1 associated protein-1 (BAP1) gene seem to lead to MPM formation, via reducing the tumor suppressor activity of BAP1 protein [9, 10]. Other mutations in critical genes, include cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF) and neurofibromatosis type-2 (NF2). Men have poorer prognosis, because it is more likely to have occupational exposure to asbestos. MPM in young people is more aggressive, because of a greater exposure to asbestos in regard to older people who have longer survival [11, 12]. The incidence of MPM arises in one to two per million of the general population per year [13].
3 Clinical Manifestation and Diagnosis
There are no specific symptoms related to MPM, so the diagnosis can delay for months [14]. The most common symptom is dyspnea, which can be presented as breath shortness or exertion. Chest wall pain can also be present, due to irritation of costal nerves or tumor infiltration into chest wall. Other, less common symptoms of MPM, include fever, weight loss, sweat and performance status decline [15]. Rare symptoms are irritative cough, phrenic nerve palsy, spontaneous pneumothorax and paraneoplastic phenomena [16]. During the physical examination can be present dullness to thorax percussion and decreased breath sounds. Thrombocytosis is a relatively common laboratory sign, whereas other laboratory abnormalities are not present [17]. Pleural effusion is present in most cases of MPM, revealed by a chest X-ray (Fig. 8.1). Differential diagnosis of the infusion includes pneumonia, tuberculosis, trauma and venous congestion.
Thoracentesis relieves the patient’s symptoms but a cytologic analysis is not reliable. Computer tomography (CT), magnetic resonance imaging (MRI) and ultrasonography (US) can be used to obtain further support for suspected diagnosis and assess the extent of the disease [18]. A thoracoscopic biopsy is often required and if the tumour is resectable, this can be during thoracotomy [19]. Prognostic factors include performance status, presence of chest pain, age, histological type and platelet count. Bad performance status, elevated white blood count, male gender and sarcomatous histological type of MPM, are associated with poorer prognosis [20]. Pain and appetite loss, are independent prognostic factors [21].
4 Histological and Molecular Characteristics: Biomarkers
There are four recognised subtypes of MPM: epithelioid (Fig. 8.2), sarcomatous, mixed and desmoplastic [22]. Epithelioid subtype is the most common and has better prognosis than the other subtypes of MPM. Differential diagnosis should be held with metastatic lung adenocarcinoma, non-small cell lung cancer (NSCLC) and mesothelial hyperplasia. There are antigens expressed by the mesothelial cells, such as calretinin, Wilm’s tumor gene product (WT-1), mesothelin, cytokeratin (CK) 5/6, thrombomodulin, podoplanin (D2-40), HBME-1 antigen etc. Biomarkers expressed by carcinoid cells, include carcinoembryonic antigen (CEA), thyroid transcription factor-1 (TTF-1), Leu-M1 (CD15), Ber-EP4, B72.3, BG-8, napsin-A. Calretinin, WT-1 and D2-40, have great specificity for MPM. Sarcomatoid type cells, express cytokeratins, vimentin and smooth muscle markers. However, there are CK-negative sarcomatoid mesotheliomas. Two positive (e.g. CK 5/6, calretinin) and two negative (e.g. CEA, TTF-1) markers, should be used to distinguish between MPM and NSCLC. Definite diagnosis of MPM is carried out by recognising fat or stromal tissue invasion of the tumor cells. When tissue invasion cannot be identified, the lesion is characterized as atypical mesothelial proliferation. Biomarkers that can be used in the diagnosis of MPM, are mesothelin, CA125, osteopontin and megakaryocyte potentiating factor (MPF), with poor sensitivity [23]. Circulating fibrinogen could also be a prognostic and predictive biomarker in MPM [24].
5 Staging
The staging system provides an estimate of the prognosis, and an assessment if the tumor is potentially resectable. The tumor, nodal, and metastasis (TNM) staging system, is often used (Table 8.1). Patients with suspected or confirmed MPM diagnosis should be assessed for therapeutic planning with CT of the thorax and abdomen. US or CT can be used to guide biopsy and drainage of pleural effusion. New-generation spiral CT should be used on MPM imaging, because enhances definition and interpretation of lesions, due to vasculature defining. Fludeoxy-glucose positron emission tomography (FDG-PET) is a more sensitive modality than CT to detect possible lymph node involvement and distant metastatic disease, and should be performed when the presence of disease in these sites will influence a management plan. FDG-PET-CT should be used in preference to FDG-PET according to availability. MRI with gadolinium enhancement can be useful where it is important to delineate tumour extension in the diaphragm, endothoracic fascia, chest wall or through iatrogenic tumour seeding [23].
6 Surgical Treatment
Thoracoscopy aids in the diagnosis and management of MPM, especially in patients with large pleural effusions. The surgeon is able to directly visualize the entire thorax space, visceral and parietal pleura and chest wall. Mediastinal structures (pericardium and mediastinal lymph nodes) can be directly evaluated to aid in determining the extent of future resection. Diaphragm can be inspected to determine the extent of disease. If diaphragmatic involvement occurs, laparoscopy can be helpful [25]. Biopsies of abnormal pleura can be performed directly. If contralateral thoracic involvement of MPM is suspected, thoracoscopy can confirm the diagnosis. After determining the extent of disease, suitability for resection must be determined and the type of resection must be decided. Extrapleural pneumonectomy (EPP), pleurectomy and decortication (P/D), and palliative limited pleurectomy are the surgical operations used in the treatment of MPM. Normal kidney and hepatic function and a Karnofsky performance status greater than 70 is required.
Additionally, the patients’ room air Pco2 must be less than 45 mmHg, Po2 greater than 65 mmHg, and an ejection fraction (EF) of 45 % or greater. A forced expiratory volume in the first second (FEV1) greater than 2 L or a predicted postoperative (PPO) FEV1 of greater than 800 mL, is also required. Patients with PPO FEV1 of less than 800 mL may be candidates for P/D rather than EPP [26]. Aim of surgery is to achieve maximum cytoreduction of the tumor (R1 resection). Surgical therapy remains the foundation of potential curative treatment for MPM. The secondary objective of surgery is to improve symptoms (evacuation of the pleural effusion and pulmonary decortication of an entrapped lung), which improves pain related to chest wall invasion of the MPM [27, 28]. The decision to perform EPP or P/D is dependent on several factors, such as the bulk of disease at the time of surgery and should be made by thoracic surgeons who are experienced in managing MPM. If minimal disease is encountered (T1) then P/D is preferable. In patients with visceral pleura involvement, EPP is appropriate for complete resection. EPP can cause pulmonary hypertension and right heart strain, so echocardiogram is used to assess cardiac function. Additionally, duplex imaging of lower extremities can assess in the diagnosis of deep venous thrombosis (DVT). These patients must take anticoagulant therapy, in order to prevent the pulmonary embolism. If the patient has diffuse disease, including chest wall involvement, EPP will leave the patient with gross residual disease and is not appropriate for this case. Therefore, the decision to perform EPP or P/D should be an intraoperative choice depending on the magnitude of disease [8].
7 Chemotherapy
Chemotherapy is used to reduce disease related symptoms, maintain or improve quality of life, and extend overall survival (OS). Candidates, should be ambulatory (i.e., an Eastern Cooperative Oncology Group [ECOG] performance status [PS] of 0 to 2 or a Karnofsky PS of ≥70), have adequate organ function, and not significant co-morbidities. Phase III trials have shown that the best chemotherapeutic combination for the first-line treatment of MPM is a platinum agent (cisplatin or carboplatin) with antifolate, such as pemetrexed or raltitrexed.
Combination of these agents, shows superior overall response rate (ORR), progression free survival (PFS), and overall survival (OS), contrary to cisplatin alone. In Vongelzang’s phase III trial compared cisplatin vs cisplatin/pemetrexed for 456 patients. For cisplatin alone, the ORR was 16,7 % and the PFS was 3,9 months, whereas for the combination cisplatin/pemetrexed, the ORR was 41,3 % and the PFS was 5,7 months [29]. In Van Meerbeeck’s phase III trials, compared cisplatin vs cisplatin/raltitrexed for 250 patients. For cisplatin alone the ORR was 13,6 % and the PFS was 4 months, whereas for the combination cisplatin/raltitrexed the ORR was 23,6 % and the PFS 5,3 months [30]. In Santoro’s phase III trial, compared the combinations of cisplatin/pemetrexed and carboplatin/pemetrexed for 1,704 patients. For the combination of cisplatin/pemetrexed the ORR was 26,3 % and the PFS was 7 months, whereas for the combination of carboplatin/pemetrexed, the ORR was 21,7 % and the PFS was 6,9 months [31]. Cisplatin or carboplatin in combination with pemetrexed have similar efficacy, and carboplatin may be substituted for cisplatin in patients who have a relative or absolute contraindication to cisplatin. Active symptoms control (ASC) includes steroids, analgesic drugs, bronchodilators and palliative radiotherapy. Addition of mitomycin, vinblastine and cisplatin (MVP) with or without vinorelbine, shows no significant difference in OS [32]. There are no sufficient data for second-line therapy in MPM. Vinorelbine plus carboplatin and gemcitabine plus cisplatin or carboplatin, show good results in this case [33, 34]. Preoperative chemotherapy is a reasonable approach in some patients with resectable MPM, using the combinations of cisplatin/pemetrexed or carboplatin/gemcitabine followed by EPP and radiotherapy (RT) [35, 36].
8 Radiotherapy
RT in MPM is used for the local control of disease, since mesothelial cells are sensitive in radiation. The target is the preoperative extent of the pleural space, which is large, irregular, and close to radiosensitive organs (lungs, heart, and liver). The role of RT is used as an integral part of trimodality therapy for early-stage disease and in the palliation of pain in locally advanced/metastatic disease.
In the first case, RT is used in doses of 4,500–5,040 centiGray (cGy) (in 180-cGy fractions) over 5 weeks in the postsurgical setting. In order to relieve the symptoms of the disease, such as pain and dyspnea, short courses are used (e.g. 300 cGy × 10 fractions). After EPP, radiation therapy must be given in high doses (54 Gy) for better results [37]. Intensity-modulated radiotherapy (IMRT) has the flexibility to deliver dose distributions that conform to complicated convex and concave target volumes, while minimizing dose to critical structures in proximity [8]. IMRT after P/D has good results in dose <40 Gy [38].
Abbreviations
- ACS:
-
Active symptoms control
- BAP-1:
-
BRCA-1 associated protein-1
- CDKN2A/ARF:
-
Cyclin-dependent kinase inhibitor 2A/alternative reading frame
- CEA:
-
Carcinoembryonic antigen
- (c)Gy:
-
(Centi) Gray
- CK:
-
Cytokeratin
- CT:
-
Computer tomography
- DVT:
-
Deep venous thrombosis
- ECOG:
-
Eastern Cooperative Oncology Group
- EF:
-
Ejection fraction
- FDG-PET:
-
Fludeoxy-glucose positron emission tomography
- FEV1 :
-
Forced expiratory volume in the first second
- IL-1β:
-
Interleukin-1β
- IMRT:
-
Intensity-modulated radiotherapy
- MPM:
-
Malignant pleural mesothelioma
- MRI:
-
Magnetic resonance imaging
- MVP:
-
Mitomycin, vinblastin, cisplatin
- NF-2:
-
Neurofibromatosis type-2
- NSCLC:
-
Non-small cell lung cancer
- ORR:
-
Overall response rate
- OS:
-
Overall survival
- P/D:
-
Pleurectomy and decortication
- PPO:
-
Predicted postoperative
- PS:
-
Performance status
- RT:
-
Radiotherapy
- SV-40:
-
Simian virus 40
- TNF-α:
-
Tumor necrosis factor-α
- TNM:
-
Tumor, nodal and metastasis
- TTF-1:
-
Thyroid transcription factor-1
- US:
-
Ultrasound
- WT-1:
-
Wilm’s tumor gene product
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Karamitrousis, V. (2015). Mesothelioma. In: de Mello, R., Tavares, Á., Mountzios, G. (eds) International Manual of Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-21683-6_8
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