Mesothelioma

Mesothelioma is a type of cancer that develops in the mesothelial or sub-mesothelial cells of various tissues.1 The most common form of mesothelioma – accounting for nearly 90% of cases – is pleural mesothelioma,2 which develops in the pleura (sheets of tissue that cover the lungs). Mesothelioma can also occur in the peritoneum, which lines the abdominal cavity; in the pericardium, which surrounds the heart; and in other tissues, including in the membrane that covers the testis.1,2

Most cases of mesothelioma are caused by exposure to asbestos or to similar mineral particles that occur naturally.3

Mesothelioma is typically diagnosed when the disease has already reached an advanced stage, meaning that most patients have a poor prognosis: in one large study of patients with malignant pleural mesothelioma, median survival was 7 months.4 Survival rates in malignant pleural mesothelioma are higher in women than in men4,5 and in patients who are diagnosed at a younger age or with early-stage disease.4 Because mesothelioma is a rare cancer, it has been difficult to identify optimal therapeutic strategies.4

Mesothelioma is a rare cancer, with incidence rates typically under 4 cases per 100,000 people. For example, the incidence rates of malignant pleural mesothelioma in the United Kingdom, France and the Netherlands are 3.4 per 100,000, 2.3 per 100,000 and 3.2 per 100,000, respectively.6

In many countries, the incidence of mesothelioma has been difficult to determine, owing to insufficient data and the fact that it is a difficult cancer to diagnose, even if histological evaluation is carried out.7 More comprehensive and recent data are available from many European countries, as well as Australia, South Africa and the United States.7 In general, the incidence of mesothelioma has increased as the effects of past exposure to asbestos have become evident; the time lag between asbestos exposure and clinical presentation can be decades.4,6

The incidence of asbestos-related disease, including mesothelioma, is expected to reach its peak in countries in which handling and importing asbestos is tightly regulated or banned (e.g. the US, where incidence is levelling off, and Europe).3,8,9 However, commercial asbestos use continues in other countries (e.g. India, Russia, China)3 and so the incidence of mesothelioma is not expected to attenuate in those regions.3,7

In line with being caused by exposure to asbestos use, incidence of mesothelioma has been reported to be up to five times higher in men than in women.2,9 It is also most often diagnosed in patients ≥65 years old.2

The main risk factor for mesothelioma is exposure to asbestos, which accounts for over 80% of cases of malignant pleural mesothelioma.6 People who have typically been exposed to commercial materials made or contaminated with asbestos include construction and engineering workers, shipbuilders, and insulators.2,3,7 Their families may also be at risk, either because they lived close to sites at which asbestos is used, or because the workers’ clothing contaminated their living environments.3,11

The term ‘asbestos’ includes six types of minerals that form fibres and are used commercially: the fibrous amphiboles cummingtonite–grunerite, actinolite, anthophyllite, riebeckite and tremolite, and the serpentine mineral chrysotile.3 Exposure to other elongated mineral particles that occur naturally and are not categorised as ‘asbestos’, such as erionite, winchite and richterite, have also been associated with mesothelioma.3 The exact pathogenesis by which asbestos gives rise to mesothelioma has not been fully elucidated, but inhaled asbestos fibres enter the pleura and the pleural space and cause chronic inflammation, DNA damage and cytotoxicity.11

Other environmental or lifestyle risk factors for mesothelioma include ionising radiation.8 Cigarette smoking is a risk factor for lung cancer when combined with exposure to asbestos.8,11 In terms of genetic risk factors, mutations in the BAP1 gene are associated with an increased susceptibility to mesothelioma.3,10

Patients with pleural mesothelioma typically present with symptoms that include shortness of breath, chest pain, pleural effusion, a mass in the chest wall, fatigue, insomnia, cough, and loss of weight and appetite.6,8 Symptoms may have developed over the course of many months6, and patients typically have a high symptom burden when they seek medical advice, compared with patients who have other types of cancer.8

An important part of any diagnostic procedure is the acquisition of a detailed occupational history to determine whether the patient may have been exposed to asbestos.6,8

Further diagnostic work-up of malignant pleural mesothelioma usually includes a chest X-ray,6 a contrast computed tomography scan of the chest and upper abdomen, and thoracentesis, with cytogenetic examination of the effusion.6,8 Examination of pleural fluid is especially important in diagnosing mesothelioma, as a definitive diagnosis cannot be reached using clinical features alone.6 However, cytological evaluation of pleural fluid is often negative or inconclusive even in patients with the disease.8

Laboratory blood tests should also be done,6 and some guidelines recommend carrying out a thoracoscopic biopsy.8 There are currently no tumour markers that facilitate identification of malignant pleural mesothelioma. Instead, certain immunohistochemical markers in effusion samples and/or tissue biopsies can be used to differentiate malignant mesothelioma from benign pleural disease and from other malignancies.6,8

Malignant pleural mesothelioma is heterogeneous and comprises three main subtypes: epithelioid, sarcomatoid, and biphasic/mixed.6 Epithelioid mesothelioma is the most common subtype, and has been associated with better outcomes than the other subtypes.8 The sarcomatoid subtype appears to be associated with a lower response rate to systemic therapy11 and a lower survival rate than the epithelioid subtype.12

Cytological analyses of effusion samples are often inconclusive or negative, even in patients with malignant mesothelioma.8 Making a definitive primary diagnosis usually requires immunohistochemical evaluation of effusion samples and/or tissue biopsies, using at least two ‘mesothelial’ markers and at least two ‘(adeno)carcinoma’ markers.6.13 The sarcomatoid subtype is even more difficult to identify, as it may not exhibit typical ‘mesothelial’ markers.6

Currently, there are a lack of accurate biomarkers to aid the diagnosis, prognosis and treatment of malignant pleural mesothelioma.13 Assessment of mesothelin in serum and pleural fluid has high specificity and low sensitivity.13 A combination of immunohistochemical markers can be used to diagnose epithelioid and biphasic types of mesothelioma; however, there is no specific marker for the sarcomatoid subtype.6,13

With regard to screening, there is no validated blood biomarker that can be used to screen people who have been exposed to asbestos for mesothelioma.6,13

Next-generation sequencing has been used to gain a better understanding of the genetic landscape of malignant pleural mesothelioma, in order to try and identify genetic markers that may inform treatment decisions in future and facilitate the use of tailored therapy. In one such study, analysis of data from 23 patients with malignant pleural mesothelioma showed that the most common gene alterations or losses were in the BAP1 (60.9%), CDKN2A/B (52.2%), and NF2 (34.8%) genes.14

Surgery is performed for the purposes of staging, and can also be carried out with curative intent in patients where a macroscopic complete resection is possible.6,8 For patients with unresectable pleural mesothelioma, or patients who are eligible for multimodality treatment, cisplatin-based doublet chemotherapy is recommended. Combination with pemetrexed is considered the standard of care by both the National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) guidelines;6,8 the ESMO guidelines also list raltitrexed as a potential combination option.6 As yet, there is no standard of care for the second-line treatment of these patients, although studies of single-agent chemotherapy and novel agents are ongoing.

The role of radiation therapy in the treatment of patients with mesothelioma has yet to be fully established. Although it can be used for palliation, it is not part of standard treatment in the adjuvant setting.6,8

In terms of emerging treatment options, a number of agents targeting angiogenesis, proliferative signalling or the immune response to tumours have been investigated in the clinic. So far, this has not seen any major advances in treatment. However, many studies are ongoing, as is research to identify and validate appropriate tumour biomarkers.15 No targeted agents are included in current clinical guidelines for the treatment of pleural mesothelioma.6,8

References: 
  1. Rudd RM. Malignant mesothelioma. Br Med Bull 2010;93:105–123.
  2. Cancer Research UK. Mesothelioma statistics. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/mesothelioma/incidence (Accessed October 2016).
  3. Carbone M, Kanodia S, Chao A, et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma. J Thorac Oncol 2016;11(8):1246–1262.
  4. Taioli E, Wolf AS, Camacho-Rivera M, et al. Determinants of Survival in Malignant Pleural Mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) Study of 14,228 Patients. PLoS One 2015;10(12):e0145039.
  5. Taioli E. Wolf AS, Camacho-Rivera M, et al. Women with malignant pleural mesothelioma have a threefold better survival rate than men. Ann Thorac Surg 2014;98(3):1020–1024.
  6. Baas P, Fennel D, Kerr KM, et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2015. 31(26):p.28.
  7. Bianchi C and Bianchi T. Global mesothelioma epidemic: Trend and features. Indian J Occup Environ Med 2014;18(2):82–88.
  8. NCCN Guidelines for Malignant Pleural Mesothelioma: Version 2.2016. Available from: https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf (Accessed October 2016).
  9. Robinson BM. Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg 2012;1(4):491–496.
  10. Roe OD. and Stella GM. Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic. Eur Respir Rev 2015;24(135):115–131.
  11. Mansfield AS, Symanowski JT, and Peikert T. Systematic review of response rates of sarcomatoid malignant pleural mesotheliomas in clinical trials. Lung Cancer 2014;86(2):133–136.
  12. van der Bij S, Koffijberg H, Burgers JA, et al. Prognosis and prognostic factors of patients with mesothelioma: a population-based study. Br J Cancer 2012;107(1):161–164.
  13. Panou V, Vyberg M, Weinreich UM, et al. The established and future biomarkers of malignant pleural mesothelioma. Cancer Treat Rev 2015;41(6):486–495.
  14. Kato S, Tomson BN, Buys TPH, et al. Genomic Landscape of Malignant Mesotheliomas. Mol Cancer Ther 2016;15(10):2498–2507.
  15. Hiddinga BI, Rolfo C, and van Meerbeeck JP. Mesothelioma treatment: Are we on target? A review. J Adv Res 2015;6(3):319–330.
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