Malignant mesothelioma causes
If you’ve started at the beginning of Meso Information, you’ve read the post what is mesothelioma. Naturally, you may be now wondering how this disease is contracted. That question is pretty involved, but it starts with asbestos.
Asbestos and Mesothelioma
Mesothelioma is officially recognized as an occupational cancer and as a signal disease for occupational asbestos exposure. Its incidence among occupationally exposed persons is more than 40 times as high. Pleural mesotheliomas have been undeniably demonstrated to be linked to exposure to asbestos.
The World Health Organization (WHO) has recognised asbestos as one of the most significant occupational carcinogens. All types of asbestos are known to cause inflammatory changes to the lung and pleurae. However, there is experimental and epidemiologic evidence to suggest that the maximum threat (from the different asbestos types) to produce disease is due to crocidolite; chrysotile, the least; with amosite occupying an intermediate position.
Though asbestos has been strongly associated with the development of malignant mesothelioma (MM), the accurate pathogenesis is yet to be established. MM is characterized by chronic inflammation, which is believed to play an intrinsic role in the origin of this disease.
Asbestos activates the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in a protracted manner, leading to an up-regulation of IL-1β and IL-18 production in human mesothelial cells. Combined with biopersistence of asbestos fibers, presumably this creates an environment of chronic IL-1β signalling in human mesothelial cells, which may promote mesothelial to fibroblastic transition (MFT) in an NLRP3-dependent manner. Taken together, there is data to suggest that asbestos induces mesothelial to fibroblastic transition in an inflammasome-dependent manner[i].
Malignant mesothelioma causes – occupational hazards: Malignant mesothelioma is a neoplasm aggressively linked with occupational and environmental inhalation exposure to asbestos fibres and other elongated mineral particles (EMPs).
The survival rate varies from 6 months to a year from the time of diagnosis. Patients have a median survival of approximately 1 year from the time of diagnosis. The interval period from first causative exposure to malignant mesothelioma development typically ranges from 20 to 40 years but can be as long as 71 years.
Hazardous occupational exposures to asbestos fibres and other EMPs have occurred in a variety of industrial operations, including mining and milling, manufacturing, shipbuilding and repair, and construction. Exposures to commercial asbestos occur predominantly during maintenance operations and remediation of older buildings containing asbestos.
An inverse relationship exists between intensity of asbestos exposure and length of the latency period.
Malignant mesothelioma causes – environmental exposures: An increased risk is also associated with increased exposure to asbestos in water (in some municipalities) where asbestos occurs naturally, in cities where there is an interaction between aggressive water and asbestos-cement pipe, or in cities whose water may be contaminated as a result of asbestos operations[ii].
An inverse relationship exists between intensity of asbestos exposure and length of the latency period. Mesothelioma generally develops after long-time exposures to asbestos. Some recent studies show that the risk increases with the duration of exposure. Asbestos can gain entry in body via gastrointestinal and respiratory tract exposure and it is then distributed to most organs via the blood or lymphatic systems.
Malignant mesothelioma causes – asbestos in buildings: Domestic exposure has been associated with household repairs, do-it yourself construction using products containing asbestos when disturbing products containing asbestos or faulty removal of construction elements that contain asbestos from old buildings[iii].
Malignant mesothelioma causes – secondary exposure: Non-occupationally exposure in persons living near sources of asbestos and familial exposures have occurred when the worker did not shower or wore the same clothes home that had been worn during work. Aside from occupational exposure, persons can be exposed to asbestos in any of the following ways:
- Private activities
- Proximity to factories where asbestos is used
- Living in areas where asbestos occurs naturally.
Talc can be contaminated with asbestos and is often used in the following products: cosmetics spray and dusting powder, insecticides, white shoe polishes, as a filler for soap, dusting powders for toy balloons, condoms, and contraceptive diaphragms[iv].
Malignant mesothelioma causes other than asbestos:
Diagnostic delays of up to six months are common.
Genetic disposition – An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop mesothelioma.
Germ line mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma[v]. Other genes are also hypothesized which are involved in hereditary cancer syndromes that could be responsible for the inherited mesothelioma predisposition. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair.
Patients carrying PTVs showed lower asbestos exposure than did all the other patients signifying that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. Germ line variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.
Simian virus 40 (a polyomavirus) may be associated with developing malignant pleural mesothelioma[vi]. Simian virus 40 (SV40) is a DNA virus isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas, lymphomas, brain and bone tumours, and sarcomas[vii].
These same tumour types have been found to contain SV40 DNA and proteins in humans. Mesotheliomas and brain tumours are the two tumour types that have been most consistently associated with SV40, and the range of positivity has varied about from 6 to 60%.
Because of the varied symptomatology and non-specific manifestations, diagnosing mesothelioma is difficult.
Diagnostic delays of up to six months are common.
Dyspnoea is the first symptom of pleural mesothelioma in 90% of cases. Pain may occur in pleural mesothelioma due to irritation of the intercostal nerves or by infiltration into the chest wall. Rarer manifestations include phrenic nerve palsy, irritative cough, paraneoplastic phenomena, and spontaneous pneumothorax. Symptomatic metastases are unusual.
The diagnosis of mesothelioma should be considered in any patient with a unilateral pleural effusion or thickening – especially if chest pain is present.
The diagnostic process for pleural mesothelioma incorporates numerous tests and requires the close cooperation of a diverse team of medical experts. A well-coordinated team comprising of radiologists, surgeons, oncologists, pathologists, pulmonologists and others can help reach the diagnosis of mesothelioma sooner. These additional specialists can be necessary because this form of cancer is so challenging to diagnose, even for highly qualified oncologists.
Symptoms rarely appear until the disease has entered its later stages, and even then they are hard to distinguish from the signs of more common respiratory illnesses. Often the symptoms are experienced at a very later stage in pleural mesothelioma.
Tests for mesothelioma
While imaging tests and tissue biopsies are the most common methods for diagnosing mesothelioma, blood tests can also help doctors identify the disease. These blood tests look for certain indicators of disease, known as biomarkers, in a patient’s blood.
The MESOMARK assay measures the quantity of SMRP in a patient’s blood serum. An assay is a test performed in a lab. Abnormally high SMRP levels may indicate the presence of mesothelioma, sometimes years before an asbestos-related cancer diagnosis is made[viii].
Non-invasive tests such as ultrasonography, computerized tomography (CT), and magnetic resonance imaging (MRI) can be used to obtain further support for the suspected diagnosis and assess the extent of disease. The diagnosis can only be definitively established by biopsy.
Thoracoscopy is the main stay in diagnosing mesothelioma, as it allows multiple biopsies with histological subtyping which is indicated for staging purposes in surgical candidates. The recommended and recently updated classification for clinical use is the TNM staging system established by the International Mesothelioma Interest Group and the International Association for the Study of Lung Cancer, which is based mainly on surgical and pathological variables, as well as on cross-sectional imaging. Contrast-enhanced computed tomography is the primary imaging procedure. Currently, the most used measurement system for MPM is the modified Response Evaluation Criteria in Solid Tumours (RECIST) method, which is based on one-dimensional measurements of tumour thickness perpendicular to the chest wall or mediastinum[ix].
VATS – Video – assisted thoracic surgery or Thoracoscopy is the most reliable and highly-recommended biopsy technique for diagnosing pleural mesothelioma. In this procedure, doctors put patients under general anesthesia before making one or two small incisions in the chest. The surgeon views the tumor through a camera fitted to the scope and collects the sample .
VATS can correctly identify patients with pleural mesothelioma with a sensitivity of 95 to 98 percent, and the procedure usually takes less than an hour. The recovery time with VATS is also significantly less than open surgical biopsy. In most patients, thoracoscopy allows complete visualization of the pleural cavity and provides high-quality biopsy samples. The diagnostic accuracy of thoracoscopy is similar to open thoracotomy, but the procedure is far less invasive, usually requiring that the patient remain in the hospital only one day[x].
Magnetic resonance imaging and functional imaging with F-fluoro-2-deoxy-D-glucose positron-emission tomography can provide additional staging information in selected cases, although the usefulness of this method is limited in patients undergoing pleurodesis.
Molecular reclassification of MPM and gene expression or miRNA prognostic models have the potential to improve prognostication and patient selection for a proper treatment algorithm; however, they await prospective validation to be introduced in clinical practice.
Transthoracic ultrasonography enables an assessment of the pleura in the presence of a pleural effusion; it is the best available means of visual guidance for pleural puncture. In addition, abdominal ultrasonography, bone scintigraphy, and sometimes MRI of the head may be needed to rule out distant metastases.
CT aids in judging the extent of tumour and to detect lymph node metastases.
MRI is the best way to determine whether the tumour has invaded the diaphragm or the chest wall.
Mesothelioma is staged on the basis of the histopathological and intraoperative findings along with the results of clinical staging tests. This scan is generally better for detecting metastasis of pleural mesothelioma to the diaphragm or mediastinum.
MRI is preferred prior to surgery.
An MRI scan can show whether the cancer has spread locally throughout the chest, which helps distinguish between stages I through III. A PET-CT scan is especially helpful at showing spread to distant organs, which can help determine if the cancer is in stage IV yet. To this end, imaging scans are crucial to reaching a prognosis because staging is the biggest determinant of prognosis.
Positron emission tomography (PET) is now coming into wider use; its main advantage is greater sensitivity for the detection of distant metastases
Thoracentesis – The sensitivity of this technique is less than 50 percent for pleural mesothelioma, meaning it accurately identifies patients with the disease less than half the time. Tumour cells are found in pleural effusion fluid in more than 50% of cases of pleural mesotheliomas, with the likelihood of positive cytology depending on the tumour subtype. Cytological abnormalities are found in both reactive and malignant processes, and negative cytology does not rule out mesothelioma.
Now that you’ve read the article on malignant mesothelioma causes, the next post in the Meso Information series is mesothelioma treatment options. Check it out to read about treatments options for those who have been diagnosed with mesothelioma.
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[i] Thompson JK, MacPherson MB, Beuschel SL, Shukla A. Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome. Am J Pathol. 2017 Mar;187(3):665-678. doi: 10.1016/j.ajpath.2016.11.008. Epub 2017 Jan 3. PubMed PMID: 28056339; PubMed Central PMCID: PMC5389358.
[ii] [USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (1980) EPA 440/5-80-022]
[iii] [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]
[iv] [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty’s Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V1 507]
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[vii] Qi F, Carbone M, Yang H, Gaudino G. Simian virus 40 transformation, malignant mesothelioma and brain tumors. Expert Rev Respir Med. 2011 Oct;5(5):683-97. doi: 10.1586/ers.11.51. Review. PubMed PMID: 21955238; PubMed Central PMCID:PMC3241931.
[viii] Amati, M., Tomasetti, M., Scartozzi, M., Mariotti, L., Alleva, R., Pignotti, E., Santarelli, L. (2008). Profiling tumor-associated markers for early detection of malignant mesothelioma: An epidemiologic study. Cancer Epidemiology, Biomarkers & Prevention; 17(1):163-170. doi: 10.1158/1055-9965.EPI-07-0607
[ix] Bonomi M, De Filippis C, Lopci E, Gianoncelli L, Rizzardi G, Cerchiaro E,Bortolotti L, Zanello A, Ceresoli GL. Clinical staging of malignant pleuralmesothelioma: current perspectives. Lung Cancer (Auckl). 2017 Aug 18;8:127-139.doi: 10.2147/LCTT.S102113. eCollection 2017. Review. PubMed PMID: 28860886;PubMed Central PMCID: PMC5571821.
[x] Boutin, C., Rey, F. (1993). Thoracoscopy in pleural malignant mesothelioma: A prospective study of 188 consecutive patients. Part 1: Diagnosis. Cancer; 72 (2). Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2819930715%2972:2%3C389::AID-CNCR2820720213%3E3.0.CO;2-V/abstract