DEFINITION
Pleural mesothelioma is a rare cancer often diagnosed in people who have been exposed to high levels of asbestos. The malignancy affects the pleura, a thin membrane of lubricating cells that lines the lungs and chest wall. It sometimes takes 10 years or more for changes to appear that are indicative of pleural disease, and even long for symptoms to manifest. These differences can include a thickening or calcification of the pleural lining, a condition commonly diagnosed as pleural plaques. Conditions like pleural calcification or the development of pleural plaques often serve as pre-cursor to mesothelioma.
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Pleural mesothelioma originates in the pleura but can quickly spread to the outer chest wall, abdomen, and heart. Pleural mesothelioma is typically fatal within 1 year of diagnosis. However, understanding and recognizing key risk factors, like asbestos exposure, will typically lead to early detection of the cancer. Those who are fortunate to receive an early diagnosis are likely to be more eligible for life-sustaining treatments such as surgical resection of the cancer. This type of treatment can extend a patient’s life years beyond that of a typical mesothelioma patient.
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ETIOLOGY
Cancers, including mesotheliomas, occur when cells in the body suffer damage to their DNA. DNA is the chemical in each of our cells that makes up our genes – the instructions for how our cells function. We usually look like our parents because they are the source of our DNA. But DNA affects more than how we look. Some genes have instructions for controlling when cells in the body grow and divide into new cells. Changes in these genes may cause cells to grow out of control, which can lead to cancer.
Asbestos exposure is the main cause of mesothelioma. After these fibers are breathed in, they travel to the ends of small air passages and reach the pleura, where they can damage mesothelial cells. This leads to inflammation and scarring. But most people exposed to asbestos, even in large amounts, do not get mesothelioma.Other factors, such as a person’s genes, may make them more likely to develop mesothelioma when exposed to asbestos.
References: Malignant mesothelioma detailed guide,NY: Springer; 2010
ASBESTOS : is a group of minerals that occur naturally as bundles of fibers. These fibers, found in soil and rocks in many parts of the world, are made of silicon, oxygen, and other elements. There are 2 main types of asbestos fibers:
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• Serpentine asbestos fibers are curly. The most common asbestos in industrial use, known as chrysotile, or white asbestos, has curly fibers.
• Amphibole asbestos fibers are straight and needle-like. There are several types of amphibole fibers, including amosite, crocidolite, tremolite, actinolite, and anthophyllite.
Amphiboles (particularly crocidolite) are considered to be more likely to cause cancer, but even the more commonly used chrysotile fibers have been linked to cancer.
Asbestos fibers are strong, resistant to heat and to many chemicals, and do not conduct electricity. Since the industrial revolution, asbestos has been used to insulate factories, schools, homes, and ships, and to make automobile brake and clutch parts, roofing shingles, ceiling and floor tiles, cement, textiles, and hundreds of other products.
People are exposed to asbestos mainly by inhaling fibers in the air they breathe. This may occur during mining and processing asbestos, making asbestos-containing products, or installing asbestos insulation. It may also occur when older buildings are demolished or renovated, or when older asbestos-containing materials begin to break down. In any of these situations, asbestos fibers tend to create a dust composed of tiny particles that can float in the air.
Inhalation of asbestos fibers has been linked to an increased risk of lung cancer in many studies of asbestos-exposed workers. In general, the greater the exposure to asbestos, the higher the risk of lung cancer. Most cases of lung cancer in asbestos workers occur at least 15 years after initial exposure to asbestos.
Studies have also linked workplace exposure to asbestos with cancers of the larynx (voice box) and ovaries.
Asbestos,American Cancer Society
Molecular Pathways and Biochemistry
•What can asbestos cause?
We have observed that in three human malignant mesothelioma cell lines, crocidolite asbestos induced the activation of the transcription factor NF-kappaB and the synthesis of nitric oxide (NO) by inhibiting the RhoA signaling pathway. The incubation with crocidolite decreased the level of GTP-bound RhoA and the activity of Rho-dependent kinase, and induced the activation of Akt/PKB and IkBalpha kinase, leading to the nuclear translocation of NF-kappaB.
This suggests that crocidolite fibers might inhibit the synthesis of isoprenoid molecules at the level of the HMGCoA reductase reaction or of an upstream step, thus impairing the prenylation and subsequent activation of RhoA. Akt can stimulate NO synthesis via a double mechanism: it can activate the inducible NO synthase via the NF-kappaB pathway and the endothelial NO synthase via a direct phosphorylation. Our results suggest that crocidolite increases the NO levels in mesothelioma cells by modulating both NO synthase isoforms.
Asbestos induces nitric oxide synthesis in mesothelioma cells via Rho signaling inhibition.Torino,2006
•The Role of HIF:
HIF
Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibre deposition in the lung may cause hypoxia and iron chelation at the fibre surface. Hypoxia-inducible factor (HIF)-1alpha, which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. The present study aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1alpha and an increased expression of Pgp. After 24-h incubation with crocidolite asbestos or with the iron chelator dexrazoxane, or under hypoxia, HMM cells were tested for HIF-1alpha activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect. Crocidolite, dexrazoxane and hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity.
Asbestos induces doxorubicin resistance in MM98 mesothelioma cells via HIF-1alpha,Torino,2008
•What happens with statins and doxorubicin?
Doxorubicin
Statin
Human malignant mesothelioma (HMM) is resistant to many anticancer drugs, including doxorubicin. Mevastatin and simvastatin, 2 inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, potentiated the intracellular accumulation and the cytotoxicity of doxorubicin in HMM cells constitutively expressing P-glycoprotein and multidrug resistance-associated protein 3. This effect of statins was nitric oxide (NO)-dependent, since it was reverted by either an NO synthase inhibitor or an NO scavenging system.All statins' effects were reverted by mevalonic acid, thus suggesting that they were mediated by the inhibition of HMGCoA reductase and were likely to be subsequent to the reduced availability of precursor molecules for RhoA.Both the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B (from Clostridium difficile) mimicked the statins' effects, enhancing doxorubicin accumulation.Simvastatin, Y27632 and toxin B elicited tyrosine nitration in the P-glycoprotein, thus providing a likely mechanism by which NO reverts the doxorubicin resistance in HMM cells.
Statins revert doxorubicin resistance via nitric oxide in malignant mesothelioma,Torino,Luglio 2006
Cancer Pathways
Malignant pleural mesothelioma, although uncommon, is highly lethal. There is a high correlation between associated environmental exposure factors, carcinogens, and its development. Carcinogenesis is also mediated by genetic defects that result in loss of tumor suppressors or over expression of proto-oncogenes. Factors such as the loss of CDK inhibition function, IGF stimulatory pathways, p14(ARF), p15(INK4b), p16(INK4a), p21, and p53 loss or mutation, VEGF and COX over expression are discussed. Correlations to potential therapeutic modalities are made.
Molecular pathways in malignant pleural mesothelioma,Epub 2005 Oct 10
somother factors that increase a person's risk of mesotelioma:
• Zeolites
• Radiation
• SV40 virus
• Age
• Gender
SYMPTOMATOLOGY
Early symptoms of mesothelioma are not specific to the disease, so at first people may ignore them or mistake them for common, minor ailments. Most people with mesothelioma have symptoms for at least a few months before they are diagnosed. Symptoms of pleural mesothelioma can include:
• Pain in the lower back or at the side of the chest
• Shortness of breath
• Cough
• Fever
• Sweating
• Fatigue
• Weight loss
• Trouble swallowing
• Hoarseness
• Swelling of the face and arms
DIAGNOSIS
Malignant pleural mesothelioma: Diagnosis and treatment,2013 Jan 14
Clinical signs are most of the time late and unspecific. Chest CT-scan, a key imaging procedure, usually shows a (unilateral) pleurisy associated with pleural nodular thickening. PET-scan associated with CT-scan may help to differenciate MPM from pleural benign tumors but it is not recommended for the diagnosis of MPM, as well as chest resonance magnetic imaging and blood or pleural fluid biomarkers, including soluble mesothelin still under investigation. The diagnosis of MPM is based on histology using essentially immunohistochemistry on pleural biopsies best obtained by thoracoscopy.
During its relative short course, this malignant neoplasm,Pleural Mesothelioma, can give local and, rarely, distant haematogenous metastases in different organs.
TREATMENT
Treatment of Mesothelioma
Doctors are constantly trying to improve on current approaches. The exact roles of surgery, radiation therapy, and chemotherapy in the treatment of mesothelioma are highly debated. Combinations of these treatments, called multimodality therapy, are now being tested and may provide the most promising option for some patients. Newer types of treatment now being studied may give patients and their doctors even more options.
Pleural Mesothelioma Chemotherapy
Mesothelioma remains a difficult cancer to treat, and doctors are constantly trying to
improve on current approaches. The exact roles of surgery, radiation therapy, and
chemotherapy in the treatment of mesothelioma are highly debated. Combinations of
these treatments, called multimodality therapy, are now being tested and may provide the
most promising option for some patients. Newer types of treatment now being studied
may give patients and their doctors even more options.
Pleural Mesothelioma Radiation
Radiation therapy can be used to shrink cancerous tumors, ease pain or prevent the recurrence of mesothelioma. It is often used in conjunction with another treatment such as surgery or chemotherapy and it's not recommended for single use because the radiation dose needed to be effective is too toxic for nearby normal tissue. While more than 50 percent of pleural mesothelioma patients experience positive results after receiving radiation therapy, it should be noted that these results are seen when radiation is used after surgery.
Multimodal Therapy
Multimodal therapy has become one of the most successful treatment approaches for pleural mesothelioma. This method combines two or more treatments, typically involving surgery, chemotherapy or radiation therapy. The stage and overall health of the patient will determine whether multimodal therapy is a valuable treatment option .
Some common treatment combinations for pleural mesothelioma include:
• Surgery followed by chemotherapy
• Surgery with radiation therapy before or after the surgery
• Radiation therapy and chemotherapy
• Radiation therapy before surgery, followed by chemotherapy
Surgery
Surgery for malignant pleural mesothelioma,2010 Jun
The role of surgery for malignant pleural mesothelioma encompasses the need for rapid diagnosis, preoperative staging and surgical resection, and also the need for a greater biological understanding of this rare and aggressive malignancy. In the multimodality treatment paradigm, the goal of surgery is to provide a macroscopic complete resection (i.e., complete removal of all grossly visible tumor). Two operations have evolved: extrapleural pneumonectomy and pleurectomy/decortication. The former is indicated for patients with advanced locally invasive disease; the latter for patients with more superficial spread of tumor that spares the lung and fissures. If critical mediastinal structures (e.g., aorta and vertebral bodies) are found to be involved at thoracotomy, the tumor is classified as T4, and pleurectomy/decortication is recommended. Despite having more advanced disease, a subset of patients with favorable prognostic factors can experience extended survival by undergoing trimodality therapy with extrapleural pneumonectomy, chemotherapy and/or radiation. The influence of surgery goes beyond diagnosis and resection.
Two operations have evolved for the surgical treatment of malignant pleural mesothelioma (MPM): extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). The goal of surgery in the multimodality treatment approach is to achieve a macroscopic complete resection, with adjuvant therapies directed at residual microscopic disease. Overall survival reported in a recent multicenter analysis of these two operations supports the use of P/D for early stage MPM provided that a complete resection is feasible; otherwise EPP will confer a survival advantage. For stage II disease, however, EPP demonstrates a possible advantage. The focus in stage III disease should remain on the ability to achieve macroscopic complete resection, rather than N2 disease. Patients with stage IV cancers have better survival if the lung is left in place.
DRUGS
• Cisplatin
• Pemetrexed
• Raltitrexed
In general, chemotherapy drugs are limited in their effectiveness against mesothelioma. As researchers have learned more about the changes in cells that cause cancer, they have been able to develop newer drugs that specifically target these changes. Targeted drugs work differently from standard chemotherapy drugs. They may sometimes work when chemotherapy drugs do not, and they often have different (and less severe) side effects. One group of targeted drugs is known as angiogenesis inhibitors. These drugs slow the growth of new blood vessels (angiogenesis), which tumors need to grow larger. Some of these drugs are already used to treat other types of cancer and are now being studied for use against mesotheliomas.
A newer type of treatment being tested on mesothelioma is gene therapy , which attempts to add new genes to cancer cells to make them easier to kill. One approach to gene therapy uses special viruses that have been modified in the lab. The virus is injected into the pleural space and infects the mesothelioma cells. When this infection occurs, the virus injects the desired gene into the cells.
Other new treatments called cancer vaccines are also aimed at getting the immune system to attack the cancer. In one approach, immune cells are removed from a patient’s blood and treated in the lab to get them to react to tumor cells. The immune cells are then given back to the patient as blood transfusions, where it is hoped they will cause the body’s immune system to attack the cancer. This approach is now being studied in clinical trials.
