Mesothelioma  is a type of cancer that develops from the thin layer of tissue that covers many internal organs (known as mesothelium). [9]  The most frequently affected area is the lining of the lungs and chest wall. [1]  [3]  Less commonly the lining of the abdomen and rarely the sac surrounding the heart,  [10]  or the sac surrounding the testicle may be affected. [1]  [11]  Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. [1] These symptoms usually appear slowly. [2]

More than 80% of mesothelioma cases are caused by exposure to asbestos. [3]  The greater the exposure, the greater the risk. [3]  In 2013, about 125 million people were exposed to asbestos at work. [12]  High rates of illness occur in people who extract asbestos, make asbestos products, work with asbestos products, live with asbestos workers or work in buildings containing asbestos. [3]  Asbestos exposure and the onset of cancer are usually about 40 years apart. [3] Washing the clothes of someone who has worked with asbestos also increases the risk. [12]  Other risk factors include genetics and simian levirus infection 40. [3]  The diagnosis may be suspected on the basis of chest X – rays and CT scans, and is confirmed by examination of the fluid produced by the cancer or by a tissue biopsy of the cancer. [2]

Prevention centers aim to reduce exposure to asbestos. [4]  Treatment often includes surgery, radiation and chemotherapy. [5]  A procedure known as pleurodesis, which involves the use of substances such as talc to heal the pleura together, can be used to prevent more fluid from accumulating around the lungs. [5] Chemotherapy often includes cisplatin and pemetrexed medications. [2]  The percentage of people who survive five years after diagnosis averages 8% in the United States. [6]

In 2015, about 60,800 people had mesothelioma and 32,000 died of the disease. [7]  [8] Mesothelioma rates vary in different regions of the world. [3]  Rates are higher in Australia, the United Kingdom and lower in Japan. [3]  It occurs in about 3,000 people a year in the United States. [13]  It occurs more often in males than in females. [3]  Disease rates have increased since the 1950s.  [3]  Diagnosis typically occurs after the age of 65 and most deaths occur around 70 years of age. [3]  The disease was rare before the commercial use of asbestos. [3]

Signs and symptoms

Pleural mesothelioma

Symptoms or signs of mesothelioma may not appear for 20 to 50 years (or more) after exposure to asbestos. Shortness of breath, cough and chest pain due to fluid accumulation in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma. [14]

Mesothelioma that affects the pleura can cause these signs and symptoms:  [14]

  • Pain in the chest wall
  • Pleural effusion, or fluid surrounding the lung
  • breathlessness
  • Fatigue or anemia
  • Wheezing, hoarseness or coughing
  • Blood in sputum (fluid) spit (hemoptysis)

In severe cases, the person may have many tumor masses. The individual may develop pneumothorax or pulmonary collapse. The disease can metastasize, or spread to other parts of the body.

Peritoneal mesothelioma

The most common symptoms of peritoneal mesothelioma are abdominal swelling and ascitic pain (an accumulation of fluid in the abdominal cavity). Other features may include weight loss, fever, night sweats, lack of appetite, vomiting, constipation and umbilical hernia. [15]  If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, difficulty swallowing, or swelling of the neck or face. [  citation needed  ]  These symptoms can be caused by mesothelioma or other, less serious conditions.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:  [  citation needed  ]

  • Abdominal pain
  • Ascites, or abnormal accumulation of fluid in the abdomen
  • A mass in the abdomen
  • Problems with bowel function
  • Weightloss

Pericardial Mesothelioma

Pericardial mesothelioma is not well characterized, but the cases observed included cardiac symptoms, including constrictive pericarditis, heart failure, pulmonary embolism, and cardiac tamponade. They also included nonspecific symptoms, including sub-sternum chest pain, orthopnea (shortness of breath while lying down) and coughing. These symptoms are caused by the tumor surrounding or infiltrating the heart. [ten]

Mesothelioma in the terminal stage 

In severe cases of the disease, the following signs and symptoms may be present:  [  citation needed  ]

  • Blood clots in the veins, which can cause thrombophlebitis
  • Disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
  • Jaundice, or yellowing of the eyes and skin
  • Low blood sugar
  • Pleural effusion
  • Pulmonary embolism or blood clots in the arteries of the lungs
  • Severe ascites

If a mesothelioma forms metastases, these most often involve the liver, adrenal gland, kidney or other lungs. [16]

Cause

Working with asbestos is the most common risk factor for mesothelioma. [17]  However, mesothelioma has been reported in some individuals without any known exposure to asbestos.

Asbestos 

The incidence of mesothelioma has been shown to be higher in populations living near natural asbestos. People may be exposed to natural asbestos in areas where mining or road construction is in progress, or where rock containing asbestos is naturally altered. Another common route of exposure is asbestos-containing soil, which is used to launder plaster and roof houses in Greece. [12] In central Cappadocia, Turkey, mesothelioma was responsible for 50% of deaths in three small villages: Tuzköy, Karain and Sarıhıdır. Initially, this was attributed to erionite. Environmental exposure to asbestos has caused mesothelioma elsewhere than in Turkey, notably in Corsica, Greece, Cyprus, China and California. [12] [18]  [19]  In the Greek mountain town of Metsovo, this exposure caused mesothelioma incidence about 300 times more than expected in asbestos-free populations, and was associated with very frequent pleural calcification called “Metsovo Lung”. [20]  [21]

The documented presence of asbestos fibers in water supplies and food products has raised concerns about the potential impact of long-term and, to date, unknown exposure of the general population to these fibers. [  citation needed  ]

Talc exposure is also a risk factor for mesothelioma; exposure can affect those living near talc mines, working in talc mines or working in talc plants. [22]

In the United States, asbestos is considered to be the leading cause of malignant mesothelioma  [23]  and has been considered “indisputably”  [24]  associated with the development of mesothelioma. Indeed, the relationship between asbestos and mesothelioma is so strong that many consider mesothelioma as a “signal” or “sentinel” tumor. [25]  [26]  [27]  [28] There is a  history of asbestos exposure in most cases.

Pericardial mesothelioma may not be associated with asbestos exposure. [ten]

Asbestos was known in ancient times, but it was not mined and widely used commercially until the end of the 19th century. Its use increased considerably during the Second World War. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not known to the public. However, naval personnel (Navy, Marine Corps and Coast Guard), shipyard workers, persons working in mines and asbestos factories, asbestos producers, heating and construction workers are more likely to develop mesothelioma. industries, and other tradespeople. Today, not  are  not  adequate to prevent or protect asbestos related cancers such as mesothelioma. [29]  Similarly, the UK Government’s Health and Safety Executive (HSE) formally states that any threshold for exposure to asbestos must be at a very low level and it is widely accepted that if such a threshold exists, it does not can not currently be quantified. For practical reasons, HSE therefore assumes that there is no “safe” threshold. Others also noted that there is no evidence of a threshold below which there is no risk of mesothelioma.There appears to be a linear dose-response relationship, with an increasing dose producing an increasing risk of disease. [31] Nevertheless, mesothelioma may be related to brief, low level or indirect exposures to asbestos. [24]  The dose required for the effect appears to be lower for asbestos-induced mesothelioma than for pulmonary asbestosis or lung cancer. [24]  Again, there is no level of safe exposure to asbestos that is known about the increased risk of mesothelioma.

The time between the first exposure and the onset of illness is between 25 and 70 years. [32]  It is hardly ever less than fifteen years old and rises to 30-40 years. [24]  [33] The duration of exposure to asbestos causing mesothelioma can be short. For example, mesothelioma cases have been documented with only 1-3 months of exposure. [34]  [35]

Occupational 

Exposure to asbestos fibers has been recognized as a health hazard at work since the early twentieth century. Numerous epidemiological studies have linked occupational exposure to asbestos with pleural plaque development, diffuse pleural thickening, asbestosis, carcinoma of the lung and larynx, gastrointestinal tumors and diffuse malignant mesothelioma. pleura and peritoneum. Asbestos has been widely used in many industrial products, including cement, brake linings, gaskets, roofing shingles, flooring products, textiles and insulation. [36]

The commercial exploitation of asbestos in Wittenoom, Western Australia, took place from 1937 to 1966. The first case of mesothelioma in the city took place in 1960. The second case occurred in 1969 and new cases began to appear more frequently. The time between initial exposure to asbestos and the development of mesothelioma ranged from 12 years and 9 months to 58 years. [37]  A cohort study of miners employed at the mine reported that 85 mesothelioma deaths occurred in 1985. In 1994, 539 mesothelioma deaths were reported in Western Australia. [  citation needed  ]

Occupational exposure to asbestos in the United States occurs primarily when people maintain buildings that already contain asbestos. About 1.3 million American workers are exposed to asbestos each year; in 2002, about 44,000 miners were potentially exposed to asbestos. [22]

Para-Occupational Secondary Exposure 

Family members and others living with asbestos workers have an increased risk of developing mesothelioma and possibly other asbestos-related diseases. [11]  [38]  [39]  This risk may be the result of exposure to asbestos dust on workers’ clothing and hair by washing a worker’s clothing or coming into contact with clothing. contaminated with asbestos. [12]  [22]  To reduce the risk of exposure of asbestos fibers to family members, asbestos workers usually have to shower and change clothes before leaving the workplace.

Asbestos in buildings 

Many building materials used in public and domestic places before the asbestos ban can contain asbestos. Those who do renovations or do-it-yourself activities can be exposed to asbestos dust. In the United Kingdom, the use of chrysotile asbestos was banned at the end of 1999. Brown and blue asbestos was banned in the United Kingdom around 1985. Buildings constructed or renovated before these dates may contain containing asbestos. citation needed  ]

Genetic disposition

In a recent study of the American white population in 2012, it was found that people with a germline mutation in their BAP1 gene are at higher risk of developing mesothelioma and uveal melanoma. [40]

Erionite

Erionite is a zeolitic mineral with similar properties to asbestos and is known to cause mesothelioma. [11] The  detailed epidemiological study has shown that erionitis causes mesothelioma especially in families with a genetic predisposition. [12]  [18]  [19]  Erionite is found in deposits in the western United States, where it is used in gravel for road surfacing, and in Turkey, where it is used to build houses. In Turkey, the United States and Mexico, erionitis has been associated with mesothelioma and has been designated a “known human carcinogen” by the US National Toxicology Program. [19]

Other

In rare cases, mesothelioma has also been associated with irradiation of the chest or abdomen, intrapleural thorium (thorotrast) as a contrast agent and inhalation of other fibrous silicates, such as erionitis. or talc. [11]  [22]  Some studies suggest that Simian Virus 40 (SV40) may act as a cofactor in the development of mesothelioma. [22]  This has been confirmed in animal studies,  [41]  [42]  but studies in humans are inconclusive. [41]  [43]  [44]

Physiopathology

Diffuse pleural mesothelioma with extensive involvement of the pericardium.

Systemic

The mesothelium consists of a single layer of cuboid flattened cells forming the epithelial lining of the body’s serous cavities, including the peritoneal, pericardial and pleural cavities. The deposition of asbestos fibers into the parenchyma of the lung can result in penetration of the visceral pleura from which the fiber can then be transported to the surface of the pleura, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma are unresolved, although it has been proposed that asbestos fibers from the lungs are transported to the abdomen and associated organs via the lymphatic system. In addition, asbestos fibers can be deposited in the gut after ingesting sputum contaminated with asbestos fibers. [  citation needed  ]

Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long asbestos thin fibers (blue asbestos, amphibole fibers) are more potent carcinogens than “feathery” fibers (chrysotile or white asbestos fibers). [24]However, there is now evidence that smaller particles can be more dangerous than larger fibers. They remain suspended in the air where they can be inhaled, and can penetrate more easily and deeper into the lungs. “We will probably find much more about the health aspects of asbestos arising from [the World Trade Center attack], unfortunately,” said Dr. Alan Fein, Chief of Pulmonary and Critical Care of the Jewish Health System. from North Shore-Long Island. . [45]

The development of mesothelioma in rats has been demonstrated following in-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans the transport of fibers to the pleura is critical for the pathogenesis of mesothelioma. This is confirmed by the observed recruitment of a significant number of macrophages and other cells of the immune system to localized lesions of asbestos fibers accumulated in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion resulted in a morphologically malignant tumor. [  citation needed  ]

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in successive stages of initiation and promotion. The molecular mechanisms that underlie the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities (see next paragraph). However, the complete in vitro transformation of normal human mesothelial cells into a malignant phenotype after exposure to asbestos fibers has not yet been realized. In general, it is believed that asbestos fibers act through direct physical interactions with mesothelium cells together with indirect effects following interaction with inflammatory cells such as macrophages.

Intracellular  

Analysis of interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to come into contact with chromosomes, often adhering to chromatin fibers or getting entangled in the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the pin apparatus can induce complex anomalies. The most common anomaly is chromosome 22 monosomy. Other common abnormalities include the structural rearrangement of chromosome arms 1p, 3p, 9p and 6q.

Common gene abnormalities in mesothelioma cell lines include suppression of tumor suppressor genes:

  • Neurofibromatosis type 2 to 22q12
  • P16  INK4A  [46]
  • P14  ARF

Asbestos has also been shown to promote the penetration of foreign DNA into target cells. The incorporation of this foreign DNA can lead to mutations and oncogenesis by several possible mechanisms:

  • Inactivation of tumor suppressor genes
  • Activation of oncogenes
  • Activation of proto-oncogenes due to the incorporation of foreign DNA containing a promoter region
  • Activation of DNA repair enzymes, which may be prone to error
  • Activation of telomerase
  • Prevention of apoptosis

Several genes are commonly mutated in mesothelioma and may be prognostic factors. These include the epidermal growth factor receptor (EGFR) and C-Met receptor tyrosine kinases that are overexpressed in many mesotheliomas. An association was found with EGFR and epithelioid histology, but no clear association was found between EGFR overexpression and overall survival. The expression of the tyrosine kinase of the AXL receptor is a negative prognostic factor. The expression of PDGFRB is a positive prognostic factor. [47]  In general, mesothelioma is characterized by loss of function in tumor suppressor genes, rather than overexpression or gain of function in oncogenes. [48]

As an environmentally induced malignant tumor, mesothelioma tumors were found to be of polyclonal origin, by performing an X inactivation test on epithelial and biphasic tumors obtained in patients. [49]  These results suggest that an environmental factor, probably exposure to asbestos, can damage and transform a group of cells in the tissue, resulting in a population of tumor cells that, although slightly, genetically different. [  citation needed  ]

Immune system 

Asbestos fibers have been shown to alter the function and secretory properties of macrophages, creating favorable conditions for the development of mesothelioma. After asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal byproducts of anaerobic cell metabolism. However, these free radicals are also known to be clastogenic (chromosome breakage) and membrane active agents thought to promote asbestos carcinogenicity. These oxidants may participate in the oncogenic process by interacting directly and indirectly with DNA, modifying membrane-associated cellular events, including oncogene activation and disruption of cellular antioxidant defenses. [the citation needed  ]

Asbestos may also have immunosuppressive properties. For example, chrysotile fibers have been shown to reduce in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress lysis of natural killer cells, and significantly reduce the viability and recovery of lymphokine-activated killer cells. In addition, genetic alterations of asbestos-activated macrophages can result in the release of mitogens from potent mesothelial cells such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) that may induce chronic stimulation. proliferation of mesothelial cells after injury by asbestos fibers. [the citation needed  ]

Diagnosis 

CXR demonstrating mesothelioma

Comments: @ CT of a patient with mesothelioma, coronal cut (the cut follows the plane which divides the body into two parts: anterior part and a posterior part). Mesothelioma is indicated by yellow arrows, the pleuralcentral effusion (collection of liquid) is marked with a yellow star. Red numbers: (1) right lung, (2) spine, (3) left lung, (4) ribs, (5) descending part of the aorta, (6) spleen, (7) left kidney, (8) right kidney, (9) liver.

Micrograph of a specimen of cytopathology of pleural fluid showing mesothelioma.

The diagnosis of mesothelioma may be suspected with imaging but is confirmed by biopsy. It must be clinically and histologically differentiated from other pleural and pulmonary malignancies, including reactive pleural disease, primary pulmonary carcinoma, pleural metastasis from other cancers, and other primary pleural cancers. [11]  Primary pericardial mesothelioma is often diagnosed after it has metastasized to the lymph nodes or lungs. [ten]

Micrographs showing mesothelioma stained in a conventional way in a trocar biopsy (higher magnifications on the right).

Imaging

Diagnosing mesothelioma is often difficult because the symptoms are similar to those of a number of other conditions. The diagnosis begins with a review of the patient’s medical history. A history of asbestos exposure may increase clinical suspicion for mesothelioma. A physical examination is performed followed by a chest X – ray and often pulmonary function tests. Radiography may reveal pleural thickening commonly observed after exposure to asbestos and increases suspicion of mesothelioma. [14]  A CT (or CAT) scanner or MRI is usually performed. If a large amount of fluid is present, abnormal cells can be detected by cytopathology if this fluid is aspirated with a syringe. [10] For pleural fluid, this is done by thoracentesis or thoracostomy (chest tube); for ascites, with paracentesis or ascites drain; and for pericardial effusion with pericardiocentesis. If the absence of malignant cells in cytology does not completely exclude mesothelioma, it is much more unlikely, especially if an alternative diagnosis can be made (eg, tuberculosis, heart failure). citation needed  ]  However, with primary pericardial mesothelioma, the pericardial fluid may not contain malignant cells and a tissue biopsy is more useful in the diagnosis. [ten]The use of conventional cytological diagnosis of malignant mesothelioma is difficult, but immunohistochemistry has greatly improved the accuracy of cytology.

Biopsy

Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. A doctor takes a tissue sample for microscopic examination by a pathologist. A biopsy can be performed in different ways, depending on the location of the abnormal area. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut across the chest wall and puts a thin, illuminated tube called a thoracoscope in the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. Alternatively, the thoracic surgeon could open the chest directly (thoracotomy). If the cancer is in the abdomen, the doctor can perform a laparoscopy. To obtain the tissue to be examined, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not produce enough tissue, an open surgical procedure may be necessary.

Immunochemistry 

Immunohistochemical studies play an important role for the pathologist in the differentiation of malignant mesothelioma from neoplastic mimetics, such as breast or lung cancer metastasized to the pleura. There are many tests and panels available, but no single test is perfect for distinguishing mesothelioma from carcinoma or even benign or malignant cancer. Positive markers indicate that mesothelioma is present; if other markers are positive, it may indicate another type of cancer, such as breast or lung adenocarcinoma. Calretinin is a particularly important marker for distinguishing mesothelioma from breast cancer or metastatic lung cancer. [11]

Typical immunohistochemical results
Positive Negative
EMA (antigen of the epithelial membrane) in a membrane distribution CEA (carcinoembryonic antigen) [11]
WT1 (Wilms tumor 1)  [11] B72.3
Calretinine  [11] MOC-3 1
Mesothelin  [11] CD15
Cytokeratin 5  [11] Ber-EP4
HBME-1 (human mesothelial cell 1) TTF-1 (thyroid transcription factor-1)  [11]
Podoplanin (PDPN)  [11] Claudin-4  [11]
Osteopontin  [11] Epithelial cell adhesion molecule (EpCAM)  [11]
The alpha estrogen receptor  [11]
Mammaglobin  [11]

Subtypes

There are three main histological subtypes of malignant mesothelioma: epithelioid, sarcomatous and biphasic. Epithelioid and biphasic mesotheliomas account for approximately 75-95% of mesotheliomas and have been well characterized histologically, whereas mesothelioma mesothelioma has not been studied extensively. Most mesotheliomas express high levels of cytokeratin 5, regardless of the subtype. [11]

Epithelioid mesothelioma is characterized by high levels of calretinin. [11]

Sarcomatous mesothelioma does not express high levels of calretinin. [11]

Other morphological subtypes have been described:

  • desmoplastic
  • Delete the cell
  • Deciduoid
  • adenomatoid
  • Glandular
  • Mucohyaline
  • Cartilaginous and bone metaplasia
  • lymphohistiocytic

Differential diagnosis 

  • Metastatic adenocarcinoma
  • Pleural Sarcoma
  • Synovial sarcoma
  • thymoma
  • Metastatic renal cell carcinoma with clear cells
  • Metastatic osteosarcoma

Staging 

The staging of mesothelioma is based on the recommendation of the international interest group on mesothelioma. [50]  TNM classification of the primary tumor, lymph node involvement and distant metastasis is performed. Mesothelioma is staged Ia-IV (one-to-four) based on TNM status. [50]  [51]

Prevention  

Mesothelioma can be avoided in most cases by preventing exposure to asbestos. The US National Institute for Occupational Safety and Health maintains a recommended exposure limit of 0.1 asbestos fiber per cubic centimeter. [22]

Screening

There is no universally accepted protocol for screening people exposed to asbestos. Screening tests could diagnose mesothelioma earlier than conventional methods, improving the prospects for survival of patients. The level of serum osteopontin may be useful for screening mesothelioma in people exposed to asbestos. The level of soluble protein bound to mesothelin is elevated in the serum of approximately 75% of patients at the time of diagnosis and it has been suggested that it may be useful for screening. [52] Physicians began testing the Mesomark assay, which measures the levels of soluble mesothelin-bound proteins (SMRP) released by mesothelioma cells. [53]

Treatment

Mesothelioma is generally resistant to radiotherapy and chemotherapy treatments. Long-term survival and remedies are extremely rare. [11] The treatment of malignant mesothelioma at anterior stages has a better prognosis. The clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity that promotes local metastases via exfoliated cells, invasion of underlying tissues and other organs in the pleural cavity and the long latency period between asbestos exposure and development. of the disease. The histological subtype and the patient’s age and state of health can also predict prognosis. Epithelioid histology responds better to treatment and has a survival advantage over sarcomatoid histology. [54]

Surgery 

The surgery alone was disappointing. In a large series, median survival with surgery (including extrapleural pneumonectomy) was only 11.7 months. [55] However, the research indicates a varied success when used in combination with radiotherapy and chemotherapy (Duke, 2008), or with one of these. A pleurectomy / decortication is the most common surgery in which the lining of the breast is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, the lining of the interior of the chest, the hemi-diaphragm and the pericardium are removed. [  citation needed  ]In localized pericardial mesothelioma, pericardectomy can be curative; When the tumor is metastasized, pericardectomy is a palliative care option. The whole tumor is not often able to be removed. [ten]

Radiation 

For patients with localized disease, who can tolerate radical surgery, radiotherapy can be given post-operatively as a consolidation therapy. The entire hemithorax is treated with radiotherapy, often at the same time as chemotherapy. Radiation therapy and chemotherapy after radical surgery have prolonged the life expectancy of some patient populations. It can also induce serious side effects, including fatal pneumonia. [56]  As part of a curative approach to mesothelioma, radiation therapy is commonly applied to the sites of insertion of the chest tube, to prevent tumor growth along the track in the chest wall. citation needed ]

Although mesothelioma is generally resistant to curative treatment by radiotherapy alone, palliative treatments are sometimes used to relieve symptoms of tumor growth, such as obstruction of a major blood vessel. Radiation therapy, when administered alone with curative intent, has never shown any improvement in the survival of mesothelioma. The dose of radiation needed to treat mesothelioma that has not been removed surgically would be beyond human tolerance. [  citation needed  ]  Radiotherapy is of some use in pericardial mesothelioma. [ten]

Chemotherapy 

Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomized controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared chemotherapy with cisplatin alone with a combination of cisplatin and pemetrexed chemotherapy (Alimta) in patients who had never received chemotherapy for malignant pleural mesothelioma and were not candidates for more aggressive “curative” surgery. . [57] This trial was the first to report a survival advantage of chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median-survival from 10 months in patients treated with cisplatin alone at 13.3 months in the patients treated with cisplatin in combination with pemetrexed who also received folate and vitamin B 12 supplementation   . Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received 500mcg of oral folic acid per day and intramuscular vitamin B  121000mcg every 9 weeks compared to patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combined pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhea were more common in the pemetrexed combination group, but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; quality of life and lung function tests were improved in the combined pemetrexed group. In February 2004, the US Food and Drug Administration approved pemetrexed for the treatment of malignant pleural mesothelioma. However, [  citation needed  ]Cisplatin and pemetrexed together give a median survival of 12.1 months. [11]

Cisplatin in combination with raltitrexed has shown a survival improvement similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. In patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine alone, although a survival benefit has not been demonstrated for these drugs. For patients in whom cisplatin can not be used, carboplatin may be substituted, but non-randomized data showed lower response rates and higher rates of hematologic toxicity for carboplatin combinations, with similar survival rates in patients receiving cisplatin. [58]

In January 2009, the US FDA approved the use of conventional therapies such as radiotherapy and chemotherapy for stage I or II mesothelioma, following a study conducted by Duke University, which found an increase nearly 50 points in remission rates.

In pericardial mesothelioma, chemotherapy – typically adriamycin and / or cisplatin – is mainly used to shrink the tumor and is not curative. [ten]

Immunotherapy 

Treatment regimens involving immunotherapy have yielded varying results. For example, intrapleural inoculation of Bacillus Calmette-Guerin (BCG) to stimulate the immune response has been found to be of no interest to the patient (although it may be beneficial for patients with bladder cancer ). Mesothelioma cells were sensitive to in vitro lysis by LAK cells following activation with interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended due to the high unacceptable levels of IL-2 toxicity and the severity of side effects such as fever and cachexia.

Heated intraperitoneal chemotherapy intraoperatively 

This technique is used in conjunction with surgery,  [59]  including in patients with malignant pleural mesothelioma. [60]  The surgeon removes as much of the tumor as possible followed by direct administration of a chemotherapy agent, heated to 40-48 ° C, into the abdomen. The fluid is infused for 60 to 120 minutes and then drained. High concentrations of selected drugs are then administered on the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of drugs into the tissues. In addition, the heating itself damages the malignant cells more than normal cells.

The multimodality therapy 

All standard approaches to the treatment of solid tumors – radiotherapy, chemotherapy and surgery – have been studied in patients with malignant pleural mesothelioma. Although surgery is not very effective in itself, surgery combined with adjuvant chemotherapy and radiotherapy (trimodality therapy) produced a significant survival extension (3-14 years) in patients with prognostic factors. favorable. [61]  However, other large series of multimodal treatment trials demonstrated only modest improvement in survival (median survival 14.5 months and only 29.6% surviving 2 years). [55] Reducing tumor mass with cyto-reduction surgery is the key to prolong survival. Two surgeries were developed: extrapleural pneumonectomy and pleurectomy / decortication. The indications for performing these operations are unique. The choice of operation depends in particular on the size of the patient’s tumor. This is an important consideration because the tumor volume has been identified as a prognostic factor in mesothelioma. [62]  Pleurectomy / decortication spares the underlying lung and is performed in patients with early stage disease when the intention is to remove all visible macroscopic tumors (macroscopic complete resection), not just palliation. [63] Extrapleural pneumonectomy is a more extensive operation that involves the resection of the parietal and visceral pleura, underlying lung, ipsilateral (same side) diaphragm, and ipsilateral pericardial. This operation is indicated for a subgroup of patients with more advanced tumors who can tolerate a pneumonectomy. [64]

Prognosis

Mesothelioma often has a poor prognosis. Typical survival despite surgery is between 12 and 21 months depending on the stage of the disease at the time of diagnosis, with about 7.5% of people surviving for 5 years. [65]

Women, young people, people with early-stage cancers and people with epithelioid cancers have better prognoses. [11]  Negative prognostic factors include sarcomatoid or biphasic histology, elevated platelet count (over 400,000), age> 50 years, white blood cell count> 15.5, low levels of glucose in pleural fluid, low albumin levels and high levels of fibrinogen. Several markers are being studied as prognostic factors, including nuclear quality, and serum c-reactive protein. Long-term survival is rare. [47]

Pericardial mesothelioma has a median survival time of 10 months. [ten]

In peritoneal mesothelioma, high expression of the WT-1 protein indicates a poorer prognosis. [11]

Epidemiology 

Although reported incidence rates have increased over the last 20 years, mesothelioma remains a relatively rare cancer. The incidence rate varies from one country to another, from a rate of under 1 per 1,000,000 in Tunisia and Morocco, to the highest rate in Great Britain, Australia and Belgium: 30 for 1,000,000 a year. [66]  For comparison, populations with high rates of smoking may have a lung cancer incidence of more than 1,000 per 1,000,000. The incidence of malignant mesothelioma currently ranges from approximately 7 to 40 per 1,000. 000,000 in Western industrialized countries, depending on the amount of asbestos exposure of populations in recent decades. [67] The Worldwide incidence is estimated to be between 1 and 6 per 1,000,000.  [11] The incidence of mesothelioma is lower than that of asbestosis because of the longer time it takes to develop; Due to the discontinuation of asbestos use in developed countries, the incidence of mesothelioma is expected to decrease. [22]  Incidence is expected to continue to increase in developing countries due to continued use of asbestos. [11]  Mesothelioma occurs more often in men than women, and the risk increases with age, but it can occur in men or women at any age. About one-fifth to one-third of all mesotheliomas are peritoneal. [  citation needed ]  Less than 5% of mesotheliomas are pericardial. The prevalence of pericardial mesothelioma is less than 0.002%; it is more common in men than in women. It usually occurs in the 50s-70s of a person. [10]  [68]

Between 1940 and 1979, about 27.5 million people were occupationally exposed to asbestos in the United States. [69]  Between 1973 and 1984, the incidence of pleural mesothelioma in Caucasian men increased by 300%. From 1980 to the late 1990s, the mesothelioma mortality rate in the United States rose from 2,000 per year to 3,000, with men being four times more likely to acquire it than women. [  citation needed  ]  More than 80% of mesotheliomas are caused by asbestos exposure. [11]

The incidence of peritoneal mesothelioma is 0.5 to 3.0 per million per year in men and 0.2 to 2.0 per million per year in women. [70]

United Kingdom

Mesothelioma accounts for less than 1% of all cancers diagnosed in the UK (about 2,600 people were diagnosed in 2011) and the 17th leading cause of cancer death (about 2,400 people died in 2012). [71]

History 

The link between asbestos exposure and mesothelioma was discovered in the 1970s. In the United States, asbestos manufacturing ceased in 2002. Workers in textile asbestos plants, product manufacturing of friction, manufacture of cement pipes and insulation and installation to maintenance workers of buildings containing asbestos. [22]

Society and culture

Notable cases  

Mesothelioma, although rare, has had a number of notable patients:

  • Malcolm McLaren, musician and director of the band Punk Rock, Sex Pistols, was diagnosed with peritoneal mesothelioma in October 2009 and died on April 8, 2010 in Switzerland. [72]
  • Steve McQueen, an American actor, was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors thought the cancer was too advanced. McQueen then looked for alternative treatments in clinics in Mexico. He died of a heart attack on November 7, 1980 in Juárez, Mexico, as a result of cancer. He may have been exposed to asbestos while serving in US Marines as a young adult – asbestos was commonly used to insulate ship piping – or because it was used as an insulating material in racing suits (McQueen was a racing enthusiast). ). [73]
  • Mickie Most, a record producer, died of peritoneal mesothelioma in May 2003, but wondered if this was due to asbestos exposure. [74]
  • Warren Zevon, an American musician, was diagnosed with pleural mesothelioma in 2002 and died about a year later. It is believed that this has caused a close exposure of childhood to asbestos insulation in the attic of his father’s studio. [75]
  • David Martin, Australian sailor and politician, died on 10 August 1990 of pleural mesothelioma. It is thought that this was caused by his exposure to asbestos on military ships during his career in the Royal Australian Navy. [76]
  • Paul Kraus, diagnosed in 1997, is considered the survivor of the world’s most living mesothelioma (in 2017). [77]

Although life expectancy with this disease is generally limited, there are notable survivors. In July 1982, Stephen Jay Gould, a renowned paleontologist, was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote “The median is not the message”  [78],  in which he argued that statistics such as median survival are useful abstractions, not fate. Gould lived another 20 years, eventually succumbing to cancer unrelated to his mesothelioma.

Legal issues 

Some people who have been exposed to asbestos have perceived damage to an asbestos-related disease, including mesothelioma. Compensation through asbestos funds or class actions is an important issue in the legal practice regarding mesothelioma.

The first lawsuits against asbestos manufacturers date back to 1929. Since then, numerous lawsuits have been filed against manufacturers and employers of asbestos for failing to put in place security measures after the links between asbestos , asbestosis and mesothelioma have been known. early in 1898). The liability resulting from the large number of lawsuits and people affected has reached billions of dollars. [79] The amounts and method of awarding compensation have been the source of many court cases, reaching the US Supreme Court, and the government’s attempts to resolve existing and future cases. However, to date, the US Congress has not intervened and there is no federal law governing the compensation of asbestos. [80] In 2013, the “Asbestos Claim Transparency Act (FACT) 2013” was passed by the US House of Representatives and sent to the US Senate, where it was referred to the Committee. of the Senate. [81] As the Senate did not vote on it before the end of the 113th Congress, he died in committee. It was reinstated at the 114th Congress, where it has not yet been submitted to the House for a vote. [82]

History

The first lawsuit against the asbestos manufacturers was instituted in 1929. The parties settled this lawsuit, and as part of the agreement, the lawyers agreed not to pursue other cases. In 1960, an article published by Wagner et al. was seminal in establishing mesothelioma as a disease arising from exposure to asbestos. [83] The article referred to more than 30 case studies of people who had suffered mesothelioma in South Africa. Some exhibitions were transitory and some were minors. Before using advanced microscopy techniques, malignant mesothelioma was often diagnosed as a variant of lung cancer. [84] In 1962 McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker. [85] The worker worked in the mill of the Wittenoom asbestos mine from 1948 to 1950.

In the city of Wittenoom, asbestos-containing waste was used to cover school yards and playgrounds. In 1965, an article in the British Journal of Industrial Medicine established that people who lived in factories and asbestos mines, but did not work there, had contracted mesothelioma.

Despite evidence that asbestos-related dust causes asbestos-related diseases, mining began in Wittenoom in 1943 and continued until 1966. In 1974, the first public warnings about the dangers blue asbestos have been published. Killer in your house? “In  Australia’s Bulletin Magazine  . In 1978, the Government of Western Australia decided to phase out the town of Wittenoom, following the publication of a health booklet, entitled “The Health Hazard at Wittenoom”, containing the results of samples taken from. air and a global medical assessment.

In 1979, the first acts of negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was created to represent the victims of Wittenoom.

In Leeds, England, the Armley asbestos disaster involved several lawsuits against Turner and Newall, where local residents who contracted mesothelioma claimed compensation for asbestos pollution from the company. factory of the company. A notable case is that of June Hancock, who contracted the disease in 1993 and died in 1997  [86].

Search

The WT-1 protein is overexpressed in mesothelioma and is being researched as a potential target for drugs. [11]

There are two high confidence miRNAs that can potentially serve as biomarkers of asbestos exposure and malignant mesothelioma. Validation studies are needed to assess their relevance. [87]

References

This article contains information from an American public domain National Cancer Institute fact sheet.
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Image Source: https://en.wikipedia.org/wiki/Mesothelioma

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