Mesothelioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Sujit Routray, M.D. [3], Fatima Shaukat, MD [4]

The association between mesothelioma and asbestos exposure was first described by Dr. Wagner in his seminal study of South African miners. It was discovered later that people who live near to factors and mines developed mesothelioma despite not working in the mines.

• The association between mesothelioma and exposure to asbestos fibers was elucidated by Dr. Wagner in his seminal study of South African miners.^[1]
• In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds.
• In 1965, an article in the British Journal of Industrial Medicine established that people who lived in the neighborhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.
• Despite proof that the dust associated with asbestos mining and milling causes asbestos related disease, mining began at Wittenoom in 1943 and continued until 1966. In 1974 the first public warnings of the dangers of blue asbestos were published in a cover story called “Is this Killer in Your Home?” in Australia’s Bulletin magazine. In 1978, the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, “The Health Hazard at Wittenoom”, containing the results of air sampling and an appraisal of worldwide medical information.
• By 1979 the first writs for negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.
• In the landmark study by Vogelzang et al., cisplatin and pemetrexed led to an objective response rate of 41% and median survival of 12.1 months, compared to 17% and 9.3 months in patients treated with cisplatin alone.^[2]

• The first lawsuits against asbestos manufacturers were in 1929.
• Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898).
• The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars.
• The amounts and method of allocating compensation have been the source of many court cases, and government attempts at resolution of existing and future cases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Sujit Routray, M.D. [3]

Mesothelioma may be classified into several subtypes based on the location (pleural, peritoneal, pericardial, cystic/multicystic, and tunica vaginalis testis), histology (epithelial, sarcomatoid, and biphasic), and potential to spread (benign and malignant).

Based on the location, mesothelioma may be classified into 5 subtypes:^[1]

• Pleural mesothelioma
• Peritoneal mesothelioma
• Pericardial mesothelioma
• Cystic/multicystic mesothelioma
• Tunica vaginalis testis mesothelioma

Based on the histology, mesothelioma may be classified into 3 subtypes:^[1]

• Epithelial
• Sarcomatoid
• Biphasic (mixed)

Based on the potential to spread, mesothelioma may be classified into 2 subtypes:^[2]

• Malignant mesothelioma
• Benign mesothelioma

• Fibrous tumor of the pleura: Fibrous tumor of the pleura is a benign tumor that forms in the visceral or parietal pleura. This type of tumor can occur in both sexes. A benign fibrous tumor of the pleura can cause symptoms similar to malignant mesothelioma, such as shortness of breath. It may also advance to form a malignant tumor. A benign fibrous tumor of the pleura can recur after surgical resection.
• Multicystic mesothelioma: Multicystic mesothelioma forms several benign cysts in the peritoneum. This type of mesothelioma most often occurs in femlaes. It may also be called benign cystic mesothelioma.
• Adenomatoid mesothelioma: Adenomatoid mesothelioma is a benign tumor that usually develops in the mesothelium of the male and female genital system. In males, this benign tumor often starts in the epididymis. In femlaes, adenomatoid mesothelioma starts in the Fallopian tubes.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2],Sujit Routray, M.D. [3]

Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species. Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences. Genes involved in the pathogenesis of mesothelioma include BAP1, CDKN2A, WT1, NF2, and TP53. On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of malignant mesothelioma cells. Based on the histology, mesothelioma may be classified into 3 subtypes: epithelial, sarcomatoid, and biphagic. Mesothelioma is demonstrated by positivity to tumor markers, such as calretinin, epithelial membrane antigen, cytokeratin, and mesothelin.

The pathogenesis of mesothelioma is influenced by the following factors:^[1][2][3][4]

• Asbestos fibres
• Radiation therapy
• Smoking

There are two types of asbestos fibers:

• Amphibole (sharp, rod-like)
• Serpentine

Asbestos fibers play the following role in the development of mesothelioma:

• The most common type of fibres found in US are the serpentine fibers, which are considered less carcinogenic than the amphibole ones.
• Following inhalation from the environment, these fibres are trapped in the lower third zone of the lung.
• They are phagocytosed by the mesothelial cells and initiate an oncogenic cascade of events which include:
  • Activation of c-Myc and c-Jun oncogene
  • Promotion of antiapoptotic genes such as Bcl-xL
  • Binding with epidermal growth factor receptor (EGFR)

• Asbestos causes DNA damage directly by mechanically interfering with the segregation of chromosomes during mitosis and indirectly by inducing mesothelial cells and macrophages, to release mutagenic reactive oxygen and nitrogen species.
• Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favor the development of mesothelioma.
• Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism.
• However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.
• The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities.
• Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques.
• The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system.
• Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
• Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in-vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis, and significantly reduce lymphokine-activated killer cell viability and recovery.
• Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

Survivors of radiation therapy have been found to develop mesothelioma according to several studies. Following cancers have been studied post-radiation therapy which are seen to develop mesothelioma:^[5][6][7]

• Non-Hodgkins lymphoma^[8]
• Testicular cancer
• Breast cancer

• Smoking has a synergistic effect on asbestos fibre inhalation in the pathogenesis of mesothelioma.

• Development of mesothelioma is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of mesothelioma include:^{[9][10][11][12][13][14]}

• BAP1
• CDKN2A
• WT1
• NF2
• TP53
• PTEN
• MSLN
• LATS2

• Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis, by several possible mechanisms:

• Inactivation of tumor suppressor genes
• Activation of oncogenes
• Activation of proto-oncogenes due to 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

The following features are seen on gross pathology of mesothelioma:^[15]

• On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that coalesce to produce a sheet-like tumor, with the pleural surface seeding of malignant mesothelioma cells.
• The growth usually starts at the inferior margins of the pleura and may invade the diaphragm.
• The lung and interlobar fissures may also be involved.

• 
  _{Mesothelioma completely encasing the lung.<ref name=grosspictureofmesotheliomaimage1>Image courtesy of Dr. Yale Rosen. Radiopaedia (original file here). Creative Commons BY-SA-NC}

Based on the histology, mesothelioma may be classified into 3 subtypes:^[16]

• Epithelial
• Sarcomatoid
• Biphasic (mixed)

• The cytological and histological diagnosis can be difficult, with mesothelial hyperplasia and metastatic adenocarcinoma appearing similar. Specific markers may be helpful in the diagnosis of mesothelioma.^[17]
• Mesothelioma is demonstrated by positivity to tumor markers, such as:^[17][18]

• Calretinin
• Epithelial membrane antigen
• Cytokeratin
• Mesothelin
• WT1
• Podoplanin
• Osteopontin
• HBME-1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatima Shaukat, MD [2]Parminder Dhingra, M.D. [3]

Common causes of mesothelioma include asbestos-fibre exposure, erionite-fibre exposure, Simian virus 40, radiation exposure and genetic predesposition^[1][2]

Mesothelioma is caused by:^[1][2]

• Asbestos-fibre exposure: causes majority of cases
• Erionite-fibre exposure
• Simian virus 40 (SV40)
• Radiation exposure
• Genetic predisposition

• The strongest and most common cause for mesothelioma is occupational exposure to asbestos, which has been widely used in building materials and many industries.^[1]
• Asbestos is naturally occurring group of mineral consisting of very fine,long and thin fibers.
• Being so fine, they can be inhaled easily and may be lodged in the smallest airways of the lung and the mesothelium, eventually leading to pleural mesothelioma.
• Sometimes, instead of inhalation, the fibers are coughed up and swallowed. This way they can settle in the peritoneum to cause peritoneal mesothelioma.
• According to the International Agency for Research on Cancer (IARC) and the US National Toxicology Program, all forms of asbestos are known to cause cancer. Most people with mesothelioma have a history of asbestos exposure.
• Mesothelioma has a long latency period, which means it usually doesn’t develop for 15–40, or more, years after exposure to asbestos.
• There are 2 types of exposure to asbestos:
  • Direct exposure affects people who come into contact with asbestos directly. This may include:^{[1] [3]}
    • Asbestos mines/mills workers
    • Asbestos products/asbestos-based products producers
    • Construction workers, carpenters and painters
    • Shipyard workers
    • Cement manufacturers
    • Insulation workers
    • Electricians and heating tradespeople
    • Plumbers
    • Demolition workers
    • Automotive industry workers, including brake and clutch repair workers
  • Indirect exposure affects people who come in contact with asbestos in other ways. This may include:^[1]
    • Family members who are exposed to asbestos from fibres brought home on a worker’s clothing
    • People who live in or near an asbestos factory or mine

• The risk of developing mesothelioma is related to how much asbestos a person was exposed to and how long the exposure lasted.
• People exposed at an early age, for a long period of time and to greater amounts of asbestos are more likely to develop mesothelioma.
• Occasionally, mesothelioma develops in people who have never been exposed to asbestos.^[4]

• Erionite is another naturally occurring mineral, happens to be a known human carcinogen associated with development of pleural and peritoneal mesothelioma.
• The group of minerals, erionite belongs to is called zeolites.^[1]
• Zeolites are chemically related to asbestos and erionite has asbestos-like fibres.
• Erionite is common in the soil in parts of Turkey and materials made with erionite are used in construction in these regions.
• High rates of mesothelioma in these areas are due to exposure to this mineral.^[1]

• People who have been treated with radiation therapy to the chest or abdomen for lymphoma, breast cancer, lung cancer, or other cancers can cause mesothelioma.^[1]
• Although the risk of mesothelioma is higher in people who have been treated with radiation therapy, mesothelioma is likely to occur in only a very small number of these people.
• There have been reports linking mesothelioma to Thorotrast (thorium dioxide). Thorotrast is a contrast medium once used for imaging tests, but it is no longer used.^[1]

• Infection with SV40 may cause mesothelioma.
• Evidence suggested the contamination of polio vaccines with SV40 from 1955 to 1963, which may have contributed to some cases of mesothelioma.
• It is thought that SV40 may act as a co-factor with asbestos in causing mesothelioma.^[1]

• Based on the fact that malignant mesothelioma clustering was observed in few families, a study was conducted in 2012 on caucasian american population to determine the genetic association.

• It was found that people with a somatic germline mutation in their BAP1 gene is associated with higher risk of developing mesothelioma and uveal melanoma.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Sujit Routray, M.D. [3]

Mesothelioma must be differentiated from pleural effusion, lung cancer, pulmonary tuberculosis, peritoneal tuberculosis, pseudomyxoma peritonei, constrictive pericarditis, ovarian cystadenoma, and mesothelial hyperplasia of the testis.

Pleural mesothelioma must be differentiated from:^{[1][2][1][2][3][4][5][6][7]}

• Pleural effusion
• Benign asbestos-related pleural disease
• Peripheral bronchogenic carcinoma
• Pleural fibrosis from infective/inflammatory source (e.g. actinomycetes, tuberculosis)
• Primary pleural tumors

• Solitary fibrous tumor of the pleura
• Pleural fibrosarcoma
• Pleural liposarcoma
• Primary pleural lymphoma
• Pleural synovial sarcoma

• Secondary lesions that can involve the pleura

• Pleural metastases
• Thymoma with pleural invasion
• Pericardial tumors with pleural invasion
• Ewing sarcoma of chest wall with pleural invasion

Peritoneal mesothelioma must be differentiated from:^[3][4]

• Peritoneal carcinomatosis
• Pseudomyxoma peritonei
• Lymphoma with peritoneal involvement
• Peritoneal involvement with tuberculosis
• Mesenteric panniculitis
• Primary peritoneal adenomatoid tumor
• Primary peritoneal papillary serous carcinoma
• Primary peritoneal serous borderline tumor
• Diffuse peritoneal leiomyomatosis
• Desmoplastic small round cell tumor arising from the peritoneum
• Solitary fibrous tumor arising the peritoneum
• Peritoneal lymphangioma
• Peritoneal inclusion cyst
• Spontaneous bacterial peritonitis (SBP)

Pericardial mesothelioma must be differentiated from:^[5]

• Heart failure
• Coronary heart disease
• Constrictive pericarditis
• Cardiomyopathy
• Tuberculosis pericarditis
• Cardiac tamponade
• Intra-atrial myxoma

Multicystic mesothelioma must be differentiated from:^[6]

• Abdominopelvic cystic lymphangioma
• Ovarian cystadenoma
• Ovarian cystadenocarcinoma
• Endometriosis
• Cystic teratoma
• Cystic mucinous tumor of pancreas

Tunica vaginalis testis mesothelioma must be differentiated from:^[7]

• Mesothelial hyperplasia of the testis
• Adenomatoid tumor of the testis
• Rete testis adenocarcinoma
• Serous papillary tumors of the testis and epididymis
• Pleomorphic rhabdomyosarcoma
• Malignant fibrous histiocytoma
• Germ cell tumors of the testis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatima Shaukat, MD [2]Parminder Dhingra, M.D. [3], Sujit Routray, M.D. [4]

Mesothelioma is a rare disease which accounts for 5-28% of all malignancies that involve the pleura. The incidence of mesothelioma is estimated to be 3,000 cases annually. The incidence of pleural mesothelioma is approximately 1 per 100,000 individuals in the United States. Males are more commonly affected with mesothelioma than females. The male to female ratio is approximately 3 to 1. The incidence of mesothelioma increases with age; the median age at diagnosis for pleural mesothelioma and peritoneal mesothelioma are 74 years and 68 years, respectively. There is no racial predilection to mesothelioma.

• Mesothelioma is a rare disease which accounts for 5-28% of all malignancies that involve the pleura.^[1]

• The incidence of mesothelioma is estimated to be 3,000 cases annually.^[2]
• The incidence of pleural mesothelioma is approximately 1 per 100,000 individuals in the United States.^[3]
• The incidence of pleural mesothelioma is approximately 1.2 per 100,000 individuals in Canada.^[3]
• The incidence of mesothelioma has decreased over several decades in the United States coincident with diminishing occupational asbestos exposure and has remained stable since 2003.^[4]

• Males are more commonly affected with mesothelioma than females. The male to female ratio is approximately 3 to 1.^[1]
• The incidence of mesothelioma increases with age; the median age at diagnosis for pleural mesothelioma and peritoneal mesothelioma are 74 years and 68 years, respectively.^[4]

• There is no racial predilection to mesothelioma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Sujit Routray, M.D. [3]

The most potent risk factor in the development of mesothelioma is asbestos exopsure. Other risk factors include erionite-fibre exposure, Simian virus 40, and radiation exposure.^[1]

• The most potent risk factor in the development of mesothelioma is asbestos exopsure.^[1]
• Other risk factors include erionite-fibre exposure, Simian virus 40, and radiation exposure.^[1]
• Specific risk factors for multicystic mesothelioma include:^[2]

• Previous abdominal surgery
• Previous pelvic inflammatory disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatima Shaukat, MD [2]Parminder Dhingra, M.D. [3]

There is insufficient evidence to recommend routine screening for mesothelioma.

• There is no universally agreed protocol for screening people who have been exposed to asbestos.
• However some research indicates that the serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma.
• The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Sujit Routray, M.D. [3]

If left untreated, mesothelioma may progress to develop dyspnea, dysphagia, pleural effusion, thrombophlebitis, constrictive pericarditis, recurrent hydrocele, and metastases, depending on the site involved. Complications of mesothelioma include pleural effusion, spinal cord compression, Horner’s syndrome, superior vena cava syndrome, hyperviscocity syndrome, pericardial effusion, cardiac tamponade, heart failure, ascites, and recurrent hydrocele. The prognosis of mesothelioma depends on the cell subtype.^[1]

• Malignant mesothelioma is usually an aggressive disease.^[1]
• The exposure to the asbestos that cause mesothelioma occurrs 25-40 years to appear.
• Metastasis outside the thoracic wall occurs late in the course of pleural mesothelioma. Common sites of metastasis for pleural mesothelioma include:^[2]

• Mediastinum
• Pericardium
• Lymph nodes
• Thoracic wall
• Contralateral lung
• Diaphragm
• Peritoneum (the membrane that lines the walls of the abdomen and pelvis, and covers and supports most of the abdominal organs)
• Liver
• Adrenal gland
• Kidney
• Brain

• Peritoneal mesothelioma does not usually spread to the lymph nodes or distant organs. Common sites of metastasis for peritoneal mesothelioma include:^[2]

• Serosa of the small and large intestine – can cause a bowel obstruction
• Unilateral or bilateral pleural cavities
• Liver
• Spleen

Common complications of pleural mesothelioma include:^[3][4][5][6]

• Difficulty swallowing
• Pain caused by pressure on the nerves and spinal cord
• Pleural effusion
• Atelectasis
• Hypercoagulability syndrome
• Spinal cord compression
• Horner’s syndrome
• Superior vena cava syndrome

Common complications of peritoneal mesothelioma include:^[7]

• Anorexia
• Weight loss
• Hypercoagulability syndrome
• Ascites

Common complications of pericardial mesothelioma include:^[8]

• Constrictive pericarditis
• Pericardial effusion
• Cardiac tamponade
• Heart failure

Common complications of tunica vaginalis testis mesothelioma include:^[9]

• Recurrent hydrocele

• Prognosis in mesothelioma is difficult to assess consistently because there is great variability in the time before diagnosis and the rate of disease progression.^[10]
• The prognostic factors for mesothelioma include:^[11]

• Cell subtype: Epithelioid mesothelioma is the most common subtype of mesothelioma and has a better prognosis than sarcomatoid or mixed (biphasic) types. Sarcomatoid subtype has the least favorable prognosis.
• Location of mesothelioma: Pericardial mesothelioma is usually associated with a poorer prognosis than the other types of mesothelioma.
• Surgical removal: Mesothelioma that can be resected has a more favorable prognosis than mesothelioma that has spread too far and is unresectable. Clear surgical margins improve prognosis. Mesothelioma is often a diffuse disease and doesn’t stay localized. This makes it difficult to get clear surgical margins.
• Stage: Stage plays a role in prognosis for people who have surgery. The stage of mesothelioma does not impact survival for people who do not have surgery. Generally, early stage mesothelioma has a better prognosis than more advanced stages. If mesothelioma has spread to the lymph nodes, it is usually associated with a less favorable prognosis.
• Symptoms: The presence of chest pain with pleural mesothelioma or excessive weight loss is associated with a poorer prognosis. Chest pain suggests there may advanced disease that is unresectable.
• Thrombocytosis: Thrombocytosis is associated with a poorer prognosis.
• Leukocytosis: Leukocytosis is associated with a poorer prognosis.
• Performance status: People with a good performance status have a better prognosis than those with a poor performance status.
• Age: Younger people have a better prognosis than older people.
• Sex: Females seem to have a better prognosis than men.
• Lactate dehydrogenase (LDH) level: People with increased LDH blood levels tend to have a less favorable prognosis than those with normal LDH levels. LDH is an enzyme in the blood that can be increased when there is damage to certain tissue or cancer.

• Mesothelioma occurring in germline BAP1 mutation carriers have been reported to be less aggressive clinically and associated with prolonged survival compared with sporadic mesothelioma.^[12]
• As discussed earlier, the prognosis of mesothelioma depends on the cell subtype. The median survival time of various subtypes of mesothelioma are tabulated below.^[1]

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