Arises primarily from the surface of serosal cells of the pleural, peritoneal and pericardial cavities and is a highly aggressive neoplasm.

Approximately 3000 cases of mesothelioma are noted each year in the United States.

Approximately 43,000 deaths worldwide are due to mesothelioma.

The incidence rate varies from less than one case for 100,000 persons in states with no asbestos industry, to 2-3 cases per hundred thousand persons in states with an asbestos industry.

The peak incidence rates with mesothelioma occurred in the 1980s and early 1990s.

Pleural mesothelioma occurs mainly in older males with the median age at 72 years, and in those who have been exposed to asbestos, although death occurs decades after exposure at approximately 32 years later.

The incidence appears to be slowly decreasing in the US, but the incidence of mortality has continue to rise in other parts of the world.

Pleural mesothelioma is the most common form of malignant mesothelioma, accounting for about 90% of cases.

Mesothelioma arises from surfaces of the peritoneum, pleura, and other sites:pericardium and tunica vaginalis testis.

The histologic subtype of epithelioid pleural mesothelioma accounts for 50-60% of cases, which is associated with the most favorable prognosis.
The sarcomatoid mesothelioma of the pleura accounts with 10% of cases and is highly invasive and drug resistant. 
A biphasic mesothelioma accounting for 30-40% of pleural Mesothelioma cases is a mosaic of the other two subtypes.

Peritoneal mesothelioma accounts for 10-15% of cases.

Most patients with malignant pleural mesothelioma present late in the course of their disease, with an asymptomatic early process.

The most common symptoms and presentation for a pleural  mesothelioma includes restlessness caused by a pleural effusion or tumor encasement of the lung and chest pain due to direct invasion of the chest wall  or mediastinum.

Most patients with pleural mesothelioma have advanced disease at presentation with a median overall survival of approximately one year and a five-year overall survival of approximately 10%.

Fatigue, anorexia, weight loss, sweats and malaise become frequent as the disease progresses.

The initial imaging study for pleural mesothelioma is a CT enhanced chest and upper abdomen study.

Pleural biopsy is the preferred diagnostic method, but pleural fluid cytology is an acceptable diagnostic method.

Immunohistochemical studies of biopsy specimens or cell block specimens may indicate the presence of at least two mesothelial markers: calretinin, cytokeratin 5/6, Wilm’s tumor 1=antigen or D2-40.

The absence of nuclear expression of BAP 1 is an important diagnostic tool.

While patients usually present with localized pleural disease on imaging studies, postpartum studies often show widespread, unsuspecting disseminated disease.

Patients with pleural effusions frequently require draining for symptom relief and diagnosis. 

Temporary catheterization of the pleural space to draw fluid off, is usually accompanied by talc administration. 

The success rate of this management is similar to that of an indwelling catheter and surgical procedures such as partial pleurectomy and pleurectomy/decortication. 

Surgical procedures however have higher complication rates and require a longer hospitalization.

Surgical resection for Mesothelioma is almost always incomplete and should be considered palliative.

Median survival following radical surgery, extra pleural pneumomectomy, is 18 months with the five-year survival rate of 14%.

It is unclear whether cytoreductive surgery prolongs the median survival in patients with malignant pleural mesothelioma.

Randomized studies evaluating radiotherapy for a malignant pleural mesothelioma have not shown any improvement in associated survival.

Sites other than the pleura or peritoneum account for 5% of cases of mesothelioma.

Estimated 43,000 deaths worldwide each year are due to malignant mesothelioma.

The mean age of death for mesothelioma in the US is 72.8 years, with a male to female mortality ratio of 4.2 to 1, as men are traditionally more likely to be employed in trades involving asbestos closure.

With equivalent exposure to asbestos men and women have a similar incidence of pleural mesothelioma.

Over half of the patients with pleural Mesothelioma never receive chemotherapy, largely because of older age, poor performance status, associated coexisting conditions.

Pemetrexed/cisplatinum improve survival.

Immune checkpoint Inhibitors Nivolumab, and ipililumab targeting programmed cell death 1 and cytotoxic T-lymphocyte antigen 4 have shown superiority as frontline treatment as compared to standard of care chemotherapy: survival 18.1 months versus 14.1 months.

The latency of exposure to asbestos to the development of mesothelioma is about 30-50 years.

Its precise path of genetic mechanisms behind the development of disease is unclear.

Factors contributing to pathogenesis includes the persistence of mineral fibers, particularly asbestos and chronic inflammation.
More than 10% of patients with malignant mesothelioma have germline variants.
Mutations in the gene in coding BRCA1- associated protein 1 (BAP1)  have been shown to accelerate asbestos induced mesothelioma and is associated with a syndrome consisting of familial cancers in humans including malignant Mesothelioma and uveal melanomas.
PALB2 and BRCA1/2 repair genes accelerated development of asbestos is induced
The Mutational landscape of mesothelioma is dominated by the inactivation of tumor suppressive genes, which include BAP1, CDKNA2A, NF2, and SETD2.
The protracted interval between exposure and diagnosis suggests that mesothelioma has a pre-malignant state..

Erionite is a carcinogenic fiber linked to mesothelioma epidemics in Turkey.

Pleural mesothelioma represents less than 1% of all cancers.

Subtypes of malignant pleural mesothelioma include epithelioid, about 60%, and non–epithelioid about 40% variants.

Non-epithelioid variants include spindle, sarcomatoid, desmoplastic, fibrous, and biphasic.

Epithelial mesotheliomas are the most common and are associated with longer life expectancy than the less common sarcomatoid or mixed mesotheliomas.

Incidence varies within and between countries: 29 per million per year in Australia and the UK, 10 million per year in the US and eight per million per year in Japan.

Exposure to asbestos fibers is the primary cause.

Malignant pleural mesothelioma is caused primarily by inhalation of asbestosis in about 80% of cases.

Characterized by a long latency from exposure to asbestos to onset of disease, indicating that multiple somatic genetic events are need to convert the normal mesothelial cell to a malignant one.

Deletions in chromosomal sites in the short (p) arms of chromosomes 1, 3, and 9 and long (q) arm of 6 repeatedly noted in such tumors.

Deletion mapping defined the most common areas of abnormality occur at 1p22, 3p21, 6q14-q21, 6q16.6q21, 6q21-q23.2 and 6q25, 9p21 and 15q11.1-15.

Loss of copy of chromosome 22 single most consistent numerical change seen.

Median survival 11 months.

Fewer than 15% of patients live longer than 5-years.

Surgical resection possible in a minority of patients.

Median survival for local disease 17 months, and for extensive disease 5 months.

Male:female 3:1.

2-3000 cases per year in the U.S.

Incidence of 2-20 cases per 1million patients in US and Canada.

The incidence is expected to peak in the next two decades in Western societies.

SV40 may be synergistic in oncogenic effects when combined with asbestos.

Most common in the fifth to seventh decades of life.

Asbestos exposure is linked to 80% of cases.

It is difficult to quantify level of asbestosis exposure by history.

Lung content analysis is more reliable estimating asbestosis exposure associated to the amount and type of exposure.

Pleural mesothelioma is the most common form and peritoneal mesothelioma is a far second, accounting for 10-30% of cases.

Contact with asbestos is the most significant risk factor for malignant pleural mesothelioma, but the relationship of asbestos exposure and other cavities is not as well defined.

In women with malignant peritoneal mesothelioma the relationship with asbestos is not clear, and many patients have no known exposure.

Most studies suggest that amosite and crocidolite exposure carry a greater risk than does exposure to chrysotile, however the latter is frequently combined with tremolite, which may be responsible for the disease.

It is not clear which asbestos fibers are most carcinogenic.

Latency from exposure to the development of malignant mesothelioma generally decades.

Low level exposure, and bystander and secondary exposures can cause the disease.

No clear cut dose response curve to asbestos and mesothelioma, and no threshold of asbestos exposure has been established.

Estimated that fewer than 5% of asbestos miners exposed to high levels of asbestos develop mesotheliomas.

Mates of workers exposed to asbestos have developed mesothelioma as a result of washing their clothes.

Develops commonly among workers in occupations with higher asbestos exposure than in the general population but is much lower than asbestos miners, suggesting high levels of exposure not necessarily correlated with increased risk of malignancy compared to moderate asbestos exposure.

About 20% of cases related to simian virus 40 (SV40), radiation and exposure to thorotrast.

Less than one third of patients selected for radical cytoreductive surgery survive 4-5 years.

Overexpression of micro-RNA-29c in resected tumor tissue associated with improved time to progression, survival and better prognosis at the surgical cytoreduction (Pass HI et al).

High Cox-2 with low p21 and p27 cell regulators are negative prognostic findings in patients treated with cytoreductive surgery (Mineo TC et al).

Soluble mesothelin-related protein has an overall sensitivity of 47% and a 96% specificity for diagnosing mesothelioma.

Plasma fibulin-3 can distinguish healthy persons with exposure to asbestos from patients with mesothelioma.

Plasma fibulin-3 levels, and plasma fibulin-3 levels can differentiate mesothelioma effusions from other malignant and benign infusions (Pass HI et al).

Median survival times using platinum-based doublets range from 12-15 months.

Thymidylate synthase (TS) expression associated with poorer clinical outcomes (Righi L et al).

IL-6 levels and VEGF elevated in serum and effusions and correlated with degree of thrombocytosis seen in these patients.

IL-6 may play a role in VEGF production in associated it is overexpressed in this disorder.

SV40 may induce VEGF expression in endothelia cells.

Upregulation by VEGF plays a role in malignant transformation of mesothelial cells.

Elevated serum and pleural effusion levels of VEGF associated with shortened survival.

IL-8 an important angiogenic factor for the development of capillaries and is elevated in pleural fluid of such patients.

Typically exposure occurs 14-40 years before the development of pleural mesothelioma, with a mean latency of 32 years.

A review of 21 studies with 1690 patients revealed that 96% of cases occurred at least 20 years after exposure to asbestos.

Patients with pleural mesothelioma often present with dyspnea, cough, chest pains, weight loss and night sweats.

Early stage pleural mesothelioma can be resected, but almost always recurs.

Pleural mesothelioma is associated with improved outcomes as it is correlated with higher intratumor infiltration by CD8 positive cytotoxic T cells.

High tumor expression of programmed cell death ligand 1 (PD-L1), which inhibits T-cell function via binding programmed cell death 1 has been associated with poor prognosis in mesothelioma with a median overall survival of five months in PD-L1 positive patients versus 14.5 months in PD-L1 negative patients.

Most cases diagnosed arise from the pleura with about 10% arising from the peritoneum and more rarely the peritoneum and tunica vaginalis of the testicle.

Primary peritoneal mesothelioma incidence 1 in 1,000,000.

Primary peritoneal mesothelioma shares biologic and clinical characteristics of pleural mesothelioma.

Primary peritoneal mesothelioma often aggressive.

Diagnosis of peritoneal mesothelioma is difficult as symptoms are nonspecific, and presentations are polymorphic.

Diagnosis for peritoneal mesothelioma often delayed, with a mean duration of 122 days from onset of symptoms to diagnosis.

Patients with peritoneal mesothelioma may have CT scans that demonstrate pleural thickening, nodules and/or omental caking.

Over three quarters of patients with peritoneal mesothelioma present with ascites

Plueural plaques are frequent with mesothelioma, being found in 88% of patients asbestos e posed with mesothelioma who had a history of exposure confirmed by lung content analysis.

The sensitivity of diagnosis to testing ascitic fluid is estimated to be about 50%.

Laparoscopy is the most definitive diagnostic method for peritoneal mesothelioma allowing macroscopic visualization and direct tissue sampling.

Malignant peritoneal mesothelioma is usually locally invasive and really metastatic past the peritoneum.

Treatment for malignant peritoneal mesothelioma is performed with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Aggressive therapy improves median survival from 6-12 months up to 34-92 months in elective cases.

Primary peritoneal mesothelioma median survival with untreated disease 4-13 months, and 6-18 months in treated patients.

Primary peritoneal mesothelioma patients mostly die from local chest extension and respiratory insufficiency.

Primary peritoneal mesothelioma may cause death by small bowel obstruction.

Diffuse malignant peritoneal mesothelioma has an incidence of 300-400 cases annually in the U.S.

Diffuse malignant peritoneal mesothelioma characterized by multiple tumor nodules of variable size, that may coalesce to form plaques or masses or uniformly cover the peritoneal surface.

Diffuse malignant peritoneal mesothelioma associated with asbestos exposure but the pathogenesis is not fully understood.

Diffuse malignant peritoneal mesothelioma usually presents with advanced disease with abdominal distension and abdominal pain.

Diffuse malignant peritoneal mesothelioma associated with death related to intestinal obstructio or starvation.

Diffuse malignant peritoneal mesothelioma usually confined to the abdominalpelvic cavity.

Incidence increasing worldwide.

Survival predictive factors in peritoneal mesothelioma include female sex, good health status, and epithelioid histology.

Higher prevalence of epithelioid type malignancy in women.

Associated with the DNA simian virus 40 that infected humans from contamination through polio vaccines between 1955-1963.

Increased incidents within industrialized nations.

No universal approach to the treatment of patients with stage I to stage III disease.

The diffuse thoracic involvement renders surgery and radio therapy ineffective when used independently.

Extrapleural pneumonectomy is preferred surgery with a median survival of less than 10 months for patients with this type of the lesion.

Adjuvant radiation after extrapleural pneumonectomy can utilize higher doses of radiation without risk of pneumonitis.

In a study of 54 patients who underwent extrapleural pneumonectomy followed by high dose external beam radiation of 54 Gy to the ipsilateral hemi-thorax: the result was a dramatic reduction in local relapse and prolong survival in patients with early-stage disease, median survival was 33.8 months for stage I and two and 10 months for stage III and four (Rusch W).

Single agent chemotherapy associated with a 20% response rate.

Combination chemotherapy associated with a 25-30% response rate.

As a single agent doxirubicin has an 18% response rate, xin 14%, high-dose methotrexate 38%, carboplatin 11%.

Cisplatin plus pemetrexed improves survival.

Platinum plus pemetrexed response rate of 41%.

Pemetrexed plus cisplatin associated with a median survival of 12 months compared to 9 months for cisplatin alone.

Pemetrexate plus cis-platinum has a median time to progression of 5.7 months (Vogelzang NJ et al).

Combination of pemetrexed, cisplatin and bevacizumab improved overall survival from pemetrexed and cisplatin (18.8 vs 16.1 months).

A combination of the durvalumab, cis-platinum, and pemetrexed showed  promising activity.

Gemcitabine/cis-platinum associated with a 48% response rate and median overall survival of 9.5 months (Byrne MJ et al).

Sugarbaker et al. reported 15% 5 year survival with multiple modality treatment a 25% survival in individuals undergoing complete surgical resection of disease.

May respond to PD-1 inhibitors: The FDA approved a combination of the monoclonal antibodies nivolumab (Opdivo) and ipilimumab (Yervoy) as first-line treatment for adults with malignant, unresectable pleural mesothelioma, 

The US Food and Drug Administration (FDA) has approved a tumor treating fields (TTF) device in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced or metastatic, malignant pleural mesothelioma.(Novocure).

PENMMELA regimen consisting of Pembrolizumab and lenvatinib had a response rate of 58%.

Pegargiminase an arginine deprivation plus chemotherapy, improves survival in patients with non-epithelial pleural mesothelioma.

TTF therapy uses electric fields to disrupt solid tumor cancer cell division.

Previously, the FDA approved Optune, another TTF delivery system from Novocure, for the treatment of glioblastoma in 2011.

The FDA approval is based on the results of the STELLAR trial, a prospective, single-arm trial of NovoTTF-100L plus chemotherapy first-line in patients with unresectable malignant pleural mesothelioma.

In the trial, 80 unresectable MPM patients treated with TTF plus chemotherapy experienced a median overall survival (OS) of 18.2 months.

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