RxPG - Mesothelioma

Malignant mesothelioma is a primary tumor of the pleura, peritoneum, pericardium, and other organs.

The male-female ratio is about 4:1

80% arise from the pleura. The mean age of patients is approximately 60 years, but the disease can occur at any age, including in childhood.

A unique feature of mesothelioma is its strong relationship with asbestos exposure. About 20% of patients have no demonstrable or anamnestic exposure to asbestos. The role of various other fibers, such as zeolites is speculated to play a role in some cases of mesotheioma.

Clinical observations also strongly suggest a genetic susceptibility to mesothelioma. Clusters of cases have been reported in some families, often by household exposure to asbestos, and also in identical twins but a clear genetic susceptibility has not yet been established.

Mesothelioma can be classified under three major histological types:

1. Epithelial or tubulopapillary, the most frequent (50 to 70% of cases)

2. Mesenchymal or fibrosarcomatous, the least common (7 to 20% of cases)

3. Mixed or biphasic, intermediate in frequency (20 to 35% of cases). The mixed type is the most characteristic, containing both epithelial and mesenchymal elements

A remarkable property of the mesothelial cell is the production of hyaluronic acid

The onset of mesothelioma is usually insidious; a common presenting symptom is persistent localized pain.

Pleural Mesothelioma

Varying degree of chest pain or dyspnea.

Pleural effusion is present initially in up to 95% of cases.

Later, tumor growth usually results in complete obliteration of the pleural space and encasement of the lung.

Cough, weight loss, and fever are not uncommon. Clubbing of fingers is seen in only few cases.

Mediastinal invasion results in dysphagia, phrenic nerve paralysis, pericardial effusion, and superior vena cava syndrome can occur. Spontaneous pneumothorax or hydropneumothorax and Horner's syndrome (ptosis, pupillary miosis and facial anhidrosis) can some time occur

Progressive invasion of the chest wall often leads to intractable pain.

Median survival is about 10 to 17 months from onset of symptoms and 9 to 13 months from diagnosis. 5-year survival probabilities is just 3%.

Peritoneal Mesothelioma

Pain and abdominal distention with ascites are almost constant in patients with peritoneal mesothelioma.

Other clinical findings include nausea and vomiting, bowel obstruction

Abdominal and pelvic masses, edema of the lower extremities, fever, hernia, hydrocele, and obstructive uropathy.

Median survival is about 10 months from onset of symptoms and 7 months from diagnosis.

With limited success of trimodality therapy for malignant mesothelioma, research continues to investigate new therapies. Immunotherapy is one of the areas under investigation. Animal models have shown that the malignant mesothelial cells evade the immune response by producing transforming growth factor-beta which is a known powerful immunosuppressant of T-cell activity. The administration of cytokines, interferon-alpha and tumor necrosis factor-alpha directly inhibit the growth of mesothelial cell lines. In clincial trials, the response rate to cytokine infusion were similar to the most efficacious chemotherapy drugs . For example, administration of IL-2, and gamma-interferon into the pleural cavity of patients with stage I or II disease has shown to be effective against mesothelial cell proliferation. IL-2 induces lymphokine-activated killer activity from the pleural mononuclear cells taken from the patients. Gamma-interferon is directly cytotoxic to the mesothelial cells and may also activate natural killer cells and macrophages. Thus, these findings may prove useful in treating mesothelioma with immune-enhancing agents.

Photodynamic therapy is an alternative approach. Protoporphyrin dye given intravenously is taken up by the tumor cells and absorbs a laser light administered into the pleural cavity. The dye is activated to produce singlet oxygen radicals. These oxygen radicals cause subsequent cell death. Depth of penetration of the dye is limited, and the ratio of uptake in normal and tumor tissue is poor. Patients must avoid sunlight for several weeks after treatment.

The newest therapy with the most potential is gene therapy. The concept entails incorporating a "suicide gene" into the DNA of the tumor cells which codes for an enzyme. This enzyme produces a toxic metabolite, causing cell death. Studies using the herpes simplex thymidine kinase gene (HSVtk) which phosphorylates the nontoxic nucleoside analog, ganciclovir. Ganciclovir is endogenously converted to a triphosphorylated form by the kinases, and this triphosphorylated form causes cell death to the mesothelial cells. Adenoviruses are used as the vectors to infect the tumor cells. Researchers have removed two portions of the adenovirus genome, E1 and E3 regions, which will prevent the virus from replicating the enzyme itself and thus, allowing it to only deliver the DNA segment. Not all the tumor cells need to be infected for the therapy to be effective. The transduced cells (infected with the gene) will transfer toxic metabolites to non-infected cells , thus killing surronding cells. This is referred to as the "bystander effect". Studies were performed in severe combined immunodeficient rats with mesothelioma treated with the adenovirus and gancyclovir into the pleural cavity.

Macroscopic tumor was eradicated in 90% of the animals, and the microscopic tumors were undetectable in 80% of the animals.