Diagnosis of mesothelioma includes history, physical exam, and histologic findings. Clinicians should have a high index of suspicion in any patient with a history of asbestos exposure 30 to 40 years prior to presentation. Exposure can occur in asbestos workers, family members of asbestos workers, and those living close to naturally occurring asbestos soil deposits. Common signs and symptoms at presentation include dyspnea, pleuritic or non-pleuritic chest pain, fatigue, weight loss, and pleural effusion. Asymptomatic patients may have pleural effusions that are found incidentally on physical exam or through radiographic studies. Thoracentesis decreases pleural effusions in 90 percent of patients, but cytologic studies of the pleural fluid are typically non-diagnostic. In suspected cases, thorascopically guided biopsy should be performed and is 98 percent diagnostic. A variety of immunohistochemistry stains should be performed to aid in diagnosis and to help distinguish mesothelioma from other lung neoplasms.
Malignant mesothelioma is classified into the histologic subtypes of epithelial, sarcomatoid, and mixed variants. Grossly, the tumors arise as firm, gray plaques and nodules that coalesce into a sheet like structure. Pleural mesothelioma typically arises in the lower chest, and early invasion into the diaphragm, chest wall, interlobar fissures and mediastinum are common. Hematologic spread can cause metastasis to the liver, lung, bone, and adrenal glands. Almost 80 percent of pleural mesothelioma cases are associated with documented exposure to asbestos, the commercial name for a group of silicate minerals that are used in cement, insulation, tiles, brake linings, and shipbuilding. Though the federal government has attempted to restrict exposure to these minerals since the 1970s, both occupational and non-occupational exposure to small amounts of asbestos can contribute to mesothelioma. Asbestos workers have almost a 50 percent chance of dying from a malignancy, primarily lung carcinoma or mesothelioma.
Mesothelioma is a malignant neoplasm that arises from the mesothelial surfaces of the pleural cavities, peritoneal cavities, tunica vaginalis, or pericardium. Approximately eighty percent of all cases arise from the pleural mesothelium. This neoplasm is relatively rare; fewer than 3000 cases are reported per year in the United States. The majority of pleural mesothelioma cases are associated with documented asbestos exposure. Patients with pleural mesothelioma commonly present with pleuritic and non-pleuritic chest pain, dyspnea, fatigue, and weight loss. Occasionally, however, patients are asymptomatic and pleural effusion is found incidentally on physical exam or through radiographic findings. Cytologic examination of pleural fluid is typically non-diagnostic. Thorascopically guided biopsy, which should be performed if mesothelioma is suspected, provides a more accurate histologic diagnosis. Treatment options include surgery, chemotherapy, radiation, trimodality therapy and investigative gene therapy. The prognosis for mesothelioma is extremely poor, with a median survival rate of 11 months.
The most favorable treatment outcome recently is reported to be that of a “trimodal” approach, consisting of a radical surgical procedure termed EPP (extra pleural pneumonectomy) in combination with chemotherapy and postoperative radiation therapy.
Extra pleural pneumonectomy involves the complete removal of the affected lung and pleura, pericardium, portions of the phrenic nerve, and the majority of the hemidiaphragm. This extensive surgery is not without significant morbidity and mortality, but it allows for higher radiation doses to be delivered to the chest cavity and it reduces the number of cancerous cells surgically.
Radiation treatment for malignant mesothelioma is more responsive than non-small cell lung cancer, but not as sensitive as is small-cell lung cancer. With malignant mesothelioma, the entire hemithorax must be radiated, creating high risk of damaging the adjacent vital organs such as the heart, esophagus, lung, liver and spinal cord. Chemotherapy for malignant mesothelioma consists of doxorubicin, cyclophosphamide, and cisplatin for four to six cycles postoperatively.
A good prognosis as the time of disease presentation is associated with the following:
Tissue histology of epithelial origin
Stage I disease
Age under 65 years
Performance status of 0 to 1 (minimal effect on health)
Lack of chest pain
The presence of symptoms for more than 6 months prior to diagnosis
A poor prognosis at the time of disease presentation is associated with the following:
Age >65 years
Sarcomatous or mixed tissue histology
Fever of unknown origin
Male gender
Poor performance status
Blood cell dyscrasias
The mean survival of patients with mesothelioma is generally between 6 and 19 months, regardless of therapeutic interventions. Most patients die from local tumor extension and respiratory failure. Also, tumor invasion may cause heart failure, stroke, arrhythmias, or even small bowel obstruction.
The TNM staging system for malignant mesothelioma was adopted in 2002. This system utilizes description of the tumor involvement, lymph node involvement, and the presence or not of distant metastasis of the tumor. Staging is then categorized based on the TNM data.
Tx refers to a tumor that cannot be assessed.
T0 is no evidence of primary tumor.
T1 through T4 refer to the extent of tumor invasion in and around the lung structures.
Nx refers to lymph nodes that cannot be assessed.
N0 implies no regional lymph node metastasis.
N1-N3 refers to the anatomical location of lymph node metastasis.
Mx refers to distant metastasis that cannot be assessed.
M0 is no evidence of distant metastasis.
M1 is any distant metastasis present.
Disease stage is then determined as Stage 1A, 1B, Stage II, III, or IV based on the TNM criteria above.
Malignant mesothelioma is a diagnostically challenging disease. Patients are often misdiagnosed initially. Accurate diagnosis and staging is important for appropriate treatment, as well as for epidemiology and possible subsequent litigation due to asbestos exposure.
Often, thoracentesis or closed pleural biopsy can establish the diagnosis of a pleural malignancy, but inadequate tissue may not distinguish mesothelioma from lung adenocarcinoma. Additionally, negative results do not rule out the disease. Video-assisted thoracoscopic biopsy (VATS) has been shown to be superior in providing the diagnosis compared to thoracentesis and pleural biopsy.
Other diagnostic studies may provide clinically useful information such as bronchoscopy, mediastinoscopy, pulmonary function tests, PET and/or CT scans. There are no useful serum tumor markers associated with malignant mesothelioma.
Malignant mesothelioma arises from mesothelial surfaces in the pleura and peritoneal cavities, the tunica vaginalis, or the pericardium. The most common presenting symptoms of pleural mesothelioma are dyspnea and chest pain. Rarely, asymptomatic patients may have a unilateral pleural effusion found incidentally on routine chest radiograph. Sixty percent of patients will have right-sided lesions, while only five percent have bilateral disease. Occasionally, the radiograph may show a pleural mass, or rind-like pleural thickening. Only 20 percent of patients diagnosed with pleural mesothelioma will show radiographic signs of asbestosis such as bibasilar interstitial fibrosis. However, most will show pleural plaques and/or calcifications.
Patients will develop shortness of breath and chest pain as the tumor invades local anatomic structures. Local invasion of thoracic structures may result in difficulty swallowing (dysphagia), hoarseness, spinal cord compression, Brachial plexus damage, and Superior vena cava syndrome. Additionally, a number of paraneoplastic syndromes can be associated with malignant mesothelioma such as DIC, thrombocytosis, Coombs-positive hemolytic anemia, hypercoagulability, hypoglycemia, and hypercalcemia of malignancy.
Most recently the TNM staging system has been used to stage mesothelioma. However, historically, the Butchart system was used and now there is also a new staging system which may be increasingly implemented, the Brigham system. The Butchart system describes how extensive the primary tumor is, whereas the TNM system defines cancers by tumor extension, lymph node involvement, and whether there are metastases. The Brigham staging identifies how resectable a lesion may be.Each system has four stages. Generally the first stage is localized disease which is easily resectable and involves no lymph nodes. In stage two, the cancer has spread and may affect lymph nodes, but is often treatable with surgical excision and adjunctive therapies. Stage three is extensive disease, often crossing internal boundaries such as the diaphragm but may still respond to debulking surgery and chemotherapy or radiation. The fourth stage in all of the systems is defined by metastatic lesions.
The prognosis is generally poor with a median survival rate of four months for patients with metastatic disease and sixteen months for those with localized disease.With a latency period of 20-40 years from exposure to presentation as well as symptoms which are often confused with other diseases, malignant mesothelioma frequently spreads beyond local disease before the patient presents with symptoms.Prognosis after treatment often depends on how completely the tumor was resected in surgery.
There are four measures of cytoreduction:
CC-0 in which no tumor is visualized
CC-1 in which nodules are seen but less than 2.5 cm; these are likely to respond to chemotherapy
CC-2 in which nodules between 2.5 and 5 cm persist
CC-3 in which nodules greater than 5cm cannot be resected. Chemotherapy and radiation may help increase rate of survival.