Malignant mesothelioma is a difficult diagnosis to establish, so the pathologist should be warned if the index of suspicion is high. The diagnosis could be work related, and a thorough discussion with the patient is warranted.
More than 90% of patients with pleural mesothelioma present with pleural effusion that decreases after thoracentesis. Cytologic examination findings are diagnostic in only 32% of patients and are suggestive in 56% of patients. Thoracoscopically guided biopsy should be performed if mesothelioma is suggested; the results are diagnostic in 98% of cases.
Careful scrutiny of routinely stained biopsy preparations is the most valuable diagnostic tool in malignant mesothelioma. A battery of commercial immunohistochemistry stains (eg, for cytokeratins, vimentin, human milk fat globulin-2, anti-Leu M1, BerEP4, carcinoembryonic antigen) can be used. 
Diagnostic features distinguishing malignant mesothelioma from adenocarcinoma include negative test results for periodic acid-Schiff stain, mucicarmine stain, carcinoembryonic antigen, and Leu M1 and positive test results for calretinin, vimentin, and cytokeratin. Electron microscopy reveals that cells have long microvilli, in contrast to adenocarcinomas, which have short microvilli.
One of the new most intriguing markers is serum mesothelin-related protein (SMRP), measured in fluid or serum. The circulating SMRP level has been reported to be elevated in 84% of patients with malignant mesothelioma and in 2% of patients with lung cancer.
Determining the extent of disease by performing a laparoscopy or magnetic resonance imaging (MRI) scan and a cardiopulmonary evaluation is important, if the patient is amenable.
Cardiopulmonary stress test
A cardiopulmonary stress test with pharmacologic agents is a reasonable choice to eliminate the possibility of evidence of silent myocardial ischemia.
Laparoscopy, thoracoscopy, and pleuroscopy
Thoracoscopy or pleuroscopy should be performed to confirm the diagnosis of mesothelioma. Laparoscopy is important for staging but is still investigational with regard to its use in evaluation for transdiaphragmatic involvement.
Gross pathology reveals that the pleural surfaces are seeded with malignant mesothelioma cells, which form grouped nodules. As the disease progresses, it covers the entire pleural space and invades the chest wall, mediastinum, and diaphragm. Microscopically, the 3 histologic types are epithelial, sarcomatous, and mixed. The epithelial type correlates with a better prognosis. 
Hollevoet et al found that megakaryocyte potentiating factor (MPF) can be used as a serum biomarker of malignant mesothelioma. MPF originates from the same precursor protein as soluble mesothelin (SM), which is currently the reference serum biomarker for malignant mesothelioma. At 95% specificity, SM had a sensitivity of 64% (cutoff = 2.00nmol/L) and MPF had a sensitivity of 68% (cutoff = 12.38ng/mL). Combining both markers did not improve the diagnostic performance. 
Pleural fluid findings in patients with mesothelioma are normally not diagnostic. The specific gravity of the pleural fluid is also nondiagnostic. Typically, the pleural fluid has less than 1000 leukocytes per microliter, few erythrocytes, elevated protein levels, and normal lactate dehydrogenase levels.
The results of cytologic examination are occasionally positive for malignant mesothelial cells; most often, however, the pleural fluid cytology results are not diagnostic. 
Savic et al used fluorescence in situ hybridization (FISH) to distinguish malignant mesothelioma from reactive mesothelial cells in effusions. Diagnosis of mesothelioma by detection of chromosomal aberrations with FISH had 79% sensitivity; positive and negative predictive values for detection of mesothelioma were 100% and 72%, respectively. 
Characteristics of new cell lines
Four new mesothelioma cell lines have been characterized based on ultrastructural and immunophenotypic analysis.  These cell lines express vimentin, cytokeratins 8 and 18, and mesothelial antigen recognized by HBME-1 monoclonal antibody. All of the lines possess surface human leukocyte antigen (HLA) class I and intercellular adhesion molecule-1 (ICAM-1).
Although HLA class II and cluster of differentiation-86 (CD-86) cannot be detected in the cell lines, HLA class II does become present following interferon gamma stimulation. Abnormal karyotypes with chromosome-6 abnormalities are found in all 4 cell lines.
Owing to the persistence of large T antigen with HLA class I and ICAM-1, large T antigen may serve as a target for cytotoxic-based immunotherapy.
Chest radiographs in malignant pleural mesothelioma show obliteration of the diaphragm; nodular thickening of the pleura; decreased size of the involved chest; radiolucent, sheetlike encasement of the pleura; or a combination of these. A loculated effusion is present in more than 50% of patients, and a major portion of the pleura is opacified by the effusion.
A computed tomography (CT) or MRI scan of the chest or a positron emission tomography (PET) scan can also be used in the diagnosis of mesothelioma.  However, the PET scan is still considered investigational for helping to differentiate between benign and malignant mesothelioma.
In a study looking at the value of fluorodeoxyglucose PET (FDG-PET) scanning in 17 patients with pleural mesothelioma, the survival period in the group with high FDG uptake was shorter than that in the low FDG group. 
Six staging categories have been proposed for mesothelioma. In 1996, Sugarbaker and associates proposed the Brigham staging system based on tumor resectability and nodal status, a system validated in a clinical trial.  To date, the accepted system is the TNM classification accepted by the International Mesothelioma Interest Group (IMIG). The stages of mesothelioma are as follows:
Stage I - Completely resected within the capsule of the parietal pleura without adenopathy (ie, ipsilateral pleura, lung, pericardium, diaphragm, or chest wall disease limited to previous biopsy sites)
Stage II - All stage I characteristics, with positive resection margins, intrapleural adenopathy, or a combination
Stage III - Local extension of disease into the chest wall or mediastinum, into the heart, through the diaphragm or peritoneum, or extrapleurally to involve the lymph nodes
Stage IV - Distant metastatic disease
The optimal preoperative staging procedures are debatable. In 1996, Sugarbaker et al recommend MRI as a standard part of staging.  Others argue that laparoscopic thoracoscopy is the best way to determine the extent of the disease. Some argue that PET scans may be helpful, but their role in staging needs to be defined.
MRI performed with different pulse sequences and gadolinium-based contrast material can improve detection of tumor extension, especially to the chest wall and diaphragm. PET scans can provide metabolic and anatomic information, especially for patients with extrathoracic or mediastinal metastasis. The appropriate role of PET scans in the management of malignant mesothelioma is still undefined.
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