Approach Considerations
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. Repeating pleural cytology may increase the chances of making a diagnosis. However, if pleural cytology is nondiagnostic in a patient with features suggestive of mesothelioma, referral for thoracoscopically guided biopsy is indicated; 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. [17]
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.
Laboratory Studies
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. [18]
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. [19]
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. [1]
Characteristics of new cell lines
Four new mesothelioma cell lines have been characterized based on ultrastructural and immunophenotypic analysis. [20] 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.
Imaging Studies
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. [21] However, the PET scan is still considered investigational for helping to differentiate between benign and malignant mesothelioma.
In a study 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. [22]
For more information, see Malignant Mesothelioma Imaging.
Staging
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. [13] To date, the accepted system is the TNM classification accepted by the International Mesothelioma Interest Group (IMIG). The stages of mesothelioma are as follows:
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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)
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Stage II - All stage I characteristics, with positive resection margins, intrapleural adenopathy, or a combination
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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
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Stage IV - Distant metastatic disease
Staging procedures
The optimal preoperative staging procedures are debatable. In 1996, Sugarbaker et al recommend MRI as a standard part of staging. [13] 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.
Histologic Findings
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. [15]
A solid pattern of mesothelioma on the right of this histologic section transitions to a spindle cell morphology on the left of the image in this predominantly sarcomatoid malignant mesothelioma.
The major growth patterns of malignant mesothelioma are epithelioid and spindled. Tumors of pure epithelioid histology can have patterns described as papillary (cells growing along exophytic fronds with vascular cores), tubulopapillary (a mixture of glandlike formations and papillary structures), and solid (see image below).
This histologic section stained with hematoxylin and eosin shows papillary structures on the right and a transition to a more solid pattern on the left.
The cells of mesothelioma often have deceptively uniform nuclei with moderate amounts of cytoplasm; the mitotic rate is often low. These are factors that can make cytologic detection of disease especially difficult and can result in significant diagnostic challenges in tissue samples of reactive pleural conditions.
Histologic variants of malignant mesothelioma, epithelioid type, include cystic growth patterns and cells that resemble decidual cells and variants that resemble small cell carcinoma. Some cases can have abundant extracellular matrix, and rare cases can produce intracellular mucin.
Tumors with spindled cell histology are called sarcomatoid. This group of tumors can be composed of spindled cells without further characterization or differentiation, which is the most common spindled pattern. However, some cases can have very bland spindled cells with minimal atypia amid abundant acellular collagen in a storiform pattern, and this variant is called desmoplastic mesothelioma when the pattern represents 50% of the tumor. [23]
Well-differentiated papillary mesothelioma represents a proliferation of bland mesothelial cells along fibrovascular cores (papillary architecture), and they are often incidentally discovered growths in the abdominal cavity, although they can also occur in the chest. These are more common in women and are not associated with asbestos exposure. These can have superficially infiltrative growth, but not deeply invasive growth into skeletal muscle or fat, and can be multifocal. While they can recur, these proliferations generally have a very indolent behavior (see image below).
Well differentiated papillary mesothelioma is characterized with a single layer of bland cuboidal cells lining fibrovascular cores, as demonstrated in this image.
Benign cystic mesothelioma is composed of multilocular, sometimes multifocal, mesothelial cysts lined by flat to cuboidal mesothelial cells. They occur more commonly in the abdomen but can be seen in the chest. They may be associated with prior surgery. While these lesions can recur, only very rare cases have been associated with subsequent mesothelial malignancy.
Fibrous mesothelioma is an obsolete term used to describe a solitary fibrous tumor not of mesothelial origin. This does not refer to sarcomatoid mesothelioma.
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Positron emission tomography (PET) scan in a male patient with known mesothelioma. Although PET scanning is not standard for the evaluation of mesothelioma, this image illustrates the extent of the disease into the mediastinum and peritoneum.
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Chest radiograph of a 58-year-old patient with mesothelioma and shortness of breath. This image reveals diffuse, left-sided pleural thickening, a pleural effusion, and ipsilateral volume loss.
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Computed tomography scan of a 58-year-old patient with mesothelioma and shortness of breath. This image shows the extensive pleural thickening that is characteristic of mesothelioma, effusion, and reduction in the volume of the affected hemithorax.
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Computed tomography scan of the chest. This image demonstrates mesothelioma that extends into the chest wall. Note the concentric left pleural thickening, pleural effusion, reduction in volume of the left hemithorax, and the tumor nodules within the chest wall.
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Magnetic resonance imaging (MRI) scan in a 72-year-old Veterans Administration patient with left-sided mesothelioma. Note that the MRI scan well delineates the soft tissues and, in particular, the thoracoabdominal interface at the diaphragm.
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Computed tomography (CT) scan in a male Veterans Administration patient with a history of asbestos exposure and an enlarging abdominal girth. This upper CT scan slice reveals the calcified pleural plaques along the diaphragmatic surface that are associated with asbestos exposure. Ascites is seen lateral to the liver. Aspiration of the ascitic fluid demonstrated mesothelioma.
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The soft-tissue window setting of this chest computed tomography (CT) scan shows the envelope-like mass along the pleural surface surrounding the lung. This was a mesothelioma.
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The classic description of malignant pleural mesothelioma is a thickening in the pleural space with encasement of the lung by a rindlike visceral pleura. These gross specimens are from an autopsy lung case with diffuse thickening of the pleura causing compression of the underlying lung tissue.
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This histologic section stained with hematoxylin and eosin shows papillary structures on the right and a transition to a more solid pattern on the left.
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A solid pattern of mesothelioma on the right of this histologic section transitions to a spindle cell morphology on the left of the image in this predominantly sarcomatoid malignant mesothelioma.
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Well differentiated papillary mesothelioma is characterized with a single layer of bland cuboidal cells lining fibrovascular cores, as demonstrated in this image.
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Immunohistochemistry helps to demonstrate that the atypical mesothelial cells in this reactive proliferation are in fact in one roughly linear layer, an important criterion supporting a benign process.
