Objectives

1. To be able to identify patients at risk for the development of malignant mesothelioma.
2. To understand how the diagnosis of malignant mesothelioma is made.
3. To understand the staging of malignant mesothelioma and important prognostic factors.
4. To understand the therapeutic options for patients with malignant mesothelioma.

Key words

asbestos; extrapleural pneumonectomy; mesothelioma; pleura; pleurectomy; pleurodesis

Abbreviations

EPP=extrapleural pneumonectomy; P/D=pleurectomy with decortication; PDT = photodynamic therapy

The incidence of malignant mesothelioma continues to increase in the United States and Europe, and by most recent estimates will continue to do so until 2020.¹ After that time, it is expected to continue to increase in other countries where the use of asbestos remains unregulated. Although a clear history of asbestos exposure is not always obtained, a history of heavy exposure makes the diagnosis more likely in a patient with a malignant pleural process. Cigarette smoking, however, does not place a patient at increased risk for the development of mesothelioma. Recently, there has been a great deal of controversy as to whether a simian virus that contaminated the polio vaccine administered from 1955 through 1961 may be contributing to the development of mesotheliomas in the United States and other countries. Although some laboratories have found evidence of this virus in tumor specimens, a recent multicenter evaluation of blinded specimens showed no evidence of this virus in specimens from 25 mesothelioma patients.² In addition, an epidemiologic impact has not yet been found.³

Because not all workers exposed to high amounts of asbestos develop mesothelioma, it is clear that unknown genetic factors increase the mesothelial cells’ susceptibility to asbestos. And although risk rises with the amount of exposure to asbestos and the fiber type, fiber numbers in the lung have not been shown to correlate with development of disease.⁴ Groups who have been associated with significant asbestos exposure and increased rates of mesotheliomas include workers in the asbestos industry, insulators, pipefitters, shipyard workers, brake mechanics, railroad workers, construction trades, household contacts of asbestos workers, and workers who perform maintenance and repair in buildings with asbestos insulation.⁵

Clinical Features

The mean age at presentation is 60 years because of the long latency (30 to 40 years, and rarely < 20 years) from the time of exposure to asbestos to the development of clinically evident disease. The incidence is higher in men, presumably because more men have worked in asbestos-related trades. However, it is not uncommon to see women with asbestos-induced mesothelioma whose asbestos exposure has come from exposure their spouses’ contaminated clothing.

Symptoms, signs, and laboratory test results are generally not specific for the disease. Most patients present with aching nonpleuritic chest pain or dyspnea.⁶ Physical examination is usually only remarkable for signs related to the presence of a pleural effusion or mass.

The pleural liquid is usually exudative in nature and is bloody more than half of the time. Cytologic analysis is diagnostic in < 40% of cases.⁷

Radiographic Evaluation

The most common findings are a moderate to large unilateral pleural effusion or unilateral pleural thickening (nodular or smooth).⁶ Invasion of soft tissues and the chest wall with rib destruction may also be seen. Later in the course of disease, there may be volume loss with a shift of the mediastinum toward the side of the primary tumor, as well as lymphatic metastases. It is important to note that pleural plaques are often not visible (28% have plaques).⁵

MRI is preferred over CT by some for staging and preoperative evaluation because it is thought to better demonstrate the extent of disease and areas of invasion (Fig 1). However, one prospective trial failed to confirm the benefit of routine MRI vs CT for staging of mesothelioma.⁸

Fluorodeoxyglucose positron emission tomography shows promise as a tool to differentiate benign from malignant disease and as an adjunct for staging. In one study, it was found to be superior to CT for detecting lymph node involvement.⁹

Figure 1. Top, CT scan of the chest shows encasement of the lung by a rind of tumor. Bottom, MRI of the same patient’s chest shows diaphragmatic invasion by the tumor. This was not evident on the CT scan.

Diagnosis

Surgical biopsy is frequently required to establish a definitive diagnosis of malignant pleural mesothelioma. Clinical features may suggest mesothelioma, but adequate tumor sampling is necessary because the cytologic features alone may suggest other cancers or benign pleural inflammation. For example, epithelial mesotheliomas can be difficult to distinguish from metastatic adenocarcinoma, and sarcomatoid mesotheliomas can look like metastatic or primary sarcoma. To resolve these differences, pathologists employ both immunohistochemistry and electron microscopy. These additional special studies usually require more tissue than can be obtained by less invasive means.

Thoracentesis with pleural fluid cytology is often the first diagnostic test performed, but as noted above, is usually not diagnostic. Image-guided needle biopsy retrieves more tissue, and its tissue is diagnostic in up to 85% of cases.¹⁰ If these approaches fail to provide a definitive diagnosis, then surgical biopsy is indicated. If the disease process has obliterated the pleural space, an incisional biopsy is the only option. However, if there is at least a small pleural effusion, thoracoscopic biopsy is the preferred approach. This can be accomplished either by insertion of a mediastinoscope directly into the pleural space, or with video-assisted thoracoscopy. Surgical biopsies provide adequate tissue for diagnosis, but mesothelioma is notorious for seeding biopsy and chest tube sites.⁷ Therefore, thoracoscopy and chest tube incisions should be placed so that if a subsequent therapeutic resection is performed, the biopsy sites can be easily excised.

The critical advantage of surgical biopsy is that it provides the larger amounts of tissue required for analysis by routine histology as well as electron microscopy and immunohistochemistry. In addition, critical information about the biologic behavior and appearance of the tumor can be obtained. Malignant mesotheliomas typically originate in the parietal pleura, especially on the diaphragmatic surface, whereas primary lung cancers metastatic to the pleura show greater visceral tumor involvement.

Ultrastructural features diagnostic of mesothelioma include cytoplasmic tonofilaments and long, sinuous microvilli. In contrast, the microvilli of adenocarcinomas are relatively short, wide, and straight. Performance of electron microscopy requires that some biopsy material be preserved in glutaraldehyde, while formalin-fixed specimens can be analyzed by immunohistochemistry. Although a variety of immunohistochemical stains have been used to differentiate adenocarcinoma of the lung and mesothelioma, none is specific, especially with less well-differentiated tumors. Because of the difficulties in establishing the diagnosis in some cases, an expert panel of pathologists from the United States and Canada was formed. In their statement, they stressed the need for the pathologist to have information about the behavior of the tumor from the radiographic and intraoperative observations as well as the need for larger specimens to permit multiple immunohistochemical stains.¹¹

Prognosis and Staging

Staging is another controversial issue related to this disease. Prior to the proposal of a TNM-based staging system by the International Mesothelioma Interest Group,¹² there had been at least six other systems proposed for staging of mesotheliomas. None of the six was clearly shown to accurately predict survival, including the most widely used, proposed by Butchart et al. ¹² The TNM-based staging system is organized in a manner similar to the system currently in use for non-small cell carcinoma of the lung. Analysis of a prospective surgical database by one institution supported the prognostic value of this system, but analysis of another database did not.

Overall, the median survival for patients is between 9 and 12 months from the time of diagnosis. Regardless of therapy, patients with the epithelial cell type do best and those with the sarcomatous cell type the worst, with mixed or biphasic falling between the two other types. In addition, advanced age (≥ 75 years), poor performance status, and a high lactate dehydrogenase level (≥ 500 IU) have all been associated with a worse prognosis.¹³

Surgical Management

The two goals of surgical therapy are palliation of symptoms and resection of tumor with therapeutic intent. Pleurodesis is an effective therapy for the dyspnea caused by recurrent pleural effusions, but is ineffective palliation for the pain caused by invasion of tumor into the chest wall and intercostal nerves. Pleurectomy with decortication (P/D) and extrapleural pneumonectomy (EPP) provide effective palliation of both symptoms and may have therapeutic benefit, but these procedures are major operations that are associated with potentially significant operative morbidity.

Pleurodesis

Pleurodesis generates intrapleural inflammation that causes pleural symphysis and obliteration of the pleural space, preventing reaccumulation of a symptomatic pleural effusion. Talc is the most effective agent for this task, and is equally effective when administered as an aerosol during thoracoscopy or as a slurry via an existing chest tube. For pleurodesis to be effective, the affected lung must be able to expand to fill the pleural space. This may not occur if tumor deposits on the visceral pleura create a “trapped” lung. Pleurodesis is ineffective in this setting because the visceral and parietal surfaces need to be in contact for pleural symphysis to occur.
If the diagnosis of mesothelioma has been confirmed and no additional biopsies are anticipated, then simple chest tube drainage and instillation of talc slurry is appropriate. Prior to chest tube placement, however, a large-volume thoracentesis should be performed. If the postthoracentesis chest radiograph demonstrates failure of the lung to expand (trapped lung), and the patient experiences minimal improvement in dyspnea, chest tube placement and pleurodesis are unlikely to be of benefit. A chest tube may evacuate the effusion, but the lung will not expand and the patient will be left with a tube draining a persistent space. In this setting, the chest tube acts as a foreign body; the longer it remains in the pleural space, the greater the risk of contamination and subsequent empyema. Placement of a Pleurx pleural catheter (Denver Biomedical; Golden, CO) is an option for these patients. With this system, an indwelling pleural catheter is placed during an outpatient procedure. Patients access the catheter at home at regular intervals to drain accumulated pleural fluid. This provides symptomatic relief without the need for prolonged hospitalization, and over a period of weeks to months, it may produce pleural symphysis.¹⁴ If the lung does expand with a large-volume thoracentesis and the patient experiences symptomatic improvement, chest tube placement is indicated. Care should be taken to avoid injury to the underlying lung and to place the tube in a dependent portion of the effusion. Larger-caliber catheters are most effective because the talc slurry can become viscous. Once talc has been instilled, daily chest radiographs should be obtained to insure that loculated collections do not form. If they do, prompt identification and catheter drainage is essential for optimal results.

If the diagnosis of mesothelioma is suspected but not confirmed, thoracoscopy should be performed. Multiple biopsy specimens can be taken and the underlying lung can be assessed intraoperatively for its ability to expand once the effusion has been drained. If the lung is not trapped, talc is insufflated at the completion of the procedure. Intraoperative talc insufflation has a success rate of better than 95% in this setting.¹⁵ As with pleurodesis performed with the chest tube already in place, vigilance against accumulation of loculated effusions in the postoperative period insures optimal results.

A particularly troublesome situation that should be avoided is any instrumentation of the pleural space that causes injury to the lung parenchyma in the setting of a trapped lung. Because the lung is unable to expand, pleural symphysis cannot occur and air leaks persist. Prolonged chest tube drainage because of the persistent air leak increases the risk of infection and empyema formation in the residual pleural space. If this situation is encountered, the chest tube usually can be removed safely, even in the presence of a sizable air leak. Early chest tube removal minimizes the risk of empyema.

Pleurectomy/Decortication and Extrapleural Pneumonectomy

The goal of surgery with therapeutic intent is to remove all gross disease. EPP involves en bloc removal of the lung along with surrounding parietal pleura, pericardium, and diaphragm. P/D preserves the underlying lung while removing all gross disease from all pleural surfaces. These are technically challenging procedures that are generally undertaken only at centers with extensive experience and expertise. EPP adheres to the oncologic principle of en bloc complete resection. In contrast, P/D is a less morbid procedure that debulks tumor, potentially delaying disease progression and enhancing the response to subsequent therapy. Although the therapeutic benefit of these procedures is controversial, both provide effective palliation. P/D relieves dyspnea by restoring lung expansion, and relieves pain by removing tumor that invades the chest wall. EPP relieves pain through the same mechanism, and may improve dyspnea by removing a nonfunctional lung that creates a right-to-left shunt and hypoxia.

Both P/D and EPP are accomplished through an extended posterolateral thoracotomy. Previous talc pleurodesis is not a contraindication to either procedure. The sixth rib is removed and the parietal pleural is bluntly dissected away from the chest wall, extending up to the apex of the chest, down to the diaphragm, and over to the pericardium medially. A second, more inferior intercostal incision is usually needed to facilitate dissection at the level of the diaphragm. The diaphragm is dissected off the underlying peritoneum and removed with the specimen. With P/D, once the pericardium is encountered medially, the dissection plane is continued onto the surface of the lung, excising the visceral pleura. In contrast, with EPP, the hilar structures are divided intrapericardially, and the lung is removed en bloc with the pleura. With both procedures, a synthetic patch (Gore-Tex; WL Gore & Associates; Newark, DE) is used to reconstruct the diaphragm. After a right pneumonectomy, reconstruction of the pericardium is also required to prevent cardiac herniation into the right chest. Both EPP and P/D involve prolonged operative times and may generate significant blood loss. One important advantage of EPP over P/D is that, with removal of the lung, postoperative radiation therapy can be delivered in much higher doses.

Preoperative evaluation of patients considered for surgery includes a thorough assessment of tumor stage, cardiac function, and pulmonary function. Because both P/D and EPP are intended to remove all gross tumor, it is essential to confirm that tumor is confined to the hemithorax. Chest CT is the essential first step. MRI is preferred by some centers for assessment of transdiaphragmatic extension of tumor, and others request fluorodeoxyglucose positron emission tomography to identify mediastinal or extrathoracic metastatic disease. Recent experience indicating that mediastinal lymph node involvement is a poor prognostic sign, especially for patients with the sarcomatoid type of mesothelioma, has led the group at the Brigham and Women’s Hospital to recommend cervical mediastinoscopy as an essential part of the staging evaluation.¹⁶ In addition, because mesothelioma may recur intraperitoneally, that group performs laparoscopy prior to opening the chest. Because both P/D and EPP are extensive procedures that place stress on the heart, echocardiography should be performed to insure that cardiac function is normal. For those patients considered for EPP, adequate pulmonary function must also be assured. Generally, a predicted postoperative FEV₁ of 1.2 L is acceptable. Often, the measured values reflect diminished function of the affected lung, and a lung perfusion scan can provide a more accurate estimate of the effect of pneumonectomy.

EPP has been approached with trepidation because the early experience was marked by an unacceptably high mortality rate of 30%. However, advances in surgical, anesthetic, and critical care techniques have dramatically lowered this figure, and experienced centers now report mortality rates of < 4%.¹⁶ This is no different from the mortality rate for a standard pneumonectomy. The most common postoperative complication is atrial fibrillation, occurring in approximately 30% of patients.

Results of P/D and EPP. The therapeutic benefit of P/D and EPP remains controversial. There are no prospective comparisons of these two procedures, or of surgery vs medical management or supportive care. Without such studies, it is difficult to conclude that surgery imparts a survival benefit. In addition, all surgical series must be interpreted with acknowledgment of inherent selection bias for patients with earlier-stage disease and better performance status.

Despite these caveats, several large series suggest that P/D and EPP may provide a survival advantage for selected patients. In 1997, Pass and colleagues¹⁷ reported on results with 78 patients from the National Cancer Institute. Thirty-nine patients underwent P/D and 39 underwent EPP. Median survival times were 14.5 and 9.4 months, respectively, after P/D and EPP. A year earlier, Rusch and Venkatraman¹⁸ also found that P/D was associated with a longer median survival than EPP. In this series, 50 patients underwent P/D and 51 underwent EPP; median survival was 18 and 10 months, respectively. However, in a follow-up report in 1999, with an additional 130 patients, the same investigators found that there was no difference in median survival between EPP and P/D.¹⁹ In general, failure after P/D is local, while failure after EPP is extrathoracic. These results are consistent with the oncologic principles of the procedures, and underscore the difficulty in surgically eradicating mesothelioma.

Sugarbaker and colleagues¹⁶ at the Brigham and Women’s Hospital have pursued an organized program of EPP followed by chemotherapy and high-dose radiation therapy. Of the patients who survived surgery (176 of 183), median survival was 19 months and 2-year survival was 38%. Five-year survival was 15%. However, patients with an epithelial cell type, clean margins after resection, and negative lymph nodes had a 2-year survival rate of 68% and 5-year survival rate of 46%. These results are encouraging, but may reflect a significant component of selection bias. In their series, Sugarbaker and colleagues¹⁶ found that only 23% of patients undergoing surgery had involved mediastinal nodes. In contrast, Rusch and Ventrakaman¹⁹ reported an incidence of 57%, and Pass and colleagues¹⁷ found lymph node metastases in 79% of their patients.

Photodynamic Therapy

In photodynamic therapy (PDT), a drug is used to make cells sensitive to a particular wavelength of light. The drug is administered IV before surgery. The patient is then taken to the operating room, as much of the tumor is removed as possible, and a light source is placed in the chest. Serious complications include myocardial perforation. This therapy was studied in a phase III trial by Pass et al.²⁰ Patients were randomized to P/D with or without intraoperative PDT. Tumor was resected to minimal disease prior to initiation of PDT. They found no difference in median survival or time to progression between the two groups. Median survival was 14 months.

Chemotherapy

Many different chemotherapeutic agents have been tried alone and in combination with limited success. It is difficult to interpret clinical trials because the number of patients is usually small and there is a lack of uniformity in staging. An extensive review of chemotherapy trials by Ryan et al²¹ that covers studies up to the late 1990s is very helpful. They concluded that the highest antitumor activity was demonstrated with the antimetabolites, small activity is seen with platinum compounds, and even less with plant alkaloids. They also found no evidence that combination chemotherapies provided survival benefit over single-agent chemotherapy.
Since that review, two trials using cisplatin in combination with gemcitabine²² or irinotecan²³ have been reported. Both demonstrated that a significant number of patients had improvement in symptoms, but there was no significant improvement in survival.

Recently, there has been considerable excitement about the use of two new antifolates, pemetrexed and raltitrexed, in mesothelioma. These agents, used in combination with platinum-based compounds, have shown promise in phase I and II studies, with a significant number of patients showing objective responses. Phase III trials are in progress to determine if the use of these agents alone or in combination is associated with improved survival.²⁴

Radiation Therapy

Although in vitro studies suggest that mesothelioma is more sensitive to radiation than non-small cell lung cancer, the clinical experience reported by radiation oncologists suggests that it is an especially radioresistant tumor. In addition, radiation of the involved chest is limited by the presence of radiosensitive organs. As a consequence, its use appears limited to adjunctive therapy for patients who have undergone EPP, and to palliative treatment of painful chest wall lesions.

Immunotherapy

Intrapleural instillation of cytokines to stimulate an immune response to the tumor has been tried at some centers. Instillation of these agents must be continuous because the half life is so short. This requires placement of an intrapleural catheter. A study of intrapleural interleukin-2 by Goey et al²⁵ found a partial response in four of 21 patients and an overall survival of 16 months. Intrapleural interferon-gamma has also been studied. Boutin et al²⁶ reported a partial response rate of 19%, but most of those patients had stage IA disease.

Gene Therapy

Molecular chemotherapy of mesothelioma is under study at two institutions in the United States. Investigators at the University of Pennsylvania instill an adenoviral vector containing the herpes simplex thimadine kinase (HSVtk) gene into the pleural space of patients.²⁷ This virus is taken up by mesothelial cells and the (HSVtk) gene product makes the cells metabolize ganciclovir to a toxic byproduct. In humans, the viral uptake is patchy, and repeated dosing is limited by the development of immunity to the virus. However, more recent results from the dose-escalation trial show promise. Investigators at Louisiana State University are using a similar strategy, but instead instill terminally irradiated ovarian cancer cells transfected with this gene.

Newer Agents Under Study

Ranpirnase [onconase (p30)] is a ribonuclease inhibitor that has been shown to have activity in this disease.²⁸ A multicenter trial is currently in progress using onconase in combination with doxorubicin vs doxorubicin alone.

Other agents undergoing clinical investigation for treatment of mesothelioma include ZD 1839 (Iressa), an epidermal growth factor inhibitor; antimesothelin monoclonal antibody toxin (the antibody carrys a potent cytotoxic agent that attaches to the mesothelin antigen on tumor cells); and antineoplastons (peptides found in the blood and urine of man with antitumor effects).

Palliation

The most distressing problem for patients and families is often the development of severe, unremitting pain that can be very difficult to control. As mentioned above, if there is a specific site of chest wall invasion, radiation can be quite useful. In severe cases, the placement of a chronic epidural catheter can provide dramatic relief without the clouded sensorium associated with narcotics.

Summary

Malignant mesothelioma can be difficult to diagnose and difficult to treat. Diagnosis requires recognition of patients at risk for the disease, knowledge of the typical radiographic and clinical features of the disease, adequate tissue sampling to permit a variety of immunohistochemical tests, and the aid of an experienced pathologist. Favorable prognostic factors include epithelial cell type, younger age, and early-stage disease. A variety of new treatments are now available and provide hope for improved quality of life and even cure in some cases.

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