Mesothelioma

INTRODUCTION

Background: Mesothelial cells normally line the body cavities, including the pleura, peritoneum, pericardium, and testis. Malignancies involving the body cavity mesothelial cells are known as malignant mesothelioma, which may be localized or diffuse. Diagnosis is difficult because fluid analysis of effusion from the tumor usually is nondiagnostic. Most, but not all, pleural malignant mesothelioma is associated with asbestos exposure.

Pathophysiology: Three major histological types of mesothelioma exist: (1) sarcomatous, (2) epithelial, and (3) mixed. Pleural mesotheliomas usually begin as discrete plaques and nodules that coalesce to produce a sheetlike neoplasm. Tumor growth usually begins at the lower part of the chest. The tumor may invade the diaphragm and encase the surface of the lung and interlobar fissures.

The tumor also may grow along drainage and thoracotomy tracts. As the disease progress, it often extends into the pulmonary parenchyma, chest wall, and the mediastinum. Pleural mesotheliomas may extend into the esophagus, ribs, vertebra, brachial plexus, and superior vena cava.

Frequency:
　

• In the US: Approximately 2000-3000 cases are diagnosed per year.

• Internationally: Frequency is 0.9 cases per 100,000 persons.

Mortality/Morbidity:

• Median survival for patients with malignant mesothelioma is 11 months. It almost always is fatal. Median mortality based on histologic types is 9.4 months for sarcomatous, 12.5 months for epithelial, and 11 months for mixed. Approximately 15% of patients have an indolent course.

• Asbestos exposure is linked to at least 50% of patients developing malignant mesothelioma. Approximately 8 million people in the United States have been exposed to asbestos in the workplace. Family members also are exposed to asbestos embedded in the worker's clothing. The combination of tobacco and asbestos exposure greatly increases the risk of developing pleural mesothelioma.

Race: No racial predilection for mesothelioma exists. Asbestos exposure is the most important factor regardless of race.

Sex: Malignant mesothelioma is more common in men, with a male-to-female ratio of 3:1. It also can occur in children; however, this is thought to be unassociated with asbestos exposure.

• Women with mesothelioma: In one case series, 86% of the tumors arose from the pleura, of which the majority were of the epithelial type; 75% had a history of exposure to asbestos and more than half were secondary to household contact with a worker exposed to asbestos (Ascoli, 1996).

• Men with mesothelioma: In the case series, men had a 45.5% history of exposure to asbestos, and 53% had occupational exposure. Most who were involved were construction workers, railroad workers, naval mechanics, bakers, explosive workers, and automobile mechanics.

CLINICAL

History:

• Dyspnea is the most common presenting symptom.

• Chest x-ray shows obliteration of the diaphragm, nodular thickening of the pleura, decreased size of the involved chest, and/or radiolucent sheetlike encasement of the pleura.

• A loculated effusion is present in over 50% of patients, and a major portion of the pleura is opacified by the effusion.

• Chest discomfort, pleuritic pain, easy fatigability, fever, sweats, and weight loss are the other common accompanying symptoms.

• Approximately 60-90% of patients may have symptoms of chest pain or dyspnea.

Physical:

• Physical findings of pleural effusion on percussion and auscultation usually are noted.

• In rare cases, malignant mesothelioma presents as cord compression, brachial plexopathy, Horner syndrome, or superior vena cava syndrome.

• Primary sites include the following:

• Pleural, 87%

• Peritoneal, 5.1%

• Pericardial, 0.4%

• Right side of the thorax more than left (ratio 1.6:1)

Causes:

• A substantial proportion of patients were exposed to asbestos in asbestos mills, shipping yards, mines, or their homes.

• The crocidolite in asbestos is associated with mesothelioma in miners, manufacturers (using asbestos), and heating and construction workers.

• Malignant mesothelioma also has been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil.

• An etiological role for simian virus 40 (SV40) in malignant mesothelioma also has been suggested.

• Interleukin (IL)-8 has a direct growth-potentiating activity in mesothelial cell lines.

WORKUP

Lab Studies:
　

• Pleural fluid findings in patients with mesothelioma: The specific gravity of the pleural fluid is nondiagnostic.

• Typically, less than 1000 leukocytes/mL, few erythrocytes, elevated protein, and normal lactate dehydrogenase (LDH) levels are present.

• Results of cytologic examination occasionally are positive for malignant mesothelial cells, but, most of the time, plural fluid cytology is nondiagnostic.

• Diagnosis

• Over 90% of cases present with pleural effusion that decreases after thoracentesis. Cytologic examination is diagnostic in only 32% of cases and is suggestive in 56% of cases. Thoracoscopically guided biopsy should be performed if suspicion of mesothelioma exists, and it is diagnostic in 98% of cases.

• Careful scrutiny of routinely stained biopsy preparations is the most rewarding component in making a diagnosis with the help of a battery of commercial immunohistochemistry stains (cytokeratins, vimentin, HMFG-2, anti-Leu M l, BerEP4, and carcinoembryonic antigen).

• Diagnostic features distinguishing malignant mesothelioma from adenocarcinoma include negative test results for periodic acid-Schiff stain, mucicarmine stain, carcinoembryonic antigen, Leu M-1, and positive test results for vimentin and cytokeratin. On electron microscopy, cells would have long microvilli in contrast to adenocarcinomas, which have short microvilli.

• Recently, 4 new mesothelioma cell lines have been characterized by ultrastructural and immunophenotypic analysis. Cell lines express vimentin, cytokeratins 8 and 18, and mesothelial antigen recognized by HBME-1 monoclonal antibody. Surface human leukocyte antigen (HLA) class I and intercellular adhesion molecule (ICAM)-l are present in all lines.

• While HLA class II and CD 86 are undetectable, HLA 2 is present after interferon gamma stimulation. All cell lines display abnormal karyotypes with chromosome 6 abnormalities. The persistence of large T antigen with HLA class I and ICAM-l points to large T antigen as a target for cytotoxic-based immunotherapy.

Imaging Studies:
　

• Imaging studies may include chest x-ray, CT scan of the chest, MRI of the chest, and positron emission tomography (PET) scans. PET scans still are investigational to differentiate between benign and malignant mesothelioma

• The optimal preoperative staging procedures are debatable. Sugarbaker et al (1996) recommend MRI as a standard part of staging. Others ague that laparoscopy/thoracoscopy is the best way to determine the extent of the disease. Some argue that PET may be helpful, but its role in staging needs to be defined.

• Preoperatively, measuring diffusion capacity of the lung is important because most of the patients have poor pulmonary reserve secondary to interstitial lung disease.

• A cardiopulmonary stress test with pharmacologic agents would be reasonable to eliminate the possibility of evidence of silent myocardial ischemia.

• In summary, it is important to determine the extent of the disease by laparoscopy or MRI and to perform cardiopulmonary evaluation if the patient is amenable.

Procedures:
　

• Thoracoscopy or pleuroscopy should be performed to confirm the diagnosis.

• Laparoscopy for staging is important but still investigational to evaluate transdiaphragmatic involvement.

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 the diaphragm. Microscopically, 3 histologic types exist?1) epithelial, (2) sarcomatous, and (3) mixed. The epithelial type correlates with a better prognosis.

Staging: No standard staging system exists, although 6 systems have been proposed. Sugarbaker and associates (1996) have proposed the Brigham staging system based on tumor resectability and nodal status, a system validated in a clinical trial. The tumor, node, metastases (TNM) classification has been proposed but still requires validation. The Brigham staging for malignant pleural mesothelioma is as follows:

• Stage I - Completely resected within the capsule of the parietal pleura without adenopathy (ipsilateral pleura, lung, pericardium, diaphragm, or chest wall disease limited to previous biopsy sites)

• Stage II - All of stage I characteristics, with positive resection margins and/or intrapleural adenopathy

• Stage III - Local extension of disease into the chest wall or mediastinum, the heart, through the diaphragm or peritoneum, or with extrapleural lymph node involvement

TREATMENT

Medical Care: Treatment options for the management of malignant mesothelioma include surgery, chemotherapy, radiation, and multimodality treatment.

• Currently, no standard therapies exist for this disease.

  　

• None of the standard treatment options has improved survival.

  　

• The most active agents are anthracycline, platinum, and alkylating agents; each producing response rates of 10-20%.

• Recently, a phase II study using cisplatin 100 mg/m² on day 1 and gemcitabine 1000 mg/m² administered intravenously on days 1, 8, and day 15 of a 28-day cycle for 6 cycles has shown response rates of 47.6 % (complete and partial response), 42.8 % (stable disease), and 9.5% (progressive disease) (Byrne, 1999). The median response duration was 25 weeks, progression-free survival was 25 weeks, and the overall survival was 41 weeks. Toxicity mainly was gastroenterologic and hematologic.

  　

• Several other combinations have been found to be active, including cisplatin/Adriamycin/mitomycin, C/bleomycin/intrapleural hyaluronidase, cisplatin/Adriamycin, and cisplatin/vinblastine/mitomycin C. The cisplatin/gemcitabine combination has yielded the best results.

  　

• With the isolation of mesothelial cell lines, several chemotherapeutic agents are being tested actively at this time to assess their efficacy. One explanation for the poor response to chemotherapy is the low apoptotic rate as evidence by low bcl-2 and bax expression. These data suggest that apoptosis is not a key phenomenon in mesothelioma development and histologic differentiation.

  　

• Numerous trials of chemotherapeutic agents have been performed, but, until recently, these studies were small, different staging systems were used, and inaccurate disease measurements were performed. Radiation: Results with radiation therapy also are disappointing. Radiation has no effect on survival, but it has caused significant palliation in 50% of patients treated for chest pain and chest wall metastasis.

• Trimodality therapy involves a combination of all 3 standard strategies (surgery, chemotherapy, and radiation). One trimodality approach involved extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. Overall survival was 45% at 2 years and 22% at 5 years.

• Lymph node involvement was a significant negative prognostic factor. Epithelial cell type had a better survival rate compared to sarcomatous or mixed type (65% versus 20% at 2 years and 27% versus 0% at 5 years).

• Survival based on the Brigham staging system was 22 months for stage I, 17 months for stage II, and 11 months for stage III.

• Overall median survival was 17 months, yielding a 2-year survival rate of 36% and a 5-year survival rate of 14%. Epithelial cell type survival was better with a 2-year survival of 68% and 5-year survival of 46%.

  　

• Different chemotherapeutic regimens found to be useful in the trimodality treatment include CAP (cyclophosphamide, Adriamycin, cisplatin); carboplatin-paclitaxel; and cisplatin, methotrexate, vinblastine. External-beam radiotherapy is delivered in standard fractionation over 5.5-6 weeks.

Surgical Care: Surgical resection has been relied on because radiation and chemotherapy have been ineffective primary treatments. Two surgical procedures have been used, (1) pleurectomy with decortication and (2) extrapleural pneumonectomy.

• Pleurectomy/decortication is a more limited procedure and requires less cardiorespiratory reserve. It involves dissection of the parietal pleura, incision of the parietal pleura, and decortication of the visceral pleura followed by reconstruction. It has a morbidity of 25% and mortality rate of 2%. It is a difficult procedure because the tumor encases the whole pleura and local recurrence rate is high.

• Extrapleural pneumonectomy is a more extensive procedure and has a higher mortality rate. Recently, the mortality rate has been lowered to 3.8%. It involves dissection of the parietal pleura, division of the pulmonary vessels, en bloc resection of the lung, pleura, pericardium, and diaphragm followed by reconstruction. It provides the best local control because it removes the entire pleural sac along with the lung parenchyma.

• With surgery alone, the recurrence rate is very high and most of the patients die after a few months. At least half of the patients who have local control with surgery will have distant metastasis on autopsy.

Consultations:

• If an infection is first suspected, a consultation with a pulmonary specialist is essential if the infection does not resolve within 2 weeks with adequate antibiotic treatment.

• Chest x-ray is mandatory for follow-up if the infection has resolved. If diffuse calcification of the pleura and a history of weight loss with chronic cough exist, a full evaluation by a pulmonary specialist and oncologist is necessary.

• A referral for thoracoscopy is warranted if the diagnosis is entertained whenever the initial workup is not diagnostic.

• Occupational history is important, and family members with exposure to asbestos also should be evaluated.

Diet: Patients usually are cachetic after surgery, chemotherapy, and radiation. Good supportive care and a regular nutritional status assessment are warranted. Patients should be referred to the nutrition team.

Activity:

• Beginning physical activity as soon as possible to prevent postoperative complications is important.

• Pulmonary physiotherapy is very helpful because of the extensive lung resection in such patients.

FOLLOW-UP

Further Inpatient Care:
　

• Factors predictive of poor survival by multivariate cox analyses include the following:

• Poor Eastern Cooperative Oncology Group (ECOG) performance status (>1, less than ambulatory status)

• Pleural involvement

• Serum LDH greater than 500 IU

• Chest pain

• Platelets greater than 400,000/mL

• Nonepithelial histology

• Age older than 75 years

Further Outpatient Care:
　

• Regular follow-up with an internist, pulmonary specialist, medical oncologist, and radiation oncologist is recommended.

Complications:
　

• The tumor recurrence rate is 50% for those treated with surgery.

• Mortality secondary to surgery has improved. Even with extensive surgery, the mortality rate in one series was 3.8% (Huncharek, 1996; Sugarbaker, 1996).

Prognosis:
　

• Without treatment, mesothelioma is fatal within 4-8 months.

• With trimodality treatment, survival was noted in some patients at 16-19 months. A few survived as long as 5 years, 14 % for all types and 46% for epithelial type. However, numbers are small.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• This diagnosis is difficult to make, so warn the pathologist if high index of suspicion exists for the disease. The diagnosis could be work-related, and a thorough discussion with the patient should be made.

• The legal implications are tremendous, primary prevention is important, and employers should limit the amount of asbestos exposure to levels as low as possible. Having work standards in place is important.

• A good working relationship between an occupational medicine specialist, the environmental hazard team, and the community at large is important.

Special Concerns:
　

• Other modalities of treatment being studied include gene therapy, cytokine-targeted therapy, and photodynamic therapy.

• Gene therapy: Phase I clinical trials have shown the safety of intratumoral gene transfer of recombinant adenovirus containing herpes simplex virus thymidine kinase, followed by ganciclovir treatment. Gene therapy trials are focusing on immunostimulation and using suicide gene therapy as a tumor vaccine. Studies are developing vaccines against SV40, which is thought to be carcinogenic.

• Cytokine-targeted therapy includes several agents, such as IL-2, alpha interferon, and tumor necrosis factor. IL-2 in stages I and II produces an overall survival rate of 16 months. Gamma interferon produced a partial response rate of 19%.

• Photodynamic therapy has been tried but has not produced improvement in survival.