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StatPearls [Internet].
Show detailsContinuing Education Activity
Malignant mesothelioma is a rare but aggressive cancer originating from mesothelial cells, which form the lining layers of the body’s viscera. The pleural layer is most commonly affected, leading to malignant pleural mesothelioma, which is strongly associated with asbestos exposure. Asbestos inhalation induces repeated pleural inflammation, disrupts mitosis, activates proto-oncogenes, and generates free radicals. While ionizing radiation and mutations in the BRCA 1 Associated Protein (BAP1) have also been linked to the disease, smoking itself does not contribute to mesothelioma. However, it increases the risk of lung cancer in conjunction with asbestos exposure. This cancer’s diagnosis and management remain challenging, with limited treatment options and poor prognosis.
This activity focuses on enhancing healthcare professionals’ understanding of malignant mesothelioma, covering key aspects such as epidemiology, genetics, clinical presentation, and management strategies. By exploring the latest research and treatment guidelines, participants will gain valuable insights into diagnosing and treating this rare malignancy. Healthcare professionals will learn how to integrate an interprofessional approach to care, ensuring patients receive the best possible outcomes, from early diagnosis to palliative management.
Objectives:
- Differentiate malignant mesothelioma from other thoracic malignancies based on imaging studies, histopathological findings, and clinical features.
- Implement evidence-based treatment protocols for malignant mesothelioma based on tumor staging, patient condition, and treatment feasibility.
- Assess the tumor’s resectability and staging using the National Comprehensive Cancer Network guidelines and imaging studies.
- Collaborate with an interprofessional healthcare team to provide comprehensive care, coordinate treatment plans, and adjust based on patient response and evolving clinical needs.
Introduction
Malignant mesothelioma is a rare and aggressive tumor arising from mesothelial cells forming the viscera lining. It is strongly associated with asbestos exposure. While mesothelioma can develop in any mesothelial layer, such as the peritoneum or pericardium, the pleural layer is most commonly affected, leading to malignant pleural mesothelioma.[1][2][3][4] Among the various forms of asbestos, amosite and crocidolite are most strongly linked to the development of malignant mesothelioma.
Etiology
Malignant pleural mesothelioma is primarily associated with asbestos exposure. Inhaling asbestos fiber can lead to repeated pleural inflammation, disruption of cellular mitosis, activation of proto-oncogenes, and the generation of free radicals. These mechanisms collectively contribute to the pathogenesis of the disease. Additionally, some studies suggest links between malignant pleural mesothelioma and other risk factors, including:[5]
- Ionizing radiation: For example, mantle radiation therapy used for Hodgkin lymphoma
- Genetic predispositions: Germline mutations in the BRCA1-associated protein 1 (BAP 1) gene
Notably, smoking is not directly linked to malignant pleural mesothelioma. However, combined smoking and asbestos exposure significantly increase the risk of lung cancer.
Occupational asbestos exposure is a key determinant in developing malignant pleural mesothelioma. Professions associated with high asbestos exposure include:
- Shipbuilding
- Mining
- Ceramics manufacturing
- Cement manufacturing involving asbestos
- Auto parts productions, especially brake lining
- Paper mill operations
- Insulation work
- Railroad repair
Current evidence does not indicate a role for alcohol, tobacco (beyond its synergistic effect with asbestos for lung cancer), or dietary factors in the development of malignant pleural mesothelioma.
Genetic makeup may influence individual susceptibility to malignant pleural mesothelioma. A loss of 1 copy of chromosome 22 is frequently observed in patients with the disease. Other chromosomal anomalies linked to malignant pleural mesothelioma include deletions in:
- Chromosomal arm 3p
- Chromosomal arm 1p
- Chromosomal arm 6q
- Chromosomal arm 9p.
Epidemiology
Malignant pleural mesothelioma has an incidence of approximately 2500 new cases annually in the US, compared to over 160,000 new cases of lung cancer reported each year. Most malignant pleural mesothelioma cases in the US have a documented history of asbestos exposure.
The median survival for malignant pleural mesothelioma is approximately 1 year, with long-term survival being extremely rare. Malignant pleural mesothelioma predominantly affects males, likely due to occupational exposure in historically male-dominated industries. The disease typically occurs after the fifth decade of life, with an average age at diagnosis of 72. There is usually a latency period of 20 to 40 years between asbestos exposure and diagnosis. Rare cases of malignant pleural mesothelioma have been reported in children. Unlike adult cases, these are unrelated to asbestos exposure and may arise from other environmental or genetic factors.[6]
The incidence of malignant pleural mesothelioma varies globally, influenced by differences in asbestos use and regulatory oversight. Countries like China, where asbestos is still widely used with limited regulation, report higher incidences of malignant pleural mesothelioma. On the other hand, in regions like Hong Kong, despite high levels of asbestos exposure, malignant pleural mesothelioma rates remain low. The underlying reasons for such geographical discrepancies remain unclear and warrant further investigation.
Pathophysiology
Malignant mesothelioma is classified into 3 histological subtypes:
- Epitheliod: The most common and associated with better prognosis and treatment outcomes than other types.
- Sarcomatoid: Least common and most aggressive subtype associated with poorer outcomes.
- Mixed (biphasic): Contains features of both epitheliod and sarcomatoid and has an intermediate prognosis.
The tumor is often multifocal, forming multiple nodules that typically originate in the parietal pleura. Malignant mesothelioma frequently spreads to the visceral pleura, followed by invasion into adjacent structures, such as the chest wall, diaphragm, or mediastinum. Lymph node involvement generally begins in the bronchopulmonary or hilar lymph nodes. From there, it can extend to the cardinal, internal mammary, or peridiaphragmatic nodes.
Unlike lung cancer, the nodal spread in malignant mesothelioma is characterized by direct local invasion rather than distant dissemination. Overall, lymph node involvement in malignant pleural mesothelioma is relatively uncommon, which distinguishes its behavior from other thoracic malignancies like lung cancer.
Histopathology
Analysis of excised tissue from malignant pleural mesothelioma typically reveals large nodules on the pleural surface. Histologically, mesothelioma is classified into 3 primary subtypes: epithelioid, sarcomatoid, and biphasic.
- Epithelioid or epithelial subtype
- The most common subtype and associated with the most favorable prognosis
- Characterized by cuboidal, columnar, or flattened cells forming tubular, gland-like structures or solid nests
- The cells exhibit eosinophilic cytoplasm, round to oval nuclei, and prominent nucleoli
- Psammoma bodies may occasionally be observed
- Sarcomatoid subtype
- Has the worst prognosis
- Composed of spindle-shaped cells arranged in fascicles or a haphazard pattern
- Cells can exhibit marked nuclear atypia and high mitotic activity, often resembling fibrosarcoma or spindle cell carcinoma
- Biphasic subtype
- Contains a combination of epithelioid and sarcomatoid components, with each comprising at least 10% of the tumor
- Prognosis depends on the relative proportion of each component
Immunohistochemistry is essential for distinguishing mesothelioma from other malignancies, including metastatic carcinoma and sarcoma. Commonly positive markers in mesothelioma include:
- Calretinin
- Wilms Tumor-1 (WT-1)
- D2-40
- Cytokeratin 5/6
In contrast, negative markers such as carcinoembryonic antigen (CEA) and Ber-EP4 are useful in ruling out metastatic adenocarcinoma. Molecular studies, such as BRCA1 associated protein (BAP1) loss and CDKN2A (p16) deletion, may support the diagnosis. [7]
History and Physical
Evaluating a patient with suspected malignant pleural mesothelioma involves a detailed history and comprehensive physical examination. These components are critical for identifying potential risk factors, understanding the clinical presentation, and guiding further diagnostic investigations.
A detailed exposure history is critical in evaluating patients with suspected malignant mesothelioma, as asbestos exposure remains the most significant risk factor. Healthcare professionals should identify occupational or environmental exposure, particularly in professions with high asbestos exposure. Given the long latency period between asbestos exposure and symptom onset, it is crucial to inquire about remote exposures that have occurred decades earlier.
Malignant pleural mesothelioma typically presents with chest pain and dyspnea, the latter often indicating the presence of a pleural effusion, which is the most common initial finding and occurs in approximately 90% of patients. In addition to these hallmark symptoms, patients may experience nonspecific systemic symptoms such as unintentional weight loss, appetite loss, cough, fatigue, and chest wall mass.
Evaluation
The evaluation of malignant pleural mesothelioma requires a combination of laboratory tests, imaging studies, and histopathological analysis to confirm the diagnosis and guide treatment. Early diagnosis is crucial for determining the stage of the disease, assessing the extent of metastasis, and selecting the most appropriate therapeutic approach.
Laboratory tests play a key role in the evaluation of malignant mesothelioma. Pleural fluid analysis, including cytology, may reveal atypical mesothelial cells; however, it is insufficienty for definitive diagnosis. Hematology and biochemistry tests, including complete blood count, liver function tests, and renal function tests, are essential for assessing the patient’s overall health and determining their suitability for invasive procedures or treatment. Elevated lactate dehydrogenase levels or anemia may suggest advanced disease. Additionally, molecular testing for BAP1 mutations and CDKN2A (p16) deletion through fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) can be used to identify specific markers for mesothelioma and differentiate it from other malignancies. The megakaryocyte potentiating factor is utilized as a serum biomarker to aid in the diagnosis.
Radiographic imaging is crucial in the evaluation and staging of malignant mesothelioma. A chest X-ray is often the first imaging study, revealing findings such as pleural thickening, effusion, or masses. Computed tomography (CT) scans with intravenous contrast are considered the standard of care for initial evaluation, providing detailed images that show pleural thickening, nodularity, effusions, and potential invasion of the chest wall or diaphragm. Additionally, thoracoscopic pleural biopsy and thoracentesis of pleural effusion with cytologic analysis are essential for confirming the diagnosis.[8][9][10]
Positron emission tomography (PET) or PET-CT scans, using fluorodeoxyglucose (FDG), are increasingly utilized to identify metabolically active lesions, detect masses, and assess treatment response. PET-CT is particularly valuable for accurately staging the disease. Additionally, magnetic resonance imaging (MRI) is employed when there is a need to evaluate soft tissue involvement, especially in cases with suspected chest wall, diaphragmatic, or mediastinal invasion.
Treatment / Management
The management of malignant pleural mesothelioma typically involves a multimodal approach, incorporating surgery, systemic therapies, radiation, and supportive care. The treatment plan is tailored to the disease stage, histologic subtype, and the patient's performance status. Potential treatment options include:
1. Surgery
Surgery is primarily indicated for early-stage malignant mesothelioma to achieve macroscopic complete resection.
- Extrapleural pneumonectomy: A radical procedure that involves the resection of the pleura, lung, pericardium, and diaphragm. It is typically reserved for highly selected patients due to the high morbidity and mortality.
- Pleurectomy and decortication: A lung-sparing alternative that removes the pleura and tumor while preserving pulmonary function. This procedure is increasingly favored due to its lower complication rates and comparable survival outcomes.
2. Systemic therapy
- Chemotherapy: The standard regimen combines pemetrexed with either cisplatin or carboplatin, often with folic acid and vitamin B12 supplementation to reduce toxicity. In eligible patients, the addition of bevacizumab, a VEGF inhibitor, may enhance treatment efficacy.
- Immunotherapy: Combination immune checkpoint inhibitors, such as nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor), are FDA-approved for unresectable mesothelioma, demonstrating improved overall survival in clinical trials. Single-agent PD-1 inhibitors like pembrolizumab may be considered for refractory cases.
3. Radiation therapy
- Adjuvant radiation: Intensity-modulated radiation therapy (IMRT) is often used postoperatively to reduce the risk of local recurrence, particularly following an extrapleural pneumonectomy (EPP).
- Palliative radiation: This is primarily used for symptom management, including alleviating chest wall pain or controlling disease-related dyspnea.[11]
4. Emerging and investigational therapies
- Tumor treating fields: A novel therapy using alternating electric fields to disrupt tumor mitosis. It has been approved in combination with chemotherapy for unresectable pleural mesothelioma.
- Targeted therapies: Research is ongoing into agents targeting mesothelioma-specific pathways, such as mesothelin, BAP1 mutations, as well as other molecular abnormalities, showing promising results.[12]
- Gene and cell therapies: Clinical trials are exploring the potential of CAR-T cells and gene-editing strategies for treating mesothelioma.[13]
5. Supportive and palliative care
- Pleural interventions: Indwelling pleural catheters or pleurodesis may be employed to manage recurrent effusions, helping alleviate symptoms.
- Symptom management: Effective pain control, nutritional support, and psychosocial care are essential for enhancing the patient's quality of life and providing comfort during treatment.
The treatment plan for mesothelioma should involve a multidisciplinary team, including surgical oncologists, medical oncologists, and radiation specialists. Enrollment in clinical trials is encouraged for eligible patients to access innovative therapies. It is advised that mesothelioma be managed by a multidisciplinary team at a high-volume center for optimal outcomes.[8][14][15][16]
Differential Diagnosis
The differential diagnoses for malignant pleural mesothelioma include the following:
- Non-small cell lung cancer
- Small cell lung cancer
- Drug-induced lung complications
- Benign pleural mass
- Lung infection
- Lung fibrosis
Surgical Oncology
For resectable disease, surgical options include either pleurectomy/decortication (P/D) for early-stage mesothelioma or EPP, which involves the resection of pleura, lung, pericardium, and diaphragm, in cases where curative resection is attempted. The choice between these procedures remains controversial due to limited evidence. EPP carries higher mortality than P/D, although this may reflect the patient population selected for each procedure. High-dose adjuvant radiotherapy following EPP can improve local control.
Prophylactic radiotherapy has been explored but remains controversial, with no definitive benefit demonstrated. Systemic chemotherapy, typically platinum-based, can be administered as neoadjuvant or adjuvant therapy. While neoadjuvant chemotherapy may increase survival in responders, its overall efficacy remains unproven. Adjuvant chemotherapy poses challenges due to the toxicity of the agents, especially after the stress of extensive surgery.
Radiation Oncology
Radiation therapy is utilized primarily for palliative purposes in malignant pleural mesothelioma. While it does not significantly impact overall survival, it can provide symptomatic relief, particularly in managing pain associated with chest wall metastasis.
Medical Oncology
For unresectable disease, platinum-based chemotherapy agents, such as cisplatin, remain the primary treatment option. However, malignant pleural mesothelioma exhibits significant resistance to chemotherapy, resulting in an uncertain survival benefit. For instance, the combination of gemcitabine and cisplatin demonstrates a response rate of 12% to 48%, yet the median overall survival remains only 9 to 13 months. Ongoing research is exploring biologic and antiangiogenic therapies as potential advancements in treatment.
Staging
Staging malignant pleural mesothelioma has been challenging due to the rarity of cases and poor survival rates. Before 1990, at least 5 staging systems were proposed, culminating in the first consensus system published in 1995. This system utilized tumor, node, and metastasis designations, drawing heavily from parenchymal lung cancer descriptors. With the establishment of a comprehensive database collecting cases from 1995 to 2013, evidence-based revisions to the 1995 staging classification were published in 2016.[17] Below are the stages of malignant mesothelioma:
- Stage I: A resected mass confined within the capsule of the parietal pleura with no lymphadenopathy.
- Stage II: Includes all the features of stage I, but margins are positive after resection. Intrapleural lymphadenopathy may be present.
- Stage III: Local invasion of the mass into the mediastinum, pericardium, chest wall, or peritoneum, often accompanied by lymphadenopathy.
- Stage IV: Characterized by the presence of distant metastatic disease.
Prognosis
Despite advancements, the prognosis for most patients with malignant pleural mesothelioma remains poor, with a median survival rate of 4 to 6 months without treatment. With appropriate treatment, some patients may achieve survival times of 15 to 18 months, and in some rare cases, 5-year survival has been reported. Tumor recurrence, particularly in surgically managed patients, remains a significant challenge to long-term outcomes.
Patients undergoing surgery may experience slightly extended survival, but the procedure is associated with a high risk of complications. These complications include arrhythmias, wound infection, deep vein thrombosis, air leaks, respiratory failure, postoperative bleeding, and myocardial infarction. Poor prognostic factors for malignant pleural mesothelioma include nonepithelial histology, poor performance status, age older than 75, dyspnea and chest pain at presentation, elevated lactate dehydrogenase levels, low hemoglobin, and significant weight loss.
Complications
Complications associated with malignant pleural mesothelioma can result from the disease itself, chemotherapy, or surgical intervention, all of which carry significant rates. Surgery, in particular, is associated with high morbidity and mortality. Notable complications include:
- Myocardial infarction
- Ventilator dependency
- Bronchial air leaks
- Postpneumonectomy stump failure
- Multiorgan failure
- Wound infections
- Renal failure, often related to cisplatinum-based chemotherapy
- Pancytopenia, as a result of chemotherapy
Postoperative and Rehabilitation Care
Patients are encouraged to participate in a rehabilitation program to regain functionality and improve overall quality of life following treatment. Nutritional support should be emphasized, as many patients are frail and emaciated, necessitating a well-balanced diet to aid recovery. Home oxygen therapy is often required to manage symptoms and enhance respiratory function.
Deterrence and Patient Education
Patient education for malignant mesothelioma involves helping individuals understand the link between asbestos exposure and the disease, as well as the long latency period that can span decades. Patients with a history of asbestos exposure should be educated on the early signs and symptoms of mesothelioma, such as persistent chest pain, shortness of breath, and unexplained weight loss, encouraging them to seek medical attention promptly. It is also important to discuss treatment options, including surgery, chemotherapy, and palliative care, while explaining the potential benefits, risks, and expected outcomes. Encouraging lifestyle modifications such as a healthy diet, regular exercise (if feasible), and smoking cessation can help improve overall health. Lastly, providing psychosocial support and connecting patients with support groups is essential to help them manage the emotional impact of the diagnosis and treatment.
Pearls and Other Issues
Key factors to keep in mind about malignant mesothelioma include the following:
- Strongly associated with asbestos exposure, particularly in occupations that are at high risk
- There is a long latency period of 20-50 years between exposure and disease onset
- Common symptoms include pleuritic chest pain, dyspnea, persistent cough, weight loss
- Diagnosis involves imaging studies such as chest x-ray, CT scan, and histopathologic evaluation
- Definitive diagnosis often requires a biopsy with cytology and tissue markers
- Early stages (I and II) may be resectable, while advanced stages (III and IV) often have poor outcomes
- Surgical options for early-stage disease include P/D and EPP
- Unresectable disease can be treated with chemotherapy (cisplatin and pemetrexed)
- Radiation therapy is used for palliation
- Prognosis is poor
Enhancing Healthcare Team Outcomes
Malignant mesothelioma is a complex disease that requires an interprofessional team, includeing an oncologist, thoracic surgeon, pulmonary specialist, radiation oncologist, and pain specialist. The cancer is difficult to diagnose, and current treatments have a limited impact on life expectancy.
According to the National Comprehensive Cancer Network Guidelines, treatment decisions are based on tumor staging, with stage III and IV malignant pleural mesothelioma considered unresectable. Less than a third of patients are candidates for definitive resection.
It is recommended that mesothelioma be treated by an interprofessional team at a high-volume center. Many patients, often frail and diagnosed late, may benefit from palliative or hospice care as the prognosis is poor, with most surviving only a few months after diagnosis is made. Even though surgery is performed, it is associated with severe life-threatening complications. The majority of patients with this malignancy succumb within 12 months.[18][19]
Review Questions
References
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- Zha L, Kitamura Y, Kitamura T, Liu R, Shima M, Kurumatani N, Nakaya T, Goji J, Sobue T. Population-based cohort study on health effects of asbestos exposure in Japan. Cancer Sci. 2019 Mar;110(3):1076-1084. [PMC free article: PMC6398882] [PubMed: 30618090]
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Disclosure: Hasnain Syed declares no relevant financial relationships with ineligible companies.
Disclosure: Jason Wallen declares no relevant financial relationships with ineligible companies.
- Continuing Education Activity
- Introduction
- Etiology
- Epidemiology
- Pathophysiology
- Histopathology
- History and Physical
- Evaluation
- Treatment / Management
- Differential Diagnosis
- Surgical Oncology
- Radiation Oncology
- Medical Oncology
- Staging
- Prognosis
- Complications
- Postoperative and Rehabilitation Care
- Deterrence and Patient Education
- Pearls and Other Issues
- Enhancing Healthcare Team Outcomes
- Review Questions
- References
- Review Metastatic Mesothelioma of the Tunica Vaginalis Presenting as Scrotal and Abdominal Nodules: A Case Report and Review of the Literature.[Am J Dermatopathol. 2025]Review Metastatic Mesothelioma of the Tunica Vaginalis Presenting as Scrotal and Abdominal Nodules: A Case Report and Review of the Literature.Gilbert A, Wieland R, Zacher N, Rieger K, Berry GJ, Novoa R. Am J Dermatopathol. 2025 Jan 1; 47(1):e6-e11. Epub 2024 Oct 31.
- Immediate Hypersensitivity Reactions (Archived).[StatPearls. 2025]Immediate Hypersensitivity Reactions (Archived).Justiz Vaillant AA, Vashisht R, Zito PM. StatPearls. 2025 Jan
- Case Control Studies.[StatPearls. 2025]Case Control Studies.Tenny S, Kerndt CC, Hoffman MR. StatPearls. 2025 Jan
- Review An evaluation of trends for mesothelioma mortality in American women: Addressing the content of a recent Morbidity and Mortality Weekly Report (MMWR).[Toxicol Ind Health. 2025]Review An evaluation of trends for mesothelioma mortality in American women: Addressing the content of a recent Morbidity and Mortality Weekly Report (MMWR).Stevens ME, Tuttle BP, Brew DW, Paustenbach DJ. Toxicol Ind Health. 2025 Jan; 41(1):40-60. Epub 2024 Oct 24.
- Review BAP1 Tumor Predisposition Syndrome.[GeneReviews(®). 1993]Review BAP1 Tumor Predisposition Syndrome.Pilarski R, Byrne L, Carlo MI, Hanson H, Cebulla C, Abdel-Rahman M. GeneReviews(®). 1993
- Malignant Mesothelioma - StatPearlsMalignant Mesothelioma - StatPearls
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