This comprehensive review examines malignant pleural mesothelioma, an aggressive cancer primarily caused by asbestos exposure with a 5-year survival rate of only 5-10%. Key findings include the limited success of surgery and radiation, recent FDA approval of immunotherapy combinations improving survival to 18.1 months, and persistent challenges due to tumor complexity. The article details diagnostic methods, treatment limitations, and emerging research directions while emphasizing that prevention through asbestos avoidance remains critical.

Understanding Malignant Pleural Mesothelioma: Causes, Diagnosis, and Treatment Advances

Table of Contents

• Introduction
• Causes of Malignant Pleural Mesothelioma
• Types and Molecular Features of Mesothelioma
• Symptoms and Clinical Presentation
• Diagnosis of Malignant Pleural Mesothelioma
• Staging of Mesothelioma
• Current Treatment Options
• Future Directions in Mesothelioma Treatment
• Key Findings from the Review
• Clinical Implications for Patients
• Limitations of Current Research
• Recommendations for Patients
• Source Information

Introduction

Malignant pleural mesothelioma is an aggressive cancer that develops in the pleurae - the protective linings surrounding your lungs. This disease accounts for 90% of all mesothelioma cases and is typically diagnosed at advanced stages, leading to poor survival rates. The 5-year survival rate remains alarmingly low at just 5-10%.

Asbestos exposure is the primary risk factor, causing a disease with a long latency period of 20-50 years. While prevention efforts have reduced cases in Western countries (U.S. deaths decreased from 14 to 11 per million between 2000-2015), the UK still reports high rates of 77 deaths per million. Unfortunately, these prevention successes haven't translated to effective new treatments for patients already diagnosed.

This review examines why mesothelioma has been so challenging to treat, including recent immunotherapy trials and how emerging insights into tumor biology might lead to better therapies. The authors emphasize that despite decades of research, treatment advances remain limited for this devastating disease.

Causes of Malignant Pleural Mesothelioma

Asbestos exposure is responsible for the overwhelming majority of mesothelioma cases. A pivotal 1960s study in South Africa first confirmed this link by identifying 33 cases where all patients had significant asbestos exposure. Asbestos was widely used because it's fire-resistant, durable, and inexpensive, but many countries have now banned it due to cancer risks.

Despite bans, global mining continues with 710,200 metric tons mined in Russia and 318,000 metric tons used in India as recently as 2017. This ongoing use in developing economies means asbestos exposure remains a worldwide health concern. While asbestos is the primary cause, other factors contribute to mesothelioma development:

• Germline mutations (inherited genetic changes) in genes like BAP1 accelerate mesothelioma development in 10% of patients
• Chronic inflammation caused by persistent mineral fibers in lung tissue
• Reactive oxygen species damaging DNA
• Mutations in DNA repair genes like PALB2 and BRCA1/2

The exact process of how asbestos causes cancer remains unclear, though mouse studies and genetic analyses continue to reveal new insights about these complex mechanisms.

Types and Molecular Features of Mesothelioma

Malignant pleural mesothelioma isn't one uniform disease but has distinct subtypes with different characteristics and outcomes. Traditionally, three main types were recognized:

• Epithelioid mesothelioma (50-60% of cases): The most common form with the best prognosis
• Sarcomatoid mesothelioma (10% of cases): Highly aggressive and resistant to treatments
• Biphasic mesothelioma (30-40% of cases): A mix of both other types

Recent research shows these subtypes exist on a spectrum rather than being completely separate categories. Molecular studies reveal that mesothelioma tumors frequently have mutations in tumor suppressor genes including:

• BAP1 (mutated in 60% of epithelioid cases)
• CDKN2A
• NF2
• SETD2

This genetic complexity explains why "one-size-fits-all" treatments often fail. Researchers have also identified a possible premalignant state similar to early-stage breast or cervical cancer, particularly linked to BAP1 gene mutations, which might open new prevention opportunities.

Symptoms and Clinical Presentation

Most patients don't experience symptoms until mesothelioma is advanced due to its slow growth pattern. When symptoms appear, they typically include:

• Breathlessness (caused by fluid buildup or tumors compressing lungs)
• Chest pain (indicating tumor invasion into chest walls)
• Fatigue and weakness
• Loss of appetite and weight loss
• Night sweats
• General malaise (feeling unwell)

These symptoms tend to worsen as the disease progresses. The long latency period between asbestos exposure and symptom onset (20-50 years) means many patients don't connect their symptoms to exposure that happened decades earlier.

Diagnosis of Malignant Pleural Mesothelioma

Diagnosing mesothelioma requires multiple approaches. Doctors typically start with imaging tests:

• Contrast-enhanced CT scans: First-choice imaging for chest and upper abdomen
• PET-CT scans: Helpful when CT results are unclear but can mistake inflammation for cancer
• MRI scans: Provide detailed views of soft tissue invasion

If imaging suggests mesothelioma, a tissue biopsy is essential for confirmation. Diagnostic methods include:

• Pleural biopsy (most reliable method)
• Pleural fluid analysis (works best for epithelioid subtype)
• Invasive procedures like mediastinoscopy when needed

Pathologists use special stains to identify mesothelioma cells under the microscope. Key diagnostic markers include:

• Positive mesothelial markers: Calretinin, cytokeratin 5/6, Wilms' tumor 1 antigen
• Absence of adenocarcinoma markers: Thyroid transcription factor 1, carcinoembryonic antigen
• Loss of BAP1 nuclear staining (in 60% of epithelioid cases)

Unfortunately, blood-based biomarkers haven't proven reliable for diagnosis or monitoring treatment effectiveness.

Staging of Mesothelioma

Staging determines how far cancer has spread using the TNM system (Tumor size, Node involvement, Metastases). The latest International Association for the Study of Lung Cancer TNM system (8th edition) categorizes progression as:

• Localized pleural disease (early stage)
• Spread to lymph nodes
• Distant metastasis (advanced stage)

However, staging mesothelioma is particularly challenging. Autopsy studies show 53% of patients had lymph node involvement, 58% had heart/pericardium invasion, and 24% had abdominal spread - findings often missed by initial scans. The TNM system also doesn't account for critical prognostic factors like:

• Histologic subtype (epithelioid vs. sarcomatoid)
• Tumor molecular features
• Patient age and overall health

This limitation makes accurate prognosis difficult using staging alone, requiring doctors to consider multiple factors when discussing outlook with patients.

Current Treatment Options

Treatment depends on cancer stage, tumor type, and patient health. All approaches should include symptom management, though early palliative care didn't improve quality of life in the RESPECT-Meso trial. Current strategies include:

Pleural Fluid Management

Most patients need drainage of fluid buildup (pleural effusion). Options include:

• Temporary catheterization with talc administration (success rate similar to surgery)
• Indwelling catheters
• Surgical procedures like partial pleurectomy (higher complication rates)

Surgical options require longer hospital stays (5-10 days) compared to catheter drainage (1-2 days).

Surgical Approaches

Surgery aims to remove visible tumors but isn't curative. Options range from least to most extensive:

1. Partial pleurectomy: Removes part of the tumor and manages fluid
2. Pleurectomy-decortication: Strips affected pleura off the lung
3. Extended pleurectomy-decortication: Adds removal of pericardium and diaphragm
4. Extrapleural pneumonectomy: Removes lung, pleura, pericardium and diaphragm

The radical extrapleural pneumonectomy has a median survival of 18 months and 14% 5-year survival. The MARS trial showed shorter survival with surgery (14.4 months) versus no surgery (19.5 months). The ongoing MARS2 trial is comparing extended pleurectomy-decortication plus chemotherapy to chemotherapy alone to clarify surgery's role.

Radiation Therapy

Radiation hasn't shown survival benefits in randomized trials. Key studies include:

• SAKK 17/04: No improvement in relapse-free survival after surgery
• PIT and SMART trials: Showed no benefit in preventing chest-wall invasion

Newer techniques like intensity-modulated radiotherapy and proton therapy are being studied to reduce side effects. The SYSTEMS-2 trial is evaluating radiation for pain control.

Tumor-Treating Fields

This FDA-approved approach uses electrical fields combined with chemotherapy. Approval was based on a phase 2 study showing activity in epithelioid mesothelioma, though randomized data confirming benefits are still lacking.

Systemic Therapies

Treatment advances have been limited. Landmark studies include:

• EMPHACIS trial (2004): First FDA-approved regimen (cisplatin + pemetrexed) improved survival from 9.3 to 12.1 months
• MAPS trial: Added bevacizumab to chemotherapy, increasing survival to 18.8 months vs 16.1 months
• CheckMate 743 trial: Nivolumab + ipilimumab immunotherapy showed 18.1 month survival vs 14.1 months with chemotherapy
• CONFIRM trial: Nivolumab alone improved survival in relapsed patients by 3 months versus placebo

Immunotherapy is now the only new FDA-approved treatment since 2004. For patients who respond initially to chemotherapy, retreatment with platinum-pemetrexed or vinorelbine may be options later.

Future Directions in Mesothelioma Treatment

Research is exploring several promising areas:

• Immunotherapy combinations: Building on the success of nivolumab+ipilimumab
• Targeted therapies: Focusing on BAP1 and other mutation pathways
• Early intervention: Targeting premalignant lesions in high-risk patients
• Maintenance therapies: Gemcitabine after initial chemotherapy
• Improved radiation techniques: Reducing damage to healthy tissue

The discovery of a premalignant "carcinoma in situ" stage similar to other cancers offers new prevention opportunities. Genetic insights may also lead to personalized treatments based on tumor molecular profiles.

Key Findings from the Review

This analysis of mesothelioma research reveals several critical facts:

• 5-year survival remains 5-10% despite decades of research
• Asbestos exposure causes >90% of cases, with 20-50 year latency
• Three histological subtypes exist: epithelioid (50-60%), biphasic (30-40%), sarcomatoid (10%)
• Germline mutations (BAP1, BRCA) accelerate development in 10% of patients
• Surgery shows no clear survival benefit (MARS trial: 14.4 vs 19.5 months)
• Immunotherapy combination (nivolumab+ipilimumab) extends survival to 18.1 months
• Over 50% of U.S. patients never receive chemotherapy due to age/comorbidities
• Autopsies reveal 53% lymph node, 58% cardiac, and 24% abdominal spread missed by scans

Clinical Implications for Patients

These findings have direct significance for patients:

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