Mesothelioma: Causes, Symptoms, Diagnosis, and Treatment

Introduction

What Is the Mesothelium?

The mesothelium is a thin serous membrane that lines several organs and body cavities. It is composed of specialized cells called mesothelial cells. Depending on the structure it lines, the mesothelium is given a specific anatomical name:

The primary function of the mesothelium is to produce a thin layer of lubricating serous fluid. This fluid allows organs to move smoothly against each other without friction. For instance, it enables the lungs to expand and contract freely within the ribcage during breathing.

What Is Mesothelioma?

Mesothelioma is a tumor arising from mesothelial cells. Tumors of the mesothelium are divided into:

• Benign forms: Rare, small, slow-growing tumors with limited capacity for local invasion or distant spread. Examples include adenomatoid tumors and cystic mesothelioma.
• Malignant forms: The true mesotheliomas, which are highly aggressive tumors with a strong tendency for local invasion and distant metastasis, are the subject of this article.

Epidemiology

Malignant mesothelioma develops in the pleura in approximately 80% of cases. Its incidence has risen significantly over the past three decades. This increase stems mainly from widespread occupational asbestos exposure that occurred several decades ago, a trend that reflects the disease’s characteristically long latency period of 10 to 40 years between asbestos exposure and tumor development.

The tumor is more common in men than women, largely because of historically greater male occupational exposure to asbestos. It most commonly manifests between the fifth and sixth decades of life.

Asbestos: The Primary Cause

The principal known cause of mesothelioma is exposure to asbestos, a naturally occurring fibrous mineral. It was once widely used in shipbuilding, the automotive industry, construction, heating systems, and protective equipment due to its exceptional heat resistance and physical durability. Its carcinogenicity was only confirmed many years after its widespread adoption, leading to legislative bans in many countries.

The prognosis of malignant mesothelioma remains poor. Because it rarely produces early symptoms, it is almost always diagnosed at an advanced stage when curative options are limited. Five-year survival rates do not exceed 20%, underscoring the critical importance of occupational surveillance and early detection in at-risk populations.

---

Causes and Risk Factors

Asbestos Exposure: The Dominant Risk Factor

The single most important risk factor for mesothelioma is asbestos exposure, whether it is occupational or environmental. Asbestos is characterized by a microscopic fibrous crystalline structure that made it invaluable in industry, but also extraordinarily dangerous when inhaled.

When asbestos fibers are inhaled, their ultrafine dimensions allow them to penetrate deep into the lung parenchyma and pleural tissue, where they:

• Deposit permanently in the pleura and lung tissue (the body cannot effectively clear them)
• Induce chronic inflammation and oxidative stress over decades
• Damage the DNA of mesothelial cells, triggering the cascade of genetic mutations that ultimately leads to malignant transformation

Beyond mesothelioma, asbestos exposure can also cause:

• Asbestosis: Chronic fibrotic lung disease
• Lung cancer (particularly when combined with smoking)
• Benign pleural lesions (pleural plaques, pleural effusions)

Smoking and Asbestos: A Dangerous Combination

While smoking alone does not appear to directly cause mesothelioma, cigarette smoking significantly amplifies the risk of developing mesothelioma in individuals already exposed to asbestos compared to non-smoking asbestos-exposed individuals. Smoking cessation is therefore a particularly critical intervention for anyone with a history of asbestos exposure.

Dose-Response Relationship

The risk of developing mesothelioma correlates with both:

• Duration of asbestos exposure (how many years)
• Intensity of exposure (how much asbestos was inhaled over time)

However, it is important to note that there is no completely safe level of asbestos exposure. Even relatively brief or low-intensity exposures have been linked to mesothelioma development in some individuals.

Other Causative Factors

Beyond asbestos, additional causes of mesothelioma include:

• Erionite exposure: A naturally occurring fibrous mineral chemically similar to asbestos, found in certain volcanic regions (notably parts of Turkey, where mesothelioma incidence is exceptionally high in exposed communities)
• Ionizing radiation to the thorax or abdomen: Therapeutic radiation administered for previous cancers can, in rare cases, induce secondary mesothelioma years later
• SV40 virus (Simian Virus 40): A viral etiology has been proposed based on molecular studies, though the causal relationship remains under active investigation
• Thorium dioxide (Thorotrast) injections: A radiocontrast agent used in radiology until the 1950s, now recognized as a carcinogen
• Genetic mutations: Germline mutations in the BAP1 gene (BRCA1-associated protein 1) are strongly associated with hereditary predisposition to mesothelioma and other cancers

Classification

By Anatomical Location

By Histological Subtype

Histological subtype is one of the most important prognostic factors in mesothelioma and significantly influences treatment selection.

---

Symptoms

The Challenge of Early Diagnosis

Mesothelioma has an insidious initial growth phase with a clinical picture that is subtle and symptoms that are non-specific and easily attributed to more common conditions. This is the primary reason early diagnosis is so difficult. It also explains why the prognosis is often poor by the time a diagnosis is finally made.

The onset of symptoms typically occurs many decades after initial asbestos exposure, by which time the tumor may already be at an advanced, locally invasive stage.

Common Symptoms

Symptoms vary according to tumor location (pleural vs. peritoneal vs. pericardial), but the most frequently reported include:

Pain:

• Chest pain (often dull and persistent, related to pleural involvement)
• Back pain
• Abdominal pain (in peritoneal mesothelioma)

Respiratory symptoms (predominantly in pleural mesothelioma):

• Dyspnea (breathlessness): Progressive difficulty breathing, worsening with tumor growth and pleural effusion accumulation.
• Dry, persistent cough: Characteristically unresponsive to standard antibiotic or anti-inflammatory therapy.
• Recurrent pleural effusion: Commonly described as “water in the lungs”, this condition involves fluid accumulation between the pleural layers. It is often the presenting finding.

Constitutional (systemic) symptoms:

• Fever
• Nausea and vomiting
• Loss of appetite and unintentional weight loss
• Profound fatigue and general malaise
• Joint pain and muscle pain

Peritoneal Mesothelioma: Specific Features

Peritoneal mesothelioma may present somewhat differently, with:

• Abdominal distension and bloating (from ascites, or fluid accumulation in the peritoneal cavity)
• Diffuse abdominal pain
• A palpable abdominal mass in some cases
• Bowel habit changes or obstruction in advanced disease

Symptom Progression

Symptoms typically develop insidiously and progressively, worsening in parallel with tumor growth. The non-specific nature of early symptoms often makes them difficult to distinguish from common respiratory infections, musculoskeletal disorders, or age-related changes. As a result, patients typically seek medical attention only when the disease has reached an advanced stage.

---

Diagnosis

The Role of Occupational History

The medical history (anamnesis) is fundamental to the diagnosis of mesothelioma. A detailed inquiry into past occupational and environmental exposures is essential:

• Any history of asbestos exposure, no matter how remote (given the 20–40 year latency period), should raise immediate clinical suspicion in a patient with compatible symptoms.
• Questions should address employment in relevant industries (shipbuilding, construction, insulation, manufacturing, mining), proximity to asbestos-containing buildings or work sites, or secondary exposure (e.g., through a family member who worked with asbestos).

Given the long latency period, exposure that occurred decades before symptom onset remains clinically relevant and must be specifically sought.

Screening in High-Risk Individuals

General population screening for mesothelioma is not recommended given the disease’s rarity. However, individuals with documented prior asbestos exposure, whether occupational or environmental, are candidates for surveillance imaging programs.

• Chest X-ray and CT scanning at regular intervals
• Pulmonary function testing

This surveillance strategy aims to detect pathological changes at the earliest possible stage, when therapeutic options are most favorable.

Imaging Studies

Biopsy: The Diagnostic Gold Standard

A definitive diagnosis of mesothelioma requires histopathological confirmation, which means examining tumor tissue under a microscope. Biopsy is obtained by:

• CT-guided percutaneous needle biopsy: A thin needle is advanced under CT guidance to obtain a tissue core from the pleural or peritoneal mass
• Video-assisted thoracoscopic surgery (VATS): Minimally invasive surgical approach that allows direct visualization of the pleural cavity and targeted biopsy of suspicious lesions; particularly useful when needle biopsy is inconclusive
• Thoracentesis (pleural fluid analysis): While cytological examination of pleural fluid can raise suspicion, it is generally insufficient alone to confirm the diagnosis due to suboptimal sensitivity

Biopsy not only confirms the diagnosis but also establishes the histological subtype: epithelioid, sarcomatoid, or biphasic. This information is critical for prognosis and treatment planning.

Staging

Following histological confirmation, mesothelioma is staged using the TNM classification system (Tumor, Nodes, Metastasis), which evaluates:

• T: Extent of local tumor involvement (pleura, lung parenchyma, diaphragm, mediastinum, chest wall)
• N: Regional lymph node involvement
• M: Presence or absence of distant metastases

Accurate staging is essential for determining whether the patient is a candidate for curative surgery or whether palliative approaches are more appropriate.

---

Treatment

Legislative Context

Many countries have enacted legislation restricting or banning the use of asbestos and establishing requirements for identifying, managing, and safely removing asbestos-containing materials in public and private buildings. Workers who are occupationally exposed to asbestos may also be eligible for compensation or other protections under applicable occupational disease regulations. Despite these measures, the long latency period of mesothelioma means that new cases can continue to occur for decades after exposure.

Factors Influencing Treatment Selection

Treatment decisions in mesothelioma depend on multiple factors:

• Disease stage: Extent of local and distant spread
• Presence of metastases: Lymph node or distant organ involvement
• Histological subtype: Epithelioid tumors respond better to multimodal treatment
• Tumor location: Pleural, peritoneal, or pericardial involvement
• Patient’s overall health and performance status: Comorbidities and functional reserve
• Patient preferences and quality-of-life considerations

The Three Pillars of Treatment

1. Surgery

Surgery is the preferred first-line approach when the disease is sufficiently localized to permit complete or near-complete resection. Common surgical procedures include:

• Pleuropneumonectomy (extrapleural pneumonectomy, EPP): Radical surgery involving removal of the affected pleura, the entire lung, part of the diaphragm, and adjacent lymph nodes. Offers the best chance of complete tumor removal in selected cases, but carries significant morbidity.

• Pleurectomy / Decortication (P/D): Removal of the tumor-bearing pleura while preserving the lung. A lung-sparing alternative to EPP, increasingly preferred due to lower surgical morbidity and comparable oncological outcomes in many centers.

• Pleurodesis: In patients with recurrent pleural effusion who are not surgical candidates, pleurodesis involves drainage of the effusion followed by instillation of a sclerosing agent (e.g., talc) into the pleural space. This causes adherence of the visceral and parietal pleural layers, substantially reducing the likelihood of effusion re-accumulation.

When curative surgery is not feasible (e.g., in cases of advanced disease or poor performance status), surgery may still play a palliative role, relieving symptoms and improving quality of life.

2. Radiotherapy

Radiotherapy is used in mesothelioma in several contexts:

• Adjuvant (post-operative) radiotherapy: Administered after surgery to “sterilize” the operative field, destroying residual microscopic tumor cells not visible to the naked eye and reducing local recurrence risk.
• Palliative radiotherapy: Used to reduce tumor bulk, also known as cytoreduction, and relieve specific symptoms. This approach is especially helpful for managing chest pain, superior vena cava obstruction, and dyspnea in patients with advanced disease that cannot be treated with curative intent.
• Prophylactic port-site irradiation: Sometimes used to prevent tumor seeding along biopsy or drain tracts.

Modern radiation techniques, such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), allow more precise targeting of tumor tissue. These methods also minimize radiation exposure to surrounding healthy structures.

3. Chemotherapy

Chemotherapy plays a central role in mesothelioma management and can be administered in two strategic contexts:

• Neoadjuvant chemotherapy: Administered before surgery with the aim of reducing tumor size and rendering it more amenable to complete resection. It also provides a biological test of the tumor’s chemosensitivity.

• Adjuvant chemotherapy: Administered after surgery to eliminate residual microscopic disease and reduce the risk of recurrence. Particularly indicated when lymph node involvement or distant spread is present.

The standard first-line chemotherapy regimen for malignant pleural mesothelioma combines:

• Pemetrexed (an antifolate agent) + Cisplatin (or carboplatin)

This combination has been the backbone of systemic treatment since its approval and has demonstrated meaningful improvements in overall survival compared to cisplatin alone.

Routes of administration:

• Intravenous (IV): Standard systemic delivery
• Intrapleural: Direct instillation of chemotherapy into the pleural space, allowing higher local drug concentrations at the tumor site with reduced systemic toxicity

Emerging and Investigational Treatments

Significant research advances are being made in mesothelioma treatment:

• Immunotherapy: Immune checkpoint inhibitors, particularly the combination of nivolumab + ipilimumab (anti-PD-1 plus anti-CTLA-4), have received approval for first-line treatment of unresectable pleural mesothelioma in many countries. This approach has demonstrated improved survival over chemotherapy alone in some patient populations.
• Targeted therapy: Ongoing research into molecular targets specific to mesothelioma (including BAP1 pathway abnormalities)
• Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A specialized surgical technique combining cytoreductive surgery with heated chemotherapy circulated directly within the peritoneal cavity; used for peritoneal mesothelioma in selected centers

Prognosis

Malignant mesothelioma carries a poor overall prognosis. Because symptoms rarely appear until the disease is advanced, most patients are diagnosed at a stage when curative treatment is no longer possible.

• Overall 5-year survival: <20%
• Median survival from diagnosis: Approximately 12–21 months depending on stage, histological subtype, and treatment received
• Epithelioid subtype is associated with the most favorable outcomes
• Early-stage disease treated with multimodal therapy (surgery + chemotherapy ± radiotherapy) offers the best survival prospects

These sobering statistics reinforce the critical importance of:

1. Primary prevention: Eliminating asbestos exposure globally
2. Occupational surveillance: Regular monitoring of at-risk workers
3. Rapid diagnosis: Promptly investigating respiratory or abdominal symptoms in any individual with a history of asbestos exposure

---

Sources and Bibliography

• Gramiccioni E, Loizzi M, Foschino Barbaro MP, Resta O, Sollitto F. Malattie dell’apparato respiratorio, II Edizione. Edizioni Minerva Medica, Torino.
• MedScape – Mesothelioma Overview