Malignant Mesothelioma

Malignant mesothelioma (usually referred to as simply “mesothelioma”) is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Chest computed tomography (CT) scan shows multifocal pleural thickening and pleural effusion. Pleural biopsy is required for confirmation and to rule out metastases from lung or breast cancer. Treatment is rarely effective, with an average survival time of < 1 year.

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Definition and Epidemiology

Definition

  • Malignant mesothelioma (MM): usually referred to as simply “mesothelioma,” as it is much more common than its benign counterpart.
  • Malignant mesothelioma is a primary malignant growth of mesothelial cells, strongly associated with prior exposure to asbestos.
  • Mesothelial cells line the body cavities, including the pleura, peritoneum, pericardium, and testis.
  • Most common site of involvement is the pleura (> 85% of cases).

Epidemiology

  • Rare; accounts for < 1% of all forms of cancer
  • Men are more commonly affected (male to female ratio = 3:1)
  • Average age at diagnosis: > 50 years
  • Typically follows prior exposure to asbestos by 2040 years

Etiology and Pathophysiology

Etiology

  • The majority of cases (> 80%) are secondary to asbestos exposure, even with < 12 years of intense exposure that occurred > 40 years ago (especially crocidolite fibers).
  • High-risk occupations without the use of proper protection (now mostly occurring in developing countries), including shipbuilding, mining, ceramics, auto manufacturing, brake-lining work, insulation work, railroad repair, plumbing, carpentry, and demolition work
  • Bystander exposure, such as by electricians and painters who work in shipyards, as well as by family members who wash workers’ clothes, is also associated with a higher risk of mesothelioma.
  • Smoking, alcohol, or diet does not increase the risk of mesothelioma (smoking in addition to asbestos exposure significantly increases the risk of lung cancer, but not mesothelioma)
  • Germline mutations in the BAP1, CDKN2A, and NF2 genes or chromosomal deletions increase susceptibility.
  • Rarely associated with irradiation of the chest or inhalation of erionite (another fibrous mineral) or talc

Pathophysiology

  • Asbestos fibers are inhaled deeply into the lung and penetrate the pleural space, where they interact with mesothelial cells and provoke a persistent inflammatory reaction, causing cycles of tissue damage and repair.
  • This process eventually leads to MM by unknown mechanisms, although many patients carry cancer susceptibility genes such as BAP1.
  • In primary peritoneal MM, the main fiber type implicated in the United States is amosite, not crocidolite as for pleural MM, and the link with asbestos exposure is significant but not as strong. 
  • Microscopically, the 3 histologic types are epithelial, sarcomatous, and mixed.
  • The usual affected site in the thoracic cavity is the parietal and not the visceral pleura.
  • Benign pleural plaques may also be formed due to chronic injury. They are well-circumscribed white plaques composed of dense, often calcified, acellular collagen.
  • Mesotheliomas are often multifocal, typically with local spread to visceral pleura, chest wall, diaphragm, and regional lymph nodes.
  • Transfer of MM to the peritoneum may occasionally occur through the lymphatic system.

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Clinical Presentation

Pleural mesothelioma

  • Onset of symptoms may not occur until > 20 years after exposure to asbestos.
  • Most common symptoms:
    • Progressive dyspnea (due to pleural effusion)
    • Chest wall pain 
  • Other symptoms: chronic cough, malaise, fever, chills, fatigue, dysphagia, and weight loss

Peritoneal mesothelioma

  • Most common symptoms:
    • Abdominal swelling and pain due to ascites
  • Other symptoms: weight loss, fever, chills, night sweats, nausea, and constipation
  • Small bowel obstruction may occur as a late complication.

Pericardial mesothelioma

  • Chest pain, cough, orthopnea, arrhythmia, dyspnea
  • Signs of constrictive pericarditis (fatigue, jugular vein distention, peripheral edema)

Diagnosis

  • Chest computed tomography (CT) scan:
    • Multiple foci of pleural thickening
    • Pleural effusion and/or pneumothorax
  • Pleurocentesis: exudative pleural effusion ± malignant cytology
  • Biopsy:
    • Obtained via video-assisted thoracoscopy or laparoscopy
    • Gross: grouped nodules on mesothelial-lined surfaces
    • Microscopy: mesothelioma cells and psammoma bodies (concentric collections of calcium, appearing like grains of sand)
  • Immunohistochemistry:
    • Used to differentiate from other malignancies involving the thorax (extension from primary tumors of the lung and metastases from extrathoracic sites)
    • Initial workup would use 2 mesothelial markers (e.g., calretinin, cytokeratin 5/6) and 2 markers for the other tumor in the differential diagnosis, on the basis of morphology (e.g., claudin-4, MOC-31) to detect carcinomas

Management

  • Generally resistant to radiation and chemotherapy 
  • Definitive surgical resection occurs in less than one-third of patients.
    • Pleurectomy
    • Pneumonectomy
    • Pericardiectomy 
  • Surgical therapy is usually combined with chemotherapy and radiation. 
  • Symptomatic treatment with painkillers, thoracocentesis, and pleurodesis
  • Most patients with pleural MM die from local extension and respiratory failure. The tumor may invade the pericardium and heart; if MM gains access to the peritoneum, small bowel obstruction may occur.

Prognosis: Median survival time is 8–14 months.

Differential Diagnosis

The following conditions are differential diagnoses for mesothelioma.

  • Benign asbestos-related pleural plaques and effusion
  • Metastatic carcinoma from lung, breast, or extrathoracic sites
    • Lung cancer: a malignancy that originates and develops within the airways or the parenchyma of the lung. Extensive spread of primary lung cancer can lead to malignant pericardial or pleural effusion.
    • Breast cancer: the development of cancerous cells from the tissues of the breast. Breast cancer is the second-largest cause of death in American women. Can metastasize to the lung and pleura, showing up on chest CT or X-ray as multiple lesions and a mostly unilateral pleural effusion
  • Pneumonia: acute or chronic inflammation of lung tissue; includes infection with bacteria, viruses, or fungi. Presents with fever, cough, malaise, altered breath sounds, and dyspnea, and can lead to pleural effusion with pleuritic chest pain.
  • Pulmonary fibrosis: a group of diseases whose specific cause is not well known in which the pulmonary parenchyma becomes damaged and scarred, leading to impaired pulmonary function. Presents as exertional dyspnea, nonproductive cough, weight loss, low-grade fevers, and fatigue
  • Pulmonary embolism: a potentially fatal clinical condition that occurs as a result of mechanical obstruction of the pulmonary artery or its branches by a thrombus, air, or fat. Presents with sudden-onset dyspnea, pleuritic pain, cough, orthopnea, and wheezing
  • Thymoma: a malignancy originating in the thymus gland. Can be asymptomatic and discovered incidentally on a chest X-ray or present with chest pain, cough, dyspnea, or paraneoplastic syndromes.

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