Malignant Mesothelioma

Malignant mesothelioma (usually referred to as simply “mesothelioma”) is the malignant growth of mesothelial cells, most commonly affecting the pleura Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, coughing, fatigue, and weight loss. Chest computed tomography (CT) scan shows multifocal pleural thickening and pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion. Pleural biopsy is required for confirmation and to rule out metastases from lung or breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer. Treatment is rarely effective, with an average survival time of < 1 year.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura, peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum, pericardium, and testis.
  • Most common site of involvement is the pleura Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer, but not mesothelioma)
  • Germline mutations in the BAP1, CDKN2A, and NF2 NF2 Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Neurofibromatosis Type 2 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 Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. 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 Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura, chest wall Chest wall The chest wall consists of skin, fat, muscles, bones, and cartilage. The bony structure of the chest wall is composed of the ribs, sternum, and thoracic vertebrae. The chest wall serves as armor for the vital intrathoracic organs and provides the stability necessary for the movement of the shoulders and arms. Chest Wall, diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm, and regional lymph nodes.
  • Transfer of MM to the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum 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 Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea (due to pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion)
    • Chest wall pain 
  • Other symptoms: chronic cough, malaise, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chills, fatigue, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, and weight loss

Peritoneal mesothelioma

  • Most common symptoms:
    • Abdominal swelling and pain due to ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Other symptoms: weight loss, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chills, night sweats, nausea, and constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Small bowel obstruction Small Bowel Obstruction Small bowel obstruction (SBO) is an interruption of the flow of the intraluminal contents through the small intestine, and is classified as mechanical (due to physical blockage) or functional (due to disruption of normal motility). The most common cause of SBO in the Western countries is post-surgical adhesions. Small bowel obstruction typically presents with nausea, vomiting, abdominal pain, distention, constipation, and/or obstipation. Small Bowel Obstruction may occur as a late complication.

Pericardial mesothelioma

  • Chest pain, cough, orthopnea, arrhythmia, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Signs of constrictive pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis (fatigue, jugular vein distention, peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema)

Diagnosis

  • Chest computed tomography (CT) scan:
    • Multiple foci of pleural thickening
    • Pleural effusion and/or pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax
  • Pleurocentesis: exudative pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion ± malignant cytology
  • Biopsy:
    • Obtained via video-assisted thoracoscopy or laparoscopy Laparoscopy Laparoscopy is surgical exploration and interventions performed through small incisions with a camera and long instruments. Laparotomy and 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 Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. The tumor may invade the pericardium and heart; if MM gains access to the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum, 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer can lead to malignant pericardial or pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. 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 Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura, showing up on chest CT or X-ray as multiple lesions and a mostly unilateral pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: acute or chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of lung tissue; includes infection with bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, viruses, or fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview. Presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, cough, malaise, altered breath sounds, and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, and can lead to pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion with pleuritic chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain.
  • Pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. 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 Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, nonproductive cough, weight loss, low-grade fevers, and fatigue
  • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. 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 Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, pleuritic pain, cough, orthopnea, and wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. 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 Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, or paraneoplastic syndromes Paraneoplastic syndromes Paraneoplastic syndromes are a heterogeneous group of disorders caused by an abnormal immune response to a neoplasm. The substances produced are not due to the direct effect of the tumor, such as metastasis, mass effect, or invasion. Antibodies, hormones, cytokines, and other substances are generated and affect multiple organ systems. Paraneoplastic Syndromes.

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