Malignant Mesothelioma

Asbestos is classified into 2 groups based on its physical properties: the serpentines, which tend to be wavy and long, and the amphiboles, which are straight and rodlike. The most important member of the serpentines is chrysotile, which makes up more than 90% of the asbestos used in the United States. The amphibole group includes crocidolite, amosite, and tremolite, which is often found as a contaminant of chrysotile ore.

The use of asbestos can be traced through history as far back as the Stone Age, when it was mixed in with earthenware pots for strength. Though the versatility of asbestos has been known since ancient times, its use did not become widespread until the Industrial Revolution in the late 19th century, when mass quantities were needed for booming textile and insulation factories. Asbestos production increased during the next century until its peak in the 1970s. Despite the well-documented health risks from exposure, asbestos remains widely used, particularly in developing countries.

Three major diseases are associated with asbestos exposure: asbestosis, lung cancer and mesothelioma. Pleural plaques are the most common manifestation of exposure. This article focuses on asbestosis, which specifically refers to the bilateral diffuse interstitial fibrosis of the lungs caused by inhalation of asbestos fibers.

The first documented case of an asbestos-related death occurred in 1906, when the autopsy of an asbestos worker revealed lung fibrosis. In 1918, insurance companies began refusing to insure asbestos workers because of increasing incidence of illnesses. The term “asbestosis” was first used in 1927 by Cooke, who reported that asbestos could cause pulmonary fibrosis. A few years later, an association between asbestos exposure and lung cancer was suggested. In 1955, epidemiologic data revealed that lung cancer was a specific health risk in asbestos workers.

Asbestos exposure is divided into 3 main categories. Primary exposure occurs in miners and millers. Secondary exposure, which is the largest and clinically most significant group, includes occupations involved in the industrial and commercial use of asbestos (eg, manufacturing plants, construction). The third category is nonoccupational (environmental or para-occupational) exposure to contaminated air. Nonoccupational exposure (eg, schools, offices) does not appear to pose significant health risks. The frequent finding of asbestos bodies in the lungs of city dwellers at autopsy, as high as 60% in New York City, suggests that environmental exposure is widespread. Asbestos fibers can remain airborne for many hours even in still conditions.
Frequency
United States

In 1978, the National Institutes of Health reported that 8-11 million people have had occupational exposure to asbestos since the early 1940s. Because of the long latency period, long-term follow-up is difficult. Calculation of disease frequency is also complicated by the dose-response relationship that exists for asbestosis. The prevalence of asbestosis appears to correlate with length of exposure. This was well demonstrated in one study that looked at the chest radiographs of asbestos workers. Asbestosis was detected in 10% of workers employed for 10-19 years, in 73% employed 20-29 years, and in 92% employed for more than 40 years. In another, Finnish study, asbestosis was found in 22% of people who had worked in the construction industry for 10 years or in the shipyards for 1 year, reflecting the higher exposures in the ship industry.
Mortality/Morbidity

Calculating the death rate from asbestosis is confounded by deaths from asbestos-related malignancies, mainly lung cancer and mesothelioma. Asbestosis mortality in the United States increased from 0.49 per million persons in 1970 to a peak of 6.73 per million persons in 2000 and then slowly declined.1 A continuing gradual decline in asbestosis mortality is expected, because of decreasing asbestos use and stricter work regulations since the 1970s. The US National Center for Health Statistics reported that deaths from asbestosis in US residents aged 15 years and older totaled 1,493 in 2000 and 1,470 in 2004.2,3,4

The National Institute for Occupational Safety and Health predicts a total of 29,667 deaths from asbestosis in the US during 2005-2027, an average of 1,290 deaths per year. Recent reports reveal that clinical asbestosis is decreasing in frequency and severity but that asbestos-related lung cancer deaths are becoming increasingly common.5
Race

The US National Center for Health Statistics reports that the race-based number of asbestosis-related deaths in 2004 in US residents aged 15 years and older is as follows2 :

* Whites – 1,370 deaths (93.2%)
* Blacks – 92 (6.3%)
* Others – 8 (0.5%)

Sex

Older white males account for most of the asbestosis-related deaths, which likely reflects the workforce demographics in the asbestos occupations several decades ago, when its use was most prevalent.

The US National Center for Health Statistics reports that the sex-based number of asbestosis-related deaths in 2004 in US residents aged 15 years and older is as follows2 :

* Males – 1,419 (96.5%)
* Females – 51 (3.5%)

Age

According to the US National Center for Health Statistics, the age-based number of asbestosis-related deaths in 2004 in US residents aged 15 years and older is as follows2 :

* Age 15-44 years – 0 (0%)
* Age 45-54 years – 16 (1.1%)
* Age 55-64 years – 107 (7.3%)
* Age 65-74 years – 313 (21.3%)
* Age 75-84 years – 706 (48%)
* Age >85 years – 328 (22.3%)
* Median age – 79 years

Presentation

Presentation and natural history

The gross pathologic picture of asbestosis ranges from mild coarsening of the lung parenchyma to honeycombing. Distribution is bilateral, with fibrosis most prominent in the subpleural zones, particularly in the lower lobes. Microscopically, the appearance ranges from a mild increase in interstitial collagen to complete distortion of lung architecture by thick fibrosis and cystic spaces. The earliest histologic findings of asbestosis are discrete areas of fibrosis in the walls of proximal respiratory bronchioles. As the disease progresses, the more distal bronchiolar and alveolar interstitium become involved. With time, greater portions of the lung are affected in a centrifugal fashion.

The microscopic diagnosis of asbestosis requires the presence of diffuse interstitial fibrosis and asbestos bodies. Inhaled asbestos exists either as uncoated fibers or asbestos bodies, which are fibers that have been phagocytized and coated with a protein-iron matrix. Uncoated fibers are visible only under electron microscopy, whereas asbestos bodies are readily detected with conventional light microscopy. The presence of more than one asbestos body has long been considered necessary for the pathologic diagnosis of asbestosis.

Asbestos bodies, however, constitute only a small fraction of the total asbestos burden in the lung, and a patient with heavy exposure may not have any detectable asbestos bodies. Therefore, the presence of asbestos bodies should be considered a marker of exposure, but their absence should not exclude it. Pathologically, the lung fibrosis seen in asbestosis cannot be distinguished from that of other interstitial diseases except for the presence of asbestos bodies. In addition, unlike other pneumoconioses, lymphadenopathy and progressive massive fibrosis tend not to occur.

Studies show that the risk of developing asbestosis and the severity of disease increase with higher exposures. However, the exact roles of fiber dose, type, and size in the pathogenic pathway remain unclear. Although a dose-dependent relationship exists with all asbestos-related disease, asbestosis is associated with the highest fiber burdens. Most asbestos workers have no histologic evidence of fibrosis, suggesting that individual variations in susceptibility may be the most important factor in disease development. Another important factor worth mentioning is cigarette smoke, which contributes to the development of cancers and, according to some investigators, may enhance development of asbestosis.

Inhalation

Pathogenesis of pulmonary asbestos-related diseases begins with the inhalation of fine asbestos fibers. The larger fibers are trapped in the nose and upper airway, which are then cleared by mucociliary transport, but those with diameters of 0.5-5 micrometers are deposited at airway bifurcations, respiratory bronchioles, and alveoli. There they cause direct injury to epithelial cells and alveolar macrophages, which attempt to engulf the fibers. Some of the fibers enter the interstitium by direct penetration across the epithelium or macrophage transport. The damaged macrophages become activated, releasing tissue-damaging reactive oxygen species and various cytokines, including tumor necrosis factor, interleukin-1, and arachidonic acid metabolites, which initiate alveolitis. Damaged epithelial cells also release inflammatory cytokines.

Inflammatory phase of alveolitis

Alveolitis is the inflammation caused by monocyte recruitment and macrophage accumulation in both the airspace and the interstitium, although lymphocytes and neutrophils also are involved. If the asbestos burden is relatively small, most fibers may be cleared and tissue reaction is limited. If fiber retention is high, the resulting alveolitis is likely to be more intense, which may cause greater tissue reaction and injury. In this latter setting, progressive fibrosis can ensue.

Fibrosis phase of alveolitis

The inflammatory phase described above is followed by the fibrosis phase, which is mediated by the various cytokines released by damaged type I pneumocytes and macrophages. Profibrosis cytokines such as fibronectin, fibroblast growth factor, platelet-derived growth factor, and insulinlike growth factor stimulate recruitment and proliferation of fibroblasts and type II pneumocytes. Initially, proliferation occurs locally at the site of asbestos deposition, but over time, the fibers may migrate to distal sites, causing further tissue damage and inflammation. The result is collagen biosynthesis, which eventually leads to fibrosis.

The size of asbestos fiber is an important determinant in pathogenesis. Longer fibers are less likely to be phagocytized and cleared by defense mechanisms, resulting in greater potential for alveolitis and subsequent fibrosis. An epidemiologic study in asbestos textile plant workers found that lung cancer and asbestosis were most strongly associated with exposure to thin fibers (<0.25 micrometers); longer fibers (>10 micrometers) showed an inconsistent association with asbestosis but were the strongest predictors of lung cancer.6

The type of fiber also appears to influence pathogenesis. Amosite and crocidolite (amphiboles), which have greater biopersistence than chrysotile, appear to have higher fibrogenic potential. The half-life of chrysotile is on the order of months, whereas that of the amphiboles is in decades. Because of fiber biopersistence, progression of disease can occur without ongoing exposure.

The progression of asbestosis may be enhanced by cigarette smoke, according to some investigators. The mechanisms are unclear but appear to be related to clearance inhibition and increased pneumocyte fiber uptake leading to overall increased retention of asbestos fibers, particularly the shorter-length fibers.

A latency period of at least 15-20 years is generally required for the clinical manifestations of asbestosis to appear after initial exposure. Studies have demonstrated that the latency period is inversely proportional to exposure level. Early epidemiologic studies from the 1930s reported a latency period of approximately 5 years, whereas more recent values are in the range of 13-20 years. This trend of increasing latency is likely related to decreasing exposures from stricter workplace regulations initiated in the 1970s.
Diagnosis

Clinical onset of symptoms in patients with asbestosis generally occurs approximately 20 years after initial exposure. The signs and symptoms associated with asbestosis are for the most part nonspecific and can resemble those found in other restrictive interstitial lung diseases.

The most prominent symptom, and usually the earliest, is the insidious onset of dyspnea on exertion. This is often progressive, despite discontinuation of asbestos exposure. Other common symptoms include a persistent dry or productive cough, chest tightness and/or pain, and wheezing.

On physical examination, the most common finding is bibasilar crackles, typically at end-inspiration, which are heard in approximately 60% of patients with radiographic evidence of asbestosis. Finger clubbing is observed in approximately 30-40% of patients and tends to be associated with more severe or advanced disease. With time, patients may develop signs of cor pulmonale. The clinician also should be vigilant for the signs of asbestos-related malignancies, such as cancers of the lung, pleura, larynx, and even stomach and pancreas.

The pulmonary function examination generally reveals a restrictive pattern with decreased vital capacity, total lung capacity, and diffusion capacity, along with arterial hypoxemia. A mild obstructive pattern also can be seen in asbestosis as a result of bronchiolar fibrosis and narrowing.

The diagnosis of asbestosis requires documentation of pulmonary fibrosis in a patient with an exposure history of sufficient duration, intensity, and latency. Pulmonary fibrosis is usually first detected on chest radiograph, but high-resolution CT (HRCT) can confirm the diagnosis in equivocal instances. Lung biopsy is seldom warranted unless another potentially reversible cause of interstitial lung disease is strongly suggested.

A less invasive means of establishing exposure is bronchoalveolar lavage, which can detect the presence of asbestos bodies. Ancillary diagnostic clues may be gained from clinical history and physical examination, including pulmonary function tests. Note that many patients with radiographic asbestosis do not manifest clinical symptoms. In addition, the chest radiograph is normal in 10-20% of patients with histologic evidence of fibrosis. Once the diagnosis has been established, asbestosis may remain static or progress but rarely regresses.

In patients with severe disease, respiratory impairment can lead to death. With increased resistance to pulmonary blood flow from fibrosis and reactive vasoconstriction secondary to alveolar hypoxia, pulmonary hypertension and cor pulmonale may develop.

Treatment

Currently, no effective treatment exists for asbestosis. Steroids and colchicine, which have been used to treat patients with idiopathic pulmonary fibrosis, have shown no benefit for asbestosis. The respiratory failure associated with advanced disease may be managed with home oxygen. All patients with asbestosis should receive a pneumococcal vaccine, an annual influenza vaccine, and prompt treatment of respiratory infections. Smoking cessation should be strongly stressed. Smoking may be associated with a higher prevalence of asbestosis and has been shown to increase the asbestos-related lung cancer mortality rate by a factor of more than 50. Long-term medical surveillance is recommended for all person with significant asbestos exposure.

Controversies

Considerable controversy exists concerning the topic of asbestosis and lung cancer. The risk of lung cancer increases with heavy asbestos exposure, and asbestosis is an indicator of high exposure; however, a significant number of lung cancers develop in the absence of radiologic asbestosis. As a result, most current opinion holds that lung cancer risk should be based on clinical and occupational histories and not the presence of asbestosis. Whether the presence of lung fibrosis contributes an added risk is uncertain and is the topic of further research

Chest radiography is the traditional modality used for the initial diagnostic evaluation of asbestosis.

“B” readings (standardized forms from the International Labour Organization, filled out by certified “B” readers to assess lung parenchymal and pleural abnormalities related to pneumoconiosis5 ) often are performed on chest radiographs. These readings have little or no clinical utility.

High-resolution computed tomography (HRCT) is more sensitive than conventional radiography in the detection of early or mild fibrosis, particularly in the subpleural zones. HRCT and standard resolution CT (SRCT) are both indicated in patients suspected of having asbestosis. HRCT can define and detect alveolitis and fibrosis earlier than SRCT. SRCT is essential in detecting lung cancer earlier than chest radiography. HRCT is excellent in defining lung parenchymal detail, whereas SRCT images the entire lung and is therefore more likely to detect a malignancy.
Limitations of Techniques

The chest radiograph is normal in 10-20% of patients with histologic evidence of asbestosis. The classic radiographic appearance of asbestosis is nonspecific, but the presence of ancillary findings, such as pleural plaques or diffuse pleural thickening, strongly suggests asbestos exposure as the cause.

Individual high-resolution computed tomography (HRCT) findings are nonspecific, but the likelihood that the fibrosis is the result of asbestos exposure increases with the number of characteristic abnormalities observed and the presence of asbestos-related abnormalities, such as pleural disease.

Tags: amosite, and tremolite, Asbestos, asbestos exposure, asbestos fibers, Asbestos production, case of an asbes, crocidolite, Lung Cancer