Malignant Pleural Mesothelioma

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Chapter 70 Malignant Pleural Mesothelioma

Tarek Meniawy, Bruce W.S. Robinson

Malignant mesothelioma is a neoplasm arising from the mesothelial surface of the pleura, peritoneum, pericardium, and tunica vaginalis, with the majority of cases arising in the pleura. Malignant pleural mesothelioma (MPM) has progressively increased in incidence worldwide, associated with increasing exposure to asbestos in the post–World War II era. The disease is preceded by a long latency period, often more than 30 years. Incidence of MPM is expected to peak in the Western world in the next one or two decades because of regulation of asbestos use and increasing public awareness of its health risks since the 1970s and 1980s. However, MPM will continue to increase in many developing countries, where asbestos remains widely used.

Epidemiology

A relationship between asbestos exposure and development of mesothelioma was first reported in 1960 by Wagner et al., who described a cohort of 33 patients who developed diffuse malignant mesothelioma after exposure to asbestos in the North Western Cape Province of South Africa. Subsequent reports in many countries indicated a rising incidence of mesothelioma. Also, it was reported that the risk of developing mesothelioma was dose dependent, with the rate increasing significantly with time from first exposure, duration of exposure, and cumulative exposure. MPM is often preceded by a prolonged latency period of 20 to 60 years.

A review by Price and Ware of mesothelioma time trends in the United States based on the April 2008 release of the Surveillance Epidemiology and End Result (SEER) data estimated that 2400 cases were diagnosed in 2008, with asbestos likely to be the cause in 58%. They also reported a possible shift in the peak incidence in the United States from a peak between 2000 and 2004 to a peak between 2005 and 2010, and that after 2042, mesothelioma cases diagnosed in the United States will be predominantly caused by “background mesothelioma” rather than asbestos-related MPM.

A similar trend is evident in other Western countries and regions, where several decades of rising incidence of MPM have peaked or will peak in the next 20 to 30 years. The regulatory laws introduced progressively since the 1970s restricted asbestos use in various industries, eventually resulting in a total ban in most developed countries and regions. Again, in many Third World and developing countries where asbestos is still widely used and mesothelioma may also be underreported, incidence will increase for decades.

Mesothelioma has also been linked to nonoccupational and environmental exposure to asbestos in multiple epidemiologic studies. Malignant mesothelioma caused by both occupational and nonoccupational asbestos exposure was notably studied in Wittenoom, Western Australia. In areas of Turkey, exposure to tremolite asbestos, commonly used in the white stucco covering walls in houses has been linked to mesothelioma. Another fibrous mineral, erionite, has been associated with MPM in three “cancer villages” in the Cappadocia region of Turkey; later reports suggested that this occurs most often in families with genetic predisposition to mineral fiber carcinogenesis.

The simian virus 40 (SV40) was proposed to act as a “co-carcinogen” with crocidolite asbestos, resulting in malignant transformation, and was shown to induce mesothelioma in hamsters. The same group subsequently demonstrated SV40 viruslike DNA sequences in patients with malignant mesothelioma. The role of SV40 in mesothelioma remains controversial.

Radiation therapy has been linked to MPM in patients followed up after treatment for non-Hodgkin lymphoma. Carbon nanotubes, which are lightweight, strong cylindrical molecules, are increasingly being incorporated into modern manufacturing processes, including electronics, sports equipment, and protective clothing. Initially believed to pose no health risks, they appear to have some similarities to asbestos and were demonstrated to cause mesothelioma when injected into mice. A role for nanotubules in human mesothelioma has not been established, although any long incubation period would make it unlikely that cases would have yet been seen.

Although smoking and asbestos exposure can multiplicatively increase the risk of developing lung cancer, smoking has not been demonstrated to have an independent association with mesothelioma.

Pathogenesis

Asbestos is a term used to describe a group of mineral fibers of two major types: serpentine and amphibole. Chrysotile is the most common serpentine asbestos used commercially and has long, curly and pliable fibers. The amphiboles, which are short, straight, and stiff, include crocidolite (blue asbestos) and amosite. Noncommercial amphiboles include tremolite, which is present in the soil in Turkey, Greece, Afghanistan and other regions.

Controversy surrounds the role of different types of asbestos fibers and the exposure threshold for malignant transformation, particularly the role of chrysotile asbestos. The general consensus is that the amphibole crocidolite is the most carcinogenic form of asbestos, and that asbestos fibers of greater length and smaller diameter (high length/width ratio) are more carcinogenic, possibly because they can penetrate farther into the pleura.

Asbestos can affect the pleura by four main processes. First, asbestos fibers can penetrate deeply into the lung and irritate the pleura, eventually leading to either scarring (plaques) or malignant transformation. The fibers may also pierce the mitotic spindle and result in chromosomal damage, with loss of chromosome 22 being the most common gross change. Third, DNA can be damaged through the formation of iron-catalyzed free radicals. Fourth, asbestos can increase expression of proto-oncogenes through phosphorylation of mitogen-activated protein (MAPK) and extracellular signal-regulated kinases (ERK) 1 and 2. In addition, the following six alterations in cell physiology that can dictate malignant growth, as described by Hanahan and Weinberg, also appear to be present in mesothelioma:

1. Mesothelioma cells have increased or dysregulated growth through both production of and response to various growth factors.

2. Mesothelioma cells express telomerase and therefore avoid telomere shortening (i.e., become “immortalized”).

3. Tumor suppressor genes such as p16 and p14, which are important in the Rb and p53 pathways, are absent in mesothelioma, allowing the tumor to avoid antigrowth signals.

4. Tumor cells evade apoptosis through increased activity of the antiapoptosis molecule Bcl-2.

5. Increased angiogenesis occurs through production of angiogenic factors such as vascular endothelial growth factor.

6. Malignant mesothelioma exists in a collagenous environment, and matrix interactions and regulation of this environment likely are related to tumor growth.

The SV40 virus may play a role in the pathogenesis of MPM and is a subject of ongoing study to clarify its role. The SV40 large T antigen (SV40Tag) can inhibit p53 and Rb tumor suppressor genes. SV40 infection is also involved in activation of various pathways, including Wnt, ERK, PI3K/Akt, and Notch-1 pathways, and has a co-carcinogenic effect with asbestos.

Pathology

Gross Pathology

Diffuse MPM is characterized by multiple pleural nodules that progress along the pleural surface, leading to circumferential thickening that encases the lung in a rindlike manner. It may also appear as a single area or multiple areas of thickening or tumor masses. Local invasion of the chest wall, lung, or mediastinum can also occur. Localized MPM is a much less common entity involving circumscribed masses that do not show the same diffuse pattern of spread along the pleura.

Histology

A definitive diagnosis of MPM is best made with an adequate biopsy in the context of compatible clinical findings. This often represents a diagnostic challenge because of the relatively low frequency of cases outside large tertiary care centers, the often limited amount of tissue available for examination, the heterogeneity of histologic appearance of the same tumor within a patient, and the differential diagnoses of benign pleural disease or other metastatic malignancies. With the increasing availability of immunohistochemical stains, molecular studies, and electron microscopy, diagnostic accuracy has improved. It remains critical for diagnosis to correlate the pathologic findings with the clinicoradiologic features to reach a definitive diagnosis.

The three main subtypes of diffuse MPM are epithelial (epithelioid), sarcomatous (sarcomatoid), and biphasic mesothelioma, with various histologic patterns within each subtype.

Epithelial Subtype

Epithelioid MPMs are the most common subtype and can be further characterized to a number of patterns. The tubulopapillary pattern contains a mixture of tubules and papillary structures (Figure 70-1). Adenomatoid and acinar patterns contain glandlike structures that should be differentiated from adenocarcinomas of other origin (e.g., lung). The solid, well-differentiated pattern has “nests” or sheets of cells that may resemble reactive mesothelium. Differentiating features from reactive mesothelial hyperplasia include stromal invasion, presence of necrosis and expansile nodules, as well as immunohistochemical staining patterns. Other types include solid, poorly differentiated, clear cell, and others.

Figure 70-1 Epithelioid mesothelioma with tubulopapillary growth pattern (hematoxylin-eosin stain [H&E]; ×200).

Sarcomatous Subtype

Sarcomatoid MPMs usually show spindle cells, often have more necrosis and atypical cells than epithelioid patterns, may contain anaplastic or giant cells, and include the lymphohistiocytoid and desmoplastic patterns (Figure 70-2). The desmoplastic pattern contains dense areas of collagen with small amounts of tumor cells, without significant atypia, and can be difficult to differentiate from nonmalignant pleural conditions such as fibrosing pleuritis; differentiating features include stromal invasion and disorganized growth with uneven thickness.

Figure 70-2 Sarcomatoid mesothelioma surrounding chest wall fat (H&E; ×200).

Biphasic (Mixed) Subtype

Biphasic or mixed MPMs contain elements from both epithelioid and sarcomatoid subtypes, with at least 10% of each required for a diagnosis of “biphasic diffuse MPM.”

Cytology

Given that many patients with MPM present with a pleural effusion, cytopathologists and surgical pathologists debate the utility of pleural effusion cytology in the diagnosis. Cell blocks of cytologic samples from pleural effusions used for immunohistochemistry panels similar to those for biopsy specimens have led to more confident diagnosis of MPM when compatible clinicoradiologic findings are present. Morphologic findings alone are not adequate because malignant and reactive epithelial cells share features that make definitive diagnosis difficult. In addition, malignant cells are not usually present in pleural effusions from sarcomatoid effusions, which may contain only reactive mesothelial cells.

The American Thoracic Society, International Mesothelioma Interest Group (IMIG), and European Respiratory Society/European Society of Thoracic Surgeons task force guidelines all acknowledge a role for cytology in the diagnosis of MPM, but favor analysis of a tissue specimen for a definitive diagnosis. In centers with substantial experience in mesothelioma, however, a diagnosis by cytopathology alone is considered possible when combined with immunocytochemical staining.

Immunohisto/Cytochemistry

Immunohistochemistry (IHC) is an important diagnostic tool in MPM. The exact makeup of panels depends on the histologic subtype and type of tumor being considered in the differential diagnosis, as well as the available antibodies. The IMIG consensus statement recommends the use of positive and negative markers with sensitivity or specificity greater than 80% and positivity that considers stain localization and percentage staining (>10%), as follows:

• Reactive mesothelial hyperplasia and epithelioid MPM may be differentiated by a combination of morphologic features and IHC staining; desmin is often positive in reactive hyperplasia, and epithelial membrane antigen (EMA) and p53 may be positive in epithelial MPM.

• Malignant mesothelioma (MM) versus metastatic malignancy (often adenocarcinoma) is a common differential diagnosis. Adenocarcinomas often contain intracellular mucin on periodic acid–Schiff stain after digestion, which is only rarely seen in MM. As a general approach, initial IHC workup may include two mesothelial markers and two markers for the malignancy being considered, as well as pancytokeratin, which is positive in almost all MPMs, except less common sarcomatoid variants. If the tumor is keratin negative, panels for other cancers (e.g., melanoma, lymphoma) would be considered.

• Positive mesothelioma markers include calretinin, keratin 5/6, WT-1 protein, and podoplanin (D2-40). Markers that favor lung adenocarcinoma include Ber-EP4, which is positive in 95% to 100% of cases, compared to less than 20% of mesotheliomas. Carcinoembryonic antigen (CEA), TTF-1, MOC-31, BG8, B72.3, and CD15 are often positive in adenocarcinoma but only in up to 10% of mesotheliomas.

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