Sterman DH, Litzky LA, Kaiser LR, Albelda SM Epidemiology and pathology of malignant mesothelioma In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009

Authors:
Daniel H Sterman, MD
Leslie A Litzky, MD
Larry R Kaiser, MD
Steven M Albelda, MD

Section Editors:
Arthur T Skarin, MD
Andrew Nicholson, MD

Deputy Editor
Michael E Ross, MD

Last literature review version 17.1: January 2009  |  This topic last updated: February 9, 2009  

INTRODUCTION — Mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or the pericardium. Eighty percent of all cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, with approximately 70 percent of cases of pleural mesothelioma being associated with documented asbestos exposure.

The epidemiology and pathology of mesothelioma will be reviewed here. The clinical presentation, evaluation, staging, and treatment of malignant mesothelioma are discussed separately.

EPIDEMIOLOGY — The annual incidence of mesothelioma in the United States is estimated to be approximately 3300 cases per year [1]. The incidence of mesothelioma in the United States appears to have peaked around the year 2000 and is now declining, secondary to control of exposure to asbestos [2].

The incidence is increasing in many other places in the world, particularly in Great Britain, where a peak of up to 2450 deaths per year expected around the year 2015 [3]. After that time, mesothelioma rates are expected to drop in England and other developed countries because of recent legislation aimed at reducing asbestos exposure in the workplace and the general environment. In contrast, mesothelioma incidence rates are predicted to increase dramatically in the Third World secondary to the poor regulation of asbestos mining and the proliferation of industrial and household utilization of asbestos [3-5].

Asbestos exposure — Asbestos is the commercial name for a group of hydrated magnesium silicate fibrous minerals. There are two major types: serpentine and amphibole. Ninety percent of the asbestos currently used in the United States is Canadian chrysotile, a serpentine fiber that is reportedly less carcinogenic [3,4].

Asbestos is valued in industry for its resistance to heat and combustion. It is still used in cement, ceiling and pool tiles, automobile brake linings, and in shipbuilding.

As many as eight million living persons in the United States have been occupationally exposed to asbestos over the past 50 years. With the acknowledgment that asbestos exposure may endanger the health of American workers, the Occupational Safety and Health Administration established 5 fibers per cubic milliliter of air as the standard acceptable exposure in 1970. This level has since been reduced to 0.2 fibers per cubic milliliter of air, but applies only to fibers longer than 5 micrometers. Workers exposed to higher concentrations of regulated fibers are mandated to use protective clothing, respirators, and showers [4].

Asbestos workers are at significant risk for the development of both non-malignant and malignant pulmonary disease.

• Approximately 8 percent of asbestos workers will die of respiratory failure secondary to asbestosis.

• More important, the average asbestos worker has a 50 percent chance of dying from a malignancy, compared to around 18 percent for the average American. The vast majority of cancers in asbestos workers involve the lung — either primary lung carcinoma or mesothelioma.

• The lifetime risk of developing mesothelioma among asbestos workers is thought to be as high as 10 percent [6]. There is a long latency of approximately 30 to 40 years from the time of asbestos exposure to the development of mesothelioma.

• There appears to be a dose-response relationship between asbestos exposure and mesothelioma. This was illustrated in cohort study of 4659 people who resided in an Australian city that produced crocidolite asbestos but who did not directly participate in its mining or milling; the incidence of mesothelioma increased significantly with greater environmental exposure, based upon the neighborhood and duration of residence [7]. In a cohort of textile workers with heavy exposure to asbestos, the risk of pleural mesothelioma was increased and was proportional to the latency period [8].

• Asbestos exposure acts synergistically with cigarette smoking to increase the risk of developing lung cancer 60 times over that of a similarly matched non-smoking, non-asbestos-exposed cohort.

• Asbestos workers are thought to have an increased risk of non-mesothelioma gastrointestinal malignancies [4,5,9,10].

Environmental, nonoccupational exposure to asbestos also can contribute to an increased risk of mesothelioma [11-16]. In certain rural areas in Greece, Turkey, and Bulgaria, soil contains remarkably high levels of tremolite asbestos fibers, and many cases of mesothelioma in these regions appear to be secondary to long-term nonoccupational asbestos exposure [11-14]. A role for nonoccupational exposure to asbestos was also supported by a study from California in which an increased incidence of mesothelioma was associated with proximity to naturally occurring asbestos deposits [15].

Asbestos is responsible for a substantial number of cases of peritoneal mesothelioma, although the relationship may be less strong than for pleural mesotheliomas [17].

Radiation therapy — Ionizing radiation to supradiaphragmatic fields may be a risk factor for the subsequent development of mesothelioma, with a long latent period between the initial treatment and the diagnosis of the second malignancy.

• A study of 77,876 NHL patients from the Surveillance, Epidemiology and End Results (SEER) database found an increased risk of mesothelioma that was limited to patients who had been treated with radiation [18]. The increased risk was highest in those who were less than 25 years of age at the original diagnosis.

• An analysis of 21,881 cases of Hodgkin lymphoma and 101,000 patients with NHL from the SEER database extended and confirmed these earlier observations [19]. Although the number of cases of mesothelioma identified was small, the risk was significantly increased and was limited to those who had received radiation.

• A population-based series of over 40,000 men treated for testicular cancer between 1943 and 2001 and followed long-term found ten excess cases of pleural mesothelioma (relative risk 4) for men treated with radiation therapy alone [20].

• The data for patients with breast cancer are conflicting. An analysis of 22,140 patients treated in 11 National Surgical Adjuvant Breast Project (NSABP) trials identified three cases of mesothelioma, all occurring in women who had received RT to the ipsilateral thorax [21]. In contrast, a SEER database cohort of over 250,000 could not identify a link between RT and subsequent development of pleural mesothelioma [22].

Although prophylactic mediastinal irradiation is no longer used in testicular germ cell tumors and its use has been sharply curtailed in patients with HL and NHL, there are a substantial number of cancer survivors who remain at risk for the late development of mesothelioma.

Carbon nanotubes — Carbon nanotubes share similar dimensions and chemical properties with asbestos [23]. Studies in animal models have shown that these particles can induce mesothelioma-like changes in susceptible strains of mice following intraperitoneal administration [24,25].

Carbon nanotubes are being used in an increasing array of applications in the workplace. Epidemiologic vigilance will be required to ensure that these are not a new etiologic source of malignant mesothelioma [23].

Viral oncogenes — Simian virus-40 (SV-40) is a polyoma virus with oncogenic potential in humans. Its actions are thought to result from inactivation of tumor suppressor genes of the retinoblastoma family by a peptide known as the SV-40 large T-antigen. Several studies have documented the presence of SV-40 nucleic acids in a large proportion of mesothelioma cases (some of which did not have obvious asbestos exposure) [26-30]. As an example, one report examined 35 archival mesothelioma specimens and found that SV-40-like sequences were present in 86 percent of cases [26]. However, the possibility that technical factors (including laboratory contamination) can produce false-positive results suggestive of SV-40 infection also has been raised [31,32].

It is possible but not unequivocally demonstrated that viral interference with tumor suppressor genes may play an important role in enabling the development of malignant mesothelioma [33]. If this hypothesis is validated, novel strategies of vaccination to prevent mesothelioma, or molecular techniques to improve early diagnosis may become possible.

Other etiologic factors — The development of malignant pleural mesothelioma has also been associated in rare cases with intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates, such as erionite. Epidemiological studies of a region in central Anatolia (Turkey) with an abnormally high incidence of pleural mesothelioma (22 per 10,000 individuals over 25 years old) implicated routine household use of a locally ubiquitous silicate, zeolite, as a potential causative agent [34].

PATHOLOGY — On gross appearance, malignant mesothelioma is a firm, grayish tumor that coalesces on the visceral and parietal pleural surfaces into discrete plaques and nodules. The lung can be completely covered with a thick rind of tumor that can reach diameters of 5 centimeters or more, despite only minimal penetration of the underlying lung parenchyma (show figure 1). Adjacent structures are involved at an early stage, with invasion of the chest wall, pericardium, diaphragm, and interlobar fissures. Seventy percent of patients will have mediastinal lymph node involvement at autopsy. Hematogenous metastases are more common than previously thought, particularly to liver, lung, bone, and adrenal glands.

Histology — Malignant mesothelioma is typically classified into three histologic subtypes — epithelial, sarcomatoid, and biphasic. This categorization is somewhat of an oversimplification, in that the larger the tissue sample, the more frequent the histologic variation. Nonetheless, the classification scheme has general diagnostic and prognostic utility. Epithelial mesotheliomas have been reported to have a better prognosis than sarcomatoid and biphasic forms [34].

• The epithelial variant is the most common, comprising 50 to 60 percent of all mesotheliomas. Typical histologic appearances of this subtype include tubulopapillary, glandular, and solid epithelioid patterns (show histology 1).

• Sarcomatoid mesotheliomas are composed of malignant spindle cells which may mimic malignant mesenchymal tumors, such as fibrosarcoma or leiomyosarcoma.

• Biphasic or mixed mesotheliomas have epithelioid and sarcomatoid features, but multiple tissue sections may be needed to demonstrate both components.

Electron microscopy — The predominant epithelial form is composed of polygonal cells with numerous long surface microvilli, prominent desmosomes, and abundant tonofilaments (show histology 2). Electron microscopy of the sarcomatoid variant reveals the presence of elongated nuclei and copious rough endoplasmic reticulum [34]. Although electron microscopy had been considered the "gold standard" in the past, a well considered immunohistochemistry panel will provide a definitive diagnosis in most cases.

Immunohistochemistry — Immunohistochemistry (IHC) has proven to be quite valuable in the differentiation of epithelioid mesothelioma from primary pulmonary or metastatic adenocarcinoma. In addition to markers that support a diagnosis of adenocarcinoma, there are now a number of commercially available antibodies that are reliable markers of mesothelial differentiation. Both sets of markers tend to be less helpful in the differential diagnosis of sarcomatoid lesions but do have some utility [35,36].

There is no single marker that has sufficiently high sensitivity and specificity for malignant mesothelioma. It is standard practice for pathologists to employ a panel of markers (both positive and negative) for the study of possible mesotheliomas (show table 1). Institutions vary somewhat in their selection of which markers to include, and panels are typically refined as publications appear with studies comparing the utility of different markers. Some general principles are summarized below:

• Common affirmative IHC markers, which can be used to support a diagnosis of malignant mesothelioma if positive include calretinin, CK5/6, the Wilms' tumor-I (WT1) antigen, thrombomodulin, mesothelin, D2-40 and podoplanin (show table 1) [37-43].

• On the other hand, a wide variety of markers can be used to support a diagnosis of adenocarcinoma as opposed to mesothelioma. In general, mesotheliomas do not stain with carcinoembryonic antigen (CEA) and Leu-M1, both of which are typically positive in adenocarcinomas. Other adenocarcinoma markers, thyroid transcription factor-1 (TTF-1), Ber-EP4, MOC-31, Bg8, and B72.3 are also commonly included in panels. The sensitivity and specificity of these markers is more variable when there is a narrower differential diagnosis (ie primary pulmonary adenocarcinoma versus epithelioid mesothelioma) than when the differential is broadened to include metastases from extrathoracic sites such as the kidney or ovary.

• Antibodies against cytokeratin (CK) proteins are strongly positive in mesothelioma, demonstrating diffuse cytoplasmic staining with perinuclear accentuation. CK reactivity usually differentiates mesotheliomas from many sarcomas, but is not consistently useful for differentiation among epithelioid lesions. In particular, CK5/6 positivity is useful for supporting the diagnosis of mesothelioma [44].

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