Diseases of the Pleura and Mediastinum

Primary Tumors of the Pleura: Mesothelioma

Primary benign and malignant tumors of the pleura are rare, and they include solitary fibrous tumor, adenomatoid tumor, pleural desmoid tumors, calcifying fibrous pseudotumor, and malignant pleural mesothelioma (MPM). For clinicians, the most frequent differential diagnosis is solitary fibrous tumor because these tumors may have features of malignancy such as poor circumscription and invasion into adjacent structures. Solitary fibrous tumors of the pleura are significantly less common than MPM and are not associated with asbestos exposure. They are generally asymptomatic at the time of diagnosis, and the radiographic features are a well-circumscribed, peripheral mass that abuts the pleural surface, frequently attached by a pedicle. Approximately 10% to 20% are classified as malignant; malignant tumors are characterized by mitoses, necrosis, atypia, and hypercellularity. Radiographically malignant tumors compared with benign tumors tend to be larger and are associated with increased likelihood of being avid on fluorodeoxyglucose–positron emission tomography (FDG-PET). Patients with malignant solitary fibrous tumors tend to have a higher recurrence rate and worse survival. The primary treatment remains complete surgical resection if feasible. Because of the rarity of solitary fibrous tumors, it is difficult to define the natural history and optimal management, but postoperative radiation and chemotherapy are not standard therapies. The primary focus of this section is MPM, the most common pleural malignancy.

Epidemiology

The association between MPM and asbestos exposure has been well established for decades; in the mid-20th century, commercial uses for asbestos were developed, which led to increased occupational exposure. Common sites of occupational exposure were asbestos mines, shipyards, cement factories, and places where work with insulation was performed. Asbestos refers to six fibrous silicate minerals found widely throughout the world, and is divided into two categories based on the chemical composition and crystalline structure : a serpentine form (i.e., chrysotile) and a thin, rodlike form (i.e., amphiboles, including crocidolite, amosite, anthophyllite, tremolite, and actinolyte). The association of the amphibole form and MPM is well established, but the association between the serpentine form and MPM is a matter of debate. The long latency period (>20 years) between asbestos exposure and the development of MPM can make identification of the type, amount, and duration of asbestos exposure difficult. There does not appear to be a linear relationship between exposure and risk of developing MPM, and it appears that prolonged exposure is required for development of MPM. This is important for workers who had sporadic or limited exposure. A higher rate of MPM has been observed among family members of workers with occupational exposure, caused by secondary exposure from clothes and close contact. Some patients with MPM will not report a known asbestos exposure, so the absence of a history of asbestos exposure should not eliminate MPM from the differential diagnosis. Less common etiologic agents associated with MPM include prior radiation therapy (RT), diagnostic use of thorium dioxide (Thorotrast), mineral fibers with similar properties (e.g., erionite), and potentially simian virus 40. In the United States, the incidence of MPM is estimated to be about 3000 cases per year. The rate increased from the 1970s to the 1990s but has now leveled off and even slightly declined.

Despite the clear association between asbestos exposure and MPM, only a minority of people with significant exposure develop MPM (~5%), and the identification of MPM clusters within certain families raises the question about the influence of genetics in carcinogenesis. A study of an MPM epidemic in Cappadocia, Turkey and the United States revealed that the risk of developing MPM is transmitted in certain high-risk families, suggesting a genetic predisposition to erionite carcinogenesis. A high incidence of MPM in some families in the United States has been linked to germline mutations of the BAP1 gene. BAP1 somatic mutations have also been identified in 25% of cases of sporadic MPM. BAP1 appears to regulate deubiquitination during the DNA damage response and the cell cycle, and mutations that affect the deubiquitination of BAP1 or the nuclear localization reduce the tumor suppressor activity of BAP1. Other potential mechanisms of carcinogenesis include direct mechanical interference of asbestos fibers with chromosome segregation during mitosis or the generation of oxidants by macrophages attempting to digest asbestos fibers. The presence of asbestos causes inflammation, and the chronic inflammation associated with the asbestos fibers contributes to the process of carcinogenesis. The mechanism of carcinogenesis from chronic inflammation appears to be related to the cytokines tumor necrosis factor–α (TNF-α) and interleukin-1β (IL-1β).

Pathology

The four subtypes of MPM according to the World Health Organization (WHO) are epithelioid, sarcomatous, biphasic epithelial (also referred to as mixed ), and desmoplastic. The epithelioid type is the most common and has a better prognosis compared with the other types. It can be difficult to distinguish MPM from reactive mesothelial hyperplasia, non–small cell lung cancer (NSCLC) with adenocarcinomatous histologic features, and metastatic adenocarcinoma. No single immunohistochemistry (IHC) stain can differentiate MPM from NSCLC with adenocarcinomatous histologic features, and a panel of IHC stains is frequently used. One practice is to test for two markers that are positive in MPM (e.g., cytokeratin AE1/AE3, keratins [e.g., CK5/6, CK7], calretinin, Wilms tumor 1 [WT1; nuclear staining], D2-40) and two that are negative for MPM (e.g., carcinoembryonic antigen [CEA] and thyroid transcription factor 1 [TTF1]) ( Table 70.1 ).

Table 70.1

Histochemistry Studies to Distinguish NSCLC and Malignant Pleural Mesothelioma (MPM)

Stain	Adenocarcinoma	MPM
Cytokeratin AE1/AE3
Keratins
Calretinin
WT1
D2 40
CEA
TTF-1

CEA, Carcinoembryonic antigen; NSCLC, non–small cell lung cancer; TTF-1, thyroid transcription factor; WT1, Wilms tumor.

Staging

The natural history of MPM is growth along the pleural surfaces of the thoracic cavity and invasion of the surrounding lung tissue and regional lymph nodes, followed by transdiaphragmatic extension, peritoneal spread, and occasionally distant metastatic disease. The staging system provides an estimate of the prognosis, and an assessment regarding whether the tumor is potentially resectable. The tumor, nodal, and metastasis (TNM) staging system is often used ( Table 70.2 ). Computed tomography (CT) of thorax and abdomen is the standard clinical staging procedure. However, several series have demonstrated that FDG-PET may improve both T and N staging and prevent futile surgery in some patients. PET-CT also has the ability to reveal extrathoracic disease, and approximately 10% to 25% of patients will have distant disease detected with PET scanning. Transdiaphragmatic extension is a contraindication to surgical resection. In one study, the use of peritoneal lavage before surgical resection demonstrated transdiaphragmatic invasion of the peritoneal cavity or peritoneal metastases in approximately 10% of patients. Surgical staging may further reduce false-negative staging findings. Surgical staging of the mediastinum includes endobronchial ultrasound and/or mediastinoscopy. Laparoscopy with peritoneal lavage is indicated when subdiaphragmatic involvement is suspected.