Malignant Mesothelioma of the Pleural Space

Introduction

Diffuse malignant pleural mesothelioma is an uncommon tumor characterized by local aggressiveness and historically poor patient prognosis. The relationship between asbestos and mesothelioma is a classic epidemiologic model of exposure leading to disease. At present, the evaluation of a patient with suspected mesothelioma can be challenging due to difficulties in securing a pathologic diagnosis and determining the appropriate management. Limited knowledge of the biology of this tumor and its poor response to conventional therapy has resulted in a variety of therapeutic approaches.

Clinical Presentation and Diagnostic Work-Up

The latency period between exposure to asbestos and the appearance of mesothelioma can be more than 15 years (median, 32 years).[1] The majority of patients seen are over 55 years of age at presentation.[2] The disease is more common in men (male-female ratio, 3:1).[3] Mesothelioma can occur in children but is thought to be unassociated with asbestos exposure.[4]

The initial clinical presentation of mesothelioma may be variable. Most series report a 2- to 3-month median time from the appearance of symptoms to diagnosis.[5]

Patients may present with nonspecific complaints, such as night sweats, weight loss, malaise, cough, and fever. Alternatively, 60% to 90% of patients may have specific complaints of dyspnea or chest pain.

Typically, dyspnea is first caused by a pleural effusion.[6] As the disease progresses, the effusion becomes loculated and the pleural space is replaced by tumor. In patients with progressive disease, dyspnea is caused by constriction over the underlying lung parenchyma.

Usually, the chest pain is initially reported as poorly localized or dull; however, as the disease progresses, the pain becomes localized due to entrapment of the intercostal nerves. Historically, the right chest has been more commonly affected than the left (60% vs 40% of cases).[7]

In advanced stages, chest and abdominal wall deformity, ascites, and cachexia are commonly observed due to uncontrollable tumor growth.[5] Metastases are infrequent; however, they have been observed in cases of advanced disease or in long-term survivors of multimodality therapy.

The physical findings of mesothelioma vary according to the stage of the disease. Decreased breath sounds on the ipsilateral side secondary to pleural effusion may be the only early finding. Once the disease is advanced, a chest or abdominal mass may be palpable. The presence of an abdominal mass is an ominous sign indicating transdiaphragmatic involvement and an unresectable tumor. Symptoms of bowel obstruction indicate very advanced disease.

Although laboratory evaluation of the mesothelioma patient is typically unremarkable, nonspecific findings, such as anemia of chronic disease, eosinophilia, and hypergammaglobulinemia, may be present.[7] Occasionally, thrombocytosis (> 400 × 10⁹/L) may be observed; it is thought to signal a worse prognosis.[8]

Radiologic Evaluation

The radiographic presentation of mesothelioma can be extremely variable, depending on the stage of the disease. Chest x-rays, as well as computed tomography (CT) and magnetic resonance imaging (MRI) of the chest, play a major role in the evaluation of this disease. Chest x-rays are helpful in showing pleural plaques, pleural thickening, pleural effusion, and parenchymal fibrosis—all of which are commonly present in mesothelioma patients. Scans of the chest improve visualization of these abnormalities and permit a better evaluation of tumor infiltration into fissures and mediastinal structures, as well as mediastinal adenopathy.

Chest wall involvement, as evidenced by distortion of the intercostal spaces and infiltration of extrapleural soft tissue or encasement of the hemidiaphragm (suggesting diaphragmatic involvement), may be more difficult to determine with CT. MRI may be more useful in detecting these abnormalities because of its ability to define the disease extent by signal alteration in T1- and T2-weighted images.[9]

The use of both CT and MRI has been demonstrated to be effective in determining resectability.[10] The radiologic signs of unresectability include the following: mediastinal organ invasion and full-thickness transdiaphragmatic involvement.

Recently, fluorodeoxyglucose positron emission tomography (PET) has been shown to be a sensitive method for diagnosing and determining the invasiveness of diffuse malignant pleural mesothelioma.[11] In addition to the aforementioned imaging modalities, two-dimensional echocardiography is utilized in the preoperative imaging work-up to rule out pericardial involvement and assess cardiac function.

Thoracocentesis, Pleuroscopy, and Thoracoscopy

Thoracocentesis is a valuable tool in the initial evaluation of a patient who presents with a pleural effusion. The fluid sample retrieved can be evaluated for macroscopic characteristics, as well as cytology and the chemistry profile. In mesothelioma, the fluid is typically clear yellow and rarely yields a diagnosis (30% to 35%) due to the difficulty in distinguishing between tumor cells and reactive mesothelial cells.[12] Recently, however, with the development of histochemical and immunohisto-chemical staining techniques, as well as electron microscopic analysis, diagnostic accuracy has improved.[13]

Closed pleural needle biopsy has also been used to rule out diffuse malignant pleural mesothelioma. The results of this technique should be interpreted with caution due to its high false-negative rate; however, with the availability of more accurate histopathologic tests, diagnostic accuracy is improving.[14]

With the evolution of minimally invasive technology, the evaluation of patients via pleuroscopy or thoracoscopy has been encouraged.[15,16] These techniques allow for better visualization of the tumor, which, in turn, improves the adequacy of tissue sample biopsies. In cases that are not amenable to pleuroscopy, open biopsy is also encouraged. It is important to place biopsy sites or incisions strategically so that they can be resected should the patient be a candidate for surgical therapy.

Mesothelioma is well known to be locally aggressive and recur at these sites.[17] If the patient is not a candidate for surgery, pleuroscopy with biopsy is still the procedure of choice at Brigham and Women’s Hospital to confirm the diagnosis of mesothelioma.

Pathology

Microscopically, the cells of origin are pluripotential cells that can differentiate into mesenchymal or epithelial cells. Three different histologic types have been described: epithelial, sarcomatous, and mixed. The histologic classification also has prognostic significance. The sarcomatous and mixed types have been shown to correlate with a poorer patient prognosis than the epithelial type.[18]

The definitive diagnosis of diffuse malignant pleural mesothelioma may be elusive. It is particularly difficult to distinguish diffuse malignant pleural mesothelioma from adenocarcinoma. Table 1[19,20] displays useful parameters to differentiate between those two pathologies.

In terms of gross pathology, the pleural surfaces of patients with mesothelioma are seeded by malignant cells. These cells grow into small nodularities that coalesce to create tumor masses. Over time, the pleural space is replaced by tumor, creating mechanical constriction of the normal lung parenchyma and pericardium. The uncontrollable tumor growth may invade the mediastinum, chest wall, or subdiaphragmatic structures. The patient usually succumbs to conditions secondary to local tumor invasion, as opposed to metastatic disease.

Staging Systems

Currently, no widely accepted staging system for diffuse malignant pleural mesothelioma exists. The first staging system, proposed by Butchart et al in 1976 and based on 29 patients,[21] is widely used. This system has two main weaknesses: (1) nodes are classified as extrathoracic or intrathoracic based on their location, rather than on tumor burden; and (2) there is no correlation between stage and survival.

In 1990, the International Union Against Cancer developed a system[22] based on tumor, nodal status, and metastases. This TNM system also had limitations and was revised in 1995 by the International Mesothelioma Interest Group (Table 2).[23] It has to be validated in a prospective, multicenter, randomized trial.

Sugarbaker and colleagues proposed the Brigham Staging System based on tumor, resectability, and nodal status[24]; this system was revised in 1998 (Table 3)[25] based on survival data from 183 patients (Figure 1).[25] For stage I disease, median patient survival was 25 months, as compared with median survival times of 20 and 16 months for patients with stage II and III disease, respectively.