Version May 2024
INTRODUCTION — Malignant mesothelioma is a rare and insidious neoplasm with a poor prognosis. It arises from mesothelial surfaces of the pleural cavity, peritoneal cavity, tunica vaginalis, or pericardium. Malignant pleural mesothelioma (MPM) is the most common type and can be difficult to treat because most patients have advanced disease at presentation.
The clinical presentation, evaluation, staging, and prognosis of MPM will be reviewed here. Epidemiology and treatment of pleural mesothelioma, as well as issues related to peritoneal mesothelioma are covered elsewhere:
●(See "Epidemiology of malignant pleural mesothelioma".)
●(See "Pathology of malignant pleural mesothelioma".)
●(See "Initial management of malignant pleural mesothelioma".)
●(See "Systemic treatment for unresectable malignant pleural mesothelioma".)
●(See "Malignant peritoneal mesothelioma: Treatment".)
CLASSIFICATION — The 2021 WHO Classification of Tumors of the Pleura proposes significant changes to the 2015 WHO Classification. Among other changes, well-differentiated papillary mesothelioma now is called well-differentiated papillary mesothelial tumor based on findings that these tumors behave in a relatively indolent fashion. The term "malignant" has been dropped as a prefix from localized and diffuse mesothelioma and mesothelioma in situ has been added to the new classification because these lesions can be recognized with certain biomarkers such as the loss of BRCA1-associated protein 1 (BAP1). Epithelioid, biphasic, and sarcomatoid subtypes remain the same, but cytologic and stromal features are more formally incorporated based on their prognostic significance. Several other changes also are proposed along with the recognition that the most frequently altered genes in diffuse pleural mesothelioma include BAP1, cyclin-dependent kinase inhibitor 2A (CDKN2A), NF2, TP53, SETD2, and SETDB1 [1-3].
CLINICAL MANIFESTATIONS — The vast majority of MPM occur in patients age 60 years and older, typically presenting decades after an exposure to asbestos with gradually worsening, nonspecific pulmonary symptoms. The epidemiology of MPM is discussed elsewhere. (See "Epidemiology of malignant pleural mesothelioma".)
Symptoms, signs, and findings on imaging are discussed in the sections below.
Symptoms — Most patients with MPM present with the gradual onset of nonspecific symptoms such as chest pain, dyspnea, cough, hoarseness, night sweats, or dysphagia, which occur in the setting of extensive intrathoracic disease. Distant metastatic spread is less common but rarely can involve the bone, liver, or central nervous system (CNS). Systemic symptoms such as fatigue and weight loss may also be present, particularly in patients with advanced disease. Symptoms may be present for months or longer prior to diagnosis.
In very rare instances, patients with mesothelioma will present with acute symptoms of local invasion of vital structures. For example, involvement of the brachial plexus or compression of the spinal cord may lead to focal neurologic deficits. Growth through the diaphragm may lead to bowel obstruction, resulting in abdominal pain, distension, and vomiting. Impingement on the superior vena cava may cause symptoms of head fullness or facial swelling. Cardiac involvement may lead to arrhythmias or heart failure. Other rare presentations of MPM include paraneoplastic syndromes [4-8], although these are generally seen in the context of advanced disease that presented earlier with more typical symptoms. Reported paraneoplastic conditions include disseminated intravascular coagulation, migratory thrombophlebitis, thrombocytosis, hypoglycemia, various neurologic disorders, renal disease, and hypercalcemia.
Physical exam findings — Common physical findings at the time of diagnosis generally are due to a pleural effusion, which is almost always present, and include unilateral dullness to percussion at the lung base, decreased air movement on the side of involvement, and asymmetric chest wall expansion during respiration. Palpable chest wall masses, as well as tumor nodules in previous incision or thoracentesis puncture sites, and scoliosis toward the side of the malignancy may be seen with advanced disease.
Findings on imaging — Chest imaging is generally done as part of the initial symptom evaluation. Typically, chest radiograph (CXR) is the initial exam, although a chest computed tomography is often pursued subsequently given limited sensitivity and specificity with CXR. Common radiographic findings for patients with pleural mesothelioma include the following:
●A unilateral pleural abnormality with a large, unilateral pleural effusion (image 1A).
●A pleural mass or rind or diffuse pleural thickening in the absence of a pleural effusion (image 1A-B).
●Pleural plaques and/or calcifications.
●Ipsilateral mediastinal shift due to encasement of lung by a thick rind of tumor and relative ipsilateral lung volume loss.
Other radiographic features concerning for malignancy, although less specific for mesothelioma, include unilateral loss of lung volume, loss of normal fat planes, and gross extension of a mass into mediastinal fat [9]. Only 20 percent of patients with pleural mesothelioma have radiographic signs of asbestosis (such as bibasilar interstitial fibrosis).
For patients who are imaged by positron emission tomography, increased uptake of fluorodeoxyglucose (FDG) is observed. (See 'Advanced imaging' below.)
DIAGNOSIS — Clinical suspicion for MPM may arise in the setting of respiratory symptoms in the context of pleural thickening or an effusion on chest imaging and a history of asbestos exposure. Although these features may raise the suspicion of MPM, a biopsy is necessary to confirm the diagnosis [10].
Evaluation — Initial evaluation of patients with suspected MPM includes contrast-enhanced computed tomography of the chest to identify pleural abnormalities and extent of disease, thoracentesis of any existing pleural effusion, and closed pleural biopsy. Further imaging for diagnosed cases of MPM, including positron emission tomography, is discussed below. (See 'Advanced imaging' below.)
However, frequently this initial approach does not provide sufficient tissue to definitively establish a diagnosis of MPM and, specifically, to differentiate it from adenocarcinoma. In such instances, surgical intervention via video-assisted thoracoscopic (VATS) biopsy or open thoracotomy should be pursued. Additionally, we evaluate with concurrent bronchoscopy at the time of surgery, as endobronchial lesions are typically not seen in mesothelioma, and their presence argues against this diagnosis. This also allows for the performance of endobronchial ultrasound (EBUS)-guided biopsies of mediastinal pleural lesions, tumor masses in the subcarinal space, and mediastinal and hilar lymph nodes ipsilateral and contralateral to the primary process, which provides staging information if MPM is diagnosed. (See 'Surgical staging' below.)
The difficulties in establishing a diagnosis of mesothelioma are illustrated by a study of 188 consecutive patients evaluated between 1973 and 1990 [11]. Thoracentesis and pleural fluid cytology yielded a diagnosis in 26 percent of cases, and thoracentesis plus closed pleural biopsy was diagnostic in 39 percent of cases. By contrast, VATS was diagnostic in 98 percent of cases. (See "Medical thoracoscopy (pleuroscopy): Equipment, procedure, and complications".)
Approximately 10 percent of patients who undergo an invasive diagnostic procedure for mesothelioma seed the biopsy site with tumor cells and later develop a chest wall recurrence. The role of prophylactic radiation therapy to prevent this complication is discussed separately. (See "Initial management of malignant pleural mesothelioma".)
Tissue diagnosis — The diagnosis of pleural mesothelioma is established by morphologic and immunohistochemical features of a cytologic or surgical specimen [10].
Most malignant mesothelioma appear as one of three histologic subtypes: epithelioid, sarcomatoid, or biphasic (mixed). Within each subgroup, a broad range of morphologic features may be present or absent, making morphology alone insufficient to establish the diagnosis in most cases. However, based on morphology and the degree of differentiation of the tumor, specific immunohistochemical markers are chosen to evaluate the specimen further. Because no single immunohistochemical marker exhibits high sensitivity or specificity, the International Mesothelioma Interest Group recommends using a panel of at least two immunoreactive and two nonimmunoreactive markers to establish the diagnosis of mesothelioma [12]. Similarly, according to several European expert groups, standard staining procedures are insufficient in approximately 10 percent of cases, justifying the use of specific markers, including BAP1 and cyclin-dependent kinase inhibitor 2A (CDKN2A [p16]), for the separation of atypical mesothelial proliferation from MPM [13]. The immunohistochemistry as well as other features of pathology are discussed in more detail elsewhere. (See "Pathology of malignant pleural mesothelioma", section on 'Histology'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of MPM includes both benign and malignant processes:
●Benign conditions – Inflammatory reactions, such as chronic organized empyema, can often mimic the dense parietal and visceral pleural thickening along with a large pleural effusion that is characteristic of mesothelioma. However, on pathologic examination, stromal invasion is present in the case of MPM but absent with benign disease. (See "Pathology of malignant pleural mesothelioma", section on 'Histology'.)
●Malignant conditions – Other malignant conditions can present in a similar clinical and radiographic pattern as mesothelioma and may share similar morphologic characteristics under microscopy. For example, certain sarcomas can present in similar fashion and infiltrate like sarcomatoid mesotheliomas and may even appear histologically similar to sarcomatoid mesothelioma. As further examples, pleural metastases of peripheral lung adenocarcinomas, as well as metastases to the pleura from a number of solid tumors (including but not limited to the lung, breast, stomach, kidney, ovary, thymus, and prostate), may grossly and histologically resemble epithelioid mesothelioma. Immunohistochemical patterns of staining can distinguish mesothelioma from these entities. (See "Pathology of malignant pleural mesothelioma", section on 'Immunohistochemistry'.)
STAGING AND PRETREATMENT EVALUATION — While virtually all patients with MPM will receive chemotherapy, one goal of staging is to identify patients who may benefit from surgical resection as well. Staging and pretreatment evaluation also establishes baseline disease burden and organ function before beginning chemotherapy [14].
Clinical staging with imaging is the initial staging evaluation for patients with MPM. However, clinical staging often underestimates the extent of disease, and pathologic staging provides a more reliable assessment of whether or not the patient is a candidate for surgical resection. (figure 1).
Staging systems — The most widely used staging system is the tumor, node, metastasis (TNM) staging system that has been adopted by the International Union Against Cancer (UICC), the American Joint Committee on Cancer (AJCC), and the European Society for Radiotherapy and Oncology (ESTRO), among others. Both the seventh edition (table 1) and the eighth edition (table 2), which went into effect on January 1, 2018, are shown [15]. In both of these editions, stage I and II disease have pleural involvement and may involve diaphragmatic muscle or pulmonary parenchyma, but lack lymph node involvement or distant metastases. In the seventh edition, stage III mesothelioma includes locally advanced disease, including cases with regional lymph node involvement; and stage IV disease includes those with locally advanced unresectable disease, contralateral lymph node involvement, supraclavicular lymph node involvement, or distant metastases. In the eighth edition of the TNM staging system, however, stage IV disease includes only those with distant metastases; other tumors previously considered stage IV, including locally advanced unresectable disease, will be considered as a subset of stage III disease.
To develop the eighth edition of the TNM system, the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group used a database with information on 3101 patients with mesothelioma diagnosed in 15 centers between 1995 and 2009 [14]. The information in this database was correlated with various prognostic factors (see 'Prognostic factors' below). A second database including 3519 patients diagnosed between 2000 and 2013 in 29 centers worldwide was developed to acquire more detailed TNM information to further refine the staging system.
Other staging systems have been developed and are used at some centers. As an example, the Brigham staging system is a modification of the older Butchart system [16]. Involvement of hilar, ipsilateral, and midline mediastinal lymph nodes categorizes a patient as stage II. In addition, the presence of positive surgical margins also qualifies for classification as stage II. Invasion of chest wall, mediastinum, heart, esophagus, or contralateral structures upstages a patient to stage III, as does extrapleural nodal involvement.
A major limitation of all of the staging systems is the difficulty in assessing the extent of disease prior to treatment. In a database study including 1056 cases in which both clinical and pathologic staging were available, clinical staging was unreliable, with approximately 80 percent of clinical stage I patients and 70 percent of stage II patients being upstaged following pathologic evaluation based upon surgery (figure 1).
Staging evaluation — The initial staging evaluation for MPM is through imaging, followed by surgical staging for those in whom surgical resection is being considered. (See "Initial management of malignant pleural mesothelioma", section on 'Patient selection and rationale for surgery'.)
Advanced imaging — For diagnosed cases of pleural mesothelioma, we obtain integrated positron emission tomography with computed tomography (PET-CT) as part of the staging assessment [10]. The use of PET aids in assessment of the mediastinal lymph nodes, for which CT has only limited sensitivity [17,18]. For patients in whom resection is being considered, additional imaging with magnetic resonance imaging (MRI) may help define the local extent of disease. MRI is particularly useful for those in whom there is a concern based on previous imaging for involvement of the brachiocephalic vessels, chest wall, central mediastinal structures, or diaphragm. For example, in the latter instance, coronal MRI images may identify extension of pleural mesothelioma through the diaphragm into the peritoneal cavity, which would preclude surgical intervention (image 2A-B) [19].
Several series have suggested that PET-CT imaging is the most reliable imaging modality for initial assessment, particularly in determining whether a tumor is resectable [20-22]. For example, in one series, 42 consecutive patients with potentially resectable disease based upon CT were assessed with PET-CT [20]. In 12 cases (29 percent), patients were reclassified as inoperable based upon the presence of a T4 lesion or distant metastasis (29 and 14 percent, respectively). In another series of 54 patients who underwent imaging followed by surgical staging, PET-CT was more accurate than CT or PET alone or MRI in assessing stage and extent of disease [21].
Early studies suggest that staging determined by volumetric CT, in which tumor volumes are calculated semiautomatically from CT measurements, may correlate with overall survival. In a study of 164 patients, volume correlated with pathologic TNM staging and overall survival, best defined by three groups with average volumes of 91, 245, and 511 cm3, associated with median overall survival of 37, 18, and 8 months, respectively [23]. Further study is indicated before incorporation into routine practice.
In an attempt to define standardized guidelines for the radiologic assessment of MPM, a multidisciplinary meeting of mesothelioma experts was held in March 2017, from which has arisen a consensus statement. Recommendations include CT with contrast optimized to visualize the tumor and 1-mm axial images acquired in soft-tissue kernel to allow for multiplanar reformats and volumetric estimation; MRI with contrast and diffusion-weighted imaging, if available; and serial fluorodeoxyglucose (FDG) PET-CT for response evaluation. Standardization of imaging protocols across centers of expertise to allow for pooling of data for future research was also recommended [24].
Surgical staging — For patients in whom imaging suggests resectable disease, we pursue extended surgical staging prior to definitive surgery. Specifically, this includes mediastinoscopy or endobronchial ultrasound (EBUS)-mediated staging of mediastinal lymph nodes. It typically also includes laparoscopy with peritoneal lavage to detect subdiaphragmatic involvement, which is most useful when there is concern for invasion of the diaphragm. Patient selection for surgical intervention is discussed elsewhere. (See "Initial management of malignant pleural mesothelioma", section on 'Patient selection and rationale for surgery'.)
Extended surgical staging has prognostic utility, but also may guide management [25,26]. For example, in a series of 118 consecutive patients, surgical staging with laparoscopy with peritoneal lavage followed by mediastinoscopy allowed 14 percent of patients to avoid an inappropriate intervention [25].
Pretreatment evaluation — For patients with MPM, we obtain routine prechemotherapy laboratory tests, including a complete blood count with platelets, liver function tests, and serum alkaline phosphatase. We also obtain lactate dehydrogenase for its prognostic utility [27-29] (see 'Prognostic scoring systems' below). For patients in whom surgical resection is being considered, we obtain pulmonary function tests prior to surgery to determine whether residual lung function after surgery will be sufficient.
Several biomarkers are selectively elevated in patients with mesothelioma. Some UpToDate experts follow soluble mesothelin-related peptides for patients on treatment, although this is not uniform. This and other biomarkers are discussed below. (See 'Biomarkers under investigation' below.)
PROGNOSIS — The prognosis of patients with MPM is poor, with overall survival being on the order of 9 to 17 months after diagnosis [30-32]. Few patients are cured [33,34]. The majority of affected patients die from local extension and respiratory failure. In some cases, tumor extension below the diaphragm may result in death from small bowel obstruction. Patients may also die from arrhythmias, heart failure, or stroke caused by tumor invasion of the heart or pericardium.
Prognostic factors — Stage and histology are the strongest prognostic factors among patients with mesothelioma, with sarcomatoid and biphasic histologic subtypes having worse outcomes compared with epithelioid mesothelioma (figure 2 and figure 3). The pure epithelioid variant is associated with the best prognosis especially if the disease can be completely resected. Other poor prognostic features include poor performance status, age >75 years, elevated lactate dehydrogenase (LDH), and hematologic abnormalities [27,35,36]. These factors are included in scoring systems discussed below. (See 'Prognostic scoring systems' below.)
Information from a database of approximately 3100 patients, developed to refine the tumor, node, metastasis (TNM) staging system, suggests the prognostic importance of histology and stage. In this database, median survivals for those with epithelial, biphasic, and sarcomatoid histology were 19, 13, and 8 months (figure 4) [14]. Based upon surgical staging when available (and clinical staging for those without surgical staging) (table 1), patients with stage I, II, III, and IV disease had median survivals of 20, 19, 16, and 11 months, respectively (figure 5).
Prognostic scoring systems — Prognostic scoring systems that incorporate both the extent of disease as well as systemic factors have been developed by the European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB). While these scoring systems were developed prior to the use of pemetrexed, which has subsequently become a standard treatment option for mesothelioma, subsequent study has supported the prognostic value of the EORTC index [37].
The EORTC reviewed data from 204 adults with MPM who were entered into five consecutive phase II trials over nine years [35]. Patients with all stages of disease were permitted. When five factors were taken into consideration (poor performance status, high white blood cell [WBC] count, male sex, sarcomatous subtype, and the certainty of the diagnosis), a good and bad prognostic group could be discerned, with one-year survival rates of 40 and 12 percent, respectively (table 3). Median survival from the date of study entry was 8.4 months. The prognostic significance of the EORTC index has subsequently been confirmed in a multivariate analysis of a phase III trial assessing cisplatin plus raltitrexed [37]. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Single-agent chemotherapy'.)
Similarly, the CALGB evaluated the impact of clinical characteristics on the survival of 337 patients with malignant mesothelioma (of any stage and arising from any anatomic site) who were enrolled in phase II treatment studies [27]. In multivariate analysis, pleural (as compared with peritoneal or pericardial) involvement, serum LDH greater than 500 international units/L, poor performance status, chest pain, platelet count over 400,000/microL, nonepithelial histology, and age older than 75 years jointly predicted poor survival. Six distinct prognostic subgroups were generated with median survival times ranging from 1.4 to 13.9 months (table 4). The median survival overall was seven months. This prognostic schema was subsequently validated in an American phase II trial evaluating the investigational agent ranpirnase and in an independent European data set [28,29].
A novel Mesothelioma Weighted Grading Scheme (MWGS) has been proposed that assigns weighted scores from 0 to 10 based on age, histologic type, necrosis, mitotic count, nuclear atypia, and BAP1 expression [38]. In 369 consecutive patients with diffuse pleural mesothelioma median survival was 17.1, 10.1, and 4.1 months for low, intermediate, and high grades based on their weighted scores. A progressive increase in score correlated with worsening overall survival.
The small number of mesothelioma patients enrolled in clinical trials and the heterogeneity of study populations has limited the identification of molecular biomarkers for prognosis. New molecular technologies, such as gene expression profiling, may eventually classify patients into distinct prognostic subgroups [39,40].
BIOMARKERS UNDER INVESTIGATION — Several biomarkers are selectively elevated in patients with mesothelioma. However, further study and validation is required before these are recommended for diagnosis of mesothelioma. Some UpToDate experts follow serial measurements of soluble mesothelin-related peptides (SMRPs) as an adjunct to imaging in monitoring treatment response in those found to have elevations at the time of diagnosis of mesothelioma.
SMRPs are found in serum or pleural fluid and are believed to be peptide fragments of mesothelin, a glycoprotein present on normal mesothelial cells and overexpressed on mesothelioma cells [41,42]. However, SMRPs are not elevated in sarcomatoid lesions, have limited sensitivity in other histologic subtypes, and are also elevated in other malignancies, and therefore are of limited diagnostic utility. A meta-analysis of 16 diagnostic studies found that the sensitivity of serum SMRPs ranged from 19 to 68 percent, depending upon the specific criterion for positivity [43]. In patients with stage I or II disease, the sensitivity was only 32 percent when a specificity criterion of 95 percent was used. SMRPs have also been measured in pleural fluid [44-46], with one retrospective study suggesting sensitivity of 67 percent and specificity of 98 percent [45].
Other biomarkers of interest include fibulin-3, osteopontin, and the secreted growth factor amphiregulin (AREG) [47-52], although more study is needed before routine clinical use. High cytosolic AREG expression may be of prognostic value and potentially useful as a stratification factor in future clinical trials. Utilizing data collected during the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456), MST1/hippo kinase expression loss was predictive of poor prognosis [53].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Pleural mesothelioma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Pleural mesothelioma (The Basics)" and "Patient education: Asbestos exposure (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction – Malignant pleural mesothelioma (MPM) is a rare insidious neoplasm that typically presents with advanced disease. (See 'Introduction' above.)
●Clinical presentation
•Most patients with MPM present with the gradual onset of nonspecific symptoms such as chest pain, dyspnea, cough, hoarseness, or dysphagia, which occur in the setting of extensive intrathoracic disease. (See 'Symptoms' above.)
•Chest imaging typically shows unilateral pleural thickening and pleural effusion. (See 'Findings on imaging' above.)
•Cigarette smoking is not a risk factor for the development of MPM.
●Evaluation – Initial evaluation of patients with suspected MPM includes computed tomography (CT) of the chest with contrast, thoracentesis of any existing pleural effusion, and closed pleural biopsy. However, if insufficient tissue is acquired to make a diagnosis, surgical intervention via video-assisted thoracoscopic biopsy or open thoracotomy should be pursued. (See 'Evaluation' above.)
●Diagnosis – The diagnosis of pleural mesothelioma is established by morphologic and immunohistochemical features of a cytologic or surgical specimen. (See 'Tissue diagnosis' above and "Pathology of malignant pleural mesothelioma".)
●Differential diagnosis – The differential diagnosis of MPM includes benign processes such as inflammatory reactions, as well as malignant processes, including metastases from other solid tumors. Evidence of stromal invasion on biopsy distinguishes mesothelioma from benign etiologies, while immunohistochemistry can distinguish mesothelioma from other malignancies. (See 'Differential diagnosis' above.)
●Staging evaluation – For diagnosed cases of pleural mesothelioma, we obtain integrated positron emission tomography (PET) with CT (PET-CT) as the initial staging assessment. For patients in whom imaging suggests resectable disease, we pursue extended surgical staging prior to definitive surgery. Specifically, this includes laparoscopy with peritoneal lavage to detect subdiaphragmatic involvement, followed by mediastinoscopy. (See 'Staging evaluation' above.)
●Prognosis – The prognosis of patients with MPM is poor, with overall survival being on the order of 9 to 17 months after diagnosis. Few patients are cured. (See 'Prognosis' above.)
●Biomarkers under investigation – Several biomarkers are selectively elevated in patients with mesothelioma, including soluble mesothelin-related peptides, fibulin-3, and osteopontin, although they are not routinely used in the diagnosis of mesothelioma. (See 'Biomarkers under investigation' above.)
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