Clinical presentation, diagnosis, and staging of malignant pleural mesothelioma

UpToDate, 2015


Introduction

Malignant mesothelioma is an insidious neoplasm with a very poor prognosis. It arises from mesothelial surfaces of the pleural cavity, peritoneal cavity, tunica vaginalis, or pericardium.

Clinical manifestations

Most patients with malignant pleural mesothelioma present with the gradual onset of pulmonary symptoms, which generally are present only when disease is relatively advanced. Typical findings on chest imaging combined with a history of asbestos exposure may raise the suspicion of a malignant mesothelioma. In rare cases, patients may present with a paraneoplastic syndrome or have symptoms from a paraneoplastic syndrome in combination with their pulmonary disease manifestations.

Clinical symptoms

Malignant pleural mesothelioma usually presents with nonspecific pulmonary symptoms (chest pain, dyspnea, cough) due to the presence of extensive intrathoracic disease. Symptoms may be present for months or longer prior to diagnosis. Systemic symptoms such as fatigue and weight loss may also be present, particularly in patients with advanced disease.

Common physical findings at the time of diagnosis generally are due to the pulmonary disease 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 and scoliosis toward the side of the malignancy may be seen with advanced disease.

Imaging

Chest imaging is generally done as part of the initial symptom evaluation. In rare cases, the diagnosis is suggested by abnormal findings on chest imaging in the absence of symptoms.

Although imaging cannot establish the diagnosis, it may provide substantial evidence suggesting the presence of mesothelioma. Typically, chest x-rays show a unilateral pleural abnormality with a large, unilateral pleural effusion (image 1A).

  • 6% of patients have right-sided lesions [1].
  • Mesothelioma occasionally presents with a pleural mass or rind or diffuse pleural thickening in the absence of a pleural effusion.
  • Only 20% of patients with pleural mesothelioma have radiographic signs of asbestosis (such as bibasilar interstitial fibrosis), although most will have evidence of pleural plaques and/or calcifications.
  • Ipsilateral mediastinal shift can be seen secondary to encasement of lung by a thick rind of tumor.
  • Most patients have significant unilateral loss of lung volume.

Increased uptake of fluorodeoxyglucose (FDG) by positron emission tomography (PET) may be a useful marker to distinguish malignant pleural mesothelioma from benign pleural disease [2,3]. PET and integrated PET-computed tomography (CT) may also have a role in assessing mediastinal lymph nodes.

As an example, in one series, FDG uptake was increased in 22 of 24 patients (91%) with mesothelioma, but none of four with benign pleural disease [2]. Similarly, in a second report increased FDG uptake was seen in 15 of 17 mesothelioma patients, compared with 0 of 14 patients with benign pleural disease [3].

Other thoracic imaging approaches (CT, magnetic resonance imaging [MRI], PET-CT) may be useful in further characterizing the extent and nature of disease involvement, but these are primarily useful in determining whether or not the patient is a candidate for surgical resection.

Tumor markers

Several biomarkers are selectively elevated in patients with mesothelioma. However, these do not yet have an established role, either in establishing the initial diagnosis or for monitoring response to therapy. Biomarkers of interest include fibulin-3, mesothelin, and osteopontin.

Mesothelin

Mesothelin is a glycoprotein that is expressed on the surface of normal mesothelial cells [4] and is highly overexpressed in malignant mesothelioma [5]. Soluble mesothelin-related peptides (SMRPs) are believed to be either cleaved peptide fragments of mesothelin, or abnormal variants of mesothelin that are unable to bind to membranes and are found in the serum.

Multiple studies have observed that SMRPs are elevated in patients with mesothelioma. A meta-analysis of 16 diagnostic studies found that the sensitivity ranged from 19 to 68%, depending upon the specific criterion for positivity [6]. In patients with stage I or II disease, the sensitivity was only 32% when a specificity criterion of 95% was used. Furthermore, the potential utility of serum SMRPs is limited to patients with epithelioid or mixed mesotheliomas and not those with sarcomatoid lesions.

SMRPs have also been measured in pleural fluid [7-9]. In a retrospective study of 52 patients with malignant mesothelioma, the assay had a sensitivity of 67% with a specificity of 98% in 84 patients with benign pleural effusions [8]. In both pleural and peritoneal fluids, elevated levels of SMRPs were observed with other malignancies, particularly ovarian and pancreatic cancer.

In patients presenting with a suspected mesothelioma, elevated SMRPs in serum, pleural effusion, or ascites fluid cannot replace a histologic diagnosis [10]. Measurement of SMRPs is commercially available (Mesomark assay) but is indicated only for monitoring patients in whom the diagnosis has already been established.

Osteopontin

Osteopontin is a glycoprotein that mediates cell-matrix interactions and is overexpressed in several types of cancer. In a study of 190 patients, osteopontin levels were higher in patients with malignant mesothelioma (133 ng/mL) than in patients with asbestos-related nonmalignant pleural disease (30 ng/mL) or no prior asbestos exposure (20 ng/mL) [11]. Pleural fluid osteopontin levels may also be helpful in distinguishing malignant mesothelioma [12,13]. At least one study suggests that osteopontin had a lower diagnostic accuracy than mesothelin in patients with suspected malignant mesothelioma [14]. To date, the clinical utility of osteopontin has not been established.

Fibulin-3

Fibulin-3 is an extracellular glycoprotein that is encoded by the epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene [15]. Initial studies from three sites found that elevated levels of fibulin-3 in the plasma had a high sensitivity and specificity (97 and 96%, respectively) in distinguishing patients with pleural mesothelioma from those with a history of asbestos exposure but without mesothelioma and from those with other malignancies or benign causes of pleural effusion. Levels of fibulin-3 fell in patients who underwent surgical resection.

Additional studies assessing the role of plasma fibulin-3 measurement will be required to determine the role of fibulin-3 as a biomarker for early diagnosis and for monitoring patients who have undergone therapy.

Paraneoplastic syndromes

Malignant mesothelioma has been associated with a wide range of paraneoplastic syndromes [16-20], although these are generally seen in the context of advanced pulmonary disease. Reported paraneoplastic conditions include disseminated intravascular coagulation, migratory thrombophlebitis, thrombocytosis, hypoglycemia, various neurologic disorders, renal disease, and hypercalcemia.

Diagnosis

The diagnosis of malignant pleural mesothelioma should always be based on the results obtained from an adequate biopsy (less commonly cytology, exfoliative and fine-needle aspiration) in the context of appropriate clinical, radiologic, and surgical findings. The diagnosis cannot be based exclusively on clinical or imaging findings even when these are combined with a history of asbestos exposure [21].

Differential diagnosis

The differential diagnosis of malignant pleural mesothelioma includes both benign and malignant processes.

  • 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.
  • Epithelial mesotheliomas can be extremely difficult to distinguish grossly and histologically from involvement of the pleura with metastatic tumor from another site. Other possible primary sources include but are not limited to the lung, breast, stomach, kidney, ovary, thymus, and prostate.
  • Sarcoma (eg, fibrosarcoma) and malignant fibrous histiocytoma can present in similar fashion and infiltrate like sarcomatous mesotheliomas.
  • The mixed-cellular type of mesothelioma can histologically resemble sarcomatoid carcinoma and synovial sarcoma.

Tissue diagnosis

When a patient presents with a significant pleural effusion, thoracentesis for cytology and closed pleural biopsy is generally the initial procedure and may be sufficient to establish the diagnosis. However, this approach may not provide enough tissue to establish the diagnosis of malignancy and to distinguish mesothelioma from other tumors.

However, establishing a tissue diagnosis and characterizing the mesothelioma can be difficult. Negative results from thoracentesis and/or pleural biopsy do not exclude the diagnosis of mesothelioma. Furthermore, even if a diagnosis of malignancy can be established by cytology, this cannot always accurately distinguish histologic subtypes or differentiate mesothelioma from adenocarcinoma, which may have implications for initial therapy.

If the initial thoracentesis and pleural biopsy is nondiagnostic, surgical intervention (via video thoracoscopic biopsy or open thoracotomy) has a higher diagnostic yield. Concurrent bronchoscopy may be helpful in distinguishing mesothelioma from metastatic adenocarcinoma of the lung, as endobronchial lesions are rarely seen in mesothelioma.

The difficulties in establishing a diagnosis of mesothelioma are illustrated by a study of 188 consecutive patients evaluated between 1973 and 1990 [22]. Thoracentesis and pleural fluid cytology yielded a diagnosis in 26% of cases, and thoracentesis plus closed pleural biopsy was diagnostic in 39% of cases. In contrast, video-assisted thoracoscopic (VATS) biopsy was diagnostic in 98% of cases.

Approximately 10% 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.

Staging

An accurate staging system is needed to guide the choice of therapy for patients with mesothelioma and ultimately to assess the results of treatment with different modalities [23].

Staging systems

The most widely used staging system is the tumor (T), node (N), metastasis (M) staging system that has been adopted by both the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) (table 1) [24].

In the TNM staging system, stages I and II disease have pleural involvement, potentially including diaphragmatic muscle or pulmonary parenchyma, but without involvement of lymph nodes, distant metastases, or locally advanced, unresectable disease. Stage III mesothelioma includes those cases with regional lymph node involvement. Stage IV includes those with locally advanced unresectable disease, contralateral lymph node involvement, supraclavicular lymph node involvement, or distant metastases.

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 [25]. 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.

Staging evaluation

Clinical staging of malignant mesothelioma is performed radiographically in patients with potentially resectable malignant mesothelioma. Although radiographic staging evaluation is warranted, accurate staging is only possible at the time of operation (figure 1).

Chest CT

Computed tomography (CT) is important in detecting invasion of the chest wall, ribs, and mediastinal structures (image 1A-B). Loss of normal fat planes, gross extension into mediastinal fat, and tumor surrounding more than 50% of a mediastinal structure all suggest tumor invasion [26]. However, the accuracy of chest CT for detecting intrathoracic lymph nodes involvement is limited [27,28].

MR imaging

In selected patients with potentially resectable disease, magnetic resonance imaging (MRI) may be useful to define the local extent of disease. Coronal MRI in particular may identify extension of pleural mesothelioma through the diaphragm into the peritoneal cavity (image 2A-B) [29].

PET and integrated PET-CT

Integrated positron emission tomography (PET)-CT imaging appears to be the most reliable imaging modality for initial assessment [30-32]. The results with this approach are illustrated by three single institution series:

  • In one series, 42 consecutive patients without evidence of T4 or M1 disease based upon CT were assessed with PET-CT [30]. In 12 cases (29%), patients were reclassified as inoperable, based upon the presence of a T4 lesion or distant metastasis (29 and 14%, respectively).
  • In another series, 54 patients with potentially resectable mesothelioma (stage II/III) were assessed with PET-CT. Surgery was used to confirm the imaging findings in 52 cases, and two patients with distant metastases were followed [31]. PET-CT was significantly more accurate than CT, MRI, or PET alone in both stage II and stage III disease.
  • In a third series, PET-CT was compared with CT in 35 patients with mesothelioma [32]. Surgical resection was excluded in 14 of 35 cases (40%) based upon the PET-CT findings, most frequently because of an increase in staging of the primary tumor.

Surgical staging

If extrapleural pneumonectomy (EPP) is still being considered after imaging studies, extended surgical staging has been advocated. In a series of 118 consecutive patients, surgical staging included laparoscopy with peritoneal lavage to detect subdiaphragmatic involvement, followed by mediastinoscopy [33]. This approach was able to avoid an inappropriate intervention in 16 patients (14%).

Mediastinoscopy plays an increasingly important role in the diagnosis and staging of mesothelioma, as studies have documented a significant negative prognostic implication of mediastinal nodal invasion [34].

Stage and prognosis

A major limitation of all of the staging systems is the difficulty in assessing the extent of disease prior to treatment.

IASLC IMIG database

In an effort to improve upon the current TNM system, the International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG) have created a database that includes information on 3101 patients with mesothelioma from 15 centers diagnosed between 1995 and 2009 [23]. The information in this database is being correlated with various prognostic factors and hopefully will provide the basis for further revisions in the staging system.

In this database, the mean patient age was 63 years and the male-female ratio was 4:1. Histologic classification was epithelial in 62%, sarcomatoid in 8%, and biphasic in 16% of cases. Approximately one-half of cases had a history of asbestos exposure, and no data on asbestos exposure was available for another 31% of cases. The database provides insights into prognosis of malignant pleural mesothelioma and may eventually facilitate revisions in the staging system.

Key findings in the initial report from this database include the following [23]:

  • In 1056 cases, both clinical and pathologic staging were available. Clinical staging was unreliable, with approximately 80% of clinical stage I patients and 70% of stage II patients being upstaged following pathologic evaluation based upon surgery (figure 1).
  • Based upon pathologic staging when available and clinical staging for those not undergoing pathologic staging (table 1), patients with stage I, II, III, and IV disease had median survivals of 20, 19, 16, and 11 months, respectively (figure 2). For patients who underwent surgery with curative intent, median survivals for stages I, II, III, and IV were 30, 22, 16, and 12 months, respectively.
  • There was a clear relationship between histologic type of mesothelioma and survival when all patients undergoing surgery were considered. Median survivals for those with epithelial, biphasic, and sarcomatoid histology were 19, 13, and 8 months (figure 3).

Prognostic scoring systems

Prognostic scoring systems that incorporate both the extent of disease, as well as systemic factors, may provide useful information. The two most widely used scoring systems were developed by the Cancer and Leukemia Group B (CALGB) and the European Organisation for Research and Treatment of Cancer (EORTC).

CALGB index

The CALGB evaluated the impact of clinical characteristics on the survival of 337 patients treated with chemotherapy for advanced disease in sequential phase II treatment studies over a 10-year period [35]. In multivariate analysis, pleural (as compared with peritoneal or pericardial) involvement, serum lactate dehydrogenase (LDH) greater than 500 IU/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. The median survival overall was 7 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 [36,37].

EORTC index

Similarly, the EORTC reviewed data from 204 adults who were entered into five consecutive phase II trials over nine years [38]. When five factors were taken into consideration (poor performance status, high white blood cell [WBC] count, male gender, 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%, respectively (table 2). Median survival from the date of study entry was 8.4 months.

The relevance of these earlier prognostic indicators is somewhat limited given that the study was performed in the pre-pemetrexed era. However, the prognostic significance of the EORTC index has subsequently been confirmed in a multivariate analysis of a phase III trial assessing cisplatin plus raltitrexed [39].

Natural history

Mesothelioma causes its morbidity and mortality primarily by local invasion. Patients typically develop shortness of breath and chest pain as the tumor gradually obliterates the pleural space and replaces any pleural fluid. As the tumor spreads, deoxygenated blood is shunted through the encased lung, leading to fatigue, dyspnea, and hypoxemia that is often refractory to supplemental oxygen. Local invasion of crucial thoracic structures can result in symptoms such as dysphagia, hoarseness, spinal cord compression, brachial plexopathy, Horner’s syndrome, or superior vena cava syndrome.

Metastases may occur to the opposite lung, brain, and other extrathoracic sites. Extension of the malignancy through the diaphragm into the abdominal cavity may occur, particularly in patients who have prolonged survival after primary aggressive therapy of their thoracic disease. Spread throughout the abdomen in a manner similar to primary peritoneal mesothelioma may be observed. In such patients, invasion of liver and other organs is rare, but bowel obstruction can be a major problem.

The majority of affected patients die from local extension and respiratory failure; 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.

Summary

  • Patients with malignant pleural mesothelioma typically present with pulmonary symptoms. Chest imaging typically shows unilateral pleural thickening and pleural effusion. Paraneoplastic syndromes can be associated with pleural mesothelioma but rarely are the initial manifestation of disease.
  • The diagnosis of malignant mesothelioma requires adequate tissue sampling and pathologic examination. The differential diagnosis of malignant pleural mesothelioma includes inflammatory reactions, which can mimic pleural mesothelioma, as well as metastases from other malignancies. Thoracentesis and closed pleural biopsy are the initial procedures in most cases. If this is not diagnostic, surgical intervention is required to obtain an adequate tissue sample.
  • Clinical staging primarily relies upon imaging studies to assess the extent of disease and determine whether or not the patient is a candidate for surgical resection. However, clinical staging often underestimates the extent of disease, and intraoperative staging provides a more reliable assessment of whether or not the patient is a candidate for surgical resection.
  • The management of patients with malignant pleural mesothelioma is discussed separately.

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