Pleural Mesothelioma - Epithelial Mesothelioma, Pleura
Histological Type
Diffuse malignant pleural mesothelioma is classified by three histological types: pure epithelial (tubopapillary), pure mesenchymal (sarcomatous) or a mixture of the two (biphasic). Several series have demonstrated that pure epithelial mesothelioma is associated with a better prognosis [14-16] and that it responds better to radical surgery [14, 17]. Fortunately, epithelial mesothelioma is the most common histological type in most series. As with lung cancer treatment, it is likely that different approaches will be required for tumors of different histological type.
Tumor Staging
Several different staging classifications have been proposed for mesothelioma, the most recent and comprehensive being that proposed by the International Mesothelioma Interest Group (IMIG) based on the tumor/node/metastasis (TNM) system [18]. The IMIG staging system has been validated by Rusch and found to correlate well with prognosis [16]. The first staging system, which the current author proposed in 1976 [14] (referred to subsequently in the literature as the Butchart staging system), still has the advantage of simplicity and relevance to prognosis and therapeutic options (Table 1); whereas the IMIG staging system (Table 2) may only be applied postoperatively or at autopsy, as it relies on histological criteria to differentiate one stage from another. It is therefore impossible to implement accurately in nonsurgical treatment regimes.
In the Butchart staging system, stage I disease is tumor which has not invaded structures beyond the parietal pleura and has not metastasized to regional lymph nodes or beyond. Its relationship to prognosis, demonstrated first in 1976 on a relatively small number of patients undergoing radical surgery [14], has been confirmed most recently in a large series of 183 patients treated by pleuropneumonectomy and adjuvant therapy. In this series patients with negative resection margins and negative lymph nodes (Butchart stage I) had significantly better survival [17].
There is very little difference between the Butchart staging system and the IMIG system in the designation of stage I, except that in the IMIG system confluent visceral pleural tumor or extension of tumor into the paraenchyma of the lung places the tumor in stage II. However, in practice, scattered foci of visceral pleural tumor (IMIG stage I) very quickly coalesce to form confluent tumor, and in early disease it is very common to encounter a mixture of scattered foci in some areas and early confluence of some foci in others. Furthermore, once the visceral pleura is involved by tumor, parenchymal lung involvement is inevitable, as microscopic tumor spreads into the lung along the fibrous septa of the pulmonary lobules. More importantly, from a practical point of view, neither confluent visceral tumor nor parenchymal pulmonary invasion prejudice complete removal of tumor by pleuropneumonectomy.
More significant differences exist between the Butchart and the IMIG staging systems in the more advanced stages. In the IMIG system, any lymph node involvement places the tumor at least in stage III, whereas in the Butchart system, ipsilateral or mediastinal intrathoracic lymph node involvement is stage II. In the author's experience, truly contralateral intrathoracic nodal involvement is very unusual. The IMIG system adopts the same nomenclature for node status as the TNM classification for lung cancer, with hilar nodes being classified as N1 and mediastinal or internal mammary nodes classified as N2. With a tumor which begins in the parietal pleura, this is illogical, as internal mammary nodes are often involved before hilar nodes. Only mediastinal nodes may be sampled by mediastinoscopy and it is therefore not possible to accurately assess nodal status fully with this procedure prior to beginning treatment. It is possible, however, to sample all nodes using frozen section histology at the time of surgical exploration.
In the Butchart staging system tumor is resectable, although with reduced prognosis, up to stage II, whereas in the IMIG system, tumor is deemed resectable up to stage III, while stage IV contains inoperable tumor, contralateral and extrathoracic nodal involvement and metastatic disease. Both staging systems have advantages and disadvantages. To avoid confusion, all further references to stage in this review article use the Butchart staging system. Readers may "convert" to the IMIG system if they wish by using Tables 1 and 2.
The problem with all staging systems is that currently available imaging techniques do not reliably identify tumor stage, especially in early disease when tumor volume is relatively small. Because of potential staging inaccuracies, therapeutic regimes which do not involve surgical treatment are more difficult to evaluate. Gross chest wall involvement with rib destruction is easily identified on computerized tomography (CT) scan; but, at the other end of the spectrum, early chest wall involvement associated with minimal pleural thickening is sometimes impossible to detect with any imaging technique and can only be identified with certainty at operation, when the parietal pleura is stripped off the chest wall by blunt dissection. As with other tumors, the larger the tumor the more likely it is to have metastasized or invaded neighboring structures. Not surprisingly therefore, total tumor volume, as measured by three-dimensional CT, correlates with nodal status, overall staging, and survival [19].
However, autopsies on individual patients with tumors of epithelial type reveal that occasional patients die from extensive tumor bulk within the hemithorax, causing respiratory failure without any spread of tumor outside the confines of the parietal pleura or lymph node involvement [14]. Despite the effect of overall tumor bulk on prognosis in most patients, locally bulky disease does not necessarily predict local invasion at that site, in the author's experience. Hence local tumor thickness per se should not be taken as evidence of inoperability. Loss of fat planes between thickened pleura and underlying structures and tumor surrounding more than 50% of a mediastinal structure do, however, raise likelihood of involvement [20].
Thoracoscopy can provide information on the degree of parietal and visceral pleural involvement, but can provide no information on invasion of underlying structures. It therefore cannot reliably predict stage Ia or Ib according to the IMIG system. Diaphragmatic muscle involvement and eventual penetration to involve the peritoneal surface is particularly difficult to detect unless it is gross in extent. Magnetic resonance imaging (MRI) provides coronal and sagittal images in addition to axial images and hence offers slightly better assessment of diaphragmatic involvement than CT [20]. Laparoscopy has proved useful in detecting diaphragmatic penetration in equivocal cases [21]. Coronal MRI images provide better assessment of apical disease [22] spread into the fissures and bone invasion [23] than CT. MRI is also useful in distinguishing between benign and malignant pleural thickening [24].
Performance Status
A detailed assessment of performance status is an essential precursor to treatment planning, particularly if radical surgical treatment is contemplated. Pleuropneumonectomy is a major surgical procedure which is suitable only for very fit patients. Once the disease is established, lung function tests unfortunately provide little guidance on pulmonary reserve, as they are dominated by the effects of the pleural effusion and pulmonary restriction caused by tumor on the lung surface. Much better information is provided by a detailed history of premorbid exercise capacity and respiratory symptoms, coupled with CT assessment of the contralateral lung. Patients being considered for radical surgery should have a history of good exercise tolerance without dyspnea prior to developing mesothelioma and should be free of chronic bronchitis or asthma. The contralateral lung should be normal on CT; evidence of emphysema or asbestosis for example should preclude radical surgery.
Cardiac assessment involves a detailed history and examination supplemented by exercise electrocardiogram and echocardiography. Radical surgery should only be contemplated in patients with normal cardiac function. Nutritional status is also important. Neither cachetic patients nor very obese patients are suitable for radical surgery. Renal function should be normal to reduce the risk of renal failure both postoperatively and following subsequent chemotherapy. Few patients over the age of 70 will be suitable for radical surgery unless exceptionally fit.
Choice of Treatment
Given that no form of treatment currently available can reliably eradicate mesothelioma, it is important to have a full and open discussion with the patient and his or her family regarding treatment options. For patients who are very elderly, frail or compromised by other medical conditions or whose disease is at an advanced stage, there is little controversy: only palliative treatment or supportive care should be advised. However, for younger, fitter patients and particularly those with early disease, the choice of treatment is more controversial. Many patients will have difficulty accepting that the disease is "incurable" or that "nothing can be done" and will wish to explore all possible therapeutic options. Nowadays many patients access the medical literature via the internet and are already well informed at the first consultation. Ethical issues in relation to clinical trials also need to be taken into consideration given that the literature contains numerous phase II trials of various chemotherapeutic agents, either alone or in combination, which produce only short-term tumor regression in a minority of patients. Hopes should therefore not be falsely raised that a "new drug" in a forthcoming trial may cure or even control the disease.