[*This article has been shortened, but no words have been changed or added].
Mesothelioma, current insights (1994)
M. Ramael1, J. Van Meerbeeck2, E. Van Marck1
EPIDEMIOLOGY OF MESOTHELIOMA.
Malignant mesothelioma is a neoplasm arising from mesothelial cells, most often of the pleura and peritoneum. Very rarely is the tunica vaginalis testis or the pericardium the primary site. ...
There is evidence that the incidence in the Western world is increasing and will peak around the years 2000-2010. This increase cannot be solely attributed to a better recognition of the disease by improved pathology techniques..... It has been quite difficult to estimate a dose-response relationship for asbestos and mesothelioma, and hence comparison between different fiber types, handling processes in different studies has also been difficult. The risk of developing a mesothelioma varies, depending on the duration and intensity of exposure. As the presence of pleural plaques on the chest roentgenogram reflects significant exposure to asbestos, an increased risk - estimated at 1/1700 - for mesothelioma may be expected in these subjects. Families of asbestos workers have an approximately 1% risk; in most cases this risk arises because of contamination of work clothes or manufactured articles.....
Clinicians are sometimes confronted with patients without any admitted asbestos exposure, neither professional, occasional or familial. These cases represent either this spontaneous "background incidence", or result from an some unobserved exposition in childhood, as asbestos has been extensively used in the past in industrial and consumer applications. ....
Familial clustering of mesothelioma indicate that host genetic factors may act; perhaps by rendering the host more susceptible to asbestos exposure. Case reports of mesothelioma developing in childhood and even in utero for which no risk factors could be identified indicate that there are probably as yet unknown factors involved in the pathogenesis of this peculiar neoplasm (5).
CLINICAL AND RADIOLOGICAL
PRESENTATION - NATURAL HISTORY.
Mesothelioma is difficult to diagnose. A high degree of suspicion is warranted whenever a patient with presumed asbestos exposure presents with dyspnea and/or chest pain. Clinical and radiological examination will disclose evidence of a large pleural effusion; about 5% of patients have bilateral disease at initial presentation. The majority of patients have a good performance status (WHO 1-2) at diagnosis, reflecting the loco regional spreading of the tumour. Patients with late stage disease often develop tumour fever, a palpable chest lump and a characteristic scoliosis toward the side of the lesion.
As the lung is encompassed by tumour and cannot fully expand, the mediastinum is pulled to the ipsilateral side. Metastatic pleural effusions always displace the mediastinum to the contralateral side with increasing volume. In one third of mesothelioma patients pleural plaques and calcifications are visible on the conventional chest X-ray. Computed tomography (CT) will, in about 50% of patients; reveal pleural calcification not large enough to be seen on chest roentgenogram. Its main importance is determining disease extent and evaluation of response to therapy. Obviously, CT cannot differentiate between a metastatic pleurisy and a mesothelioma.
The following are findings which can be helpful in this differential diagnosis:
1: circumferential "rind-like" thickening (>1 cm) of the parietal pleura;
2: nodular masses on the lower parietal, diaphragmatic, pericardial or mediastinal pleura;
3: volume loss of the involved hemithorax;
4: involvement of the visceral pleura in the main lung fissure.
The latter is often also visible on the roentgenogram of the chest and represents one of the most specific radiological signs in the presence of a known asbestos exposure (13).
The natural history of mesothelioma is dismal with a median survival of less than 1 year (8-11 months). Patients generally die of local extension and respiratory failure. Tumour extension in surrounding organs may result in small bowel obstruction, arhythmias or heart failure. Invasion of thoracic wall and spine can result pain syndromes which are difficult to treat.
At autopsy 50% of mesothelioma patients have distant metastases. Five year survival rates are <5%, mostly occurring in patients with good initial performance score, limited disease extent and epithelial histology. These are the foremost important prognostic factors, as ascertained by uni- and multivariate analyses in the limited number of prospective randomized studies(14).
DIAGNOSTIC PROCEDURES AND STAGING. Malignant mesothelioma remains a diagnostic challenge for the clinician and the pathologist. An adequate biopsy specimen should be obtained. The sensitivity of the cytological examination of pleural fluid and "simple" pleural biopsy is low, the former because of the difficult differentiation from reactive mesothelial cells, the latter because mesothelioma mostly arises from the lower part of the parietal and/or the diaphragmatic pleura, out of reach for the "blind" technique of pleural biopsy.
Needle aspiration or biopsy under CT or ultrasound guidance can be helpful in obtaining a pathology specimen. The size of the sample will, however, often be too small to allow the pathologist to make a confident diagnosis and perform immunohistochemistry. We restrict this technique to those patients who are unwilling or unable to undergo a thoracoscopy.
Thoracoscopy (or pleuroscopy) is an endoscopic technique which is gaining more and more popularity in the hands of experienced pulmonologists and thoracic surgeons. As a diagnostic technique it can be performed under local anesthesia with sedation. After aspiration of pleural fluid, a pneumothorax is installed. Complete inspection of the involved hemithorax is frequently possible (16). Biopsy under direct vision of macroscopic abnormal and normal parietal, diaphragmatic, costal and visceral pleura impossible. The size and number of the samples is seldom limited by pain or dyspnea. Disease extent in the thorax can be appreciated as a first step in staging. When intrapleural therapy is considered (see further) talc or another sealing agent can be sprayed and/or a drain/porta-cath left in place. This safe and accurate technique has a good cost-benefit ratio, low toxicity and high sensitivity in the diagnosis of mesothelioma.
Surgical biopsy is the method of choice in patients without pleural fluid. Since mesothelioma is generally locally invasive, extensive work-up of other sites is usually unnecessary, unless the patient has specific symptoms, or is included in a clinical trial....
As disease extent is one of the most important prognostic factors and intrapleural treatment likely to be the most active in disease confined to the pleural cavity, it will become of crucial importance to properly select stage I disease patients for clinical trials. We and others feel that CT is unable to confidently differentiate between local and locally invasive disease in the diaphragm, chest wall, pericardium and mediastinum. Magnetic Resonance Imaging (MRI) will undoubtedly become the procedure of choice for staging mesothelioma, for it allows sagittal and coronal re-constructions and hence better visualization of possible involvement of different layers of the adjacent structures. Confirmation of disease extent should then be sought by means of thoracoscopy........
TREATMENT
There is no standard treatment for mesothelioma, as one of the therapeutic modalities; surgery, radio-or chemotherapy; has been shown in randomized prospective studies to improve survival compared to natural history. The following is a summary of published experience (25).
1: Radical surgery or extrapleural pleuropneumonectomy is a major surgical procedure aiming at removing the tumour by excising lung, ipsilateral parietal and mediastinal pleura, diaphragm and pericardium. Prolene patches are inserted to close the pleural cavity from the peritoneum. The procedure does not provide microscopically tumour-free margins and must be followed by adjuvant therapy. In view of the significant operative mortality (>15%), its application is reserved for a minority of patients with disease confined to stage I and medically fit to undergo the procedure. This selection bias accounts for the observed survival advantage which is, however, not statistically significant.
2: Pleurectomy offers best local control of pleural fluid, with acceptable mortality (<3%). Its use can be advocated in patients with good performance status, rapid and symptomatic fluid accumulation and a good expanding lung. No influence on survival is observed.
3: Radiotherapy is also problematic since differences between tumour cytotoxicity and pulmonary tolerance are small and radiation pneumonitis may significantly impair quality of life. There is no evidence that radiosensitizers improve responsiveness to external radiation. Radiotherapy has limited usefulness in the palliation of painful lumps, vena cava superior compression and the prevention of metastatic seeding along a thoracic puncture site.
4: The response rate to single agent chemotherapy is low (<20%) with the highest response rate for doxorubicin, mitomycin and ifosfamide. Combination of several drugs has not resulted in a cumulative response, neither has dose-intensification of one of them. Only a few randomized trials have been conducted, showing no obvious advantage of one drug regimen above the other. So, no standard systemic chemotherapy can be proposed.
5: The combination of pleurectomy with or without intraoperative brachytherapy, followed by external beam radiotherapy has led to prolonged survival in highly selected patients, but the overall results have been disappointing. Radical surgery followed by combination chemotherapy and limited field radiotherapy has led to a median survival of 16 months and an overall 3 year survival of 42% in 32 patients with epithelial cell type disease. Pleurectomy followed by intrapleural and systemic chemotherapy resulted in a median survival of 17 months and a overall 2-year survival of 40%.
From these phase II studies it appears that combined modality treatment is feasible and may prolong survival in carefully selected patients. The results should however be confirmed in a prospective randomized manner based on careful pre-treatment staging. As long as no chemotherapy regimen is identified to be active in >30-40% of patients, there is no place for any approach using induction (or neo-adjuvant)chemotherapy, followed by surgery in responders.
6: Intracavity therapy in mesothelioma is theoretically attractive because it may expose the tumour to very high concentrations of drug while sparing normal tissues from drug-related systemic toxicity. Preliminary results with cytotoxic agents have shown good pleurodesis, but less cytolysis than expected. Intrapleural immunotherapy with gamma interferon and interleukin-2 have been associated with an objective response rate of 16% mostly in stage I patients (17). The major theoretical obstacle to tumour control by the intrapleural route is the shallow depth of free-surface drug diffusion and the dispersion of the drug throughout the pleural space. This form of therapy may only be useful in selected patients with early stage disease or in combination with surgical resection of all gross tumour.
7: The use of photodynamic therapy following surgical resection has been investigated in a phase I trial. Its preliminary data regarding toxicity and feasibility are sufficiently promising to proceed further to a phase II study. Other proposed experimental procedures are intrapleural hyperthermia and gene therapy. At the time of writing, little is known about their possible clinical application.
STRATEGIES FOR THE FUTURE.
How asbestos causes mesothelioma is still an enigma. The exact molecular pathway of the pathogenesisis obscure as no specific abnormality has been found so far in oncogenes and suppressor genes. The main research efforts must be directed to the detection of specific aberrations at the molecular level. These data have to be combined with chromosomal abnormalities, clinical data, and biological behavior of this tumour. Such investigations would disclose specific mesothelioma markers useful in diagnosis, therapy and prognosis. The detection of certain surface-antigens on mesothelioma cells make some authors dream of vaccinating high risk individuals. Another important research area is the resistance to chemotherapy of most mesotheliomas. ....
As no standard treatment is available for mesothelioma patients, each attempt to treat should be considered experimental with only a low chance of benefit. As most patients present in stages I or II, which carry the best prognosis, they will be the obvious target for clinical trials. As in advanced non-small cell lung cancer, any progress will only be made by new and/or combined treatment approaches. These must be validated by randomizing them against best supportive care with palliative procedures like pleurectomy. The intraserosal route might also be ideal for reinoculation of adoptive T-cells after in-vitro activation by IL-2 or after genetic manipulation. For the time being, the role of the clinician will mainly consist of relieving symptoms of pain, dyspnea and cough. In view of the better prognosis of limited disease cases, a plea can be made to screen high risk individuals periodically by CT. Subjects who already developed a so-called "benign asbestos pleurisy" have a tremendously increased risk for developing a mesothelioma in later years. According to some, these patients should be treated with a parietal pleurectomy at the time of their first pleurisy.
Obviously, the main task of the authorities is to avoid and reduce asbestos exposure by appropriate legislation. However, with the latency period in mind, mesothelioma must be expected to occur up to 40 years after its industrial and consumer use stopped.
In addition the basic comprehension of the role of growth factors, oncogenes and suppressor genes may lead to an improved more accurate diagnosis and a novel optimized biotherapy perhaps resulting in a cure of this harsh merciless disease.