SCREENING FOR MESOTHELIOMA

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1 SCREENING FOR MESOTHELIOMA Current recommendations for screening of patients who have been exposed to significant amounts of asbestos is that screening is not undertaken because there is no effective early intervention that alters the outcome. (First Consult) ARGUMENTS FOR - May decrease anxiety of patient who have had asbestos exposure to exclude MM - Asbestos-exposed workers have justifiable anxiety about their future and seek reassurance from the medical profession. - Early detection will result in early treatment (however prognosis seems to be more closely linked to cell type than timing of treatment - patients with the epithelial cell type do best and those with the sarcomatous cell type the worst, with mixed or biphasic falling between the two other types) ARGUMENTS AGAINST - There is no effective treatment so screening will not change outcomes - Low prevalence of the disease even in high-risk cohorts - All screening mechanisms have high false-positive rate, leading to unnecessary further investigations. - Imaging exposes the patient to radiation (and all of the associated risks) with little benefit TECHNIQUES High sensitivity = low number of false negatives

2 High specificity = low number of false positives X-Ray Has been used in the past but not overly sensitive or specific as a screening tool (couldn t find the exact figures) LDCT Sensitivity is around 36% - 56% and specificity was 88%-100% respectively.

3 Parallel to the development of low-dose spiral computed tomography (CT) scan in the screening of lung cancer, investigators have looked at its role in the early detection of mesothelioma. These efforts have been hindered by the low prevalence of the disease even in high-risk cohorts and the much higher prevalence of nonmalignant nodules detected by this sensitive, but not overly specific, technique. SMRP Tumour Marker Sensitivity of 84% and specificity of % Several other retrospective series have since confirmed this diagnostic accuracy and suggested a possible role in monitoring disease response and relapse. Soluble mesothelin related protein (SMRP) (trade name MESOMARK available through Fujirebio Lab) is a split product of the cell membrane bound antigen mesothelin, involved in intercellular contact, and abundant on serosal cells of the pleura and peritoneum. In 2005 QLM said - Note: There is no Medicare item number for this test. As the reagent cost at this stage is particularly high, we are obliged to levy a non-refundable charge. With increasing use of the test, it would be hoped that the cost per test will fall. For a detailed overview of the SMRP test please contact your local Medical Liaison Officer. Osteopontin - Tumour Marker Studies show a sensitivity of 84% and a specificity of 88% at a cutoff value of 62.4 ng of osteopontin per milliliter. The results of an osteopontin-based screening project conducted by renowned mesothelioma specialist Harvey Pass determined that 9.5 ng of osteopontin per milliliter of blood could guarantee a diagnosis of Stage I mesothelioma with 100 percent sensitivity. Megakaryocyte Potentiating Factor Tumour Marker Sensitivity 91% NSW Health has said - Biomarkers for the diagnosis of malignant mesothelioma currently have limited use in clinical practice. Soluble mesothelin-related protein (SMRP), megakaryocyte potentiating factor (MPF) and osteopontin have shown the most potential as biomarkers However, each has its limitations. SMRP and MPF have good sensitivity and specifi city for epithelioid mesothelioma but are not sensitive to sarcomatoid mesothelioma and have poor sensitivity to biphasic mesothelioma Osteopontin lacks specificity for mesothelioma A recent prospective study examined the use of SMRP as a screening tool for the early detection of mesothelioma in asbestos-exposed people. The study found that SMRP was unlikely to be useful as a screening tool in asymptomatic people as it had a high false-positive rate. Although this fi nding may change with longer follow-up. SMRP and osteopontin may be useful in a clinical context, particularly

4 in conjunction with other investigations, for diagnostic purposes, prognosis and monitoring response to treatment in mesothelioma patients.21 Further research and clinical trials are needed before biomarkers gain a routine role in clinical practice. SECONDARY PREVENTION Initial studies showed that Retinol (Vit A) in people exposed to asbestos show a beneficial relationship between plasma levels of retinol and level and rate of decline of lung function. The dose was retinyl palmitate (25,000 IU per day) Regular five-yearly evaluation of the programs showed that taking part was consistently associated with lower rates of death, however after 15 years there was no significant reduction of mesothelioma rate in those taking Vitamin A. As a result, it was decided that it was not the Vitamin A that was having an effect but some other aspect of the program. Additionally, other studies elsewhere have shown similar results where taking Vitamin A did not reduce the risk of developing lung cancer. In October 2007 the provision of Vitamin A ceased, and the program was renamed as the Asbestos Review Program. de Klerk NH, Musk AW, Ambrosini GL, et al: Vitamin A and cancer prevention II: Comparison of the effects of retinol and beta-carotene. Int J Cancer 1998; 75: Reference: Omenn, GS. 'Chemoprevention of lung cancer: The rise and demise of Beta - Carotene'. Annual Review of Public Health 1998; 19: DEFINITIONS Asbestosis Clinical Features Asbestosis is a chronic inflammatory and fibrotic medical condition affecting the parenchymal tissue of the lungs caused by the inhalation and retention of asbestos fibres. Asbestosis specifically refers to interstitial (parenchymal) fibrosis from asbestos, and not pleural fibrosis or plaquing. Signs and Symptoms The signs and symptoms of asbestosis do not manifest until years after the exposure. The primary symptom of asbestosis is generally the slow onset of dyspnea, especially on exertion. Clinically advanced cases of asbestosis may lead to respiratory failure. On auscultation of the lungs there may be inspiratory rales. The characteristic pulmonary function finding in asbestosis is a restrictive pattern. This manifests as a reduction in lung volumes, particularly the vital capacity (VC) and total lung capacity (TLC). The TLC may be reduced through alveolar wall thickening; however this is not always the case. Large airway

5 function, as reflected by FEV1/FVC, is generally well preserved. In the more severe cases, the drastic reduction in lung function due to the stiffening of the lungs and reduced TLC may induce right-sided heart failure (cor pulmonale). In addition to a restrictive defect, asbestosis may produce reduction in diffusion capacity and arterial hypoxemia. Diagnosis The abnormal chest x-ray and its interpretation remain the most important factors in establishing the presence of pulmonary fibrosis. The findings usually appear as small, irregular parenchymal opacities, primarily in the lung bases. Using the ILO Classification system, "s", "t", and/or "u" opacities predominate. CT or high-resolution CT (HRCT) are more sensitive than plain radiography at detecting pulmonary fibrosis (as well as any underlying pleural changes). More than 50% of people affected with asbestosis develop plaques in the parietal pleura, the space between the chest wall and lungs. Once apparent, the radiographic findings in asbestosis may slowly progress or remain static, even in the absence of further asbestos exposure. Rapid progression suggests an alternative diagnosis. Treatment There is no curative treatment for asbestosis. Oxygen therapy at home is often necessary to relieve the shortness of breath and correct underlying hypoxia. Supportive treatment of symptoms includes respiratory physiotherapy to remove secretions from the lungs by postural drainage, chest percussion, and vibration. Treatment of any underlying Chronic Obstructive Pulmonary Disease. Caseation of smoking is critical. Immunization against pneumococcal pneumonia and annual influenza vaccination is important. Silicosis Clinical Features Silicosis, also known as Potter's rot, is a form of occupational lung disease caused by inhalation of crystalline silica dust, and is marked by inflammation and scarring in forms of nodular lesions in the upper lobes of the lungs. It is a type of pneumoconiosis. It may often be misdiagnosed as pulmonary edema (fluid in the lungs), pneumonia, or tuberculosis. Patients with silicosis are particularly susceptible to tuberculosis (TB) infection known as silicotuberculosis. The reason for the increased risk 3 fold increased incidence is not well understood. It is thought that silica damages pulmonary macrophages, inhibiting their ability to kill mycobacteria. Even workers with prolonged silica exposure, but without silicosis, are at a similarly increased risk for TB. Pulmonary complications of silicosis also include Chronic Bronchitis and airflow limitation (indistinguishable from that caused by smoking), non-tuberculous Mycobacterium infection, fungal lung infection, compensatory emphysema, and pneumothorax. There are some data revealing an association between silicosis and certain autoimmune diseases, including nephritis, Scleroderma, and Systemic Lupus Erythematosus, especially in acute or accelerated silicosis.

6 In 1996, the International Agency for Research on Cancer (IARC) reviewed the medical data and classified crystalline silica as "carcinogenic to humans." The risk was best seen in cases with underlying silicosis, with relative risks for lung cancer of 2-4. Numerous subsequent studies have been published confirming this risk. In 2006, Pelucchi et al. concluded, "The silicosis-cancer association is now established, in agreement with other studies and meta-analysis Signs and Symptoms Dyspnea (shortness of breath) exacerbated by exertion Cough, often persistent and sometimes severe Fatigue Tachypnea (rapid breathing) which is often labored Loss of appetite and weight loss Chest pain Fever Gradual dark shallow rifts in nails eventually leading to cracks as protein fibers within nail beds are destroyed. In advanced cases, the following may also occur: Cyanosis (blue skin) Cor pulmonale (right ventricle heart disease) Respiratory insufficiency Diagnosis There are three key elements to the diagnosis of silicosis. First, the patient history should reveal exposure to sufficient silica dust to cause this illness. Second, chest imaging (usually chest x-ray) that reveals findings consistent with silicosis. Third, there are no underlying illnesses that are more likely to be causing the abnormalities. Physical examination is usually unremarkable unless there is complicated disease. Also, the examination findings are not specific for silicosis. Pulmonary function testing may reveal airflow limitation, restrictive defects, reduced diffusion capacity, mixed defects, or may be normal (especially without complicated disease). Most cases of silicosis do not require tissue biopsy for diagnosis, but this may be necessary in some cases, primarily to exclude other conditions. For uncomplicated silicosis, chest x-ray will confirm the presence of small (< 10 mm) nodules in the lungs, especially in the upper lung zones. Using the ILO classification system, these are of profusion 1/0 or greater and shape/size "p", "q", or "r". Lung zone involvement and profusion increases with disease progression. In advanced cases of silicosis, large opacity (> 1 cm) occurs from coalescence of small opacities, particularly in the upper lung zones. With retraction of the lung tissue, there is

7 compensatory emphysema. Enlargement of the hilum is common with chronic and accelerated silicosis. In about 5-10% of cases, the nodes will calcify circumferentially, producing so-called "eggshell" calcification. This finding is not pathognomonic (diagnostic) of silicosis. In some cases, the pulmonary nodules may also become calcified. Treatment Silicosis is an irreversible condition with no cure. Treatment options currently focus on alleviating the symptoms and preventing complications. These include: Stopping further exposure to silica and other lung irritants, including tobacco smoking. Cough suppressants. Antibiotics for bacterial lung infection. TB prophylaxis for those with positive tuberculin skin test or IGRA blood test. Prolonged anti-tuberculosis (multi-drug regimen) for those with active TB. Chest physiotherapy to help the bronchial drainage of mucus. Oxygen administration to treat hypoxemia, if present. Bronchodilators to facilitate breathing. Lung transplantation to replace the damaged lung tissue is the most effective treatment, but is associated with severe risks of its own. For acute silicosis, Whole-lung lavage (see Bronchoalveolar lavage) may alleviate symptoms, but does not decrease overall mortality. Experimental treatments include: Inhalation of powdered aluminium, d-penicillamine and polyvinyl pyridine-n-oxide. Corticosteroid therapy. The herbal extract tetrandine may slow progression of silicosis. Mesothelioma Clinical Features About 5-9% of occupationally exposed individuals will develop pleural malignant mesothelioma Mesothelioma (or, more precisely, malignant mesothelioma) is a rare form of cancer that develops from transformed cells originating in the mesothelium, the protective lining that covers many of the internal organs of the body. It is usually caused by exposure to asbestos.

8 The most common anatomy site for the development of mesothelioma is the pleura (the outer lining of the lungs and internal chest wall), but it can also arise in the peritoneum (the lining of the abdominal cavity), and the pericardium (the sac that surrounds the heart), or the tunica vaginalis (a sac that surrounds the testis). Malignant pleural mesothelioma (MPM) is a rare tumor with a generally poor prognosis, mainly associated with earlier occupational exposure to asbestos. Latency time from first exposure to a presentation of usually 3 to 5 decades. The epidemic of new cases of MPM is therefore still ongoing despite prohibitions against asbestos use in the 1980s and 1990s. The median age at diagnosis for MPM is in the sixth decade of life and overall survival after diagnosis averages less than 1 year. In recent years, an effect from chemotherapy has been repeatedly proven, and although, in many cases, an improvement of survival and quality of life has been observed, there is no cure. Radiotherapy has limited use; surgery has been used in early cases but not in any randomized study, and, in the vast majority of cases, recurrence is the rule. Signs and Symptoms Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma. Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face. Diagnosis Diagnosing mesothelioma is often difficult. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe. For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure). Using conventional cytology diagnosis of malignant mesothelioma is difficult, but immunocytochemistry has greatly enhanced the accuracy of cytology. Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. mirview Meso is a microrna-based molecular diagnostic tool that helps to differentiate malignant pleural mesothelioma from peripheral adenocarcinomas of the lung or metastatic carcinomas involving the lung pleura. The sensitivity and specificity of this test have been shown to be about 95 percent and 96 percent. No other test is known to be this accurate in the diagnosis of mesothelioma.

9 Treatment 1) Surgery 2) Chemotherapy 3) Radiation Therapy Often two or more of these are combined in the course of treatment. No curative treatment exists. If patients have localised tumours (which are rare), they may be suitable for surgical treatment by extrapleural pneumonectomy. However, most patients can only be offered palliative therapy. The most important palliation is effective pleurodesis, usually using talc.

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