Introduction
The incidence of mesothelioma continues to increase; it has a poor prognosis and definitive diagnosis is often difficult to obtain . In Europe, 5,000 people die annually from mesothelioma and in Britain the incidence is rojected to peak in 2011–2015 at 1,950–2,450 deaths per year. The prognosis is poor with a study in the USA showing a 1-year survival of 64% from onset of symptoms and median survival of 10 months. A British study found a median survival of 14 months from the onset of symptoms.
Clinical Presentation
The most common clinical presentation forpatients is progressive dyspnoea and/or chest wall pain. Dyspnoea at presentation is usually caused by a pleural effusion but as the disease progresses this can be caused by pleural restriction. At presentation 90% patients have a pleural effusion with 10% patients having little or no fluid [30]. The effusion is usually unilateral (95%). The chest wall pain is usually caused by significant chest wall invasion. Other symptoms include a dry cough, weight loss, fever, fatigue or night sweats. The patient may also present after abnormalities are found on a routine chest radiograph [2] or present with minimal non-specific symptoms with the diagnosis only becoming apparent with time.
A detailed occupational history is important, although sometimes difficult because of the time that has elapsed since the exposure. Common prior occupational exposures include laggers, pipefitters, plumbers, heavy construction or shipbuilding industry workers and those working aboard ships, especially in the boiler room. 4.3 Investigation of Pleural Effusion Mesothelioma may be suspected on presentation because of the history, including exposure and symptoms, and abnormalities on the chest radiograph. If a pleural effusion is present then the initial investigations should be a diagnostic/therapeutic pleural aspiration and contrast-enhanced computed tomography (CT). The contrast allows differentiation between thickened pleura,
pleural effusion and underlying collapsed or aerated lung, allowing a detailed look at the pleura including whether the pleural thickening is irregular, circumferential and involves the mediastinal border. It also aids decisions regarding the next, most appropriate, investigation. Pleural aspiration is a simple investigation that can be performed, under ultrasound guidance, in clinic at the initial review and should be sent for cytology with immunocytochemistry if appropriate
Cytology
The diagnostic sensitivity of pleural cytology with malignancy has been reported at about 60%; however, the reported sensitivity for mesothelioma has been reported as much lower than this at 20–32% . This number included those that were suspicious but not diagnostic for mesothelioma. If only the positive results were included and the suspicious results excluded, the sensitivity decreased to 16%. However, it is worth noting that if cytology is positive then the median time to diagnosis is reduced. In one study, this time was reduced from an average of 12 to 4 weeks. It often proves difficult to differentiate between reactive mesothelial cells secondary to an inflammatory response and malignant cells; therefore, pleural tissue is often required to confirm the diagnosis. Immunocytochemistry can help to differentiate between mesothelioma and adenocarcinoma. Sending a second sample if the first was negative has been shown to increase the yield for malignancy by a further 27%; however, in the case of mesothelioma it is unlikely to be this successful and likely to delay diagnosis further. Repeated thoracocenthesis has also been shown to increase the number of pleural loculations which could have an impact on later investigations such as thoracoscopy.
The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) guidelines on the management of mesothelioma state that it is not recommended to make a diagnosis of mesothelioma based on cytology alone because of the high risk of diagnostic error.
Investigation of Pleural Thickening with No Effusion
Benign causes of pleural thickening commonly include previous pleural infection or haemothorax and benign asbestos-related pleural thickening. When seen at the lung apices it is generally due to prior infection from tuberculosis or fungi. It is uncommon for asbestos to cause apical pleural thickening. CT changes suggesting malignancy as opposed to benign pleural thickening are (1)circumferential thickening, (2) nodular pleuralthickening, (3) parietal pleural thickening >1 cm and (4) mediastinal pleural involvement. Whilst these changes were specific (100%, 94%, 94% and 88%, respectively), they were not overly sensitive (41%, 51%, 36% and 56%, respectively), and did not allow differentiation of mesothelioma from other cancers. If there is evidence suggesting malignancy, these patients will require a pleural biopsy. The thoracic CT scan is helpful in deciding which method would be most suitable
Percutaneous Pleural Biopsy Techniques
Abrams Needle
The use of a blind closed needle biopsy (BCNB) was first described by Abrams in 1958 . It provided an alternative to an open pleural biopsy, which requires a general anaesthetic . Compared to other pleural biopsy techniques it is inexpensive and can be carried out under local anaesthetic. Chakrabarti et al. found no difference in the diagnostic sensitivity between respiratory registrars and their more junior counterparts . Although low yields were reported when diagnosing mesothelioma, it was hoped that this might be improved with the advent of improved histopathological tests. Radiologically Guided Percutaneous Pleural Biopsy Pleural thickening, whether benign or malignant, is frequently not uniform, and imageguided
biopsy facilitates selection of the most appropriate biopsy site. It also enables safe biopsies in the absence of a pleural effusion. Percutaneous pleural biopsy has been described with both transthoracic ultrasound (US) and CT as image guidance modalities. CT-guided biopsy permits access to areas not easily accessible to ultrasound such as pleural lesions near or behind ribs or along the paravertebral surfaces [50]. Higher sensitivities have been reported with C than with US-guided biopsies although there have been no trials
directly comparing them [49]. Metintas et al. looked at 30 patients with mesothelioma who underwent CT-guided closed needle biopsy. This was diagnostic in 25 (83.3%) . Adams et al. reviewed 21 cases of mesothelioma that had received an image-guided biopsy in their work up (6 US and 15 CT). Their diagnostic sensitivity was 86%. It is also worth noting that of these, four patients had a pleural thickness of
less than 5 mm and all of these biopsies were successful. Cutting needle biopsy has been shown to be more sensitive than fine needle aspiration in the diagnosis of malignancy and the difference is even more marked with mesothelioma with a sensitivity of 93 versus 50% in favour of using a cutting needle. The overall sensitivity can be increased with a combination of both techniques. Complications occur in less than 5% patients using image-guided pleural biopsy techniques and include pneumothorax, intrapleural bleeding, subcutaneous haematoma and damage to the diaphragm and abdominal viscera.
Positron Emission Tomography (PET) CT
PET scans are increasingly being used in the evaluation of patients with mesothelioma [58]. F-fluoro-2-deoxy-d-glucose (FDG)–PET has been shown to accurately differentiate benign pleural disease from mesothelioma. In one study of 98 patients with 63 pleural malignancies, FDG-PET had a sensitivity for detecting malignancy of 96.8% and a specificity of 88.5% and appeared to confirm malignant pleural disease that cannot be identified at CT . Neither of the two malignancies that did not show FDG were mesothelioma. Another study of nine patients with mesothelioma showed that all the primary tumours were FDG positive. Although no trials have looked at PET-CT being used to increase the diagnostic yield of CT-guided biopsies, there may be a role for this in the future, particularly in those patients who clinically appear to have mesothelioma but have already had negative biopsies and are not suitable for thoracoscopic/surgical biopsies.
Thoracoscopy
Thoracoscopy was first described in 1910 . It provides a means of diagnosis for effusions of unknown cause and is particularly important in the diagnosis and management of malignant pleural mesothelioma . It is now recommended by the European Respiratory Society and the European Society of Thoracic Surgeons
and the British Thoracic Society early in the diagnostic pathway of patients with a symptomatic exudative pleural effusion of unknown cause. Thoracoscopy can be performed by surgeons under general anaesthetic – Video-Assisted Thoracoscopic Surgery (VATS) but increasingly is being performed by physicians under local anaesthetic – Local Anaesthetic Thoracoscopy (LAT). In the UK the number of
centres offering LAT has increased from 11 in 1999 to 37 in 2009 . Thoracoscopy allows direct visual assessment of the pleura and subsequent biopsy of the abnormal areas as well the option of a therapeutic
talc poudrage at the same time. Success rates for pleurodesis via thoracoscopy are generally very good and can be as high as 86% at 1 month.
Local Anaesthetic Thoracoscopy
This allows direct visualisation of the pleura and the option of a therapeutic procedure without the need for a general anaesthetic. This is an important advantage over VATS as many patients requiring thoracoscopy have comorbidities and a reduced performance status leading to significant risk from a general anaesthetic.
It should, however, be noted that across Europe many physicians carrying out thoracoscopy choose to perform this in the presence of an anaesthetist (and often a GA). Boutin et al. reviewed 188 cases of mesothelioma that had undergone thoracoscopy . 185/188 (98.4%) were diagnosed after thoracoscopy with a 100% specificity. These results have been mirrored in a number of recent studies with the sensitivity for the diagnosis of mesothelioma ranging from 88% to 100% with a specificity of 100% . The thoracoscope can be flexible, semirigid or rigid. One study comparing the use of rigid with flexible thoracoscope looked at 30 consecutive patients with pleural effusion of unknown cause. The first 10 underwent rigid thoracoscopy whilst the following 20 underwent thoracoscopy with both rigid and flexible thoracoscope. Of those with a final diagnosis of mesothelioma 13/15 (87%) were diagnosed at thoracoscopy. Three biopsies were more informative with the flexible thoracoscope whilst
eight were more informative with the rigid thoracoscope. Two biopsies from the flexible thoracoscope were upgraded from reactive pleurisy to mesothelioma by the rigid thoracoscope biopsies. Overall, it was felt that the rigid instrument as superior because it was easier to manipulate and obtain larger biopsies. Munavvar et al. trialled the use of a semirigid thoracoscope, hoping to combine the advantages of the flexible
and rigid instruments. They correctly diagnosed 15/15 patients with mesothelioma and did not appear to experience the difficulties previously described with the flexible thoracoscope.
Video-Assisted Thoracoscopic Surgery
VATS usually requires general anaesthesia and the placement of a dual lumen tube. VATS is therefore more expensive and time consuming than LAT . There have been no trials directly comparing it to LAT; however, the diagnosticefficacy of the two methods appears comparable. Harris et al. performed VATS on 182 patients. Of the 98 patients with malignancy 29 sensitivity for malignancy was 95% with a specificity
of 100% though they did not state what malignancies the 5 false negatives were. Grossebner et al. reported on 25 patients referred with suspected mesothelioma . Of these 23 had mesothelioma and all were diagnosed from VATS biopsy. Comparing complications and length of stay in hospital is difficult because more extensive procedures are often carried out in the VATS groups and there are no recent trials looking
purely at diagnosis with or without pleurodesis. Studies looking at complications from VATS often include patients with conditions such as empyema that require the extensive breaking down of adhesions, which is more difficult with LAT. However, complications do seem higher with VATS; de Groot et al. reported that nine (26%) of their patients had a major complication whilst Harris et al. reported one death (due
to pulmonary laceration), major complications in 15% (haemorrhage, prolonged air leak, empyema, pneumonia, wound infection, congestive cardiac failure, entering peritoneum, biopsy pneumothorax, myocardial infarction, post operative seizure) and minor complications in 8% (subcutaneous emphysema, fever, hypotension, intercostal neuritis). However, Viskum et al. reported no deaths in their series of 566 examinations with air embolism and cardiac dysrhythmias occurring in less than 1%.
Open Biopsy
Prior to thoracoscopy, this was the next stage in the diagnostic pathway if closed needle biopsy failed. It is now required only if there is obliteration of the pleural space and CT-guided biopsy is not possible or has failed to reach a diagnosis. Its main complication is intractable chest wall pain. Of all the pleural Biopsy techniques, this technique has the highest rate of tract seeding
Prophylactic Radiotherapy
Mesothelioma seeding along pleural intervention tracts is well recognised and present as subcutaneous nodules of varying size. O’Rourke et al. recorded the characteristics of 12 patients that had subcutaneous nodules. 75% reported mild pain, 17% slight pain and 8.3% moderate pain with ulceration in 1 patient. A review of the literature on tract seeding of mesothelioma [34] found that this ranged from 0% to 48% with the risks highest after thoracotomy (24%) and thoracoscopy (9–16%) and lower for smaller incisions such as needle biopsy (0–22%). A recent study of 212 patients who did not receive prophylactic radiotherapy
showed that there was an overall rate of tract seeding of 13.2% . Seeding was more common after thoracotomy (25.8%) versus thoracoscopy and closed needle biopsy or CT-guided biopsy (11.0%). 157 patients received chemotherapy and 26 received multi-modal therapy which may explain why the recurrence rate was lower than the 40% reported by Boutin et al. in the control arm of their trial of prophylactic
radiotherapy. Boutin showed no tumour seedling in the intervention arm (21 Gy in three fractions) and this trial result led to national guidelines promoting the practise of giving prophylactic radiotherapy after pleural interventions in patients with mesothelioma . Recent trials, however, have failed to support its
use. Bydder et al. randomised 43 patients (58 sites) to receive a single dose of radiotherapy (10 Gy) or no radiotherapy [12] whilst O’Rourke et al. recruited 61 patients (60 sites) to have three fractions of 7 Gy or no radiotherapy. Both studies showed no difference in tumour seeding between their control and treatment groups (10% control vs 7% radiotherapy and 10% control vs 13% radiotherapy, respectively).
Important differences between the trials were that all of the patients in Boutin’s original trial underwent a thoracoscopy (with a large chest wall incision) whilst only 23–39% in the two more recent trials did. There was also a difference in the radiotherapy regime in Bydder trial. All of these trials are underpowered and there is therefore still the
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