**6. Staging of mesothelioma**

of fat-like spaces within the organising pleuritis further giving the appearance of fat invasion [67]. Reactive proliferation of the surrounding stroma fibroblasts and spindled mesothelial cells can resemble sarcomatoid mesothelioma, whilst dense, fibrous pleuritis with low cellular

Because of the difficulties differentiating benign from malignant mesothelial cells on morpho‐ logical grounds, other techniques have been developed to this end. Unfortunately, immuno‐ histochemistry is of limited value, with poor sensitivity and specificity [68], but the identification of mutated genes may be more fruitful. The discovery that the majority of mesothelioma has loss of 9q21 led to the recent development of fluorescence in-situ hybridi‐ sation techniques looking for homozygous deletions of the p16INK4a gene. Loss of p16 in this assay appears to be 100% specific for mesothelioma [40] [69]. Another avenue which has found commercial application is diagnosis through the pattern of downregulation of specific

Immunohistochemistry is indispensable for the differentiation between primary pleural mesothelioma and secondary malignancies. A number of markers for each of mesothelioma and the carcinoma should be used to improve the diagnostic specificity. The International Mesothelioma Interest Group (IMIG) recommends the use of at least 2 mesothelial markers and 2 markers of the tumour under consideration, and if no diagnosis could be arrived at, an expanded panel could be used [64]. Epithelioid mesothelioma markers include Wilms Tumour 1 (WT-1), calretinin. cytokeratin 5 or 5/6. Thyroid transcription factor-1 (TTF-1) is useful for the differentiation of lung adenocarcinoma, whilst CYFRA 21-1, SCCA and p63 are useful squamous cell carcinoma markers. Markers can also be selected for secondary malignancies

Many subtypes of mesothelioma have been described, but a single tumour can harbour several subtypes, so they are best broadly grouped into three types: epithelioid, sarcomatoid and mixed or biphasic. The epithelioid type is the most common (60%) whilst the other two types comprise 20% each [71]. The histological type not only determines the main differential diagnoses, but is also a predictor of response to treatment and one of the most powerful

The symptoms of MPM typically present insidiously with vague symptoms [75]. The charac‐ teristic symptoms are pain in half the patients, breathlessness in a third, and constitutional symptoms in less than 10%. At the beginning, symptoms are usually ill-defined and mild, but as the disease progresses, the initial heaviness becomes an ache and pain that interferes with

content can resemble desmoplastic sarcomatoid mesothelioma.

**4.4. Differentiating MPM from other pleural malignancies**

microRNAs [70].

136 Principles and Practice of Cardiothoracic Surgery

of other tissue origin.

**4.5. Histological subtypes**

prognostic predictor [72] [73] [74].

**5. Clinical features**

The purpose of staging is threefold: it allows stratification of patients by the anatomical extent of disease into groups with similar prognosis, enables comparison of results between studies and facilitates treatment decision-making by determining the role of specific therapies in these subgroups. However, the staging of mesothelioma is hampered by two difficulties, firstly it has a non-spherical and non-concentric plate-like growth pattern and secondly, there is a lack of understanding of the natural history of mesothelioma. This is reflected in the fact there has been six different staging systems over the last 30 years [77] [78] [79] [80] [81] [82] [83]. Only the later systems adopted the TNM model, and most have not been independently validated.

The lack of an organ within which mesothelioma grows and the way it encroaches insidiously onto contiguous structures make clinical staging by imaging challenging. This is particularly the case with T-staging. The latest International Mesothelioma Interest Group (IMIG) staging system recognises that mesothelioma starts on the parietal pleura (T1a), and the spreads onto the visceral pleura as isolated and scattered foci (T1b), which becomes confluent (T2). These features are not easily resolvable on imaging and require direct visualisation with thoraco‐ scopy or open surgery. Nevertheless, most tumours present at the T3 and T4 stages. Here, the preoperative determination of invasion into the chest wall, mediastinum, diaphragm or pericardium is crucial to the separation of potentially resectable (T3) from unresectable (T4) tumour, but in practice this is not an exact science. The visual distinction between a contiguous structure and an invaded structure can be a difficult call. When compared to the pathological stage, both CT and MRI have an accuracy of only 50-60% in most categories, but MRI may be marginally more superior in the diagnosis of diaphragmatic and chest wall invasion on account of the signal changes in these structures [84].

Nodal metastases portends a grave prognosis in patients with mesothelioma who underwent resection [80] [85] and so accurate staging of nodal involvement is crucial for the selection of patients for radical treatment and prognostication. However, several factors complicate the assessment of nodal disease. Firstly, our knowledge of nodal staging is hampered by the fact that bronchopulmonary nodes are not routinely sampled in radical pleurectomy-decortication, or routinely reported in extrapleural pneumonectomy specimens. Secondly, the current IMIG staging system adopted the lung cancer nodal classification for mesothelioma. However, early anatomical studies has already showed that lymphatic drainage of the pleura occurs first to the chest wall (internal mammary) and paravertebral lymph nodes, whilst there is little flow upstream through the lung parenchyma to the N1 stations [86]. Indeed, the survival of patients with N1 disease does not appear to be any better than those with N2 disease [87] [88] [89] whilst the extramediastinal nodes (internal mammary, pericardial, diaphragmatic) are associated with better prognosis [90]. Finally, within the mediastinal nodes there are differences in outcomes: involvement of upper mediastinal nodes is associated with worse prognosis [90]. This is compatible with the hypothesis that mesothelioma starts basally and progresses apically.

dehydrogenase, and *biomarkers* such as mesothelin and megakaryocyte potentiating factor [96] [95] [97]. These have been variously combined into different prognostic scores. Amongst the various scores, different factors take on different prognostic significance in different series and ultimately, the few consistent predictive factors are age, performance status, histology and stage. A gene ratio based test for molecular staging using the relative expression of four genes, namely *TM4SF1, PKM2, ARHGDIA*, and *COBLL1*, has been described and internally validated in a prospective patient set from the same institution [98]. This test was more powerful at predicting overall survival than either histology or lymph node involvement, and when combined with these, was able to differentiate three subgroups with very different outcomes [99]. Nevertheless, the test suffers the same limitation as the current staging system in its

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Many tumours grow as spherical masses and linear measurements which correlate well to tumour volume can usually be taken on cross-section imaging for the assessment of response to treatment. The sheet like growth pattern of MPM over many different topologically complex surfaces meant objective measure of mesothelioma responses is difficult and subject to significant interobserver variation, the standard criteria for response assessment may therefore

The WHO criteria was introduced in 1979 to determine whether there was a complete response, partial response, stable disease or disease progression [100] and was based in part on evalua‐ tion of breast cancer response by palpation. Without stipulating the assessment protocol or measurement process, it proposed taking bidimensional measurements and obtaining the product of the longest tumour diameter with the greatest perpendicular measurement. This led to significant variation in the assessment method, and made comparison of reporting from different trials difficult. The Response Evaluation Criteria In Solid Tumour (RECIST) guideline was proposed in 2000 to try to address some of these problems [101]. It moved onto unidi‐ mensional assessment and measured changes in the longest tumour diameter on standardised imaging protocols. However, for tumours like mesothelioma, the choices of longest tumour diameter are many and subject to interpretation and bias. To improve on this, a modification of the RECIST criteria for mesothelioma was proposed to assess response by summating the perpendicular thickness of the tumour rind in two positions at three levels into a unidimen‐ sional measurement, and repeating the measurements at the same position [102]. Where appropriate for a lesion, bidimensional assessment can still be used. Within this system, a complete response is defined as complete disappearance of all tumour, a partial response by at least 30% reduction in the measurement on two occasions 4 weeks apart, progressive disease as increase in the measurement by 20% or appearance of new lesions, and stable disease as

those who fulfilled neither the partial response nor progressive disease criteria.

This system was validated and showed correlation to lung function and survival outcomes [102]. Nevertheless, there is still significant overlap in survival between those with stable

requirement for pathological data following resection.

**7. Assessment of treatment response**

be unsuited to it.

Radiologically, the nodes are frequently obscured by the pleural thickening, and there is little correlation between nodal size and disease involvement in mesothelioma [85], so that imaging modalities based on structural criteria perform poorly at discriminating between involved and uninvolved nodes. CT and MRI has an accuracy of about 50% for nodal staging and so cannot be relied on [84]. For this reason, functional imaging such as PET and PET-CT have been investigated for their role in staging. PET alone has poor spatial resolution, but when combined with CT, increases the specificity of the PET and the sensitivity of the CT. PET-CT is more accurate for staging resectable disease than CT, MRI or PET, through its ability to diagnose distant metastases [91]. For nodal staging, the accuracy for mediastinal nodal involvement in PET-CT is about 60-66% [92] [93], therefore invasive techniques such as mediastinoscopy are still required for accurate nodal staging given its potent impact on prognosis [90]. In practice, in a population with a 'resectable tumour on CT' and mandatory mediastinoscopy, PET-CT was able to prevent futile surgery in an additional 29% patients [92].

The current staging system has several deficiencies. Firstly, it was developed with surgical patients in mind and requires intraoperative and pathological assessment. As a result, clinical staging is highly inaccurate and correlates with pathological staging less than 50% of the time [89]. Secondly, it successfully stratifies survival in only some [94] and not other surgical series [83]. Thirdly, most patients end up belonging to stage III with little differentiation within. Fourthly, it does not predict survival in nonsurgical patients such as those following chemo‐ therapy alone [95]. There are other prognostic factors which are more powerful at stratifying prognosis of mesothelioma patients. Cell type is an important prognostic determinant, the hazard ratio for death following trimodality therapy is several fold higher than nodal status and overall stage [83] [95].

Numerous other prognostic factors have been found to be associated with survival in meso‐ thelioma. They include *clinical factors* such as age, performance status and asbestos burden, *laboratory indices* such as haemoglobin, platelet count, white cell count and serum lactate dehydrogenase, and *biomarkers* such as mesothelin and megakaryocyte potentiating factor [96] [95] [97]. These have been variously combined into different prognostic scores. Amongst the various scores, different factors take on different prognostic significance in different series and ultimately, the few consistent predictive factors are age, performance status, histology and stage. A gene ratio based test for molecular staging using the relative expression of four genes, namely *TM4SF1, PKM2, ARHGDIA*, and *COBLL1*, has been described and internally validated in a prospective patient set from the same institution [98]. This test was more powerful at predicting overall survival than either histology or lymph node involvement, and when combined with these, was able to differentiate three subgroups with very different outcomes [99]. Nevertheless, the test suffers the same limitation as the current staging system in its requirement for pathological data following resection.

### **7. Assessment of treatment response**

Nodal metastases portends a grave prognosis in patients with mesothelioma who underwent resection [80] [85] and so accurate staging of nodal involvement is crucial for the selection of patients for radical treatment and prognostication. However, several factors complicate the assessment of nodal disease. Firstly, our knowledge of nodal staging is hampered by the fact that bronchopulmonary nodes are not routinely sampled in radical pleurectomy-decortication, or routinely reported in extrapleural pneumonectomy specimens. Secondly, the current IMIG staging system adopted the lung cancer nodal classification for mesothelioma. However, early anatomical studies has already showed that lymphatic drainage of the pleura occurs first to the chest wall (internal mammary) and paravertebral lymph nodes, whilst there is little flow upstream through the lung parenchyma to the N1 stations [86]. Indeed, the survival of patients with N1 disease does not appear to be any better than those with N2 disease [87] [88] [89] whilst the extramediastinal nodes (internal mammary, pericardial, diaphragmatic) are associated with better prognosis [90]. Finally, within the mediastinal nodes there are differences in outcomes: involvement of upper mediastinal nodes is associated with worse prognosis [90]. This is compatible with the hypothesis that mesothelioma starts basally and progresses

Radiologically, the nodes are frequently obscured by the pleural thickening, and there is little correlation between nodal size and disease involvement in mesothelioma [85], so that imaging modalities based on structural criteria perform poorly at discriminating between involved and uninvolved nodes. CT and MRI has an accuracy of about 50% for nodal staging and so cannot be relied on [84]. For this reason, functional imaging such as PET and PET-CT have been investigated for their role in staging. PET alone has poor spatial resolution, but when combined with CT, increases the specificity of the PET and the sensitivity of the CT. PET-CT is more accurate for staging resectable disease than CT, MRI or PET, through its ability to diagnose distant metastases [91]. For nodal staging, the accuracy for mediastinal nodal involvement in PET-CT is about 60-66% [92] [93], therefore invasive techniques such as mediastinoscopy are still required for accurate nodal staging given its potent impact on prognosis [90]. In practice, in a population with a 'resectable tumour on CT' and mandatory mediastinoscopy, PET-CT

The current staging system has several deficiencies. Firstly, it was developed with surgical patients in mind and requires intraoperative and pathological assessment. As a result, clinical staging is highly inaccurate and correlates with pathological staging less than 50% of the time [89]. Secondly, it successfully stratifies survival in only some [94] and not other surgical series [83]. Thirdly, most patients end up belonging to stage III with little differentiation within. Fourthly, it does not predict survival in nonsurgical patients such as those following chemo‐ therapy alone [95]. There are other prognostic factors which are more powerful at stratifying prognosis of mesothelioma patients. Cell type is an important prognostic determinant, the hazard ratio for death following trimodality therapy is several fold higher than nodal status

Numerous other prognostic factors have been found to be associated with survival in meso‐ thelioma. They include *clinical factors* such as age, performance status and asbestos burden, *laboratory indices* such as haemoglobin, platelet count, white cell count and serum lactate

was able to prevent futile surgery in an additional 29% patients [92].

apically.

138 Principles and Practice of Cardiothoracic Surgery

and overall stage [83] [95].

Many tumours grow as spherical masses and linear measurements which correlate well to tumour volume can usually be taken on cross-section imaging for the assessment of response to treatment. The sheet like growth pattern of MPM over many different topologically complex surfaces meant objective measure of mesothelioma responses is difficult and subject to significant interobserver variation, the standard criteria for response assessment may therefore be unsuited to it.

The WHO criteria was introduced in 1979 to determine whether there was a complete response, partial response, stable disease or disease progression [100] and was based in part on evalua‐ tion of breast cancer response by palpation. Without stipulating the assessment protocol or measurement process, it proposed taking bidimensional measurements and obtaining the product of the longest tumour diameter with the greatest perpendicular measurement. This led to significant variation in the assessment method, and made comparison of reporting from different trials difficult. The Response Evaluation Criteria In Solid Tumour (RECIST) guideline was proposed in 2000 to try to address some of these problems [101]. It moved onto unidi‐ mensional assessment and measured changes in the longest tumour diameter on standardised imaging protocols. However, for tumours like mesothelioma, the choices of longest tumour diameter are many and subject to interpretation and bias. To improve on this, a modification of the RECIST criteria for mesothelioma was proposed to assess response by summating the perpendicular thickness of the tumour rind in two positions at three levels into a unidimen‐ sional measurement, and repeating the measurements at the same position [102]. Where appropriate for a lesion, bidimensional assessment can still be used. Within this system, a complete response is defined as complete disappearance of all tumour, a partial response by at least 30% reduction in the measurement on two occasions 4 weeks apart, progressive disease as increase in the measurement by 20% or appearance of new lesions, and stable disease as those who fulfilled neither the partial response nor progressive disease criteria.

This system was validated and showed correlation to lung function and survival outcomes [102]. Nevertheless, there is still significant overlap in survival between those with stable disease and those with partial response, even following optimisation of the cut-off criteria for each group [103]. This has significant implications for the clinical relevance of studies which use response as their primary outcome measure instead of survival.

**8.2. Symptom palliation**

however at 20-30%.

non-small cell lung cancer patients [110].

The symptoms of mesothelioma are severe and debilitating, leaving many patients miserable for their remaining time. In particular, the severity of pain and breathlessness exceeds that in

Malignant Pleural Mesothelioma and the Role of Non–Operative Therapies

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141

Early on in the disease, breathlessness is due to pleural effusion compressing the lung and can be managed effectively by drainage. If the lung reexpands following drainage, pleurodesis can prevent reaccumulation. Most studies concern the management of malignant pleural effusions in general which include some cases of mesothelioma. Randomised trials for the use of sclerosant (drainage alone vs drainage with sclerosant), between different sclerosants and between techniques (bedside vs thoracoscopic) for malignant pleural effusions in general favoured the use of talc pleurodesis and thoracoscopy [111] [112]. One subsequent large randomised trial did suggest equivalence between bedside talc slurry and thoracoscopic talc pleurodesis [113], but the frequent need to obtain tissue for diagnosis usually favours the thoracoscopic approach. The recurrence rate following thoracoscopic pleurodesis remains

As the disease progresses, a trapped lung develops where the visceral tumour forms a constricting cortex over the lung preventing pleural apposition. Talc pleurodesis in such situations risks infection from long term drainage and contamination of a fixed space. VATS pleurectomy and decortication has been advocated as a palliative procedure which does not aim for complete macroscopic clearance, but tries to achieve lung reexpansion. There seems to be some short-term improvement in pain and dyspnoea [114] without detriment to survival [115] [116]. Recruitment to the randomised trial for VATS decortication (MesoVATS) has now

Recently, the use of long term tunnelled pleural catheters for effusions with underlying trapped lung has shown promise with very short hospital stay, low morbidity and better patient tolerability. It compared favourably with bedside talc slurry [118]. Even in patients with trapped lung, long term drainage could ultimately result in pleural symphysis, and the drain could eventually be removed in a fifth of patients [119]. Furthermore, chemotherapy can

As the disease progresses, the effusion disappears and is replaced by a constricting tumour and a contracted hemithorax. Management of breathlessness at this stage is difficult. A palliative pleurectomy could be performed to relieve the restriction on ventilation and chest wall pain but there is significant morbidity associated with such an extensive operation. On the other hand, self-help breathlessness management techniques and opioids can help to

Pain is also a significant symptom that could be difficult to manage. In addition to the WHO pain ladder, radiotherapy can improve chest wall pain in 50-60% patients [120] although unfortunately in most cases the relief is not sustained [121]. There is some suggestion that hyperthermia may increase the response rate to radiotherapy for pain control [122]. In addition, there is a significant neuropathic component to the pain, so early referral to a specialist pain

management team may help to improve the quality of life in the final months.

closed, and the results should be available in the near future [117].

safely continue in the presence of such drains.

relieve the sensation of dyspnoea.
