**4. Diagnosis**

Pleural diseases are common and the causes are diverse, but there is also considerable overlap in the clinical manifestatations of these conditions. Because of this, MPM is notoriously difficult to diagnose, both radiologically and pathologically.

#### **4.1. Radiology**

Radiologically, pleural malignancy is often suspected on clinical history and an abnormal chest radiograph showing pleural effusion or thickening. Computed tomography can be helpful in distinguishing malignant from benign pleural processes [49]. Whilst direct invasion of surrounding structures is diagnostic of malignancy, mediastinal pleural thickening, nodules in the pleura and thickness >1cm predict malignancy with a sensitivity of 40-70% and specificity of 64-96%. In differentiating mesothelioma from secondary pleural malignan‐ cies, mediastinal pleural involvement and rind-like encasement of the lung shows a sensitivity/specificity of 85%/67% and 70%/85% respectively. Magnetic resonance imaging (MRI) has a similar performance to CT at distinguishing benign from malignant processes on the basis of morphology, but signal intensity is a useful additional feature which improves the ability to differentiate between the two [50] [51]. PET-CT is less helpful for the differen‐ tiation of benign from malignant pleural diseases and is more valuable in staging than in diagnosis [52]. Interpretation is confounded by inflammatory and infective pleural condi‐ tions and recent talc pleurodesis [53] [54]. Nevertheless, none of these modalities are absolutely specific so, irrespective of radiological findings, diagnosis of mesothelioma requires pathological confirmation.

#### **4.2. Obtaining tissue for diagnosis**

The mesothelium is a flattened layer of pluripotent mesodermal-derived epithelial cells on the surface of the pleura and mesothelioma can be morphologically diverse. Two main issues face the pathologist trying to establish a diagnosis of mesothelioma. Firstly, mesothelial prolifera‐ tion is common in benign conditions, and differentiating benign from malignant mesothelial proliferation can be very difficult with many benign processes showing atypical features and mimicking invasion. Secondly, of the malignant pathologies affecting the mesothelium, secondary malignancies are by far the most common and mesothelioma is rare. Determining that a pleural malignancy is primary can also be very difficult.

The quality of tissue available to the pathologist greatly influences the ability to make a diagnosis. Fluid from a pleural effusion is helpful at narrowing the differential diagnosis but it has poor sensitivity (about 50-60%) for the diagnosis of malignancy, and in most studies the negative predictive value is around 70% [55]. However, a diagnosis may be more forthcoming when aspiration cytology is repeated [56]. For the specific diagnosis of mesothelioma, cytology has an overall sensitivity of about 30-50%, and is almost useless at diagnosing sarcomatoid mesothelioma (20% sensitivity) [57].

concomitant loss of INKa/ARF [47]. Indeed functionally, loss of INKa/ARF appears to be permissive for NF2 tumourigenesis [48]. Thus, the evidence points to mutations in INKa/ARF and NF2/merlin as driver mutations central to the pathogenesis of mesothelioma. As a result of the genetic instability conferred by these tumour suppressor gene mutations, a large number of genetic lesions appear causing dysregulation of growth factor expression and signalling,

Pleural diseases are common and the causes are diverse, but there is also considerable overlap in the clinical manifestatations of these conditions. Because of this, MPM is notoriously difficult

Radiologically, pleural malignancy is often suspected on clinical history and an abnormal chest radiograph showing pleural effusion or thickening. Computed tomography can be helpful in distinguishing malignant from benign pleural processes [49]. Whilst direct invasion of surrounding structures is diagnostic of malignancy, mediastinal pleural thickening, nodules in the pleura and thickness >1cm predict malignancy with a sensitivity of 40-70% and specificity of 64-96%. In differentiating mesothelioma from secondary pleural malignan‐ cies, mediastinal pleural involvement and rind-like encasement of the lung shows a sensitivity/specificity of 85%/67% and 70%/85% respectively. Magnetic resonance imaging (MRI) has a similar performance to CT at distinguishing benign from malignant processes on the basis of morphology, but signal intensity is a useful additional feature which improves the ability to differentiate between the two [50] [51]. PET-CT is less helpful for the differen‐ tiation of benign from malignant pleural diseases and is more valuable in staging than in diagnosis [52]. Interpretation is confounded by inflammatory and infective pleural condi‐ tions and recent talc pleurodesis [53] [54]. Nevertheless, none of these modalities are absolutely specific so, irrespective of radiological findings, diagnosis of mesothelioma

The mesothelium is a flattened layer of pluripotent mesodermal-derived epithelial cells on the surface of the pleura and mesothelioma can be morphologically diverse. Two main issues face the pathologist trying to establish a diagnosis of mesothelioma. Firstly, mesothelial prolifera‐ tion is common in benign conditions, and differentiating benign from malignant mesothelial proliferation can be very difficult with many benign processes showing atypical features and mimicking invasion. Secondly, of the malignant pathologies affecting the mesothelium, secondary malignancies are by far the most common and mesothelioma is rare. Determining

angiogenesis and apoptosis, conferring on the cell the phenotype of malignancy.

to diagnose, both radiologically and pathologically.

requires pathological confirmation.

**4.2. Obtaining tissue for diagnosis**

that a pleural malignancy is primary can also be very difficult.

**4. Diagnosis**

134 Principles and Practice of Cardiothoracic Surgery

**4.1. Radiology**

Tissue for histopathology can be obtained by percutaneous or thoracoscopic means. Of the percutaneous methods, the Abram's needle has the highest yield, but is only similar to cytological diagnosis [58] [59]. Although pneumothorax can be expected in 15% of patients, few require intervention and the overall complication rate is low in safe hands [60] [61]. The addition of image guidance to target areas with >5mm pleural thickening significantly improves the diagnostic yield to >80% and reduces the rate of complications [61].

Thoracoscopy allows direct visual inspection and target selection, at the same time enabling greater amounts of tissue to be obtained, thereby improving the diagnostic yield for malig‐ nancy to about 95%. Video-assisted thoracoscopy requires a general anaesthetic and single lung ventilation and may be less suited to frail patients, however, it offers the opportunity to proceed to other procedures such as opening up loculations, pleurodesis or insertion of an indwelling drain in case of trapped lung.

Thoracotomy and pleural excision remains the gold-standard for diagnosis of mesothelioma. Whilst pleural biopsy, both open and close, have a high sensitivity for the diagnosis of mesothelioma, the sensitivity for the determination of tissue subtype is approximately 80-86% and is less accurate for non-epithelioid subtypes [62] [63].

#### **4.3. Differentiating benign from malignant mesothelial proliferation**

The separation of benign from malignant mesothelial proliferation can be extremely difficult. Most processes that affect the pleural space, from pneumothorax to thoracic surgery, pulmo‐ nary diseases to systemic diseases cause a degree of pleuritis with a degree of reactive mesothelial hyperplasia. This hyperplasia can be accompanied by quite florid cytological atypia, sometimes more florid than seen in some mesothelioma. Therefore, cytological features of a specimen are not helpful in the diagnosis of malignant mesothelioma [64].

Whilst invasion necessarily implies malignancy, benign processes in the pleura can also produce features that mimic invasion. To demonstrate invasion requires surrounding fat and stroma within the biopsy specimen, that is a reason why the diagnostic yield is higher with larger surgical specimens which contain the full thickness of the pleura and the deeper surrounding tissue. To illustrate the difficulty in clinching a diagnosis, even expert members of the US-Canadian Mesothelioma Reference Panel disagree 22% of the time on selected cases referred to them [65] [66].

Some benign histological features can appear ominous, one such is entrapment, where organising pleuritis within the pleural space overlying a pleural surface gives the deceptive appearance of mesothelial invasion. This can be complicated by the concomitant appearance 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 content can resemble desmoplastic sarcomatoid mesothelioma.

sleep, and the breathlessness would often force the patient to stop working. Medical attention

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Physical examination is helpful insofar as suggesting a pleural effusion or pleural thickening, but is nonspecific for the diagnosis of MPM. Peripheral stigmata of pulmonary diseases such as clubbing and hypertrophic pulmonary osteoarthropathy are not features of MPM, and

In those with large effusion, drainage may lead to rapid improvement of symptoms but a trapped lung is also common. As the disease progresses, less fluid is produced and there is progressively more pleural thickening, eventually the fluid disappears and the chest becomes contracted and filled with tumour. Local invasion of the chest wall can result in intractable pain and paresthesia, whilst invasion of the contralateral pleural space, pericardial space or through the diaphragm usually herald a rapid deterioration. Distant spread is common but is

The outlook for patients with mesothelioma is bad. For patients who present asymptomatically on a chest radiograph, the median survival is 20 months with best supportive care [76], and it is with this baseline in mind that we should evaluate noncomparative studies on new therapies.

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

is usually only sought after a median of 3.5 months of progressing symptoms [76].

palpable lymphadenopathy is rare.

**6. Staging of mesothelioma**

of the signal changes in these structures [84].

usually less symptomatic than the primary site.

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 microRNAs [70].

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

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 of other tissue origin.

#### **4.5. Histological subtypes**

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