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Multimodality Imaging Assessment of Malignant Pleural Mesothelioma
C H A P T E R
2 Multimodality Imaging Assessment of Malignant Pleural Mesothelioma M.A. Mazzei1, F. Gentili1, P. Tini1,2, L. Pirtoli2 and L. Volterrani1 1
Department of Medical, Surgical and Neuro Sciences, Unit of Diagnostic Imaging, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy 2Department of Medical, Surgical and Neuro Sciences, Unit of Radiation Oncology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
INTRODUCTION Malignant pleural mesothelioma (MPM) is a tumor arising from the mesothelial or submesothelial cells and it is the most common primary cancer that emerges in the pleura [1,2]. In more than 70% of the cases, a relationship with exposure to asbestos is detected and the disease generally occurs in the fifth and sixth decades of life with a higher incidence in men than in women (80% vs 20%) [3]. Other suggested etiological factors include exposure to other mineral fibers (e.g., zeolite or erionite), chronic inflammation and scarring (e.g., tuberculosis and empyemas), irradiation and intrapleural thorium dioxide, genetic factors, and the viral oncogene Simian virus SV40 (a contaminant in a high number of human vaccines) [4]. MPM is officially recognized as an occupational neoplasm and the latency between the first asbestos exposure and tumor development is 20 40 years; therefore worldwide, the incidence is increasing and it is expected to peak in the year 2020 [5]. In the United States, MPM occurs in approximately 2500 persons per year and almost 72,000 cases are expected to occur in the next 20 years [6]. In Italy, the asbestos epidemic continues and is even increasing because of the country’s industrial history. Up to the end of the 1980s Italy was the second largest asbestos producer in Europe after the Soviet Union and the largest in the European Community, with a peak between 1976 and 1980 [7]. Furthermore asbestos imports to Italy reached a peak when they were already falling in the United Kingdom and United States and the consumption curve of asbestos shows a
Malignant Pleural Mesothelioma DOI: https://doi.org/10.1016/B978-0-12-812724-7.00003-4
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© 2019 Elsevier Inc. All rights reserved.
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lag time of about 10 years compared with many other industrialized countries [8]. The most tumorigenic asbestos fiber is thought to be crocidolite, with other subtypes including amosite and chrysotile (“blue,” “brown,” and “white” asbestos, respectively). The microscopic presence of “asbestos (ferruginous) bodies” in bronchoalveolar lavage is evidence of previous exposure to asbestos [4]. Frequently the disease is diagnosed in an advanced stage, since clinical manifestations are nonspecific, so the patient prognosis is poor with a median survival of 9 17 months [9]. Although the precise pathophysiological origin of the tumor is unknown, MPM initially involves the parietal pleura, forming gray-white pleural plaques, and subsequently involves the visceral pleura, spreading along pleural surfaces, including the interlobar fissures, encasing and compressing the lung. The disease is usually diffuse rather than focal, typically invasive, involving the diaphragm, chest wall, and pericardium. MPM more often affects the inferior hemithorax, probably under the force of gravity and the right side, probably because of its greater pleural surface. Nodal metastases are present in 40% 45% of cases at diagnosis time whereas hematogenous spread tends to occur in the advanced phases of the disease [4]. Recently the staging system of MPM has been updated in the 8th edition of American Joint Committee on Cancer, which substituted the 7th edition, given the known inaccuracies in pretreatment staging with current diagnostic techniques and considering overall survival (OS) in different stages; the major changes affect T and N parameters: the categories T1a (tumor limited to the parietal pleura) and T1b (tumor involving the visceral pleura) were collapsed into a single T1 category, whereas regarding N parameter, metastases in the ipsilateral bronchopulmonary or hilar lymph nodes (N1) and any ipsilateral intrathoracic lymph nodes (previously N2) were collapsed into a single category (N1) [10 16]. However, T3 and T4 categories, which describe locally advanced but potentially resectable tumors and technically unresectable tumors respectively, were unchanged [17]. On this basis, key goals of imaging in MPM are to make possible the early detection of the disease, optimizing accuracy for anatomic involvement of unresectable planes, improving prognostication, and assessing response to treatment [18]. In this chapter, the features of MPM in different diagnostic techniques are shown. Moreover the problem of recurrence monitoring, the assessment of response to treatment, and potential differential diagnoses of MPM are proposed. A brief reference to MPM screening is also discussed.
DIAGNOSIS Chest Radiography Chest radiography is generally the first imaging technique to depict abnormalities of MPM, because of its availability and widespread use. Unilateral pleural effusion is the most common finding of MPM (30% 80% of patients) together with diffuse pleural thickening (60%) and pleural masses (45% 60%) [19]. On occasion, the pleural thickening may be minor and, indeed, may be obscured by what appears to be a simple pleural effusion [4]. Tumor growth leads to nodular thickening of interlobar fissures and lung encasement with volume loss, elevation of ipsilateral hemidiaphragm, ipsilateral mediastinal shift, and
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narrowing of the intercostal spaces [20,21]. Clearly visible pleural plaques, often calcified, which are the commonest radiographic manifestation of asbestos exposure, coexist only in 20% of cases [22]. However it is difficult to make a definitive diagnosis based on plain radiographs, especially in the early stages, since imaging findings are not specific [23]. From a technical point of view, chest radiography should be performed in posteroanterior (PA) and laterolateral projection; sometimes addictional projection (e.g., Hessen projection) may be useful to highlight a small amount of pleural effusion in symptomatic patients with visible pleural plaques.
Chest Digital Tomosynthesis Digital tomosynthesis (DTS) is a type of limited angle tomography that allows reconstruction of multiple image planes from a set of projection data acquired over a limited range of an X-ray tube movement. The advantages of DTS, as compared with conventional radiography, include depth localization and improved conspicuity of structures achieved by removing the visual clutter associated with the overlying anatomy. Although DTS does not have the potential and high resolution of computed tomography (CT), it provides relatively high-resolution images in the coronal or sagittal planes, improving the visualization both of parenchymal and mediastinal alteration, with a lower dose than CT. In recent years some authors have reported the advantage of chest digital tomosynthesis in the detection of pleural plaques and asbestosis [24]; however this technique could be used also to improve the detection of the remaining asbestos-related pleuropulmonary disease, including the early detection of MPM.
Computed Tomography Computed tomography (CT) is the next imaging modality of choice in the suspicion of MPM and it is often sufficient for disease staging and treatment planning. CT is also useful in finding out pleural plaques (PPs) in patients who are unaware of their exposure to asbestos. Moreover the presence of PPs may help in considering asbestosis as a cause of MPM to offer a compensation to these patients [25]. A recent Japanese study even found that in lung cancer patients the plaque extent had a significant positive relationship with the asbestos body concentration in lung tissue that represents a biomarker of past exposure [26]. From a diagnostic point of view, in most screenings for pneumoconiosis, a chest radiograph is used as the standard method, but this procedure has important limitations in the detection of early subtle PPs, whereas a CT scan enables diagnosis of thin or tiny noncalcified plaques [27]. Experienced CT readers can diagnose PPs with high confidence in most cases, which show the typical findings of bilateral, multiple, localized, pleural thickenings sparing the costophrenic angles. However, the CT features of PPs are sometimes equivocal in challenging cases and if the radiologists are not skilled in occupational diseases pleural plaques could be underreported [25,28,29]. CT allows an accurate delineation of the pleural disease and differentiation of pleural thickening from pleural fluid; in particular a pleural thickening that is nodular, circumferential, and greater than 1 cm in thickness is highly suggestive of malignant pleural disease,
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including MPM [30]. In cases of MPM with osteocartilaginous differentiation, ossification or calcification may be seen in regions of pleural thickening or pleural masses [31]. An accurate staging is pivotal for treatment decision making, distinguishing patients with early stages (T1, T2) or potentially resectable tumors (T3) from cases with technically unresectable tumors (T4); tumors with diffuse extension or multifocal masses in the chest wall, direct transdiaphragmatic extension to peritoneum, direct extension to the contralateral pleura, mediastinal organs, spine, and transmural invasion of the pericardium are considered unresectable [32] (Fig. 2.1). Regarding the mediastinal involvement, an encasement of more than 50% of the circumference of the esophagus or trachea with an obliteration of fat planes is strongly indicative of their invasion [33]. Involvement of the pericardium may result in pericardial effusion, thickening, nodules, and masses; despite the difficulty in distinguishing nontransmural from transmural pericardial involvement, the persistence of epicardial fat suggests nontransmural involvement [20]. Extension of the tumor into the chest wall may result in obliteration of extrapleural fat planes, invasion of intercostal muscles, and rib displacement or destruction [22]. Moreover in determining transdiaphragmatic tumor extension, the presence of clear fat plane between the inferior surface of the diaphragm and the adjacent abdominal organs is the best finding to confirm
FIGURE 2.1 (A, B) Coronal (A) and sagittal (B) CT images reconstruction in a patient with mesothelioma. Chest CT should be extended to diaphragmatic pillars (arrows in A and B).
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that MPM is confined to the chest [20]. Although the CT accuracy in predicting MPM resectability is considered limited in the literature (sensitivity, specificity, and accuracy respectively about 90%, 50%, and 70%), CT scans in these studies were obtained at 7 10 mm of slice thickness, most of them without contrast agent administration and all of this is not acceptable [4]. Technical CT parameters are fundamental for reaching the correct diagnosis and staging the disease. A thin slice thickness (1.25 mm) and a reconstruction interval at least half of the effective slice thickness improves spatial resolution and allows high quality multiplanar reformations whereas reference mAs and kVp should be adjusted on the basis of patient size obtain to optimal signal to noise ratio. Moreover the contrast agent administration is mandatory with a scan delay of about 50 seconds (late arterial phase) from the start of the injection with a later phase (delay 4 5 minutes) to optimize tumor uptake. Therefore further studies to evaluate CT accuracy for T parameter assessment are necessary by employing this technique at the state of the art. Contrast-enhanced CT scan should be performed from the upper abdomen to the thoracic inlet to accurately evaluate the entire diaphragm and completed by a CT scan of the abdomen and brain to complete the staging of the disease (Fig. 2.2). Furthermore a high resolution CT scan of the lung, before contrast media administration, is strongly recommended to diagnose asbestosis or to better characterize possible lung nodules. Tumor volume has been reported to be a valuable prognostic factor for survival in patients with MPM [21,22,34,35] and, from this prospective, Optiz and colleagues enlisted 28 patients for assessing the possibility of preoperative CT-based tumor volume in predicting the weight of tumor resected after complete surgical resection. The analysis revealed a
FIGURE 2.2 (A, B) Contrast-enhanced CT in a 72-year-old man with diagnosis of biphasic malignant mesothelioma shows the neoplastic infiltration of the mediastinal fat (arrows in A) and the nontransmural involvement of the pericardium (arrow in B), defining a clinical T3 tumor (potentially resectable).
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moderate correlation between CT-based tumor volume and tumor weight whereas no significant correlation was observed between clinical T stage and tumor weight [35]. At the same time some publications [36 38] suggested that pleural tumor thickness may provide more accurate T categorization than the current anatomic descriptors; in particular a breakpoint of 5 mm of maximal pleural thickness or 13 mm for the sum of pleural thickness measured at the upper, mid, and lower regions was found to be prognostic. A greater pleural thickness also correlates with the presence of nodal metastases. Therefore further studies are necessary to determine whether measurements of pleural thickness should replace the current descriptors of T categories. CT constitutes the primary technique for detecting intrathoracic nodal involvement. The regional lymph node map and nomenclature for MPM are adapted from those used for lung cancer [39]. Mediastinal lymph nodes, specifically paratracheal, hilar, subcarinal, paraesophageal, and paraaortic, that are 10 mm or larger in short diameter, are considered abnormal. In addition, MPM often metastasizes to lymph nodes not involved by lung cancer, including the internal mammary, peridiaphragmatic, and intercostal lymph node, which have no specific size criteria and their visualization is considered abnormal. CT is also fundamental for detecting metastases; biphasic and sarcomatoid subtypes of MPM display a more aggressive behavior compared with the epithelial subtype and may present with distant metastases at diagnosis [23]. The most common sites of metastatic are distant lymph nodes, intraabdominal disease, and controlateral lung [10,11]. Pulmonary metastases may manifest as nodules, masses, or lymphangitic carcinomatosis, with thickening and nodularity of the interlobar septa.
Magnetic Resonance Magnetic resonance (MR) is not generally employed to evaluate MPM because of long imaging time, cost reasons, and limited availability. Although modern cross-sectional imaging provides higher spatial resolution, limitations in tissue contrast remain a challenge for staging of MPM. This limitation is a challenge on CT where separating mesothelioma, diaphragm, chest wall, and pericardium from one another is a difficult task due to their partial overlapping in Hounsfield units (HU) distributions and close spatial proximity to one another [18,40]. Since MR has superior tissue contrast, it is sometimes employed to further characterize mesothelioma cases suspicious for local invasion, even if subtle local invasion can still be a challenge to detect at imaging [18]. In the literature there are only a few works that compared MR and TC accuracy to predict resectability in patients with biopsy-proven MPM and they go back to the 1990s and 2000s. Patz and colleagues [33] compared MR with CT in 34 patients undergoing thoracotomy and they found a slightly higher sensitivity of MR than CT for predicting resectability at the diaphragm and chest wall (100% vs 94%); however it should be noted that CT scans were acquired with a slice thickness of 10 mm in axial mode so multiplanar reformations were not possible. Heelan and colleagues [41] compared the accuracy of MR and CT for staging 65 MPM patients and they found MR more accurate for detecting endothoracic fascia involvement, solitary foci of chest wall invasion, and for assessing diaphragmatic invasion, even if these findings did not change the surgical management. To determine the optimal tumor
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enhancement after intravenous contrast agent injection, Katz conducted a study in patients undergoing MR for preoperative staging purpose; since they performed multiple acquisitions after contrast agent injection, a time enhancement curve could be constructed and the best peak tumor enhancement was estimated to occur at a delayed phase (about 280 seconds); however further studies are necessary to determine the impact of delayed phase enhancement on radiologic MPM staging accuracy [18]. Diffusion weighted MRI (DWI), based on the diffusivity of water molecules within the tissues, has the potential to reveal tissue characteristics; through this technique, signal loss can be quantitatively assessed with the apparent diffusion coefficient (ADC), which depends on restriction of water molecule diffusion by membranes and macromolecules [42]. Since this technique has been widely investigated in the evaluation of numerous solid tumors, Gill et al., in 2010, evaluated its role for distinguishing MPM histological subtypes. They analyzed 57 MPM cases and found that the ADC of the epithelioid subtype was statistically significantly higher than the ADC values of the biphasic and sarcomatoid subtypes [42]. In fact, sarcomatoid MPM is composed of spindle-shaped cells with high cellularity whereas epithelioid MPM is composed of tubular and cuboidal cells; moreover sarcomatoid MPM often shows a storiform pattern, which can further restrict water diffusion. The ADC values of biphasic MPM have a wide range of overlap with the ADC values of other subtypes since it consists of a mixture of both epithelial and sarcomatoid cells. Although the histologic subtype of MPM is usually determined by video-assisted thoracoscopy, with a diagnostic accuracy higher than 95%, the procedure is invasive and may lead to seeding of tumors along the surgical incision or chest tube track in as many as 20% of patients [4]. Therefore DWI is a promising, noninvasive technique, which has great potential in the noninvasive diagnosis of MPM subtypes [42]. MR can also be used to assess uncommon post-operative complication, such as chylothorax, by using MR lymphangiography protocol; in this exam the contrast media injected into the inguinal nodes and drained by lymphatic system allows to localize precisely the leakage site of lymphatic channels [43 46].
PET and PET/CT Functional imaging with 18F-FDG-PET allows the noninvasive investigation of tumor metabolism and extent and it is complementary to conventional imaging modalities in the diagnosis and preoperative staging of MPM. FDG uptake in MPM can range from moderate to high, depending on histologic subtype; generally epithelial subtype tumors tend to be less metabolically active than the mixed and sarcomatoid subtypes [22,41]. The main disadvantage of 18F-FDG-PET imaging is the limited spatial resolution and lack of anatomical landmarks; therefore hybrid 18F-FDG-PET/CT systems have been introduced and their use has been rapidly incorporated in daily clinical practice [47]. Many studies have demonstrated the clinical utility of 18F-FDG-PET and 18F-FDG-PET/CT, using a visual analysis or semiquantitative measurements (maximum standardized uptake value [SUV max]) for diagnosing MPM with a sensitivity of 60% 100% and a specificity of 78% 100% [48 50]. Otherwise these techniques have poor sensitivity for small cancers because of the lack of the tumor uptake and limited spatial resolution of current 18F-FDG-PET/CT scanners,
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which is around 5 mm [51]. Moreover they have been proved to be inadequate for defining locoregional tumor extent. In this regard Pinelli et al. in 2014 evaluated 32 patients with histologically confirmed MPM after medical thoracoscopy who underwent 18F-FDGPET/CT scan before diagnosis; they assessed whether the metabolic activities of pleural tumors detected with 18F-FDG-PET/CT correlated with findings assessed by thoracoscopy and demonstrated only a fair agreement between the two techniques in determining visceral and diaphragmatic pleural involvement [52]. 18F-FDG-PET and 18F-FDG-PET/CT have been studied in the detection of mediastinal nodal metastases but unfortunately their accuracy has been proved to be very low [53,54], since node smaller than 1 cm may harbor metastases and not have uptake; therefore false negative may result. On the other hand, enlarged nodes with uptake on 18F-FDG-PET/CT may be reactive or inflammatory and not contain metastatic tumor; in fact many MPM patients underwent pleurodesis, pleural biopsies, and chest tube placement, which may cause an inflammatory response with enlarged nodes, thus resulting in false positive cases [17]. Regarding M parameter, 18 F-FDG-PET/CT shows a high accuracy in identifying intrathoracic and extrathoracic metastatic disease. 18F-FDG-PET/CT at diagnosis is useful to predict the prognosis by measuring SUV, which showed an independent prognostic value, although there is no agreement on SUV max cutoff for predicting survival in prognostic studies [52,53].
MONITORING RECURRENCE There is no agreement on follow-up timing in patients with MPM who underwent multimodality treatment with a curative intent. Otherwise since the recurrence rate (local recurrence and distant metastases), is very high (70% 80%), mainly in the first year, close imaging follow-up is pivotal in detecting the relapse [55]. There is probably no role for chest radiography or MRI in follow-up whereas contrast-enhanced CT (CECT) or 18F-FDGPET/CT are generally requested by clinicians every 3 4 months. 18F-FDG-PET/CT, after radical pleurectomy, aids in differentiating recurrent tumor from granulation tissue, since irregular and nodular soft tissue along the resection margins can be seen in both cases; furthermore, serial 18F-FDG-PET/CT scans can differentiate tumor, which shows a progressive increase in 18F-FDG uptake, from granulation tissue, which shows stable or decreased 18 F-FDG avidity over time [23,34]. Niccoli-Asabella et al. analyzed 57 patients in follow-up after single or multimodal treatments for epithelioid MPM, who underwent 18F-FDG-PET/ CT and CECT. 18F-FDG-PET/CT was performed at least 60 days after surgery or 30 days from the last chemotherapy whereas CECT scan was performed within 30 days before 18 F-FDG-PET/CT. The clinical disease progression, at least 12 months long, was considered as the gold standard. CECT was considered positive for pleural recurrence in patients who have detection of a pleural thickening; positive for lymph node involvement when at least one lymph node with transverse diameter greater than 1 cm was reported; and positive for lung, chest wall, and skeletal involvement in cases in which at least one lesion was descripted in these sites. The PET/CT scans were analyzed visually and semiquantitatively; a SUV max of 2.0 was used for differentiating benign from malignant lesions. The authors found a moderate concordance between the two imaging techniques for detecting patients with recurrent MPM post single or multimodality treatments; both methodologies
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showed a high sensitivity but 18F-FDG-PET/CT was more specific. Despite this, technical CT parameters were different between the two techniques; moreover, no explicit mention is made as to lesion contrast uptake analysis for distinguishing benign from malignant findings [56].
ASSESSMENT OF RESPONSE TO TREATMENT MPM grows on the pleural surface by sheet-like extension leading to an irregular rindlike tumor encasing the lung [57]. Conventional size measurement criteria (WHO and the most recent RECIST), used on CT to determine reproducibly solid tumor response to treatment, evaluate bidimensional or unidimensional tumor diameters, assuming a spherical tumor growth pattern [58,59]. However this assumption cannot be applied in MPM because of the nonspherical growth pattern; moreover without a clear definition of the measurement method the selection of measurements sites could be applied differently by different investigators [60]. The major problems in applying the RECIST criteria to MPM are in the interpretation of the meaning and placement of the “longest unidimensional diameter” of the target tumor mass since the lesions follow the inner curve of the chest wall, making its measure difficult. For this reason the modified RECIST (mRECIST) criteria were developed in 2003 by M.J. Byrne. Tumor thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on transverse cuts of the CT scan. Transverse cuts at least 1 cm apart and related to anatomical landmarks were chosen to allow reproducible measurements on the following assessments. The sum of the six measurements defined a pleural unidimensional measure and all the other bidimensionally measurable lesions were measured unidimensionally according to standard RECIST criteria. Complete response, partial response, and progressive disease were defined on the basis of conventional RECIST criteria (CR 5 disappearance of all target lesions; PR 5 at least a 30% reduction; PD 5 an increase of at least 20%) considering total tumor measurement; however a confirmed response required a repeat observation on two occasions 4 weeks apart. The authors evaluated, by using these criteria, chemotherapy response in 73 patients with histologically or cytologically confirmed MPM and found a statistically significant difference in survival between responding and nonresponding patients. More recently, in 2016, Kanemura et al. [61] compared mRECIST criteria on CT and 18F-FDG-PET/CT to evaluate chemotherapy response in 82 histologically confirmed MPM patients who were treated with three cycles of cisplatin and pemetrexed or carboplatin and pemetrexed. Metabolic response was subdivided in complete metabolic response (CMR, complete disappearance of abnormal uptake), partial (PMR, $ 25% reduction in SUVmax), stable metabolic disease (SMD, # 24% increase or ,25% reduction in SUVmax) and progressive metabolic disease (PMD, $ 25% increase in SUVmax) and time to progression (TTP) and overall survival (OS) were compared between metabolic responders and nonresponders. The authors found 62 cases to have stable disease according to mRECIST criteria whereas, among them, 18F-FDG-PET/CT showed 2 cases of CMR, 18 cases of PMR, 24 cases of SMD, and 18 cases of PMD with a significantly shorter TTP in the PMD group, suggesting that a careful assessment of metabolic response may be beneficial for monitoring the treatment course. However it is important to remember that in
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patients treated with talc pleurodesis, response to chemotherapy evaluated through 18FFDG-PET/CT may be underestimated since this procedure usually determines pleural inflammation resulting in an increase in SUV [62], therefore in such cases mRECIST criteria seem to be more reliable.
DIFFERENTIAL DIAGNOSES AND SCREENING MPM is a rare malignant cancer arising from the pleura that typically affects individuals directly or indirectly exposed to asbestos, showing several CT features in common with metastatic pleural malignancies. Several studies investigated the possibility of CT to differentiate MPM from metastatic carcinomas of the pleura, primarily lung and breast cancers, considering the pathological analysis as the reference standard. Karam M et al. in 2014 conducted a retrospective study of 55 pleural malignancy (17 cases of MPM and 38 cases of metastatic carcinoma) and the most prevalent findings in the MPM group were pleural thickening (88.2%) followed by loculated effusion (58.8%) and thickening of the interlobar fissure (47.1%) whereas among the metastatic group, the most common findings were free pleural effusion (71.7%), mostly massive, followed by lung parenchyma infiltration (65.8%) and pleural thickening (63.2%) [63]. Ng et al. [64] in their study on 70 MPM patients reported that pleural thickening (94%) and pleural effusion (76%) were the most common pretreatment findings whereas Wang et al. [65] defined the presence of unilateral pleural effusion, nodular pleural thickening, and thickening of interlobar fissure the key findings of MPM. A study by Yilmaz et al. in 2005 [66] showed that the involvement of interlobar fissure (sensitivity 30% and specificity 92%) and pleural thickening greater than 1 cm (sensitivity 60%, specificity 77%) were the most common findings of MPM. Metintas and colleagues, who reviewed 99 MPM and 39 metastatic pleural malignancies, found that ring-like pleural involvement, mediastinal pleural involvement, and pleural thickness more than 1 cm were independent CT findings for differentiating between MPM and metastatic diseases with a sensitivity and specificity of 70% 85% and 59% 82%, respectively [67]. However, CT findings should not be dissociated from an accurate oncological anamnesis for trying to perform a differential diagnosis [68,69]. Moreover MPM has to be differentiated from benign asbestos pleural effusion (BAPE), a complication of chronic exposure to asbestos that may be asymptomatic or associated with pain, fever, and dyspnea. Kato et al. in 2016 [70] analyzed 36 and 66 patients with pathologically confirmed diagnosis of BAPE and MPM respectively, preceded by thorax CT scans. The authors found mediastinal pleural thickening significantly more prevalent in MPM patients than in BAPE whereas the presence of pleural effusion was not significantly different between the two groups. Interestingly they found that pleural plaques were more prevalent in the BAPE group than in the MPM group, undermining the diagnostic utility of pleural plaques for the MPM diagnosis. However, since just a few CT scans were performed after contrast media administration, no conclusion is possible about the eventual added value of pleural enhancement analysis for the differential diagnosis. Okten et al. [71] in another work reported that parietal pleural thickening greater than 1 cm was helpful in distinguishing BAPE from MPM although they also used criteria such as circumferential and nodular pleural thickening (Fig. 2.3).
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FIGURE 2.3 (A C). CT scan in a 77-year-old man with a history of asbestos exposure shows small calcified pleural plaques (arrowhead in a) and mild pleural effusion (arrows in A C) without any nodular pleural thickening. Video-assisted thoracic surgery (VATS) demonstrates chronic inflammation without any neoplastic proliferation.
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FIGURE 2.3 (Continued).
Regarding the possibility of a CT screening program for MPM, there is no consensus since benign pleural abnormalities and MPM may overlap in their presentation, therefore an imaging finding clearly indicative of an “early mesothelioma” can not be defined [72]. However, exposure to asbestos is a well-known risk factor for lung cancer [25]; in fact it has been demonstrated that for every one mesothelioma case there are two asbestosrelated lung cancer cases [73], therefore screening should be focused to lung cancer as primary point, using spiral CT for detection and perfusion CT for a definitive diagnosis; infact, in such case, an early diagnosis and treatment improve significantly the prognosis of patients [74 78].
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2 Multimodality Imaging Assessment of Malignant Pleural Mesothelioma M.A. Mazzei1, F. Gentili1, P. Tini1,2, L. Pirtoli2 and L. Volterrani1 1
Department of Medical, Surgical and Neuro Sciences, Unit of Diagnostic Imaging, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy 2Department of Medical, Surgical and Neuro Sciences, Unit of Radiation Oncology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
INTRODUCTION Malignant pleural mesothelioma (MPM) is a tumor arising from the mesothelial or submesothelial cells and it is the most common primary cancer that emerges in the pleura [1,2]. In more than 70% of the cases, a relationship with exposure to asbestos is detected and the disease generally occurs in the fifth and sixth decades of life with a higher incidence in men than in women (80% vs 20%) [3]. Other suggested etiological factors include exposure to other mineral fibers (e.g., zeolite or erionite), chronic inflammation and scarring (e.g., tuberculosis and empyemas), irradiation and intrapleural thorium dioxide, genetic factors, and the viral oncogene Simian virus SV40 (a contaminant in a high number of human vaccines) [4]. MPM is officially recognized as an occupational neoplasm and the latency between the first asbestos exposure and tumor development is 20 40 years; therefore worldwide, the incidence is increasing and it is expected to peak in the year 2020 [5]. In the United States, MPM occurs in approximately 2500 persons per year and almost 72,000 cases are expected to occur in the next 20 years [6]. In Italy, the asbestos epidemic continues and is even increasing because of the country’s industrial history. Up to the end of the 1980s Italy was the second largest asbestos producer in Europe after the Soviet Union and the largest in the European Community, with a peak between 1976 and 1980 [7]. Furthermore asbestos imports to Italy reached a peak when they were already falling in the United Kingdom and United States and the consumption curve of asbestos shows a
Malignant Pleural Mesothelioma DOI: https://doi.org/10.1016/B978-0-12-812724-7.00003-4
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lag time of about 10 years compared with many other industrialized countries [8]. The most tumorigenic asbestos fiber is thought to be crocidolite, with other subtypes including amosite and chrysotile (“blue,” “brown,” and “white” asbestos, respectively). The microscopic presence of “asbestos (ferruginous) bodies” in bronchoalveolar lavage is evidence of previous exposure to asbestos [4]. Frequently the disease is diagnosed in an advanced stage, since clinical manifestations are nonspecific, so the patient prognosis is poor with a median survival of 9 17 months [9]. Although the precise pathophysiological origin of the tumor is unknown, MPM initially involves the parietal pleura, forming gray-white pleural plaques, and subsequently involves the visceral pleura, spreading along pleural surfaces, including the interlobar fissures, encasing and compressing the lung. The disease is usually diffuse rather than focal, typically invasive, involving the diaphragm, chest wall, and pericardium. MPM more often affects the inferior hemithorax, probably under the force of gravity and the right side, probably because of its greater pleural surface. Nodal metastases are present in 40% 45% of cases at diagnosis time whereas hematogenous spread tends to occur in the advanced phases of the disease [4]. Recently the staging system of MPM has been updated in the 8th edition of American Joint Committee on Cancer, which substituted the 7th edition, given the known inaccuracies in pretreatment staging with current diagnostic techniques and considering overall survival (OS) in different stages; the major changes affect T and N parameters: the categories T1a (tumor limited to the parietal pleura) and T1b (tumor involving the visceral pleura) were collapsed into a single T1 category, whereas regarding N parameter, metastases in the ipsilateral bronchopulmonary or hilar lymph nodes (N1) and any ipsilateral intrathoracic lymph nodes (previously N2) were collapsed into a single category (N1) [10 16]. However, T3 and T4 categories, which describe locally advanced but potentially resectable tumors and technically unresectable tumors respectively, were unchanged [17]. On this basis, key goals of imaging in MPM are to make possible the early detection of the disease, optimizing accuracy for anatomic involvement of unresectable planes, improving prognostication, and assessing response to treatment [18]. In this chapter, the features of MPM in different diagnostic techniques are shown. Moreover the problem of recurrence monitoring, the assessment of response to treatment, and potential differential diagnoses of MPM are proposed. A brief reference to MPM screening is also discussed.
DIAGNOSIS Chest Radiography Chest radiography is generally the first imaging technique to depict abnormalities of MPM, because of its availability and widespread use. Unilateral pleural effusion is the most common finding of MPM (30% 80% of patients) together with diffuse pleural thickening (60%) and pleural masses (45% 60%) [19]. On occasion, the pleural thickening may be minor and, indeed, may be obscured by what appears to be a simple pleural effusion [4]. Tumor growth leads to nodular thickening of interlobar fissures and lung encasement with volume loss, elevation of ipsilateral hemidiaphragm, ipsilateral mediastinal shift, and
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narrowing of the intercostal spaces [20,21]. Clearly visible pleural plaques, often calcified, which are the commonest radiographic manifestation of asbestos exposure, coexist only in 20% of cases [22]. However it is difficult to make a definitive diagnosis based on plain radiographs, especially in the early stages, since imaging findings are not specific [23]. From a technical point of view, chest radiography should be performed in posteroanterior (PA) and laterolateral projection; sometimes addictional projection (e.g., Hessen projection) may be useful to highlight a small amount of pleural effusion in symptomatic patients with visible pleural plaques.
Chest Digital Tomosynthesis Digital tomosynthesis (DTS) is a type of limited angle tomography that allows reconstruction of multiple image planes from a set of projection data acquired over a limited range of an X-ray tube movement. The advantages of DTS, as compared with conventional radiography, include depth localization and improved conspicuity of structures achieved by removing the visual clutter associated with the overlying anatomy. Although DTS does not have the potential and high resolution of computed tomography (CT), it provides relatively high-resolution images in the coronal or sagittal planes, improving the visualization both of parenchymal and mediastinal alteration, with a lower dose than CT. In recent years some authors have reported the advantage of chest digital tomosynthesis in the detection of pleural plaques and asbestosis [24]; however this technique could be used also to improve the detection of the remaining asbestos-related pleuropulmonary disease, including the early detection of MPM.
Computed Tomography Computed tomography (CT) is the next imaging modality of choice in the suspicion of MPM and it is often sufficient for disease staging and treatment planning. CT is also useful in finding out pleural plaques (PPs) in patients who are unaware of their exposure to asbestos. Moreover the presence of PPs may help in considering asbestosis as a cause of MPM to offer a compensation to these patients [25]. A recent Japanese study even found that in lung cancer patients the plaque extent had a significant positive relationship with the asbestos body concentration in lung tissue that represents a biomarker of past exposure [26]. From a diagnostic point of view, in most screenings for pneumoconiosis, a chest radiograph is used as the standard method, but this procedure has important limitations in the detection of early subtle PPs, whereas a CT scan enables diagnosis of thin or tiny noncalcified plaques [27]. Experienced CT readers can diagnose PPs with high confidence in most cases, which show the typical findings of bilateral, multiple, localized, pleural thickenings sparing the costophrenic angles. However, the CT features of PPs are sometimes equivocal in challenging cases and if the radiologists are not skilled in occupational diseases pleural plaques could be underreported [25,28,29]. CT allows an accurate delineation of the pleural disease and differentiation of pleural thickening from pleural fluid; in particular a pleural thickening that is nodular, circumferential, and greater than 1 cm in thickness is highly suggestive of malignant pleural disease,
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including MPM [30]. In cases of MPM with osteocartilaginous differentiation, ossification or calcification may be seen in regions of pleural thickening or pleural masses [31]. An accurate staging is pivotal for treatment decision making, distinguishing patients with early stages (T1, T2) or potentially resectable tumors (T3) from cases with technically unresectable tumors (T4); tumors with diffuse extension or multifocal masses in the chest wall, direct transdiaphragmatic extension to peritoneum, direct extension to the contralateral pleura, mediastinal organs, spine, and transmural invasion of the pericardium are considered unresectable [32] (Fig. 2.1). Regarding the mediastinal involvement, an encasement of more than 50% of the circumference of the esophagus or trachea with an obliteration of fat planes is strongly indicative of their invasion [33]. Involvement of the pericardium may result in pericardial effusion, thickening, nodules, and masses; despite the difficulty in distinguishing nontransmural from transmural pericardial involvement, the persistence of epicardial fat suggests nontransmural involvement [20]. Extension of the tumor into the chest wall may result in obliteration of extrapleural fat planes, invasion of intercostal muscles, and rib displacement or destruction [22]. Moreover in determining transdiaphragmatic tumor extension, the presence of clear fat plane between the inferior surface of the diaphragm and the adjacent abdominal organs is the best finding to confirm
FIGURE 2.1 (A, B) Coronal (A) and sagittal (B) CT images reconstruction in a patient with mesothelioma. Chest CT should be extended to diaphragmatic pillars (arrows in A and B).
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that MPM is confined to the chest [20]. Although the CT accuracy in predicting MPM resectability is considered limited in the literature (sensitivity, specificity, and accuracy respectively about 90%, 50%, and 70%), CT scans in these studies were obtained at 7 10 mm of slice thickness, most of them without contrast agent administration and all of this is not acceptable [4]. Technical CT parameters are fundamental for reaching the correct diagnosis and staging the disease. A thin slice thickness (1.25 mm) and a reconstruction interval at least half of the effective slice thickness improves spatial resolution and allows high quality multiplanar reformations whereas reference mAs and kVp should be adjusted on the basis of patient size obtain to optimal signal to noise ratio. Moreover the contrast agent administration is mandatory with a scan delay of about 50 seconds (late arterial phase) from the start of the injection with a later phase (delay 4 5 minutes) to optimize tumor uptake. Therefore further studies to evaluate CT accuracy for T parameter assessment are necessary by employing this technique at the state of the art. Contrast-enhanced CT scan should be performed from the upper abdomen to the thoracic inlet to accurately evaluate the entire diaphragm and completed by a CT scan of the abdomen and brain to complete the staging of the disease (Fig. 2.2). Furthermore a high resolution CT scan of the lung, before contrast media administration, is strongly recommended to diagnose asbestosis or to better characterize possible lung nodules. Tumor volume has been reported to be a valuable prognostic factor for survival in patients with MPM [21,22,34,35] and, from this prospective, Optiz and colleagues enlisted 28 patients for assessing the possibility of preoperative CT-based tumor volume in predicting the weight of tumor resected after complete surgical resection. The analysis revealed a
FIGURE 2.2 (A, B) Contrast-enhanced CT in a 72-year-old man with diagnosis of biphasic malignant mesothelioma shows the neoplastic infiltration of the mediastinal fat (arrows in A) and the nontransmural involvement of the pericardium (arrow in B), defining a clinical T3 tumor (potentially resectable).
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moderate correlation between CT-based tumor volume and tumor weight whereas no significant correlation was observed between clinical T stage and tumor weight [35]. At the same time some publications [36 38] suggested that pleural tumor thickness may provide more accurate T categorization than the current anatomic descriptors; in particular a breakpoint of 5 mm of maximal pleural thickness or 13 mm for the sum of pleural thickness measured at the upper, mid, and lower regions was found to be prognostic. A greater pleural thickness also correlates with the presence of nodal metastases. Therefore further studies are necessary to determine whether measurements of pleural thickness should replace the current descriptors of T categories. CT constitutes the primary technique for detecting intrathoracic nodal involvement. The regional lymph node map and nomenclature for MPM are adapted from those used for lung cancer [39]. Mediastinal lymph nodes, specifically paratracheal, hilar, subcarinal, paraesophageal, and paraaortic, that are 10 mm or larger in short diameter, are considered abnormal. In addition, MPM often metastasizes to lymph nodes not involved by lung cancer, including the internal mammary, peridiaphragmatic, and intercostal lymph node, which have no specific size criteria and their visualization is considered abnormal. CT is also fundamental for detecting metastases; biphasic and sarcomatoid subtypes of MPM display a more aggressive behavior compared with the epithelial subtype and may present with distant metastases at diagnosis [23]. The most common sites of metastatic are distant lymph nodes, intraabdominal disease, and controlateral lung [10,11]. Pulmonary metastases may manifest as nodules, masses, or lymphangitic carcinomatosis, with thickening and nodularity of the interlobar septa.
Magnetic Resonance Magnetic resonance (MR) is not generally employed to evaluate MPM because of long imaging time, cost reasons, and limited availability. Although modern cross-sectional imaging provides higher spatial resolution, limitations in tissue contrast remain a challenge for staging of MPM. This limitation is a challenge on CT where separating mesothelioma, diaphragm, chest wall, and pericardium from one another is a difficult task due to their partial overlapping in Hounsfield units (HU) distributions and close spatial proximity to one another [18,40]. Since MR has superior tissue contrast, it is sometimes employed to further characterize mesothelioma cases suspicious for local invasion, even if subtle local invasion can still be a challenge to detect at imaging [18]. In the literature there are only a few works that compared MR and TC accuracy to predict resectability in patients with biopsy-proven MPM and they go back to the 1990s and 2000s. Patz and colleagues [33] compared MR with CT in 34 patients undergoing thoracotomy and they found a slightly higher sensitivity of MR than CT for predicting resectability at the diaphragm and chest wall (100% vs 94%); however it should be noted that CT scans were acquired with a slice thickness of 10 mm in axial mode so multiplanar reformations were not possible. Heelan and colleagues [41] compared the accuracy of MR and CT for staging 65 MPM patients and they found MR more accurate for detecting endothoracic fascia involvement, solitary foci of chest wall invasion, and for assessing diaphragmatic invasion, even if these findings did not change the surgical management. To determine the optimal tumor
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enhancement after intravenous contrast agent injection, Katz conducted a study in patients undergoing MR for preoperative staging purpose; since they performed multiple acquisitions after contrast agent injection, a time enhancement curve could be constructed and the best peak tumor enhancement was estimated to occur at a delayed phase (about 280 seconds); however further studies are necessary to determine the impact of delayed phase enhancement on radiologic MPM staging accuracy [18]. Diffusion weighted MRI (DWI), based on the diffusivity of water molecules within the tissues, has the potential to reveal tissue characteristics; through this technique, signal loss can be quantitatively assessed with the apparent diffusion coefficient (ADC), which depends on restriction of water molecule diffusion by membranes and macromolecules [42]. Since this technique has been widely investigated in the evaluation of numerous solid tumors, Gill et al., in 2010, evaluated its role for distinguishing MPM histological subtypes. They analyzed 57 MPM cases and found that the ADC of the epithelioid subtype was statistically significantly higher than the ADC values of the biphasic and sarcomatoid subtypes [42]. In fact, sarcomatoid MPM is composed of spindle-shaped cells with high cellularity whereas epithelioid MPM is composed of tubular and cuboidal cells; moreover sarcomatoid MPM often shows a storiform pattern, which can further restrict water diffusion. The ADC values of biphasic MPM have a wide range of overlap with the ADC values of other subtypes since it consists of a mixture of both epithelial and sarcomatoid cells. Although the histologic subtype of MPM is usually determined by video-assisted thoracoscopy, with a diagnostic accuracy higher than 95%, the procedure is invasive and may lead to seeding of tumors along the surgical incision or chest tube track in as many as 20% of patients [4]. Therefore DWI is a promising, noninvasive technique, which has great potential in the noninvasive diagnosis of MPM subtypes [42]. MR can also be used to assess uncommon post-operative complication, such as chylothorax, by using MR lymphangiography protocol; in this exam the contrast media injected into the inguinal nodes and drained by lymphatic system allows to localize precisely the leakage site of lymphatic channels [43 46].
PET and PET/CT Functional imaging with 18F-FDG-PET allows the noninvasive investigation of tumor metabolism and extent and it is complementary to conventional imaging modalities in the diagnosis and preoperative staging of MPM. FDG uptake in MPM can range from moderate to high, depending on histologic subtype; generally epithelial subtype tumors tend to be less metabolically active than the mixed and sarcomatoid subtypes [22,41]. The main disadvantage of 18F-FDG-PET imaging is the limited spatial resolution and lack of anatomical landmarks; therefore hybrid 18F-FDG-PET/CT systems have been introduced and their use has been rapidly incorporated in daily clinical practice [47]. Many studies have demonstrated the clinical utility of 18F-FDG-PET and 18F-FDG-PET/CT, using a visual analysis or semiquantitative measurements (maximum standardized uptake value [SUV max]) for diagnosing MPM with a sensitivity of 60% 100% and a specificity of 78% 100% [48 50]. Otherwise these techniques have poor sensitivity for small cancers because of the lack of the tumor uptake and limited spatial resolution of current 18F-FDG-PET/CT scanners,
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which is around 5 mm [51]. Moreover they have been proved to be inadequate for defining locoregional tumor extent. In this regard Pinelli et al. in 2014 evaluated 32 patients with histologically confirmed MPM after medical thoracoscopy who underwent 18F-FDGPET/CT scan before diagnosis; they assessed whether the metabolic activities of pleural tumors detected with 18F-FDG-PET/CT correlated with findings assessed by thoracoscopy and demonstrated only a fair agreement between the two techniques in determining visceral and diaphragmatic pleural involvement [52]. 18F-FDG-PET and 18F-FDG-PET/CT have been studied in the detection of mediastinal nodal metastases but unfortunately their accuracy has been proved to be very low [53,54], since node smaller than 1 cm may harbor metastases and not have uptake; therefore false negative may result. On the other hand, enlarged nodes with uptake on 18F-FDG-PET/CT may be reactive or inflammatory and not contain metastatic tumor; in fact many MPM patients underwent pleurodesis, pleural biopsies, and chest tube placement, which may cause an inflammatory response with enlarged nodes, thus resulting in false positive cases [17]. Regarding M parameter, 18 F-FDG-PET/CT shows a high accuracy in identifying intrathoracic and extrathoracic metastatic disease. 18F-FDG-PET/CT at diagnosis is useful to predict the prognosis by measuring SUV, which showed an independent prognostic value, although there is no agreement on SUV max cutoff for predicting survival in prognostic studies [52,53].
MONITORING RECURRENCE There is no agreement on follow-up timing in patients with MPM who underwent multimodality treatment with a curative intent. Otherwise since the recurrence rate (local recurrence and distant metastases), is very high (70% 80%), mainly in the first year, close imaging follow-up is pivotal in detecting the relapse [55]. There is probably no role for chest radiography or MRI in follow-up whereas contrast-enhanced CT (CECT) or 18F-FDGPET/CT are generally requested by clinicians every 3 4 months. 18F-FDG-PET/CT, after radical pleurectomy, aids in differentiating recurrent tumor from granulation tissue, since irregular and nodular soft tissue along the resection margins can be seen in both cases; furthermore, serial 18F-FDG-PET/CT scans can differentiate tumor, which shows a progressive increase in 18F-FDG uptake, from granulation tissue, which shows stable or decreased 18 F-FDG avidity over time [23,34]. Niccoli-Asabella et al. analyzed 57 patients in follow-up after single or multimodal treatments for epithelioid MPM, who underwent 18F-FDG-PET/ CT and CECT. 18F-FDG-PET/CT was performed at least 60 days after surgery or 30 days from the last chemotherapy whereas CECT scan was performed within 30 days before 18 F-FDG-PET/CT. The clinical disease progression, at least 12 months long, was considered as the gold standard. CECT was considered positive for pleural recurrence in patients who have detection of a pleural thickening; positive for lymph node involvement when at least one lymph node with transverse diameter greater than 1 cm was reported; and positive for lung, chest wall, and skeletal involvement in cases in which at least one lesion was descripted in these sites. The PET/CT scans were analyzed visually and semiquantitatively; a SUV max of 2.0 was used for differentiating benign from malignant lesions. The authors found a moderate concordance between the two imaging techniques for detecting patients with recurrent MPM post single or multimodality treatments; both methodologies
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showed a high sensitivity but 18F-FDG-PET/CT was more specific. Despite this, technical CT parameters were different between the two techniques; moreover, no explicit mention is made as to lesion contrast uptake analysis for distinguishing benign from malignant findings [56].
ASSESSMENT OF RESPONSE TO TREATMENT MPM grows on the pleural surface by sheet-like extension leading to an irregular rindlike tumor encasing the lung [57]. Conventional size measurement criteria (WHO and the most recent RECIST), used on CT to determine reproducibly solid tumor response to treatment, evaluate bidimensional or unidimensional tumor diameters, assuming a spherical tumor growth pattern [58,59]. However this assumption cannot be applied in MPM because of the nonspherical growth pattern; moreover without a clear definition of the measurement method the selection of measurements sites could be applied differently by different investigators [60]. The major problems in applying the RECIST criteria to MPM are in the interpretation of the meaning and placement of the “longest unidimensional diameter” of the target tumor mass since the lesions follow the inner curve of the chest wall, making its measure difficult. For this reason the modified RECIST (mRECIST) criteria were developed in 2003 by M.J. Byrne. Tumor thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on transverse cuts of the CT scan. Transverse cuts at least 1 cm apart and related to anatomical landmarks were chosen to allow reproducible measurements on the following assessments. The sum of the six measurements defined a pleural unidimensional measure and all the other bidimensionally measurable lesions were measured unidimensionally according to standard RECIST criteria. Complete response, partial response, and progressive disease were defined on the basis of conventional RECIST criteria (CR 5 disappearance of all target lesions; PR 5 at least a 30% reduction; PD 5 an increase of at least 20%) considering total tumor measurement; however a confirmed response required a repeat observation on two occasions 4 weeks apart. The authors evaluated, by using these criteria, chemotherapy response in 73 patients with histologically or cytologically confirmed MPM and found a statistically significant difference in survival between responding and nonresponding patients. More recently, in 2016, Kanemura et al. [61] compared mRECIST criteria on CT and 18F-FDG-PET/CT to evaluate chemotherapy response in 82 histologically confirmed MPM patients who were treated with three cycles of cisplatin and pemetrexed or carboplatin and pemetrexed. Metabolic response was subdivided in complete metabolic response (CMR, complete disappearance of abnormal uptake), partial (PMR, $ 25% reduction in SUVmax), stable metabolic disease (SMD, # 24% increase or ,25% reduction in SUVmax) and progressive metabolic disease (PMD, $ 25% increase in SUVmax) and time to progression (TTP) and overall survival (OS) were compared between metabolic responders and nonresponders. The authors found 62 cases to have stable disease according to mRECIST criteria whereas, among them, 18F-FDG-PET/CT showed 2 cases of CMR, 18 cases of PMR, 24 cases of SMD, and 18 cases of PMD with a significantly shorter TTP in the PMD group, suggesting that a careful assessment of metabolic response may be beneficial for monitoring the treatment course. However it is important to remember that in
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patients treated with talc pleurodesis, response to chemotherapy evaluated through 18FFDG-PET/CT may be underestimated since this procedure usually determines pleural inflammation resulting in an increase in SUV [62], therefore in such cases mRECIST criteria seem to be more reliable.
DIFFERENTIAL DIAGNOSES AND SCREENING MPM is a rare malignant cancer arising from the pleura that typically affects individuals directly or indirectly exposed to asbestos, showing several CT features in common with metastatic pleural malignancies. Several studies investigated the possibility of CT to differentiate MPM from metastatic carcinomas of the pleura, primarily lung and breast cancers, considering the pathological analysis as the reference standard. Karam M et al. in 2014 conducted a retrospective study of 55 pleural malignancy (17 cases of MPM and 38 cases of metastatic carcinoma) and the most prevalent findings in the MPM group were pleural thickening (88.2%) followed by loculated effusion (58.8%) and thickening of the interlobar fissure (47.1%) whereas among the metastatic group, the most common findings were free pleural effusion (71.7%), mostly massive, followed by lung parenchyma infiltration (65.8%) and pleural thickening (63.2%) [63]. Ng et al. [64] in their study on 70 MPM patients reported that pleural thickening (94%) and pleural effusion (76%) were the most common pretreatment findings whereas Wang et al. [65] defined the presence of unilateral pleural effusion, nodular pleural thickening, and thickening of interlobar fissure the key findings of MPM. A study by Yilmaz et al. in 2005 [66] showed that the involvement of interlobar fissure (sensitivity 30% and specificity 92%) and pleural thickening greater than 1 cm (sensitivity 60%, specificity 77%) were the most common findings of MPM. Metintas and colleagues, who reviewed 99 MPM and 39 metastatic pleural malignancies, found that ring-like pleural involvement, mediastinal pleural involvement, and pleural thickness more than 1 cm were independent CT findings for differentiating between MPM and metastatic diseases with a sensitivity and specificity of 70% 85% and 59% 82%, respectively [67]. However, CT findings should not be dissociated from an accurate oncological anamnesis for trying to perform a differential diagnosis [68,69]. Moreover MPM has to be differentiated from benign asbestos pleural effusion (BAPE), a complication of chronic exposure to asbestos that may be asymptomatic or associated with pain, fever, and dyspnea. Kato et al. in 2016 [70] analyzed 36 and 66 patients with pathologically confirmed diagnosis of BAPE and MPM respectively, preceded by thorax CT scans. The authors found mediastinal pleural thickening significantly more prevalent in MPM patients than in BAPE whereas the presence of pleural effusion was not significantly different between the two groups. Interestingly they found that pleural plaques were more prevalent in the BAPE group than in the MPM group, undermining the diagnostic utility of pleural plaques for the MPM diagnosis. However, since just a few CT scans were performed after contrast media administration, no conclusion is possible about the eventual added value of pleural enhancement analysis for the differential diagnosis. Okten et al. [71] in another work reported that parietal pleural thickening greater than 1 cm was helpful in distinguishing BAPE from MPM although they also used criteria such as circumferential and nodular pleural thickening (Fig. 2.3).
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FIGURE 2.3 (A C). CT scan in a 77-year-old man with a history of asbestos exposure shows small calcified pleural plaques (arrowhead in a) and mild pleural effusion (arrows in A C) without any nodular pleural thickening. Video-assisted thoracic surgery (VATS) demonstrates chronic inflammation without any neoplastic proliferation.
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FIGURE 2.3 (Continued).
Regarding the possibility of a CT screening program for MPM, there is no consensus since benign pleural abnormalities and MPM may overlap in their presentation, therefore an imaging finding clearly indicative of an “early mesothelioma” can not be defined [72]. However, exposure to asbestos is a well-known risk factor for lung cancer [25]; in fact it has been demonstrated that for every one mesothelioma case there are two asbestosrelated lung cancer cases [73], therefore screening should be focused to lung cancer as primary point, using spiral CT for detection and perfusion CT for a definitive diagnosis; infact, in such case, an early diagnosis and treatment improve significantly the prognosis of patients [74 78].
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