Diagnostic Imaging and workup of Malignant Pleural Mesothelioma.

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1 Diagnostic Imaging and workup of Malignant Pleural Mesothelioma. A pictorial essay Luciano Cardinale, Francesco Ardissone*, Dario Gned, Nicola Sverzellati**, Edoardo Piacibello, Andrea Veltri Department of Radiology, S. Luigi Hospital, University of Turin, Turin, Italy *Department of Thoracic Surgery, S. Luigi Hospital, University of Turin, Turin, Italy ** Department of Clinical Sciences, Section of Radiology, University of Parma, Parma, Italy Abstract. Malignant pleural mesothelioma is the most frequent primary neoplasm of the pleura and its incidence is still increasing. This tumor has a strong association with exposure to occupational or environmental asbestos, often after a long latent period of years. Plain chest radiography (CXR) is usually the first-line radiologic examination, but the radiographic findings are nonspecific due to its limited contrast resolution and they need to be complemented by other imaging modalities such as computed tomography (CT), magnetic resonance (MR), Positron emission tomography computed tomography (PET-CT) and ultrasound (US).The aim of this paper is to describe the radiological features of this malignancy, underlining the peculiarity of each of the radiological examination: Chest X-Ray, CT-scan, MRI, FDG-PET and ultrasound focusing on technical, diagnostic workup, based on the literature evidence and according to our experience. Introduction Malignant pleural mesothelioma (MPM) is the most frequent primary neoplasm of the pleura. Its incidence has been increasing as a result of the growing occupational and environmental exposure to asbestos fibres. As the latency period between asbestos exposure and disease onset is at least 20 years, the highest incidence is seen in the sixth through eighth decade of life, and as most cases develop as a result of occupational exposure, men are more frequently affected than women, being the rates 15 and 3 cases per million, respectively [1, 2]. Although lesions originate in the parietal pleura, it usually spreads into the visceral one very quickly and tend to coalesce, forming a sheet-like rind encasing the entire lung. The posterior and inferior portions of the hemithoraces are most frequently involved, probably owing to gravitational factors, leading to hypomobility and retraction of the basal regions with effects on respiratory function [3]. In the advanced stage, malignant pleural mesothelioma spreads primarily by local extension throughout the pleural cavity, with subsequent invasion of the chest wall, mediastinum, diaphragm and into the peritoneal cavity or retroperitoneum [4]. 1

2 Lymph node involvement are relatively common, while are infrequent distant metastases during the early stages of the disease [5]. The diagnosis of this neoplasm is often made at a late stage and the prognosis is still very poor with a median survival from diagnosis of under a year with supportive care alone. Make efforts to achieve early diagnosis and to obtain an accurate selection of patients that may benefit from the radical surgery is mandatory. This pictorial review is divided into two parts; in the first one we illustrate and describe the spectrum of imaging features of MPM at Chest Radiography (CXR), Computed Tomography (CT), Magnetic Resonance (MR), Positron Emission Tomography Computed Tomography (PET-CT) and Ultrasonography (US), in the second one we propose a diagnostic pathway according to our experience. Imaging Chest X-Ray is usually the first-line radiologic examination, but the radiographic findings are nonspecific due to its intrinsic limitation and need to be complemented by others imaging modalities such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography Computed Tomography (PET-CT) and Ultrasound (US). Computed tomography (CT) is the mainstay imaging technique for primary assessment of pleural disease after CRX and affords improved sensitivity for identification of malignant pleural process. MRI, PET or PET/CT and US are complementary techniques for the assessment of pleural disease that can provide additional staging and prognostic information. Plain chest radiography (CXR) CXR due to its widespread use, is often the first modality to depict imaging abnormalities suggesting MPM. The initial chest radiographic appearances of MPM may range from normal, in early disease, to a complete lung opacity, depending on the amount of pleural effusion [6]. Unexplained unilateral pleural effusion is the most common form of presentation at CXR. However, the effusion may be also accompanied by ancillary signs like focal or diffuse pleural thickening with slight mediastinal retraction due to pleural mediastinal structures freezing caused by restrictive action of the pleural tumor peel (Fig 1). Mesothelioma can also present at CXR as a discrete, well-circumscribed mass without effusion in less than 25% of patients on their initial chest radiograph (Fig 2).[7] Plaques related to asbestos exposure may be present in 20% of cases (Fig 3) [7] Computed tomography (CT) 2

3 Computed tomography (CT) has been the mainstay in the clinical evaluation of MPM (disease staging and clinical evaluation). Key CT findings that suggest the diagnosis include unilateral pleural effusion, nodular pleural thickening, and interlobar fissure thickening. The growth pattern is characterized by involvement of the entire pleura and interlobar space, which leads to tumoral encasement of the lung with a rindlike appearance (Fig 4) [8] Several studies have described the CT features of MPM; one of the largest series included 229 patients with pleural thickening (n = 197, 90%) classified as diffuse (n = 138, 63%) (Fig.5), nodular (n = 49, 22%) (Fig.6) and mass-type (n = 16, 7%) (Fig.7), pleural effusion was found in 173 patients (79%), involvement of the interlobar fissures in 159 (73%) (Fig.8), mediastinal pleural involvement in 170 (78%) and mediastinal lymphadenopathy in 54 (25%). [9] Concerning the differential diagnosis with benign diffuse pleural disease, the neoplastic nature of the thickening may therefore be hypothesized in the presence of circumferential involvement (95-100% specificity), nodularity (94% specificity), thickness >10 mm (94% specificity) and involvement of the mediastinal border (88% specificity) [10,11]. However, in these studies the sensitivity of these signs altogether is low, ranging from 30% to 60% [11, 12]. Recently Hallifax et al. [13] examined 370 patients with suspected malignant pleural disease to assess the sensitivity and specificity of CT in detecting pleural malignancy (primary and metastatic) prior to definitive histology obtained via thoracoscopy CT scans were reported as malignant in 144, giving a sensitivity of 68% (95% CI 62% to 75%). Of the 159 patients with benign disease, 124 had CT scans reported as benign: specificity 78% (72% to 84%). The positive predictive value of a malignant CT report was 80% (75% to 86%), with a negative predictive value of 65% (58% to 72%). Magnetic resonance (MR) MR imaging, although not routinely used to evaluate MPM, with its excellent contrast resolution, may be superior to CT in distinguishing benign from malignant lesions (sensitivity 100% and specificity 93%) [14-16]. The combination of morphological data and information on signal intensity has been found to increase significantly the sensitivity and specificity of MR imaging [17]. Pleural mesothelioma is characterized, compared with adjacent chest wall musculature, by intermediate or slightly hyperintense signal on T1-weighted sequences (Fig.9A,Fig.9B) compared to the surrounding healthy tissue and by a more intense signal on T2-weighted sequences (Fig. 10).[18] The signal of pleural mesothelioma may be further enhanced by using gadolinium-based paramagnetic contrast material. Contrast-enhanced T2-weighted fat suppressed sequences (Fig.11) are the most sensitive sequences for detecting enhancement of the interlobar fissures and for the detection of tumor invasion of adjacent structures [14]. Furthermore, diffusion-weighted MRI (DWI) can reveal tissue characteristics based on the diffusivity of water molecules within the tissues. With this technique, signal loss can be quantitatively assessed with the apparent diffusion coefficient (ADC), which depends on restriction of water molecule diffusion by cell membranes and macromolecules, indirectly providing information about tissue cellularity. This tool can be useful for differentiating malignant pleural disease (and eventually distinguish sarcomatoid from epithelioid subtype,because ADC of the 3

4 epithelioid subtype of MPM is higher than that of the sarcomatoid subtype) (Fig.12) from benign lesions.[18] Heelan and colleagues [14] found MR imaging superior to CT in revealing invasion of the diaphragm (55% accuracy for CT versus 82% for MR imaging) and in showing endothoracic fascia or solitary resectable foci of chest wall invasion (46% accuracy for CT versus 69% for MR imaging). Even though no comparative studies of the last generation technology scan CT and MR imaging haven t been published, the use of high quality CT multiplanar reformations have decreased the gap with MR imaging, particularly for assessing the diaphragm and chest wall involvement. MR imaging anyway is indicated for equivocal lesions that need to be evaluated by higher contrast resolution. Positron-emission tomography (PET-CT) Functional imaging can provide important information about metabolism and proliferation of the tumours: in particular 18 F-Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) and PET/CT emerged as important methods for the diagnosis and in particular for staging of MPM. Classical PET/CT findings in malignant pleural mesothelioma are commonly a unilateral circumferential or near-circumferential pleural and fissural thickening that shows 18 F-FDG avidity and SUV value (standardized uptake value) greater than [20] MPM may start as one or two pleural nodules that later grow in size or number. PET-CT scanning is very useful for limited subtle pleural thickening (with or without pleural effusion) (Fig 13). PET-CT may be also useful to guide choice of biopsy site, because the sites of greatest FDG uptake can be identified and targeted for tissue sampling (Fig.14). Qualitative assessment with FDG PET was shown to correctly identify malignancy with sensitivity of 95-97% and specificity of 78 92% [21][22] [23]. Bénard et al. [21] showed that an FDG PET SUVmax cutoff value of 2.0 differentiated benign from malignant disease with sensitivity of 91% and specificity of 100%. In another study of 83 patients, with integrated PET/CT showed 100% sensitivity, 94.8% specificity, and 97.5% accuracy in identifying malignant disease, which was confirmed by histopathologic examination [24]. A meta-analysis about the diagnostic accuracy of 18 F-FDG PET and PET/CT in the differential diagnosis between malignant and benign pleural lesions [25] found a sensitivity 95% (95% confidence interval [95%CI]: 92 97%), specificity 82% (95%CI: 76 88%), LR+ 5.3 (95%CI: ), LR 0.09 (95%CI: ), DOR 74 (95%CI: ). They concludes that the method is an accurate diagnostic imaging methods in the differential diagnosis between malignant and benign pleural lesions; nevertheless, possible sources of false-negative and false-positive results should be kept in mind. False positive results may be seen in cases of parapneumonic effusion and both tuberculous and uraemic pleural disease. Some cases of malignant mesothelioma are low-grade tumours and may not be avid on 18 F-Fluorodeoxyglucose [26-28]. Ultrasonography (US) 4

5 Ultrasonography is an excellent modality for detecting fluid collections in the pleural space [29], however, it is less sensitive for the detection and characterization of pleural thickening than CT, RM and PET-CT, which are the best imaging options [30]. A small study has shown ultrasonography to have 73% specificity and 100% sensitivity for pleural malignancy when pleural nodules or thickening are seen with pleural fluid [31]. Pleural thickening most often appears hypoechoic, but increased echogenicity with focal acustic shadowing in presence of calcification and chronicity [32-36]. Complex patterns of pleural effusion with fibrinous stranding and septations are better visualized by ultrasonography than CT (Fig. 15). The real-time monitoring have made the use of US guidance more widespread to obtain biopsies of the chest wall and pleural lesions. US may occasionally provide additional staging information when diaphragm involvement is suspected [14,18,19]. Diagnostic pathway: our experience Based on our experience and our facilities, we adopted a diagnostic pathway as much as rational and cost-effective as possible in a high-risk area. The chest X-ray (CXR) remains the first imaging modality for the approach to patients for whom malignant pleural mesothelioma (MPM) is suspected. The CXR finding of the pleural plaques, according to our opinion, does not require additional investigations, whereas recurrent unilateral pleural effusion not related to any known etiology such as infection or congestive heart failure should be further investigated by CT with contrast medium. Technical CT factors are very important for reaching the correct diagnosis. The last generation CT technology (> 32 detector rows) allows thin-section volumetric acquisitions providing an isotropic data set, which can be reconstructed in any plane. As a result, these multiplanar reformations allow to easily evaluating the presence of very limited pleural thickening. Employment of a contrast medium is mandatory, the CT scanning delay should be also set at 80 seconds to optimize the maximum pleural tumor uptake (Fig. 16) and the field-of- view (FOV) due to the tumor growth through the diaphragmatic pillars had to cover a wide area from the lung apex to the to L3. According to the MDCT findings, the subsequent diagnostic workup may be summarized as follows: 1. In patients presenting with dyspnea due to a pleural effusion, if the clinician has any suspicion that a malignancy a US guide thoracentesis should be performed as the initial diagnostic procedure. 2. Presence of gross irregular pleural masses (with or without pleural effusion) should be further investigated by US or CT guided-biopsy, given for granted that CT remains the primary imaging modality used to evaluate MPM. 3. A limited irregular pleural thickening (with or without pleural effusion) may be evaluated by PET-CT scanning. 4. Recurrent pleural effusion without any visible abnormality at CT scan should be directly investigated by thoracoscopy. 5

6 MRI may be used instead of CT scanning when there are contraindications to iodinated contrast medium. Conclusion Imaging of MPM is a challenge because the pleural surface has a complex shape, asymmetric growth and tendency to infiltrate locally along tissue planes. Each imaging modality has its advantages and limitations, but their rational and cost-effective combined use is crucial in determining the most appropriate treatment options for patients with MPM. References 1. Pisani RJ, TV Colby, D.E. Williams (1988) Malignant mesothelioma of the pleura. Mayo Clin Proc. 63(12): p Rusch VW (2009) Diffuse malignant mesothelioma. In: Shields TW, LoCicero J III, Reed CE, Feins RH (eds) General thoracic surgery. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, pp Ferragalli B, Bonomo L (2003) Malignant Pleural Diseases. Radiol Med. (105): p Brenner J, Sordillo PP, Magill GB, Golbey RB (1982). Malignant mesothelioma of the pleura: review of 123 patients. Cancer 49: Flores RM (2008) The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg,136(3): p Cardinale L (2013) Diffuse neoplasms of the pleural serosa. Radiol Med. 118(3): p Crotty TB, Myers JL, Katzenstein AL (1994) Localized malig- nant mesothelioma. A clinicopathologica and flow cytomet- ric study. Am J Surg Pathol;18:357e Pass HI, Pogrebniak HW (1993) Malignant pleural meso- thelioma. Curr Probl Surg,30: Omer Tamer Dogan, Ismail Salk, Fikret Tas, Kursat Epozturk, Cesur Gumus (2012) Thoracic CT in Malignant Mesothelioma. Iran J Radiol;9(4) 10. Maffessanti M, Tommasi M, Pellegrini P (1987) Computed tomography of free pleural effusions. Eur J Radiol. 7(2): p Leung AN, Muller NL, Miller RR (1990) CT in differential diagnosis of diffuse pleural disease. Am J Roentgenol. 154(3): p Metintas M (2002) Computed tomography features in malignant pleural mesothelioma and other commonly seen pleural diseases. Eur J Radiol. 41(1): p Hallifax RJ, Haris M, Corcoran JP, Leyakathalikhan S, Brown E (2014) Role of CT in assessing pleural malignancy prior to thoracoscopy. Thorax;0:1 2. doi: /thoraxjnl Heelan RT (1999) Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. AJR Am J Roentgenol. 172(4): p Gill RR (2009) Current trends in radiologic management of malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 21(2): p Knuuttila A (2001) Evaluation of pleural disease using MR and CT. With special reference to malignant pleural mesothelioma. Acta Radiol. 42(5): p Patz EF Jr (1992) Malignant pleural mesothelioma: value of CT and MR imaging in predicting resectability. AJR Am J Roentgenol. 159(5): p Gill RR, Umeoka S (2010) Diffusion-weighted MRI of malignant pleural mesothelioma: preliminary assessment of apparent diffusion coefficient in histologic subtypes. AJR Am J Roentgenol. 195(2):W doi: /AJR

7 19. Zucali PA, Giaccone G (2006) Biology and management of malignant pleural mesothelioma. Eur J Cancer. 42(16): Yildirim H, Metintas M, Entok E (2009) Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestosrelated benign pleural disease: an observational pilot study. J Thorac Oncol; 4: Bénard F, Sterman D, Smith RJ, Kaiser LR, Albelda SM, Alavi A (1998) Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest; 114: Duysinx B, Nguyen D, Louis R (2004) Evaluation of pleural disease with 18-fluorodeoxyglucose positron emission tomography imaging. Chest 23. Kramer H, Pieterman MR (2004) PET for the evaluation of pleural thickening observed on CT. J Nucl Med; 45: Orki A, Akin O, Tasci AE (2009) The role of positron emission tomography/computed tomography in the diagnosis of pleural diseases. Thorac Cardiovasc Surg; 57: Treglia G, Sadeghi R (2014) Diagnostic accuracy of 18F-FDG-PET and PET/CT in the differential diagnosis between malignant and benign pleural lesions: a systematic review and meta-analysis. Academic Radiology. 26. Fiore D (2006) Imaging before and after multimodal treatment for malignant pleural mesothelioma. Radiol Med. 111(3): p Wang ZJ (2004) Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET. Radiographics. 24(1): p Flores RM (2003) Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 126(1): p Rahman N, Davies RJO, Gleeson FV (2007) Investigating suspected malignant pleural effusion. BMJ,334: McLoud T, Flower C (1991) Imaging the pleura: sonography, CT and MR imaging. AJR Am J Roentgenol;156: Qureshi NR, Rahman NR, Gleeson FV (2009) Thoracic ultrasound in the diagnosis of malignant pleural effusion. Thorax.64: Mathis G (2008) [Introduction--emergency ultrasonography]. Ultraschall Med. 29(4): p Gorg C (2005) Colour Doppler ultrasound mapping of chest wall lesions. Br J Radiol. 78(928): p Saito T, Kobayashi H, Kitamura S (1988) Ultrasonographic approach to diagnosing chest wall tumors. Chest. 94(6): p Bandi V (2008) Ultrasound vs. CT in detecting chest wall invasion by tumor: a prospective study. Chest. 133(4): p Popic Ramac J (2010) The possibilities and limitations of direct digital radiography, ultrasound and computed tomography in diagnosing pleural mesotelioma. Coll Antropol. 34(4): p

8 Figure legends 1. Malignant pleural mesothelioma. Standard Posteroanterior (PA) chest X-ray showing a diffuse pleural thickening (black arrow) with volume loss in the left hemithorax. 2. Malignant pleural mesothelioma. Standard Posteroanterior (PA) chest X-ray demonstrate a slightly lobular masses in the right hemithorax that abuts the chest wall without pleural effusion but with erosion on second rib. 3. Malignant pleural mesothelioma. Standard Posteroanterior (PA) chest X-ray showing a right pleural effusion associated with calcified plaques (white arrows) due to previous asbestos exposure. 4. Malignant pleural mesothelioma. Contrast-enhanced computed tomography (CT) scan demonstrates a circumferential irregular pleural thickening (white arrow) prevailing localized at the level of mediastinal pleura. Note also the presence of limphoadenopathy. 5. Malignant pleural mesothelioma. Contrast-enhanced computed tomography (CT) scan demonstrates a right very subtle circumferential pleural thickening (white arrow) with a little hemithorax retraction. 6. Malignant pleural mesothelioma. Contrast-enhanced computed tomography (CT) scan in axial (a) and sagittal (b) planes demonstrates extensive irregular and nodular (white arrows) thickening of the costal and diaphragmatic pleura of the left hemithorax, with pleural effusion. 7. Malignant pleural mesothelioma. Standard Posteroanterior (PA) chest X-ray (b) and Contrast-enhanced computed tomography (CT) scan (a) demonstrates a well-marginated rounded oval mass in the right paracardiac space (white arrows). Initially was suspected a solitary fibrous tumor of the pleura. 8. Malignant pleural mesothelioma. Standard posteroanterior, lateral (a, b) chest X-ray and computed tomography (CT) (c,d) shows a diffuse irregular pleural thickening (white arrows) with involvement of the interlobar fissures. 9. Malignant pleural mesothelioma. T1-Weighted (in out phase) Magnetic Resonance (MR) image shows a hypointense (in phase,a) pleural lesion infiltrating left thoracic wall without signal loss (out phase, B), demonstrating absence of fat tissue. Note also a small malignant nodule at the level of posterior diaphragmatic pleura. 10. Malignant pleural mesothelioma. T2-Weighted (HASTE) Magnetic Resonance (MR) image shows a pleural mass (black arrow) infiltrating thoracic wall with irregular hyperintense signal because of presence of fibrous tissue inside tumor lesion. Note also a small nodule associated with pleural effusion in the posterior side (white arrow). 11. Malignant pleural mesothelioma. T2-Weighted Fat Saturated (FS) Magnetic Resonance (MR) image shows a hyperintense lesion (white arrow) without signal loss because of absence of fat tissue inside. Note also bilateral axillary linphoadenopathy (black arrow), pleural thickening and a small malignant nodule in the posterior diaphragmatic pleura. 12. Malignant pleural mesothelioma. Diffusion-weighted MR image (b = 750 s/mm2) shows pleural tumor (A) and thickened left pleura as having higher signal intensity than adjacent skeletal muscle, with restricted diffusion with low ADC values (B) (1-1.5). 13. Malignant pleural mesothelioma. PET/CT scans show a very small nodules of increased FDG uptake in the basal recesses of the right hemithorax. 14. Malignant pleural mesothelioma. PET/CT scans show a mass of increased FDG uptake in the basal right hemithorax. 15.Malignant pleural mesothelioma. Axial US scan (a) through the right upper abdominal quadrant allows visualization of the liver and diaphragm as well as the supradiaphragmatic hypoechoic regular and subtle thickening of the diaphragmatic pleura. As well is present a fibrinous septaeted pleural effusion. Contrastenhanced computed tomography (CT) scan (b) well demonstrates diaphragmatic pleural thickening, pleural effusion but not septaetions. (c) thoracoscopy of the same patient shows the septated malignant effusions (white arrows). 8

9 16. Malignant pleural mesothelioma. Contrast-enhanced computed tomography (CT) scan in arterial (a) and portal phases (b). This example shows that the pleural ticknening is less evident in a more arterial phase than with a seconds scan delay. 9

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