1 doi: /icvts Interactive CardioVascular and Thoracic Surgery 12 (2011) Best evidence topic - Thoracic oncologic What is the best way to diagnose and stage malignant pleural mesothelioma? a a b b, Imran Zahid, Sumera Sharif, Tom Routledge, Marco Scarci * a Imperial College London, South Kensington Campus, London SW7 2AZ, UK b Department of Thoracic Surgery, Guy s Hospital, Great Maze Pond, London SE1 9RT, UK Received 14 September 2010; accepted 13 October Summary A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was which diagnostic modality wcomputed tomography (CT), positron emission tomography (PET), combination PETyCT and magnetic resonance imaging (MRI)x provides the best diagnostic and staging information in patients with malignant pleural mesothelioma (MPM). Overall, 61 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that fluorodeoxyglucose (FDG)-PET is superior to MRI and CT but inferior to PET-CT, in terms of diagnostic specificity, sensitivity and staging of MPM. Four studies reported outcomes using FDG-PET to diagnose MPM. PET diagnosed MPM with high sensitivity (92%) and specificity (87.9%). Mean standardised uptake value (SUV) was higher in malignant than benign disease (4.91 vs. 1.41, P ). Lymph node metastases were detected with higher accuracy (80% vs. 66.7%) compared to extrathoracic disease. Three studies assessed the utility of PET-CT to diagnose MPM. Mean SUV was higher in malignant than benign disease (6.5 vs. 0.8, P-0.001). MPM was diagnosed with high sensitivity (88.2%), specificity (92.9%) and accuracy (88.9%). PET-CT had low sensitivity for stage N2 (38%) and T4 (67%) disease. CT-guided needle biopsy definitively diagnosed MPM after just one biopsy (100% vs. 9%) much more often than a blind approach. CT had a lower success rate (92% vs. 100%) than thoracoscopic pleural biopsy but was equivalent to MRI in terms of detection of lymph node metastases (Ps0.85) and visceral pleural tumour (Ps0.64). CT had a lower specificity for stage II (77% vs. 100%, P-0.01) and stage III (75% vs. 100%, P-0.01) disease compared to PET-CT. Overall, the high specificity and sensitivity rates seen with open pleural biopsy make it a superior diagnostic modality to CT, MRI or PET for diagnosing patients with MPM Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Diagnosis; Malignant mesothelioma; Fluorodeoxyglucose-positron emission tomography; Computed tomography 1. Introduction A best evidence topic in thoracic surgery was constructed according to a structured protocol. This is fully described in the ICVTS w1x. 2. Three-part question In wpatients with malignant mesotheliomax is wfdg-petx superior to wct or MRIx in terms of wdiagnostic specificity, sensitivity and tumour stagingx. 3. Clinical scenario You are at a multidisciplinary meeting and review a 61- year-old retired plumber, with past asbestos exposure, who presented with chronic cough and shortness of breath. Computed tomography (CT)-scan identified a right-sided pleural effusion with thickening of the parietal pleura and loss of volume on the affected side. You suspect it could be malignant mesothelioma but are unsure as to which *Corresponding author. Tel.: q ; fax: q address: (M. Scarci) Published by European Association for Cardio-Thoracic Surgery diagnostic modality would provide a definitive diagnosis and stage the disease accurately. You resolve to check the literature yourself. 4. Search strategy Medline search 1950 to August 2010 was performed using the OVID interface wmalignant pleural mesothelioma.mpx AND wimaging.mpx AND wdiagnosis.mpx. 5. Search outcome Sixty-one papers were found using the reported search. From these, 14 papers provided the best evidence to answer the clinical question. These are presented in Table 1. In addition, the reference list of each paper was searched. 6. Results Four studies reported outcomes using fluorodeoxyglucosepositron emission tomography (FDG-PET) to diagnose suspected malignant pleural mesothelioma (MPM). Bernard et al. w2x diagnosed MPM with high sensitivity (92%) and
2 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. Best evidence papers Bernard et al., (1998), Chest, Single centre experience Sensitivity 92% FDG-PET is a highly USA, w2x involving 28 patients sensitive diagnostic tool Specificity 75% for malignant Retrospective cohort study All patients underwent mesothelioma (level 2b) FDG-PET Accuracy 89% FDG-PET can Diagnosis was confirmed by Detection of lymph 12 accurately differentiate thoracoscopic biopsy (ns21), node metastases Specificity 83% between benign and pleural biopsy (ns4), Accuracy 80% malignant disease cytology (ns1), clinical follow-up (ns1) and pleural Mean SUV Malignant: 4.91"2.90 decortication (ns1) Benign: 1.41"0.63 (P ) Tumourylung ratio Malignant: 12.97"9.23 Benign: 2.69"1.31 (P ) Yamamoto et al., (2009), Single centre experience Accuracy (%) 88.2 FDG-PET effectively Nucl Med Commun, involving 33 patients distinguishes malignant Japan, w3x Sensitivity (%) 87.5 from benign pleural All patients had FDG-PET disease Retrospective cohort study Specificity (%) 87.9 (level 2b) MPM diagnosis confirmed by histopathology Mean SUVdelayed vs. Malignant disease: SUV early 9.39"7.70 vs. 7.72"6.08 SUVearly spet 60 min post (P-0.001) F-FDG injection SUVdelayedsPET 120 min post Benign disease: F-FDG injection 3.27"3.26 vs. 2.92"2.45 (PsNS) Malignant vs. benign disease: 9.39 vs (P-0.01) Mavi et al., (2009), Single centre experience over Mean SUV early Group A: 5.0"2.2 Dual time point Mol Imaging Biol, USA, seven years (% of SUV max) Group B: 4.6"1.7 FDG-PET can w4x Group C: 1.6"0.4 accurately differentiate All patients (P ) malignant mesothelioma Retrospective cohort study underwent FDG-PET from benign pleural (level 2b) (ns55) Mean SUV delayed Group A: 5.8"2.8 disease (% of SUV max) Group B: 5.3"2.0 Patients divided into: Group C: 1.4"0.3 FDG-PET could not Group A: (P ) distinguish between New diagnosis MPM (ns28) newly diagnosed MPM Group B: and long standingy Recurrent MPM (ns16) recurrent disease Group C: Benign pleural disease (ns11) Best Evidence Topic SUVearlysPET 60 min post F-FDG injection SUVdelayedsPET 90 min post F-FDG injection Flores, (2005), Lung Cancer, Single centre experience over Accuracy 98.3% FDG-PET accurately USA, w5x five years diagnoses malignant Mean SUV Overall: 6.6 (range ) mesothelioma and can Retrospective cohort study All patients underwent N0 N1 disease: 5.3"2.1 distinguish mediastinal (level 2b) FDG-PET (ns63) N2 disease: 8.6"3.4 lymph node involvement from Detection of N2 disease 78"10% localyno lymph node (area under ROC) metastases Detection of T4 Sensitivity: 19% tumours Specificity: 91% (Continued on next page)
3 256 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. (Continued) Detection of Accuracy: 66.7% extrathoracic disease Yildrim et al., (2009), Single centre experience over Accuracy (%) 90.3 FDG-PETyCT is a J Thorac Oncol, Turkey, three years involving 31 patients highly effective w6x Sensitivity (%) 88.2 diagnostic tool for All patients underwent malignant Retrospective cohort study FDG-PETyCT Specificity (%) 92.9 mesothelioma (level 2b) MPM diagnosis confirmed by Mean SUV Malignant: 6.5"3.4 histopathology Benign: 0.8"0.6 (P-0.001) Tan et al., (2010), Single centre experience over Sensitivity 94% FDG-PET-CT is a J Thorac Oncol, UK, four years involving 25 patients highly accurate w7x Specificity 100% diagnostic tool for All patients underwent detecting recurrence of Retrospective cohort study FDG-PET-CT for suspected Detection of MPM 88.9% mesothelioma (level 2b) disease recurrence (ns11) or recurrence surveillance (ns14) SUVmax of recurrent 8.9"4.0 (range 4.4) disease Erasmus et al., (2005), Single centre experience Determine tumour T Accuracy: 63% PET-CT can detect J Thorac Cardiovasc Surg, involving 29 patients stage Understaged disease: 29% malignant mesothelioma USA, w8x Overstaged disease: 8% but has comparatively All patients underwent low sensitivity and Retrospective cohort study FDG-PET-CT T4 disease detection Sensitivity: 67% specificity, especially (level 2b) Specificity: 93% for advanced disease Final disease staging Accuracy: 83% consisted of laproscopy" Main errors were related bronchoscopyymediastinoscopy Determine tumour N Accuracy: 35% to failure to identify stage Understaged disease: 35% transpericardial and Overstaged disease: 29% transdiaphragmatic disease N2 disease detection Sensitivity: 38% Specificity: 78% Accuracy: 59% Overall accuracy 72% Attanoos and Gibbs, (2008), Single centre experience over Definitive diagnosis on CT-guided: 100% Open pleural biopsy is Histopathology, UK, w9x seven years first biopsy Blind closed: 9% the most accurate and effective method to Retrospective cohort study Open pleural biopsy (ns21) Inadequate biopsy Blind closed: 32% obtain a pleural biopsy (level 2b) CT-guided closed-percutaneous biopsy (ns5) Biopsy specimen size Closed: range 1 15 Amongst closed Blind closed percutaneous (mm) Open: range percutaneous biopsies, a biopsy (ns36) CT-guided approach is Accuracy of open Specificity: 100% superior to a blind All patients had diffuse biopsy Sensitivity: 95% approach malignant mesothelioma Chamberlain et al., (2008), Single centre experience Success rate VACT: VACT conducted from Eur J Cardiothorac Surg, UK, involving 41 patients Overall: 66.6% the right side can w10x Right-sided approach: effectively diagnose VACT (ns15) 76.9% MPM but is associated Retrospective cohort study Conventional preoperative Left-sided approach: 0% with high (13%) (level 2b) staging (ns26) complication and high Mean operative time VACT: 71 min (range failure rates All patients had suspected 65 90) MPM due to a history of asbestos exposure and Conversion rate to VACT: 33.3% suggestive pleural biopsies video-assisted thoracoscopic surgery (VATS) (Continued on next page)
4 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. (Continued) Time to radical surgery VACT: 28"17 (days) Conventional: 87"56 (P-0.001) Gerbaudo et al., (2002), Single centre experience of 15 Sensitivity (%) CT: 83 (95% CI: 64 93) F-FDG-CI is a sensitive J Nucl Med, USA, w11x consecutive patients F-FDG-CI: 97 (95% CI: and accurate diagnostic 80 99) method to detect Retrospective cohort study All underwent CT followed malignant mesothelioma (level 2b) by F-FDG-CI Specificity (%) CT: 80 (95% CI: 30 98) F-FDG-CI: 80 (95% CI: F-FDG-CI has specific Diagnosis confirmed by 80 99) advantage over CT with histopathology and regards to detection of immunohistochemistry Accuracy (%) CT: 82 diffuse chest wall disease F-FDG-CI: 94 and lymph node metastases Agreement with biopsy CT: 82 (ks0.47, P-0.003) results (%) F-FDG-CI: 94 (ks0.77, P ) Detection of diffuse CT: 33% chest wall disease F-FDG-CI: 100% Detection of mediastinal CT: 75% lymph node metastases F-FDG-CI: 88% Detection of CT: 100% extrathoracic metastases F-FDG-CI: 100% Heelan et al., (1999), Single centre experience Detection of disease CT: 0.55 CT and MRI are equally AJR Am J Roentgenol, USA, involving 65 patients with invading diaphragm MR: 0.82 as effective at detecting w12x biopsy-proven malignant (area under ROC) (Ps0.01) disease involving visceral mesothelioma pleura and mediastinal Retrospective cohort study Detection of visceral CT: 0.67 lymph nodes (level 2b) All patients underwent CT pleural tumour MR: 0.58 and MR imaging (area under ROC) (Ps0.64) MR imaging is superior to CT in detection of Imaging was followed by a Detection of lymph CT: 0.49 disease invading surgical procedure: node involvement MR: 0.51 diaphragm and EPP (ns34), (area under ROC) (Ps0.85) endothoracic fascia thoracotomyqpartial pleurectomy (ns13), Detection of disease CT: 0.46 thoracotomyqbiopsy (ns13), invading endothoracic MR: 0.69 laproscopyqbiopsy (ns4), fascia (Ps0.05) supraclavicular node biopsy (area under ROC) (ns1) Groessebner et al., (1999), Single centre experience Biopsy success rate 100% CT-scan is a sensitive Eur J Cardiothorac Surg, UK, involving 25 patients imaging modality for w13x CT accuracy 92% malignant mesothelioma All patients were referred Prospective cohort study after CT-scan for confirmation Mortality rate 0 (level 1b) of MPM using VATS pleural biopsy Best Evidence Topic Nanni et al., (2004), Single centre experience Concordance between Overall stage match: 60% FDG-PET staged Cancer Biother Radiopharm, involving 15 patients PET and CT Exact TNM match: 27% malignant mesothelioma Italy, w14x more accurately than All patients underwent PET upstaged disease Two patients (13%) CT, leading to a change Retrospective cohort study FDG-PET and CT in management protocol (level 2b) PET downstaged disease Four patients (27%) in three patients (20%) MPM diagnosis confirmed by histology and mediastinoscopy Plathow et al., (2008), Single centre experience Overall accuracy (%) MRI: PETyCT is the optimal Invest Radiol, Switzerland, involving 54 patients CT: diagnostic tool for w15x PET: detection and staging of PET/CT: 100 malignant mesothelioma (Continued on next page)
5 258 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. (Continued) Retrospective cohort study Patients underwent MRI, CI Stage specific Stage II: PET and MRI alone are (level 2b) PET and PET/CT accuracy (%) MRI: 80 both accurate and CT: 77 sensitive diagnostic All patients had epithelial PET: 86 methods MPM PETyCT: 100 PETyCT vs. MRI: P-0.05 CT alone is inferior to PETyCT vs. CT: P-0.01 MRI, PET alone or PETyCT vs. PET: P-0.05 PETyCT as it significantly Stage III: underestimates patients MRI: 90 with stage III disease CT: 75 (P-0.05) PET: 83 PETyCT: 100 PETyCT vs. MRI: P-0.05 PETyCT vs. CT: P-0.01 PETyCT vs. PET: P-0.05 Stage IV: PET: 100 PETyCT: 100 Sensitivity and Stage II: specificity (%) MRI: 87.5 and 87.5 CT: 100 and 69.2 PET: 100 and 84.6 PETyCT: 100 and 100 Stage III: MRI: 91 and 100 CT: 75 and 100 PET: 83 and 100 PETyCT: 100 and 100 FDG-PET, fluorodeoxyglucose-positron emission tomography; SUV, standardised uptake value; MPM, malignant pleural mesothelioma; ROC, area under receiver operating curve; CT, computed tomography; VACT, video-assisted cervical thoracoscopy; F-FDG-CI, FDG-dual head gamma-camera coincidence imaging; MRI, magnetic resonance imaging; NS, not significant. specificity (75%). Malignant and benign disease were accurately distinguished by differences in mean standardised uptake value (SUV) (4.91"2.90 vs. 1.41"0.63, P ) and tumourylung ratios (12.97 vs. 2.69, P ). Lymph node metastases were detected with high accuracy (80%). Yamamoto et al. w3x observed large increases in delayed (120 min post- F-FDG injection) compared to early (60 min post- F-FDG injection) SUV measurements in malignant (7.72 vs. 9.39, P-0.001) but not in benign disease (2.92 vs. 3.27, PsNS). Similarly, Mavi et al. w4x reported lower mean SUV (1.6 vs. 5.0 vs. 4.6, P ) with benign pleural disease compared to newly diagnosed MPM and recurrent MPM, respectively. Flores w5x used FDG-PET to identify N2 disease with an accuracy of 78% and reported a higher mean SUV (8.6 vs. 5.3) than N0yN1 disease. Extrathoracic disease was identified with low accuracy (66.7%). PET was sensitive for only 19% of T4 tumours. Three studies used a combination of FDG-PET and CT to diagnose MPM. Yildrim et al. w6x identified MPM with high specificity (92.9%) and sensitivity (88.2%). Large differences were observed between the mean SUV (6.5 vs. 0.8, P-0.001) of malignant and benign disease. Tan et al. w7x showed that PET-CT identified recurrence of MPM with high accuracy (88.9%), specificity (100%) and sensitivity (94%) with a mean SUV of 8.9"4.0. Erasmus et al. w8x found FDG- PET-CT determined tumour T stage and N stage with accuracies of 63% and 35%, respectively. PET-CT understaged tumour T and N stage in 29% and 35% of patients and overstaged disease in 8% and 29% of patients, respectively. PET-CT had low sensitivity for T4 (67%) and N2 (38%) disease with most errors occurring due to failure to identify transpericardial and transdiaphragmatic disease. Two studies observed outcomes of pleural biopsy and thoracoscopy in diagnosing patients with MPM. Attanoos and Gibbs w9x compared the effectiveness of open pleural (ns21), CTguided closed (ns5) and blind closed percutaneous needle biopsies (ns5). CT-guided biopsy made a definitive diagnosis after just one biopsy (100% vs. 9%) much more often than a blind approach, which produced an inadequate sample in 32% of patients. Open pleural biopsy was 95% sensitive and 100% specific for MPM and biopsied larger tissue samples (range mm vs mm) than the closed approach. Chamberlain et al. w10x conducted videoassisted cervical thoracoscopy (VACT) (ns15) and compared it to conventional preoperative staging protocols (ns26). VACT produced a success rate of 76.9% from a right-sided approach (ns13) but a 0% success rate from a left-sided approach (ns3) due to operative difficulties. VACT greatly reduced time to radical surgery (28 vs.
6 I. Zahid et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) days, P-0.001) compared to conventional preoperative MPM staging protocols. Five studies compared the effectiveness of CT to other diagnostic modalities in identifying MPM. Gerbaudo et al. w11x compared CT to FDG-dual head gamma-camera coincidence imaging (F-FDG-CI). F-FDG-CI diagnosed MPM with equivalent specificity (80% vs. 80%) but greater sensitivity (97% vs. 83%) and accuracy (94% vs. 82%) than CT. There was strong agreement of F-FDG-CI (94%, ks0.77, P ) and CT (82%, ks0.47, P-0.003) with pleural biopsy results. F-FDG-CI detected diffuse chest wall disease (100% vs. 33%) and mediastinal lymph node metastases (88% vs. 75%) more accurately than CT. Heelan et al. w12x compared CT with magnetic resonance imaging (MRI) in 65 patients. With regards to areas under receiver operating curves (ROC), CT was equivalent to MRI in terms of detection of lymph node metastases (0.49 vs. 0.51, Ps0.85) and visceral pleural tumour (0.67 vs. 0.58, Ps0.64) but inferior to MRI at detecting disease invading the diaphragm (0.55 vs. 0.82, Ps0.01) and endothoracic fascia (0.46 vs. 0.69, Ps0.05). Grossebner et al. w13x analysed 25 patients and showed that CT had a lower success rate (92% vs. 100%) than thoracoscopic pleural biopsy. Nanni et al. w14x compared FDG-PET with CT and reported high concordance rates (60%) between the two modalities. PET upstaged disease in 13% and downstaged disease in 27% of patients, which resulted in a change in the management protocol of 20% of patients. Plathow et al. w15x compared diagnostic utility of PET-CT with CT, PET and MRI in 54 patients. PET-CT had a higher accuracy than CT, PET and MRI for stage II (100% vs. 77% vs. 86% vs. 80%, P-0.01) and stage III (100% vs. 75% vs. 83% vs. 90%, P-0.01) tumours. CT demonstrated much lower sensitivities (75% vs. 91% vs. 83% vs. 100%) at detecting MPM than MRI, PET and PET-CT, respectively. 7. Clinical bottom line There are many diagnostic modalities to identify patients with malignant mesothelioma. Currently there is no consensus as to which single modality should be used to confirm diagnosis prior to surgery. The studies above have shown that PET-CT is superior to FDG-PET, MRI and CT in terms of specificity and sensitivity of disease detection and staging of MPM. However, surgical pleural biopsy still provides the most accurate definitive diagnosis but is a more invasive procedure than PET-CT. References w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. 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