Does positron emission tomography offer prognostic information in malignant pleural mesothelioma?

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1 doi: /icvts Interactive CardioVascular and Thoracic Surgery 12 (2011) Best evidence topic - Thoracic oncologic Does positron emission tomography offer prognostic information in malignant pleural mesothelioma? a a b b, Sumera Sharif, Imran Zahid, Tom Routledge, Marco Scarci * a Imperial College London, South Kensington Campus, London SW7 2AZ, UK b Department of Thoracic Surgery, Guy s Hospital, London SE1 9RT, UK Received 14 September 2010; received in revised form 17 December 2010; accepted 4 January 2011 Summary A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether positron emission tomography is useful in the diagnosis and prognosis of malignant pleural mesothelioma (MPM). Altogether 136 papers were found using the reported search, of which 15 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 of these papers are tabulated. We conclude that fluorodeoxyglucose-positron emission tomography (FDG-PET) accurately differentiates benign from malignant pleural disease, helps detect recurrence and provides prognostic information in terms of staging, survival and mortality. Eleven studies evaluated the role of FDG-PET in the diagnosis and prognosis of MPM. Malignant disease had a higher standardised uptake value (SUV) (6.5"3.4 vs. 0.8"0.6; P-0.001) than benign pleural disease. Shorter median survival (9.7 vs. 21 months; Ps0.02) was associated with high SUV ()10) than low SUV (-10). PET accurately upstaged 13% and downstaged 27% of cases initially staged with computed tomography (CT). In patients undergoing chemotherapy, higher total glycolytic volume led to a lower median survival (4.9 vs months; Ps0.09), while a decline in FDG uptake was associated with a longer time to tumour progression (14 vs. 7 months; Ps0.02). Four studies observed the role of FDG-PET-CT in the diagnosis and prognosis of MPM. SUV was found to be higher in MPM compared to benign pleural disease (6.5 vs. 0.8; P-0.001). A higher SUVmax was observed in primary pleural lesions of metastatic (7.1 vs. 4.7; Ps0.003) compared to non-metastatic disease. Patients who underwent surgery had equivalent survival to those excluded based on scan results (20 vs. 12 months; Ps0.3813). One study compared the utility of PET and PET-CT in the diagnosis and prognosis of mesothelioma. PET-CT was found to be more accurate than PET in terms of staging (P-0.05) disease. Overall, PET accurately diagnoses MPM, predicts survival and disease recurrence. It can guide further management by predicting the response to chemotherapy and excluding surgery in patients with extrathoracic disease. Combined PET-CT has additional benefits in accurately staging disease Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Malignant mesothelioma; Positron emission tomography; Diagnosis; Prognosis 1. Introduction A best evidence topic was constructed according to a structured protocol. This is fully described in ICVTS w1x. 2. Three-part question In wpatients with malignant pleural mesotheliomax is wpositron emission tomographyx superior to wcomputed tomography or magnetic resonance imagingx in terms of wdiagnostic, staging and prognostic data providedx. 3. Clinical scenario You are at a multidisciplinary meeting and review a 55- year-old male with a confirmed histological diagnosis of malignant pleural mesothelioma (MPM). You are asked whether positron emission tomography (PET) would provide *Corresponding author. Tel.: q ; fax: q address: marco.scarci@mac.com (M. Scarci) Published by European Association for Cardio-Thoracic Surgery additional diagnostic or prognostic information. You are unsure about the extent to which PET may have a role and resolve to check the literature yourself. 4. Search strategy Medline search 1950 to August 2010 was performed using OVIDSP interface. (exp MesotheliomayOR mesothelioma.mp) AND (exp Positron-Emission TomographyyOR positron emission tomography.mp. or PET.mp) 5. Search outcome One hundred and thirty-six papers were found using the reported search. From these, 15 papers provided the best evidence to answer the question. These are presented in Table 1. In addition, the reference list of each paper was searched.

2 S. Sharif et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1. Best evidence papers Mavi et al., (2009), Single-centre experience, SUV max1 (%, 60 min Group A: 5.0"2.2 18F-FDG-PET uptake Mol Imaging Biol, USA, w2x over seven years using post-fdg injection) Group B: 4.6"1.7 increases with time in 18F-FDG-PET (ns55) Group C: 1.6"0.4 MPM and decreases Cohort study with time in benign (level 2b) Group A: SUV max2 (%, 90 min Group A: 5.8"2.8 pleural disease. Dual- Primary MPM (ns28) post-fdg injection) Group B: 5.3"2.0 time point imaging is Group C: 1.4"0.3 therefore effective in Group B: differentiating benign Recurrent MPM (ns16) DSUV max (%) Group A: 12.8"8.4 from malignant pleural Group B: 13.8"9.2 disease Group C: Group C: 9.6"19.1 Benign pleural disease SUVmax calculation (ns11) Group AqB) Group C and its change over (P ) time were higher in Group A vs. Group B MPM patients (P)0.05) Yamamoto et al., (2009), Single-centre experience Mean SUVdelayed vs. MPM: 18F-FDG uptake Nucl Med Commun, using 18F-FDG-PET SUV early 9.39"7.70 vs. 7.72"6.08 increased in all MPM Japan, w3x (ns33) (P-0.001) cases over time Benign pleural disease: Cohort study MPM (ns17) 3.27"3.26 vs. 2.92"2.45 There was no (level 2b) Benign pleural disease (PsNS) significant difference in (ns16) benign pleural disease Mean SUV MPM)benign pleural SUVearly s PET 60 min disease (P-0.01) post-18f-fdg injection SUVdelayed s PET 120 min Detecting MPM on Sensitivity, specificity post-18f-fdg injection PET and overall accuracy: 88% Flores, (2005), Single-centre experience FDG uptake in Group A: ns59 PET is useful in Lung Cancer, USA, w4x over five years using primary tumour one false-negative: predicting survival and FDG-PET (ns63) stage 1a mediastinal nodal Cohort study metastases in patients (level 2b) Group A: Median survival SUV-4 vs. SUV)4 with MPM PET prior surgery (ns60) (months) 24 vs. 14 (P-0.04) AUC of 78% is Group B: Hazard ratio (HR) for SUV)4 HRs3.3 useful in predicting PET postsurgery (ns3) death (Ps0.03) mediastinal nodal disease. Patients with SUV N0 N1: 5.3"2.1 a higher SUV in the N2: 8.6"3.4 primary tumour are more likely to have Area under ROC N2: 78"10% mediastinal nodal (AUC) curve of SUV metastases PET correctly identified six patients who had unresectable tumour because of extrathoracic disease Best Evidence Topic Flores et al., (2006), Single-centre experience Median survival High SUV ()10) vs. There is a near linear J Thorac Cardiovasc Surg, over seven years using (months) low SUV (-10) correlation of USA, w5x 18F-FDG-PET (ns137) 9.7 vs. 21 (Ps0.02) increasing SUV with poor survival. Cohort study Risk of death High SUV ()10) SUV)10 is a risk (level 2b) HR: 1.9 (P-0.01) factor for MPM SUV HR: 1.05 (P-0.01) High SUV has a 1.9 times greater risk of death than low SUV (-10) Each unit increase in SUV increases the risk of death by 5% (Continued on next page)

3 808 S. Sharif et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1 (Continued) Bernard et al., (1999), Single-centre experience Mean SUV Deceased vs. survivors High FDG uptake J Nucl Med, over two years of patients 6.6"2.9 vs. 3.2"1.6 indicates shorter USA, w6x with MPM (ns22) patient survival. SUV correlating with High SUV ()4.03) vs. Patients with lower Cohort study FDG-PET scan: duration of survival low SUV (F4.03) SUVs tended to be at a (level 2b) seven patients died lower stage and the 5.3 months after scan Cumulative survival at 17% vs. 86% (P-0.01) extent of primary 12 months tumour involvement (T stage) also tended to be lower Nowak et al., (2010), Single-centre experience Survival PET volume (Ps0.008) PET volume was a Clin Cancer Res, over three years using SUV max (Ps0.055) significant predictor of Australia, w7x FDG-PET (ns93) survival. SUV max trended towards Cohort study All patients had known significance only (level 2b) MPM Ceresoli et al., (2006), Single-centre experience Metabolic response Responders vs. Early metabolic J Clin Oncol, Italy, w8x over one-year ns20 MPM non-responders evaluation showed a patients undergoing 40 vs. 60% good correlation Prospective cohort study permetrexed chemotherapy between the decline in (level 2b) Median time to 14 vs. 7 months FDG uptake and the Metabolic response (MR): tumour progression (Ps0.02) outcome of patients decrease of 25%y) in tumour FDG uptake as Survival Responders ) No correlation was measured by SUV non-responders (Ps0.07) found between time to 87.5% alive at tumour progression 15.1 months and radiological response evaluated by CT Francis et al., (2007), Single-centre experience Median TGV on PET Patients with PR: Fall in TGV was J Nucl Med, Australia, over two years MPM 30% of baseline value associated with w9x patients (ns23) (range: 11 71%) improved patient Patients with SD: survival unlike a fall in Prospective cohort study Patients underwent 71% of baseline value SUV max (level 2b) 18F-FDG-PET before and (range: 8 113%) after one cycle of Semiquantitive chemotherapy % Change in TGV 69 (P-0.001) 18F-FDG-PET using compared with CT TGV may predict CT response: response to Partial response (PR) ns7 Fall in TGV predictive Ps0.015 chemotherapy and Stable disease (SD) ns13 of improved survival patient survival after Not measurable (NM) ns3 one cycle of treatment Magnitude of TGV% Ps TGV: change and survival A 10% reduction in Increase ns4 TGV after Decrease ns18 TGV-60% superior HR: 0.22; Ps0.03 chemotherapy was Not evaluable ns1 to smaller change associated with a 36% reduction in the risk of HR for 10% change in 0.64 death TGV post-chemo Median survival (months) Fall in SUVmax and improved survival Increased TGV vs. decreased TGV 4.9 vs (Ps0.09) Ps0.097 Nanni et al., (2004), Single-centre experience PET stage 60% PET enabled accurate Cancer Biother over six months MPM corresponded to CT staging of MPM, Radiopharm, Italy, w10x patients (ns15) stage altering management of three cases which Prospective cohort study Staging (ns5) Upstaged by PET 13% included the (level 2b) Post-therapy (ns10) exclusion of surgery in Downstaged by PET 27% one case and FDG-PET following CT alteration of Change in management 20% chemotherapy in two (Continued on next page)

4 S. Sharif et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1 (Continued) Yan et al., (2009), Single-centre experience 18-month survival Preoperative PET vs. Preoperative PET was Ann Thorac Surg, over 23 years (ns456) no preoperative PET strongly associated Australia, w11x FDG-PET 45 vs. 26% (P-0.012) with 18-month survival in patients Prospective cohort study Preoperative PET (ns42) with MPM (level 2b) No preoperative PET (ns414) PET was used to exclude extrathoracic EPP (ns59) spread of disease PyD (ns250) Pleurodesisybiopsy (ns147) Wilcox et al., (2009), Single-centre experience Upstaged following ns13 Integrated CT-PET is Clin Lung Cancer, USA, over six years using CT-PET excellent for detecting w12x CT-PET (ns35) nodal and distant Survival (months) Group A vs. Group B metastases allowing Cohort study Group A: 20 vs. 12 (Ps0.3813) accurate staging of (level 2b) EPP (ns8) patients with MPM to Mortality rate Group A: 80%, median prevent futile Group B: follow-up 14 months attempts at resection Excluded from surgery based on CT-PET results Group B: 79%, median (ns14) follow-up four months Group C: Parietal pleurectomy (ns2) Group D: Excluded from surgery based on functional statusypatient preference (ns11) Yildirim et al., (2009), Single-centre experience Detected by FDG- MPM: 15 18F-FDG-PETyCT J Thorac Oncol, Turkey, over two years using PET-CT Benign asbestos-related imaging is a highly w13x 18F-FDG-PET-CT (ns31) pleural effusion (BAPE) accurate and reliable and diffuse pleural non-invasive test to Observational pilot study Malignant disease: thickening (DPE): 13 differentiate MPM (level 2b) MPM (ns17) Sensitivity: 88.2% from benign pleural Specificity: 92.9% disease Benign disease: Overall accuracy: 90.3% BAPE (ns9) 90.3% DPE (ns5) Mean SUV max MPM vs. benign disease 6.5"3.4 vs. 0.8"0.6 (P-0.001) Lee et al., (2009), Single-centre experience Detection of Nine patients (eight Patients with Mol Imaging Biol, over three years diagnosed metastases previously undetected) extrathoracic Australia, w14x MPM using 18F-FDG- metastases had a PET-CT (ns46) Mean SUVmax of Metastases vs. no significantly higher Retrospective primary pleural lesions metastases: SUVmax in the primary cohort study Metastases (ns9) 7.1 vs. 4.7 (Ps0.003) pleural lesion at all (level 2b) No metastases (ns37) stages of disease Survival (months) 4 vs. 8 (P-0.05) prevention Best Evidence Topic Tan et al., (2010), Single-centre experience Mean SUVmax of 8.9" FDG-PET-CT is J Thorac Oncol, UK, w15x over four years (ns25) recurrent disease useful in diagnosing 18F-FDG-PET-CT disease recurrence after Retrospective post-multimodality Detection of ns17 (sensitivity 94%) multimodality cohort study therapy for MPM recurrence: therapy for MPM (level 2b) Recurrence ns18 Identification of no ns7 (specificity 100%) No recurrence ns7 recurrence Plathow et al., (2008), Single-centre study PET: Accuracy of Stage II: 86 PET and PET-CT Invest Radiol, Germany, experience of epithelial staging (%) Stage III: 83 enables detection of w16x MPM diagnosed using newly found distant PETyPET-CT (ns54) (Continued on next page)

5 810 S. Sharif et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Table 1 (Continued) Cohort study Sensitivity and Stage II: 100 and 84.6 metastases and (level 2b) specificity (%) Stage III: 83 and 100 therefore can prevent Stage IV: 100 and 100 unnecessary surgery in some cases PET-CT: Accuracy of 100 staging (%) Stage II and III: PET-CT vs. MRIyPET (P-0.05) PET-CT vs. CT (P-0.01) Sensitivity and All stages: 100% specificity SUV, standardised uptake value; FDG-PET, fluorodeoxyglucose-positron emission tomography; MPM, malignant pleural mesothelioma; TGV, total glycolytic volume; CT, computed tomography. 6. Results Eleven studies evaluated the role of PET in MPM. Mavi et al. w2x reported greater 18F-fluorodeoxyglucose (FDG) uptake over time with both primary MPM (DSUVmaxs12.8" 8.4%) and recurrent MPM (DSUVmaxs13.8"9.2%) but lower uptake in benign pleural disease (DSUVmaxs 9.6"19.1%). Malignant disease had higher SUV max (5.0"2.2 vs. 1.6"0.4, P ) than benign disease. Yamamoto et al. w3x observed large increases in delayed (120 min post-18f-fdg injection) compared to early (60 min post-18f-fdg injection) standardised uptake valve (SUV) measurements in malignant (7.72"6.08 vs. 9.39"7.70, P-0.001) but not in benign disease (2.92"2.45 vs. 3.27"3.26, PsNS). Mean SUV was higher in malignant disease (P-0.01). MPM was detected with a sensitivity, specificity and overall accuracy of 88%. Flores w4x observed higher SUV in N2 disease (8.6"3.4) than N0 N1 disease (5.3"2.1). The area under the receiver operating curve (AUC) of SUV was a strong predictor of N2 disease (78"10%). SUV of -4 was associated with a longer survival than a SUV of )4 (24 vs. 14 months; P-0.04), with the latter having a hazard ratio (HR) for death of 3.3 (Ps0.03). In 2006, Flores et al. w5x assessed survival in 137 patients with MPM over seven years. A high SUV ()10) was associated with a shorter survival (9.7 vs. 21 months; Ps0.02) and 1.9 times greater death risk (P-0.01) than low SUV (-10). Bernard et al. w6x analysed 22 patients with MPM and reported higher mean SUV in deceased patients (6.6"2.9 vs. 3.2"1.6) compared to those that survived. The cumulative survival at 12 months in patients who had high SUVs ()4.03) was lower than those who had a low SUV (F4.03) (17% vs. 86%; P-0.01). Nowak et al. w7x reported PET to be a significant predictor of survival (Ps0.008) in patients with MPM and SUVmax to trend towards significance only (Ps0.055). Ceresoli et al. w8x evaluated response to chemotherapy using FDG-PET. Responders (G25% reduction in FDG uptake) had a longer median time to tumour progression (14 vs. 7 months; Ps0.02) and longer survival (Ps0.07) than non-responders. Similarly, Francis et al. w9x observed the role of serial 18F-FDG-PET in assessing the response to chemotherapy after one cycle. Patients with a partial response had a lower median total glycolytic volume (TGV) (30% vs. 71% of baseline) compared to those with stable disease. Reduction in TGV was predictive of improved survival (Ps0.015). Nanni et al. w10x compared 18F-FDG-PET to computed tomography (CT) and found 60% concordance in staging disease. However, 13% of patients were upstaged and 27% downstaged by PET, leading to a change in management in 20%. Yan et al. w11x reported greater 18-month survival in patients with preoperative compared to postoperative FDG-PET (45% vs. 26%; P-0.012). Four studies evaluated the combination of PET-CT in the diagnosis and prognosis of mesothelioma. Wilcox et al. w12x observed that 13 patients were upstaged following the use of PET-CT. There was no significant difference in survival between patients who had extrapleural pneumonectomy (ns8) and those excluded from surgery based on scan results (ns14) (20 vs. 12 months; Ps0.3812). Yildrim et al. w13x reported 18F-FDG-PET-CT detected MPM (ns17) and benign pleural disease (ns14) with high sensitivity (88.2%), specificity (92.9%) and overall accuracy (90.3%). The mean SUVmax was higher in MPM than benign pleural disease (6.5"3.4 vs. 0.8"0.6; P-0.001). Lee et al. w14x detected metastases in nine patients with MPM of which eight had previously been undetected. The primary pleural lesions in patients with metastases had higher mean SUV max (7.1 vs. 4.7; Ps0.003) and shorter survival (four vs. eight months; P-0.05) than those of non-metastatic disease. Recently, Tan et al. w15x reported the use of 18F- FDG-PET-CT in diagnosing disease recurrence postmultimodality therapy for MPM. Seventeen of 18 cases were detected (sensitivity 94%) and in seven patients no recurrence was identified (specificity 100%). The mean SUV max of recurrent disease was 8.9"4.0. One study compared the accuracies of PET and PET-CT in diagnosing and staging MPM. In 2008, Plathow et al. w16x analysed the accuracy of PET in staging 54 patients with epithelial MPM. For stage II disease PET had an accuracy of 86% with sensitivity and specificity of 100% and 84.6%, respectively. For stage III disease, PET had similar accuracy of 83% with sensitivity and specificity of 83% and 100%, respectively. PET-CT was found to be more accurate than PET (P-0.05) and was observed to have 100% sensitivity and specificity for all disease stages.

6 S. Sharif et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) Clinical bottom line PET is useful diagnostic tool to identify and stage MPM and differentiate it from benign pleural disease. The above studies have found PET to be useful in the prediction of survival, determination of mortality risk and detection of metastases and recurrent disease. However, the combination of PET-CT produced superior diagnostic results than PET alone, highlighting the need for further prospective studies to refine the role of PET and PET-CT in different settings of MPM. References w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2: w2x Mavi A, Basu S, Cermik TF, Urhan M, Bathaii M, Thiruvenkatasamy D, Houseni M, Dadparvar S, Alavi A. Potential of dual time point FDG-PET imaging in differentiating malignant from benign pleural disease. Mol Imaging Biol 2009;11: w3x Yamamoto Y, Kameyama R, Togami T, Kimura N, Ishikawa S, Yamamoto Y, Nishiyama Y. Dual time point FDG PET for evaluation of malignant pleural mesothelioma. Nucl Med Commun 2009;30: w4x Flores R. The role of PET in the surgical management of malignant pleural mesothelioma. Lung Cancer 2005;49(Suppl 1):S27 S32. w5x Flores RM, Akhurst T, Gonen M, Zakowski M, Dycoco J, Larson SM, Rusch VW. Positron emission tomography predicts survival in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2006;132: w6x Bénard F, Sterman D, Smith RJ, Kaiser LR, Albelda SM, Alavi A. Prognostic value of FDG PET imaging in malignant pleural mesothelioma. J Nucl Med 1999;40: w7x Nowak AK, Francis RJ, Philips MJ, Miliward MJ, van der Schaaf AA, Boucek J, Musk AW, McCoy MJ, Segal A, Robins P, Byrne MJ. A novel prognostic model for malignant meosthelioma incorporating quantitative FDG-PET imaging with clinical parameters. Clin Cancer Res 2010;16: w8x Ceresoli G, Chiti A, Zucali PA, Rodari M, Lutman RF, Salamina S, Incarbone M, Alloisio M, Santoro A. Early response evaluation in malignant pleural mesothelioma by positron emission tomography with w18fxfluorodeoxyglucose. J Clin Oncol 2006;24: w9x Francis RJ, Byrne MJ, van der Schaaf AA, Boucek JA, Nowak AK, Phillips M, Price R, Patrikeos AP, Musk AW, Millward MJ. Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial F-FDG PET scans. J Nucl Med 2007;48: w10x Nanni C, Castellucci P, Farsad M, Pinto C, Moretti A, Pettinato C, Marengo M, Boschi S, Franchi R, Martoni A, Monetti N, Fanti S. Role of 18F-FDG PET for evaluating malignant pleural mesothelioma. Cancer Biother Radiopharm 2004;19: w11x Yan TD, Boyer M, Tin MM, Sim J, Kennedy C, McLean J, Bannon PG, McCaughan BC. Prognostic features of long-term survivors after surgical management of malignant pleural mesothelioma. Ann Thorac Surg 2009;87: w12x Wilcox BE, Subramaniam RM, Peller PJ, Aughenbaugh GL, Nichols III FC, Aubry MC, Jett JR. Utility of integrated computed tomography-positron emission tomography for selection of operable malignant pleural mesothelioma. Clin Lung Cancer 2009;10: w13x Yildirim H, Metintas M, Entok E, Ak G, Ak I, Dundar E, Erginel S. Clinical value of fluorodeoxyglucose-positron emission tomographyycomputed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease. J Thorac Oncol 2009;4: w14x Lee ST, Ghanem M, Herbertson RA, Berlangieri SU, Byrne AJ, Tabone K, Mitchell P, Knight SR, Feigen M, Scott AM. Prognostic value of 18F-FDG PETyCT in patients with malignant pleural mesothelioma. Mol Imaging Biol 2009;11: w15x Tan C, Barrington S, Rankin S, Landau D, Pilling J, Spicer J, Cane P, Lang-Lazdunski L. Role of integrated 18-fluorodeoxyglucose positron emission tomography-computed tomography in patients surveillance after multimodality therapy of malignant pleural mesothelioma. J Thorac Oncol 2010;5: w16x Plathow C, Staab A, Schmaehl A, Aschoff P, Zuna I, Pfannenberg C, Peter SH, Eschmann S, Klopp M. Computed tomography, positron emission tomographyycomputed tomography and magnetic resonance imaging for staging of limited pleural mesothelioma. Invest Radiol 2008;43: ecomment: What is the best way to diagnose and stage malignant pleural mesothelioma? Authors: Stefano Cafarotti, Department of Thoracic Surgery, Catholic University, Rome, Italy; Venanzio Porziella, Stefano Margaritora, Pierluigi Granone doi: /icvts a We have read with great interest the article by Sharif et al. w1x reporting on the role of positron emission tomography-computed tomography (PET- CT) imaging in the diagnosis and prognosis of malignant pleural mesothelioma (MPM). There are many diagnostic modalities to identify patients with MPM. Currently, there is no consensus as to which single modality should be used to confirm diagnosis prior to surgery. Increasingly, PET-CT is playing a crucial role in the assessment of patients with known or suspected MPM due to its capacity for: 1. differentiation from benign pleural diseases, 2. high sensitivity in preoperative staging for the selection of appropriate surgical candidates, 3. post-treatment surveillance for recurrence, 4. evaluation of therapeutic response. PET-CT seems to be superior to other imaging modalities in detecting more extensive disease involvement, and in identifying unsuspected occult distant metastases. However, surgical or radiological pleural biopsy still provides the most accurate definitive diagnosis in MPM, as reported by the authors themselves in another published paper w2x, although it is a more invasive procedure than PET-CT. If indeed it is true that PET-CT increases the accuracy of overall staging in patients with MPM and significantly improves the selection of patients for curative surgical resection, it is also true that histological confirmation is required and mandatory due to the evidence that histological subtype is an established prognostic factor in malignant pleural mesothelioma w3x. The current diagnostic gold standard is principally based on light microscopic examination of hematoxylin-eosin and immunohistochemical stains of large tissue sections or cellular tissue. Indeed pathological diagnosis of MPM and classification of histological findings into one of the three subtypes (epithelial, sarcomatoid, biphasic) are necessary to evaluate the impact on prognosis. In conclusion, to achieve accurate diagnosis of MPM, obtaining cellular or large tissue samples in the initial examination is recommended. The integration of PET-CT and biopsy offers the best way to diagnose and stage MPM. References w1x Sharif S, Zahid I, Routledge T, Scarci M Does positron emission tomography offer prognostic information in malignant pleural mesothelioma? Interact CardioVasc Thorac Surg 2011;12: w2x Zahid I, Sharif S, Routledge T, Scarci M. What is the best way to diagnose and stage malignant pleural mesothelioma? Interact Cardio- Vasc Thorac Surg 2011;12: w3x Kao SC, Yan TD, Lee K, Burn J, Henderson DW, Klebe S, Kennedy C, Vardy J, Clarke S, van Zandwijk N, McCaughan BC. Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. J Thorac Oncol 2011 Jan 24. wepub ahead of printx. Work in Editorial New Ideas Progress Report Protocol Institutional Report ESCVS Article Proposal for Bailout Procedure Negative Results Follow-up Paper State-of-the-art Best Evidence Topic Nomenclature Historical Pages Brief Case Report Communication