Pleural effusion in patients with extrapleural primary malignancies

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1 ORIGINAL ARTICLE Differentiation Between Malignant and Benign Pleural Effusion in Patients With Extra-Pleural Primary Malignancies Assessment With Positron Emission Tomography-Computed Tomography Jacob S. Toaff, MD,* Ur Metser, MD,* Maya Gottfried, MD, Odelia Gur, MD, Maher E. Deeb, MD, Gennady Lievshitz, MD,* Diego Mercer, MD, and Einat Even-Sapir, MD, PhD* Objectives: We sought to define an accurate diagnostic approach for differentiating benign from malignant pleural effusion on positron emission tomography computed tomography (PET-CT). Material and Methods: PET-CT studies of 31 patients with primary extrapleural malignancy and pleural effusion were reviewed retrospectively. CT parameters assessed were size and density (Hounsfield units, or HU) of the effusion and density (HU) and morphology of any solid pleural abnormality. Interpretation of PET data included review of the attenuation-corrected and nonattenuation-corrected images. Results: PET-CT parameters that were found to be significant in identifying malignant pleural effusion included focal increased uptake of 18-fluorodeoxyglucose in the pleura (P ) and the presence of solid pleural abnormalities on CT (P 0.002): the sensitivity was 86% and 71%, respectively, and the specificity was 90% for each of the 2 parameters. A PET-CT pattern composed of pleural uptake and increased effusion activity on nonattenuationcorrected images was associated with sensitivity of 95%, specificity of 80%, positive predictive value of 91%, negative predictive value of 89%, and accuracy of 90%. Conclusions: On PET-CT, the presence of concomitant pleural abnormalities is the most accurate criterion in determining the malignant nature of pleural effusion. Received October 13, 2004 and accepted for publication, after revision, December 12, From the *Departments of Nuclear Medicine, Hematology, and Radiology, Tel-Aviv Sourasky Medical Center; Lung Cancer Unit, Meir Hospital Sapir Medical Center, Tel-Aviv; Department of Cardio Thoracic Surgery, Shaare Zedek Medical Center, Jerusalem; and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Reprints: Einat Even-Sapir, MD, PhD, Department of Nuclear Medicine, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel-Aviv, Israel. evensap@tasmc.health.gov.il. Copyright 2005 by Lippincott Williams & Wilkins ISSN: /05/ Key Words: PET-CT, pleural, effusion, malignant, lung cancer (Invest Radiol 2005;40: ) Pleural effusion in patients with extrapleural primary malignancies such as lung cancer, melanoma, or lymphoma may represent metastatic disease or reactive fluid collection or be the result of other nonmalignant disease processes such as infection. The diagnosis of malignant pleural effusion adversely affects the staging and prognosis and may alter the therapeutic approach. In nonsmall cell lung cancer, for instance, patients are unlikely to benefit from surgical resection if they have stage IIIB or stage IV disease. Malignant pleural effusion indicates locally extensive tumor (stage T4) and stage IIIB disease. 1 In Hodgkin disease and non-hodgkin lymphoma, malignant pleural effusion upgrades the stage to IV. 2 Several tests have been used to assess the nature of effusion in oncologic patients, including thoracocentesis with cytologic and/or biochemical analysis, computed tomography (CT), magnetic resonance imaging, blind or open-needle biopsy, and thoracoscopy. 3 Positron emission tomography (PET) using 18-fluorodeoxyglucose (FDG) has been shown to be an accurate imaging modality in differentiating benign from malignant disease processes, and previous reports have suggested that PET is an accurate diagnostic tool in differentiating benign from malignant pleural effusion in patients with malignant disease. 4 9 The CT part of the PET-CT may be the first to identify the presence of unexpected pleural effusion, increasing the need to differentiate malignant from benign pleural involvement when interpreting the PET-CT study. The purpose of the current study was to define the most accurate criteria to be used for such differentiation. We evaluated various CT and PET parameters, characterizing Investigative Radiology Volume 40, Number 4, April 2005

2 Investigative Radiology Volume 40, Number 4, April 2005 Differentiation Between Malignant and Benign Pleural Effusion pleural effusion in patients with primary extrapleural malignant diseases undergoing evaluation by PET-CT. MATERIALS AND METHODS Patient Population We conducted a retrospective study of 31 patients (25 men and 6 women; age range, years; mean age, 64 years) who had pleural effusion on PET-CT. Patients enrolled in the current study met the following inclusion criteria: (1) definitive pathologic diagnosis of a primary extrapleural malignancy and (2) definitive pathologic diagnosis of the pleural involvement. A positive malignant pleural effusion was concluded either by thoracocentesis of effusion or pleural biopsy performed within 6 weeks of the PET-CT examination. A negative pleural effusion was concluded if at least 2 cytologic results were negative for malignancy. Patients with pleural effusion who had (1) neither a cytologic nor a histologic assessment of the pleural disease, (2) a time gap longer than 6 weeks between thoracocentesis and PET-CT, or (3) a single negative cytologic result were not enrolled. PET-CT Scanning Patients were asked to fast for at least 4 hours before undergoing the examination. All patients had glucose levels less than 150 mg/dl. The patients received an intravenous injection of MBq (10 18 mci) of 18 F-FDG. Data were acquired minutes after injection using an integrated in-line PET-CT system (Discovery LS; GE Medical Systems). Data acquisition was as follows: CT scanning was performed first, from the head to the midthigh, with 140 kv, 80 ma, a tube rotation time of 0.5 seconds, a pitch of 6, and a 5-mm section thickness, which matched the PET section thickness. Immediately after CT scanning, a PET emission scan was obtained that covered the identical transverse field of view. The acquisition time was 5 minutes per table position. PET image datasets were reconstructed iteratively using CT data for attenuation correction, and coregistered images were displayed on a workstation (Xeleris, Elgems, Israel). Interpretation of 18 F-FDG PET-CT Images were interpreted by 2 specialists, in a consensus reading. Physicians interpreting the PET/CT data (U.M., E.E.S.) were blinded to the final diagnosis of the pleural abnormality. A third physician (Y.T.), who did not participate in the interpretation of the PET/CT, was responsible for assessment of the final diagnosis of the pleural findings. The parameters assessed on the CT data were size, location, and density (Hounsfield units, or HU) of the pleural effusion and density (HU) and morphology of any solid pleural abnormality. Pleural effusion size was defined as the maximal anteroposterior depth on supine images. Solid pleural abnormalities were defined as either diffuse or nodular thickening (Fig. 1). The interpretation of PET data included review of both the attenuation corrected (AC) and nonattenuation-corrected (NAC) images. On the AC images, 18 F-FDG uptake in the pleural effusion and pleural abnormalities was visually classified using a 3-grade-scale: grade 1 less than mediastinal activity; grade 2 equal or greater than mediastinal activity but less than liver activity; and grade 3 equal or grater than liver activity. On the NAC images, uptake in the fluid and/or pleural lesions was considered positive if equal to or greater than lung activity and negative if less (Fig. 2). The maximal standard uptake values (SUVs) of the fluid and pleural lesions were recorded. The PET CT-fused images were used to assess the exact anatomic location of 18 F-FDG uptake, thus allowing the differentiation between increased uptake in pleural layers and increased uptake within the effusion itself. Statistical Analysis The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy in differentiating benign from malignant pleural disease were calculated for CT and PET parameters. For nonparametric parameters (the presence of pleural abnormalities and FDG uptake relative to lung, mediastinal, and liver activity) 2 test and the Fisher exact test were used. For parametric parameters (HU, fluid size, and SUV) the Mann Whitney U test was used. A receiver operating curve analysis was used to assess the size, HU and SUV measured in pleural effusion, which best separated between benign and malignant effusion. Logistic regression for all CT and PET parameters was performed. Statistical analysis was performed using the SSPS for windows package, version 11 (Chicago, IL). RESULTS Malignant Effusion Twenty-one patients had malignant pleural disease based on thoracocentesis (n 19) and pleural biopsy (n 2). Primary sites of malignancy were lung cancer (nonsmall cell lung cancer, n 12; small cell lung cancer, n 2), lymphoma (n 5), ovarian cancer (n 1), and melanoma (n 1). On CT images, pleural effusion was unilateral in all patients but one. Pleura Eighteen of the 21 patients had pleural abnormalities. All solid pleural abnormalities detected on the CT part of the study in 15 patients were associated with increased uptake on AC and NAC images and were graded 3 on the AC images. The pleural surface was nodular (n 13), diffusely thickened (n 2), or normal (n 6) on CT. The mean density of these solid pleural abnormalities was HU, range HU. In 3 additional patients, focal increased uptake was detected in the corresponding location of the pleura, although CT imaging failed to detect a clear pleural abnormality. The 2005 Lippincott Williams & Wilkins 205

3 Toaff et al Investigative Radiology Volume 40, Number 4, April 2005 FIGURE 1. Malignant pleural involvement. The images from left to right represent CT, attenuation corrected PET, nonattenuationcorrected PET, and a fused PET-CT images. Upper row, a band of pleural thickening on CT image (arrow) with increased FDG uptake (arrow). Middle row, a pleural nodule on CT image (arrow) with corresponding increased FDG uptake (arrow). Bottom row, an area of increased pleural uptake on fused PET-CT images (arrow) is located in otherwise barely visible area of pleural thickening on CT image (arrow). Please note that despite the malignant pleural involvement, the effusion itself does not show increased FDG uptake both on the attenuation-corrected and nonattenuation-corrected PET images. mean SUV in pleural abnormalities was , range Effusion The mean effusion size was cm, range cm, and the mean density was HU, range-1-20 HU. On NAC PET images, 8 of 21 patients (38%) had increased uptake in the pleural effusion (equal or greater than lung uptake). On the AC PET images, uptake in the pleural effusion was graded 1 (less than mediastinal activity) in 9 patients, 2 (equal or greater than mediastinal activity but less than liver activity) in 4 patients, and 3 (equal or grater than liver activity) in 8 patients. The mean SUV in the pleural effusion was , range In 3 patients, we identified increased 18 F-FDG uptake within the fluid in dependent location (posterior when the patient is in supine position). Benign Effusion Ten patients had benign pleural effusion based on thoracocentesis (n 9) and thoracoscopy (n 1). Primary sites of malignancy were nonsmall cell lung cancer (n 5): small cell lung cancer (n 1) and lymphoma (n 4). The pleural surface was nodular in only 1 patient and normal in 206 the 9 remaining patients. On CT images, pleural effusion was unilateral in all cases. The mean size was cm, range cm, and the mean density was HU, range On NAC PET images, one patient had increased uptake in the pleural effusion. On the AC PET images, uptake in the pleural effusion was graded 1 in 4 patients, 2 in 4 patients, and 3 in 2 patients. Mean SUV in the pleural effusion was , range Differentiation Between Malignant and Benign Effusion Table 1 summarizes the results of received operating curve analysis for the size, density (HU), and uptake (SUV) in the pleural effusion and the sensitivity, specificity, PPV, NPV, and accuracy of CT and PET parameters in differentiating benign and malignant pleural disease. Two parameters were found statistically significant in differentiating between benign and malignant effusion on univariable analysis: solid pleural abnormalities on CT images detected in 15 of 21 patients with malignant pleural disease (P 0.002) and increased uptake in the pleural region on PET images detected in 18 of the 21 patients (P ). The sensitivity of PET in identifying pleural involvement was higher than that of CT alone. However, the 2005 Lippincott Williams & Wilkins

4 Investigative Radiology Volume 40, Number 4, April 2005 Differentiation Between Malignant and Benign Pleural Effusion FIGURE 2. Pleural effusion. The images from left to right represent CT, attenuation-corrected (AC) PET, nonattenuation-corrected (NAC) PET, and fused PET CT images. Upper row, the fluid (long arrow) is attenuated compared with the lung (short arrow) on NAC PET image. Midddle row, the fluid activity (long arrow) is similar to the activity in the aorta (arrowhead) on AC PET image. The PET lesion on the right is uptake in the primary lung tumor. This finding was clearly visualized when applying a lung CT windowing. The latter, however is not appropriate for assessment of pleural abnormalities on the CT data. Bottom row, fluid uptake (long arrow) is similar to that in liver (arrowhead) on AC PET image and to the lung (arrowhead) on NAC PET image. CT allowed us, on the fused images, to accurately locate the increased FDG uptake in the pleura and not in the adjacent fluid, lung, or chest wall. Only 1 of the 10 patients with benign effusion had nodular pleural thickening with increased FDG uptake (false positive). This patient had nonsmall cell cancer of the lung, and his effusion was parapneumonic. Although increased uptake within the fluid on NAC was associated with a high PPV (89%), none of the parameters of the effusion itself was statistically significant on univariable analysis in differentiating benign from malignant effusion. For assessment of the pleural fluid alone, we used a logistic regression analysis to find a combination of parameters that may assist in differentiating between benign and malignant effusion. Using a stepwise forward selection method, a model was obtained that identified the combination of pleural effusion size (P 0.016) and increased uptake on NAC PET images in the effusion (P 0.013) as adequate for differentiation. The probability for malignancy based on combination of these 2 parameters is illustrated in Table 2. Increased fluid FDG uptake on NAC images had a probability for malignancy, which varied between 81% and 98% as fluid size increased. Two of 3 patients with malignant effusion who did not have a concomitant pleural abnormality had increased FDG uptake on NAC PET. A PET-CT pattern composed of pleural uptake and increased effusion activity on NAC images was associated with sensitivity of 95%, specificity of 80%, PPV of 91%, NPV of 89%, and accuracy of 90%. DISCUSSION Metastatic involvement of the pleura may be present in various extrapleural malignancies. However, not all cases of pleural effusion found in these patients indicate metastatic disease and may often be the result of cardiac failure, infection, or other benign causes. Malignant pleural effusion upgrades the stage, precludes resection of the primary tumor, and heralds a grave prognosis for the patient; hence, it is of major importance to correctly differentiate between benign and malignant pleural effusion. 1,2 Morphologic imaging, including CT and magnetic resonance imaging, cannot be relied 2005 Lippincott Williams & Wilkins 207

5 Toaff et al Investigative Radiology Volume 40, Number 4, April 2005 TABLE 1. The Diagnostic Accuracy of CT and PET in Differentiating Malignant From Benign Pleural Effusion Parameter SEN SPE PPV NPV AC CT Presence of solid pleural abnormalities Effusion density HU cutoff* Effusion size 10-cm cutoff* cm cutoff* PET Effusion Increased uptake on AC images Grade 3 cutoff Grade 2 cutoff SUV 1.7 cutoff* Increased uptake on NAC images Pleural abnormalities Increased uptake on PET images *Determined by ROC analysis. CT, computed tomography; PET, positron emission tomography; SEN, sensitivity; SPEC, specificity; PPV, positive predictive value; NPV, negative predictive value; AC, accuracy. TABLE 2. Logistic Regression Analysis: The Probability of Malignant Effusion Based on a Combination of Pleural Effusion Size and Increased Uptake in the Effusion on Nonattenuation-Corrected Images Increased FDG Uptake in Pleural Effusion (NAC) Pleural Effusion Size (cm) Probability of Malignant Effusion (%) No 1 12 Yes 1 81 No 3 21 Yes 3 88 No 6 38 Yes 6 95 No 9 60 Yes 9 98 upon when performed alone Invasive modalities often are warranted to establish the diagnosis of the effusion, the most common being thoracocentesis. Cytologic analysis of pleural effusion identifies malignancy in approximately two thirds of the cases of malignant pleural effusion. 13 Often, a repeated thoracocentesis is performed, which identifies a positive specimen in another 30% of cases. 14 Similarly, biochemical analysis of the pleural fluid fails to accurately differentiate between benign and malignant effusion Thoracoscopy has an excellent diagnostic yield ( 95%) 18 but is invasive and requires a trained surgical staff and appropriate facilities. 208 Several recent studies have shown FDG-PET to have an important role in differentiating benign from malignant pleural effusion in patients with nonpleural malignancies with sensitivity ranging between 88% and 100% and specificity of 67% to 94%. 4 9 Schaffler et al, 8 in a study involving 92 patients with nonsmall cell lung cancer and pleural abnormalities, showed that the respective sensitivity, specificity, PPV, NPV, and accuracy of FDG-PET in detection of pleural involvement were 100%, 71%, 63%, 100%, and 80%. When CT findings performed separately were combined with those of PET, the specificity increased from 71% to 76%, the PPV increased from 63% to 67%, and the accuracy increased from 80% to 84%. The relatively low specificity and PPV were caused by false positive increased FDG uptake in infection. Duysinx et al 7 evaluated the ability of FDG-PET to differentiate between benign and malignant pleural disease in 98 patients who presented with pleural thickening and/or an exudative pleural effusion. The respective sensitivity, specificity, PPV, and NPV were 96.8%, 88.5%, 93.8%, and 93.9%. Functional imaging with FDG has been reported to be of clinical value in various human malignancies. 19,20 Recently, the use of PET-CT hybrid systems for the evaluation of patients with malignant diseases has become more common. Detection of a pleural effusion on the CT part of the study may be, in some cases, the first imaging modality to identify the presence of pleural effusion. When interpreting the PET-CT study, a question emerges as to what is the most accurate diagnostic approach to determine the nature of this effusion. The anatomic congruity between the CT and PET scans performed consecutively without moving the patient 2005 Lippincott Williams & Wilkins

6 Investigative Radiology Volume 40, Number 4, April 2005 Differentiation Between Malignant and Benign Pleural Effusion between scans provides an option to define the precise anatomic location of increased FDG uptake (ie, in areas of nodular pleural thickening, in pleural fluid, or normal appearing pleural surface). The aim of this study was to define an approach to pleural effusion based on various parameters that may be determined on the CT and PET parts of the study. As indicated by the results of the current study, abnormality of the pleura itself is the most accurate sign for malignancy when assessing the nature of pleural effusion detected on PET-CT. PET was more sensitive than CT alone in identifying pleural involvement. In addition to being positive in 15 patients with a corresponding pleural abnormality on CT, it identified pleural involvement in 3 additional patients in whom increased uptake was detected in the pleural layer, although no corresponding CT abnormality was identified. This pleural involvement would have been overlooked on CT alone. However, CT allowed us, based on the fused images, to accurately relate this increased FDG uptake to the pleura and not to adjacent fluid, lung, or chest wall. A single case of false-positive increased pleural uptake with morphologic CT pleural abnormalities was caused by infection. As for the effusion itself, the combination of large effusion with increased FDG uptake on NAC images was found to be highly suggestive for malignancy, reaching a probability of 98%. Identifying this effusion pattern was of particular importance in patients who did not have concomitant pleural abnormalities. In this study, better results were achieved for NAC images than for AC images in differentiating malignant from benign effusion. In a previous publication by Wahl et al, 21 it was shown that in lung cancer, the target-to-background (ie, lesion to blood) ratios are significantly higher for NAC images than for AC images. The latter could also be the cause for the current study s results assessing chest abnormalities. Focal increased uptake within the posterior portion of the fluid, is a finding that, although relatively infrequent (3/21 patients with malignant pleural effusion), was highly specific for malignancy. A possible explanation for this finding may be uptake in malignant cells accumulating in dependent location when data are acquired in the supine position. The main limitation of our study is the relatively small number of patients, a result of our strict inclusion criteria. Studies with a larger number of patients need to be conducted to validate our results. In addition, this study was retrospective. However, the physicians interpreting the PET CT were blinded to the final diagnosis of the pleural abnormality whereas a third physician who did not participate in imaging interpretation was responsible for assessment of the final diagnosis. In conclusion, the most accurate parameter to be considered when identifying pleural effusion on PET-CT is the presence of increased FDG uptake in the pleura, whether associated with pleural CT abnormality or not. Increased FDG uptake in the effusion itself on NAC images, especially in large effusions, has a high probability for malignant effusion. ACKNOWLEDGMENTS The authors thank Rony Rona for her assistance with the cytologic analysis of the pleural effusion. REFERENCES 1. Mountain CF. Revisions in the international system for staging lung cancer. Chest. 1997;111: Armitage JD, Longo DL. Malignancies of lymphoid cells. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. 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