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Published online before print April 22, 2004, 10.1148/radiol.2313030785
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(Radiology 2004;231:858-865.)
© RSNA, 2004

Nuclear Medicine

Non–Small Cell Lung Cancer: Evaluation of Pleural Abnormalities on CT Scans with 18F FDG PET1

Gottfried J. Schaffler, MD, Gerald Wolf, MD, Helmut Schoellnast, MD, Reinhard Groell, MD, Alfred Maier, MD, Freya M. Smolle-Jüttner, MD, Michael Woltsche, MD, Gerlinde Fasching, MD, Rudolf Nicoletti, PhD and Reingard M. Aigner, MD

1 From the Departments of Radiology (G.J.S., G.W., H.S., R.G., R.N., R.M.A.), Surgery (A.M., F.M.S.J.), and Pulmonology (G.F.), University Hospital Graz, Auenbruggerplatz 9, A-8036 Graz, Austria; and Department of Pulmonology, County Hospital Hörgas-Enzenbach, Gratwein, Austria (M.W.). Received May 25, 2003; revision requested July 17; final revision received October 29; accepted November 6. Address correspondence to G.J.S. (e-mail: gottfried.schaffler@kfunigraz.ac.at).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the accuracy of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in differentiation of pleural malignancy and cancer-unrelated pleural disease in patients with non–small cell lung cancer (NSCLC) and pleural abnormalities at computed tomography (CT).

MATERIALS AND METHODS: In 92 patients, pleural abnormalities were detected at contrast material–enhanced thoracic CT, which was performed for newly diagnosed NSCLC (n = 41) or restaging (n = 51). CT findings were negative for pleural malignancy when pleural effusion with attenuation of 10 HU or less and/or rib fractures with no evidence of pathologic fracture were present; findings were indeterminate when pleural effusion with attenuation greater than 10 HU and/or solid pleural abnormalities without osseous destruction of the chest wall were present; and findings were positive if any osseous destruction of the chest wall adjacent to a pleural mass was present. All patients underwent FDG PET. Findings were negative for pleural malignancy if pleural activity was absent, equal to, or less than mediastinal background activity; findings were positive if pleural activity was higher than mediastinal background activity. Reading of CT and FDG PET scans was first performed separately and then was combined. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPP), and accuracy were calculated for CT and FDG PET separately and for CT and FDG PET combined, with cytologic and/or histologic analysis as standard of reference.

RESULTS: In detection of pleural malignancies, CT findings were indeterminate in 65 (71%) patients and true-negative in 27 (29%). Respective sensitivity, specificity, PPV, NPV, and accuracy of FDG PET in detection of pleural malignancies were 100%, 71%, 63%, 100%, and 80%; and those of CT and FDG PET combined, 100%, 76%, 67%, 100%, and 84%.

CONCLUSION: Findings suggest that a negative FDG PET scan for indeterminate pleural abnormalities at CT indicates a benign character, while positive findings on an FDG PET scan are sensitive for malignancy.

© RSNA, 2004

Index terms: Lung neoplasms, 60.321, 60.33 • Lung neoplasms, CT, 60.12112, 60.12115 • Lung neoplasms, PET, 60.12163 • Pleura, CT, 66.12112 • Pleura, neoplasms, 66.317, 66.33 • Pleura, PET, 66.12163


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Lung cancer is the most frequent cause of cancer-related death in the Western world (1). Standardized guidelines regarding noninvasive and invasive procedures were established to provide accurate information regarding the status of primary or recurrent non–small cell lung cancer (NSCLC) (2,3). The strong rationale for accurate staging is to provide prognostic information and to select patients who will benefit from surgery (3). Patients who are unlikely to benefit from surgical resection are those with stage IIIB or IV disease; these include patients with contralateral or supraclavicular lymph node metastases (stage N3), distant metastases (stage M1), or locally extensive tumor (stage T4) (3). T4 stage tumors are those that invade vital mediastinal structures and are also associated with malignant pleural effusion and/or diffuse pleural metastases. Conversely, tumors that locally invade the chest wall are considered technically resectable and are classified as stage T3.

Computed tomography (CT) has become the major imaging modality of choice for the evaluation of patients with NSCLC. In patients with NSCLC, any pleural abnormality depicted at CT, either pleural effusion or solid pleural thickening, is highly suggestive of a T4 stage tumor, until proved otherwise (4–7). Since CT, as well as magnetic resonance (MR) imaging, may be ineffective in the differentiation between locally extensive disease with malignant pleural effusion or distant pleural metastases and benign cancer-unrelated pleural abnormalities, further invasive diagnostic procedures are frequently required (4–7).

Whole-body positron emission tomography (PET) with fluorine 18 (18F) fluorodeoxyglucose (FDG) has proved useful for primary and recurrent lung cancer, particularly in determining the presence of both regional lymph nodes and distant disease (8–18). Preliminary results regarding the potential role of FDG PET in pleural diseases are promising (3,19–22). However, because of the limited number of patients and a variable primary cancer included in previous studies, authors have advocated further investigation on this issue (3,19–22).

The aim of this study was to evaluate the accuracy of 18F FDG PET in the differentiation of pleural malignancy and cancer-unrelated pleural disease in patients with NSCLC and pleural abnormalities at CT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A retrospective computer-based data search yielded names of 442 patients who underwent 18F FDG PET for the evaluation of a pulmonary mass at the University Hospital Graz between September 1998 and December 2002. Of these, 334 patients had histologically proved NSCLC. Only patients who met the inclusion criteria were included in the study.

The inclusion criteria were (a) contrast material–enhanced thoracic CT and whole-body 18F FDG PET for staging or restaging purpose; (b) a definitive diagnosis of any pleural abnormality obtained with diagnostic thoracentesis or biopsy; and (c) performance of CT first, followed by 18F FDG PET and cytologic or histologic analysis within a 2-week period. The exclusion criterion was any cancer-related therapy administered between the CT and 18F FDG PET study.

The final study group consisted of 92 patients with abnormalities of the pleural space. The mean patient age was 57.9 years (range, 43–81 years). There were 62 men (mean age, 57 years; age range, 43–78 years) and 30 women (mean age, 63 years; age range, 49–81 years). There was no statistically significant difference in patient age between men and women (P > .05, two-sample t test). The subtypes of all histologically proved NSCLCs of the study group are listed in Table 1. The mean interval between 18F FDG PET and the cytologic and/or histologic analysis of the pleura was 8 days (range, 0–14 days).


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  		TABLE 1. Subtypes of Histologically Proven NSCLC in Newly Diagnosed and Restaged Lung Cancer

 
Patients in the study were divided into two groups: Group A included all patients who had a newly diagnosed NSCLC (n = 41) and group B included all patients who underwent 18F FDG PET and thoracic CT for the purpose of restaging NSCLC after therapy (surgery and chemotherapy and/or radiation therapy) (n = 51). In group B, the mean interval between the end of therapy and 18F FDG PET was 24 weeks (range, 12–112 weeks).

To avoid bias, the medical records were reviewed by one of the authors (H.S.) who was not involved in the interpretation of CT and PET data. Since this was a retrospective study, it included only patients undergoing routine thoracic CT and 18F FDG PET for staging or restaging purpose. No institutional review board approval and no informed consent were required for the review of the patient data, per our institutional guidelines. However, all patients undergoing 18F FDG PET at our institution signed informed consent to document that they had been informed in a proper way regarding the basic principles of this imaging modality.

Imaging Studies and Interpretation
CT study.—All patients underwent routine contrast-enhanced thoracic CT. One hundred milliliters of nonionic contrast agent (Ultravist; Schering, Berlin, Germany) containing 300 mg of iodine per milliliter was intravenously administered. CT scans were obtained either with a spiral (Somatom Plus4; Siemens, Erlangen, Germany) or an electron-beam (Evolution; Siemens) scanner, with a section thickness of 4 or 6 mm, respectively.

Although differences exist between CT findings of benign and those of malignant pleural abnormalities, the value of CT in the determination of malignant pleural disease without chest wall invasion is somewhat limited. The only CT finding with highly positive predictive value (PPV) is bone destruction adjacent to a lung mass or obvious extension of the mass beyond the ribs into the chest wall (4,6,7,23). For the purpose of this study, the transverse CT scans were reevaluated at our institution by a board-certified radiologist (R.G.) with 10 years experience interpreting thoracic CT findings and 2 years experience interpreting 18F FDG PET findings, with specific regard to identification and classification of abnormalities of the pleural space. The following criteria were used: (a) a pleural effusion with attenuation of 10 HU or less was classified as transudate and was thus unlikely to be a pleural malignancy, (b) rib fractures with no evidence of pathologic fracture were classified as benign, (c) a pleural effusion with attenuation greater than 10 HU and/or solid pleural abnormalities without adjacent osseous destruction were classified as indeterminate, and (d) a pleural mass associated with osseous destruction of the chest wall was classified as positive for malignancy. Isolated abnormalities of the pleura on a CT scan were counted separately, whereas contiguous pleural abnormalities were counted as one lesion. The radiologist was blinded to other clinical or radiologic information.

18F FDG PET study.—PET scanning was performed by using a dedicated PET scanner (ECAT EXACT HR+; Siemens/CTI, Knoxville, Tenn). The transverse field of view was 15.5 cm, and 63 image planes were produced. Transmission scans were obtained by using rotating germanium 68 rod sources after 18F FDG injection. Transmission scans were reconstructed by using filtered back-projection with a three-dimensional smoothing. Emission scans from the base of the skull to the pelvis were obtained starting 60–70 minutes after the injection of 300–375 MBq 18F FDG. Acquisition time per bed position was 9 minutes, two-thirds of this time was used for emission data acquisition and one-third was used for transmission data acquisition. Images were reconstructed with attenuation-weighted ordered-subset expectation maximization by using emission scans and reprojected attenuation maps as inputs. All ordered-subset expectation maximization reconstructions were performed with two iterations and eight subsets. Emission data were corrected for scatter, random events, and dead-time losses by using the manufacturer’s software.

All patients fasted for 4–6 hours prior to 18F FDG PET scanning. Prior to fasting, they were recommended to eat only a high-protein low-carbohydrate meal to minimize cardiac activity. All patients were tested for a normal glucose level (range, 80–120 mg/dL [4.4–6.7 mmol/L]) immediately before beginning 18F FDG PET scanning. The pixel size was 3 mm in a 128 x 128 array. Only the thoracic sequences were extracted from the whole-body 18F FDG PET scan for further visual analysis. Images were reconstructed in all three standard planes and were reviewed in consensus by one nuclear medicine physician (G.W.) with 4 years experience interpreting 18F FDG PET scans and one board-certified radiologist (G.J.S.) with 3 years experience interpreting 18F FDG PET scans using film hard-copy images in combination with an interactive video display during a joint reading session to assess focal or diffuse pleural 18F FDG uptake. The nuclear medicine physicians were blinded to other clinical or radiologic information. In the case of diffuse pleural 18F FDG uptake, the area with the maximum pleural 18F FDG uptake was considered to be representative of pleural abnormality.

The 18F FDG uptake in the pleura was classified by using the following three-point grading scale (22): grade 0, no pleural activity; grade 1, increased pleural activity but less than or equal to the mediastinal background activity; and grade 2, pleural activity higher than mediastinal background activity. According to previous reports, a pleural abnormality with higher activity than that of the mediastinum on the attenuation-corrected images was considered malignant (19–22).

CT and 18 F FDG PET.—Combined reading of the corresponding CT and 18F FDG PET scans for all patients was performed by using the same criteria as those described earlier. Both CT and PET images were reviewed in consensus by two board-certified radiologists (R.G., G.J.S.) with 2 and 3 years of experience interpreting 18F FDG PET scans during a joint reading session on two reporting stations (MagicView 1000, Siemens, Erlangen [CT scans]; and Sun Ultra 60, Sun Microsystems, San Antonio, Tex [PET scans]) positioned side by side. Both physicians were blinded to other clinical or radiologic information.

Chemical, Cytologic, and Histologic Studies and Interpretation
Chemical, cytologic, or histologic analyses were performed for the final diagnosis of pleural abnormalities detected at CT.

In chemical analyses, pleural effusions were classified as exudates or transudates according to the criteria of Light et al (24). An exudate was considered if pleural effusion met at least one of the following three criteria: (a) ratio of pleural fluid total protein to serum total protein greater than 0.5, (b) ratio of pleural fluid lactic dehydrogenase to serum lactic dehydrogenase greater than 0.6, and (c) pleural fluid lactic dehydrogenase level greater than two-thirds of the upper limit of the normal value for serum lactic dehydrogenase. If the pleural effusion did not meet any of the criteria, it was considered to be a transudate. In addition, pleural effusions were evaluated with cytologic examinations for the presence of infectious organisms.

When chemical and cytologic analyses were negative or inconclusive, biopsy with histologic evaluation was performed to obtain final diagnosis. For that purpose, video-assisted thoracic surgery was performed by one of two board-certified thoracic surgeons (A.M., F.M.S.J.) with 10 years experience in this procedure, or ultrasonographically (US) guided biopsy was performed by one of two board-certified pulmonologists (G.F., M.W.) with 6 years experience in this procedure.

The chemical, cytologic, and/or histologic evaluation of the pleura was performed by at least one of three board-certified pathologists with at least 6 years experience performing these procedures. Chemical analysis yielded the final diagnosis in 38 patients (15 patients in group A and 23 patients in group B); in the remaining 54 patients, biopsy with histologic evaluation was necessary to obtain the final diagnosis (26 patients in group A and 28 patients in group B).

Statistical Analysis
According to the criteria described earlier, sensitivity, specificity, PPV, negative predictive value (NPV), and accuracy of CT and 18F FDG PET in identification of pleural malignancies were calculated for the whole study group, as well as separately for groups A and B. Analysis was performed for CT and 18F FDG PET separately and for CT and 18F FDG PET combined. Chemical, cytologic, and/or histologic results served as standard of reference in both analyses. No specific statistical software was used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Table 2 shows the chemically, cytologically, and/or histologically proved diagnosis of pleural abnormalities for the whole study group, as well as separately for groups A and B. Ninety-two pleural abnormalities were present in 92 patients.


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  		TABLE 2. Chemically, Cytologically, and/or Histologically Proven Diagnosis of Pleural Abnormalities

 
CT Reading
According to the criteria described earlier, CT findings were indeterminate in 65 patients. In the remaining 27 patients, CT findings were correctly reported as negative for pleural malignancy. By disregarding the fact that a report concerning the presence or absence of pleural malignancies was impossible in most cases (71% indeterminate analyses), CT had a specificity and an NPV of 100%.

18F FDG PET Reading
Pleural 18F FDG uptake was assigned grade 0 in 23 patients, grade 1 in 21 patients, and grade 2 in 48 patients (Table 3). All nonspecific pleural effusions (Fig 1) and all pleural scars (Fig 2) were correctly reported as negative for pleural malignancy. Three of five rib fractures with reactive pleuritis (Fig 3) and 15 of 16 pleural empyemas (Fig 4) were reported as false-positive for pleural malignancy. All pleural malignancies were correctly reported malignant (Fig 5).


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  		TABLE 3. Appearance of Pleural Abnormalities on 18F FDG PET Scans of the Whole Study Group

 


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  		Figure 1a. Images obtained after lobectomy of left lower lobe (18 months after surgery) in a 56-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows large left pleural effusion (arrows). (b) Coronal PET scan shows normal FDG uptake in left hemithorax. Intense FDG uptake in heart represents normal variation depending on metabolic status of myocardium. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan at level of lower lobes of lung shows normal pleural FDG uptake (grade 0) (arrows). Thoracentesis revealed transudate within left pleural space.

 


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  		Figure 1b. Images obtained after lobectomy of left lower lobe (18 months after surgery) in a 56-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows large left pleural effusion (arrows). (b) Coronal PET scan shows normal FDG uptake in left hemithorax. Intense FDG uptake in heart represents normal variation depending on metabolic status of myocardium. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan at level of lower lobes of lung shows normal pleural FDG uptake (grade 0) (arrows). Thoracentesis revealed transudate within left pleural space.

 


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  		Figure 1c. Images obtained after lobectomy of left lower lobe (18 months after surgery) in a 56-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows large left pleural effusion (arrows). (b) Coronal PET scan shows normal FDG uptake in left hemithorax. Intense FDG uptake in heart represents normal variation depending on metabolic status of myocardium. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan at level of lower lobes of lung shows normal pleural FDG uptake (grade 0) (arrows). Thoracentesis revealed transudate within left pleural space.

 


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  		Figure 2a. Images in a 63-year-old man with shortness of breath and NSCLC in the right upper lobe. (a) Transverse CT scan at level of upper lobes shows mild thickening of right pleura (indeterminate lesion) (arrow). (b) Coronal PET scan shows mild increased FDG uptake in right upper lobe and marked FDG uptake within mass (arrow) at the right hilum, representing squamous cell cancer. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows mild increased pleural FDG uptake (arrow) (grade 1). Histologic examination revealed postinflammatory scar tissue.

 


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  		Figure 2b. Images in a 63-year-old man with shortness of breath and NSCLC in the right upper lobe. (a) Transverse CT scan at level of upper lobes shows mild thickening of right pleura (indeterminate lesion) (arrow). (b) Coronal PET scan shows mild increased FDG uptake in right upper lobe and marked FDG uptake within mass (arrow) at the right hilum, representing squamous cell cancer. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows mild increased pleural FDG uptake (arrow) (grade 1). Histologic examination revealed postinflammatory scar tissue.

 


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  		Figure 2c. Images in a 63-year-old man with shortness of breath and NSCLC in the right upper lobe. (a) Transverse CT scan at level of upper lobes shows mild thickening of right pleura (indeterminate lesion) (arrow). (b) Coronal PET scan shows mild increased FDG uptake in right upper lobe and marked FDG uptake within mass (arrow) at the right hilum, representing squamous cell cancer. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows mild increased pleural FDG uptake (arrow) (grade 1). Histologic examination revealed postinflammatory scar tissue.

 


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  		Figure 3a. Images obtained after lobectomy of left lower lobe in a 63-year-old man with NSCLC. (a) Transverse CT scan just below carina shows subacute left rib fracture (12 weeks after surgery) with adjacent pleural soft tissue (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake in left lateral chest wall. Dotted line crosses area with the most FDG-avid uptake of left lateral chest wall and represents level at which a and c were obtained. (c) Transverse PET scan at level just below carina shows increased FDG uptake (arrow) in lateral chest wall (grade 2). US-guided biopsy revealed immature scar tissue without evidence of malignancy.

 


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  		Figure 3b. Images obtained after lobectomy of left lower lobe in a 63-year-old man with NSCLC. (a) Transverse CT scan just below carina shows subacute left rib fracture (12 weeks after surgery) with adjacent pleural soft tissue (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake in left lateral chest wall. Dotted line crosses area with the most FDG-avid uptake of left lateral chest wall and represents level at which a and c were obtained. (c) Transverse PET scan at level just below carina shows increased FDG uptake (arrow) in lateral chest wall (grade 2). US-guided biopsy revealed immature scar tissue without evidence of malignancy.

 


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  		Figure 3c. Images obtained after lobectomy of left lower lobe in a 63-year-old man with NSCLC. (a) Transverse CT scan just below carina shows subacute left rib fracture (12 weeks after surgery) with adjacent pleural soft tissue (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake in left lateral chest wall. Dotted line crosses area with the most FDG-avid uptake of left lateral chest wall and represents level at which a and c were obtained. (c) Transverse PET scan at level just below carina shows increased FDG uptake (arrow) in lateral chest wall (grade 2). US-guided biopsy revealed immature scar tissue without evidence of malignancy.

 


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  		Figure 4a. Images obtained after lobectomy of right lower lobe (6 months after surgery) in a 73-year-old man with NSCLC. (a) Transverse CT scan at level of right diaphragm reveals right-sided pleural effusion with subtle pleural enhancement (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake (arrows) in right hemithorax, with mediastinal shift to the right. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows diffuse increased pleural FDG uptake in right hemithorax (grade 2) (arrows). US-guided biopsy revealed empyema, without evidence of malignancy.

 


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  		Figure 4b. Images obtained after lobectomy of right lower lobe (6 months after surgery) in a 73-year-old man with NSCLC. (a) Transverse CT scan at level of right diaphragm reveals right-sided pleural effusion with subtle pleural enhancement (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake (arrows) in right hemithorax, with mediastinal shift to the right. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows diffuse increased pleural FDG uptake in right hemithorax (grade 2) (arrows). US-guided biopsy revealed empyema, without evidence of malignancy.

 


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  		Figure 4c. Images obtained after lobectomy of right lower lobe (6 months after surgery) in a 73-year-old man with NSCLC. (a) Transverse CT scan at level of right diaphragm reveals right-sided pleural effusion with subtle pleural enhancement (indeterminate lesion) (arrows). (b) Coronal PET scan shows diffuse increased FDG uptake (arrows) in right hemithorax, with mediastinal shift to the right. Dotted line represents level at which a and c were obtained. (c) Transverse PET scan shows diffuse increased pleural FDG uptake in right hemithorax (grade 2) (arrows). US-guided biopsy revealed empyema, without evidence of malignancy.

 


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  		Figure 5a. Images obtained after lobectomy of right lower lobe (12 months after surgery) in a 65-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows pleural fluid with pleural thickening (indeterminate lesion) (arrows point to both). (b) Coronal PET scan shows diffuse increased FDG uptake in right chest wall. Dotted line shows level at which c was obtained. (c) Sagittal PET scan shows increased pleural FDG uptake (grade 2) (arrows). US-guided biopsy revealed exudative pleural effusion with histologically proved diffuse pleural malignancy.

 


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  		Figure 5b. Images obtained after lobectomy of right lower lobe (12 months after surgery) in a 65-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows pleural fluid with pleural thickening (indeterminate lesion) (arrows point to both). (b) Coronal PET scan shows diffuse increased FDG uptake in right chest wall. Dotted line shows level at which c was obtained. (c) Sagittal PET scan shows increased pleural FDG uptake (grade 2) (arrows). US-guided biopsy revealed exudative pleural effusion with histologically proved diffuse pleural malignancy.

 


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  		Figure 5c. Images obtained after lobectomy of right lower lobe (12 months after surgery) in a 65-year-old man with NSCLC. (a) Transverse CT scan at level of lower lobes shows pleural fluid with pleural thickening (indeterminate lesion) (arrows point to both). (b) Coronal PET scan shows diffuse increased FDG uptake in right chest wall. Dotted line shows level at which c was obtained. (c) Sagittal PET scan shows increased pleural FDG uptake (grade 2) (arrows). US-guided biopsy revealed exudative pleural effusion with histologically proved diffuse pleural malignancy.

 
For the whole study group, 18F FDG PET alone had a sensitivity of 100%, specificity of 71%, PPV of 63%, NPV of 100%, and accuracy of 80% in identification of pleural malignancy. In group A, 12 of 18 benign lesions were correctly reported negative, and all pleural malignancies were correctly reported positive (Table 4). Sensitivity was 100%, specificity was 67%, PPV was 79%, NPV was 100%, and accuracy was 85%. In group B, 32 of 44 benign lesions were correctly reported negative, and all pleural malignancies were correctly reported positive (Table 5). Sensitivity was 100%, specificity was 73%, PPV was 37%, NPV was 100%, and accuracy was 76%.


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  		TABLE 4. Appearance of Pleural Abnormalities on 18F FDG PET Scans of 41 Patients in Group A

 

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  		TABLE 5. Appearance of Pleural Abnormalities on 18F FDG PET Scans of 51 Patients in Group B

 
Combined Reading of CT and 18F FDG PET Scans
The combined reading of 18F FDG PET and thoracic CT scans helped identify three rib fractures with adjacent solid pleural abnormalities, which were correctly reported as negative for pleural malignancy at CT but had increased 18F FDG uptake. The pleural activity was higher than mediastinal background activity at 18F FDG PET, which led to a false-positive report. Biopsy findings revealed reactive pleuritis without evidence of malignant tissue. In the remaining 89 patients, combined interpretation of 18F FDG PET and CT scans did not alter the outcome. Thus, 18F FDG PET and CT combined had a sensitivity of 100%, specificity of 76%, PPV of 67%, NPV of 100%, and accuracy of 84% in identification of pleural malignancy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
As many as 15% of all patients diagnosed with NSCLC will present with pleural effusion (23,25). Pleural effusion with or without solid pleural thickening does not necessarily represent a locally extensive tumor (stage T4), which would preclude the patients from surgery in otherwise potentially resectable stage of disease. However, radiologic differentiation of malignant and benign pleural lesions is limited by the fact that the decision is based on morphologic features, which may be unspecific and misleading (4,6,7,23). Pleural effusion with attenuation of 10 HU or less is classified as transudate and is unlikely to be associated with a malignancy (4,6,7,23). This is in accordance with the findings in this study, in which none of the 22 patients with a transudate at CT showed evidence of pleural malignancy. However, by keeping in mind that there is a broad overlap in CT findings indicating benign or malignant pleural abnormalities, it is not surprising that 71% of the pleural abnormalities were classified as indeterminate. We are aware that patients in our study were highly selected; nevertheless, the high percentage of indeterminate pleural abnormalities clearly demonstrates the limitation of morphologic criteria to enable differentiation between benign and malignant pleural lesions.

Several studies have already addressed the potential role of an increased 18F FDG uptake in identification of pleural malignancy (19–22). Preliminary results of 18F FDG PET indicate a promising role of this noninvasive functional imaging modality to overcome some of the limitations of CT in the assessment of pleural abnormalities (4,6,7,19–22). However, previous studies were limited by the heterogeneity of the primary cancers and the limited number of patients (19–22). In the present study, 18F FDG PET had a sensitivity and NPV of 100% in the detection of pleural malignancy. However, the specificity and PPV were only 71% and 63%, respectively, since even in combination with CT, PET cannot reliably help in distinguishing between acute inflammation and malignancy (26). The high NPV and the low PPV are in contrast with those in a study by Erasmus et al (22), which was performed in the early 1990s with a limited number of patients. They reported a PPV and NPV of 95% and 67%, respectively. However, only three patients with benign pleural effusion were included in that study.

The physician reading film hard-copy images should be aware that increased 18F FDG uptake in the pleura, particularly in patients after cancer-related therapy, may represent an unspecific finding, which needs close correlation with morphologic imaging but does not necessarily indicate pleural malignancy (26). Authors of studies dealing with complications (ie, pneumonia, acute pleuritis, wound infection, or pleural effusion) following lung surgery reported an incidence between 9% and 34% (27–31). Thus, trauma-related abnormalities of the pleura and chest wall should be considered, particularly in patients who have undergone surgery, and combined interpretation of CT and 18F FDG PET scans is recommended to avoid false-positive interpretation of the 18F FDG PET scan.

Biochemical analysis of pleural fluid is reported to have an accuracy in the range of 66%–96% (2,24,32,33). However, pleural fluid analysis is dependent on the acquisition of enough fluid. Considering the high sensitivity of 18F FDG PET, this noninvasive modality overcomes this limitation and may provide an accurate means to evaluate pleural disease when pleural fluid analysis is impossible or when the results are questionable. This is supported by the fact that in eight (35%) of 23 patients in this study with primary NSCLC, chemical analysis of the pleural fluid revealed exudates, but they were negative for malignant cells. In these eight patients, 18F FDG uptake was pathologically increased (grade 2) at PET, and findings from video-assisted thoracic surgery revealed pleural malignancy. Thus, we agree with Erasmus et al (22), who have already postulated that patients with primary NSCLC and an increased 18F FDG uptake in the pleura should undergo further evaluation for pleural metastases by means of biopsy, even if findings from cytologic analysis of pleural effusion were negative.

Compared with the cytologic analysis of pleural fluid, video-assisted thoracic surgery of the pleura is reported to have an improved accuracy (>95%) in the diagnosis of pleural malignancy (34,35). 18F FDG PET is particularly valuable in this setting because it helps identify patients in whom an additional staging examination such as biopsy is required. 18F FDG PET can help pinpoint the areas of maximal disease activity and may therefore be used as a guide to select the most appropriate area of biopsy for better yield. Furthermore, the high NPV of 18F FDG PET in this study indicates that lesions considered negative on 18F FDG PET scans (grades 0 and 1) are benign and do not need further invasive diagnostic work-up. Thus, 18F FDG PET may help to prevent complications associated with invasive procedures such as video-assisted thoracoscopy, as well as to prevent unnecessary hospitalization of these patients (34,35).

Compared with sensitivity, the lack of high specificity of 18F FDG-avid lesion regarding pleural malignancy is somewhat disappointing. However, considering the results of this study, there was a broad overlap of 18F FDG accumulation in empyema and pleural malignancy, which was responsible for the overwhelming cases of false-positive interpretations of 18F FDG PET studies (83%). Despite the fact that empyema has no effect on the staging of NSCLC, it represents a serious potentially life-threatening disease, and the identification of these 18F FDG-avid lesions will have a substantial effect on patient care.

The visual classification system used in this study for the characterization of the pleura was introduced by Lowe et al (25). It has been shown to be a simple and reliable classification system for the purpose of this study and for the daily routine interpretation of 18F FDG PET studies. Standardized uptake values were not obtained during this study, since this procedure is not performed routinely for 18F FDG PET at our department. In addition, cutoffs of standardized uptake values have already been used for the differentiation between benign and malignant thoracic disorders. However, these study findings indicate an obvious potential for some overlap between benign and malignant diseases (36).

Several drawbacks limited this study. First, a potential limitation of this retrospective study was the bias introduced by our selection criteria and lack of reliable classification criteria of pleural abnormalities in NSCLC other than attenuation values equal to water and circumscribed osseous destruction of the thoracic rib cage adjacent to a pleural mass. This selection process resulted in a 71% prevalence of indeterminate pleural abnormalities at CT, which is likely higher than would be expected in the general population of patients undergoing whole-body 18F FDG PET for NSCLC. Second, only one radiologist interpreted the CT images. This may have added some bias. Third, during this study, CT and 18F FDG PET studies were performed separately within a 2-week period, whereas the ideal imaging method would be performance of only one study. Recently, integrated PET/CT in-line systems have been introduced that provide "hardware" co-registered PET and CT images. With CT providing a precise and rapid anatomic reference map, these PET/CT in-line systems may further enhance the use of PET in the setting discussed here. Another potential limitation is that not all patients underwent open pleural biopsy as a standard.

In conclusion, indeterminate pleural abnormalities at CT are frequently observed in patients with NSCLC. Among these patients, further examination with 18F FDG PET can help identify patients with benign pleural abnormalities and therefore help avoid unnecessary biopsy. A positive 18F FDG PET scan is sensitive for malignant pleural tissue, but it needs close correlation with morphologic imaging to prevent false-positive results (ie, rib fractures). In cases of positive findings at 18F FDG PET in indeterminate pleural lesions at CT, further evaluation for malignancy is recommended, and by its metabolic nature 18F FDG PET can help direct biopsy procedures to sites of the highest likelihood of malignancy.


   FOOTNOTES
 
Abbreviations: FDG = fluorodeoxyglucose, NPV = negative predictive value, NSCLC = non–small cell lung cancer, PPV = positive predictive value

Author contributions: Guarantors of integrity of entire study, G.J.S., R.M.A.; study concepts and design, G.J.S.; literature research, H.S., G.J.S.; clinical studies, A.M., F.M.S.J., M.W., G.F.; data acquisition, G.J.S., G.W., R.M.A.; data analysis/interpretation, H.S., G.W., R.G., G.J.S.; statistical analysis, H.S., R.N.; manuscript preparation, G.J.S., H.S.; manuscript definition of intellectual content, G.J.S., A.M.; manuscript editing, G.J.S.; manuscript revision/review, G.J.S., R.M.A., A.M.; manuscript final version approval, all authors


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 DISCUSSION
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