Diagnostic Efficacy of PET-FDG Imaging in Solitary Pulmonary Nodules

clinical investigations Diagnostic Efficacy of PET-FOG Imaging in Solitary Pulmonary Nodules* Potential Role in Evaluation and Management Naresh A. Dewan, M.D., F.C.C.P.; Naresh C. Gupta, M.D.; Usa S. Redepenning, M.D.; james J Phalen, M.D.; and Mathis P. Frick, M.D. Background: Positron emission tomography (PET), a new noninvasive imaging modality, utilizing 2-[F-18]-0uoro-2deoxy-D-glucose (FDG), has demonstrated increased FDG uptake in lung tumors. Objective: To determine the diagnostic efficacy of PETFOG imaging in differentiating benign from malignant solitary pulmonary nodules. Patient selection: A prospective study of 30 patients who presented with indeterminate solitary pulmonary nodules less than 3 em in size based on chest radiograph and computed tomographic (Cf) scan. Setting: Two tertiary care medical centers in Omaha, Neb: Creighton University Medical Center and the Omaha Veterans Administration Medical Center. Measurements: Positron emission tomographic imaging of the lung was performed I h after intravenous injection of 10 mCi of F-18-FDG. Qualitative analysis of the images was performed independently by two observers by visual identification of the areas of increased FDG uptake in the lung nodules. Semiquantitative analysis was performed using computation of differential uptake ratio (DUR). Histologic specimens were obtained in 29 patients (thoracotomy 20, transthoracic needle aspiration biopsy 8, bronchoscopy

solitary pulmonary nodules are parenchymal lung lesions that are usually well defined and less than 4 em in diameter. An estimated 130,000 new benign or malignant solitary pulmonary nodules are discovered each year in the United States.' It is estimated that about 40 to 50 percent of all solitary pulmonary nodules and 90 percent of benign nodules are infectious granulomas. 2 The only two definite criteria for benign solitary pulmonary nodules are the presence of central, concentric, or stippled calcification as seen on chest radiographs or computed tomographic (CT) scan 3 and stability of the nodule for more than 2 years. *From the Departments of Medicine, Division of Pulmonary and Critical Care and Radiology, Creighton University and Veterans Affairs Medical Center, Omaha. Manuscript received December 2, 1992; revision accepted March 23, 1993. Reprint requests: Dr. Dewan, Pulmonary Section, Suitt• .3820, St. joseph HoSJJital, Omaha 681.31

1).

Results: Positron emission tomographic imaging correctly identified 27 of 30 pulmonary nodules. Diagnostic accuracy was high with sensitivity of 95 percent and specificity of 80 percent. The positive and negative predictive value of PET imaging for solitary pulmonary nodules was 90 percent and 89 percent, respectively. The DUR values were significantly higher for malignant nodules (mean± SD, 5.55 ± 2. 79) than benign nodules (mean±SD, 0.95±0.99) (p
Other criteria that may support the diagnosis of benign nodules include (1) transthoracic fine needle aspiration biopsy specimen showing a specific benign process, and (2) patients younger than 35 years. Although fine needle aspiration biopsy specimen of the nodule may provide a diagnosis in up to half of the benign nodules, 4 •5 a nonspecific diagnosis of benign nodules is not universally accepted.s-H At present, plain chest radiographs and CT are the most common imaging modalities used to differentiate benign from malignant nodules. Despite significant advancement in the use of these techniques, a substantial proportion of solitary pulmonary nodules remain radiographically indeterminate. 9-ll It is evident that current noninvasive methods that assess morphologic details are not satisfactory in separating benign from malignant nodules. A new noninvasive test that can predictably differentiate benign from malignant CHEST I 104 I 4 I OCTOBER, 1993

997

nodules could significantly change the evaluation and treatment of patients with solitary pulmonary nodules. Positron emission tomography (PET), a new noninvasive imaging modality using2-[F-18]-8uoro-2-deoxyO-glucose (FOG), has demonstrated increased glucose metabolism in malignant cells. 12- 15 Recent studies with PET imaging have documented increased FOG uptake by lung tumors 16• 17 as compared with normal tissue. More recently, in a prospective study of 20 patients with solitary pulmonary nodules up to 4 em in size, we demonstrated that PET-FOG imaging was highly accurate in differentiating benign from malignant nodules. 18 There were no false-positive or false-negative cases in this limited study. Factors that increase the probability of malignancy include the following: 19 (1) age greater than 35 years; (2) irregular margins of the nodule; (3) absence of calcification; (4) amount of cigarette smoking; and (5) size of the nodule. In a recent study of lung nodules larger than 3 em, 98 percent of the nodules were malignant and only 2 percent were benign.9 Because size of the nodule is an important factor in determining the probability of malignancy, it was believed that it would be more useful to assess the utility of PETFOG imaging in differentiating benign from malignant pulmonary nodules less than 3 em in size. Therefore, we analyzed the 18 cases previously studied along with 12 additional new patients and report our results in 30 patients with solitary pulmonary nodules less than 3 em .

METHODS lbtient Selecticm

Thirty subjects who presented for evaluation of solitary pulmonary nodules of 3 em or less were enrolled in this study. Subjects were evaluated at Creighton University Medical Center and the Veterans Affairs Medical Center in Omaha. All patients had plain chest radiographs, and Cf scan of the chest and mediastinum was obtained in 25 patients. With the exception of one patient who had eccentric calcification, all solitary pulmonary nodules were noncalcified and were judged to be indeterminate on the basis of chest radiograph and Cf scan. Final diagnosis was established by obtaining tissue either by thoracotomy, transthoracic fine needle aspiration biopsy, or bronchoscopy. The study was approved by the Institutional Review Board at Creighton University, and all patients gave informed consent. PET l100ging The PET imaging of the entire chest region was performed using the methodology as previously described.•• BrieHy, PET images were obtained with a scanner (Siemens-CTI-ECAT Scanner 931/08/ 16, Siemens Medical Systems, Iselin, NJ; CTI , Knoxville, Tenn) that produces 15 slices of 8-mm thickness and has a reconstructed in-plane resolution of approximately 5 to 7 mm. PET imaging was performed 1 h after intravenous administration of 10 mCi of F-18FDG. Transmission scans were obtained in all patients before FDG administration, for attenuation <.'Orrection of emission data. A<:quisition was done over 10 to 15 min to obtain a minimum of 10 million counts per direct plane and a total of 220 million counts. Patients were carefully repositioned by using skin marking to ensure an identical field of view for emission and transmission scanning. The transaxial images were reconstructed into transaxial, coronal, and sagittal views. Qualitative analysis of the images was performed by visual identification of areas of increased FDG uptake in hoth lung fields. The most important feature looked for was the appearance of a relatively bright area within the confines of the lung nodule (Fig 1). The images were also superimposed over transmission

FtcURE 1. PET-FDG (left) and Cf scan (right) in a 77-year-old man with a 3-cm nodule in left upper lobe; transthoracic needle aspiration demonstrated non-small-cell carcinoma. Note the intense metabolic activity (bright yellow and red) on the emission scans obtained in transaxial projection.

998

PET-FOG Imaging for Solitary Pulmonary Nodules (Dewan eta/)

Table I- Demographic and Clinical Data in 30 Patient3 With Solitary Pulmonary Nodules

No. Sex, M:F Mean age, yr Size, em <1 <1.5 <2 <2.5 <3

Malignant

Benign

Total

20 14:6 69.8

10 8:2 56.3

30 22:8 65.3

4 7 16 18 20

4 5 9 10 10

8 12 25 28 30

images for anatomic correlation. The PET images were interpreted blindly by two experienced nuclear medicine physicians separately with good agreement between the two observers. The semiquantitative index, differential uptake ratio (DUR), was also computed for all patients by drawing a region of interest over the solitary pulmonary nodule on the transaxial images. These calculations relate activity found in tissue to the dose injected and the patient's mass."' Radiotracer PET counts were also corrected for radioactive decay from the time of injection. Small circular regions consisting of 12 pixels (0.8 em•) were drawn over the area of the pulmonary nodule that showed the most intense FDG uptake . In some cases, where the nodule could not be identified on the PET or transmission scan because of decreased or absent FDG uptake, the region of interest was drawn in its location as extrapolated from

the chest radiograph and cr scan. The OUR was then computed as follows: Mean PET countslpi.xeVs X calibration factor Injected dose (mCi)lbody weight (kg) where the calibration factor= (microcurieslml)l(countslpi.xeVs)

Statistical Analysis Diagnostic efficacy of PET-FDG imaging in differentiating benign from malignant solitary pulmonary nodules was determined by calculating sensitivity, specificity, and positive and negative predictive value as follows: Sensitivity

True Positives x 100 percent

True Positives+ False Negatives . _..:;T.:..ru::..e.:..N:..;.:;ega=ti=-·v..=e.:..s_x...:1:..::00..:..£pe..::.:..rce:..:..::n.:..t_ SpecillCity= True Negatives+ False Positives p . . ped" . Val True Positives x 100percent osJtive r Jctive ue =True Positives+ False Positives . p . Val __T_ru___;.e_N_e"'ga'-ti-'-·v_e.;.:s_X-=-100'-'--'pe'-"-"r=-ce.:..n.:..t~ Negative r ed"1ctive ue = True Negatives+ False Negatives

REsuLTS

Thirty subjects who had solitary pulmonary nodules up to 3 em in size were analyzed. Demographic and clinical data are listed in Table 1. There were 22 men and 8 women with a mean age of65.3 years (range, 38 to 89 years). Overall, 20 patients had malignant

Table 2-Correlation of Clinical, Histologic, and PET Results in 30 lbtient3 With Solitary Pulmonary Nodules• Patient No./ Age, yr/Sex Benign 1139/M 2174/M 3168/M 4157/F 5/64/M 6/68/M 7138/M 8/63/M 9/41/F 10151/M Malignant 11172/M 12172/M 13165/M 14/62/M 151731M 16/69/M 17/41/F 18/81/F 19/63/M 2W76/M 21174/F 22189/M 23169/M 24184/F 251731M 26164/M

27n21F 28177/M 29n21M 30150/F

*+

Nodule Size, em

PET Scan

1.5 1.0 2.5 1.8 1.0 1.0 2.0 1.5 2X 1.5 2

Neg Neg Neg Neg Neg Neg Neg Neg Pos+ Pos+

2 1.5 1.0 1.5 1.0 2.0 1.5 l.2X2 1 0 .6 l.5X2 1X2 2X2.75 l.8X2.2 2.0 2.0 2.0 3.0 l.4X 2.2 l.5X2

Pos Pos Neg++ Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos

DUR

Histologic Features

Biopsy Mode

0.47 0 . 15 0.82 0 .40 0 .92 0.42 0 .75 0 .27 1.92 3.38

Granuloma Hamartoma Carcinoid Nonspecific in8ammation Organizing pneumonia Histoplasmosis Stable nodule size over 3 yr Necrotizing granuloma Caseating granuloma with histoplasma Caseating granuloma with histoplasma

Thoracotomy Thoracotomy Thoracotomy Bronchoscopy Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy

Melanoma Adenocarcinoma Scar adenocarcinoma Squamous cell carcinoma Scar adenocarcinoma Adenocarcinoma Scar adenocarcinoma Scar adenocarcinoma Adenocarcinoma Adenocarcinoma Small-cell carcinoma Adenocarcinoma Non-small-cell carcinoma Squamous cell carcinoma Small-cell carcinoma Melanoma Bronchoalveolar adenocarcinoma Non-small-cell carcinoma Adenocarcinoma Adenocarcinoma

TINA Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy Thoracotomy TINA TINA TINA TINA TINA TINA Thoracotomy TINA Thoracotomy Thoracotomy

8.17 11.77 1.67 6.79 3.23 5.86 5.65 3 .26 2.61 6.11 2.3 3.88 2.83 6.88 11.71 6.07 4.27 4.81 5.74 7.30

=false positive; + + =false negative; TINA= transthoracic needle aspiration. CHEST I 104 I 4 I OCTOBER, 1993

999

nodules and 10 had benign nodules. Size of Solitary Pulmonary Nodule All benign nodules were less than 2.5 em and 9 of 10 benign nodules were less than 2 em. Overall, 25 of the 30 nodules were less than 2 em in size. Six patients had a history of previous malignancy. Two patients had metastatic melanoma, and one patient with previously resected squamous cell carcinoma was found to have a second primary in the lung. Two patients had carcinoma of the breast resected several years earlier, and both were found to have a primary lung cancer. One patient had a history of carcinoma of the prostate, but the pulmonary nodule was a benign necrotizing granuloma. Correlation of clinical, histologic, and PET imaging results in 30 patients with solitary pulmonary nodules is shown in Table 2. Histologic specimens were obtained in 29 patients. Twenty patients had thoracotomy, eight had transthoracic fine needle aspiration biopsy, and one had bronchoscopy. One patient who did not have tissue confirmation had a stable solitary pulmonary nodule over 3 years. PET-FDG Imaging PET imaging correctly identified malignancy in 19 of 20 patients with malignant pulmonary nodules (adenocarcinoma, 12; squamous cell carcinoma, 2; non-small-cell carcinoma, 2; small-cell carcinoma, 2; and melanoma, 2). PET-FDG uptake was not increased in one patient with a 1-cm solitary pulmonary nodule and thoracotomy identified scar adenocarcinoma. PET imaging correctly identified eight often benign nodules. Histologic specimens were obtained by thoracotomy in eight of ten patients with benign nodules that demonstrated the following: histoplasmosis, 3; granuloma, 2; hamartoma, 1; carcinoid, 1; organizing pneumonia, 1. The histology of carcinoid was benign and was thus included under benign nodules. There were two false-positive cases and both had caseating granulomas with active inflammation and Histoplasma organisms. One patient who had normal findings on bronchoscopy showing nonspecific inOammation had a stable solitary pulmonary nodule over 2 years. The DUR values ranged from 1.67 to 11 .77 (mean±SD, 5.55±2.79) for malignant nodules and were significantly greater than benign nodules (mean± SD, 0.95±0.99) (p<0.001). The DUR indices were greater than 2 for all true-positive cases and were less than 1 for all true-negative cases. Two falsepositive cases had DURs of 1.92 and 3.38, and one false-negative case had a DUR of 1.67 (Table 2). Overall, PET imaging correctly identified 27 of 30 solitary pulmonary nodules. Diagnostic accuracy was high with sensitivity of 95 percent and specificity of 80 percent. The positive and negative predictive values of PET imaging for detecting malignancy in solitary 1000

pulmonary nodules were 90 percent and 89 percent, respectively. DISCUSSION

Our study has demonstrated that the use of PETFOG imaging, a new noninvasive test, has a high degree of accuracy in differentiating benign from malignant solitary pulmonary nodules less than 3 em in size. Analysis of the two false-positive cases revealed the following data. In one patient, review of the chest radiographs showed a 2-cm nodule that was not present on chest radiographs done 12 weeks earlier, suggesting rapid growth. In the second patient, the nodule was not well defined, and a repeat CT scan of the chest done 6 weeks later, prior to thoracotomy, showed a slight change in the character of the nodule. Both patients underwent thoracotomy, and histologic study demonstrated caseating granulomas with active inOammation and Histoplasma. Although some of the previous reports have demonstrated increased FDG uptake on PET imaging studies in patients with aspergilloma, lung abscess, and granulomas.21 •22 However, not all granulomas in our study showed increased FDG uptake. This suggests that FDG uptake may be increased to some extent in some granulomas that demonstrate acute inflammatory process with epithelial cells and histiocytes. There is some debate about the lower limit of the size of the solitary pulmonary nodule that can be correctly identified by PET imaging. 22 The detectability of a lesion on PET scan may depend on the size of the lesion, instrument resolution, and radio-tracer concentration. A small lesion with very high FDG uptake could potentially be detected even though its size is close to the resolution limit. Additional factors that may hamper the detection of very small lesions include partial volume effect and respiratory motion. In our study, a lesion as small as 0.6 em demonstrated increased uptake ofFDG. However, one false-negative result was seen in a patient with a 1-cm solitary pulmonary nodule. Review of the histologic features indicated that most of the nodule was occupied by fibrotic scar tissue, with a few islets of malignant cells at the periphery. This suggests that a critical mass of metabolically active malignant cells may be required for PET imaging to demonstrate increased uptake of FDG. The primary interpretation of PET scans was done by qualitative visual analysis of the areas of increased FDG uptake in the lung nodule. Semiquantitative analysis was also performed by computing DUR for all lung nodules. While the mean DUR index in malignant nodules was significantly greater than benign nodules, there was some overlap. The DUR indices were greater than 2 for all true-positive cases and were less than 1 for all true-negative cases. Two PET-FOG Imaging for Solitaly Pulmonary Nodules (Dewan et el)

false-positive cases had OURs between 1 and 4 and one false-negative case had a OUR of 1.67. The use of OUR indices as compared with visual analysis for differentiating benign from malignant nodules needs further investigation. Current options in the evaluation and management of indeterminate solitary pulmonary nodules include bronchoscopy, transthoracic fine needle aspiration biopsy, thoracotomy, and observation. 19 •23 Observation is usually favored in individuals with low probability for malignancy or in those individuals who are high-risk candidates for thoracotomy, either due to poor lung function or associated cardiovascular disease.24 Bronchoscopy with transbronchial biopsy is considered the least invasive procedure with an overall complication rate under 5 percent. 25 Bronchoscopy is commonly performed in patients with solitary pulmonary nodules larger than 2 em, and a diagnostic result is obtained in 40 to 80 percent of cases, 26 •27 depending on the size and location of the nodule. A definite diagnosis is obtained in less than 10 percent of the patients with nodules less than 2 em in size, and a bronchoscopy is usually not done. Transthoracic fine needle aspiration biopsy of the lung is generally performed for peripheral solitary pulmonary nodules. 28 Although a diagnosis can be established in 90 to 95 percent of nodules larger than 2 em, the yield is approximately 60 percent for malignant nodules less than 2 em in size, and less than 20 to 30 percent for benign nodules.29 Fine needle aspiration biopsy of the lung is an invasive procedure that carries a 30 percent risk of pneumothorax and a 12 percent risk ofhemoptysis. 30 In most patients with malignant nodules who are suspected to have either primary lung cancer or solitary metastases, and in most patients with nonspecific diagnoses of benign nodules, a thoracotomy is ultimately required for definitive evaluation and management. It is thus evident that there is no single "best approach" to manage all solitary pulmonary nodules. Under ideal circumstances, one would hope for prompt thoracotomy in patients with malignant pulmonary nodules with minimum preoperative invasive diagnostic procedures. On the other hand, patients with benign nodules should be spared the risk and expense of thoracotomy and other invasive diagnostic studies. Our study demonstrates that PET-FOG imaging is highly accurate in detecting malignancy in solitary pulmonary nodules <3 em with positive and negative predictive values of 90 percent and 89 percent, respectively. The use of this noninvasive test can have significant clinical implications in the treatment of patients with solitary pulmonary nodules and can offer several potential benefits. An abnormal PET-FOG imaging study in a patient with solitary pulmonary nodule would obviate the need for any further invasive

diagnostic studies, and the patient could be directly referred for thoracotomy. Early diagnosis of malignancy is important as the 5-year survival in patients who undergo resection for malignant nodules under 3 em in diameter is between 50 and 80 percent. 3 1.32 Also, prethoracotomy identification of patients with high suspicion for malignancy is usually beneficial. Some patients who are reluctant to permit thoracotomy may be more agreeable if they know they have a high likelihood of a malignancy. In patients who have concurrent illness and a significantly higher surgical risk, thoracotomy may be justifiable if malignancy is first proven or strongly suspected. On the other hand, a negative PET imaging study, suggesting a benign process, could potentially save a patient from thoracotomy and other invasive diagnostic studies. This will not only eliminate the morbidity and mortality of thoracotomy, but also has the potential for significant cost savings. In summary, PET-FOG imaging of the lung is a new noninvasive diagnostic test that is highly accurate in differentiating benign from malignant solitary pulmonary nodules. Used in the right clinical setting, PET imaging could complement CT scanning in the evaluation and treatment of patients with solitary pulmonary nodules. ACKNOWLEDGMENTS: The writers thank Walter J. O'Donohue, Jr, M.D., for helpful suggestions and review of the manuscript, and Dee Peters for secretarial assistance .

REFERENCES 1 Stoller JK, Ahmad M, Rice 1W Solitary pulmonary nodule. Cleve Clin J Med 1988; 55:68-74 2 Lillington GA. Pulmonary nodules: solitary and multiple. Clin Chest Med 1982; 3:361-67 3 Siegelman SS, Khouri NF, Leon FP, Fishman EK, Braverman RM, Serhouni EA. Solitary pulmonary nodules CT assessment. Radiology 1986; 160:307-12 4 Khouri NF, Meziane MA, Zerhouni EA. Fishman EK, Siegelman SS. The solitary pulmonary nodule: assessment, diagnosis and management. Chest 1987; 91 :128-33 5 Conces DJ Jr, Schwenk GR, Doering PR, Giant MD. Thoracic needle biopsy: improved results utilizing a team approach. Chest 1987; 91:813-16 6 Levine MS, Weiss JM, Herrell JH . Transthoracic needle aspiration biopsy following negative flheroptic bronchoscopy in solitary pulmonary nodules. Chest 1988; 93:1152-55 7 Calhoun P, Feldman PS, Armstrong P. The clinical outmme of needle aspiration of the lung when cancer is not diagnosed. Am Thorac Surg 1986; 41 :592-96 8 Winning AJ, Mcivor J, Seed WA. Interpretation of negative results in fine needle aspiration of discrete pulmonary lesions. Thorax 1986; 41:875-79 9 Zerhouni EA, Stitik FP, Siegelman SS . CT of the pulmonary nodule: amoperative study. Radiology 1986; 160:319-27 10 CaskeyCI, Zerhouni EA. Thesolitarypulmonarynodule. Semin Roentgenol 1990; 25:8.'5-95 11 Huston J III, Muhm J Jr. Solitary pulmonary nodules: evaluation with aCT reference phantom . Radiology 1989; 170:653-56 12 Warburg 0. The metabolism of tumors. lst ed. New York: Richard R. Smith, 1931; 129-69 CHEST I 104 I 4 I OCTOBER, 1993

1001

13 Hatanaka M. Transport of sugars in tumor cell membranes. Biochem Biophys Acta 1974; 355:77-104 14 DiChiro G, Dela Par RL, Brooks RA. Glucose utilization of cerebral gliomas measured by F-18 8uorodeoxyglucose and positron emission tomography. Neurology 1982; 32:1323-29 15 Wahl RL, Hutchins GD, Bushsboaum DJ, Liebert M, Grossman HB, Fisher S. F-18 8uoro deoxyglucose uptake into human tumor xenografts. Cancer 1991; 67:1544-50 16 Nolop KB, Rhodes LG, Boudin LH , Carney NP, KrauszT, Jones T, et al. Glucose utilization in vivo by human pulmonary neoplasm . Cancer 1987; 60:2682-89 17 Kubota K, Matsuzawa T, Fujiwara I, Ito M, HatazawaJ, Ishiwata K, et al. Differential diagnosis of lung tumor with positron emission tomography: a prospective study. J Nucl Med 1990; 31:1927-33 18 Gupta NC, Frank AR, Dewan NA, Redepenning LS, Rothberg ML, Mailliard ML, et al. Solitary pulmonary nodules: detection of malignancy with PET with 2-[F-18]-0uoro-deoxy-D-glucose. Radiology 1992; 184:441-44 19 Lillington GA. Management of solitary pulmonary nodules. Dis Mon 1991; 5:271-318 20 Wood HQ, Gigle RE, Field B, Russ G. Experience of tissue isotope distribution. J Nucl Med 1975; 16:958-59 21 Kubota K, Matsuzawa T, Fujiwara T, Hatazawa J, Ito M, Abe K. Comparison of C-11 methionine and F-18-ftuorodeoxyglucose for differential diagnosis oflung tumor. JNucl Med 1989; 30:78889 22 Strauss LG, Conti PS. The application of PET in clinical oncology. J Nucl Med 1991; 22:623-48

1002

23 Midthun DE, Swensen SJ, Jett JR. Clinical strategies for solitary pulmonary nodule. Annu Rev Med 1992; 43:195-208 24 Cummings SR, Lillington GA, Richard RJ. Estimating the probability of malignancy in solitary pulmonary nodules: a bayesian approach. Am Rev Respir Dis 1986; 134:449-52 25 Herf SM , Suratt PM , Arora NS. Deaths and <:omplications associated with transbronchial biopsy. Am Rev Respir Dis 1977; 115:708-ll 26 Fletcher EC, Levin DC. Flexible fiberoptic bronchoscopy and 8uoroscopically guided transbronchial biopsy in the management of solitary pulmonary nodules. West J Med 1982; 136:47783 27 Wallace JM , Deutsch AL. Flexible fiberoptic bronchoscopy and percutaneous needle lung aspiration biopsy for evaluating the solitary pulmonary nodule. Chest 1982; 81:665-71 28 Swensen SJ, Jett Jr, Payne HS, Viggiano RW, Pairolen PC, Trastec VG. An integrated approach to the evaluation of the solitary pulmonary nodule. Mayo Clin Proc 1990; 65:173-86 29 Bergquist TH, Bailey PB, Cortese DA, Miller WE . Transthoracic needle biopsy: accuracy and complications in relation to location and type oflesion. Mayo Clin Proc 1980; 55:475-81 30 Lillington GA. Hazards of transthoracic needle biopsy of the lung. Ann Thorac Surg 1989; 48:163-64 31 Williams DE , Pairolero PC, Davis CS , Bematz PE, Payne WS, Taylor WF, et al. Survival of patients treated for stage I lung cancer. J Thorac Cardiovasc Surg 1981; 82:70-6 32 Ishida T, Yano T, Maeda K, Kaneko S, Tateishi M, Sugimachi K. Strategy of lymphadenectomy in lung cancer three centimeters or less in diameter. Ann Thorac Surg 1990; 50:708-13

PET-FOG Imaging for Solitary Pulmonary Nodules (Dewan eta/)