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Ann Thorac Surg 1995;60:1348-1352
© 1995 The Society of Thoracic Surgeons
Departments of Surgery and Radiology, Duke University Medical Center, Durham, North Carolina
| Abstract |
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Methods. From March 1992 to July 1993, all patients with indeterminate focal pulmonary abnormalities were eligible for FDG PET imaging. In 53 patients, serial chest radiographs or computed tomograms were available and doubling time was computed. The FDG activity within the lesion was expressed as a standardized uptake ratio.
Results. The mean standardized uptake ratio (± SD) was 5.9 ± 2.7 in 34 patients with cancer, versus 2.0 ± 1.7 in 19 with benign disease (p < 0.001). Using a criterion of standardized uptake ratio 2.5 or greater for malignancy, the accuracy of PET was 92% (49 of 53). The standardized uptake ratio was significantly correlated with doubling time (r = -0.89; p = 0.002).
Conclusion. These data suggest a direct relation between tumor growth and FDG uptake in lung cancer. The technique of FDG PET demonstrates exceptional accuracy and may permit prompt diagnosis of lung cancer.
| Introduction |
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Focal pulmonary abnormalities frequently present a diagnostic challenge. The malignant potential of a radiographically indeterminate pulmonary abnormality is often suggested by rapid growth, or a brief doubling time. With conventional chest imaging techniques, however, the prospective calculation of doubling time potentially delays the diagnosis and treatment of patients with lung cancer. Furthermore, chest radiography and computed tomography have varying sensitivities, ranging from 52% to 80%, and lack sufficient specificity to provide a definitive diagnosis [1, 2]. Thus, invasive biopsy is often performed. Recently, growing interest has focused on imaging modalities that rely on metabolic rather than anatomic properties of lung cancer to guide medical therapy. One example is positron emission tomography (PET).
Positron emission tomography using the glucose analogue fluoride-18 fluorodeoxyglucose (FDG) detects the enhanced glucose metabolism characteristic of certain neoplastic cells. We postulated that if glucose metabolism measured by FDG uptake correlates with tumor growth rate assessed radiographically, then PET may allow prompt diagnosis of lung cancer.
| Material and Methods |
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The technical and procedural details of PET imaging in the chest have been reported [3]. In summary, patients fasted for 4 hours before study and were positioned in the PET unit so that the pulmonary abnormality was near the center of the longitudinal field of view. The PET unit (4096 Plus; General Electric Medical Systems, Milwaukee, WI) produced 15 axial images along a 97-mm longitudinal field with a spatial resolution of about 5 mm. Image processing and reconstruction were performed using a VAX 4000-300 computer system and a VAX 3100 work station (Digital Equipment, Marlboro, MA). After January 1993, a second PET unit was added (Advance; General Electric Medical Systems). This unit produced 35 axial images along a 150-mm longitudinal field; image processing and reconstruction were performed using a Hewlett Packard Apollo Series 765. Transmission scans were obtained using 68Ge pin sources to correct for soft-tissue attenuation and to localize the radiographic abnormality. Emission scans were obtained over a 20-minute period starting 30 minutes after intravenous injection of 10 mCi (370 MBq) of FDG. In our later experience, emission scans were acquired starting 60 minutes after FDG injection on the basis of studies using dynamic PET imaging. These studies established the optimum scanning protocol for distinguishing benign from malignant pulmonary lesions [4]. Fluoride-18 fluorodeoxyglucose was synthesized in our laboratory using standard methods [5]. A region of interest was chosen on the emission images to include the area of highest FDG activity, corresponding to the radiographic abnormality. The mean activity in the region of interest (ROI) was corrected for radioactive decay, and a standardized uptake ratio (SUR) was calculated according to the formula:
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To minimize observer bias, the region of interest was selected and SUR computed by a nuclear medicine physician (VJL) without prior knowledge of the patient's clinical history, physical examination, or laboratory data (including all cytology and biopsy reports).
For the calculation of doubling time, the following requirements were met: (1) Serial imaging studies were performed at the same facility using standard techniques; (2) all pulmonary lesions had distinct radiographic margins (infiltrates and ill-defined opacities were excluded); (3) patients treated with radiotherapy or chemotherapy during the interval between imaging studies were excluded; and (4) at least two chest radiographs or computed tomography scans were available, taken a minimum of 60 days apart. The maximum and perpendicular diameters of the lesion were measured, and the calculated average was defined as the tumor diameter (d). The doubling time (DT) was computed using the formula [6]:
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where d0 and dt are the tumor diameter measurements (mm) separated by a time interval t (days).
Histopathologic diagnosis was obtained in all patients by transbronchial or transthoracic needle aspiration biopsy or open lung biopsy, with one exception. This patient was followed with regularly scheduled plain chest radiographs for more than 2 years, with gradual resolution of the abnormality.
Calculations of sensitivity, specificity, and accuracy were done using standard equations. Comparison of SUR values between groups with benign and malignant disease was performed using a two-sided, unpaired Student's t test. The null hypothesis was rejected at the
= 0.05 significance level. The mean ± standard deviation are reported.
| Results |
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| Comment |
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Malignant tumor cells often display enhanced glucose metabolism and uncontrolled growth. Since the original description by Warburg and colleagues in 1923 [12], others have verified the increase in activity of key glycolytic enzymes in cancer cells [13]. The concomitant rise in cellular glucose uptake can be measured using PET with the glucose analogue FDG. Fluoride-18 fluorodeoxyglucose enters the cell through facilitated transport, undergoes phosphorylation by hexokinase, and becomes trapped intracellularly. Because the metabolism of phosphorylated FDG is extremely slow, its rate of appearance within the cell correlates directly with glycolytic flux [13]. Thus, FDG PET measures the augmented glucose metabolism characteristic of malignant cells in vivo. In several experimental and clinical studies, significant increases in FDG uptake have been demonstrated in all types of lung cancer [1416].
Glucose metabolism measured by FDG PET correlates with the doubling time of malignant pulmonary lesions. In this study, the cellular uptake of FDG and the calculated doubling time of indeterminate pulmonary lesions were inversely related. Thus, high levels of glucose metabolism were associated with shorter tumor doubling times, or faster rates of tumor growth. Other studies have confirmed the relation between glucose metabolism measured by FDG PET and the growth rate in different tumor types. In a study of 23 patients with primary cerebral tumors, DiChiro and co-workers [17] were the first to establish a link between the glycolytic activity measured by FDG PET and the rate of tumor growth in vivo. They postulated that a progressive increase in glucose metabolism accompanied the transformation from a slow to rapidly growing, poorly differentiated tumor [17]. In a study of 13 patients with malignant head and neck tumors, Minn and associates [18] examined the relation between glucose metabolism measured by FDG PET and tumor proliferative activity assessed by DNA flow cytometry. Their findings suggested that glucose metabolism correlated directly with the proportion of cells in the S phase of the cell cycle [18]. Similarly, Okada and colleagues [19] compared FDG uptake and cellular proliferative activity in 23 patients with malignant lymphoma of the head and neck. Using a monoclonal antibody directed against a nuclear antigen present only in proliferating cells (Ki-67), they demonstrated that Ki-67 immunoreactivity as well as the number of cellular mitoses observed under light microscopy increased in proportion to FDG uptake [19]. These data suggest that in certain tumor cell types, glucose metabolism measured by FDG PET varies proportionately with tumor growth.
Based on the preceding evidence that indeterminate focal pulmonary lesions can be differentiated by doubling time or growth rate and that doubling time is proportionate to glucose metabolism, it is reasonable to conclude that benign and malignant pulmonary lesions can be separated by quantitating glucose metabolism using FDG PET. Indeed, in this cohort of patients, the mean FDG activity in malignant lesions was significantly higher than in benign lesions. Using the previously derived criterion for malignancy of SUR 2.5 or greater, FDG PET demonstrated a sensitivity of 100%, a specificity of 79%, and an accuracy of 92%. These values are similar to those reported recently by Scott and colleagues [20] in a series of 47 patients who underwent diagnostic screening for lung cancer. Furthermore, FDG PET compares favorably with other more invasive diagnostic modalities currently in use, such as transthoracic needle aspiration biopsy [21, 22] and fiberoptic bronchoscopy [23, 24]. We suggest that by exhibiting superior sensitivity in the diagnosis of benign disease, combined with lower morbidity and less cost, FDG PET may be the preferred diagnostic modality in selected patients with focal pulmonary abnormalities.
In summary, indeterminate focal pulmonary lesions can be differentiated on the basis of doubling time. For malignant lesions, doubling time correlates with glucose metabolism measured by FDG PET. In our cohort of patients, we observed a direct relation between tumor growth rate assessed radiographically and FDG uptake in lung cancer. Thus, by quantitating glucose metabolism, FDG PET can differentiate benign from malignant pulmonary lesions with exceptional sensitivity and specificity.
| Footnotes |
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Address reprint requests to Dr Wolfe, Duke University Medical Center, PO Box 3507, Durham, NC 27710.
| References |
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