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Imaging Proliferation in Lung Tumors with PET: ¹⁸F-FLT Versus ¹⁸F-FDG

¹ Department of Nuclear Medicine, University of Ulm, Ulm, Germany
² Department of Thoracic Surgery, University of Ulm, Ulm, Germany
³ Department of Pathology, University of Ulm, Ulm, Germany
⁴ Department of Internal Medicine II, University of Ulm, Ulm, Germany

	ABSTRACT

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Recently, the thymidine analog 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT) was suggested for imaging tumoral proliferation. In this prospective study, we examined whether ¹⁸F-FLT better determines proliferative activity in newly diagnosed lung nodules than does ¹⁸F-FDG. Methods: Twenty-six patients with pulmonary nodules on chest CT were examined with PET and the tracers ¹⁸F-FDG and ¹⁸F-FLT. Tumoral uptake was determined by calculation of standardized uptake value (SUV). Within 2 wk, patients underwent resective surgery or had core biopsy. Proliferative activity was estimated by counting nuclei stained with the Ki-67–specific monoclonal antibody MIB-1 per total number of nuclei in representative tissue specimens. The correlation between the percentage of proliferating cells and the SUVs for ¹⁸F-FLT and ¹⁸F-FDG was determined using linear regression analysis. Results: Eighteen patients had malignant tumors (13 with non–small cell lung cancer [NSCLC], 1 with small cell lung cancer, and 4 with pulmonary metastases from extrapulmonary tumors); 8 had benign lesions. In all visible lesions, mean ¹⁸F-FDG uptake was 4.1 (median, 4.4; SD, 3.0; range, 1.0–10.6), and mean ¹⁸F-FLT uptake was 1.8 (median, 1.2; SD, 2.0; range, 0.8–6.4). Statistical analysis revealed a significantly higher uptake of ¹⁸F-FDG than of ¹⁸F-FLT (Mann–Whitney U test, P < 0.05). ¹⁸F-FLT SUV correlated better with proliferation index (P < 0.0001; r = 0.92) than did ¹⁸F-FDG SUV (P < 0.001; r = 0.59). With the exception of 1 carcinoma in situ, all malignant tumors showed increased ¹⁸F-FDG PET uptake. ¹⁸F-FLT PET was false-negative in the carcinoma in situ, in another NSCLC with a low proliferation index, and in a patient with lung metastases from colorectal cancer. Increased ¹⁸F-FLT uptake was related exclusively to malignant tumors. By contrast, ¹⁸F-FDG PET was false-positive in 4 of 8 patients with benign lesions. Conclusion: ¹⁸F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ¹⁸F-FDG and might be more useful as a selective biomarker for tumor proliferation.

Key Words: ¹⁸F-FLT • ¹⁸F-FDG • Ki-67 • proliferation • lung cancer

	INTRODUCTION

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PET using the glucose analog ¹⁸F-FDG enables noninvasive tissue characterization based on metabolic differences between benign and malignant tumors. Several studies have found ¹⁸F-FDG PET to have a high sensitivity for staging lung cancer (1–3). However, ¹⁸F-FDG uptake is not tumor specific, and false-positive findings can occur in inflammatory lesions (4). Therefore, many efforts have been made to develop more selective tracers. In contrast to ¹⁸F-FDG uptake values, proliferative activity as measured by Ki-67 immunostaining has been shown to be a specific sign of malignant tumors (5). Furthermore, immunohistochemical studies using various biomarkers for proliferation showed significantly decreased survival in patients with highly proliferating tumors (6). In clinical studies, ¹⁸F-FDG uptake correlated with proliferative activity (7,8) and survival in non–small cell lung cancer (NSCLC) (9,10).

¹¹C-Thymidine was the first radiotracer for noninvasive imaging of tumor proliferation (11). The short half-life of ¹¹C and rapid metabolism of ¹¹C-thymidine in vivo make the radiotracer less suitable for routine use. Hence, the thymidine analog 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT) was recently introduced as a stable proliferation marker with a suitable nuclide half-life (12). ¹⁸F-FLT is phosphorylated to 3'-fluorothymidine monophosphate by thymidine kinase 1 and reflects thymidine kinase 1 activity in A549 lung cancer cells (13). In a first clinical study, our group demonstrated proliferation-dependent ¹⁸F-FLT uptake in NSCLC (14).

We devised a prospective study to evaluate whether PET with the novel tracer ¹⁸F-FLT better determines tumoral proliferation and better differentiates benign from malignant lung tumors than does PET with ¹⁸F-FDG.

	MATERIALS AND METHODS

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Patients
This prospective study included 26 patients (17 men, 9 women) with a mean age of 62 ± 9.9 y (range, 37–77 y; Table 1). PET with both tracers, ¹⁸F-FDG and ¹⁸F-FLT, was planned for 30 consecutive patients. Four patients had to be excluded from the study because only ¹⁸F-FDG or ¹⁸F-FLT PET was performed. Patients were selected when pulmonary nodules on CT scans strongly suggested a malignant tumor. Sixteen patients underwent resective surgery up to 14 d after ¹⁸F-FLT and ¹⁸F-FDG PET. In the other 10 patients, core-biopsy specimens were used for histopathologic evaluation. All patients gave written consent to participate in this study, which was approved by the local ethical committee.

Immunostaining and Morphometric Analysis
The detailed protocol for immunostaining was published elsewhere (5). Briefly, formalin-fixed and paraffin-embedded sections (5 µm) of resected specimens and biopsy samples were dewaxed, rehydrated, and microwaved in 0.01 mol/L citrate buffer for 30 min. For immunostaining, the monoclonal murine antibody MIB-1 (Dianova), specific for human nuclear antigen Ki-67, was used in a 1:500 dilution. Sections were lightly counterstained with hematoxylin. As a positive control for proliferating cells, sections of human lymph node tissue were used. The primary antibody was omitted on sections used as negative controls. Histopathologic slides were examined by a pathologist who was unaware of the patients’ clinical data.

An area with high cellularity was chosen for the evaluation of MIB-1 immunostaining. All epithelial cells with nuclear staining of any intensity were defined as positive. Proliferative activity was described as the percentage of MIB-1–stained nuclei per total number of nuclei in the sample. With light microscopy, 600 nuclei per slide and 3 slides per case were evaluated for Ki-67 expression to minimize tissue-sampling error. Representative images of each slide were transferred to the computer frame by a video camera using the computer-assisted imaging system OPTIMAS 6.2 (Media Cybernetics, Inc.).

¹⁸F-FLT Synthesis and PET Imaging
In accord with the method of Machulla et al. (15), benzoyl-protected anhydrothymidine was used for ¹⁸F-FLT synthesis. Radiosynthesis was performed in a PET tracer synthesizer from nuclear interface. After nucleophilic introduction of ¹⁸F-fluoride accompanied by an anhydro-ring opening, the benzylated intermediate was cleaved using 1% NaOH solution. ¹⁸F-FLT was purified via preparative high-performance liquid chromatography.

¹⁸F-FLT and ¹⁸F-FDG PET examinations were performed on consecutive days within 2 wk before resective surgery or core biopsy. PET was performed using a high-resolution full-ring scanner (ECAT EXACT or ECAT HR+; Siemens/CTI), which produces 47 or 63 contiguous slices per bed position. Axial field of view is 15.5 cm per bed position. Five bed positions were measured for each patient, covering a total field of view of 77.5 cm. The emission scan included the thorax and abdomen for all patients. Patients fasted for at least 6 h before undergoing PET. Static emission scans were obtained 45 min after injection of 265–370 MBq of ¹⁸F-FLT (mean, 334 MBq) or 345–550 MBq of ¹⁸F-FDG (mean, 391 MBq). The acquisition time was 10 min per bed position. Four-minute transmission scans with a ⁶⁸Ge/⁶⁸Ga ring source were obtained for attenuation correction after tracer application. Images were reconstructed using an iterative reconstruction algorithm described by Schmidlin (16).

All images were evaluated by 2 experienced nuclear medicine physicians. For calculation of standardized uptake value (SUV), circular regions of interest were drawn containing the area with focally increased pulmonary ¹⁸F-FLT and ¹⁸F-FDG uptake (lesional diameter at spiral CT, 4–48 mm).

Data Analysis
Data are presented as mean, median, range, and SD. The amount of Ki-67–positive cells and the SUVs for ¹⁸F-FDG and ¹⁸F-FLT were compared using linear regression analysis. Differences were considered statistically significant at P < 0.05. ¹⁸F-FDG and ¹⁸F-FLT uptakes were compared using the Mann–Whitney U test.

	RESULTS

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¹⁸F-FDG PET
All malignant lesions except 1 carcinoma in situ (NSCLC, patient 13) showed focally increased and easily detectable ¹⁸F-FDG uptake (Table 1). The mean ¹⁸F-FDG SUV in all visible lesions was 4.1 (median, 4.4; SD, 3.0; range, 1.0–10.6). The mean maximum ¹⁸F-FDG uptake was 6.9 (median, 7.0; SD, 5.8; range, 1.4–22.7).

The mean ¹⁸F-FDG SUV in the 13 patients with NSCLC was 5.6 (median, 5.5; SD, 2.6; range, 1.0–10.6; Fig. 1), and the mean maximum ¹⁸F-FDG SUV was 9.7 (median, 10.1; SD, 5.5; range, 1.4–22.7). Four of the 8 patients with benign lesions presented with focal ¹⁸F-FDG uptake. The reviewers visually interpreted 2 of 8 nodules as malignant. Histopathologic examination revealed unifocal tuberculoma in one patient (patient 21; mean ¹⁸F-FDG SUV, 1.1; maximum ¹⁸F-FDG SUV, 1.8; Fig. 2) and focal bronchiolitis in another patient (patient 19; mean ¹⁸F-FDG SUV, 6.9; maximum ¹⁸F-FDG SUV, 10.3). Inflammatory lesions were suspected in the other 2 patients. Tissue sampling was not performed because clinical follow-up at 3 mo indicated benign lesions (a 1 x 2 cm nodule disappeared on CT performed at the 3-mo follow-up examination, and a 2 x 3 cm nodule decreased to 1 x 1 cm). Mean ¹⁸F-FDG SUVs in these lesions were 2.2 and 3.0, respectively, and maximum ¹⁸F-FDG SUVs were 2.9 and 4.3, respectively.

View larger version (79K): [in this window] [in a new window]   FIGURE 1. Patient 5, with NSCLC in left upper lobe. (A) Transaxial 18F-FLT PET scan demonstrates high 18F-FLT uptake (arrow) in tumor margin. 18F-FLT uptake in vertebral column, scapula, and ribs represents proliferating bone marrow. (B and C) Corresponding 18F-FDG PET and CT scans show high 18F-FDG uptake in tumor margin and primary lung tumor. (D) On Ki-67 immunohistochemistry, Ki-67–positive nuclei (brown) demonstrate high proliferation rate of 54%, and hematoxylin background staining reveals Ki-67–negative nuclei (blue).

View larger version (65K): [in this window] [in a new window]   FIGURE 2. Patient 21, with history of colorectal cancer and suggestive nodule in right middle lobe, for which histopathology revealed solitary tuberculoma. (A) Transaxial 18F-FDG PET scan demonstrates moderate 18F-FDG uptake (arrow) in tumor. (B) No focal tracer accumulation is seen in corresponding 18F-FLT PET scan. (C) Corresponding CT scan shows pulmonary nodule in right middle lobe. (D) On Ki-67 immunohistochemistry, 5% of nuclei show immunoreactivity to Ki-67 antigen.

In pulmonary metastases, the mean ¹⁸F-FLT SUV was 1.1 (median, 1.3; SD, 0.8; range, 0.8–2.1), and the mean maximum ¹⁸F-FLT SUV was 1.6 (median, 1.9; SD, 1.3; range, 1.0–3.4). In the 1 patient with pulmonary metastases from colorectal cancer (patient 15), the metastases showed no ¹⁸F-FLT uptake (Fig. 3). Another patient, with small cell lung cancer (patient 14), showed weak but easily detectable ¹⁸F-FLT uptake (mean ¹⁸F-FLT SUV, 1.7). No benign tumors showed focal ¹⁸F-FLT uptake. Hence, SUV was not determined for these tumors.

View larger version (64K): [in this window] [in a new window]   FIGURE 3. Patient 15, with pulmonary metastases from colorectal cancer. (A) Transaxial 18F-FDG PET scan demonstrates high 18F-FDG uptake (B) in metastatic nodule in right middle lobe. (B) 18F-FLT PET scan shows no tumoral 18F-FLT accumulation. (C) Corresponding CT scan shows pulmonary nodule in right middle lobe. (D) On Ki-67 immunohistochemistry, 12% of nuclei exhibit immunoreactivity to Ki-67–specific antibody MIB-1, indicating low proliferative activity.

Ki-67 Immunohistochemistry
Regional lymph nodes serving as a positive control showed an intense nuclear staining with Ki-67 antibody. In control sections, for which the primary antibody was omitted, no positive nuclear staining was visible.

All malignant tissue specimens contained Ki-67–positive cells. Stained nuclei belonged mainly to epithelial cells, and a very small portion belonged to inflammatory cells. Ki-67 positivity ranged from 1% to 70% of sampled epithelial nucleus profiles (median, 35%). The mean fraction of Ki-67–positive nuclei was 33% (SD, 6.5%). In 6 cases, more than 40% of nuclei showed immunoreactivity for Ki-67 antigen. In NSCLC, the mean proliferation fraction was 37.8% (median, 40%; SD, 19.1%; range, 10%–70%). In pulmonary metastases, the mean proliferative fraction was lower (11.5%; median, 11%; SD, 9%; range, 1%–23%).

Ki-67–positive cells were present in only 1 specimen with benign disease (patient 21, with tuberculoma; Ki-67 index, 5%). Seven benign tissue specimens showed no immunoreactivity to Ki-67 antigen. The range for Ki-67–positive cells was 0%–5%. Ki-67–positive nuclei belonged mainly to inflammatory cells rather than to epithelial cells. The mean of Ki-67–positive cells in benign lesions was 1% (SD, 1.4).

In all lung tumors, linear regression analysis indicated a highly significant correlation between ¹⁸F-FLT SUV and Ki-67 index (P < 0.0001; r = 0.92; Fig. 4). Between Ki-67 and ¹⁸F-FDG SUV, statistical analysis also revealed a significant correlation (P < 0.001; Fig. 4) but a weak correlation coefficient (r = 0.59).

View larger version (10K): [in this window] [in a new window]   FIGURE 4. Linear regression analysis of mean tumoral SUVs of 18F-FLT and 18F-FDG and proliferation fraction (percentage of Ki-67–positive tumor cells). Mean 18F-FLT SUV: significant correlation for P < 0.0001, r = 0.92. Mean 18F-FDG SUV: significant correlation for P < 0.001, r = 0.59.

	DISCUSSION

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Despite high sensitivity, false-positive findings can occur with ¹⁸F-FDG PET, especially in inflammatory lesions (4). Concordantly, focal ¹⁸F-FDG uptake was present in 4 of our study patients with inflammatory or other benign lesions (1 case of bronchiolitis, 1 of tuberculoma, and 2 of undefined benign lung tumors). The relatively high number of false-positive findings in the present series is related to patient selection. Other studies with more patients found specificities averaging 78% for ¹⁸F-FDG PET in detecting lung cancer (3). Recently, unspecific ¹⁸F-FDG uptake has been reported in inflammatory cells such as macrophages (19). Furthermore, many other factors have been reported to influence ¹⁸F-FDG uptake, such as upregulation of glucose transporter 1 receptors (20,21), number of viable tumor cells (22), microvessel density, or hexokinase expression (23). In pancreatic cancer, we previously demonstrated that proliferation was a specific sign for malignancy (5) and clearly differentiated benign from malignant tumors. Therefore, a marker specific for proliferation could reduce false-positive PET findings.

A significant correlation between ¹⁸F-FDG uptake and proliferative activity was also found for breast cancer (24) and NSCLC (7). However, the low correlation coefficient (r = 0.41–0.73) indicated that ¹⁸F-FDG uptake reflects proliferation only in part. In agreement with these findings, the correlation coefficient was as low as 0.59 (r² = 0.35) in our study. That means that only 35% of ¹⁸F-FDG uptake in lung tumors can be explained by proliferative activity.

Various nucleoside analogs have been assessed for imaging proliferation (25–27), but ¹⁸F-FLT is probably the best approach so far. ¹⁸F-FLT turned out to be stable in vivo (12) and accumulates in lung cancer cells in a proliferation-dependent manner (13). Furthermore, thymidine kinase 1 was revealed as the key enzyme responsible for intracellular trapping of ¹⁸F-FLT (28). However, the detailed uptake mechanism is still unknown, and the influence of other factors, such as expression of nucleoside transporters, remains to be determined.

For patients with pulmonary nodules, our data show a highly significant correlation between tumoral ¹⁸F-FLT uptake and proliferative activity as indicated by Ki-67 immunostaining. The correlation coefficient was 0.92 (r² = 0.85). In contrast to the lower correlation coefficient observed for ¹⁸F-FDG, 85% of tracer uptake can be explained by proliferative activity. In agreement with this finding, no ¹⁸F-FLT uptake was visible in nonproliferating tumors. ¹⁸F-FLT PET may therefore be used for the differentiation of benign from malignant lung tumors.

However, 2 patients with NSCLC (1 case of carcinoma in situ and 1 of large cell carcinoma with low proliferative activity), and another patient with pulmonary metastases from colorectal cancer with a proliferation rate of 12%, showed no ¹⁸F-FLT uptake but clear uptake of ¹⁸F-FDG. Compared with ¹⁸F-FDG, ¹⁸F-FLT seems less sensitive for staging disease in patients with malignant lung tumors. Further studies with larger patient populations are needed to determine the diagnostic accuracy of ¹⁸F-FLT PET in detecting malignant tumors.

Several studies have reported that ¹⁸F-FDG PET can be used to assess therapeutic response in various tumors (29–33). A first in vitro study demonstrated that ¹⁸F-FLT uptake in esophageal cancer cells was modified early after incubation with various cytotoxic drugs (34). Hence, ¹⁸F-FLT may be an alternative for therapeutic monitoring. However, for evaluation of ¹⁸F-FLT as a marker for therapy response, large clinical trials are needed.

	CONCLUSION

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¹⁸F-FLT correlates significantly better with the proliferative activity of lung tumors than does ¹⁸F-FDG. ¹⁸F-FLT may therefore be the superior PET tracer for assessment of therapy response and outcome. Because of 3 false-negative findings in our preliminary study, ¹⁸F-FLT PET may be less adequate than ¹⁸F-FDG for primary staging in patients with known lung cancer but may be more accurate for differentiation of unclear lung lesions.

	FOOTNOTES

 
Received Nov. 27, 2002; revision accepted Feb. 19, 2003.

For correspondence or reprints contact: Andreas K. Buck, MD, Department of Nuclear Medicine, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.

E-mail: andreas.buck{at}medizin.uni-ulm.de

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				J. Tian, X. Yang, L. Yu, P. Chen, J. Xin, L. Ma, H. Feng, Y. Tan, Z. Zhao, and W. Wu A Multicenter Clinical Trial on the Diagnostic Value of Dual-Tracer PET/CT in Pulmonary Lesions Using 3'-Deoxy-3'-18F-Fluorothymidine and 18F-FDG J. Nucl. Med., February 1, 2008; 49(2): 186 - 194. [Abstract] [Full Text] [PDF]

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				D. J. A. Margolis, J. M. Hoffman, R. J. Herfkens, R. B. Jeffrey, A. Quon, and S. S. Gambhir Molecular Imaging Techniques in Body Imaging Radiology, November 1, 2007; 245(2): 333 - 356. [Abstract] [Full Text] [PDF]

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				P. Workman, E. O. Aboagye, Y.-L. Chung, J. R. Griffiths, R. Hart, M. O. Leach, R. J. Maxwell, P. M. J. McSheehy, P. M. Price, and J. Zweit Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst, May 3, 2006; 98(9): 580 - 598. [Abstract] [Full Text] [PDF]

				C. S. Yap, J. Czernin, M. C. Fishbein, R. B. Cameron, C. Schiepers, M. E. Phelps, and W. A. Weber Evaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F- Fluorodeoxyglucose-Positron Emission Tomography. Chest, February 1, 2006; 129(2): 393 - 401. [Abstract] [Full Text] [PDF]

				L. M. Kenny, D. M. Vigushin, A. Al-Nahhas, S. Osman, S. K. Luthra, S. Shousha, R. C. Coombes, and E. O. Aboagye Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [18F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods Cancer Res., November 1, 2005; 65(21): 10104 - 10112. [Abstract] [Full Text] [PDF]

				A Saleem Potential of PET in oncology and radiotherapy Br. J. Radiol., November 1, 2005; Supplement_28(1): 6 - 16. [Full Text] [PDF]

				M. E. Juweid and B. D. Cheson Role of Positron Emission Tomography in Lymphoma J. Clin. Oncol., July 20, 2005; 23(21): 4577 - 4580. [Full Text] [PDF]

				W. Chen, T. Cloughesy, N. Kamdar, N. Satyamurthy, M. Bergsneider, L. Liau, P. Mischel, J. Czernin, M. E. Phelps, and D. H.S. Silverman Imaging Proliferation in Brain Tumors with 18F-FLT PET: Comparison with 18F-FDG J. Nucl. Med., June 1, 2005; 46(6): 945 - 952. [Abstract] [Full Text] [PDF]

				D. R. Aberle, C. Chiles, C. Gatsonis, B. J. Hillman, C. D. Johnson, B. L. McClennan, D. G. Mitchell, E. D. Pisano, M. D. Schnall, and A. G. Sorensen Imaging and Cancer: Research Strategy of the American College of Radiology Imaging Network Radiology, June 1, 2005; 235(3): 741 - 751. [Abstract] [Full Text] [PDF]

				J. Leyton, J. R. Latigo, M. Perumal, H. Dhaliwal, Q. He, and E. O. Aboagye Early Detection of Tumor Response to Chemotherapy by 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography: The Effect of Cisplatin on a Fibrosarcoma Tumor Model In vivo Cancer Res., May 15, 2005; 65(10): 4202 - 4210. [Abstract] [Full Text] [PDF]

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				C. Waldherr, I. K. Mellinghoff, C. Tran, B. S. Halpern, N. Rozengurt, A. Safaei, W. A. Weber, D. Stout, N. Satyamurthy, J. Barrio, et al. Monitoring Antiproliferative Responses to Kinase Inhibitor Therapy in Mice with 3'-Deoxy-3'-18F-Fluorothymidine PET J. Nucl. Med., January 1, 2005; 46(1): 114 - 120. [Abstract] [Full Text] [PDF]

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