Chest ACCP Education Calendar
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yap, C. S.
Right arrow Articles by Weber, W. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yap, C. S.
Right arrow Articles by Weber, W. A.
(Chest. 2006;129:393-401.)
© 2006 American College of Chest Physicians

Evaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F- Fluorodeoxyglucose-Positron Emission Tomography*

Cecelia S. Yap, MS; Johannes Czernin, MD; Michael C. Fishbein, MD; Robert B. Cameron, MD; Christiaan Schiepers, MD, PhD; Michael E. Phelps, PhD and Wolfgang A. Weber, MD

* From the Department of Molecular and Medical Pharmacology (Ms. Yap, and Drs. Czernin, Schiepers, Phelps, and Weber), Ahmanson Biological Imaging Center/Nuclear Medicine; the Department of Pathology and Laboratory Medicine (Dr. Fishbein); and the Department of Surgery (Dr. Cameron), Division of Cardiothoracic Surgery, UCLA School of Medicine, Los Angeles, CA.

Correspondence to: Wolfgang A. Weber, MD, Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center/Nuclear Medicine, UCLA School of Medicine, AR-144 CHS, Los Angeles, CA 90095-6948; e-mail: wweber{at}mednet.ucla.edu

Abstract

Study objectives: 18F-fluorodeoxyglucose (FDG) is the most widely used positron emission tomography (PET) imaging probe used for the diagnosis, staging, restaging, and monitoring therapy response of cancer. However, its specificity is less than ideal. A new molecular imaging probe (18F-deoxyfluorothymidine [FLT]) has been developed that might afford more specific tumor imaging. The aims of this study were as follows: (1) to compare the use of FDG-PET and FLT-PET for tumor staging, (2) to compare the degree of FDG and FLT uptake in lung lesions, and (3) to determine the correlation between PET uptake intensity and tumor cell proliferation.

Design: FDG-PET and FLT-PET scans were performed in 11 patients with solitary pulmonary nodules and another 11 patients with known non-small cell lung cancer (NSCLC). Tracer uptake was assessed quantitatively by standardized uptake values (SUVs). Histologic evaluation of tissue samples obtained from biopsy specimens or surgical resections served as the "gold standard." Tumor cell proliferation was assessed by Ki-67 staining.

Results: Pathology verification was available from 99 tissue samples in the 22 patients (29 pulmonary lesions, 66 lymph node stations, and 4 extrapulmonary lesions). Thirty-three samples (33.3%) were positive for tumor tissue (22 pulmonary, 9 lymph node stations, and 2 extrapulmonary). FDG-PET findings were false-positive in three pulmonary lesions, while FLT-PET findings were false-positive in one lesion. There were two false-negative findings by FDG-PET and six false-negative findings by FLT-PET. FDG uptake of the malignant lesions was significantly higher than FLT (maximum SUV, 3.1 ± 2.6 vs 1.6 ± 1.2 [mean ± SD]; p < 0.05). A significant correlation was observed between FLT uptake of pulmonary lesions and Ki-67 labeling index (r = 0.60, p = 0.02) but not for FDG uptake (r = 0.27, p = not significant).

Conclusions: Compared to FDG-PET, detection of primary and metastatic NSCLC by FLT-PET is limited by the relatively low FLT uptake of the tumor tissue. Thus, FLT-PET is unlikely to provide more accurate staging information or better characterization of pulmonary nodules than FDG-PET. Nevertheless, the correlation between FLT uptake and cellular proliferation suggests that future studies should evaluate the use of FLT-PET for monitoring treatment with cytostatic anticancer drugs.

Key Words: fluorodeoxyglucose • fluorothymidine • non-small cell lung cancer • positron emission tomography

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and PET/CT is now used to diagnose, stage, and restage malignancies and to monitor treatment effects in cancer patients. In lung cancer, PET accomplishes these tasks with a higher accuracy than conventional anatomic imaging.1 Further, the sensitivity of FDG-PET for characterizing solitary pulmonary nodules is high, at approximately 90%.2 Nevertheless, limitations remain. Foremost among these is the unspecific nature of FDG uptake in cancer. Accumulation of FDG in inflammatory cells such as macrophages, fibroblasts, and in some benign tumors can also result in increased FDG uptake because these cells require glucose as their substrate for energy production.34 Thus, the specificity of FDG-PET for characterizing lung nodules and staging of cancer is only approximately 80%.

Imaging of cellular proliferation provides an alternative approach for the diagnosing and staging of lung cancer. Recently, 18F-fluorothymidine (FLT), a radiolabeled analog of thymidine, has been synthesized for imaging tumor cell proliferation in humans.56 FLT is retained in proliferating tissues through the enzyme thymidine kinase 1 (TK1) that phosphorylates FLT to FLT-5 phosphate, which is essentially trapped in tumor cells. Studies789 in cell cultures and animal models have suggested that tumor FLT uptake in vitro and in vivo is correlated with tumor cell proliferation. A similar correlation has also been observed in two clinical studies,101112 while one other study13 did not confirm such correlation. One consistent finding in these studies10111213 was that the degree of FDG uptake is considerably higher than that of FLT. Thus, the sensitivity of FLT-PET for cancer staging might be limited. However, the specificity of FLT for tissue characterization might be superior to that of FDG, and the ability of FLT and FDG-PET for cancer staging has not been systematically compared. The aims of the present study were as follows: (1) to determine the accuracy of FLT and FDG-PET for diagnosing and staging of non-small cell lung cancer (NSCLC); (2) to compare the degree of uptake by FDG and FLT; and (3) to investigate the relationship between the degree of FDG and FLT tumor uptake and Ki-67 labeling index, an established immunohistochemical marker of tumor cell proliferation.

Materials and Methods

Patient Population
Patients undergoing clinical whole-body FDG-PET scans for characterization of indeterminate pulmonary nodules or staging of NSCLC were eligible for this prospective study. Patients with other malignancies and those who had received cancer treatment within the past 5 years were excluded. Twenty-two patients (11 women and 11 men; average age, 66 ± 11 years ± SD]) consented to undergo an additional FLT-PET scan. The study was approved by the UCLA Institutional Review Board.

The FLT-PET scans were performed within 1 month of the clinical FDG-PET studies (mean, 16 ± 23 days; range, – 4 to 31 days). No treatment was performed between the two scans. The average time interval between FLT-PET and histologic verification by surgical resection or biopsy was 18 ± 15 days (range, 4 to 51 days; median, 14 days) for 19 patients. In the other two patients, one patient (patient 1) was followed up for 201 days, and the other patient (patient 10) was followed up for 84 days. Patient 1 initially presented with a solitary pulmonary nodule found on CT, but this was negative on both FDG-PET and FLT-PET. The patient was then followed up with CT scans until a slight increase in size was reported, at which time the patient opted for surgical resection. Histology demonstrated benign fibrosis. Patient 10 had abnormal findings on CT and FDG-PET and FLT-PET scans. However, because of the patient’s poor lung function and worsening interstitial lung disease, wedge biopsy was delayed.

FDG-PET Image Acquisition and Reconstruction
FDG-PET studies were performed on the Siemens EXACT PET scanner (CPS Innovations; Knoxville, TN).14 Patients were instructed to fast for at least 6 h prior to FDG-PET imaging. All patients had serum glucose levels < 120 mg/dL at the time of FDG injection. Whole-body emission scans were acquired 60 min after IV injection of approximately 0.21 mCi/kg of FDG. Data were acquired in the two-dimensional mode. Both emission (4 min per bed position) and transmission (3 min per bed position) scans were performed in all patients. Standard iterative image reconstruction algorithms were applied.1516

FLT-PET Image Acquisition and Reconstruction
Preparation of FLT was carried out as described previously.17 Five millicuries (approximately 185.2 MBq) of FLT were injected IV, and image acquisition commenced 60 min thereafter.18 This relatively low activity was chosen to minimize the radiation exposure of patients and to comply with the radiation safety regulation for investigational radiopharmaceuticals at University of California, Los Angeles. To compensate for the lower amount of injected activity, images were acquired in three-dimensional mode. Emission, transmission, as well as image reconstruction protocols were otherwise performed as described above.

PET Image Interpretation and Staging
FDG-PET and FLT-PET images were presented to an experienced reader (J.C.) in a random sequence and evaluated in a blinded fashion. Sites of increased FDG and FLT uptake corresponding to primary tumors, lymph nodes, and distant disease sites were recorded. PET and clinical and pathologic TNM stages were established using the International System for Staging Lung Cancer adopted by the American Joint Committee on Cancer and the Union Internationale Centre le Cancer.19

PET Quantitative Analysis
Regions of interest (ROIs) were placed manually over areas of abnormal FDG and FLT accumulation. Maximum standardized uptake values (maxSUVs) normalized to patient body weight were calculated. maxSUVs were used in order to minimize the effect of partial volume effects on the uptake values. For lesions visible on FDG but not on FLT scans, an ROI was drawn on FLT scans in the area approximately corresponding to the area of increased FDG uptake. For lesions not visible on both FDG and FLT, ROIs were drawn on both the FDG and FLT scans in the area corresponding to the area of abnormality on CT.

Immunohistochemical Staining with Ki-67
Paraffin-embedded tissue blocks were recut, and representative sections of 3 to 4 µm were obtained for immunohistochemical staining (MIB-1, 1:100 dilution; Dako; Carpinteria, CA), a murine antibody specific for the Ki-67 human nuclear antigen. The immunohistochemistry was performed according to standard protocol and routine at our institution.20 Sections of human lymph node tissue were used as positive control for cell proliferation. For the negative control, normal mouse serum (Dako) was used in place of the primary antibodies. No significant staining was observed in the negative controls.

The Ki-67 labeling index reflects cell proliferative activity and is defined as the percentage of nuclei stained per total number of nuclei in the sample. Ki-67 labeling index was determined through computerized morphometry as previously described.21 The total number of tumor cells counted, including both positive and negative cells, ranged from 500 to 2,000 in three fields. Only nuclei of tumor cells staining definitely brownish were judged positive. Areas adjacent to the biopsy scar were excluded in evaluating Ki-67. Representative areas were imaged, and images were transferred to the computer frame by a video camera using a computer-assisted imaging program (Image-Pro Plus; Media Cybernetics; Silver Spring, MD).

Statistical Analysis
Data are presented as mean, range, and SD. The relationship between tumor cell proliferation rates (Ki-67 staining) and FDG or FLT SUVs was assessed using linear regression analysis; p < 0.05 was considered significant. Sensitivity, specificity, and accuracy were calculated using standard formulae, and statistical significance was determined with the McNemar test.

Results

Pathology Findings
Tissue diagnosis of the pulmonary lesions was established through surgical resection or thoracotomy in 15 patients and by biopsy in 7 patients. Fourteen of the patients also underwent mediastinoscopy.

Pathology information from a total of 99 tissue samples obtained from these procedures was available for verification of and comparison between imaging findings of FDG-PET and FLT-PET. Twenty-nine samples were obtained from pulmonary lesions, 66 from lymph node stations (N1 or hilar or intrapulmonary, n = 15; N2/N3 ipsilateral mediastinal and contralateral involvement, n= 51) and 4 from other, extrapulmonary metastatic lesions (pleural, n = 2; rib, n = 1; liver, n = 1). Malignancy was found in 33 samples (22 pulmonary lesions, 9 lymph node stations, and 2 extrapulmonary lesions: liver, n = 1; pleural lesion, n = 1). Thus, 33% of the samples revealed malignancy, and 67% were benign.

Pathologic verification of 7 of the 11 indeterminate pulmonary nodules revealed malignancy (NSCLC, n = 6; metastatic acinic cell parotid carcinoma, n = 1). In one patient (patient 6) with an indeterminate pulmonary nodule, FDG-PET demonstrated a previously unknown liver lesion. Biopsy of this lesion revealed relapsed metastatic colorectal cancer (in complete remission for 6 years). Since the pulmonary nodule demonstrated similar metabolic activity as the liver lesion, it was regarded to be a metastasis of colorectal cancer and so no biopsy of this lesion was performed. Benign processes (fibrosis, pneumonia and fibrosis, and granuloma) were diagnosed in the remaining three patients, respectively.

Hence, in our study population of 22 patients, the final diagnosis was NSCLC in 17 patients (77%), metastatic pulmonary lesions of other primary tumors in 2 patients, and benign processes in 3 patients (Fig 1 , Table 1 ). In patients with NSCLC, 9 of the 66 nodal samples (14%) were positive for tumor tissue: N2 (mediastinal, n = 6) and N1 (intralobar; n = 3).


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Final diagnosis of patients referred for evaluation of pulmonary nodules and the diagnoses of lung cancer in the study population.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Patient and Data Summary*

 
FDG-PET Findings
Thirty-two of the 99 pathology-verified lesions (23 pulmonary lesions, 7 lymph node stations, and 2 extrapulmonary metastases) exhibited increased FDG uptake (Table 2 ). FDG-PET findings were true-positive in 20 pulmonary lesions, true-negative in 4 lesions, false-positive in 3 lesions, and false-negative in 2 lesions. The three false-positive FDG-PET findings were explained by interstitial pneumonia and granulomatous inflammation while two false-negative findings occurred in a patient with adenocarcinoma (1.9 cm) and in another patient with pulmonary metastases of acinic cell carcinoma of the parotid (0.7 cm). FDG-PET findings were true-negative in a patient with focal interstitial fibrosis.


View this table:
[in this window]
[in a new window]

  		Table 2. Tabulation of the True-Positive, True-Negative, False-Positive, and False-Negative Findings for FDG-PET and FLT-PET, Stratified by Pulmonary Lesions, Lymph Node Stations, and Other, Extrapulmonary Lesions for the 99 Tissue Samples Evaluated by Histopathology

 
FDG-PET findings were true-positive in four and false-negative in five of the nine malignant lymph node stations. In three patients, the involved lobar lymph nodes were in close proximity to or embedded by the primary tumor. FDG findings were true-negative in 54 of 57 benign lymph node stations and false-positive in 2 lymph nodes stations with granuloma. The other false-positive finding was due to misinterpreting a tumor extension as positive nodal involvement. Of the four extrapulmonary lesions sampled, two were confirmed to have malignant involvement while the other two were benign. FDG-PET findings were true-positive for the two malignant metastases and true-negative for the two benign lesions. On a lesion-by-lesion analysis that included 29 pulmonary lesions, 66 lymph node stations, and 4 extrapulmonary lesions, FDG-PET had an accuracy of 87% (86 of 99 lesions), with a sensitivity of 79% (26 of 33 lesions) and a specificity of 91% (60 of 66 lesions).

FLT-PET Findings
Verification of the 29 pulmonary lesions against pathology revealed that FLT-PET findings were true-positive in 16 lesions, true-negative in 6 lesions (Fig 2 ), false-positive in 1 lesion, and false-negative in 6 lesions. Three of the six false-negative FLT-PET findings occurred in pure bronchioloalveolar carcinoma (n = 1) and adenocarcinoma with prominent bronchioloalveolar features (n = 2). The sole false-positive finding occurred in a patient with nonspecific interstitial pneumonia (FLT SUV, 1.8; Fig 3 ).


Figure 2
View larger version (63K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. FDG-PET, FLT-PET, CT scans, and Ki-67 stain (original x 40) of a patient with solitary pulmonary nodule (patient 11). Images in the top row show coronal maximum intensity projections of the FDG-PET and FLT-PET scans, respectively. Images in the middle row are transaxial sections through the nodule. A small hypermetabolic pulmonary nodule on FDG-PET and CT (arrow) was worrisome for malignancy, but no corresponding FLT uptake was seen. Biopsy revealed the presence of nonnecrotizing granulomatous and chronic inflammation, with organizing pneumonia. Thus, FDG-PET and CT findings were false-positive, while FLT-PET findings were true-negative.

 

Figure 3
View larger version (61K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. FDG-PET, FLT-PET, CT scans, and Ki-67 stain (original x 40) from a patient referred for evaluation of pulmonary abnormality (patient 10). On FDG-PET and CT, the abnormality appeared partly nodular and seemed suspicious for malignancy (arrow). Mildly increased FLT uptake was also noted so malignancy could not be ruled out. Wedge biopsies verified the presence of NSIP, cryptogenic organizing pneumonia, and fibrosis. Hence, both FDG-PET and FLT-PET findings were false-positive for malignancy.

 
FLT-PET findings were true-positive in three of nine malignant lymph node stations but false-negative in six stations. Similar to FDG-PET, three false-negative findings occurred in lobar lymph nodes in close proximity to the primary tumor. FLT findings were true-negative in all but one of 57 lymph node stations without metastatic involvement. This false-positive finding also occurred for FDG-PET and was due to erroneously regarding part of a tumor as positive nodal involvement. FLT-PET findings were true-negative for two and false-negative for the other two of the four extrapulmonary lesions (Table 2, Fig 4 ).


Figure 4
View larger version (89K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. Coronal maximum intensity projections of FDG-PET and FLT-PET scans of a patient with newly diagnosed adenocarcinoma in the right lung who was referred for staging (patient 18). FDG revealed abnormal findings in bilateral lungs, while FLT findings were negative. In this case, FDG-PET findings were true-positive for primary cancer in the right lung (biopsy prior to PET scans at another institution), while FLT findings were false-negative. A subsequent mediastinoscopy also revealed that FDG-PET findings were true-positive for contralateral nodal involvement but FLT findings were false-negative.

 
On a lesion-by-lesion analysis that included 29 pulmonary lesions, 66 lymph node stations, and 4 extrapulmonary lesions, FLT-PET had an accuracy of 84% (83 of 99 lesions), with a sensitivity of only 58% (19 of 33 lesions) and a specificity of 97% (64 of 66 lesions). Overall, 77 of the 99 lesions were correctly identified by both FDG and FLT, while 7 lesions were incorrectly identified by both. FDG was correct while FLT was incorrect in the identification of 10 lesions, whereas FLT was correct and FDG was incorrect in the identification of 5 lesions. The difference in accuracy and specificity of FDG-PET and FLT-PET in disease detection did not reach statistical significance (p = 0.59 and p = 0.18, respectively). The p value for differences in sensitivity of FDG-PET and FLT-PET was 0.058.

Patient-Based Analysis and Staging
On a patient-by-patient analysis of pathologic and clinical staging (Table 3 ), 3 of the 22 patients were without disease, 10 had surgically resectable disease (stage IA-IIIA), while 7 had unresectable disease (stage IIIB and IV). Staging by FDG classified two patients as disease free, 10 patients as surgical candidates, and 10 patients as nonsurgical candidates. Staging by FLT, however, classified 6 patients as disease free, 11 patients as surgical candidates, and 5 patients as nonsurgical candidates.


View this table:
[in this window]
[in a new window]

  		Table 3. TNM Staging of Patients Using FDG-PET and FLT-PET and Comparison With Pathologic and Clinical Stage*

 
Overall, FDG-PET understaged three patients (14%) and overstaged six patients (27%), whereas FLT-PET understaged eight patients (36%) and overstaged two patients (9%). Of the discordant staging, FDG-PET overstaged one patient from having operable disease to having inoperable disease, while FLT-PET understaged four patients with stage IV disease as being surgically operable.

Ki-67 Immunohistochemical Staining
Ki-67 immunohistochemical staining was evaluated for 25 lesions (Table 1). These 25 lesions were retrospectively selected for Ki-67 staining on the basis of tissue availability and consisted mainly of primary lesions. Involved lymph nodes were selected in cases in which tissue from primary lesions was not available for staining. Each of the 22 patients had at least one Ki-67–stained tissue sample, except for one patient whose original biopsy was performed at another institution (patient 19, Table 1).

The Ki-67 labeling index averaged 23 ± 20% (median, 16%) and ranged from 4 to 70% for the 25 lesions. The Ki-67 labeling index for the 22 malignant lesions averaged 25 ± 20% (median, 19%), while that for the 3 benign lesions had a mean of 9 ± 5% (median, 6%).

Comparison of FDG and FLT Uptake and Correlation With Proliferative Activity
For 15 pulmonary lesions, the Ki-67 labeling index could be correlated with FDG and FLT uptake in the PET studies (due to technical reasons, standardized uptake value [SUV] could not be calculated in four FDG and in three FLT studies, Table 1). Only pulmonary lesions were included in this analysis because nodal involvement by malignancy occurred in several patients in a small area of the lymph node, and the Ki-67 staining was likely not performed on the most representative section of the lymph nodes since serial sectioning was not routinely carried out.

FDG SUVs were greater than FLT SUVs (3.0 ± 2.9 vs 1.6 ± 1.2, p = 0.02). Similarly, FDG uptake was greater than FLT in pulmonary lesions that were malignant (n = 12; 3.4 ± 3.0 vs 1.8 ± 1.3, p = 0.03). Extending SUV quantification into the correlation with Ki-67 labeling index in the 15 pulmonary lesions with FDG SUV and FLT SUV, a modest but statistically significant correlation was found for FLT (r = 0.60, p = 0.02), but no correlation was found for FDG (r = 0.27, p = not significant) [Fig 5 ].


Figure 5
View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5. Correlation of Ki-67 with FDG SUV (left, A; r = 0.27, p = not significant) and with FLT SUV (right, B; r = 0.60, p = 0.02) for pulmonary lesions.

 
Discussion

This prospective study confirms that FLT uptake in NSCLC is correlated with cellular proliferation, whereas no significant correlation was observed for FDG uptake. Furthermore, it shows that tumor FLT uptake is only half of FDG uptake, leading to a low sensitivity of FLT-PET for detection of NSCLC (58%).

Compared to previous reports,10111213 tumor FLT uptake was less closely correlated with cellular proliferation in this study (Table 4 ). Since the sample sizes of our study as well as of the previous studies are relatively small, differences in the correlation coefficients may be due to random errors and should not be overinterpreted. Nevertheless, it is instructive to briefly discuss some differences between this and previous studies, in order to illustrate general methodologic problems in assessing tumor proliferation with FLT-PET.


View this table:
[in this window]
[in a new window]

  		Table 4. Comparison of Ki-67 Labeling Index and FLT SUV in Thoracic Lesions in Relevant Studies*

 
In the present study, the Ki-67 labeling index and, consequently, FLT uptake were relatively low. Hence, statistical measurement errors had a greater influence on the FLT SUVs. However, two studies evaluating tumor proliferation in a total of 232 patients with NSCLC reported mean Ki-67 labeling indexes of 19.3%22 and 19.4%,23 respectively, which are comparable to our study. Furthermore, lesion size was relatively small in our study; hence, calculation of SUVs was, to a greater extent, confounded by partial volume effects, which could cause an underestimation of the true FLT uptake. Techniques for correction of partial volume effects for spherical lesions with a known diameter in a homogeneous background have been described.10 However, in the present study, several lesions demonstrated an irregular shape and were located close to the pleura. For these lesions, background activity was not homogeneous and correct measurement of lesion size was difficult. Since partial volume correction factors become very large when the size of the lesion is < 1 cm,10 even small inaccuracies in the lesion size would introduce large errors in the correction factors. Therefore, partial volume correction was not used in the present study.

Local radiation safety regulations permitted us to inject only a relatively small dose of FLT (185 MBq). To compensate for this, FLT scans were acquired in "three-dimensional mode," which provides a higher sensitivity but is more subject to artifacts caused by random and scattered coincidence events.14 Since previous studies used two-dimensional acquisition, this may also have contributed to the differences in the correlation between FLT uptake and Ki-67 labeling. However, it appears unlikely that this is a major factor, since studies have indicated that noise equivalent count rates for a three-dimensional scan of the thorax after injection of 185 MBq of FDG are similar to a two-dimensional scan after injection of 370 MBq of FDG,24 and that image contrast is not significantly different.25

Finally, one may speculate that tumor-specific differences in utilization of the thymidine salvage pathway and de novo thymidine synthesis need to be considered. FLT is not incorporated into DNA, and cellular FLT uptake mainly reflects the activity of the cytosolic TK1, which phosphorylates FLT to FLT phosphate.8 Generally, significant TK1 activity is observed only during the late G1 and S phases.8 However, loss of cell cycle-specific regulation of TK1 has been reported in cancer cells,26 which may influence the correlation between FLT uptake and Ki-67 labeling.

With respect to tumor staging, FLT-PET is clearly limited by its low sensitivity. Only 58% of all histologically verified primary tumors or metastases were correctly identified by FLT-PET. This low sensitivity is due to the low FLT uptake in malignant lesions, which was only half that of FDG in this study as well as a prior study.12 Major discordance in tumor staging, ie, from operable stages (I-IIIA) to inoperable stages (IIIB and IV) and vice versa, occurred in just one patient with FDG-PET (overstaged from IA to IIIB) but in four patients with FLT-PET (all understaging from IV to IA; Table 3).

While the major limitation of FLT-PET for staging of NSCLC is its low sensitivity, it is important to note that there were also two false-positive FLT findings in the current study. These occurred in a tumor extension erroneously identified as nodal involvement and in inflammatory tissue (Ki-67, 15%). In the latter patient, wedge biopsies indicated the presence of nonspecific interstitial pneumonia (NSIP) with fibrosis pattern and also cryptogenic organizing pneumonia or bronchiolitis obliterans organizing pneumonic. These inflammatory lung diseases are accompanied by lymphocytic infiltrates and involve growth factors that lead to elevated proliferation.27 Increased FLT uptake by inflammatory processes has also been reported by other groups2829 evaluating FLT-PET for staging of melanoma and laryngeal cancer. Thus, the specificity of FLT-PET for tumor tissue is not 100%. This finding appears to be related to two factors: (1) proliferation of lymphocytes, and (2) nonspecific increase in the accumulation of FLT due to increased perfusion and vascular permeability.

Because of its low sensitivity, FLT-PET does not appear to be able to replace FDG-PET for tumor staging or for characterization of pulmonary nodules as benign or malignant. Nevertheless, the significant correlation between FLT uptake and tumor cell proliferation, which now has been confirmed in several studies,303132 suggests future clinical trials should evaluate the use of FLT-PET for assessing changes of tumor cell proliferation during therapy. In this context only, an intra-individual comparison of FLT uptake has to be performed. Therefore, many of the factors that may adversely affect the correlation between FLT uptake and tumor cell proliferation are expected to cancel out. It will also be interesting to study whether FLT uptake is correlated with patient survival, since several studies33343536 have reported that the proliferation index is a prognostic factor in NSCLC.

Footnotes

Abbreviations: FDG = 18F-fluorodeoxyglucose; FLT = 18F-fluorothymidine; maxSUV = maximum standardized uptake value; NSCLC = non-small cell lung cancer; NSIP = nonspecific interstitial pneumonia; PET = positron emission tomography; ROI = region of interest; SUV = standardized uptake value; TK1 = thymidine kinase 1

Received for publication October 12, 2004. Accepted for publication June 22, 2005.

References

  1. Dwamena, BA, Sonnad, SS, Angobaldo, JO, et al (1999) Metastases from non-small cell lung cancer: mediastinal staging in the 1990s: meta-analytic comparison of PET and CT. Radiology 213,530-536[Abstract/Free Full Text]
  2. Gould, MK, Maclean, CC, Kuschner, WG, et al Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001;285,914-924[Abstract/Free Full Text]
  3. Kubota, R, Kubota, K, Yamada, S, et al Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med 1994;35,104-112[Abstract/Free Full Text]
  4. Shreve, PD, Anzai, Y, Wahl, RL Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19,61-77[Abstract/Free Full Text]
  5. Shields, AF, Grierson, JR, Dohmen, BM, et al Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4,1334-1336[CrossRef][ISI][Medline]
  6. Mier, W, Haberkorn, U, Eisenhut, M [18F]FLT: portrait of a proliferation marker. Eur J Nucl Med 2002;29,165-169
  7. Toyohara, J, Waki, A, Takamatsu, S, et al Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29,281-287[CrossRef][Medline]
  8. Rasey, JS, Grierson, JR, Wiens, LW, et al Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 2002;3,1210-1217
  9. Seitz, U, Wagner, M, Neumaier, B, et al Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29,1174-1181[CrossRef][Medline]
  10. Vesselle, H, Grierson, J, Muzi, M, et al In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 2002;8,3315-3323[Abstract/Free Full Text]
  11. Buck, AK, Schirrmeister, H, Hetzel, M, et al 3-deoxy-3-[F-18]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002;62,3331-3334[Abstract/Free Full Text]
  12. Buck, AK, Halter, G, Schirrmeister, H, et al Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med 2003;44,1426-1431[Abstract/Free Full Text]
  13. Dittmann, H, Dohmen, BM, Paulsen, F, et al [(18)F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging 2003;30,1407-1412[CrossRef][Medline]
  14. Wienhard, K, Eriksson, L, Grootoonk, S, et al Performance evaluation of the positron scanner ECAT EXACT. J Comput Assist Tomogr 1992;16,804-813[ISI][Medline]
  15. Meikle, SR, Dahlbom, M, Cherry, SR Attenuation correction using count-limited transmission data in positron emission tomography. J Nucl Med 1993;34,143-144[Abstract/Free Full Text]
  16. Meikle, SR, Hutton, BF, Bailey, DL, et al Accelerated EM reconstruction in total-body PET: potential for improving tumour detectability. Phys Med Biol 1994;39,1689-1704[CrossRef][Medline]
  17. Grierson, JR, Shields, AF Radiosynthesis of 3'-deoxy-3'-[18F]fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol 2000;27,143-156[CrossRef][Medline]
  18. Vesselle, H, Grierson, J, Peterson, LM, et al 18F-Fluorothymidine radiation dosimetry in human PET imaging studies. J Nucl Med 2003;44,1482-1488[Abstract/Free Full Text]
  19. Mountain, CF Revisions in the International System for Staging Lung Cancer. Chest 1997;111,1710-1717[Abstract/Free Full Text]
  20. Sarantopoulos, GP, Gui, D, Shintaku, P, et al Immunohistochemical analysis of lung carcinomas with pure or partial bronchioloalveolar differentiation. Arch Pathol Lab Med 2004;128,406-414[Medline]
  21. Terasaki, H, Niki, T, Matsuno, Y, et al Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization. Am J Surg Pathol 2003;27,937-951[CrossRef][ISI][Medline]
  22. Haga, Y, Hiroshima, K, Iyoda, A, et al Ki-67 expression and prognosis for smokers with resected stage I non-small cell lung cancer. Ann Thorac Surg 2003;75,1727-1732[Abstract/Free Full Text]
  23. Carvalho, PE, Antonangelo, L, Bernardi, FD, et al Useful prognostic panel markers to express the biological tumor status in resected lung adenocarcinomas. Jpn J Clin Oncol 2000;30,478-486[Abstract/Free Full Text]
  24. Lartizien, C, Comtat, C, Kinahan, PE, et al Optimization of injected dose based on noise equivalent count rates for 2- and 3-dimensional whole-body PET. J Nucl Med 2002;43,1268-1278[Abstract/Free Full Text]
  25. Raylman, RR, Kison, PV, Wahl, RL Capabilities of two- and three-dimensional FDG-PET for detecting small lesions and lymph nodes in the upper torso: a dynamic phantom study. Eur J Nucl Med 1999;26,39-45[CrossRef][Medline]
  26. Schwartz, JL, Tamura, Y, Jordan, R, et al Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med 2003;44,2027-2032[Abstract/Free Full Text]
  27. Drent, M, du Bois, RM, Poletti, V Recent advances in the diagnosis and management of nonspecific interstitial pneumonia. Curr Opin Pulm Med 2003;9,411-417[CrossRef][ISI][Medline]
  28. Cobben, DC, Jager, PL, Elsinga, PH, et al 3'-18F-fluoro-3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? J Nucl Med 2003;44,1927-1932[Abstract/Free Full Text]
  29. Cobben, DC, van der Laan, BF, Maas, B, et al 18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET. J Nucl Med 2004;45,226-231[Abstract/Free Full Text]
  30. Oyama, N, Ponde, DE, Dence, C, et al Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation. J Nucl Med 2004;45,519-525[Abstract/Free Full Text]
  31. Barthel, H, Cleij, MC, Collingridge, DR, et al 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63,3791-3798[Abstract/Free Full Text]
  32. Sawyers, C Targeted cancer therapy. Nature 2004;432,294-297[CrossRef][Medline]
  33. Poleri, C, Morero, JL, Nieva, B, et al Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histopathologic and immunohistochemical analysis. Chest 2003;123,1858-1867[Abstract/Free Full Text]
  34. Puglisi, F, Minisini, AM, Aprile, G, et al Balance between cell division and cell death as predictor of survival in patients with non-small-cell lung cancer. Oncology 2002;63,76-83[Medline]
  35. Dosaka-Akita, H, Hommura, F, Mishina, T, et al A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis. Cancer Res 2001;61,2500-2504[Abstract/Free Full Text]
  36. Pence, JC, Kerns, BJ, Dodge, RK, et al Prognostic significance of the proliferation index in surgically resected non-small-cell lung cancer. Arch Surg 1993;128,1382-1390[Abstract]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yap, C. S.
Right arrow Articles by Weber, W. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yap, C. S.
Right arrow Articles by Weber, W. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS