| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Clinical Investigation |
1 Department of Nuclear Medicine, University Hospital of Bonn, Bonn, Germany; 2 Department of Radiology, University Hospital of Bonn, Bonn, Germany; 3 Department of Surgery, University Hospital of Bonn, Bonn, Germany; and 4 Department of Pathology, University Hospital of Bonn, Bonn, Germany
Correspondence: For correspondence or reprints contact: Holger Palmedo, MD, Department of Nuclear Medicine, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. E-mail: holger.palmedo{at}ukb.uni-bonn.de
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Key Words: integrated PET/CT • differentiated thyroid cancer • 18F-FDG PET • Hürthle cell tumor • iodine negative
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Low expression of the sodium-iodine symporter seems to be one main reason for the lack of iodine uptake that may be present at primary diagnosis or that develops during the further course of disease (5). Patients with DTC may have only iodine-negative tumor lesions or both iodine-negative and iodine-positive tumor tissue (6). Consequently, the presence of iodine-negative tumor tissue decreases the accuracy of iodine scintigraphy, which is routinely used for staging and restaging patients. This can lead to the situation in which tumor tissue is not detected by iodine scintigraphy and will remain without further treatment (7).
PET with 18F-FDG has been able to improve the diagnostic work-up of these patients with iodine-negative DTC (6,7). Studies on the value of 18F-FDG PET for DTC have concentrated on patients in whom radioiodine scintigraphy is negative but metastatic spread is associated with an increase of thyroglobulin (TG) level or unclear morphologic findings. It has been shown that 18F-FDG PET is the most accurate method in this situation, and sensitivities and specificities range between 85% and 94% (7–11). For the treatment of iodine-negative tumor tissue, surgery is the only curative therapy option. Exact localization of 18F-FDG tumor foci is mandatory for successful resection of cancer in these cases.
Integrated PET/CT is a new imaging modality that might have advantages over the diagnostic work-up by PET alone or by separate PET and morphologic imaging. We hypothesized that the diagnostic accuracy of integrated PET/CT would be significantly higher than that of PET alone or of side-by-side PET and CT. The more accurate definition of tumor location should also result in better decision making for therapy.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
-camera 131I whole-body scintigraphy meeting high-quality requirements, decision of a nuclear medicine physician (not involved in data evaluation) that no pathologic accumulation of radioiodine could be found on whole-body scintigraphy, previous total thyroidectomy, and radioiodine ablation. Exclusion criteria were as follows: positive test for TG antibodies, administration of CT contrast medium within the previous 6 mo, positive iodine urine test performed on the day of scintigraphy, pregnancy, or an age of <18 y. This was a prospective study. The findings of PET, CT, and fused imaging were compared with histopathology (tumor grading (4)) or clinical follow-up results as a gold standard. The evaluation of imaging was performed directly after imaging, and the results were used for further clinical decision making. All patients were informed about the study and had given written consent according to the Declaration of Helsinki. The ethical committee and the radiation safety committee had given approval.
Imaging
All data were acquired with a combined PET/CT in-line system (Biograph; Siemens Medical Solutions). This camera integrates a PET scanner (Ecat HR+; Siemens) with a dual-section helical CT scanner (Somatom; Siemens) and allows the acquisition of coregistered CT and PET images in one session.
All patients were studied (also for PET/CT) after a 4-wk withdrawal of L-thyroxin (first a 2-wk substitution with triiodothyronine, then complete withdrawal). 131I whole-body scintigraphy was performed 3–4 d after administration of 370 or 1,110 MBq 131I using a standard -camera with high-energy collimator. The interval between 131I scintigraphy and PET/CT was 1 wk.
The patients fasted at least 4 h before injection of 370 MBq 18F-FDG. Scanning was started 60–90 min after the injection (5–7 bed positions; acquisition time, 5 min/bed position). Blood glucose levels did not exceed 150 mg/dL (8.3 mmol/L). No intravenous contrast agent was administered. Initially, patients were examined in the supine position with arms elevated, and CT scanning was started at the level of the cervicothoracic region with the following parameters: 40 mAs; 130 kV; slice thickness, 2.5 mm; pitch, 1.5. The CT scans were acquired during breath holding within the normal expiration position and reached caudally to the midthigh. PET over the same region was performed immediately after acquisition of the CT images (5 min/bed position). Afterward, a second data acquisition set from the base of the skull to the upper thoracic region was initiated with the patient's arms positioned next to the body. For this second part of the examination, the same parameters were used for CT and PET. The CT data were used for attenuation correction, and images were reconstructed as 5-mm slices applying a standard iterative algorithm (ordered-subset expectation maximization).
Interpretation
Images were interpreted at a workstation equipped with fusion software (Syngo; Siemens) that provides multiplanar reformatted images and enables display of the PET images (with and without attenuation correction), CT images, and fused PET/CT images in any percentage relation.
Analysis of images was performed as a multistep image interpretation (12). During the first step of analysis, PET and CT images were scored blindly and independently by 2 nuclear medicine physicians and 2 radiologists. For this purpose, a 5-point scale was used: a score of 0 indicated that the lesion was normal; a score of 1 indicated that the lesion was probably normal; a score of 2 indicated that the lesion was equivocal; a score of 3 indicated that the lesion was probably abnormal; and a score of 4 indicated that the lesion was abnormal.
The second step of data analysis consisted of a consensus reading by both groups. During the consensus reading, first a virtual (meaning mental) fusion of PET and CT images was scored on the 5-point scale; afterward, the "real" fusion (i.e., coregistered) PET/CT images were also scored with the same 5-point scale. The 5-point interpretation was applied to every lesion as well as to the patient. If no consensus was achieved, the results were to be part of a special-case analysis.
A lesion was categorized as 0 or 1 if it did not follow the physiologic 18F-FDG uptake patterns and was not thought to represent a tumor site. These lesions showed uptake of low intensity or were located at the anatomic regions of organs or structures that can be associated with nontumoral 18F-FDG uptake, such as blood vessels, a field of recent surgery, vocal cords (symmetric uptake), salivary glands, and brown fat tissue. Lesions categorized as 3 or 4 had focal uptake of high intensity and were assigned to one of the anatomic areas described below. If readers could not decide whether a lesion was benign or malignant on the basis of the previous criteria, the lesion was classified as 2.
Interpretation of separate PET and CT images, of side-by-side PET and CT images, and of fused PET/CT images also included the anatomic localization of 18F-FDG uptake sites. The following regions were used for anatomic assignment of tumor lesions: midline of neck (upper, medium, lower third), cervicolateral (upper, medium, lower third), pretracheal/prelaryngeal, lateral to the trachea, retrotracheal/retrolaryngeal, supraclavicular, mediastinal (upper, medium, lower third), hilar, lung (upper, medium, lower third, ventrally/dorsally located), and bone as appropriate.
A lesion was considered as true-positive if the score was 2–4 and if histopathology was positive or if it showed progression at follow-up sessions. A finding was considered as true-negative (score of 0–1) if histology was negative or if follow-up examinations did not show any pathologic result in the region of concern for at least 18 mo. A lesion was considered as false-positive if the score was 2–4 and if histopathology was negative or if it showed no progression at follow-up sessions. A finding was considered as false-negative if the score was 0–1 and if histology was positive or if follow-up examinations showed growth of the lesion(s). Follow-up examinations were performed every 3–6 mo and consisted basically of measurement of TG levels and sonography of the neck. In the case of elevated TG levels but no suspicious findings on sonography, additional investigations were performed as indicated: bone scintigraphy with 99mTc-methylene diphosphonate, CT of the thorax, CT/MRI of the neck and mediastinum, or repeated PET/CT. If sonography revealed suggestive lesions, it served as the further follow-up method to determine whether progression was present. If suspected tumor lesions were visualized, or better visualized, by only one of the imaging modalities, definition of progress or nonprogress was met by analyzing exclusively this single modality. In the case of different tumor sites, several imaging modalities were used as appropriate for the specific region.
Interpretation of side-by-side PET and CT and of fused PET/CT images also included a special analysis of anatomic localization of 18F-FDG uptake sites in addition to the categorization. Localizations with 18F-FDG accumulation scored 2 or higher were related to a definite anatomic structure on CT images during side-by-side analysis. For definite comparison of feasibility for localizing lesions, the location of lesions as demonstrated by side-by-side interpretation was compared with the lesion location on fused images. For verification of the localization accuracy, surgical reports and histology as well as imaging procedures during follow-up were used as the gold standard.
Additional information obtained by integrated PET/CT images was considered as diagnostically relevant if one or more of the following criteria were met: anatomic location of suspicious lesion was not truly indicated by side-by-side interpretation but by fused imaging, new tumor sites were diagnosed by fused imaging, or false-positive lesions were identified as true-negative by fused imaging. A finding was considered as therapeutically relevant if it resulted in the prevention of surgery or if reduction of tumor volume could be enhanced by extension of surgical resection to areas that would not have been included in a standard resection. Lymph node dissection of the lateral and central cervical compartment was considered as the standard surgical procedure.
Statistical Analysis
The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of PET alone and PET/CT were calculated on the basis of the true-positive and true-negative findings as described in the same anatomic region with a lesion-based and a patient-based analysis. The McNemar test (
2 test) was used for comparison of the sensitivity and specificity of PET alone with those of fused PET/CT (and for calculation of localizing accuracy comparing side-by-side PET and CT with fused PET/CT) with a confidence level of 95% (P < 0.05 was considered significant).
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Forty patients were included in the study (23 papillary and 17 follicular cancers). The patient characteristics are given in Table 1. After total thyroidectomy, 6 patients were suspected of having iodine-negative tumors because oxyphilic tumor cells were present in the primary tumor. Thirty-four patients were included because of elevated TG levels and negative iodine scintigraphy. All of these patients underwent previous total thyroidectomy and ablative radioiodine treatment. Histology and clinical follow-up served as the gold standard in 17 and 23 cases, respectively. There were 19 tumor-positive and 21 tumor-negative patients as classified by the gold standard. Thirteen patients had either local recurrence or lymph node metastases without distant metastatic disease. Five patients showed both lymph node and distant metastases (lung, bone), and 1 patient demonstrated exclusively lung metastases. No patient study was excluded from primary analysis because of disagreement on the consensus reading. For the evaluation of lymph nodes and local recurrence, 70 lesions were analyzed, as shown in Table 2. For the evaluation of distant metastases, 57 lesions were scored, as shown in Table 3.
|
|
|
|
|
False-negative findings on PET were observed in 3 of 4 patients with lung metastases. In these 3 patients, 37 lung metastases that had a diameter of <5 mm were identified on CT images of PET/CT. These 3 patients with lung metastases showed additional regional disease (1 with lymph node metastases, 2 with local recurrences) accumulating 18F-FDG with high intensity. One of the 4 patients with iodine-negative lung disease showed a true-positive PET finding indicating 2 solid lung metastases, which were removed surgically.
False-positive findings on PET and PET/CT (also side-by-side PET and CT) were found in 2 patients (total of 5 lesions) revealing 18F-FDG uptake in bilateral hilar lymph nodes due to sarcoidosis and in acute inflammatory cervical lymph nodes. PET showed an additional 3 false-positive patients who were also false-positive with side-by-side PET and CT.
For the T and N staging, PET alone and PET/CT showed the same sensitivity but PET/CT had a higher specificity (91%) than PET (76%). However, this was not statistically significant (P = 0.2). For M staging, the sensitivity and specificity of PET/CT (100% each) was higher than the probabilities of PET (84% and 95%). The differences were not significant for sensitivity (P = 0.07) and specificity (P = 0.14) on a per-patient basis but were significant on a per-lesion analysis for sensitivity (P < 0.001).
For overall staging, the sensitivity and specificity of PET/CT (95% and 91%, respectively) were also better than those of PET (79% and 76%, respectively). The differences were not significant for sensitivity (P = 0.15) and specificity (P = 0.2). However, diagnostic overall accuracy was significantly better for PET/CT (93%) than that for PET alone (78%) (P = 0.049). When diagnostic accuracy was calculated on a per-lesion basis, there were 121 and 79 true findings (sum of true-positive and true-negative findings of a total of 127 lesions) for PET/CT and PET, respectively. This difference was highly significant (P < 0.0001).
Of the 6 patients with Hürthle cell carcinoma at primary diagnosis, 2 had high 18F-FDG accumulation in lymph node metastases. One patient showed a false-negative finding on PET as well on PET/CT at a site of a mediastinal lymph node metastasis that demonstrated iodine uptake under ablative therapy.
Side-by-Side PET and CT and PET/CT: Therapeutic Relevance
Side-by-side PET and CT interpretation led to discordant results in 73 (57%) of 127 lesions in different anatomic regions (Table 6).
|
In 17 (74%) of the 23 patients with suggestive 18F-FDG PET findings, fused PET/CT correctly localized the site of the lesion(s), which was not possible by side-by-side interpretation of both methods. This group also comprises the 3 patients with 5 lesions for which fused PET/CT led to a conversion of false-positive findings into true-negative findings. This results in a probability of 60% (3/5) for conversion by fused PET/CT if PET presents a false 18F-FDG–positive patient. These 3 patients did not undergo surgery because PET/CT identified false-positive PET findings (that were also false-positive with side-by-side PET and CT, showing 4 false-positive local findings and 1 false-positive distant finding). One of these 3 patients demonstrated a focal, unilateral cervical 18F-FDG accumulation, with CT showing only normal-sized lymph nodes (misinterpreted as lymph node metastasis). The 18F-FDG accumulation could be identified on PET/CT as uptake in a cervical joint. Furthermore, this young patient revealed intense, unilateral 18F-FDG uptake in the lower abdomen (misinterpreted as distant metastasis by side-by-side PET and CT) that was identified as physiologic ovary accumulation by PET/CT. The second patient was scored as suspicious for local recurrence and supraclavicular lymph node metastasis on side-by-side PET and CT. By image overlay with PET/CT, these findings were truly categorized as benign findings corresponding to unilateral accumulation at the vocal cords (Fig. 1) and to 18F-FDG accumulation at the sternoclavicular joint due to degenerative alterations. The third patient demonstrated an intense 18F-FDG uptake near her tracheostomy that was misinterpreted on side-by-side PET and CT but not on PET/CT. During follow-up of these 3 patients over >2 y, no increase of TG levels was measured, confirming that no recurrent tumor was present at the time of imaging.
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
It was shown recently that 18F-FDG PET is able to reveal iodine-negative tumor tissue with a diagnostic accuracy that is higher than that of other imaging modalities (7). In our study, the overall sensitivity and specificity for the detection of tumor tissue by 18F-FDG PET were 79% and 76%, respectively. These values are within the range of the diagnostic accuracies that have been reported previously by others demonstrating a sensitivity and specificity of 80%–95% and 70%–85%, respectively (6–11). The lower sensitivity in our group might be explained by the 3 patients with false-negative lung metastases.
One limitation of 18F-FDG PET, especially in the region of the neck, is the possibility of false-positive 18F-FDG accumulations leading to the diagnosis of lymph node metastases and, consequently, to the potential scheduling of a futile operation (14). In our study, specificity for detecting lymph node metastases could be increased by PET/CT in comparison with PET alone and side-by-side PET and CT (from 76% to 91%). Three patients (60% of the cervical false-positive findings) were identified on PET/CT as having a physiologic or nontumoral cervical 18F-FDG accumulation that was classified as lymph node metastases by PET alone and side-by-side PET and CT.
Although sensitivity on a per-patient basis for lymph node metastasis detection was equal for PET and PET/CT, sensitivity for M staging was increased from 84% to 100% on PET/CT. This was achieved in 3 patients by PET/CT detection of small and miliary lung metastases that were not diagnosed by PET alone. This confirms the findings of previously reported studies showing that 18F-FDG PET is not able to adequately assess miliary lung metastases smaller than 6 mm. It is unclear whether this is generated from motion artifacts on inspiration and expiration or from a lower metabolic activity of the lung metastases (15).
One important aspect of our study was evaluation of the therapeutic relevance of PET/CT. In clinical routine, treatment of DTC is dominated by the combination of surgical tumor removal and subsequent application of radioiodine (16). Whereas this approach is almost optimal for patients with iodine-accumulating tumors, it is inappropriate if only iodine-negative tumors are present. In this case, complete surgical removal of iodine-negative tissue is the only curative treatment option. Furthermore, it seems important to diagnose and remove iodine-negative tumor tissue as early as possible because prognosis of this tumor subgroup is essentially worse than that of most DTCs (13). Therefore, it is crucial to be able to precisely localize an iodine-negative and 18F-FDG PET–positive tumor to enhance complete resection and cure of the patient (17–19). For this purpose, additional morphologic imaging is necessary to help localize the 18F-FDG–positive focus.
To determine whether PET/CT would be helpful in this situation, we performed a second analysis and compared it with a side-by-side interpretation of PET and CT images. This side-by-side interpretation revealed that 57% (73/127) of all scored lesions in different anatomic regions were discordant. One reason for this is a positive PET finding without a corresponding CT finding—for example, when the lymph nodes of the affected area are not enlarged or when CT images show an abnormality at a different anatomic region. In this situation, it is not possible to precisely localize the suspected tumor tissue for surgical resection. In our study, this situation was observed in 17 patients (74% of PET patients with suggestive lesions) in whom PET/CT could correctly localize the tumor, as confirmed by histopathology and follow-up. In this group, 3 patients were identified as having benign findings that prevented futile surgical treatment. In ten 18F-FDG–positive tumor patients, the surgical resection of iodine-negative tumor tissue was extended to additional regions after PET/CT clearly identified the location of tumor lesions that were not localized by side-by-side PET and CT. This resulted in an efficient tumor volume reduction by surgery. If only standard lymph node resection of the lateral and central compartment of the neck had been performed in this group, a relevant amount of 18F-FDG–positive tumor tissue would have been unnecessarily retained.
One limitation of our study seems to be that CT was performed without a contrast agent. However, in patients with DTC, CT is generally done without the application of a contrast agent to avoid blockage of iodine uptake. This also applies to patients in whom iodine-negative tissue is suspected, because iodine-negative and iodine-positive tissue may coexist in one patient. Another aspect is that diagnosis of lymph node metastases by morphologic imaging, including MRI and contrast-enhanced CT, is defined predominantly by the size of the nodes. Therefore, we strongly believe that, in patients with nonenlarged lymph nodes but positive 18F-FDG accumulation, the optimal strategy is fusion of images gained by integrated PET/CT irrespective of the use of a contrast agent. Another limitation of the study is that the minimal time for follow-up of patients was 18 mo. Although 18F-FDG avidity is a predictor of reduced survival (20), this study did not determine the outcome of therapy.
Overall, integrated PET/CT changed the treatment in 48% of patients with a true-positive 18F-FDG PET finding. Additionally, a futile operation was prevented in 3 patients. We consider these results as highly relevant for therapeutic decision making about patients with thyroid cancer and, therefore, would recommend a diagnostic algorithm as shown in Figures 3 and 4. Thereafter, integrated PET/CT would be proposed in all patients in whom iodine-negative tumor tissue is suspected. Alternatively, separated PET and CT could be performed initially, followed by integrated PET/CT only in cases of discordant findings.
|
|
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
References |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
|---|
Related articles in JNM:
This article has been cited by other articles:
|
|
 |
|
  R. T. Kloos Approach to the Patient with a Positive Serum Thyroglobulin and a Negative Radioiodine Scan after Initial Therapy for Differentiated Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1519 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Finkelstein, P. W. Grigsby, B. A. Siegel, F. Dehdashti, J. F. Moley, and B. L. Hall Combined [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) for Detection of Recurrent, 131I-Negative Thyroid Cancer Ann. Surg. Oncol., January 1, 2008; 15(1): 286 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 A. Shammas, B. Degirmenci, J. M. Mountz, B. M. McCook, B. Branstetter, B. B. Bencherif, J. M. Joyce, S. E. Carty, H. A. Kuffner, and N. Avril 18F-FDG PET/CT in Patients with Suspected Recurrent or Metastatic Well-Differentiated Thyroid Cancer J. Nucl. Med., February 1, 2007; 48(2): 221 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. O, I. R. Yoo, S. H. Kim, H. S. Sohn, and S. K. Chung Clinical Significance of Small Pulmonary Nodules with Little or No 18F-FDG Uptake on PET/CT Images of Patients with Nonthoracic Malignancies J. Nucl. Med., January 1, 2007; 48(1): 15 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Israel and A. Kuten Early Detection of Cancer Recurrence: 18F-FDG PET/CT Can Make a Difference in Diagnosis and Patient Care J. Nucl. Med., January 1, 2007; 48(1_suppl): 28S - 35S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Czernin, M. Allen-Auerbach, and H. R. Schelbert Improvements in Cancer Staging with PET/CT: Literature-Based Evidence as of September 2006 J. Nucl. Med., January 1, 2007; 48(1_suppl): 78S - 88S. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
