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Recombinant Human Thyrotropin Stimulation of Fluoro-D-Glucose Positron Emission Tomography Uptake in Well-Differentiated Thyroid Carcinoma

Division of Nuclear Medicine, Department of Radiology (B.B.C., P.P., C.C., R.W., P.L.), and Division of Endocrinology and Metabolism, Department of Medicine (M.E., P.L.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Address all correspondence and requests for reprints to: Bennett B. Chin, M.D., Duke University School of Medicine, Department of Radiology, Division of Nuclear Medicine, Box 3949, DUMC Erwin Road–Duke North, Room 1410, Durham, North Carolina 27710. E-mail: chin0004{at}mc.duke.edu.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
TSH stimulates thyrocyte metabolism, glucose transport, and glycolysis. 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) is a glucose analog used in positron emission tomography (PET) to detect occult well-differentiated thyroid carcinoma. The objective of this study was to examine the effects of recombinant human TSH (rTSH) on FDG PET uptake in patients with residual or recurrent disease. Seven patients with well-differentiated thyroid carcinoma, negative 131-I scintigraphy, and biochemical evidence of residual disease were randomized and prospectively studied with FDG PET both on thyroid hormone suppression and rTSH stimulation within 1 wk. All lesions seen on the TSH suppression scans were seen on the rTSH stimulation studies. rTSH stimulation studies identified four additional lesions not seen on TSH suppression. One patient was positive on rTSH stimulation alone. The mean (2.54 ± 0.72 vs. 1.79 ± 0.88) and maximum (2.49 ± 0.95 vs. 1.74 ± 0.81) lesion to background ratios were significantly higher with rTSH stimulation, compared with TSH suppression (P = 0.02 for both). rTSH stimulation improves the detectability of occult thyroid metastases with FDG PET, compared with scans performed on TSH suppression.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
DESPITE THE EFFICACY of surgery, 131-iodine (131-I), and TSH-suppressive T₄ therapy for well-differentiated epithelial thyroid cancers, many patients suffer disease recurrence (1, 2). Radioiodine scanning can often detect the presence and location of this thyroid cancer tissue when it is iodine avid (3, 4). However, in one fifth of patients with remaining disease, the circulating tumor marker thyroglobulin reveals that thyroid cancer tissue is present, even though radioiodine imaging is negative. In these patients, a variety of other imaging techniques, including scintigraphy with other radionuclide agents (1, 2, 3), cervical sonography (5), computer-assisted tomography (6), magnetic resonance imaging (7), and positron emission tomography (PET) (8), have been reported to localize remaining thyroid cancer tissue in some patients. ¹⁸Fluoro-2-deoxyglucose (FDG) PET scanning has been shown to be particularly useful in patients with remaining thyroid carcinoma who have negative 131-I scintigraphy (9, 10, 11).

The sensitivity of diagnostic techniques that depend on thyrocyte functions, such as thyroglobulin production (12) and iodine concentration (13), is enhanced by the tissue-specific actions of TSH. TSH stimulation has traditionally been affected by temporary withdrawal of thyroid hormone therapy and more recently by use of recombinant TSH (rTSH) (14, 15). Consequently, we hypothesized that TSH would also increase FDG uptake by increasing glucose transport and/or glycolytic activity, as had been shown in cultured thyrocytes (16, 17), increasing the sensitivity and specificity of FDG PET for localizing and quantifying remaining disease in thyroid cancer patients.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Study patients

The Johns Hopkins Institutional Review Board approved this study and all study patients prospectively gave written informed consent. Study patients are described in Table 1. There were seven patients (four males and three females; mean age, 47 yr; range, 29–66) with eight primary foci of well-differentiated thyroid carcinomas (papillary carcinoma in seven patients and an additional Hürthle cell variant of follicular cell carcinoma in one patient). All patients had previously undergone total or near total thyroidectomy (mean, 7 yr previously; range, 1–15) and postoperative 131-I ablation of thyroid bed remnant tissue (one to three treatments; administered dose, 10,953 ± 6,929 MBq; range, 3,700–17,094).

All study patients were in stable medical condition and able to undergo adequate FDG PET scanning with no histories of diabetes mellitus or claustrophobia. In the three female study patients, pregnancy was excluded by serum human chorionic gonadotropin testing before scanning.

Study protocol and immunoassays

Study patients had two FDG PET-computed tomography (CT) fusion scans (as described below) separated by 7 d. The basal scan was performed while the patient was on TSH-suppressive T₄ therapy alone; the rTSH-stimulated scan was performed after two 0.9-mg im doses of rTSH (TSH alfa; Thyrogen, Genzyme Corp., Cambridge, MA), which were administered 24 and 48 h before imaging, while patients continued the same T₄ dose. Study patients were assigned randomly to undergo either the basal scan or the rTSH scan first. Blood sampling was performed immediately before FDG injection for measurement of the serum TSH (Tosoh Nexia; Tosoh Bioscience, South San Francisco, CA) and thyroglobulin (Nichols Advantage; Nichols Institute Diagnostics, San Clemente, CA) concentrations.

FDG PET scanning. Data acquisition and image reconstruction. After iv administration of FDG 555MBq (15 mCi) and a 45- to 50-min uptake phase, imaging was performed using a commercial combined PET-CT scanner (Discovery LS; General Electric Medical Systems, Waukesha, WI). A whole-body CT scan was performed with this four-slice multidetector helical scanner. Acquisition parameters included detector row configuration 4 x 5 mm, pitch 6:1, gantry rotation speed of 0.8 sec per revolution, table speed of 30 mm per gantry rotation, 140 kV(p), and 80 mA. Whole-body emission scans (5 min per field of view, two-dimensional acquisition) were performed. Study patients maintained their arms resting at their sides and were instructed to breathe normally during all image acquisitions. The emission images were reconstructed with the ordered subset expectation maximization implementation of iterative reconstruction (two iterations, 28 subsets). Attenuation-corrected emission data were obtained using the CT reconstructed with filtered back projection, a bilinear fit of attenuation coefficients, and a Gaussian filter with 8 mm full width at half maximum (FWHM) to match the PET resolution.

Image interpretation. Studies were interpreted independently by two board-certified nuclear medicine physicians (B.C.C. and C.C.), who were aware of the patients’ study entry criteria but blinded to patient identity, history, correlative imaging, and study phase, i.e. whether it was the basal or rTSH-stimulated scan. All PET studies were interpreted in randomized order using a computer workstation (GE eNTEGRA, Haifa, Israel). The total number of lesions in each study patient was tabulated. Each lesion was characterized regarding certainty of diagnosis and certainty of localization. Lesion localization was assessed for each lesion identified and graded on a 3-point scale (0, unknown localization; 1, probable localization; 2, definite localization). The diagnostic impression of lesion etiology was assessed for each lesion identified and graded on a 5-point scale (0, definitively benign; 1, probably benign; 2, equivocal; 3, probably malignant; 4, definitively malignant). In cases of discordant interpretations between the two nuclear medicine physicians’ individual interpretations (n = 1), a consensus reading session was performed by the two readers; consensus was then achieved in all cases.

Quantitative data analysis. Region of interest analysis was obtained with a commercially available fusion software package on the scanner’s workstation (eNTEGRA, ELGEMS). The anatomic locations of focal abnormalities were noted on the coregistered CT scans to facilitate consistent region of interest analysis on paired scans. Using the transaxial PET data sets, regions of interest were visually drawn around focal abnormalities with the boundaries visually estimated at approximately 50% of the peak activity. Adjacent background regions that did not include the abnormalities were drawn in the same manner. The maximum count, mean count, and SD were quantified in the lesions and in the background regions for each study. The lesion to background (L/B) ratios were calculated for each lesion (Table 2). To quantify differences when a lesion was identified on a single scan, a L/B ratio of 1 was assigned to the unidentified lesion; however, calculations were performed both with and without this assignment. The standardized uptake value (SUV) corrected for lean body mass was also calculated for each of the lesions as previously described (18). The differences in FDG uptake between scans were expressed as bias (percentage) with the uptake in the TSH-suppressed state as the standard. Bias was defined as:

where A represents the activity or L/B ratio in lesions in the TSH-suppressed basals can, and A_TSH represents the corresponding activity in the rTSH-stimulated scan.

All data are expressed as the mean ± SD. The Wilcoxon signed-rank test was used for comparisons between groups (JMP; SAS Institute, Cary, NC). Mean differences were considered statistically significant for P < 0.05. For a type I error of 0.05, a sample size of 7 (estimated mean SUV of 5.0 and SD of 2.0) detects a 50% increase in SUV with a power of 0.79.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Serum TSH and thyroglobulin concentrations (Table 1)

On the day of their basal PET-CT scan, while taking TSH-suppressive T₄ therapy, all patients had a low serum TSH concentration (0.2 ± 0.2 mU/liter, mean ± SD; range, <0.005–0.47 mU/liter) The mean serum TSH concentration was significantly higher on the day of the patients’ rTSH-stimulated PET-CT scan (118 ± 43.8 mU/liter; range, 70–189; P < 0.001), confirming that rTSH was administered.

All seven patients had a detectable serum thyroglobulin concentration on the day of their basal PET-CT scan (7.0 ± 7.3 ng/dl; range, 0.9–19.3). In six of the seven study patients, the serum thyroglobulin concentration was higher on the day of their rTSH-stimulated scan (21.0 ± 28.0 ng/dl). No patient had interfering circulating antithyroglobulin antibodies.

PET-CT scans

Both basal and rTSH-stimulated PET scans were negative in three patients. In four patients, five FDG-positive foci were seen on the basal scans. All five of these abnormalities and four additional FDG-positive foci were seen in two patients on the rTSH-stimulated scans. In one of these patients, three foci were seen only on rTSH-stimulated scan. There was no correlation between the appearance of additional foci on rTSH-stimulated PET scans and the difference between basal and rTSH-stimulated thyroglobulin levels.

Comparison of the quantitative L/B ratios in regions of interest observed with rTSH-stimulated studies vs. basal studies showed mildly increased mean region of interest activity in three lesions (11.5–37.1%) and mildly decreased mean activity in two lesions (-10.2 and -11.3%). The L/B ratio for maximum activity showed similar results with a mild increase in three lesions (31.8–41.8%) and a mild decrease in two lesions (-20.7 and -21.5%) after rTSH stimulation. The four lesions identified only on rTSH stimulation studies showed a mean L/B ratio of 2.4 (range, 1.7–3.0). In a paired comparison limited to the five lesions seen on both scans, both the mean L/B ratios (2.62 ± 0.84 vs. 2.42 ± 0.65) and maximum L/B ratios (2.71 ± 1.19 vs. 2.33 ± 0.57) were higher after rTSH than basally; but this difference was not significant (P = 0.31 for both). However, if all nine lesions seen on one or both scans were included (by assigning the lesions not visualized on the basal scans a L/B ratio of 1), the mean (2.54 ± 0.72 vs. 1.79 ± 0.88) and maximum (2.49 ± 0.95 vs. 1.74 ± 0.81) L/B ratios were significantly higher after rTSH stimulation (P = 0.02 for both).

Similarly, a paired comparison of SUV values in the five lesions seen on both scan showed higher mean SUV values after rTSH-stimulation (mean, 2.0; range, 1.2–2.8) than in basal studies (mean, 1.8; range, 1.3–2.4; however, this difference was of borderline statistical significance (P = 0.06). Paired comparison of maximum SUV between rTSH-stimulated and basal studies was not statistically significant (P = 0.3).

No differences in elucidation of additional disease foci, L/B ratios, or SUV values on the rTSH-stimulated PET scans were observed when the rTSH study was performed first or second.

Clinical correlation and follow-up studies

During routine follow-up of the three thyroglobulin-positive, radioiodine scan-negative study patients who had negative basal and rTSH-stimulated FDG PET scans, no new clinical evidence of disease was seen over 5–7 months of subsequent follow-up. Furthermore, their serum thyroglobulin concentrations on thyroid hormone suppression therapy were no higher after than at the time of PET scanning (2.7 ± 1.6 vs. 3.8 ± 2.4 ng/ml). All four study patients with positive FDG PET scans had biopsy confirmation of thyroid carcinoma at the site of at least one FDG-positive site: one in a preceding biopsy and three in subsequent biopsies. Subsequently, patient 4, whose basal PET scan identified only two disease sites whereas the rTSH-stimulated scan demonstrated a third mediastinal site (Figs. 1 and 2), underwent cervical and mediastinal exploration. Papillary carcinoma was confirmed histologically in nine of 19 resected lymph nodes, including a 2.5-cm perithymic mass that had not been clearly seen on the CT scan. After surgical excision of these lesions, repeat rTSH-stimulated PET-CT study showed disappearance of all foci, and the patient’s rTSH-stimulated serum thyroglobulin decreased to 1.0 ng/dl. In patient 3, the FDG PET scans were positive both basally and after rTSH at a site of previous tumor resection. In patient 7, correlation of the FDG PET focus with CT localization confirmed the presence of a cervical abnormality that corresponded to a 3.5 x 5 x 6 mm lymph node by sonography. Despite its normal sonographic appearance, it proved on fine needle aspiration biopsy and subsequent surgical excision to contain metastatic papillary thyroid carcinoma. Patient 6 also had a cervical biopsy performed in the region of PET positivity and was found to have recurrent metastatic papillary carcinoma.

View larger version (52K): [in this window] [in a new window]   FIG. 1. Coronal FDG PET images in patient 4. Left, Image obtained during TSH suppression showing single faint focus of activity in the prevascular space. Right, Image after rTSH administration scan showing two foci, with the previously identified focus of activity more intense and focal.

View larger version (77K): [in this window] [in a new window]   FIG. 2. Transaxial images FDG PET images in patient 4, with tranaxial slice at the level of the lower focal abnormality seen in Fig. 1. Images on TSH-suppressive T4 therapy (top row) and after rTSH stimulation (bottom row). CT images (left column), FDG PET images (middle column), and PET-CT fusion images (right column). The rTSH-stimulated CT scan shows a lymph node in the prevascular space (white arrow, left lower image). The rTSH-stimulated FDG PET scan shows focal activity in this region (black arrow, center lower image). The rTSH-stimulated PET-CT fusion image confirms that the focal FDG activity colocalizes with the CT-demonstrated lymph node (white arrow, right lower image). Subsequent surgery confirmed recurrent metastatic papillary thyroid cancer in this location, and a postoperative rTSH-stimulated FDG PET-CT scan after excision (data not shown) confirmed disappearance of both the mass and focal FDG activity.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In thyroid cancer patients whose residual disease was suspected on the basis of serum thyroglobulin detectability but not radioiodine scanning, this study shows that FDG PET imaging after rTSH stimulation reveals more lesions in a greater number of patients with a significantly increased tumor to background ratio than paired scans done during TSH-suppressive T₄ therapy. Furthermore, in some cases, this incremental information altered patient management in a manner that appears to have improved the outcome of subsequent surgery.

The first observation demonstrating higher FDG uptake attributable to TSH stimulation in thyroid carcinoma was a case report of a patient studied before and after discontinuation of thyroid hormone therapy (19). In this case, there was a 64% increase in SUV with endogenous TSH stimulation. Two subsequent small trials confirmed that endogenous TSH stimulation after thyroid hormone withdrawal produced higher FDG uptake in sites of disease and visualization of additional lesions. In 10 patients with well-differentiated thyroid carcinoma studied before and after thyroid hormone was discontinued, Moog et al. (20) found that endogenous TSH stimulation resulted in an average increase of 63% in tumor to background ratio. In a similar study of eight patients, van Tol et al. (21) observed that FDG PET imaging during endogenous TSH stimulation showed better lesion contrast and additional detected lesions when compared with the TSH suppressed scans.

Our findings extend the previous report by Petrich et al. (22), who found that rTSH-stimulated FDG PET scanning in 30 thyroid cancer patients with negative or equivocal 131-I scintigraphy revealed more lesions (78 vs. 22) in a higher proportion of patients (19 vs. 9) with a higher tumor to background ratio (5.5 vs. 2.5) and higher SUV (2.77 vs. 2.05) compared with scans performed during TSH suppression. However, our study differs in three respects. First, patients in our trial were randomly assigned to have either basal or rTSH-stimulated scanning first, followed by the other study only 1 wk later. In contrast, Petrich et al. (22) always performed rTSH-stimulated scans second and after a mean of 9.3 ± 8.8 wk, making it possible that their findings may have reflected disease progression rather than greater sensitivity FDG PET scanning after rTSH. Second, this investigation was performed with a combined in-line PET-CT fusion scanning for attenuation correction and precise coregistration. With this technique, benign causes of increased FDG uptake in muscle, adipose tissue, and degenerative articulations can be identified and more readily excluded as sites of residual disease. Precise localization may also aid the patient and surgeon by decreasing surgical time required to locate and remove a tumor, and also by decreasing the potential for false-negative results. Ultrasound of the neck has previously been successfully used in the follow-up evaluation of patients with suspected recurrence (23). The CT examination may similarly provide anatomic information, identifying potential sites of recurrence or localization for biopsy as reported in our investigation. Additional studies are necessary to evaluate potential improvements in diagnostic accuracy and additional indications for this new combined modality. Third, the current study was limited to patients with a relatively low tumor burdens; all of our patients had suppressed thyroglobulin levels less than 20 ng/ml. This is clinically important because successful detection and resection of residual disease can be more difficult in this patient population.

Certain aspects of the current findings deserve comment. First, the rTSH dosing regimen that we used was identical with that previously recommended for 131-I scintigraphy. It is not known whether a more prolonged period of rTSH stimulation would yield scans that were even more sensitive. Conversely, it is possible that a single or lower rTSH dose would be equally effective. Second, the patients in this study included a relatively high percentage of thyroglobulin-positive, radioiodine scan-negative patients with negative FDG PET scans (43%) that was higher than in some previous studies (9), reflecting the patients’ relatively low tumor burden. Consequently, this limits the power of this study to confirm significant changes in tumor SUV. The apparently paradoxical lower L/B ratios and maximum SUV after rTSH seen for two lesions is within the range of known variability for SUV measurement (24). Third, although a rise in serum thyroglobulin after rTSH in this study was not seen in one patient and less than 10% in two others, blood sampling was obtained only 24 h after the second rTSH dose, a time that has previously been shown not to be optimal for detecting maximal thyroglobulin levels (25). Fourth, the relatively short duration of follow-up in patients with negative FDG PET scans does not permit us to define precisely how many have significant nonlocalized disease, i.e. false-negative studies.

In conclusion, among patients with circulating thyroglobulin revealing the presence of residual thyroid carcinoma, but previous negative 131-I scintigraphy, rTSH-stimulated FDG PET-CT fusion scanning improved localization of remaining disease. This information has the potential to alter the subsequent management, particularly defining the feasibility and extent of additional surgery. In comparison with endogenous TSH stimulation, the use of rTSH for PET imaging has the advantage of avoiding the morbidity of hypothyroidism and risk of tumor progression associated with temporary discontinuation of thyroid hormone therapy.

	Acknowledgments

 
We thank Kit Carson and the staff of the General Clinical Research Center for assistance with statistical analysis and planning of this study. We also thank Laura Marshall, Greg Brooks, and the other members of the PET center for assistance with this study.

	Footnotes

 
This work was supported by Johns Hopkins University School of Medicine General Clinical Research Center, NIH/NCRR Grant M01 RR00052 (to B.B.C.).

Abbreviations: CT, Computed tomography; FDG, 2-deoxy-2-[18F]fluoro-D-glucose; 131-I, 131-iodine; L/B, lesion to background ratio; PET, positron emission tomography; rTSH, recombinant human TSH; SUV, standardized uptake value.

Received June 16, 2003.

Accepted September 25, 2003.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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