^99mTc-Depreotide Scintigraphy Versus¹⁸F-FDG-PET in the Diagnosis of Radioiodine-Negative Thyroid Cancer

Abstract

Background: Papillary and follicular thyroid cancer were found recently to express somatostatin receptors (SSTRs). ^99mTc-depreotide binds with high affinity to SSTRs 2, 3, and 5.

Aim: The aim of this study was to evaluate the feasibility of applying ^99mTc-depreotide scintigraphy to search for radioiodine-negative thyroid cancer; comparison is made to a standard approach using ¹⁸F-fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG-PET).

Patients and Methods: Ten radioiodine-negative patients with suspicion of recurrent or metastatic thyroid cancer were investigated with ^99mTc-depreotide scintigraphy and ¹⁸F-FDG-PET, performed with a time interval that ranged from 1–8 wk. Locoregional recurrence and metastases were confirmed by ultrasonography and/or computed tomography, together with cytology or histological examination in selected cases.

Results: True-positive results were obtained in nine patients (90%) with ^99mTc-depreotide scintigraphy and in seven patients (70%) with ¹⁸F-FDG-PET. ^99mTc-depreotide scintigraphy gave better results in terms of detection of recurrent or metastatic disease compared with ¹⁸F-FDG-PET in three patients, whereas ¹⁸F-FDG-PET identified metastatic disease that was not seen with ^99mTc-depreotide in only one patient. ^99mTc-depreotide scintigraphy portrayed lesions in three patients with negative morphological imaging.

Conclusions: Results indicate a potential value of ^99mTc-depreotide scintigraphy for the diagnosis of thyroid cancer in the setting of detectable thyroglobulin and negative radioiodine scan. Furthermore, ^99mTc-depreotide adds complementary information regarding the SSTR status of lesions, which may be helpful for individual therapy planning in this group of patients, which is hard to manage clinically.

THE PROGNOSIS OF patients with differentiated thyroid cancer is very good, and most patients enjoy prolonged disease-free intervals after appropriated thyroid surgery and, when necessary, ¹³¹I-therapy (1). However, in a subset of patients, thyroid cells lack or lose over time the capacity to concentrate radioiodine, while the synthesis of thyroglobulin is maintained (2). Lack of radioiodine uptake in thyroid cancer is usually associated with increased growth rate and larger tumor load (3) and is seen in approximately 50% of patients with distant metastases (4). The discovery of tumor foci, even if no radioiodine uptake is present, may lead to further treatment, such as surgery or external radiotherapy. However, localizing radioiodine-negative thyroid cancer may be very difficult, especially if radiological explorations are negative (5). ¹⁸F-Fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG-PET) imaging is able to detect poorly differentiated metastases and is considered nowadays as a major diagnostic tool in such patients (6, 7).

Papillary and follicular thyroid cancer were found to overexpress somatostatin receptors (SSTRs) 3, 4, and 5 (8, 9) and thus offer the possibility of SSTR-targeted imaging and therapy. In recent studies, we found that SSTR scintigraphy with ¹¹¹In-DOTA-d-Phe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) and ¹¹¹In-DOTA-lanreotide has a high diagnostic capacity for recurrent disease in patients with thyroid cancer and can detect lesions that may be not portrayed even by ¹⁸F-FDG-PET (10). Despite the effectiveness of ¹¹¹In-labeled SSTR ligands (10–13), there is, however, a need for labeling somatostatin analogs with ^99mTc because of its optimal physical properties, wide availability, cost effectiveness, and lower radiation burden for the patient than that of ¹¹¹In (14). Depreotide (formerly known as P829), a synthetic peptide containing a sequence that mimics the binding domain of somatostatin and that can be labeled stably with ^99mTc (14), was introduced into the clinical practice and initially used for the evaluation of solitary lung nodules as uptake is seen in small-cell and non-small-cell lung cancer (15, 16). ^99mTc-depreotide was found to bind with high affinity to SSTRs 2, 3, and 5 (16). Consequently, the potential role of this tracer in other SSTR-expressing tumors is now under investigation.

The aim of this study was to evaluate the capacity of ^99mTc-depreotide scintigraphy for detecting radioiodine-negative thyroid cancer; a comparison is made with ¹⁸F-FDG-PET.

Patients and Methods

Ten consecutive patients [seven females, three males; age, 47–78 (mean, 66) yr] with histologically proven well-differentiated follicular (seven patients) or papillary (three patients) thyroid cancer at diagnosis were selected for this study. Before enrollment, patients had given informed consent in accordance with the guidelines of the local ethics committee.

All patients had undergone radical surgery (total thyroidectomy with or without node dissection) 3–20 (mean, 10) yr earlier, followed by adjuvant radioiodine therapy. Cumulative activity of ¹³¹I ranged from 9–27 (mean, 17) GBq [243–730 (mean, 459) mCi]. Recurrent or metastatic disease was suspected because of detectable thyroglobulin levels, which were increasing over the past 6 months. No patient exhibited abnormal radioiodine uptake on posttreatment scan at the time of enrollment.

Each patient was investigated with a ^99mTc-depreotide and a ¹⁸F-FDG-PET scan. The time interval between the studies ranged from 1–8 (mean, 5) wk. All patients were on hormonal replacement therapy with T₄ at the time of the studies.

^99mTc-depreotide was prepared from a commercially available kit (NeoSpect; Amersham Health, Buckinghamshire, UK). The iv-injected dose per patient was 740 MBq (50 μg peptide) of ^99mTc-depreotide. Scintigraphic imaging was performed with a double-head gamma camera and a high-resolution collimator. ^99mTc-depreotide images were obtained at 1 h after injection. Planar acquisitions of total body and single-photon emission computer tomography of head, neck, thorax, and abdomen (in selected cases) were performed.

¹⁸F-FDG-PET scans were obtained at 1 h after iv injection of 370 MBq ¹⁸F-FDG using a dedicated full-ring PET scanner, with an axial field of view of 15.2 cm and a maximum resolution of 3.8 mm transaxially and 4.0 mm axially. Attenuation-corrected scans were performed using the built-in ⁶⁸Ge sources.

Studies were compared for the final analysis lesion by lesion and were ruled as matching or mismatching. The tumor uptake on scintigraphic images was scored according to the scale suggested by Krenning et al. (11), ranging from 0 (no uptake) to 4+ (intense uptake). Scintigraphic and ¹⁸F-FDG-PET results were rated as false positive if no corresponding lesions were found on conventional imaging within the follow-up period or were not verified by cytology or histology. Lesions were considered as false negative if they were not detected on these studies but were seen on conventional imaging and showed progression during the follow-up period or were confirmed by cytological or histological examination. Follow-up ranged from 6–48 (mean, 25) months.

Results

Details of tumor sites visualized with ^99mTc-depreotide scintigraphy and ¹⁸F-FDG-PET are given in Table 1. Overall, true-positive results were obtained in nine patients (90%) with ^99mTc-depreotide and in seven patients (70%) with ¹⁸F-FDG-PET. ^99mTc-depreotide and ¹⁸F-FDG-PET showed an equivalent scan result in five patients; in five other patients there were discrepancies. ^99mTc-depreotide gave better results in terms of detection of recurrent or metastatic disease compared with ¹⁸F-FDG-PET in three patients (Fig. 1), whereas ¹⁸F-FDG-PET portrayed metastases not seen with ^99mTc-depreotide in one patient. Discrepant results between ^99mTc-depreotide and ¹⁸F-FDG-PET in the individual patient resulting in a “flip/flop” phenomenon (positive ^99mTc-depreotide but negative ¹⁸F-FDG-PET at one site and negative ^99mTc-depreotide but positive ¹⁸F-FDG-PET at another site) were found in one patient.

Fig. 1.

^99mTc-depreotide scan [total body anterior view (A), coronal SPECT slice (B)] shows increased activity at a locoregional recurrence in a radioiodine-negative patient with follicular thyroid carcinoma (patient 5, Table 1). Hepatobiliary excretion and nonspecific activity in the bowel are observed. ¹⁸F-FDG-PET (C) (anterior view) was interpreted as negative.

TABLE 1.

Patients’ characteristics and results of different diagnostic procedures

No.	Age (yr)	Sex	Histology	Tg (ng/ml)	99mTc-depreotide [size of lesions (cm)]	rF-FDG-PET	Tumor confirmation procedure
1	52	F	Follicular	35	Lung (1.0–1.8) +	Lung	CT, histol, 3 months later
2	78	F	Follicular	8	Mediastinum (2.0) ++	Negative	CT, cytology, 4 months later
3	51	F	Follicular	29	Negative (1.3)	Mediastinum	CT, cytology
4	47	F	Follicular	16	Lung (1.8–2.0) +	Negative	CT, cytology
5	70	F	Follicular	30	LR (2.0) +++	Negative	US, cytology
6	77	F	Papillary	105	Cervical (1.6) ++, lung (0.9–1.5) ++, mediastinum (1.0–1.5) ++	Cervical, lung, mediastinum	US, CT
7	75	F	Papillary	104	Cervical (2.5) ++, lung (1.0–1.5) ++	Mediastinum, lung	US, CT
8	71	M	Follicular	37	LR (6.0) +++, lung (1.5) +	LR, lung	US, CT, cytology
9	50	M	Follicular	10,790	Lung (1.5–2.0) +++	Lung	CT, histol, 3 months later
10	70	M	Papillary	4,282	LR (3.0) ++, lung (2.0–2.5) +, mediastinum (4.5) ++	LR, lung, mediastinum	US, CT

Uptake score: +, faint uptake; ++, clear uptake but less than liver uptake; +++, uptake comparable with liver uptake. F, Female; M, male; Tg, thyroglobulin (under T^d suppression); LR, locoregional recurrence; CT, computed tomography; histol, histological examination; US, ultrasonography.

There was one false-positive finding with ^99mTc-depreotide scintigraphy and ¹⁸F-FDG-PET. In both studies, enhanced tracer accumulation was shown in lung metastases but also in a lung lesion that was proven to be a granulomatous lesion.

Three patients with positive ^99mTc-depreotide scintigraphy, two of them also with positive ¹⁸F-FDG-PET, had negative morphological imaging at the time of scintigraphic studies. Lung metastases in two patients and metastases in mediastinum in another patient were subsequently confirmed 3 and 4 months later, respectively (Table 1).

Discussion

Since the introduction of ^99mTc-depreotide into clinical practice (14), scintigraphy with this compound has been proven to have high diagnostic efficacy in the evaluation of thoracic nodules (15, 17). In this study, we evaluated the efficacy of ^99mTc-depreotide scintigraphy in radioiodine-negative thyroid cancer in a pilot series of 10 patients. We found that ^99mTc-depreotide scintigraphy yields a high diagnostic capacity (90% positivity in this study) for recurrent or metastatic disease in patients with thyroid cancer and detectable thyroglobulin where thyroid cancer tissue does not concentrate radioiodine rendering false-negative results on ¹³¹I-whole-body scintigraphy. In this series of patients, ^99mTc-depreotide scintigraphy showed a higher diagnostic capacity than ¹⁸F-FDG-PET, which is considered the main diagnostic tool in patients with radioiodine-negative thyroid cancer. Furthermore, it is worth pointing out that an early diagnosis of metastatic disease could be obtained with ^99mTc-depreotide in three patients. This high diagnostic efficacy is most probably due to the overexpression of SSTRs 3 and 5 reported for papillary and follicular thyroid cancer (8, 9) and the high affinity of ^99mTc-depreotide for these SSTRs (16). Moreover, these results seem to confirm the existence of overexpression or up-regulation of SSTRs in thyroid cancer cells that do not concentrate radioiodine, in concordance with our recent findings obtained with ¹¹¹In-DOTA-lanreotide and ¹¹¹In-DOTA-TOC (10). Larger studies that include other forms of thyroid cancer and more patients with papillary thyroid cancer, and that compare ^99mTc-depreotide with other SSTR radioligands, are needed to evaluate the value of ^99mTc-depreotide in the diagnostic work-up of thyroid cancer.

It is important to note that we found a “flip/flop” phenomenon between ^99mTc-depreotide and ¹⁸F-FDG-PET in one patient. ¹⁸F-FDG-PET-uptake in radioiodine-negative lesions has been considered to represent rapid tumor growth and poor differentiation (7). We observed previously a flip/flop phenomenon between ¹⁸F-FDG-PET and SSTR scintigraphy with ¹¹¹In-DOTA-lanreotide and ¹¹¹In-DOTA-TOC in 11% of patients and between radioiodine uptake and SSTR scintigraphy with these radioligands in 17% of patients (10). Feine et al. (18) also reported a flip/flop phenomenon between ¹⁸F-FDG-PET and radioiodine uptake in thyroid cancer patients. These data seem to reflect different thyroid cancer cell differentiation in individual patients (19). Taken together, these data confirm the need for a multimodality diagnostic approach to radioiodine-negative thyroid cancer.

Hepatobiliary excretion and nonspecific accumulation of ^99mTc-depreotide in the bowel (Fig. 1) may result in false results in the abdomen. This may explain the lower sensitivity of ^99mTc-depreotide than ¹¹¹In-DTPA-d-Phe¹-octreotide scintigraphy in patients with neuroendocrine tumors (18). We found a false-positive result with ^99mTc-depreotide in a granulomatous lung lesion, probably caused by nonspecific uptake in cells that play a role in granulomatous diseases, such as activated lymphocytes, which may also bear SSTRs (12). Thus, care should be taken when interpreting a focus of positive uptake of ^99mTc-depreotide.

In many patients with identifiable radioiodine-negative lesions, surgery and radiotherapy may not be feasible owing to inoperability, previous radiotherapy, or additional distant metastases. Conventional chemotherapy is often ineffective (20). The use of SST analogs may be taken into consideration as an alternative treatment option when surgery or radiotherapy are not indicated.

Data indicate that ^99mTc-depreotide scintigraphy is capable of locating lesions of thyroid carcinomas that do not concentrate radioiodine and, in some patients, this imaging method may be more sensitive than ¹⁸F-FDG-PET. Furthermore, ^99mTc-depreotide takes advantage of the greater availability of gamma camera imaging and ^99mTc from generators, as well as of the low cost of this radionuclide. Moreover, ^99mTc-depreotide scintigraphy delivers information regarding the SSTR status of tumors, which may contribute to decision making regarding individual therapy.

We are grateful to all technologists involved in the preparation and quality control of radiopharmaceuticals and in the acquisition and processing of data. We thank the clinical collaboration of Drs. Kurt Kletter, Clemens Novotny, Silvia Wogritsch, Ingrid Hurtl, and Brigitte Gorz.

Disclosure Statement: The authors have nothing to declare.

Abbreviations:

 
• ¹⁸

  F-FDG-PET,

 
• ¹⁸

  F-Fluorodeoxyglucose-positron emission tomography;

 
• ¹¹¹In-DOTA-TOC,

  ¹¹¹In-DOTA-d-Phe¹-Tyr³-octreotide;

 
• SSTR,

  somatostatin receptor.