a Department of Radiological Sciences, Unit of Nuclear Medicine and b Clinical

Transcription

1 Original article Clinical usefulness of 99m Tc-MIBI scintigraphy in the postsurgical evaluation of patients with differentiated thyroid cancer Alfredo Campennì a, Maria A. Violi b, Rosaria M. Ruggeri b, Alessandro Sindoni a, Mariacarla Moleti b, Francesco Vermiglio b and Sergio Baldari a Objective 99m Tc-methoxyisobutyl isonitrile (MIBI) has been reported to show considerable clinical utility in the study of many neoplastic diseases. The aim of our study was to investigate the possible role of 99m Tc-MIBI in the initial follow-up of patients with differentiated thyroid cancer (DTC) for detecting residual thyroid uptake and/or loco-regional/distant metastases. Methods Eighty-two patients with DTC (61 women, 21 men; mean age: 49 years) were studied after total or near-total thyroidectomy (not earlier than 3 months after thyroidectomy but before they underwent radioiodine therapy). About 20 min after the intravenous administration of 370 MBq of 99m Tc-MIBI, planar images (and, if necessary, tomographic images, single photon emission tomography) of the cervical and thoracic regions were recorded and compared with posttherapy radioiodine scanning and thyreoglobulin serum levels. Results MIBI scans detected thyroid remnants in 53 of 82 patients (65%) and metastatic foci in 10 of 11 (91%) patients, in whom a standard activity of 1110 MBq of 131 I administered following MIBI scan had shown the presence of thyroid remnants or metastatic foci, respectively. One metastatic patient was false negative for both MIBI scan and post- 131 I dose whole body scan. Conclusion Our data indicate that an MIBI scan has a high sensitivity in detecting metastatic lesions from DTC. Therefore, an MIBI scan after thyroidectomy and immediately before radioiodine treatment may be clinically useful for choosing the best therapeutic approach in terms of either ablative or therapeutic 131 I activity for both thyroid remnants and/or DTC metastases and for evaluating surgical reappraisal of metastatic lymph nodes. Nucl Med Commun 31: c 2010 Wolters Kluwer Health Lippincott Williams & Wilkins. Nuclear Medicine Communications 2010, 31: Keywords: differentiated thyroid cancer, iodine-131, metastatic disease, 99m Tc-MIBI scan, thyroid imaging a Department of Radiological Sciences, Unit of Nuclear Medicine and b Clinical and Experimental Department of Medicine and Pharmacology, Unit of Endocrinology, University of Messina, Italy Correspondence to Alfredo Campennì, MD, Dipartimento di Scienze Radiologiche, U.O.C. di Medicina Nucleare, A.O.U. Policlinico G. Martino di Messina, v. Consolare Valeria, 1, Messina, Italy Tel: ; fax: ; alfredo.campenni@alice.it Received 5 September 2009 Revised 10 October 2009 Accepted 13 October 2009 Introduction Differentiated thyroid carcinomas (DTCs) are among the most curable neoplasms [1 3]. The initial treatment consists of total or near total thyroidectomy. Most patients also receive radioablation of any remaining normal or neoplastic thyroid tissue with 131 I [1 3]. At present, many patients are treated with standard activity of radioiodine ranging between 1110 and 3700 MBq [1,4], to both detect/ablate thyroid remnants and detect/ treat metastatic lesions that are hard to ascertain before radioiodine treatment. In fact, a diagnostic scan with low activity ( MBq or 4 5 mci) of 131 I may be nondiagnostic despite measurable serum levels of thyreoglobulin (Tg) because of the persistence of small metastases still able to take up radioiodine but too small to be detected [4 8]. Moreover, diagnostic 131 I scanning, performed before the ablative treatment, may limit the 131 I therapy effectiveness and reduce the sensitivity to radioiodine, because the tracer itself can reduce the 131 I uptake by the neoplastic tissue ( stunning effect) [4,9,10]. Finally, as reported in a meta-analysis by Maxon and Smith, about one fourth of the recurrences and metastases from DTC do not concentrate 131 I [11], thus suggesting the need to find, in such cases, alternative diagnostic tools. Therefore, several alternative procedures have been evaluated in the management of DTC patients including 201 Tl chloride and 99m Tc-methoxyisobutyl isonitrile ( 99m Tc-MIBI) scans [12 21] and, more recently, positron emission tomography with fluorodeoxyglucose [19 21]. In this study, we focused our attention on the clinical usefulness of the 99m Tc-MIBI scan in the early phases of the management of DTC patients. 99m Tc-MIBI, a lipophilic cationic molecule, was used primarily for myocardial perfusion studies [22]. Today this tracer is also used for c 2010 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MNM.0b013e

2 99m Tc-MIBI scan in differentiated thyroid cancer Campennì et al. 275 the study of many neoplastic diseases, such as breast and lung cancers [23 25]. The mechanism of 99m Tc-MIBI uptake in tumors is not influenced by the levels of thyroidstimulating hormone (TSH). 99m Tc-MIBI seems to enter the tumor cells by passive diffusion, and its uptake and retention depend on the negative transmembrane and mitochondrial potentials of malignant cells [23,26]. For DTC metastases, a 99m Tc-MIBI scan showed high sensitivity, which is, in some studies, even higher than that of iodine imaging [1,5,7,10,25,27 33]. Furthermore, some researchers have highlighted various advantages of 99m Tc-MIBI in comparison with 131 I, such as (i) no need to discontinue L-T4 therapy before scintigraphy; (ii) better quality of the images and possibility of performing single photon emission tomography (SPET) on the region of interest (i.e. thorax) and (iii) easier and more time saving scintigraphy by MIBI labeling with 99m Tc. For these reasons, 99m Tc-MIBI has been proposed as a radiotracer complementary to 131 I in the very first approach to DTC patients [28,32]. Our study was therefore aimed at evaluating the clinical usefulness of 99m Tc-MIBI in planning post-surgical therapy and initial follow-up of DTC patients. In particular, we assessed whether this radiotracer, used immediately before radioiodine treatment, might actually reveal the presence of remnants and, in particular, of metastatic foci. Patients and methods A total of 82 consecutive patients with DTC (61 women; mean age 49 ± 13.6 years, range 16 81; 21 men; mean age 48 ± 18.2 years, range years), referred to our division from January 2007 to April 2008, were enrolled into this study. All patients had earlier undergone total or near-total thyroidectomy (Tx). The papillary histotype was diagnosed in 54 of the 82 patients (39 female, 15 male; 33/54 were pure papillary, and 21/52 were the follicular variant), while the follicular histotype was diagnosed in 28 of 82 patients (22 females, six males; 3/28 Hurtle cell variant). One or more risk factors (primary disease size > 1.5 cm, vascular invasion and/or capsule invasion) were present in 40 of 82 patients (49%; 27 female, 13 male). The patients were studied not earlier than 3 months after thyroidectomy but before they underwent radioiodine therapy. All patients were euthyroid with suppressed TSH (< 0.01 miu/ml) under levo-thyroxine (L-T4) therapy at the time of recruitment. 99m Tc-MIBI scintigraphy of the head, neck and thoracic regions was performed a few days before discontinuing L-T4 therapy. Twenty minutes after the intravenous administration of 370 MBq of 99m Tc-MIBI, two planar images (magnification 1 and 2, matrix and , respectively) of the cervical and thoracic regions were taken. Images (10 min per frame) were obtained using a g-camera (single circular head) equipped with low-energy high-resolution parallel-hole collimator. A photopeak of 140 kev with symmetrical 20% window was used. In any case an additional SPET study of the region under examination was carried out. The SPET study was carried out with a dual-headed g-camera (Picker Axisis) equipped with low-energy high-resolution parallel-hole collimators; the images were acquired with matrix, 1801 rotation, a 31 step-and-shoot technique and an acquisition time of 30 s per frame. Then, patients discontinued L-T4 therapy for 5 weeks before performing the 131 I scan and received triiodothyronine supplements for the first 3 weeks of L-T4 withdrawal. A low-iodine diet regimen for 15 days before testing was a prerequisite for all patients. Patients were then studied and treated over 1 week according to the following procedure: Day 1: Sampling for TSH, FT3, FT4, Tg, and anti-tg antibodies (Tg-Ab). Serum Tg was measured by immunoradiological measure assay (IRMA) test with a normal range of ng/ml and a limit of detection at 1.6 ng/ml. Tg-Ab, which would affect Tg measurement, was determined with the immunoradiometric assay using a commercially available kit (by CIS, Gif-sur-Yvette, France). The range was less than 100 IU/l in normal patients. The recovery test for detecting possible interference in Tg assay was systematically carried out in all patients, irrespective of Tg-Ab positiveness; Oral administration of tracer activity of 131 I(3.7MBq); Day 2: 24 h radioiodine thyroid uptake (RTU) measurement followed by scan of the neck (64 64 matrix with highenergy general-purpose parallel hole collimator); Day 3: Oral administration of radioiodine therapy at low activity (1110 MBq); Day 7: 131 I posttherapy whole-body scan (WBS). During the follow-up, the patients underwent ultrasonography (US) of the neck, Tg measurements (with and without L-T4 therapy) and diagnostic (185 MBq) radioiodine WBS. Magnetic resonance or computed tomography imaging of the neck and/or other regions (i.e. thorax) was performed, when necessary, using standard protocols. Results All patients were euthyroid with suppressed TSH (< 0.01 miu/ml) under L-T4 therapy on the day of MIBI imaging. During L-T4 withdrawal, all patients had serum

3 276 Nuclear Medicine Communications 2010, Vol 31 No 4 TSH levels up to 20 miu/ml. Average TSH values were 80 ± 65 miu/ml (range, ). Serum Tg levels were under the limit of detection (< 1.6 ng/ml) in 31 of 82 (38%) patients. The remaining 51 patients (62%) had detectable values of Tg, ranging from 1.7 to 4000 ng/dl (median 10.9). In all but six patients Tg-Ab values were negative. Data concerning 99m Tc-MIBI, RTU measurement, and 131 I WBS results in our 82 DTC patients are summarized in Table 1. RTU (range %; mean: %) was detected in all patients with radioiodine tracer activity and afterwards highlighted by 131 I WBS post-therapeutic activity, whereas MIBI uptake in the thyroid bed, according to the presence of residual thyroid tissue, was detected only in 53 of 82 patients (65%) (Fig. 1, panels a and b, respectively). RTU values were inversely related to serum TSH levels (r 2 =0.2; P < 0.05). Table 1 Radioiodine thyroid uptake, MIBI and 131 I scans results in the 82 patients with differentiated thyroid cancer Scintigraphic imaging No. of patients (%) with positive scan (total no. of patients = 82) Radioiodine thyroid uptake a 82 (100%) (mean ± SD, range) (10 ± 9.9%, %) 131 I whole-body scan b Thyroid remnants 82 (100%) Lymph node metastases 10 (12%) Distant metastases 2 (2.4%) MIBI scan Thyroid remnants 53 (65%) Lymph node metastases 10 (12%) Distant metastases 2 (2.4%) MIBI, methoxyisobutyl isonitrile. a After 131 I tracer activity of 3.7 MBq. b After 131 I therapeutic activity of 1110 MBq. The 99m Tc-MIBI scan revealed abnormal uptake of the tracer outside the thyroid bed, thus suggesting the presence of metastatic disease, in 10 of 82 patients (12% of all patients), that is 10 of the 11 patients who turned out having metastatic disease (91% of the metastatic patients). In 9 of these 10 patients (90%), metastatic lymph nodes were observed (laterocervical diameter < 1 cm and/or mediastinal) (Fig. 2, panel a) and in two of them bone metastases were also detected (sternum and dorsal vertebrae). The same results were obtained with 131 I posttherapy WBS (Fig. 2; panel b) with a 99m Tc-MIBI/ 131 I concordance of 100%. The presence of metastatic disease and its localization were also confirmed by US and magnetic resonance or computed tomography imaging. In 6 of the 11 metastatic patients (54.5%), the 99m Tc- MIBI scan revealed either the residual thyroid tissue or the metastases uptake without discriminating between residual normal tissue and residual neoplastic tissue. In the 11 metastatic patients, RTU was 1,1, 2, 2, 4, 4, 8, 10, 15, 17, 30% (median 4%) with Tg levels of 52.8, 238, 92.7, 33.6, 33, 2334, 438, 4000, 2150, 48, 334 ng/dl (median 238), respectively. Of the 72 patients with both 99m Tc-MIBI and 131 I scans negative for metastases, 41 (57%) had detectable levels of serum Tg before radioiodine (median 8.9; range, ), whereas in 31 of 72 (43%) patients serum Tg was undetectable (< 1.6 ng/ml). One patient with both 99m Tc-MIBI and posttherapy 131 I scans negative and detectable levels of serum Tg before radioiodine (238 ng/dl) had metastatic disease (false negative). The histological type of the primary tumor in such a patient was the follicular. During the follow-up, serum Tg remained detectable and lymph-node metastases Fig. 1 (a) (b) SCINT. WHOLE BODY 131 I POST-DOSE 242 Anterior neck θ Anterior view of 99m Tc-methoxyisobutyl isonitrile (MIBI) (a) and 131 I (b) scans, both showing thyroid remnants (white and blue arrows). The patient had undergone near-total throidectomy for papillary thyroid cancer. Thyreoglobulin value was 19.7 ng/ml. MIBI scan showed mild uptake in the thyroid bed. 131 I scan confirmed the presence of thyroid remnants.

4 99m Tc-MIBI scan in differentiated thyroid cancer Campennì et al. 277 Fig. 2 (a) 99m Tc-MIBI (b) 131 I scan Anterior neck and thorax Anterior Jugulum Anterior view of 99m Tc-methoxyisobutyl isonitrile (MIBI) (a) and 131 I (b) scans in a patient who had previously undergone near-total thyroidectomy for follicular thyroid cancer (thyreoglobulin: 2334 ng/ml). MIBI images showed abnormal uptake in the upper mediastinum (red arrows). 131 I scan (b) was positive, and confirmed the presence of metastatic foci (red arrows). In this case, MIBI scan (a) revealed no area of focal tracer uptake in the thyroid bed, whereas 131 I scan (b) showed residual thyroid uptake (blue arrow). were detected in the neck by US. The patient underwent surgical removal of the lymph nodes and histological findings confirmed the US suspicion. In contrast, in a patient with relatively high values of Tg (80 ng/ml) and no evidence of extrathyroidal uptake of the two radiotracers (thyroid remnants, with RTU: 14%), follow-up showed that both 99m Tc-MIBI and 131 I posttherapy scans were actually negative. No evidence of disease was shown during 12 months of follow-up in the other patients with both negative 99m Tc-MIBI and radioiodine scans. Discussion In this study, we evaluated the utility of 99m Tc-MIBI as a radiotracer complementary to radioiodine in the follow-up of DTC patients. 99m Tc-MIBI presents many advantages: (i) 99m Tc has favorable physical characteristics, such as a short physical life, which permits it to be administrated in large doses with better image resolution and low radiation burden on the patients with respect to 131 I; (ii) MIBI uptake in thyroid carcinoma is independent of TSH stimulation and it could be used without stopping L-T4 therapy; (iii) 99m Tc-MIBI accumulates in nonfunctioning metastases, which usually fail to concentrate 131 I because of its mechanism of cell uptake, dependent on cellular mitochondrial content and metabolism [23,26]. The 99m Tc-MIBI uptake is not specific to thyroid cancer, even though several studies have reported the high sensitivity and specificity of the radiotracer in detecting functional and nonfunctional thyroid cancer metastases [17,28 34]. In fact, Ugor et al [17] showed an overall concordance between the 131 I, 201 Tl and MIBI scans of 70%, with a concordance between thyroglobulin levels and 201 Tl and MIBI scans of 83%. Rubello et al. [28] also found a high sensitivity (93.5%) to MIBI, during suppressive therapy, when used to detect cervical metastatic lymph nodes, particularly those not having 131 I uptake. In this latter study, sensitivity increased to 97.8%, with an improvement in specificity as well, if the MIBI scan was combined with US. Miyamoto et al. [32] reported very high sensitivity (100%) from MIBI in 27 patients presenting cervical lymph node metastases. Nemec et al. [33] also found a sensitivity of MIBI of 80.9% for cervical lymph nodes. In the study by Ronga et al. [34], the MIBI scan showed good sensitivity mainly in detecting mediastinal nodes, and it showed a higher (but non statistically significant) sensitivity in detecting 131 I-negative metastases compared with those with 131 I uptake. In agreement with data from the literature, we showed a 100% sensitivity and specificity of 99m Tc-MIBI scan in detecting metastatic foci in our patients, studied after thyroidectomy and before radioiodine ablation. In our

5 278 Nuclear Medicine Communications 2010, Vol 31 No 4 series, the 99m Tc-MIBI scan revealed metastatic disease in 10 of 82 patients; in 9 of them metastatic lymph nodes (cervical and/or mediastinal) were detected and in 2 of them bone metastases (sternum and dorsal vertebrae) were also shown. These results confirm the high sensitivity of 99m Tc-MIBI in visualizing metastases not only in the neck, but also in the mediastinum and in distant sites. However, it has to be pointed out that in our series all metastases detected by 99m Tc-MIBI were also visualized by 131 I, with a 99m Tc-MIBI/ 131 I concordance of 100%. In our series, the MIBI scan as well as the 131 I scan failed to detect the site of metastatic disease only in one patient affected by follicular thyroid cancer. In contrast, we found that the 99m Tc-MIBI scan showed a low sensitivity in visualizing thyroid remnants (65% of patients), compared with 131 I sensitivity (100%). This latter is a limit of the 99m Tc-MIBI scan because the detection and subsequent ablation of thyroid remnants with 131 I is considered essential to improve the diseasefree time interval and survival, and to allow the use of Tg as a tumor marker during follow-up. As regards the Tg levels during L-T4 withdrawal, our data confirm its high sensitivity in indicating the presence of metastases, particularly in distant sites as observed in the two patients with bone metastases. In one nonmetastastic patient with relatively high Tg values and low residual thyroid uptake, the 99m Tc-MIBI scan was actually negative. On the basis of our results and the data of the literature, the MIBI scan shows high sensitivity in detecting local metastases, both those with 131 I uptake as in our series or those without 131 I uptake as shown in other studies [28,34]. Conclusion We conclude that the 99 Tc-MIBI scan seems very useful in identifying patients with metastatic disease after thyroidectomy and before 131 I scan, as it may distinguish in advance high-risk from low-risk patients. Consequently, the 99m Tc-MIBI scan might play a prognostic role and allow us to choose the best therapeutic approach for each patient. However, because of its low sensitivity in detecting thyroid remnants, 99m Tc-MIBI scan cannot be used as a predictor of 131 I scan results and the visualization of thyroid remnant by radioiodine is necessary for the correct management of DTC patients. Therefore, the 99m Tc-MIBI scan is not an alternative to the radioiodine scan, but it might be a complementary method for providing useful diagnostic information. In conclusion, we propose the 99m Tc-MIBI scan as a first level diagnostic procedure, along with serum Tg determination and US, in the early post-surgical evaluation of DTC patients before radioiodine therapy. 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