FULL PAPER Tc-99m MIBI SCINTIGRAPHY IN FOLLOW-UP OF POST-THERAPY DIFFERENTIATED THYROID CARCINOMA (DTC) Yudistiro R, Kartamihardja AHS, and Masjhur JS Department of Nuclear Medicine, School of Medicine Universitas Padjadjaran, Dr. Hasan Sadikin Hospital, Bandung, Indonesia. POSTER PRESENTATION 4 th International Conference on Radiopharmaceutical Therapy New World Hotel, Ho Chi Minh City, Vietnam 28 Nov 2 Dec 2011
Tc-99m MIBI SCINTIGRAPHY IN FOLLOW-UP OF POST- THERAPY DIFFERENTIATED THYROID CARCINOMA (DTC) Yudistiro R, Kartamihardja AHS, and Masjhur JS Department of Nuclear Medicine, School of Medicine Universitas Padjadjaran, Dr. Hasan Sadikin Hospital, Bandung, Indonesia. Abstract Background. Long terms follow-up should be performed in post-therapy DTC patients by measuring serum thyroglobulin (Tg-off) and Thyroglobulin-antigen antibody (AbTg) level in stimulating TSH level every 6-12 months. NaI-131 scintigraphy is done to detect location of remnant thyroid and/or metastases. 1 NaI-131 scintigraphy has several disadvantages, such as patient s discomforts and stunning effect. 99m Tc-methoxyisobuthyisonitrile (MIBI) is routinely used as tumor seeking agent; the advantages of 99m Tc-MIBI scintigraphy in follow-up of post-therapy DTC patients is still controversy. Diagnostic performance of imaging can be measured by image resolution which is resulted from uptake ratio. Objective. To evaluate the uptake ratio and diagnostic value of 99m Tc-MIBI and NaI-131 scintigraphy using Tg-off level as gold standard. Methods. 99m Tc-MIBI and NaI-131 scintigraphy were done in 56 patients posttotal thyroidectomy and radiothyroablation with NaI-131 who underwent follow up. Maximum counts activity was analyzed from region of interest (ROI) of lesion and background to measure uptake ratio. Background ROI was made in thigh projections.
Conclusion. 99m Tc-MIBI scintigraphy is not better than NaI-131 scintigraphy by using Tg-off as gold standard. NaI-131 scintigraphy is still the best methood in follow-up of post-therapy DTC patients. Keywords: Tc-99m MIBI, NaI-131, Thyroglobulin, Differentiated Thyroid Carcinoma Introduction Long terms follow-up should be performed in post-therapy DTC patients by measuring serum thyroglobulin (Tg-off) and Thyroglobulin-antigen antibody (AbTg) level in stimulating TSH level every 6-12 months. The aim of this long terms follw-up is to early detect of remnant malignancy, relapse and far metastases, and monitoring of thyroid stimulating hormone (TSH) suppression. American Thyroid Association 2009 Guidance recommend the use of thyroglobulin-off (Tg-off) serum level as indicator and anti thyroglobulin antibody (Tg-Ab) as validator of Tg-off. 1,2 NaI-131 scintigraphy is done to detect location of remnant normal thyroid and/or metastases with high specificity. 3 NaI-131 scintigraphy has several disadvantages, such as patient s discomforts due to they have to stop thyroid hormone substitution in order to reach TSH stimulation condition at least 10 times of normal limits. In this hypothyroidism condition, patient will suffer due to decrease metabolic activity. Stunning effect is also the other disadvantage of using NaI-131 as diagnostic agent, particularly it is done with high dose and duration between diagnostic test and time of treatment is very close. NaI-131 scintigraphy should be done at 24 and 48 hours post administration of NaI-131, so the procedure is take long time. 4
Some studies found discordance between Tg-off serum level result and NaI-131 scintigraphy in post radioiodine ablation patient with DTC. High Tgoff serum level with negative NaI-131 scintigraphy was found in 10-15% of patient with DTC after radioiodine ablation, and on the other hand positive NaI- 131 scintigraphy with low Tg-off serum level were found even less. 4,5 New and non-invasive imaging modalities is a challenge to replace NaI- 131 as diagnostic modality to detect and localize malignancy after radioiodine ablation without stopping TSH substitution and suppression. Radiopharmaceuticals could be used for this imaging modality are 201 Tl, 99m Tctetrofosmin, 99m Tc-MIBI, 111 In-octreotide, 123 I and 18 F-FDG. 4,6,7 99m Tc-methoxyisobuthyisonitrile (MIBI) is a cationic lipophilic. It will be accumulated in mitochondria following intravenous injection. 8 99m Tc-MIBI has been used as a routine tumor seeking agent, since it can be accumulated in malignant cell, such as nasopharynx, lung, parathyroid, breast cancer, multiple myolema and ostegenic sarcoma. 9-14 The advantages of 99m Tc-MIBI scintigraphy in follow-up of post-therapy DTC patients is still controversy. The aim of this study was to evaluate the uptake ratio and diagnostic value of 99m Tc- MIBI and NaI-131 scintigraphy using Tg-off level as gold standard. Material and methods Subjects were patient with DTC who came to Departement of Nuclear Medicine Dr. Hasan Sadikin General Hospital for following up after radioiodine ablation. Subject should be under TSH stimulation with TSH serum level > 30uIU/ml as an obligatory for Tg-off level test and NaI-131 scintigraphy.
Measurement of Tg-off serum level and TSH using dual high affinity monoclonal antibody method in immunoradiometric assay (IRMA), and radioimmuno assay is use for Tg-Ab serum level. 99m Tc-MIBI scintigraphy was done 15 minutes and 4 hours after intravenous incjetion of 10-15 mci (370-555 MBq) of radiopharmaceutical. Total body image was taken by using gamma camera with low energy high resolution, energy setting in 140 KeV, matrix size 256x256, 3.0 zooming and window width 20%. NaI-131 scintigraphy was done after 4-6 weeks without TSH suppression or TSH serum level > 30 miu/ml. NaI-131 image was taken 24-48 hours after oral administration of 2 mci (74%) NaI-131 by using gamma camera with high energy collimator, energy setting in 364 KeV, matrix size 256x256, 3.0 zooming and window width 20%. Uptake ratio from both images was calculated from radioactivity counts taken from region of interest (ROI) of the target and background. Statistic analysis Statistic analysis was used SPSS program for windows version 13.0 with degree of confidence interval 95% and significance if p value < 0.05. Bivariate analysis was used to evaluate the different uptake between 99m Tc-MIBI and NaI- 131 by using non-parametric test from Wilcoxon test. Diagnostic test was used to determine sensitivity, specificity, PPV, NPV and accuracy.
Results This study was involving 56 subjects consist of 10 (17.9%) male and 46 (82.1%) female, aged range 13-75 years old (X= 44.2 +14.8). Histopathological finding was 46 (82.1%) papillary, 9 (16.1) follicular and 1 (1.8%) Hurtle cell. Positive Tg-off serum level was found in 15 (26.8%) and negative 41 (73.2%). Positive Tg-Ab level was found in 25 (44.6%) and negative in 31 (55.4%). Positive 99m Tc-MIBI Scintigraphy was found in 13 (23.2%) and negative in 43 (76.8%). Positive Na-I 131 scintigraphy wa found in 18 (32.1%) and negarive in 38 (67.9). Median and ranged uptake ratio of 99m Tc-MIBI and Na-I 131 were 2.03 (1.8-3.2) and 1.67 (0.2-2.5) respectively. Wilcoxon-test with confidence interval 95% showed there was no significance different between 99m Tc-MIBI and Na-I 131 uptake ratio with p value =0.068. The results showed 7 (46.7%) out 13 subject with positive 99m Tc-MIBI Scintigraphy were postive Tg-off serum level. and 35 (85.4%) out of 43 subject with negative 99m Tc-MIBI Scintigraphy were negative Tg-off serum level as well. McNemar test with confidence interval 95% showed that there was no significance different between 99m Tc-MIBI Scintigraphy and Tg-off in validation of following up DTC patients after radioiodine ablation with p value =0.791. Sensitivity, specificity, PPV, NPV and accuracy of 99m Tc-MIBI Scintigraphy for following up patient with DTC after radioiodine ablation were 46.7%, 85.4%, 53.8%, 81.4% and 75% respectively. The results showed 12 (80%) out 18 subject with positive Na-I 131 scintigraphy were postive Tg-off serum level, and 35 (85.4%) out of 38 subject with negative Na-I 131 scintigraphy were negative Tg-off serum level as well. McNemar test with confidence interval 95% showed that there was no significance different
between Na-I 131 scintigraphy and Tg-off in validation of following up DTC patients after radioiodine ablation with p value =0.508. Sensitivity, specificity, PPV, NPV and accuracy of Na-I 131 scintigraphy for following up patient with DTC after radioiodine ablation were 80.0%, 85.4%, 66.7%, 92.1% and 83.9% respectively. (table 1) Tabel 1. Diagnostic value of 99m Tc-MIBI Scintigraphy and Na-I 131 scintigraphy. Variable Thyroglobulin Diagnostic Value Positive Negative Sensitivity Specificity PPV NPV Accuracy 99m Tc-MIBI Scintigraphy 46.7 % 85.4 % 53.8 % 81.4 % 75 % Positive 7 6 Negative 8 35 NaI-131 Scintigraphy 80.0 % 85.4 % 66.7 % 92.1 % 83.9 % Positive 12 6 Negative 3 35 A B FIGURE 1. Tc-99m MIBI scintigraphy in 53 years old male with positive Tg-off and negative AbTg showed pathological uptake (arrow) in thyroid bed (A), while in NaI-131 there is no pathological uptake in thyroid bed (B)
A B FIGURE 2. Tc-99m MIBI scintigraphy in 33 years old female with negative Tg-off and positive AbTg showed pathological uptake (arrow) in thyroid bed (A), while in NaI-131 there is no pathological uptake in thyroid bed (B) False positive may be due to inflammation or muscle activity. Discussion 99m Tc-MIBI has been using as tumor seeking agent in many studies. This radiopharmaceutical can be use to detect malignancy in solitary thyroid nodule. 15 This study showed there is no significance different uptake ratio between 99m Tc-MIBI Scintigraphy and NaI-131 scintigraphy, but median uptake of 99m Tc-MIBI Scintigraphy was higher compared to NaI-131 scintigraphy. This differences could be due to difference gamma ray energy level of 99m Tc-MIBI more ideal for gamma camera detector compared to NaI-131. Sensitivity and specificity of both modalities were similar to other studies. The sensitivity and specificity of 99m Tc-MIBI Scintigraphy were 36-100% and 89-94% respectively, while NaI-131 scintigraphy were 47-84% and 96-99% respectively. 10 Low sensitivity of 99m Tc-MIBI Scintigraphy could be due to high backgroud uptake of 99m Tc-MIBI. ROI of background was taken from soft tissue (sceletal muscle) which is consist a lot of mitochondria, while NaI-131 is
not taken up by sceletal muscle. The other reason of low sensitivity of 99m Tc- MIBI Scintigraphy due to metabolic and blood flow degradation, and cell membrane disorder of thyroid cell after radioiodine ablation. On the othe hand the sensitivity of NaI-131 scintigraphy was higher due to this radiopharmaceutical will be taken by both normal thyroid tissue and thyroid cancer. 10 This study showed 8 subjects with positive Tg-off serum level, but negative on 99m Tc-MIBI Scintigraphy considered as false negative. False negative result of 99m Tc-MIBI Scintigraphy could be due to the size of cancer too small (microcarcinoma) to be detected with gamma camera with spatial resulution >0.5 cm. 16 False positive result of 99m Tc-MIBI Scintigraphy was observed in 6 subjects could be due to high uptake in sceletal muscle. It is recommended not to do physical exercise to whom 99m Tc-MIBI Scintigraphy procedure will be applied. False negative result in NaI-131 scintigraphy could be due to uptake mechanism disorder, dedifferentiated tumor cell, and microcarcinoma. False positive results of NaI-131 scintigraphy could be due to normal uptake of choroidal flexus, salivary gland, gastric mucous, and urinary tract. 4 In this study 25 subject with postive Tg-Ab showed 16 subjects with negative Tg-off and 9 positive. Four out of 16 subjects showed positive 99m Tc- MIBI Scintigraphy and 1 subject showed positive NaI-131 scintigraphy. In 8 out of 9 subject showed positive NaI-131 scintigraphy. Positive 99m Tc-MIBI Scintigraphy was observed in all subject with positive Tg-off and positive Tg- Ab. This results showed that 99m Tc-MIBI Scintigraphy has capability to detect more remnant thyroid cancer in all subject with postive Tg-Ab.
The advantage of 99m Tc-MIBI Scintigraphy was the procedure could be done in TSH suppresion and no stunning effect. The patient could continue to take thyroid hormone substitution. Conclusion The conclusion of this study were 99m Tc-MIBI scintigraphy was not better procedure than NaI-131 scintigraphy as following up patients with DTC after radioiodine ablation by using Tg-off as gold standard. NaI-131 scintigraphy is still the method of choice in follow-up patients with DTC after radioiodine ablation. References 1. Schlumberger M, Pacini F. Follow-up: Lessons from the pass. In Papillary and follicular thyroid carcinoma. Paris: Nuclean 2006;h:147-63. 2. ATA (American Thyroid Association) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2009;19:1167-99. 3. Caron NR, Clark OH. Well differentiated thyroid carcinoma. Scandinavian Journal of Surgery 2004;93:261-71. 4. Ma C, Kuang A, Xie J, and Ma T. Possible explanations for patients with discordant findings of serum thyroglobulin and 131 I Whole body scanning. J Nucl Med 2005;46:1473-80. 5. Masjhur JS and Kartamihardja. Buku Pedoman Tatalaksana Diagnostik dan Terapi Kedokteran Nuklir. RS Hasan Sadikin/Fakultas Kedokteran Universitas Padjadjaran
6. Ronga G, Fiorentino A, Paserio E, Signore A, Todino V, Tumarello MA et al. Can I-131 whole body scan be replaced by thyroglobulin measurementin the post-surgical follow up of differentiated thyroid carcinoma? J Nucl Med 1990;31:1766-71 7. Kloos RT. Approach to the patient with positive serum thyroglobulin and a negative radioiodine scan after initial therapy for differentiated thyroid cancer. J Clin Endocrinol Metab. 2008;93(5):1519-25. 8. Arbab AS, Kizumi K, Toyama K and Araki T. Uptake of Technetium-99m Tetrofosmin, Technetium-99m MIBI and Thallium-201 in tumor cell lines. J Nucl Med 1996;37:1551-56. 9. Hidayat B, AHS. Kartamihardja, dan Masjhur JS. Deteksi keganasan payudarah menggunakan Technetium-99m Sestamibi. MKB. 2002; 34(1) 10. Fujie et al. Diagnostic Capabilities of I-131, Tl-201 and Tc-99m MIBI Scintigraphy for Metastatic Differentiated Thyroid Carcinoma after Total Thyroidectomy. Acta Med. Okayama 2005;59(3):99-107. 11. Kucuk NO, Kulak HA and Aras G. Clinical importance of technetium-99m methoxyisobuthylisonitrile (MIBI) scintigraphy in differentiated thyroid carcinoma patients with elevated thyroglobulin levels and negative I-131 scanning results. Annals of Nuclear Medicine, 2006;20(6):393-97 12. Eng Ng DC, Sundram FX and Sin AE. 99m Tc-sestamibi and 131 I whole body scintigraphy and initial serum thyroglobulin in the management of differentiated thyroid carcinoma. J Nucl Med 2000;41:631-35. 13. Miyamoto S, Kasagi K, Misaki T, Alam MS and Konisi J. Evaluation of technetium-99m MIBI scintigraphy in metastatic differentiated thyroid carcinoma. J Nucl Med 1997;38:352-56.
14. Al Saleh, Safwat R, Al-Shammeri I, Naseer MA, Hooda H and Al- Mohannadi S. Comparison of Whole Body Scintigraphy with Tc-99m methoxyisobuthylisonitrile and Iodine-131Na in Patients with Differentiated Thyroid Cancer. G.J.O 2007;1(1):29-33. 15. Fukumoto M. Single-photon agents for tumor imaging: Tl-201, Tc-99m MIBI, and Tc-99m Tetrofosmin. Annal of Nucl Med 2004;18:79-95. 16. Bizhanova A and Kopp P. minireview: The Sodium-Iodide Sympoter NIS and Pendrin in Iodide Homeostasis of the thyroid. Endocrinology 2009;150:1084-90.