CASE REPORT 
Annals of Nuclear Medicine Vol. 14, No. 4, 293-298, 2000 
Uptake of 99mTc-tetrofosmin, 99mTc-MIBI and 201Tl in malignant thymoma 
Teisuke HASHIMOTO, Kazunori GOTO, Yuji HISHINUMA, Kazuhisa YACHUDA, Yoshiaki SUGIOKA, Kazuhiro ARAI, Shusaku HARADA and Masabumi GOTO 
Department of Radiology, Dokkyo University School of Medicine 
99mTc-tetrofosmin, Thallium-201-chloride (201Tl) and 99mTc-MIBI imagings were performed in a patient with malignant thymoma. Tracer uptake in the primary tumor was demonstrated. The tumor-to-background ratios of planar and SPECT imagings were 1.60 and 1.98 for 99mTc-tetrofosmin, 1.12 and 2.09 for 201Tl, and 1.19 and 1.80 for 99mTc-MIBI, respectively. In another patient 99mTc-tetrofosmin and 201Tl imagings were performed. Not only the primary tumor but also the direct invasions and metastatic lesions (bone metastases) were clearly detected. The tumor-to-back-ground ratios of planar and SPECT imagings were 2.31 and 2.78 for 99mTc-tetrofosmin and 2.45 and 3.58 for 201Tl, respectively. In 99mTc-tetrofosmin scintigraphy we acquired delayed images, and the tumor-to-background ratios of planar and SPECT delayed images were 1.20 and 1.86, the retention ratios were -1.11 and -0.92 and the retention indices were -48.1 and -33.1, respectively. Our preliminary results suggest that 99mTc-tetrofosmin is useful in detecting not only the primary tumor but also metastatic lesions from malignant thymoma. 
Key words: thymoma, 99mTc-tetrofosmin, 201Tl, 99mTc-MIBI, SPECT 
INTRODUCTION 
99mTc-1,2-bis(bis(2-ethoxyethyl)phosphino)-ethane(tetrofosmin), a lipophilic monovalent cation, has recently been introduced as a new technetium-labeled pharmaceutical for myocardial perfusion studies. 99mTc-tetrofosmin and 99mTc-MIBI are now widely used in myocardial perfusion imaging. 201Tl, a cationic material, is a useful tracer for detecting various tumors including thymoma 99mTc-tetrofosmin as well as 99mTc-MIBI have shown potential utility as a tumor imaging agent for parathyroid adenoma,1 breast cancer,2-4 lung cancer,5-8 thyroid cancer9,10 and other tumors.11,12 We report patients with malignant (invasive) thymoma who underwent 201Tl, 99mTc-MIBI and 99mTc-tetrofosmin imagings. 

Received December 8, 1999, revision accepted February 2, 2000. 
For reprint contact: Teisuke Hashimoto, M.D., Department of Radiology, School of Medicine, Dokkyo University, 880 Kitakobayashi, Mibu-machi, Shimotsuga, Tochigi 321-0293, JAPAN. 

CASE REPORTS 
Case 1 
A sixty-seven-year-old man entered our hospital complaining of double vision and right eyelid ptosis. A tensilon test was positive and a clinical diagnosis of myasthenia gravis was made. Thoracic CT revealed an anterior mediastinal tumor (Fig. 1). The result of CT guided biopsy was a malignant thymoma. We obtained informed consent from the patient. 99mTc-tetrofosmin and 201Tl imagings were performed. The patient was injected with 99mTc-tetrofosmin (740 MBq) and underwent planar and SPECT imagings 10 min after the injection. 201Tl (222 MBq) was injected and planar and SPECT imagings were performed 10 min after the injection. A large field of view dual detector gamma camera and computer system (GCA7200A, Toshiba) equipped with low-energy, high resolution, parallel hole collimators were used. Anterior and posterior simultaneous planar images (512 x 512 matrix, 1500 k counts) were acquired. The energy discriminator was centered on 71 keV for 201Tl and 140 keV photopeak for 99mTc with a 20% window. Subsequently single photon emission computed tomography (SPECT) data were acquired. The dual detector gamma camera rotated through 180deg. in a circular orbit in 60 steps of 50 sec each for 201Tl and 99mTc SPECT. Butterworth and Shepp & Logan filters were used to reconstruct tomographic images. The parameter of Butterworth filter was order 8, and the cut-off frequency was 0.15 cycles/pixel for both tracers. As seen in Figures 2, 3 and 4, thoracic coronal SPECT images of 99mTc-tetrofosmin, 201Tl and 99mTc-MIBI show the accumulation of each tracer in the tumorous lesion corresponding to the anterior mediastinal tumor on X-ray CT. The tumor-to-background ratios of planar and SPECT imagings were 1.60 and 1.98 for 99mTc-tetrofosmin, 1.12 and 2.09 for 201Tl, and 1.19 and 1.80 for 99mTc-MIBI, respectively. 
Case 2 
A sixty-six-year-old man came our hospital because abnormal pleural thickening was pointed out in a routine chest X-ray. Thoracic CT revealed an anterior mediastinal tumor (Fig. 5) and involvement of the sternum, subcutaneous fat tissue and adjacent mediastinal structures (aorta), pleural disseminations and rib invasions (Fig. 6). The result of CT guided biopsy indicated an invasive thymoma. We obtained informed consent from the patient. 99mTc-tetrofosmin 201Tl and 99mTc-MIBI imagings were performed. The patient was injected with 99mTc-tetrofosmin (740 MBq) and underwent planar and SPECT imagings 10 min and 3 hours after the injection. 201Tl (222 MBq) and 99mTc-MIBI (740 MBq) were injected for the patient. Planar and SPECT imagings were obtained 10 min after the administration of both tracers. A 99mTc-tetrofosmin thoracic anterior planar image showed increased tracer uptake in the primary mediastinal tumor and right humeral bone metastasis (Fig. 7A). A posterior thoracic planar image showed ribs and thoracic vertebral bone metastases and direct rib invasions from pleural disseminations of malignant thymoma (Fig. 7B). Thoracic coronal SPECT (Fig. 8A) and transaxial SPECT (Fig. 8B) images of 99mTc-tetrofosmin clearly showed intense tracer activity in the primary anterior mediastinal tumor, direct sternum and subcutaneous fat tissue invasions and involvement of adjacent mediastinal structures (aorta, superior vena cava, mediastinum and pericardium), pleural disseminations and bone metastases in the rt humeral bone, ribs and thoracic vertebrae. Thoracic coronal SPECT (Fig. 9A) and transaxial SPECT (Fig. 9B) images of 201Tl show tracer uptake in the primary tumor, direct sternum and subcutaneous fat tissue invasions and adjacent mediastinal invasions (aorta, superior vena cava and pericardium), pleural disseminations and bone metastases (rt humeral bone, ribs and thoracic vertebrae). The tumor-to-background ratios of planar and SPECT imagings were 2.31 and 2.78 for 99mTc-tetrofosmin, and 2.45 and 3.58 for 201Tl respectively. In 99mTc-tetrofosmin scintigraphy we acquired delayed images, and tumor-to-background ratios of planar and SPECT delayed images were 1.20 and 1.86, the retention ratios were -1.11 and -0.92, and retention indices were -48.1 and -33.1, respectively. The retention ratio was obtained as follows: Delayed ratio - Early ratio. The retention index was obtained by means of the following equation: Delayed ratio - Early ratio/Early ratio x 100. 
DISCUSSION 
201Tl uptake of various tumors has been reported including malignant and benign thymic tumor.13-14 The tumor seeking properties of 99mTc-MIBI are also well known.15-17 99mTc-tetrofosmin has recently been used as a new myocardial perfusion imaging agent, and has also shown potential utility as a tumor imaging agent for such conditions as parathyroid adenoma,1 breast cancer,2-4 lung cancer,5-8 thyroid cancer9,10 and other tumors.11,12 Although 99mTc-tetrofosmin uptake in mediastinal tumor was reported,18 there is no report on 99mTc-tetrofosmin uptake in bone and distant metastases from malignant thymoma. 
There are several physical limitations to 201Tl. The energy emitted is lower, the half-life is longer and the radiation dose to the patient is relatively higher. Compared with 201Tl, 99mTc has some advantages over 201Tl such as higher emitted energy, shorter half-life, smaller radiation dose, larger injected dose and better image quality. 
As for the tumor-to-background (normal lung) ratio, in the planar images of case 1, the tumor-to-background ratio of the 99mTc-tetrofosmin (1.60) and 99mTc-MIBI (1.19) was superior to that of 201Tl (1.12). But the tumor-to-background ratio of the SPECT images, 99mTc-tetrofosmin (1.98) and 99mTc-MIBI (1.80) was inferior to that of 201Tl Cl (2.09). In the planar images of case 2, the tumor-to-background ratio of the 99mTc-tetrofosmin (2.31) was inferior to that of 201Tl (2.45) and in the SPECT images the tumor-to-background ratio of the 99mTc-tetrofosmin (2.78) was also inferior to that of 201Tl (3.58). The 201Tl tumor-to-background ratio was greater than that of 99mTc-tetrofosmin. This might be due to 99mTc-tetrofosmin showing higher uptake than 201Tl in the normal lung. The 99mTc-tetrofosmin tumor-to-background ratio was greater than that of 99mTc-MIBI, and this might be due to 99mTc-tetrofosmin being cleared faster than 99mTc-MIBI19 from both the lungs and liver. Despite the better physical properties and imaging quality of 99mTc, it is disappointing that 99mTc-tetrofosmin did not always outperform 201Tl in the tumor-to-background ratio. But 99mTc-tetrofosmin was judged to be comparable to 201Tl on visual estimation and almost comparable to 201Tl as to its tumor-to-background ratio also. 
The early tumor-to-background ratios calculated from 99mTc-tetrofosmin planar and SPECT imagings were higher than the delayed ratios, suggesting that the early imaging with 99mTc-tetrofosmin might be the better choice for detecting malignant thymoma. 
201Tl is a K+ analogue. The uptake of 201Tl by cells is related to cell membrane potential and Na+, K+ ATPase activity and might involve other K+ channels.20,21 201Tl remains in the cytosolic compartment,21 whereas 99mTc-MIBI is localized mostly inside mitochondria due to negative mitochondrial membrane potential.22,23 99mTc-tetrofosmin is a monovalent lipophilic cation that rapidly enters the myocardial cells due to its lipophilic properties.24,25 The uptake of both 99mTc-tetrofosmin and 99mTc-MIBI is related to the Na+, K+ pump, and Na+/K+ antiport systems.26 
The mechanism of uptake of 99mTc-MIBI and 99mTc-tetrofosmin into malignant cells and its exact localization are not yet clear. The uptake of both tracers is known to depend on regional blood flow and on the mitochondrial content,27 because 99mTc-MIBI and 99mTc-tetrofosmin in vitro studies,28 appear to indicate that there is a connection with the multidrug resistance of P-glycoprotein, the 170-kDa protein coded by MDR1 (mammalian multidrug resistance gene). In addition, it was reported that accumulation of 99mTc-tetrofosmin in breast tumor cells in vitro is related to a p-glycoprotein similar to 99mTc-MIBI.28 
The chemosensitivity of a tumor is important for its management. Increased expression of transmembranous p-glycoprotein, the product of multidrug resistance 1 gene, has resulted in multidrug resistance. The multidrug resistance p-glycoprotein system functions as an energy dependent efflux pump which reduces the amount of intracellular transporting cytotoxic agents, MIBI and tetrofosmin, in tumor cells. The accumulations of 99mTc-MIBI and 99mTc-tetrofosmin are inversely proportional to the level of p-glycoprotein expression.29-31 Therefore the accumulation of 99mTc-tetrofosmin in tumors provides us not only with the localization of the primary tumor and metastatic lesions but also the chemosensitivity of the tumor, which may predict the response to chemotherapy and selection of therapy management. 
In conclusion, 99mTc-tetrofosmin imaging would be helpful in detecting both the primary tumor and metastatic lesions from malignant thymoma. Further investigations and larger clinical trials are needed to justify the potential usefulness of this tracer as a tumor detecting imaging agent. 
REFERENCES 
1. Ishibashi M, Nishida H, Hiromatsu Y, Kojima K, Tabuchi E, Hayabuchi N. Comparison of technetium-99m MIBI, technetium-99m-tetrofosmin, ultrasound and MRI for localization of abnormal parathyroid glands. J Nucl Med 39: 320-324, 1998. 
2. Rambaldi PE, Mansi L, Procaccini E, Di Gregorio F, Del Vecchio E. Breast cancer detection with 99mTc-tetrofosmin. Clin Nucl Med 20: 703-705, 1995. 
3. Mansi L, Rambaldi PF, Procaccini E, Di Gregorio F, Laprovietera A, Pecori B, et al. Scintimammography with technetium-99m tetrofosmin in the diagnosis of breast cancer and lymph node metastases. Eur J Nucl Med 23: 932-939, 1996. 
4. Takayama T, Kinuya S, Sugiyama M, Hashiba A, Takeda R, Tonami N. 99mTc-tetrofosmin uptake in bone metastases from breast cancer. Ann Nucl Med 12: 293-296, 1998. 
5. Basoglu T, Sahin M, Coskun C, Koparan A, Bernay I, Erkan L. Technetium-99m-tetrofosmin uptake in malignant lung tumours. Eur J Nucl Med 22: 687-689, 1995. 
6. Matsunari I, Kinuya S, Nishikawa T, Matoba M, Murakita K, Ohguchi M, et al. Technetium-99m tetrofosmin uptake in lung cancer: comparison with thallium-201. Ann Nucl Med 10: 143-145, 1996. 
7. Schillaci O, Danieli R, Tavolaro R, Scopinaro F. 99mTc-tetrofosmin accumulation in lung cancer and its metastases. Clin Nucl Med 22: 46-47, 1997. 
8. Takekawa H, Takaoka K, Tsukamoto E, Kanegae K, Kozeki Y, Yamaya A, et al. Visualization of lung cancer with 99mTc-tetrofosmin imaging: comparison with 201Tl. Nucl Med Commun 18: 341-345, 1997. 
9. Kosuda S, Yokoyama H, Katayama M, Yokokawa T, Kusano S, Yamamoto O. Technetium-99m tetrofosmin and technetium-99m sestamibi imaging of multiple metastases from differentiated thyroid carcinoma. Eur J Nucl Med 22: 1218-1220, 1995. 
10. Lind P, Gallowitsch HJ, Langsteger W, Kresnik E, Mikosch P, Gomez I. Technetium-99m-tetrofosmin whole-body scintigraphy in the follow-up of differentiated thyroid carcinoma. J Nucl Med 38: 348-352, 1997. 
11. Kostakoglu L, Uysal U, Ozyar E, Demirkazik FB, Hayran M, Atahan L, et al. A comparative study technetium-99m sestamibi and technetium-99m tetrofosmin single-photon tomography in the detection of nasopharyngeal carcinoma. Eur J Nucl Med 24: 621-628, 1997. 
12. Soderlund V, Jonsson C, Bauer HCF, Brosjo O, Jacobsson H. Comparison of technetium-99m-MIBI and technetium-99m-tetrofosmin uptake by musculoskeletal sarcomas. J Nucl Med 38: 682-686, 1997. 
13. Tonami N, Shuke N, Yokoyama K, Seki H, Takayama T, Kinuya S, et al. Thallium-201 single photon emission computed tomography in the evaluation of suspected lung cancer. J Nucl Med 30: 997-1004, 1989. 
14. Fukuda T, Itami M, Sawa H. A case of thymoma arising from undescending thymus-high uptake of thallium-201 chloride. Eur J Nucl Med 5: 465-468, 1980. 
15. Aktolun C, Bayhan H, Kir M. Clinical experience with Tc-99m MIBI imaging in patients with malignant tumors, preliminary results and comparison with Tl-201 . Clin Nucl Med 17: 171-176, 1992. 
16. Waxman A, Nagaraj N, Ashok G. Sensitivity and specificity of Tc-99m methoxy isobutyl isonitrile (MIBI) in the evaluation of primary carcinoma of the breast: Comparison of palpable and nonpalpable lesions with mammography. J Nucl Med 35: 22, 1994. 
17. Ziegels P, Nocaudie M, Hugo D, Deveaux M, Detourmignies L, Wattel E, et al. Comparison of technetium-99m-methoxyisobutylisonitrile and gallium-67 citrate sacnning in the assessment of lymphomas. Eur J Nucl Med 22: 126-131, 1995. 
18. Isibashi M, Fujimoto K, Ohzono H, Meno S, Hayabuchi N. 99mTc tetrofosmin uptake in mediastinal tumours. Brit J Radiol 69: 1134-1138, 1996. 
19. Higley B, Smith FW, Smith T, Gemmell HG, Gupta PD, Gvozdanovic DV, et al. Technetium-99m-1,2-bis[bis(2-ethoxyethyl)phosphino]ethane: Human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. J Nucl Med 34: 30-38, 1993. 
20. McCall D, Zimmer LJ Katz AM. Kinetics of thallium exchange in culture rat myocardial cells. Cir Res 56: 370-376, 1985. 
21. Brismar T, Collins VP, Kesselberg M. Thallium-201 uptake relates to membranous potential and potassium permeability in human glioma cells. Brain Res 500: 30-36, 1989. 
22. Piwnica-Worms D, Kronauge JF, Delmon L. Uptake and retention of hexakis(2-methoxyisobutyl isonitrile)technetium(I) in cultured chick myocardial cells. Circulation 82: 1926-1938, 1990. 
23. Carvalho PA, Chiu ML, Kronauge JF. Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts. J Nucl Med 33: 1516-1521, 1992. 
24. Kelly JD, Forster AM, Higley B. Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med 34: 222-227, 1993. 
25. Mousa SA, Williams SJ, Sands H. Characterization of in vivo chemistry of cations in the heart. J Nucl Med 28: 1951-1957, 1987. 
26. Arbab AS, Koizumi K, Toyama K, Arai T, Araki T. Ion transport systems in the uptake of 99mTc-tetrofosmin, 99mTc-MIBI and 201Tl in a tumour cell line. Nucl Med Commun 18: 235-240, 1997. 
27. Platts EA, North TL, Pickett RD. Mechanism of uptake of technetium-99m tetrofosmin. 1: uptake into isolated adult rat ventricular myocytes and subcelluar localization. J Nucl Med 37: 1578-1582, 1996. 
28. Ballinger JR, Banneman J, Boxen I. Technetium-99m-tetrofosmin as a substrate for p-gycoprotein: in vitro studies in multidrug-resistant breast tumor cells. J Nucl Med 37: 1578-1582, 1996. 
29. Cordobes MD, Starzec A, Delmon-Moingeon L. Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression. J Nucl Med 37: 286-289, 1996. 
30. Del Vecchio S, Ciarmiello A, Potena MI. In vivo detection of multidrug-resistant (MDRI) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients. Eur J Nucl Med 24: 150-159, 1997. 
31. Fujii H, Nakamura K, Kubo A, Enomoto K, Ikeda T, Kubota T, et al. Preoperative evaluation of the chemosensitivity of breast cancer by means of double phase 99mTc-MIBI scintimammography. Ann Nucl Med 12: 307-312, 1998.