Figure 2. 50-year-old patient with papillar thyroid carcinoma, negative posttherapeutic 1311-WBS 10 days after a treatment dose of 5550 MBq, thyroglobulin 25 ng/ml. FDG PET coronal slice showing a small lesion in the right neck (arrow) that proved to be a small metastasis of papillary thyroid cancer.
Similar to other neuroendocrine tumors as described above, uptake of FDG appears to be low, and theoretically radiolabeled amino acids might perform better in these calcitonin producing tumors (75). Preliminary experience using C11-methionine does not seem to confirm this expectation (76). Recent experience with the catecholamine precursor amino acid 18F-DOPA and PET appears to be more promising. In a small group Hoegerle found more lymph node metastases ofMTC. using l8F-DOPA PET than with any other modality (77). Also lsF-DOPA PET was reported to be able to detect a medullary thyroid cancer lesion in a MEN2a patient (78).
Thallium-201 (Tl-201) is a potassium analogue. This positively charged ion is actively transported over the cell membrane by an ATP-dependant sodium/potassium transport system and localizes non-specifically in thyroid cells, as well as in other tissues with high cellularity and high perfusion. Additional mechanisms of entry have not been excluded. Originally Tl-201 has been developed for myocardial perfusion imaging, for which it is still routinely used, but it also accumulates in kidney, stomach, liver, spleen, testes, salivary glands, large bowel and in thyroid tissue (79). Several reports have suggested that comparison between early and delayed Tl-201 images could distinguish between benign and malignant thyroid diseases, but usually results in benign and malignant tissues overlap and have not lead to sound clinical application (80,81).
Tl-201 is an isotope that decays by electron capture to Mercury-201. Mercury 201 emits characteristic gamma rays of 68-90 keV and much smaller amount of gamma rays of 135 keV and 167 keV. The half-life of Tl-201 is 73.1 hours. Tl-201 is normally administered as thallium chloride and rapidly disappears from the blood with a half-life between 30 seconds and 3 minutes. Peak uptake in the thyroid occurs 5-10 minutes after injection.
The relative long half-life and the poor physical characteristic of the radiopharma-ceutical limit the injected dose (3-5 mCi). The low photon energy causes a relatively large radiation burden and is also less suitable for imaging, because of scattered and absorbed radiation. This results in low image quality.
Tl-201 imaging for thyroid cancer does not require withdrawal of thyroid hormones or restriction of iodine intake. Imaging, using a low-energy collimator, is usually performed 10-20 minutes after intravenous injection of Tl-201, because at that time tumor/background ratio is highest. The accumulation in tumoral tissues remains constant between 20-60 minutes. Supine anterior and posterior whole-body scans are acquired. Additional or delayed images can be obtained 3-4 hours postinjection to differentiate malignant tissues (slower washout) from benign tissues (82).
The primary value of Tl-201 is the analysis of patients with a negative scan and elevated thyreoglobulin levels. Several studies discuss the usefulness of Tl-201 in the localization of metastatic disease (83,84,85,86). The combination of 1311 with Tl-201 scintigraphy resulted in a sensitivity for recurrent tumor of 90-100% at a specificity of 95%-100%. Adding also the information from thyroglobulin measurements even further increases diagnostic yield. Tl-201 alone generally depicts approximately half of all thyroid cancer lesions. Few reports have specifically addressed the value of Tl-201 scintigraphy in patients with negative 1311 scans.
Tl-201 scintigraphy seems to be most value in the localization of local metastases and in mediastinal lymph nodes. Sensitivity has been reported between 55-94%, specificity between 82-97% (85,86,87). The large variety in sensitivity can be attributed to the different methods of disease confirmation, the variability in location of metastases and the different selection of the patients.
Although most published studies were performed with planar images, SPECT imaging shows a 25% increase in sensitivity, especially for chest, neck and micronodular pulmonary metastases (88).
In the small study of Shiga et al. (89) Tl-201 scintigraphy seems to provide similar information in the detection of metastatic lesions after total thyroidectomy compared with FDG-PET.
There have been several studies of Tl-201 uptake in medullary thyroid carcinoma, most of them with a limited number of patients and in comparison with DMSA-V or
MIBG. The non-specific uptake of this tracer in background tissues and low tumoral uptake probably cause the relatively low sensitivity. DMSA-V scintigraphy has shown to be clearly superior to Tl-201 (90). Another study showed Tl-201 superior to MIBG. Although non-specific, Tl-201 may be be useful in individual clinical setting.
Although only limited comparison data of FDG PET and Tl-201 scintigraphy are available, but FDG PET is considered to be clearly superior.
TECHNETIUM-99M-SESTAMIBI (METHOXY-ISOBUTYL-ISONITRILE) General mechanism
Technetium-99m-sestamibi (Tc-99m-sestamibi) is a lipophilic cationic agent that primary localizes in the mitochondria.Tc-99m-sestamibi accumulates in the mitochondria secondary to a negative potential of the mitochondria. Tc-99m-sestamibi uptake is driven by a negative transmembrane potential and up to 90% of the intracellular tracer is found in the mitochondria. The uptake is an energy dependant process. Tc-99m-sestamibi is also a substrate for the transmembrane P-glycoprotein drug efflux pump (91).
The affinity for mitochondria probably generates the specific uptake in Hurthle cell carcinoma, which is often poorly iodine concentrating, but rich in mitochondria. Similar to Tl-201, Tc-99m-sestamibi uptake in thyroid cancer cell is independent of TSH stimulation, although one report mentioned a TSH dependent uptake (92).
Tc-99m-sestamibi is obtained by elution from a Tc generator, which contains the parent isotope molybdenum-99 (Mo-99). Mo-99 is a radionuclide with a half-life of 66 hours. The isolated 140 keV gamma emission of Tc-99m is ideally suited for gamma camera imaging. The 6 hr halflife is very convenient for radiopharmaceutical production on a day to day basis. The commercial production of generators, which can be eluted up to 1 week, make Tc99m very easily available. These factors make Tc-99m the most used radioisotope in nuclear imaging in general. A kit preparation for radiolabeling of Tc-99m to sestamibi is commercially widely available.
Tc-99m-sestamibi scintigraphy does not require any patient preparation and no thyroid hormone withdrawal. The favorable scan characteristics and the relative short half-life of Tc-99m (6 hours) in comparison to 131I (8 days) enable the use of relatively larger doses which increases image quality. This is a clear advantage over Tl-201.
Imaging is usually performed early, 10-30 minutes after tracer administration, and repeated 3 hours later. Others only image 60 minutes p.i., which might be less sensitive.
Tc-99m-sestamibi is only applied in papillary and follicular thyroid carcinoma.
The application of Tc-99m-sestamibi scanning is in patients with a negative 131-scan and an elevated thyroglobulin. In many instances Tc-99m-sestamibi has shown predilection to concentrate in the same abnormal sites as Tl-201.
Tc-99m-sestamibi scanning is particularly sensitive for the detection of nodal metastases. One study reported more sensitivity than high doses 1311 (93), another found the lowest sensitivity for lung metastases (94). Especially in high risk patient with a negative 1311 scan a combination of MIBI and ultrasound may be useful in detecting lymph node metastases (95).
The data about the clinical application in thyroid cancer and value of Tc-99m Tetro-fosmin, Tc-99m Pertechnate, Tc-99m Furifosmin is very limited and the results are conflicting. All three tracers are characterized by accumulation in the mitochondria by a different and not clearly understood mechanism.
Of the limited published data on Tc-99m tetrofosmin high sensitivities are mentioned (>85%) (96,97) in papillary and follicular thyroid carcinoma. No additional value is found in medullary thyroid carcinoma (90).
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