European Nuclear Medicine Guide
2- [99mTc]Tc-methoxyisobutylisonitrile ([99mTc]Tc-sestamibi)
Na[99mTc]TcO4 or Na[123I]I, for dual-tracer imaging.
A. [99mTc]Tc-sestamibi ( [99mTc]Tc-tetrofosmin)
[99mTc]Tc-sestamibi (MIBI) is a lipophilic cation that, crossing the cell membrane by means of thermodynamic driving forces, enters reversibly into the cytoplasm for a passive distribution. Then, the radiocompound is strongly retained or sequestered due to the large negative transmembrane potential and passes the mitochondrial membrane, using a different electrical gradient, remaining sequestered by the large negative transmembrane potentials. Uptake mechanisms in tumors and thyroid are described in chapters 8.4 and 10.10 [6, 7, 29-32].
MIBI uptake is normally noted both in thyroid and parathyroid, the latter showing a greater uptake for gram of tissue. An increased activity is generally observed in hyper-functioning parathyroid(s), because of the high number of mitochondria, mainly due to the presence of oxyphil cells [33-35].
As for thyroid nodules, [99mTc]Tc-MIBI uptake, retention and wash-out are dependent on the pathophysiological parameters reported in bibliography [6, 7, 29-32, 36], with a faster wash-out in thyroid respect to hyper-functioning parathyroid. Therefore, better results may be obtained using a dual-phase acquisition (i.e. dual-phase single tracer parathyroid scintigraphy); in rare individual cases, not showing this differential behaviour [37], a SPECT/CT (preferred to SPECT alone) is required to increase the diagnostic performance [38-41].
Based on the different distribution of MIBI, captured both by thyroid and parathyroid, and iodomimetic radiotracers, concentrated only in thyroidal tissue, a dual phase double tracer parathyroid scintigraphy, associated with subtraction technique, is also suggested to highlight intra-thyroidal parathyroid lesions. Using this approach, a rigorous methodology is mandatory to avoid artefacts and consequent diagnostic errors.
A difficult analysis of parathyroid pathologies may be determined by the concomitant presence of a multinodular goiter, in presence of thyroid nodules concentrating MIBI. Although there are no accurate differential criteria to distinguish between concentrating thyroid or intra-glandular parathyroid nodules, the identification of the parathyroid lesion can sometimes be aided by US and/or with SPECT/CT. SPECT/CT is particularly useful in the evaluation of ectopic lesions and/or in patients with altered neck anatomy [38-41].
Having been proposed in 80’s, using Tl-201 chloride [42], parathyroid scintigraphy with technetiated radiotracers started to be performed in the 90s, also using, as alternative to MIBI, [99mTc]Tc-tetrofosmin, a lipophilic cation with a similar pharmacokinetics to MIBI, in presence of some differences, mainly in wash-out [43-46]. Since tetrofosmin is less commonly used for parathyroid imaging, everything described below will concern MIBI, unless specifically stated.
B. Radiotracers for Thyroid scintigraphy (sodium iodide symporter (NIS) radiotracers)
As subtraction radiotracers, utilized for the associated thyroid scintigraphy, may be used:
[99mTc]pertechnetate , taken up by thyroid but not organified.
Na[123I]I, showing an organ/background ratio higher than for Na[99mTc]TcO4, is concentrated by functioning thyroid tissue and organified.
Further information may be acquired either in the chapters 8.1 and 8.2, concerning Thyroid Scintigraphy with NIS radiotracers, and in the EANM practice guideline/SNMMI procedure standard for RAIU and thyroid scintigraphy [47].
Detailed indications and recommendations for parathyroid scintigraphy with MIBI are available in the 2021 EANM practice guidelines for parathyroid imaging [48] and in the paper « An essential practice summary of the new EANM guidelines for parathyroid imaging ». [49]
At the present, in accordance with chapter 8.6: Parathyroid PET with choline / methionine, PET radiotracers may be preferred, when available, mainly when ectopic intrathoracic adenomas or lesions lower than 1 cm are suspected.
MIBI finds its main indications in patients affected by primary-hyperparathyroidism. A cost/effective choice may be taken in account, considering the clinical picture, the diagnostic question, or the department schedule, in case the PET exam requires longer waiting times. Planar parathyroid scintigraphy coupled with SPECT/CT remains indicated as premise to a radioguided surgery.
MIBI indications approved by the European Medicines Agency (EMA), are the following:
Preoperative localization of hyperactive parathyroid(s) in patients with established primary hyperparathyroidism or tertiary hyperparathyroidism (tHPT) in patients with chronic kidney disease) in nephropathic patients.
In patients undergoing first minimally invasive or unilateral neck exploration in pHPT and in those undergoing reoperation for persistent or recurrent pHPT. Also, parathyroid scintigraphy may help to distinguish between patients suitable for minimally invasive surgery and those who require bilateral neck exploration. In sHPT (or tHPT), because of a lower sensitivity, the indication may depend on the surgeon’s preferences. If bilateral neck exploration is performed as primary operation, imaging may not contribute significantly, as the exploration of all parathyroids during surgery is however required. Instead, an intraoperative PTH assay may help to determine the success of the surgery. In case of reoperation, imaging may help to better guide the surgeon.
The only absolute contra-indication is pregnancy.
Although stopping breastfeeding is not recommended, an interruption up to 24 h almost completely eliminates radiation to the infant. In case of suspension, to safely store breast milk beforehand is suggested to continue breastfeeding even during suspension. This strategy may be indicated mainly when Na[99mTc]TcO4, requiring a 12-h interruption, or Na[123I]I administration, which obliges the suspension of breastfeeding, for at least 3 weeks [50,51].
As reported by G. Treglia [51], the pooled detection rate of MIBI-SPECT/CT in the preoperative planning of patients with PHPT is 88% (95% CI = 84% to 92%) and 88% (95% CI = 82% to 92%) on a per patient-based and per lesion-based analysis, respectively.
Further information can be derived from the chapter 8.6: Parathyroid PET with choline/methionine, in which the MIBI data are compared with those obtained with PET.
The suggested activities to administer are:
[99mTc]Tc-sestamibi: 400-500 MBq
For dual tracer imaging, Na[99mTc]TcO4: 185-444 MBq and 123I NaI: 7.5-22 MBq. [88]
In paediatrics, the activities should be modified according to the EANM paediatric dosage card (https://www.eanm.org/publications/dosage-calculator/). The minimum recommended activity to administer is 80 MBq.
The doses can be lowered up to 50%, when advanced tools, equipped with more sensitive detectors, are available.
The effective dose for MIBI is 9.0 µSv/MBq, with the highest organ absorbed dose at kidneys (36 µGy/MBq) and gallbladder (39 µGy/MBq). The effective dose for Na[123I]I is 150 µSv/MBq (iv administration) [50], with the highest absorbed dose at the thyroid (2.7 mGy/MBq). The range in effective dose for MIBI is 4.5-6.3 mSv per single procedure and 1.7-4.0 mSv due to the reduced MIBI component in a dual-tracer protocol imaging procedure. The radiation exposure defined above is reduced when more sensitive advanced tools are available, allowing the administration of lower activities. The contribution of X-rays has to be calculated when a SPECT/CT is used.
Caveat:
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Also a single-head gamma camera can be used for planar images which must include anterior views of the neck and the upper thorax in all cases. Early (10–15 min post-injection) and delayed (1.5–2.5 h) high count images are obtained. Additional SPECT/CT considerably improves the interpretation of findings of individual procedures, with main reference to the evaluation of ectopic thoracic nodules and lesions lower than 1 cm.
Any extra-physiological focus of MIBI uptake in neck/mediastinum (planar/SPECT) is rated as positive, however readers should take into consideration possible false positive findings like: thyroid nodules with MIBI uptake, lymph nodes, brown fat, thymus, salivary tissue, muscle. To increase accuracy a careful correlation between SPECT and US is suggested. Corresponding nodule(s) in the CT part of SPECT/CT increases specificity. Subtraction analysis: any focus of MIBI uptake after subtraction is rated as positive. Major Pitfalls are proliferating thyroid nodules.
Discontinuation of either thyrostatic drugs (thiamazol, methimazole or propylthiouracil) or L-T4 is recommended if dual phase or dual tracer (subtraction) protocol is used, because they reduce iodine-mimetic tracer uptake in the thyroid. One-week drug withdrawal is generally sufficient but a longer period should always be considered, if possible, in patients with a long history of L-T4 treatment (especially if serum TSH is (sub)-suppressed) or when propylthiouracil is used. Similarly, iodine-containing contrast media should be avoided for at least 6 weeks before dual tracer imaging.
No preparation for dual-phase MIBI parathyroid scintigraphy is needed. However, the use of calcium channel blockers may influence MIBI uptake in parathyroid parenchyma; a careful medication history is always recommended.
The detailed recommendations are available in the 2021 EANM parathyroid guidelines [38].