European Nuclear Medicine Guide
2- [99mTc]Tc-methoxyisobutylisonitrile ([99mTc]Tc-sestamibi)
[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 sequestered and passes the mitochondrial membrane, using a different electrical gradient, remaining sequestered by the large negative transmembrane potentials. In malignant tumors, mainly when showing an increased growing rate and an enhanced metabolic activity, a higher early uptake of MIBI can be determined through an augmented blood flow, in presence of a rise in the electrical gradient of the mitochondrial membrane compared to normal cells. The latter behaviour could probably be involved also in the slower wash-out, more frequently observed in malignant nodules [6,7].
More in-depth in vitro and in vivo oncological studies have been conducted in breast cancer, demonstrating that the uptake and clearance of MIBI, the latter calculated comparing early and delayed scans, are correlated with histological, molecular and biochemical markers and may give information on various cellular processes, such as apoptosis, proliferation, P-glycoprotein (P-gp) expression and neoangiogenesis. While the early uptake reflects the mitochondrial status, affected by both apoptosis and proliferation, the clearance depends on the activity of drug transporters such as P-gp (8). For these reasons, MIBI has been proposed to evaluate a priori multidrug resistance (MDR) in many neoplasms, tracing the expression of MDR-related proteins (such as P-gp and Bcl-2), also providing useful information in patients undergoing radiotherapy or radioiodine therapy (9-12).
Concerning thyroid diseases, since the MIBI uptake mechanism is different from that of the iodomimetic radiotracers and independent of TSH (Thyroid-Stimulating Hormone) (13,14), its use may be linked to conditions in which a reduced or absent uptake of these radiotracers is determined. Therefore, the use of [99mTc]Tc-sestamibi is indicated in presence of a pharmacological interference for Sodium Iodide Symporter (NIS) dependent radiotracers, i.e. radioiodine and [99mTc]Tc-pertechnetate, occurring [99mTc]Tc-sestamibi concentration exclusively in the presence of viable cells, a reduced or absent uptake at the level of a thyroiditis with cellular destruction is observed. (15)
In the 1990s, MIBI scintigraphy was widely adopted for the differential diagnosis of hypofunctioning thyroid nodules, as identified by conventional scintigraphy, that appeared solid on ultrasound (US). In particular, it was demonstrated that an absent or low uptake of MIBI may exclude malignancy, because of a high negative predictive value (NPV). Unfortunately, a great number of false positive results were evidenced in concentrating nodules (16,17). Therefore, the procedure has been almost completely abandoned, especially due to the progress of US and cytology.
Interestingly, there is no competition of [99mTc]Tc-sestamibi with [18F]FDG PET/CT which has found a role, in the management of patients who have already been diagnosed with thyroid carcinoma, as a prognostic negative marker in characterizing dedifferentiated neoplastic lesions. On the contrary, [99mTc]Tc-sestamibi presents more favourable physiopathological premises in the first diagnosis of malignancy, since thyroid neoplasms are almost all well differentiated. This means that their increase in growth and metabolism develops in an oxygen-dependent context, traced by [99mTc]Tc-sestamibi better than by FDG. In fact, being neo-angiogenesis, glycolysis and hypoxia rarely present at the clinical onset of the thyroid neoplastic disease, FDG doesn’t allow a reliable differentiation at the time of first diagnosis.
More recently, the application of [99mTc]Tc-sestamibi has been re-considered as a useful procedure in a small number of well recruited patients. When the examination is applied as a second diagnostic line exclusively on patients who meet strict inclusion criteria, a satisfactory diagnostic accuracy can be achieved. In particular, because of the different kinetics of [99mTc]Tc-sestamibi between neoplastic and normal cells, mainly involving the role of mitochondria, a reliable diagnosis of malignancy can be attained when comparing early and delayed scans and a wash out rate is calculated. On the basis of different pharmacokinetics, a slower wash out is generally observed in the case of malignant tumors (18-20)
[99mTc]Tc-sestamibi is already routinely available in many departments for myocardial and/or parathyroid scintigraphy. Therefore, it may be immediately available also for the study of patients with thyroid pathologies.
Although the 2019 “EANM practice guideline/SNMMI procedure standard for RAIU and thyroid scintigraphy” (21) reported that “imaging with specific tracers such as 99mTc-sestamibi (99mTc-MIBI) and 18F-fluorodeoxyglucose (18FDG) may be useful in selected cases to help in discriminating benign from malignant thyroid nodules”, remaining this indication also in the “SNMMI Procedure Standard/EANM Practice Guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version”, published in 2022 (22), this technique has not been largely used in the clinical practice.
Nevertheless, the procedure has had a recent revival for two main reasons: 1) the spread of a non-oncological indication, linked to the study of functional thyroid diseases in patients in whom the uptake of iodomimetic radiotracers is made impossible by their lack of uptake, for example, as a result of a pharmacological interference (23-26); 2) the differential diagnosis of thyroid nodules, obtained by adopting a dual phase semi-quantitative procedure and defining a threshold, applying it to a restricted category of selected patients (18).
[99mTc]Tc-sestamibi as a surrogate for traditional thyroid scintigraphy, in case of pharmacological interference.
This procedure is an alternative to thyroid scintigraphy with Sodium Iodide Symporter (NIS) dependent radiotracers, i.e. radioiodine and [99mTc]Tc-perthecnetate, in the cases in which there is competition at the transporter level, and consequently interference on their concentration mechanism. This condition can be determined by an iodine load, as occurs after the administration of iodinated contrast media (25) or by drugs, such as amiodarone (26), which can also have a cytotoxic effect. Since the uptake of MIBI is not tissue-specific, its role in the characterization of a suspicious thyroid mass, especially in the thoracic region, is ancillary and always requires SPECT/CT for the necessary anatomical correlation. A possible indication of MIBI, rarely used, can be also found as ancillary whole body technique in patients undergoing therapy with radioiodine (27).
[99mTc]Tc-sestamibi in differential diagnosis of amiodarone-induced thyrotoxicosis
A suspicious hyperthyroidism may be present in patients undergoing chronic therapy with amiodarone. In these cases, thyroid scintigraphy with NIS-dependent radiotracers is not feasible, due to the absence of uptake from pharmacological interference. Together with US and haematochemical data, MIBI can be useful as a complementary procedure for differentiating amiodarone-induced thyrotoxicosis type 1 (AIT-1), which more frequently develops in patients with pre-existent thyroid pathology, because of the excessive iodine-induced hormone synthesis and release, compared to AIT-2, depending on a destructive thyroiditis, determined by a direct cytotoxic effect of the drug, generally on patients without underlying thyroid diseases. Using a quantitative approach, based on the comparison between early and delayed scan, also the mixed pattern AIT-3, characterized by the simultaneous presence of both AIT-1 and AIT-2, may be reliably identified, allowing the adoption of a more precise therapeutic strategy in all the patients (26).
[99mTc]Tc-sestamibi in differential diagnosis of thyroid cancer.
Having been proposed many years ago for the differential diagnosis of thyroid nodules, hypo-concentrating on traditional thyroid scintigraphy and solid at ultrasounds, the clinical indication of a thyroid scintigraphy with MIBI (i.e. molecular thyroid scintigraphy) has almost completely disappeared, due to an unsatisfactory diagnostic accuracy, mainly determined by a low specificity. Nevertheless, the procedure is still cited in the 2019 (21) and 2022 SNMMI-EANM guidelines (22), due to its high negative predictive value (NPV).
In the most recent years, interest has revived, as demonstrated by a multicentre European trial recruiting exclusively patients with nodules bigger than 1 cm, hypofunctioning at thyroid scintigraphy, EU-TIRADS 4 or 5 at US, Bethesda III/IV, i.e. with an indeterminate fine needle aspiration cytology (20). Furthermore, the application of a semi-quantitative method for evaluating wash out between early and delayed scans may increase specificity, and consequently diagnostic accuracy, stimulating the use of the procedure in selected patients without a diagnosis using a standard approach. Therefore, actually, the method is considered a valuable diagnostic tool in a well recruited restricted number of patients.
[99mTc]Tc-sestamibi in patients undergoing chemotherapy, radiotherapy and radiodine therapy.
This indication could be possible, as evidenced by information reported above in breast cancer, although MIBI has not yet been used for this purpose in patients with thyroid neoplasms. Its application to the small number of subjects undergoing chemo or radiotherapy, in the presence of undifferentiated thyroid tumors, could be particularly interesting. However, to justify this indication, it is clearly necessary to acquire confirmative data from in vitro and clinical research, which are not currently available.
The only absolute contra-indication is pregnancy.
Although many authors do not recommend stopping breastfeeding, it has been demonstrated that an interruption up to 4-24 h almost completely eliminates radiation to the infant. It is suggested to safely store breast milk beforehand, to continue breastfeeding even during any possible suspension [28].
[99mTc]Tc-sestamibi in differential diagnosis of amiodarone-induced thyrotoxicosis
As demonstrated in a multicentre trial (26), using a visual evaluation of early (10min) and delayed (60 min) scan, since the uptake of MIBI is linked to cell viability, differentiation between AIT-1 and AIT-2 will occur on the basis of a normal and/or increased uptake in the case of the first one, respect to a reduced and/or absent concentration in patients with the latter. Using a quantitative approach, based on the calculation of the wash-out index, a reliable individuation also of the mixed AIT-3 pattern, including both AIT-1 and AIT-2, may be achieved, giving important information in defining therapeutic strategies.
[99mTc]Tc-sestamibi in differential diagnosis of thyroid cancer.
As demonstrated in a recent European multicentre trial (20), including 358 patients with 365 nodules larger than 1 cm, best results and a consequent useful clinical role may be achieved when the procedure is applied only in patients with thyroid nodules hypo or iso-concentrating on traditional thyroid scintigraphy, with an EU-TIRADS ultrasound pattern 4-5, indeterminate on cytology (Bethesda III/IV). In the standard visual procedure, three MIBI patterns may be observed, with a nodular concentration lower (negative), equal (dubious) or higher (probably malignant) than the surrounding thyroid tissue. A MIBI negative pattern allows to exclude the presence of malignant tumors. Better results, because of an increased specificity, may be achieved comparing early (10 min) and delayed (60 min) scans and calculating a wash-out index (WOind). Using the WOind cut-off of -19%, proposed by Campennì and colleagues (18), the following results have been obtained: sensitivity 100%, specificity 90.9%, NPV 93%, PPV 80%, accuracy 100%. In other words, adopting this procedure in nodules concentrating MIBI, in presence of a WOind < 19%, a malignant tumor is highly suspicious.
The suggested activity to administer is
[99mTc]Tc-sestamibi: 370 MBq. Based on the adoption of more performing scanners, this dose can be reduced
In paediatric nuclear medicine, 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 (also less, when more advanced tools are available).
The effective dose coefficient is 0.009 mSv/MBq, corresponding to ~3.3 mSv for a standard 370 MBq administration.” [3]. The organ with the highest absorbed dose is the kidneys: 36 µGy/MBq and the gallbladder wall: 39 µGy/MBq.
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.".
[99mTc]Tc-sestamibi in differential diagnosis of amiodarone-induced thyrotoxicosis.
Since the concentration of the radiopharmaceutical presupposes cell viability, the AIT-1 pattern is characterized by a normal and/or increased uptake, compared to that of AIT-2, in which a reduced concentration is evident, as a consequence of a cellular damage. Using a quantitative procedure comparing early and delayed images, an AIT-3 pattern, including areas of AIT-1 and AIT-2, can be also defined.
[99mTc]Tc-sestamibi in differential diagnosis of thyroid cancer
The recruitment of patients has to be made only in presence of the inclusion criteria reported above. Using a qualitative visual analysis, three patterns may be individuated using MIBI: a) hypo-intense nodule: benign; b) iso-intense: malignancy is possible; c) hyper-intense: malignancy is probable.
Best results may be obtained using a quantitative procedure based on the wash-out analysis calculated between early and late scans. Adopting the ROC-derived threshold of -19%, in iso- and hyper-intense nodules a slow wash-out index individuate a malignant nodule at a high probability.
As further information, using a quantitative analysis a differential diagnosis may be obtained between follicular adenoma, showing a high wash-out, respect to oncocytic adenoma, presenting a slow WOind, probably because of differences in number and function of mitochondria.
None
In both major clinical indications, i.e. differential diagnosis of amiodarone-induced thyrotoxicosis and of the thyroid nodule, more important than spatial resolution is the two-point technique comparing early and delayed scans. In differential diagnosis of thyroid cancer, only nodules >1cm, already detected by traditional scintigraphy are evaluated. In this sense, planar images are preferable, SPECT being useful only in particular cases. SPECT/CT, characterized by a greater dosimetric load, is justified only in rare occasions, as in the case in which one intends to evaluate the thyroid nature of a mediastinal mass in patients in whom traditional scintigraphy is not performable.