European Nuclear Medicine Guide
[99mTc]Tc-2-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 radiopharmaceutical irreversibly passes the mitochondrial membrane, using a different electrical gradient, remaining sequestered by the large negative transmembrane potentials. In malignant tumours, 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 the presence of a rise in the electrical gradient of the mitochondrial membrane compared to normal cells [271,272]
More in-depth in vitro and in vivo oncological studies have been conducted in breast cancer, demonstrating that MIBI’s uptake and clearance, 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. Being high the first pass extraction, allowing a study also few minutes after the i.v. injection, a wash-out may be observed when comparing initial and delayed scans. 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 (3). For these reasons, MIBI has been proposed to evaluate a priori multidrug resistance (MDR) to some chemotherapeutic drugs, tracing the expression of MDR-related proteins (such as P-gp and Bcl-2), also providing useful information in patients undergoing radiotherapy (273-276).
Occurring MIBI’s concentration exclusively in the presence of viable cells, a reduced or absent uptake at the level of fibrosis, necrosis and/or a-cellular lesions is observed. This behaviour has been also observed using[99mTc]Tc-tetrofosmin, utilized in 90’s for the same purposes, showing a similar, but not fully overlapping uptake mechanism (277- 280).
The clinical role of a procedure depends not only on its own capabilities, but also on the limits of the methods competing to give the same answer. Furthermore, a possible indication may be found in defining an original contribution, not only in diagnosis, but also for other indications, such as prognostic stratification and relationship with therapy.
The diagnosis of breast cancer until the 90s was centered almost exclusively on the use of Digital Mammography (Mx), at the time predominantly analogue, in a context in which both ultrasounds and cytology did not contribute to completely resolve all the diagnostic questions. Likewise, Magnetic Resonance (MRI) was not yet widely applied as functional technique and/or using contrast media. Therefore, Scintimammography (SMM) with MIBI or [99mTc]Tetrofosmin, found a wide diffusion in indefinite cases after a standard evaluation (281- 286). Since, at the present, Tetrofosmin is no longer used for this purpose, we will focusalmost exclusively on breast imaging with MIBI, Molecular Breast Imaging (MBI), when performed with advanced dedicated machines (see below).
The advantage of SMM is linked to its independence from the density of the breast tissue, with the ability to evaluate also the post-surgical and radiotherapy condition, which is difficult to study with alternative methods, when searching for local recurrence. Furthermore, being the positivity connected to an increased uptake, in the presence of a low or absent concentration in the normal breast, a favourable tumour/background ratio may be achieved, allowing detection, in some cases, of lesions under 1 cm also using standard gamma cameras. MIBI may also allow a whole body evaluation, which led to the possibility of identifying metastases at level of lymph nodes of the axilla and of the internal mammary chain, being detectable also other involved lymph nodes and distant metastases.
Based on the diagnostic scenario present in the 90s, main clinical indications for SMM were identified by Food and Drug Administration (FDA) as a second-line procedure after Mx, in the evaluation of undiagnosed breast lesions, and by the European Medicines Agency (EMA), for detection of suspected breast cancer when Mx was equivocal, inadequate, or indeterminate. A possible role was also suggested to diagnose local tumour relapse after surgery and/or radiotherapy, i.e. in a critical condition to be assessed with traditional techniques. Although affected with a low sensitivity in this context, SMM was also proposed in detecting non-palpable and/or occult breast tumours (287). Since the sentinel node technique was not yet widespread and FDG-PET was dedicated to other indications, another application was proposed in staging, with particular attention to lymph node involvement. A further indication was suggested in evaluating locally advanced breast cancer and tumour response to therapy. Despite its capability to study apoptosis, proliferation and the activity of drug transporters, the proposal to use MIBI , as tracer of the expression of MDR-related proteins (such as P-gp and Bcl-2), didn’t find a wide diffusion, also because of conflicting results (288).
In the actual scenario, also competing radionuclide procedures, such as lymph node sentinel’s technique, which has acquired a primary role in staging, and PET have been widely applied. In particular, FDG-PET demonstrated a comparable and/or better capability with respect to MIBI in evaluating advanced breast cancer and/or tumour response, finding a role in prognostic stratification, staging and follow up, mainly because of a superior whole-body analysis. Using FDG, a more precise and accurate breast analysis can be obtained using dedicated machines (Positron Emission Mammography, PEM), while new radiotracers have been introduced, such as F-18 Fluoro-estradiol (FES), useful for prognostic characterization and the relationship with therapy (289, 290)
In agreement with alternative methods, even SMM with gamma emitters, currently performed almost exclusively with MIBI, has had a methodological implementation, expressed at first with the adoption of new scanners allowing a higher sensitivity (289-291). One technological improvement has been obtained by using compact single head flat detector systems with compression panel of breast tissue. In this way, an increased sensitivity has been obtained either optimizing the distance between lesion and detector and improving image quality by reducing breast motion and by decreasing scatter events from myocardium and liver. Even more effective has proven to be the adoption of a dual-panel detector system, utilizing cadmium zinc telluride (CZT) detectors. The introduction of technologically advanced dedicated devices has determined the birth of the new definition, “molecular mammography”. More precisely, the term molecular breast imaging (MBI) may be applied to all nuclear medicine and advanced MRI techniques for breast imaging. Nevertheless, this definition is mainly associated with MIBI studies, when performed with dedicated breast scanners, utilizing dual-head solid-state cadmium-zinc-telluride (CZT) detectors and innovative collimators. Using these tools, an improved spatial resolution, shorter imaging times, and lower-activities may be administered. A new era for SMM, now MBI, opens (292-295).
In particular, MBI is able to detect a higher number of lesions smaller than 1 cm, although diagnosis of tumours less than 0.5 cm remains critical in the majority of cases. Therefore, MBI can find a clinical role also as a second line integration to standard techniques, i.e. Mx (or Tomosynthesis) and US, in screening of breast cancer, being competitive with respect to PEM and standard MRI. Nevertheless, MRI, including functional sequences and contrast medium, remains the first choice in individuals with breast implants or in women with genetic risk of breast cancer, not diagnosed with Mx and US.
The entry into the market of several stereotactic biopsy devices, based on MIBI scintigraphic techniques, has allowed the birth of an innovative biopsy technique (296-298), guided on the most active viable part of the breast lesion, quite possibly the most malignant. This procedure is competitive respect to the corresponding MRI guided biopsy, affected by higher costs and a major technical complexity.
Using MIBI, positivity is defined by the presence of a focal concentration in lesions with metabolically active cells. With respect to histopathology, negative results may be observed in slow growing tumours, mainly in presence of a low cellularity, such as in pure mucinous carcinoma. In lesions under 1-2 cm, false negatives are more probably due to invasive lobular carcinomas and invasive ductal carcinomas, being high the rate of undetectable carcinomas when in situ. A greater concentration is generally associated with a higher probability of malignancy. False negative results are mainly observed in presence of subcentimetric tumours and are dependent on spatial resolution of the used device, being less numerous in MBI, which present better performances. Sensitivity is also influenced by cellularity, growing rate, histology and by the spatial configuration of the cancer cells, a tumour being more easily detectable as a mass and not as a layer (7,8). Using MBI, the evaluations of tumours adherent to the chest wall or in axilla is more difficult for technical problems.
Although quantitative methods have been proposed (299) there are currently no reliable methods or thresholds to differentiate benign from malignant lesions. Since MIBI’s uptake may be also present in metabolically active non-malignant cellular lesions, false positive results may be observed more frequently in the following cases: a) Benign conditions, such as fibroadenomas, papillomas, pseudoangiomatous stromal hyperplasia, fat necrosis, fibrocystic change; b) Atypical lesions, such as atypical ductal or lobular hyperplasia; c) normal mammary tissue or lymph nodes. An increased MIBI’s uptake may be also observed at level of a post-surgical active scar, after biopsy or radiotherapy, or in presence of inflammation. These latter accumulations are generally differentiable, thanks to the anamnesis and/or to the integration with morphostructural data, also because the activity decreases over time. In particular, using MIBI, inflammation represents a minor problem in comparison with FDG, being the uptake in benign inflamed lesion uncommon and sometimes distinguishable from tumour lesions (277, 300).
A new information, identifiable as a breast cancer risk factor, is achievable with MBI: Background Parenchymal Uptake (BPU), indicating the level of radiotracer activity in normal fibroglandular tissue in comparison to subcutaneous fat (301). BPU is defined visually as photopenic, minimal/mild, moderate, or marked and may fluctuate with menstrual cycle or exogenous hormone use. Although it doesn’t significantly affect diagnostic accuracy, BPU has to be taken into account either to better define lesion's uptake and to individuate risk categories (see below).
A lower rate of false positive results may be achieved when MBI are evaluated together with the clinical history and with data acquired using alternative studies, mainly when associated with a morphostructural information.
To define actual indications for breast scintigraphy with MIBI, using technologically different tools, it has to be remembered that all the techniques are affected by the same causes of false positive results and that diagnostic accuracy is mainly determined by the spatial resolution of the utilized scanner, being also conditioned, for some devices, by technical issues, which make more difficult to analyse certain areas (302,303).
Substantially overlapping results between MBI and SMM are obtainable in evaluating locally advanced breast cancer (LABC) and neo-adjuvant chemotherapy (NAC) response. In this field interesting results could arrive from a wider application of reliable quantitative methods (304,305). Conversely, MBI, when available, has to be chosen when lesions under 1 cm are suspected, as in screening, in the diagnosis of non-palpable lesions and/or occult tumours, in the definition of multicentricity or bilaterality, important information to be acquired in patients diagnosed with carcinoma to decide therapeutic strategies. In this context, the possibility to avoid surgery in patients with pathologic nipple discharge, safely excluding malignancy, has also been recently proposed (306).
Similarly, biopsy guidance is best obtained with ad hoc equipment and/or when suggested by MBI, which better defines the heterogeneity of uptake at the level of a lesion with a complex structure. On the contrary, SMM using standard scanners may be preferred when an evaluation of masses adjacent to the chest wall is required, as may happen in cases of suspected recurrence, or when identification of a lymph node involvement is relevant. In these conditions, SPECT/CT is the most suitable method, without prejudice to the need to evaluate its justification for the greater dosimetric load.
To better understand, when multiple technological tools are available, the best cost/effective choice, we remember that:
1) MBI may detect a larger number of lesions under 1 cm, finding a role as second (or third line procedure) in screening and in better identifying multicentric and/or bilateral lesions. Conversely, it is affected by a worst capability in evaluating lesions adherent to the chest wall and lymph node involvement.
2) SPECT/CT is negatively affected by a higher radiation dose. The hybrid tool may give better results with respect to SPECT standalone as a guide for the surgeon. More useful information may be acquired in better defining lesions adherent to the chest wall or lymph node involvement. With regard to this last indication, sentinel node technique, normally applied in staging protocols, provides information on the direction of lymph flow, but not on the metastatic involvement. In this context, SPECT/CT with MIBI could find an interesting role in identifying lymph nodes metastases of the internal mammary chain, frequent for tumours located in the internal quadrants, being lymph node MIBI’s uptake highly associated with malignancy. This information could be of great value in considering a modification of the surgical technique and/or of the irradiation field after the intervention (307).
3.) SMM, traditional. This technique is performed using standard gamma cameras, also including new tools utilizing advanced detectors, such as CZT, but a multipurpose scanner design. The use of newer detectors may allow the adoption of lower doses and/or faster scans, but it doesn’t permit the achievement of the same sensitivity of MBI, which remains the preferred approach as second (or third, after MRI) line procedure in screening and in the definition of multicentre and/or bilateral cancer.
On the basis of the information reported above, at the present, the following indications may be suggested:
Screening. Being Mx (or Tomosynthesis) the standard procedure, MBI, not limited by dense breast tissue or implants, may be individuated as alternative to US, MRI and CEM in cases in which a reliable result was not achieved by them, due to the unavailability or ineffectiveness of the antagonistic methods. It has been calculated that, using MBI, an incremental cancer detection rate of 8.8 per 1,000 Mx exams may be obtained, with better values than tomosynthesis and ultrasounds, almost comparable to abbreviated MRI, although lower than full-protocol MRI (15 per 1,000 exams). This latter procedure has to be therefore considered the first integration to Mx, mainly in patients at high genetic risk, as suggested by The American College of Radiology, which published appropriateness criteria for supplemental breast cancer screening Guidance on MBI (307). MBI can be considered a valid choice when MRI is unavailable or is contraindicated for the patient.
Preliminary results of the prospective multicenter Density MATTERS trial, comparing MBI versus tomosynthesis for supplemental screening in women with dense breasts, showed an incremental cancer detection rate for MBI beyond tomosynthesis of 9.3 per 1,000 screened, with 6 invasive cancers seen only on MBI. In the similar trial E A1141 of the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network, abbreviated breast MRI versus tomosynthesis demonstrated an incremental invasive cancer detection rate of 7 per 1,000 screened, slightly lower than that of MBI.
Local Tumour Extent. MBI, although limited for evaluation of lymph nodes and of lesions adherent to chest wall, can be indicated, mainly in patients who cannot perform MRI, to detect multifocal, multicentric, or contralateral malignancy, showing comparable results with CEM. It has to be remembered that, for lesions less than 1 cm, the number of false negative regards mainly invasive lobular and invasive ductal carcinomas, including many tumours in situ. For the evaluation of lesions adherent to the chest wall and of lymph node involvement, with main reference to those of the internal mammary chain, the best procedure is SPECT/CT.
Neoadjuvant therapy (NAT). MBI, such as SMM, may predict pathologic response and evaluation of residual disease after NAT, showing a higher specificity respect to MRI (90% vs 60%), in presence of a lower sensitivity (70% vs 83%). Although the good accuracy of MBI and SMM for residual disease assessment, a surgical confirmation is however still required.
Guided Biopsy. In lesions with a complex structure, MIBI may individuate the viable part of the mammary tumour, with the highest uptake generally associated with the most malignant component. Therefore, MBI (or SMM) may direct other procedures, such as ultrasound-guided biopsy, to increase the accuracy of the histologic analysis, pointing biopsy on the most suspicious section of the neoplasm.
More recently, integrated MBI equipped with a biopsy attachment, such as other integrated gamma imaging dedicated machines, able to guide biopsy (296-296), have become available on the market. Having been demonstrated their efficacy, they may be considered more cost/effective respect to MRI guided biopsy, affected by a higher price and by a greater complexity, in presence of similar results. MBI can help to differentiate between scar tissue and recurrence of disease in patients who underwent surgery, radiotherapy, or biopsy.
Imaging biomarkers may define risk stratification. MBI (or SMM) may be used to describe breast density, associated with an increased breast cancer risk. Using MIBI the so called Background Parenchimal Uptake (BPU), an independent risk factor for breast cancer, may be considered (301-303). In particular, mild, moderate, or marked elevated BPU is associated with a higher cancer risk, with the greatest hazard ratio (3.5) when observed among postmenopausal women. Preliminary results suggest that patients showing a high BPU would benefit from supplemental screening or preventive options.
A priori evaluation of multidrug resistance (MDR). The MIBI’s wash-out, calculated comparing early and delayed scans, may trace the expression of MDR-related proteins (such as P-gp and Bcl-2), also providing useful information in patients undergoing radiotherapy. Information may be also acquired on apoptosis, proliferation and neoangiogenesis. The possibility to utilize the MIBI dual phase breast imaging (also as planar SMM) in individuating chemoresistance for the drugs utilizing MDR-related proteins has recently been reconsidered, after previous studies had led to conflicting results (288).
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 h almost completely eliminates radiation to the infant. In case of suspension of breastfeeding, not mandatory, it has been suggested to safely store breast milk beforehand, to continue breastfeeding even during any possible suspension [302].
Overall sensitivity in the detection of primary breast cancer is dependent on the device, being higher when using MBI respect to standard SMM. The biggest difference is identifiable in lesions under 1 cm, for which MBI has a significantly higher sensitivity. Likewise, the ability to identify multiple or contralateral lesions is significantly better. As mentioned above, the best ability to evaluate lesions adjacent to the chest wall and in lymph node staging can be obtained with SPECT/CT.
Using appropriate procedures, sensitivity and specificity values over 80%, with differences between palpable and non-palpable lesions, are generally achieved, reaching values over 90% for palpable masses (283). Conversely, using SMM to diagnose non-palpable lesions the sensitivity drops to a percentage around 50%, in the presence of a high specificity, which approaches 100%. On the contrary, in this subset, using MBI, a sensitivity greater than 50% is observed, remaining high the false negative rate in lesions smaller than 0.5 cm. Using MBI for lesions under 1 cm, although a higher possibility of false positive results respect to SMM, the specificity remains high.
A lesion larger than 1-2 cm without uptake is almost certainly negative, with rare false negatives, due to slow-growing tumours with low cellularity. As seen above, for lesions under 1 cm false negatives are also dependent on the shape of the tumour, being lower the rate in lesions structured as a nodule. Furthermore, the sensitivity is also dependent on the amount of concentration, generally lower in invasive lobular carcinomas respect to invasive ductal carcinomas. Because of many of the reasons reported above, tumours in situ are frequently negatives.
At the present, there are no thresholds clinically available to distinguish the uptake values between true and false positives. The definition of true positivity increases significantly in the presence of high uptake, especially if evaluated in light of the anamnesis and comparing information deriving from related diagnostic imaging.
Data from e Taillefer, summarizing 39 studies, to evaluate the diagnostic accuracy obtainable by SMM with MIBI (283). In 5663 patients with Breast Cancer (BC), the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 83.8%, 86.4%, 83.8%, 86.4%, and 85.2%, respectively. The sensitivity for non-palpable tumours, positives at Mx, ranged from 50% to 86%, and there was a significant difference in sensitivity between palpable (95%) and non-palpable lesions (72%). The BC lesions less than 5 mm in diameter were not detected. The sensitivity and specificity for axillary lymph node were 76% and 88%, respectively. The SPECT imaging did not significantly improve the detectability of BC. When the location of lesions overlapped the heart or the liver, SPECT imaging would be valuable. Sun et al. (284) in a meta-analysis based on 19 studies, utilizing a single-panel gamma imaging system, reported a pooled sensitivity and specificity for palpable BC of 95 % and 80 %, respectively. Subgroup analysis indicated that the sensitivity for detecting sub-centimetre BC and DCIS was 84 % and 88%, respectively. The most common false-positive lesions were fibrocystic change, fibroadenoma, and benign breast tissue. The false-negative lesions were sub-centimetre invasive ductal carcinoma and DCIS.
The suggested activity to administer for a standard procedure, using gamma cameras, is still:
[99mTc]Tc-MIBI in adults: 740-1110 MBq
Using MBI and/or other scanners equipped with advanced detectors, as CZT, the activity can be reduced to 300-600 MBq. For MBI-guided biopsy procedures, a higher administered activity (600–800 MBq) is suggested to guarantee a more reliable and fast procedure. Similarly, performing SPECT makes preferable to adopt higher activities, to speed up the procedure. T.
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 but, using newer tools, lower activities may be utilized.
The effective dose for [99mTc]Tc-MIBI in adults is 9 µSv/MBq. The organ with the highest absorbed dose is the gallbladder wall: 39 µGy/MBq.
Using the 740–1,100MBq standard activities, the range in effective dose in adults for [99mTc]Tc-MIBI is: 6.7-10 mSv per procedure, being lower when using newer more sensitive scanners and therefore lower activities (240–300MBq) with consequent reduction of the radiation exposure, estimated to be 1.1mGy, compared with 3.0–4.5mGy with mammography and tomosynthesis. U
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."
Either performing SMM or MBI, standard views are preferably chosen similarly to Mx, although SMM is born and was developed mainly utilizing the prone position and dedicated scanning tables, which would allow the study of the breast in a pendulous position. At present, planar imaging should include as standard cranio-caudal (CC) and mediolateral oblique (MLO) projections, acquired using gentle compression.
The interpretation is simple, because any focus of MIBI uptake > breast background is rated as positive. Higher uptake is more probably associated with malignancy. The absence of concentration individuates a benign pattern. The final diagnosis is however obtained on the basis of anamnesis and related examinations, able to reduce the number of false positive results.
Using MBI it has been proposed to define also the Background parenchymal uptake (BPU), i.e. the activity at level of the breast parenchyma in comparison to subcutaneous fat, assessed visually as photopenic, minimal/mild, moderate, or marked.
If a lesion is identified, the intensity of uptake within the lesion (absent, mild, moderate, or marked), mass or non-mass uptake, and the distribution are described. The location and size of any finding are described by the quadrant or clock face position as well as depth or distance from the nipple. The final assessment and management recommendations should be provided on every MBI examination. More frequent false positive results and pitfalls have been reported above.
On the basis of the level of suspicion, determined on lesion distribution, intensity, and morphology, MBI or SMM can be included in the Assessment categories parallel those of the Breast Imaging Reporting and Database System (BI-RADS) (309), describing the following categories: 0 (incomplete, needs additional imaging); 1 (negative, routine follow-up); 2 (benign, routine follow-up); 3 (very low likelihood of malignancy); 4 (suspicious, consider biopsy); 5 (highly suggestive of malignancy, take appropriate action); 6 (known malignancy, take appropriate action). In presence of a category 3, a MBI follow up at 6 months is recommended to observe lesion’s behaviour over time. While a decreased MIBI’s concentration individuate benignity and the increase in size or intensity requires a biopsy, the stationary condition suggest a further follow-up at 12 and 24 months, before a final decision. Category 4 or 5 determine the need of a biopsy. An interventional strategy is also suggested for suspicious MBI abnormalities, occult on Mx and/or US. The MBI-guided biopsy is also indicated when stereotactic Mx-guided biopsy is technically challenging and/or MRI-guided biopsy cannot be performed.
Small lesions, especially those less than 5 mm, are difficult to detect with current MBI technology. Posterior lesions close to the chest wall may be difficult to include in the MBI field of view. The axilla cannot be reliably imaged with planar MBI acquisitions due to positioning limitations.
None. Fasting state is optional, although it may slightly decrease physiologic hepatic extraction ameliorating tracer availability, also reducing scatter radiation.
More precisely, when the patient is fasting and heated with a blanket before and during the first minutes after MIBI’s injection, the BPU may be influenced. Similarly, the menstrual cycle may have an effect. Performing screening MBI during the follicular phase may minimize background parenchymal uptake (BPU), and the menstrual cycle phase may be included in the report when BPU information is requested, although scheduling based on menstrual cycle phase is not necessary.
Although no significant changes in diagnostic accuracy are obtainable by adopting these behaviours, all of them should be taken into account, when a biopsy or a quantitative evaluation is planned.
The detailed recommendations are available in the EANM Oncology Guidelines and/or can be obtained from the papers reported in the bibliography.