Breast cancer has been one of the most common cancers for women in the Western Hemisphere. In recent decades, Korean women have also become more susceptible to breast cancer, and its incidence has been increasing up to approximately 40% [1]. It is a very heterogeneous disease entity that is more difficult to diagnose than to treat. Therefore, early diagnosis and treatment can improve the prognosis of breast cancer. The diagnosis of patients with breast cancer has used various methods including clinical examination and imaging modalities such as ultrasonography (US), mammography (MMG), and magnetic resonance imaging (MRI). Although all these modalities can be used to detect breast lesions, and the sensitivity has been reported 96% in other previous studies, each imaging modality does have its own downside [2]. The sensitivity of breast mammography decreases in patients with dense breasts or who received estrogen treatment. Ultrasonography has not been able to detect microcalcifications. Breast MRI might raise the risk of unnecessary biopsy or operation due to higher rates of false positivity [3-6].

In 1994, Khalkhali et al. [7] reported first that breast scintimammography using ^99mTc-sestamibi could be used as a breast screening modality. It was a physiological approach toward the breast lesions rather than an anatomical view. The malignant cells usually had higher vascularity and mitochondrial activities, which was more prone to uptake a large quantity of injected isotopes compared to the normal cells [8,9]. The authors reported that the sensitivity, specificity, positive predictive value, and negative predictive value were 95.8%, 86.8%, 82.1%, and 97.1%, respectively [7]. Since then, technological advancements and progress have been made in high-resolution breast-specific gamma imaging with ^99mTc-sestamibi scintimammography (MIBI scan). The sensitivity and specificity of breast-specific gamma imaging have been reported as 89%–96%, 60%–90%, respectively [10-14].

The usefulness of MIBI scan has been continuously reported as an adjunct modality for detecting breast cancers as an alternative to core-needle biopsy in confirming an initial diagnosis [15,16]. Although most previous studies were oriented to recurrence or in conjunction with other modalities, there have only been a limited number of reports directly comparing MIBI scan with other modalities.

The diagnostic value of MIBI scan in breast cancer and its correlation with conventional diagnostic images may be necessary to recapture the current agenda of breast cancer diagnostic modalities, and this study has focused on those factors of MIBI scan and evaluated the very value thereof. In this study, patients without symptoms or signs were not included, as its diagnostic values were not for simple screening among the general populous. Thus, we aimed to evaluate the usefulness breast MIBI scan to reveal it as a potential diagnostic alternative.

The mean age was 49.2± 9.37 years old (range from 26 to 85 years old). Of the 801 breast lesions, 166 lesions (20.7%) proved to be malignant lesions whereas 635 lesions (79.3%) proved to be benign lesions (Table 1). The detection results of breast MIBI scan were divided into three categories: 236 positive intensity uptakes (29.5%), 565 negative intensity uptakes (70.5%), and 67 suspicious abnormal intensity uptakes (8.4%). The pathologic reports were also allocated into four subgroups: 122 invasive cancers (15.2%), 44 non-invasive cancers (5.5%), 194 proliferative benign lesions (24.2%), and 441 non-proliferative benign lesions (55.1%).

The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were 83.5%, 84.9%, 59.1%, and 95.2%, respectively. In comparison to the general modalities, ultrasonography and mammography, the specificity and negative predictive values of MIBI scan displayed ‘better’ diagnostic power by 71%–21% and 4%, respectively (Table 2). Values for all the modalities showed statistical significance so that they could be compared directly. The general screening modalities plus the MIBI scan have greatly improved specificity and positive predictive values by at least 30% (Table 3). Especially, the specificity of MIBI scan plus general diagnostic modalities dramatically increased up to 85.2% compared to general modalities (6.8%).

There were 92 lesions assigned to BI-RADS category 3 or less in the breast ultrasonography, but only 8 lesions (8.69%) showed positive intensity uptakes in the MIBI scan whereas 84 lesions (91.3%) were negative intensity uptakes (Table 4). There were 435 lesions detected in the breast mammography, but only 192 lesions (44.1%) showed positive intensity uptakes in the MIBI scan whereas 243 lesions (55.8%) were negative intensity uptakes.

There were 33 axillary lesions positive intensity uptakes in the MIBI scan whereas 768 lesions were negative intensity uptakes. Among those 33 axillary positive lesions, 22 lesions (66.6%) were related to the malignant lesions. Although there was a definite focal intensity uptake for the axillary area in the MIBI scan, 66.6% of the detection rate was not sufficient to assure its results (Table 5).

The purpose of this study was to compare the diagnostic results of MIBI scan, ultrasonography, and mammography in breast lesions and to analyze the final pathologic results. MIBI scan had a sensitivity and specificity of 83.7% and 84.9%, respectively, and had a significantly greater specificity and negative predictive value compared with mammography and ultrasonography (P<0.001). It also had a greater positive predictive value compared with mammography and ultrasonography (P< 0.001), but the positive predictive value (59.1%) would not have a diagnostic power over the general modalities due to significantly lower values compared to previous studies which reported their values ranging from 68% to 72% [13,14]. Kim et al. [12] also reported a similar result that MIBI scan had better NPV compared with mammography in breast cancer patients with dense breast (84.8% vs. 50.0%). However, they enrolled all breast cancer patients with only consideration of breast density without any benign lesions.

There has been a recent resurgence in gamma imaging of the breast with the advancement gamma cameras in the past decade. Zhou et al. [17] reported that the development of a high-resolution, small field-of-view dedicated breast gamma imaging system has overcome 2 major limitations of gamma breast imaging (tumor localization and detection of sub-centimeter lesions) that previously prevented its wide adaptation. The authors also mentioned that breast gamma imaging is not influenced by breast density similar to MRI and can obtain much improved specificity, even though it retained equivalent sensitivity as MRI [16-18].

Gamma breast imaging provides physiologic data in breast cancer imaging via 2 mechanisms. First, the radioactive tracer ^99mTc -sestamibi is distributed evenly throughout the circulatory system. Neo-angiogenesis occurs within the tumor microenvironments to support their increased proliferations. Thus, the pharmaceutical delivery to these lesions is enhanced [8]. Second, ^99mTc-sestamibi binds mitochondria within tumor cells specifically. Due to a higher cytoplasmic mitochondrial density in the tumor cells comparing to the normal breast cells or benign tumor cells, ^99mTc-sestamibi can better remain in the tumor cells [9]. These 2 mechanisms make gamma breast imaging highly sensitive and specific [18]. Therefore, MIBI scan shows the focal intensity uptake in the malignant lesions providing a more definite diagnosis (Fig. 1).

Although such a relationship plays an important role in the MIBI scan mechanism, this does not mean ^99mTc-sestamibi does not bind with normal tissue. In patients with dense breast tissue, ^99mTc-sestamibi could bind with normal breast tissue more intensely than in patients with fatty breast tissue. This may play a role in causing artifacts hindering tumor detection (Figs. 2, 3). This also might be a possible factor for the lower sensitivity of MIBI scan for younger women [14].

Hur et al. [13] commented that MIBI scintimammography might be one of the new possible modalities for preoperative evaluation compared to conventional images, because the high detection rate for malignant lesions in breasts was nearly equivalent to conventional imaging. However, the authors also mentioned that there was no superior benefit for multicentric or multifocal lesions or axillary metastasis compared to conventional imaging.

Contrary to the above reports, Edwards et al. [10] evaluated how often MIBI scan and MRI would influence surgical management in patients with breast cancer. The authors basically assumed that MIBI scan had greater sensitivity and specificity than standard imaging; its use should affect surgical management. They analyzed 163 patients divided into 2 groups; 118 had MIBI scan and 45 had MRI. The conversion rates of eligible BCS to mastectomy were 11.9% in MIBI scan to 28.9% in MRI, respectively. These results demonstrate that MIBI scan did not overestimate the extent of disease to which it would change surgical management. They concluded that MIBI scan is a useful adjunct in the surgical management of breast cancer that can be safely used in place of MRI [10].

Although we did not evaluate MRI in this study, it already has proved to have better sensitivity in discriminating breast cancer over other imaging modalities including ultrasonography, breast mammography, and MIBI scan [6,19]. However, MRI has a high false-positive rate in differentiating breast lesions in patients with breast cancers [20]. Therefore, the MIBI scan could be used to correctly diagnose benign lesions in women with suspicion of breast malignancy on MRI [15,16,19].

The diagnostic usefulness between MIBI scan and conventional imaging (i.e., ultrasonography/breast mammography) have been investigated and evaluated throughout many previous studies. In a direct comparison among these modalities, MIBI scan would provide a possibly “better” method to detect breast cancer that would be unveiled based on higher specificity and negative predictive values as in this study. In other words, MIBI scan can provide higher specificity and negative predictive values, meaning the negative results are benign lesions. Therefore, the ‘real’ diagnostic power for breast cancer over conventional imaging modalities could provide a confident differential diagnosis and help in avoiding any unnecessary procedures such as a fine-needle or core-needle biopsies.

This study has some limitations. First, this is a retrospective study that could lead to selection bias and a reduced statistical power. Second, we only enrolled patients with breast lesions without considering individual menstrual cycles that could affect the accuracy of conventional images. The radiotracer uptake in the breast could be influenced by hormonal changes throughout the cycle. Further prospective studies with a larger group are required to validate the diagnostic power of MIBI scan in comparison with the general modalities.

The mainstay diagnosis for breast cancers has been ultrasonography and breast mammography although other extensive imaging modalities including MR breast, positron emission tomography-computed tomography, and whole body bone scan could be used for the furtherer evaluations. BI-RAD category 4 or higher lesions have performed by needle biopsy rather than observation.

The usefulness of MIBI scan has been currently a controversial imaging technique that still requires further study and needs to be proven of its diagnostic values. Nonetheless, the results from this study have presented that MIBI scan might be one of the key modalities in detecting breast cancer along with conventional modalities.

There are some concerns of MIBI scan, such as the amount of radiation exposure, high expense, and others factors which might be an obstacle for some patients. These would be the disadvantages of MIBI scan as a routine screening modality.

MIBI scan may offer an alternative diagnostic tool for “invasive” biopsy procedures, because its superior specificity and negative predictive value provided confident results on non-proliferative benign lesions in this study. It also could be a good diagnostic modality for extremely dense breasts on mammography and post operative follow-up study for breast cancer patients, especially breast conserving surgery. Nonetheless, further investigation is necessary in those extremely dense cases or in postoperative follow-up.