Retrospective and comparative analysis of 99mTc-Sestamibi breast specific gamma imaging versus mammography, ultrasound, and magnetic resonance imaging for the detection of breast cancer in Chinese women

Diagnosing breast cancer during the early stage may be helpful for decreasing cancer-related mortality. In Western developed countries, mammographies have been the gold standard for breast cancer detection. However, Chinese women usually have denser and smaller-sized breasts compared to Caucasian women, which decreases the diagnostic accuracy of mammography. However, breast specific gamma imaging, a type of molecular functional breast imaging, has been used for the accurate diagnosis of breast cancer and is not influenced by breast density. Our objective was to analyze the breast specific gamma imaging (BSGI) diagnostic value for Chinese women. During a 2-year period, 357 women were diagnosed and treated at our oncology department and received BSGI in addition to mammography (MMG), ultrasound (US) and magnetic resonance imaging (MRI) for diagnostic assessment. We investigated the sensitivity and specificity of each method of detection and compared the biological profiles of the four imaging methods. A total of 357 women received a final surgical pathology diagnosis, with 168 malignant diseases (58.5 %) and 119 benign diseases (41.5 %). Of these, 166 underwent the four imaging tests preoperatively. The sensitivity of BSGI was 80.35 and 82.14 % by US, 75.6 % by MMG, and 94.06 % by MRI. Furthermore, the breast cancer diagnosis specificity of BSGI was high (83.19 % vs. 77.31 % vs. 66.39 % vs. 67.69 %, respectively). The BSGI diagnostic sensitivity for mammographic breast density in women was superior to mammography and more sensitive for non-luminal A subtypes (luminal A vs. non-luminal A, 68.63 % vs. 88.30 %). BSGI may help improve the ability to diagnose early stage breast cancer for Chinese women, particularly for ductal carcinoma in situ (DCIS), mammographic breast density and non-luminal A breast cancer.


Background
Breast cancer is the leading type of new cancer cases and the second leading cause of cancer related deaths in females worldwide [1]. During the past 30 years, the incidence and mortality of breast cancer in Chinese women has gradually increased and has become a primary cause of death, with more than 1.6 million people diagnosed and 1.2 million people dying of the disease each year [2,3]. The current guidelines suggest that breast cancer screening and diagnostic imaging modalities include mammography (MMG) and ultrasound (US) for women at average risk and magnetic resonance imaging (MRI) for high-risk women [4]. These methods can detect early stage breast cancer and reduce mortality. Despite their effectiveness, these traditional imaging methods have limitations that complicate the standardization of image quality and can affect the diagnostic accuracy of the breast examination. The diagnostic accuracy of MMG is affected by mammographic breast density, with decreased sensitivity in patients with dense breasts [5]. For MRI, a variable degree of background parenchyma enhancement (BPE) of normal fibro-glandular tissue occurs. Marked BPE can cause a higher abnormal interpretation rate and may influence the accuracy of MRI [5,6]. Notably, the mean age at diagnosis of breast cancer in China is 45-55 years, which is considerably younger than for Western females. Young women usually have a smaller proportion of fat content relative to the fibro-glandular tissue in their breasts compared to older, Chinese women, who usually have denser and smaller-sized breasts compared to Caucasian women [2]. Therefore, the traditional imaging modalities have a low diagnostic value in China.
Breast specific gamma imaging (BSGI) is a physiologic approach to breast imaging using a high resolution, small-gamma camera and a tracer agent called 99m Tc-Sestamibi (MIBI), and molecular breast imaging has significantly improved in recent years with the development of breast optimized imaging [7,8]. MIBI retention in tumor cells is determined by the cellular and mitochondrial membrane potential and the presence of an ATP-powered efflux pump, such as P-glycoprotein, which can transport foreign substances out of cells. However, unlike MMG, BSGI performance is independent of breast density [7,9,10]. Furthermore BPE is likely related to the blood volume and vascular permeability of normal breast tissue; therefore, it is predicted not to influence the background MIBI uptake. The sensitivity (Se) and specificity (Sp) of BSGI from a meta-analysis of 8 studies, including 2183 lesions, were 95 % (95 % CI 93-96 %) and 80 % (95 % CI 78-82 %), respectively, and were not affected by the breast density [11]. This was better than the reported sensitivity and specificity for the largest breast MRI study (n = 821), with 88.1 % (95 % CI, 84.6-91.1 %) and 67.7 % (95 % CI, 62.7-71.9 %), respectively [12]. Therefore, the Society of Nuclear Medicine (SNM) recommended BSGI particularly for breast patients with breasts technically too difficult to examine using conventional mammography, including radiodense breast tissue, implants, free silicone, or paraffin injections [13].
Chinese women have denser breasts, and recent research also indicated that women with higher breast density are at an increased risk of breast cancer, and this is one of the highest risk factors for the prediction of breast cancer risk. Therefore, a useful and accurate breast imaging method is necessary. The development of a dedicated breast gamma imaging system has overcome these limitations and has returned scintimammography to the forefront of breast imaging. This was a retrospective study analyzing BSGI performed as an adjunct imaging method for Chinese women to detect breast cancer.

Patients
The hospital ethics committee approved this study. Written informed consent was obtained from each patient. A total of 357 breast disease patients who were diagnosed and treated at the oncology department (Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China) from June 2012 to January 2015 were included in this single-institution study. Patients were first identified by reviewing the BSGI database, and 357 patients who underwent BSGI were reviewed. The including criteria were as follows: 1) female patients 18-years-old and older; 2) pathological proof of non-metastatic breast cancer; and 3) received ultrasound (US), mammography (MMG) and breast-specific gamma imaging (BSGI) before diagnosis. Clinicopathological characteristics, including age, menstrual state, histological type, grade, hormone receptors, HER2 and the clinical stage at diagnosis were obtained from the medical files at our institution and were included in a unique dedicated database.

Imaging and pathologic review Pathologic review
The histological type and grade were defined using the World Health Organization classification system. ER and PR tumor status are normally determined by immunohistochemistry (IHC) testing. Samples that have at least 1 % of cells staining positive for ER are considered ER-positive. Breast cancer tumors are classified as HER2positive if they are scored as a 3 or more by an IHC method defined as a uniform membrane staining for HER2 in 10 % or more of tumor cells or have demonstrated HER2 gene amplification by a fluorescence in situ hybridization (FISH) method (single probe, average HER2 copy number ≥ 6.0 signals/cell; dual probe HER2/CEP17 ratio ≥ 2.0 with an average HER2 copy number ≥ 4.0 signals/cell; dual probe HER2/CEP17 ratio ≥ 2.0 with an average HER2 copy number < 4.0 signals/cell; HER2/ CEP17 ratio < 2.0 with an average HER2 copy number ≥ 6.0 signals/cell) [14].

Ultrasound review
For the ultrasound examination, we used high-end equipment (IU Elite®; Philips Healthcare, Best, Netherlands), and all findings were documented in two perpendicular planes. The ultrasound positives were defined by an expert as highly suspected and suggestive of biopsy or operation.

Mammography review
The mammographic reports of the mammography were prospectively evaluated by one radiologist and reviewed (Selenia®, Hologic, Santiago, USA). The mammographic breast density was visually estimated according to the American College of Radiology Breast Imaging-Reporting and Data System classification and classified as follows: almost entirely fat (less than 25 % of breast comprising glandular tissue), having scattered fibroglandular densities (25-50 % of breast comprising glandular tissue), heterogeneously dense (51-75 % of breast comprising glandular tissue), and extremely dense (more than 75 % of breast comprising glandular tissue). Mammography positives were defined by an expert according to BI-RADS® Assessment Categories.

MRI review
Breast MRIs were performed on a 1.5 T system (Aera®, Siemens, München, Germany). Pre-contrast images of the dynamic series were subtracted from the postcontrast images to selectively highlight the enhancing structures. No parallel imaging was applied. MRI positives were defined by an expert as highly suspected and suggestive of biopsy or operation.

BSGI review
The patients were injected with 740-925 MBq (15-20 mCi) technetium-99 m sestamibi (Shanghai GMS Pharmaceutical Co., Ltd) into an arm vein. Craniocaudal and mediolateral views were performed of both breasts using a high-resolution, small field-of-view gamma camera optimized for breast imaging. Imaging was initiated immediately after injection of the isotope. Craniocaudal and mediolateral views were performed for both breasts The images were obtained with a high-resolution, small field-of-view, breast-specific gamma camera (Dilon 6800 Gamma Camera; Dilon Technologies, Newport News, VA). BSGI positives were defined by an expert as highly suspected or having a tumor-to-normal tissue ratio (TNR) > 1.82.

Data analysis
The statistical analyses were performed using SPSS, version 20. The comparison between BSGI and US, MMG and MRI, and BSGI diagnostic values for different clinicopathological variables were calculated using either χ 2 tests with continuity correction or Fisher's exact test. All statistical tests were two sided and considered significant when p ≤ 0.05.

Patient characteristics
There were 357 patients documented in our study. Of these, 287 patients underwent BSGI, US, and MMG, and 166 patients underwent all four imaging tests (BSGI, US,  (Fig. 1). The median age of the study patients was 48.2 y and ranged from 32 to 75 y. The distribution of breast patient pathology was 168 malignant diseases (58.5 %), which was a combination of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and ductal carcinoma in situ (DCIS), and 119 benign diseases (41.5 %).

Value of BSGI, US, MMG and MRI for detecting breast cancer
When BSGI is combined with other examination techniques (MMG, US and MRI), we found that the accuracy for the detection of malignant breast lesions for BSGI combined with US was superior to BSGI + MMG or BSGI + MRI ( Table 2).

Sensitivity of BSGI, US, MMG and MRI in different traits of breast cancer
For premenopausal and postmenopausal women, the sensitivity of BSGI was not superior to breast US, MMG and MRI (Fig. 3a). The four breast density categories for breast composition are defined by the visually estimated content of fibroglandular dense tissue within the breasts. In the heterogeneously dense and extremely dense group, BSGI sensitivity was superior to MMG (82.35 % vs. 77.94 %; 85.45 % vs. 65.45 %, respectively) (Fig. 3c). For tumor grade and molecular subtype sensitivity analysis, the four imaging tests were not significantly different ( Fig. 3b and d).
For  (Fig. 4a). The TNR differed significantly between luminal-A and non-luminal-A breast cancer (p < .0001) (Fig. 4b).  False-positive and false-negative findings of BSGI We had 20 cases of false-positive BSGI findings. The pathology of false-positive BSGI lesions is shown in Table 4. We also analyzed the false-negative findings according to the breast cancer traits. The majority of false-negative malignant tumors had an extensive intraductal component (11/33), were high grade (9/33) and were diagnosed as Paget's disease (2/33).

Discussion
To our knowledge, this study is the first to evaluate the diagnostic value of breast specific gamma imaging for Chinese women. We found that BSGI could be used in a work-up of suspicious breast lesions. The visual and semi-quantitative analyses (TNR cut-off value 1.82) as combined for detecting primary breast cancer [15]. Comparison of the sensitivity and specificity of BSGI to  [16,17]. Combined with our research, evidence suggests that BSGI, as a functional imaging test, is an extremely useful adjunct test for its ability to identify breast cancer with high diagnostic performance, and it was not influenced by menstrual state, tumor grade, or tumor size [16,18,19]. Due to the limitations of the examination methods, axilla are hard to test, but BSGI has a higher specificity for detecting axillary lymph node metastasis [20]. Screening mammography has been the gold standard for breast cancer detection for the past 30 years [21,22], but recent studies have questioned this screening because it does not reduce breast cancer mortality [23]. MRI is currently recommended by the American Cancer Society in patients with high risk, but there are issues with sensitivity resulting in increased false positive rates leading to numerous benign biopsies or operations [24]. Studies demonstrated that BSGI has an equal sensitivity with a higher specificity than MRI as an adjunct imaging modality for the diagnosis of breast cancer. Additional advantages include greater ease of imaging for the patient, lower cost, and an easy read for the radiologist or surgeon [18,25,26]. Specifically in China, women have   ). Therefore, BSGI may help classify the sub-type of an invasive ductal carcinoma in addition to its pathology.

Limitations of BSGI
BSGI has several limitations as a breast imaging modality. Patients are exposed to radiation from the BSGI test of approximately 6.29-9.44 mSv [8,28]. BSGI may be recommended for patients with suspicious breast lesions or dense breasts by conventional methods, using lower doses and longer acquisition times [29]. Second, this is a plane test, and there may be insufficient positioning [16,30]. Finally, BSGI was the least sensitive for detecting axillary lymph nodes.

Conclusion
In summary, BSGI showed a borderline sensitivity but a higher specificity than US/MMG/MRI for diagnosing breast lesions, and it has a high sensitivity for discriminating DCIS. BSGI may play a crucial role in discriminating breast lesions and can be used to evaluate newly diagnosed breast cancer patients with dense breasts. Semiquantitative analysis as a parameter of BSGI may help classify the sub-type of an invasive ductal carcinoma in addition to the pathology. Because Chinese women have unique breast density, BSGI may improve the early detection of breast cancer to reduce breast cancer morbidity and mortality.