University of Pisa
Department of Translational Research and New Technologies
in Medicine and Surgery
Residency Program in Diagnostic Radiology
(2012-2017)
Chairman: Prof. Davide CaramellaMolecular breast imaging: correlation with mammographic,
sonographic and histopathological features of suspicious breast lesions.
Supervisors Candidate Prof. Davide Caramella, MD Dr. Giulia Angelini, MD Dr. Carolina Marini, MD Prof. Duccio Volterrani, MD Academic Year 2015-2016
ABSTRACT
OBJECTIVES
The current guidelines suggest combined imaging modalities including digital mammography (DM), ultrasound (US) and magnetic resonance imaging (MRI) for cancer detection and staging. MRI represents the most sensitive technique to evaluate suspicious breast lesions and to identify multifocal, multicentric and contralateral cancer, however many conditions (obesity, allergies, pacemakers, metallic devices and claustrophobia) may hinder its execution. In this scenario, radionuclide imaging with 99mTc-Sestamibi Molecular Breast Imaging (MBI) may represent an adjunct modality to radiologic traditional imaging, in particular when MRI cannot be performed or in selected cases. The purpose of this study is to compare the diagnostic performance of MBI compared to DM and DM+US in a retrospective work.
MATERIAL AND METHODS
We retrospectively enrolled 50 women (mean age 63.5 years ±11.7) between May 2015 and May 2017, with a total of 70 breast lesions (benign and malignant) histologically identified by core needle biopsy (CNB) and surgery. All women underwent DM, US and MBI. Histopathological analyses of tumoral lesions included nuclear grading and molecular subtype evaluation. DM/US findings were categorized according to BI-RADS® and considered as positive with a score ≥ R4b/U4b. Mammographic breast density was visually estimated. MBI was performed 10 minutes after iv injection of 296 MBq of 99mTc-Sestamibi (99mTc-MIBI)
by using gamma-camera in semiconductor cadmium zinc telluride (CZT) for single photon planar imaging of the immobilized breast. MBI was interpreted in conjunction with DM+US and qualitatively evaluated as positive (focal moderate or marked increased uptake) or negative (completely negative or mild uptake). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated in order to assess the diagnostic capacity of MBI, DM and DM+US compared to histological examination, by using SPSS 24®.
RESULTS
Pathological analysis of the 70 suspicious breast lesions demonstrated 59 malignant foci of tumor:
38 no special type, 14 ductal carcinoma in situ, 5 invasive lobular carcinoma, 1 invasive tubulo-lobular carcinoma and 1 mucinous carcinoma. Molecular subtypes of invasive lesions were: 18 luminal A, 18 luminal B, 3 HER 2 and 1 basal-like (hormonal data not available for 5 tumors). Eleven benign lesions were detected: 1 lobular carcinoma in situ, 2 papillomas, 2 fibroadenomas, 6 adenosis and/or fibrosis. MBI demonstrates the highest sensitivity (86.4% vs 83.1% by DM+US and 67.8% by DM) but the lowest specificity (36.4% vs 54.6% by DM+US and 72.7% by DM). MBI sensitivity is superior or equal to DM and DM+US in all categories of in situ/invasive, molecular subtypes, grading, breast density and lesion size (dichotomized as ≤ or > 1 cm). On the contrary, MBI sensitivity is inferior in premenopausal women and superior in postmenopausal women compared both to DM and DM+US. Furthermore, our results show that MBI is influenced by menopausal status (p=0.029), while it is not correlated to breast density and lesion size (p=0.859 and p=0.807, respectively).
CONCLUSIONS
Our initial experience with MBI supports the use of this modality in addition to DM/US, especially when MRI may not be performed. Currently, MBI remains a second choice compared to MRI due to its limitations of exposing women to a certain dose of radiation and lacking detailed spatial definition. However, our results about MBI independence from breast density and lesion size may represent a valid starting point to promote further larger studies.
BACKGROUND
Breast cancer is the leading cause of cancer-related death among females worldwide. In 2012, estimated 1.7 million cases and 521900 deaths occurred. Female breast cancer incidence rates vary with the highest rates in Western Europe and the United States [1], increasing after the introduction of mammography screening, and continuing to grow with the ageing of the population. Prevalence is increasing, as a consequence of increased incidence and of improvements in treatment outcomes. In 2012 in Italy, incidence was of 50000 women diagnosed with an annual prevalence of 45000 [2]. In Italy, as in most Western countries, mortality rate has decreased in recent years, especially in younger age groups, because of improved treatment and earlier detection [3].
The current European guidelines suggest regular mammography for screening and combined imaging modalities including digital mammography (DM), ultrasound (US) and magnetic resonance imaging (MRI) for cancer detection and staging [4]. Mammography, which is based on an anatomical approach, is currently the standard screening modality for breast cancer with a sensitivity reported to be 75–85%, but decreasing up to 40% in women with dense breast [5]. Thus, the ability of mammography to discriminate between breast lesions depends on the difference in density between lesions and normal breast tissues [6, 7]. Magnetic resonance imaging (MRI) is an effective adjunct diagnostic tool in breast cancer patients, evaluating anatomical and biological features of the tumor due to DWI, perfusion, spectroscopy and contrast enhancement. It may identify multifocal, multicentric and contralateral lesions [8]. Although MRI has a higher sensitivity than mammography, the benefit of MRI is diminished by its low specificity [9-11]. Moreover, marked background parenchymal enhancement can cause a higher abnormal interpretation rate and may influence the accuracy of MRI [12]. Furthermore, obesity, allergies, pacemaker, metallic devices and claustrophobia may hinder the execution of MRI.
Radionuclide imaging with 99mTc-Sestamibi (99mTc-MIBI) Molecular Breast Imaging (MBI) may be a valuable alternative to radiologic traditional imaging in this context, in particular when MRI cannot be performed or in selected cases. Current MBI has its origins in scintimammography, which was developed in the 1990s and has been the subject of considerable investigation over the last 10–15 years. It utilized conventional gamma cameras to image focal breast uptake of 99mTc-MIBI and had relatively poor sensitivity for small and non-palpable lesions [13]. The reason of its
poor sensitivity should be sought in the large dead space at the edge of the conventional gamma camera, necessitating placing the patient in the prone position with the camera positioned laterally. This caused a significantly decreased resolution due to the increased distance between the camera and the breast [14]. Besides, images could only be obtained in the medial-lateral and anterior-posterior planes, making it difficult to directly compare scintimammography with DM. In an attempt to overcome the limitation of conventional scintimammography, several small field of view gamma cameras have been developed permitting the breast to be imaged in a similar manner and orientation to conventional DM [15]. In particular, MBI may be of clinical usefulness for the detection of breast cancer, high-risk populations, diagnostic ambiguity, technically challenging breast imaging and for monitoring treatment response in neo-adjuvant chemotherapy [16]. MBI also shows high sensitivity for the detection of ductal carcinoma in situ (DCIS), subcentimetric cancers and high-risk lesions, such as atypical ductal hyperplasia (ADH) or lobular neoplasia [17, 18].
Aim of this study is to correlate MBI with mammographic, sonographic and histopathological features in suspicious breast lesions.
MATERIAL AND METHODS
Patients
We retrospectively enrolled 50 women, between May 2015 and May 2017, with 70 breast lesions correctly identified by biopsy and/or surgery. All the patients underwent clinical examination, DM, US and MBI, showing at least a lesion considered either suspicious or highly suggestive of malignancy on the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS®) scale [19, 20]. All these cases were unable to undergo MRI for various reasons (allergy, claustrophobia, choice of the patient, obesity, metallic devices), but they required a second level exam for assistance in characterizing a suspicious lesion (with previous doubtful DM and US) or in staging multicentric or bilateral breast cancer. Eligible patients included those subjected to both DM and US and MBI and a histopathologic analysis of the lesion.
Histopathological analysis
Surgical specimens were obtained in 44 women who underwent surgery (quadrantectomy or mastectomy or large excision), while histological results from CNB were evaluated in 6 women not submitted to surgery. We reviewed the histologic type (no special type carcinoma NST, ductal carcinoma in situ DCIS, invasive lobular carcinoma ILC, and others, including mucinous carcinoma and tubulo-lobular carcinoma), the presence of in situ component, nuclear grade, ER status, PR status, human epidermal growth factor receptor 2 (ERBB2, formerly HER2) status, Ki-67 or MIB-1 index and tumor size.
Tumors were considered positive for ER when more than 1% of tumor cells showed positive staining by immunohistochemistry and positive for PR when more than 20% of tumor cells showed positive staining. The expression of HER2 was assessed by immunohistochemistry (IHC). A validated dual probe fluorescence in situ hybridization (FISH) was used in case of HER2 overexpression by IHC score (defined as either 2+ IHC staining, namely intense stain of > 10% of tumor cells).
Ki-67 score was considered high when > 20%, according to the median values of our laboratory [4]. Molecular subtypes (luminal A, B, HER2 and basal like) were assessed in all invasive lesions (hormonal data were not available in 5 tumors). Tumor size was determined with reference to the largest diameter of the surgical specimen and then dichotomized in ≤ and > 1 cm.
Digital mammography and ultrasound
All patients underwent DM or tomosynthesis with synthetic 2D view, performed in accordance to the guidelines and to the technical requirements of the Breast Unit. After digital transmission into our imaging archive, mammograms (2D view in case of tomosynthesis) were evaluated on dedicated workstations by an experienced breast radiologist (15 or 20 years of experience). Mammographic findings were described as mass, asymmetry, distortion and microcalcifications. Breast density was visually estimated according to BI-RADS® and classified in the known 4 categories [19, 21]. For the US examination, high-end equipment was used and both breasts were examined using a high-frequency (9–13 MHz), high-resolution linear array transducer in radial and antiradial directions. Positive findings were defined by an expert as moderately or highly suspicious and suggestive of biopsy or operation
(≥ R4b or U4b), according to BI-RADS® (table 1). Table 1. Final BI-RADS® assessment category.
MBI
MBI utilizes dual-head cadmium zinc telluride (CZT) dedicated gamma camera (fig 1) to allow simultaneous acquisition from both sides of the immobilized breast (Discovery NM 750b, GE Medical System, Waukesha, WI, US). Since the breast is positioned in direct contact with the detectors, there is minimal decreased resolution related to minimal dead space.
Two methods are used -compared to scintimammography- with the goal of increasing count sensitivity while maintaining adequate spatial resolution for detection of small tumors: collimator optimization and widened energy acceptance window.
First, the use of opposing dual-head detectors ensure that the greatest distance a lesion may be from either collimator is half the lightly compressed breast thickness, which is on average 3 cm, as observed in clinical studies. Secondly, the tailing phenomenon of CZT technology improves count sensitivity due to the wider energy
window utilized. The use of a wider energy window allows additional scattered counts in the image, but most of the scattered photons in the 110–154 keV energy window originate in the breast itself and do not come from the torso[22].
These technologies increase the sensitivity of the system by a factor of about 2.8 to 3.6 compared to conventional scintimammography. Furthermore, this procedure limits the dose to the patient due to the possibility of administering a smaller activity (296 MBq vs 740 MBq) obtaining an effective dose to the breast of 2.4 mSv compared to 9 mSv of scintimammography [23-25].
MBI was performed 10 minutes after the intravenous injection of 296 MBq of 99m
Tc-MIBI in the arm contralateral to the affected breast. Craniocaudal and mediolateral oblique views were performed for both breasts, applying a moderate compression to avoid the overlap of mammary parenchyma. MBI, visually interpreted in conjunction with mammograms and ultrasound, resulted as either positive (focal increased uptake) or negative (completely negative or mild uptake).
No hypersensitivity reactions were observed. When possible, in almost all patients, MBI was performed before biopsy, since recent diagnostic or therapeutic invasive procedures can cause false positive 99mTc-MIBI uptake [26]. The uptake of this radiotracer is affected by angiogenesis, regional blood perfusion, and mitochondrial membrane potential. In particular, mitochondrial density is a reflection of the proliferative activity of cells; thus, the accumulation of MIBI is higher in tumor cells than in normal breast tissue.
Statistical analysis
Continuous data (age and tumor size) were described by mean and standard deviation (SD). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated in order to assess the diagnostic capacity of MBI, DM and DM+US compared to histological examination. Furthermore, to evaluate the agreement between diagnostic methods, McNemar and K Cohen tests were applied. Finally, to compare the sensitivities, the two-proportion z-test was used. All analyses, descriptive and inferential, were performed by the SPSS® v.24 technology.
RESULTS
We analyzed 50 patients, with a mean age of 63.5 years ±11.7 (SD); 43 women were in postmenopause, only 7 were in premenopause. All these women underwent DM, US and MBI. DM examination revealed 25 masses, 11 clusters of microcalcifications, 4 distortions and 3 asymmetries. DM+US revealed 54 suspicious lesions, while MBI identified 58 focal uptakes. Seventy breast lesions were correctly detected by CNB and/or surgery. In particular, pathological correlation demonstrated 59 malignant foci of tumor:
38 NST, 14 DCIS, 5 ILC, 1 invasive tubulo-lobular carcinoma and 1 mucinous carcinoma. Molecular subtypes of invasive lesions were: 18 luminal A, 18 luminal B, 3 HER2 and 1 basal like (hormonal data were not available for 5 tumors).
Mean diameter of the tumor was 1.8 cm ±1.2 (SD).
Eleven benign lesions were detected: 1 LCIS, 2 papillomas, 2 fibroadenomas, 6 adenosis and/or fibrosis.
We evaluated sensitivity, specificity, positive predictive value (PPV), negative predicitive value (NPV), accuracy, Cohen’s Kappa and p value from McNemar test for DM, DM+US and MBI compared to histological results (table 2).
MBI demonstrates the highest sensitivity (86.4% vs 83.1% by DM+US and 67.8% by DM) but the lowest specificity (36.4% vs 54.6% by DM+US and 72.7% by DM). The
highest PPV belongs to DM with a value of 93.02%, while 90.7% is the value for DM+US and 87.9% for MBI.
MBI shows a value of 33.4% as NPV, whereas DM 29.6% and DM+US 37.5%. Diagnostic accuracy is equal for MBI and DM+US, both 78.6% while DM alone shows a lower value, 68.8%.
Both DM and DM+US and MBI show a fair agreement with values of 0.255, 0.317 and 0.22 respectively.
The comparison between DM, DM+US or BMI and histological results shows p-values of 0.001, 0.302 and 0.99, respectively.
There are eight false-negative MBI cases, four of which are positive on DM+US. The size of these lesions is 0.3, 1.4, 2 and 2.5 cm (fig 2), respectively. Two lesions are visible only at US, while two lesions are visible both at DM (mass and microcalcifications) and US. Two are DCIS, and two lesions are NST.
There are seven false-positive MBI cases, four of which are negative on DM+US. These four cases result in benign biopsy findings (2), papilloma (1) (fig 3) and fibrosis (1). The other three cases positive on DM+US are fibroadenomas (2) and lobular carcinoma in situ (1).
MBI reveals six cancers undetected by DM+US, in particular 3 NST measuring 0.3, 0.8 (fig 4), 1 cm and 3 DCIS measuring 1.5, 1.5 and 4 cm.
Fig 2. DM shows a cluster of microcalcifications, seen as an hypoechoic irregular area at US, missed at MBI (DCIS, 2.5 cm).
Fig 3. False positive of MBI, showing a focal uptake behind the nipple with negative DM and US (papilloma).
Fig 4. MBI shows one small focal uptake not detected by DM+US, confirmed by second look US (NST, 0.8 cm).
Tables 3-9 display sensitivity of MBI, DM and DM+US in different traits of breast cancer (nuclear grade, in situ/invasive, in situ component, molecular subtype, lesion size) and different traits of women (breast density, menopausal status).
MBI sensitivity is superior or equal to DM and DM+US in all categories of in situ/invasive, molecular subtype, grading, breast density and lesion size (dichotomized as ≤ and > 1 cm). On the contrary, MBI sensitivity is inferior in premenopausal women and superior in postmenopausal women compared both to DM and DM+US.
Regarding menopausal status, in premenopausal women, MBI sensitivity is significantly inferior compared to DM+US (57.1% vs 85.7%), while in postmenopausal women MBI sensitivity is similar to DM+US and significantly superior to DM (90.4% vs 82.7% and 69.2%, respectively) (table 3). Dichotomizing breast density in two categories (fatty + scattered fibroglandular vs heterogeneously + extremely dense) MBI sensitivity is significantly superior to DM in dense breast
group (85.7% vs 57.1%), whereas MBI shows similar sensitivity to DM+US (87.1% vs 83.9% in fatty breast and 85.7% vs 82.1% in dense breast) (table 4). For tumor grade, the sensitivity of MBI is significantly higher compared to sole DM for grading 2 (95.6% vs 65.2%) (table 5). For lesion size (dichotomized as ≤ 1 cm or > 1 cm) MBI is significantly more sensitive than sole DM for small lesions (table 6). For invasive/in situ lesions, MBI sensitivity is significantly superior compared to DM with these values: 90.7% vs 72.1% and 76.9% vs 53.8%, respectively (table 7).
Furtherly, MBI sensitivity is significantly higher in absence of in situ component compared to DM (87.5% vs 62.5%); meanwhile, MBI sensitivity is significantly lower compared to DM+US in presence of in situ component (87.5% vs 99%) (table 8). The sensitivity of MBI in detecting luminal A breast cancer is significantly superior compared to DM. Sensitivity values about HER2 and basal like will not be discussed due to excessively small samples (table 9).
Moreover, the sensitivity of MBI is compared to different DM finding, without statistically significant differences (96% masses, 100% distortions, 100% asymmetries and 90% of microcalcifications). The sensitivity of MBI for tumors missed at DM+US turns out to be 60%.
DM DM+US MBI Sensitivity (40/59) 67.8% (49/59) 83.1% (51/59) 86.4% Specificity 72.7% (8/11) 54.6% (6/11) 36.4% (4/11) PPV 93.02% (40/43) (49/54) 90.7% (51/58) 87.9% NPV 29.6% (8/27) 37.52% (6/16) 33.4% (4/12) Accuracy (48/70) 68.6% (55/70) 78.6% (55/70) 78.6% Kappa 0.255 0.317 0.22 Mc Nemar 0.001 0.302 0.999 Table 2. Diagnostic performance of imaging modalities. McNemar, p-value for comparison of imaging modalities and histologically confirmed results; NPV, negative predictive value (describes the ability of a negative test to rule out malignancy); PPV, positive-predictive value (describes the ability of a positive test to predict malignancy)
Table 7. Sensitivity of all techniques in “in situ” or invasive cancer.
Table 9. Sensitivity of all techniques in all molecular subtypes of cancer.
DISCUSSION
MBI is a molecular imaging modality with an important role in detecting newly diagnosed breast cancer, in high-risk populations, and in cases with remaining diagnostic concerns. It developed from the imaging modality of breast scintigraphy and offers superior intrinsic spatial resolution than a conventional gamma camera. Recent data report a sensitivity of 83–100% for MBI in detecting breast cancer [22, 27, 28]. In our study, its sensitivity is 86.4%, reached by visual analysis, superior to both DM and DM+US (67.8% and 83.1%, respectively). Moreover, MBI correctly
identifies 60% of mammo-sonographically occult cancers, while only 4 lesions remained completely undetected. MBI reveals 3 invasive lesions missed by DM+US, all ≤ 1 cm in dense or extremely dense breast and 3 in situ lesions, all > 1 cm in scattered fibroglandular and dense breast. These results corroborates other studies showing that MBI could reveal mammographically occult breast cancer equally well in women with dense and non-dense breast with sensitivity values of 87.1% and 85.7%, respectively (vs 77.4% and 57.1% of DM) with no significant difference between MBI cancer detection and breast density (p=0.859) [29-31].
We further show that the sensitivity of MBI is not correlated to the dimension of the lesion (p=0.807) and is superior to both DM (p=0.005) and DM+US (p=0.271) for lesions ≤ 1 cm. Combined with our research, evidence suggests that MBI allows a reliable detection of cancers smaller than 1 cm due to high-resolution, small-field-of-view, dedicated gamma camera, developed to overcome the limitations of a traditional gamma camera.
Menopausal status significantly affects the sensitivity of MBI, which is 57.1% and 90.4% in pre- and postmenopausal women, respectively (p=0.029), even if we evaluated only 7 premenopausal women. A wider sample size will provide more reliable results. Literature shows few data about the correlation between menstrual status and MBI, but majority of studies reveals that 99mTc-MIBI uptake fluctuates significantly in normal mammary tissues in synchrony with the female reproductive cycle [32, 33]. Variable effects of the menstrual cycle on background parenchymal uptake may explain MBI low sensitivity in premenopausal women of our study, in which we did not consider menstrual phase.
Regarding molecular subtypes, our study suggests a higher sensitivity of MBI to detect luminal A cancer compared to DM (88.9% vs 61.1% and p=0.009) and similar compared to DM+US (88.9% vs 77.8%, p=0.297). These results need further studies, since in the literature, different conclusions are reported [34, 35].
MBI sensitivity is superior to both DM and DM+US in detecting invasive and in situ cancer, showing significantly higher values if compared to sole DM (p=0.022 and p=0.018). MBI sensitivity does not correlate with the presence of in situ component, whereas it happens for DM+US.
LIMITATIONS
some correlations. Besides, this is a retrospective analysis of a selected women group unable to undergo MRI and thus it is not an entirely representative sample. Furthermore, MBI images, according to the 2010 guideline of Society of Nuclear Medicine and Molecular Imaging, were analyzed and interpreted visually; however, visual analysis alone is rather subjective and remains reader dependent.
CONCLUSIONS
Our initial experience with MBI supports the use of this modality for breast cancer detection, suggesting that its real contribution is the improvement in sensitivity when it is evaluated in addition and based on DM+US findings, whereas its low specificity is offset by possible further US second look (the same workflow used for MRI). MBI has turned out to be a reliable alternative technique to MRI in selected cases, since both demonstrate high sensitivity and provide useful functional information. Currently, MBI remains a second choice compared to MRI due to its limitations of exposing women to a certain dose of radiation and lacking detailed spatial definition. However, the advantage shown by MBI of being independent from breast density and lesion size may represent a valid starting point to promote further studies on larger series of patients.
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