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Emerging Techniques and Molecular Imaging in Breast Cancer
Emerging Techniques and Molecular Imaging in Breast Cancer Wei Tse Yang, MD The sensitivity of screening mammography is limited in the evaluation of dense breasts, with as few as 45% of cancers visible in extremely dense breasts. Supplementary imaging for improved sensitivity in women with dense breasts is necessary to overcome this limitation. Emerging technologies that advance the applications of digital mammography include digital breast tomosynthesis and dedicated breast cone-beam computed tomography. Molecular imaging goes beyond structural imaging. A functional imaging technique that provides information on the biology, physiology, and metabolic pathways of cancer might help to improve the sensitivity and specificity of breast cancer diagnosis, facilitate early assessment of treatment response, and help individualize therapy options for patients. Advanced magnetic resonance, nuclear medicine, and optical imaging techniques in the realm of molecular imaging will be explored in this article. Semin Ultrasound CT MRI 32:288-299 Published by Elsevier Inc.
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creening mammography is the gold standard for breast cancer screening and is associated with up to 40% mortality reduction rate. Mammographic sensitivity decreases significantly in dense breasts, with sensitivity reported to be as low as 45% in women with extremely dense breasts.1-3 Supplemental imaging with higher sensitivity for cancer detection is necessary for women with dense breasts. Conventional breast imaging methods including mammography, sonography, and dynamic contrast-enhanced magnetic resonance imaging (MRI) are anatomy- and morphology-based imaging techniques that have achieved success in the detection and diagnosis of most but not all small cancers. The inability to detect all early cancers that would be amenable to effective treatment is an impediment to further improvement of patient outcomes. Emerging breast technologies include advanced digital applications in mammography: digital breast tomosynthesis (DBT), dedicated breast computed tomography (DBCT), intravenous and dual energy subtraction mammography; nuclear medicine techniques: positron emission mammography (PEM) and breast-specific gamma imaging (BSGI); MRI techniques: single-voxel MR spectroscopy (MRS) and diffusionweighted imaging (DWI); and diffuse optical tomography
Breast Imaging Section, Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Wei Tse Yang, MD, Breast Imaging Section, Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. E-mail: wyang@ mdanderson.org
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0887-2171/$-see front matter Published by Elsevier Inc. doi:10.1053/j.sult.2011.03.003
(DOT), an emerging technique that is cheap and portable and provides functional information on normal and malignant tissue of the breast.
Advanced Digital Applications in Mammography An inherent limitation of conventional mammography is the 2-dimensional (2-D) planar approach that creates pseudolesions caused by undercompression of normal glandular tissue and allows superimposed breast tissue to obscure small masses and areas of architectural distortion. Full-field digital mammography has improved dynamic range, tissue contrast, and the ability to post-process digital images. Advanced digital applications with 3-dimensional (3-D) opportunities include DBT and DBCT.
DBT DBT is an emerging digital imaging modality in which tomographic images of the breast are generated from multiple 2-D x-ray projection images. A series of usually 7-9 low-dose projection images are recorded as the mammographic unit moves gradually in a small arc over the compressed breast.4,5 The total dose is similar to single-view breast examination. The digital information is processed by the computer and displayed on a workstation as hundreds of raw images at selected slice thicknesses. Each individual slice presents a planar mammogram in either the craniocaudad or mediolateral oblique view and can be reconstructed at specified slab
Emerging techniques and molecular imaging in breast cancer or slice thicknesses to address spatial resolution issues and signal-to-noise ratio problems. A reader preference study in a screening recall population that evaluated DBT versus conventional mammography reported preference for DBT to be equal in 50%, superior in 37%, and inferior in 11%, when compared with conventional mammography.6 A subjective reader study that involved 9 readers and used 30 mixed diagnostic cases comprising twothirds masses versus one-third calcifications rated DBT better in up to 67% of cases.7 DBT is perceived as providing improved characterization and margin assessment of masses in preliminary studies. A reader study with 4 readers to assess margins of masses scheduled for biopsy reported incremental visible mass margin for all readers.8 Helvie et al8 compared DBT with conventional mammography in analyzing diagnostic image sets of masses scheduled for biopsy and reported 36.5% increase in the number of masses detected by DBT. An incremental detection rate of cancer of 40% was also reported for a small number (n ⫽ 7) of cancers in this same cohort by Helvie et al, whereas an incremental detection rate of 40% was noted by Lo et al9 without increased detection of cancers (n ⫽ 4). A large study from the Netherlands, however, reported no benefit with DBT.10 A total of 513 diagnostic digital mammograms were compared with DBT by a single observer, who reported similar sensitivity of 92.9% for both digital mammography and DBT and similar specificity of 86.1% and 84.4% for DBT and digital mammography, respectively, in the detection of cancer. The literature is scarce regarding the clinical detection and characterization of microcalcifications with DBT.11 Because in-plane versus out-of-plane resolution is different for calcification visualization, the assessment of microcalcifications requires further study. This problem might be addressed by developing maximum intensity projection (MIP) images consisting of thick slices, up to 1 or 2 cm, for calcification review. Advanced digital mammographic technology such as DBT is an exciting new development for breast cancer screening and diagnostic applications. Patient acceptance is expected to be high. Positive preliminary results require validation in larger prospective clinical trials. If DBT is successful in clinical trials, reading thresholds, reading times, recall rates, and biopsy indications will need to be addressed. Development of biopsy capabilities with DBT will be essential to address lesions that are seen only with DBT. Physician and technologist training will be necessary. The significant increase in the number of images for physician review with DBT will have considerable downstream impact on workflow and archiving. Other new digital mammography systems include contrast-enhanced digital mammography that provides information on neovascularity related to tumor angiogenesis. The potential advantages compared with MRI include low cost, simple installation on existing mammography systems, and superior patient acceptance from decreased time on the imaging system. Considerations need to be given to intravenous iodinated contrast requirements and adverse contrast reactions in a screening setting.12-18
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Figure 1 DBCT.(A) Koning Breast CT System including gantry, patient table, and free-standing operator’s console with radiation barrier. The gantry is self-shielded for radiation safety, obviating the need for lead walls. (B) Illustration shows patient lying prone with 1 breast pendant through tabletop opening into the imaging field. High-power mammography-style x-ray tube and flat-panel detector designed for cone-beam imaging are illustrated. (Images courtesy of Koning Corporation.) (Color version of figure is available online.)
DBCT Breast CT has higher contrast resolution than projection radiography (10⫻) and high signal-to-noise ratio, eliminates overlapping structures, demonstrates better x-ray penetration, and uses dose levels comparable to mammography.19,20 A flat-panel detector enabled cone-beam CT scanner of the breast has been studied in the experimental setting (Fig. 1A).21 The patient lies prone with 1 breast in a pendant position through a tabletop opening into the imaging field (Fig. 1B). The x-ray tube and flat-panel detector rotate around the breast in a 360° arc while obtaining data (Fig. 1B). The scanner developed at the University of Rochester uses pulsed
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290 x-ray sources and 10-second acquisition, with the capability of obtaining 300 views at 30 frames per second and at 49 kVp. The University of California Davis scanners use a PaxScan (Varian Medical Systems, Inc, Palo Alto, CA) 4030CB detector system and a continuous (nonpulsed) x-ray source operating at 80 kVp. At 30 frames per second, this system acquires 500 frames or projection images during a 16.6-second acquisition sequence. The short scan time on both scanners is a tremendous advantage in terms of the breath-hold examination. The first prospective comparison of noncontrast DBCT with screen film mammography was reported in 2008.22 Lesion conspicuity in both modalities was subjectively ranked by a single experienced breast imager, who reported equivalent overall conspicuity of benign and malignant breast lesions on DBCT to mammography but noted that masses were significantly more conspicuous on DBCT than microcalcifications22 (Figs. 2-4). Although these preliminary results are interesting, multireader multicenter studies are necessary to establish the true benefit and reproducibility of this new and emerging technique for imaging the breast. A second study published in 2010 reported on radiation dose, breast coverage, and image quality in 23 women aged 40 years and older with Breast Imaging Reporting and Data System (BIRADS) 1 and 2 mammograms.23 The authors concluded that DBCT can be used to image the entire breast from the chest wall to the nipple with spatial and contrast resolution adequate for the detection of masses and calcifications at a radiation dose within the range of conventional mammography. Preliminary results from contrast-enhanced DBCT show promise in the diagnostic evaluation and delineation of disease extent in a study of 50 patients with BIRADS 4 and 5 lesions who underwent both MRI and DBCT (noncontrast and contrastenhanced). Although most cancers were visible on both MRI and DBCT, there were cancers not visible on MRI but visible on contrast-enhanced DBCT and cancers that were visible on MRI but not seen on non– contrast-enhanced DBCT.24 Another study evaluated BIRADS 4 and 5 lesions on both unenhanced and contrast-enhanced CT and showed that intravenous contrast increased the conspicuity of malignant lesions.25 Patient tolerance of the DBCT table is similar to the stereotactic biopsy procedures, with reported discomfort in the neck and the back region. The limitations of breast CT include the identification of calcifications for screening, inadequate coverage of the axillary tail, and a need for dose reduction. This might be a barrier to using DBCT as a screening tool.
Nuclear Medicine Techniques Alternate screening methods for the detection of breast cancer and characterization of breast lesions in women with dense breasts are necessary to address the limitation of mammographically occult cancers (even when palpable) in women with dense breasts. Adjunct imaging techniques to detect, characterize, and monitor response are necessary to improve the performance of breast cancer imaging.
Figure 2 DBCT. A 67-year-old woman presents with a palpable finding in the left breast. (A) Left mediolateral oblique mammogram shows grouped coarse heterogeneous calcifications with segmental distribution (arrows). (B) Breast CT without contrast administration shows coarse heterogeneous calcifications with segmental distribution (arrows) in upper outer quadrant. Four-in-one display of coronal, axial, 3-D reconstruction, and sagittal CT scans starting from top left, clockwise. Final histopathology showed papillary carcinoma. (Images courtesy of Posy Seifert, MD, Elizabeth Wende Breast Care LLC.)
PEM PEM is a Food and Drug Administration (FDA) approved high spatial resolution (2 mm), dedicated breast positron emission tomography device that can provide anatomical and functional information. Dual moving head detectors are
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Figure 3 DBCT. A 51-year-old woman presents for screening. (A) Left craniocaudad mammogram shows a lobular mass with indistinct margins (arrow). (B) 3-D volume rendering of left breast shows lobular mass with circumscribed margins (arrow). Major vessels are visualized without contrast administration. (C) 3-D MIP of section of same breast shows circumscribed margins to this lobular mass (arrow). Vessels down to 1 mm in size are visible without contrast administration and might impact biopsy planning. Final histopathology showed fibroadenoma. (Images courtesy of Avice O’Connell, MD, University of Rochester Medical Center.)
mounted opposite each other on compression paddles attached to a portable compact scanner to obtain tomographic images of the breast. Ten to 15 mCi of fluorine 18 (18F) fluorodeoxyglucose (FDG) is injected intravenously in the arm contralateral to the side of the abnormality after a minimum 4-hour fast and appropriate blood glucose level confirmation. Each breast is gently immobilized and scanned in the craniocaudad and mediolateral oblique positions for between 4 and 10 minutes per view. Preliminary studies with FDGPEM showed 90% sensitivity in the depiction of invasive and in situ ductal carcinoma (10/11 ductal carcinoma in situ [DCIS] [91%], 33/37 invasive breast cancers [89%], 5/8 invasive cancers 1 cm or smaller [62.5%]).26 A recent multicenter study compared the performance of PEM with MRI in evaluating the extent of disease in ipsilateral breasts with cancer and in evaluating the impact on surgical management.27 Four hundred seventy-two women with newly diagnosed breast cancer who were candidates for breast-conserving surgery underwent contrast material– enhanced MRI and 18F FDG-PEM in randomized order. PEM and MRI had comparable breast-level sensitivity, although MRI had greater lesion-level sensitivity and more accurately depicted the need for mastectomy. PEM had greater specificity at the breast and lesion levels (Fig. 5). Integration of PEM and MRI increased cancer detection to 61 of 82 breasts (74%) versus 49 of 82 breasts (60%) identified with MRI alone (P ⬍ 0.001). FDG has been cleared for use in imaging cancers, and a breast biopsy guidance device that has been FDA approved
will be critical in the histologic evaluation of lesions seen only with PEM that are occult on mammography, sonography, and MRI.28 PEM has the capability to measure hypermetabolic tumor cells that can potentially contribute to the analysis and identification of functional differences in breast cancer subtypes, thereby aiding in treatment selection and monitoring of response to therapy.29 PEM will be an important platform for the exploitation of novel radiotracers such as 18-fluorothymidine (FLT), an agent that can potentially measure proliferation and serve as a surrogate biomarker for treatment response and drug discovery.
BSGI Nuclear medicine imaging of the breast requires intravenous administration of a radiotracer (technetium 99m methoxyisobutyl isonitrile [MIBI]) and a camera that detects radiotracer activity. Tc 99m sestamibi, originally used for myocardial perfusion imaging, has found success as a tumor seeking agent because radiotracers preferentially accumulate in tumor cellular mitochondria (Fig. 6), with minimal to no uptake in benign tissue. Tc 99m sestamibi accumulation in cancer cells is dependent on regional blood flow, plasma and mitochondrial membrane potential, angiogenesis, and tissue metabolism. BSGI employs a detector composed of thallium doped sodium iodide crystals [NaI(Tl)], while molecular breast imaging (MBI) is performed using a high-resolution, small field-
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Figure 4 DBCT. A 70-year-old woman presents with a palpable finding in right breast. (A) Spot compression right craniocaudad mammogram shows an irregular high-density mass with indistinct margins (arrow). (B) Sagittal and (C) coronal CT scans of right breast performed without contrast administration demonstrate an irregular mass with indistinct margins (arrow). Final histopathology showed invasive ductal cancer. (Images courtesy of Avice O’Connell, MD, University of Rochester Medical Center.)
of-view device that uses a cadmium zinc telluride solid state detector and addresses the limited tumor visibility (minimum size, 15-20 mm) of large field-of-view sestamibi imaging. This detector provides optimal pixel size for system spatial resolution and sensitivity and is targeted at 95% detectability rate of lesions 5 mm in diameter. For both BSGI and MBI, the breast is positioned and compressed in a manner similar to a mammogram examination after intravenous injection of 20 mCi of technetium sestamibi. Routine craniocaudad and mediolateral oblique images are obtained, with additional images as necessary (Fig. 6). Images are obtained at 100,000 counts per image, which requires between 4 and 10 minutes per view, resulting in an approximate 45-minute total examination time. An early study with a prototype camera recruited 50 patients with 28 cancers (mean size, 11 mm; range, 3-60 mm), 71% of which were nonpalpable.30 This study confirmed that it was feasible to image and detect subcentimeter cancers with higher sensitivity than was previously reported with large field-of-view imaging.30 Another study involved 146 consecutive women who underwent BSGI and had subsequent biopsy of 167 suspicious lesions, with 83 malignant lesions at histopathology. BSGI had overall sensitivity of
96.4% for the detection of cancer, sensitivity of 97% (65 of 67) for the detection of invasive cancers (mean size, 10 mm), and sensitivity of 93.8% (15 of 16) for the detection of DCIS (mean size, 18 mm).31 These single institution studies have provided encouraging data on the role of BSGI in the detection of occult cancer in women with newly diagnosed breast cancer and have demonstrated improved visualization of nonpalpable invasive cancers ⬍1 cm size. BSGI has also demonstrated comparable high sensitivity in the diagnosis of DCIS compared with mammography or MRI. A recent study reported sensitivity of 91%-94% for the detection of DCIS by using BSGI, compared with 77%-96% for MRI.32-35 A recent publication comparing a dual-headed MBI camera versus single-headed camera for the detection of cancer in 88 women reported sensitivity of 90% compared with 80%, respectively.36 For invasive cancers measuring ⬍1 cm, sensitivity was 82% compared with 68% for the single-headed camera. A dedicated dual-head gamma imaging system was compared with mammography in screening 1007 asymptomatic women with mammographically dense breasts and additional risk factors.37 All women underwent mammography and gamma imaging after intravenous injection of 740 mBq (20 mCi) technetium 99m sestamibi. The reference
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Figure 5 PEM versus MRI. (A) Axial postcontrast MIP MRI shows bilateral irregular enhancing masses suspicious for malignancy; one is in the central right breast (arrow), and one is in the medial left breast (short arrow). Right craniocaudad (B) and mediolateral oblique (C) PEM images show a corresponding irregular mass (arrows) with increased FDG uptake. Final histopathology showed invasive ductal cancer, confirming true-positive PEM and MRI. Left craniocaudad (D) and mediolateral oblique (E) PEM images show no corresponding uptake in a normal breast. Final histopathology obtained via MRI-guided biopsy showed fibrocystic change, confirming true-negative PEM and false-positive MRI. (Images courtesy of James Rogers, MD, Swedish Medical Center, Seattle, WA.) (Color version of figure is available online.)
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Figure 6 BSGI. (A) Tile image showing right and left craniocaudad and mediolateral oblique images in 30-year-old woman who presents with dense breasts and thickening. Extensive increased activity is seen throughout the right upper outer quadrant (long arrows), exceeding 12 cm in size. Two axillary nodes demonstrate increased uptake (arrows). (B) Extended craniocaudad views can be performed to image lateral abnormalities (arrow), as with mammography. (C) Right craniocaudad mammogram shows dense breast and smaller area of focal asymmetry and associated pleomorphic microcalcifications that measures 5 cm (arrow). (D) Transverse gray scale ultrasound of the right breast shows a hypoechoic mass that measures 3 cm (arrow) and is significantly less extensive than the BSGI images.
Emerging techniques and molecular imaging in breast cancer standard was cancer diagnosis or 12-month follow-up findings. The diagnostic yield, sensitivity, specificity, and positive predictive values were determined for mammography, gamma imaging, and both combined. Gamma imaging in addition to mammography significantly increased the detection of node-negative breast cancer in dense breasts by 7.5 per 1000 women screened (95% confidence interval, 3.615.4). Women at increased risk for breast cancer may benefit from adjunct gamma imaging, which has a reported negative predictive value of 94%-98%.37 Dose reduction with equivalent performance is critical in the context of high-risk screening that involves serial imaging. Research is ongoing to determine whether detector modification will permit success of molecular imaging with doses as low as 5 mCi. Issues that require consideration include establishing clear guidelines and indications for nuclear medicine imaging of the breast that might be linked to reimbursement, scan time, cost of the unit, and incremental advantage over conventional imaging with mammography, ultrasound, and MRI. Appropriate terminology and a nuclear medicine lexicon for breast imaging are critical for responsible clinical practice. An FDA-approved gamma-guided stereotactic localization device is available that can facilitate biopsy of lesions identified only with BSGI. This application will require clear indications for biopsy. As more data on BSGI and MBI emerge and mature, these new imaging technologies might be considered for imaging women with dense breasts who are unable or unwilling to undergo a breast MRI examination.
MRI Techniques MRS MRS is a technique that is used to suppress water and lipid signals to enhance the weaker signals from hydrogen atoms of metabolites with small molecular weights. Breast MRS is predicated on the detection of the choline peak and its derivatives (total choline [tCho]) at 3.2 ppm. Choline is an essential molecule for fatty acid synthesis during cell membrane production. Detection of the choline peak and an elevated tCho reflect an increase in the concentration of choline that is more frequently observed in malignant lesions,38-42 and a tCho peak greater than twice the adjacent spectral noise level has been proposed as an index of the probability of malignancy.43 Clinical MRS data can in principle be acquired as either single-voxel or multi-voxel modes. In single-voxel MRS, a rectangular volume of interest of variable size is outlined by the radiologist or technologist after the gadolinium-enhanced series. The MR signals outside the region of interest are suppressed, resulting in a single MR spectrum reflecting the metabolite profile of the volume of tissue outlined. In general, minimal voxel sizes of approximately 1 cm cube or more are necessary to produce spectra with adequate signalto-noise ratio in a reasonable time frame. Although multivoxel MRS can theoretically provide higher spatial resolution than single-voxel MRS, multi-voxel MRS has not found success in the breast. This is because breast MRI or MRS is
295 performed with phased array coils, and the product software to date has not been optimized in combining multi-voxel spectral data that are acquired by different channels of a phased array coil. The use of MRS has been suggested as an adjunct to dynamic contrast-enhanced MRI to increase specificity in defining malignant lesions. A 100% sensitivity of tCho depiction by MRS for malignant nonmass enhancements was reported, with an increase in the positive predictive value for suspicious enhancing nonmass lesions from 20% to 63% with the incorporation of MRS criteria into the diagnostic algorithm in several studies.44 Its true impact on clinical imaging and diagnosis remains uncertain at this time.
DWI DWI involves the application of pairs of large magnetic gradients that decrease the relative MR signal intensity of different tissues in proportion to the amount of free diffusion of their water molecules and can be performed via the application of a single set of diffusion gradients in a single orientation. DWI is generally applied with T2-weighted echo-planar imaging (EPI), an extremely rapid imaging technique that allows a short examination time and reduction of patient motion artifacts. However, EPI is complicated by high sensitivity to local magnetic field variations and uncompensated eddy currents, both of which can result in severe image distortion and artifacts.45-47 The amount of signal loss of water molecules in tissue is exponentially proportional to the degree of diffusion for a given diffusion gradient strength. When DWI is performed, 1 or more sets of diffusion-weighted images can be produced and viewed. In addition, an apparent diffusion coefficient (ADC) pixel map can be calculated from the component diffusion-weighted images produced from 2 or more DWI sets. Invasive breast cancers demonstrate restricted diffusion (lower ADC) relative to normal or benign breast tissue (Fig. 7). This reduced diffusivity of water in invasive cancers will render these lesions bright on diffusion-weighted images and can potentially help identify malignant lesions when dynamic contrast-enhanced imaging is equivocal. Benign lesions with high intrinsic T2 signal intensity might also appear bright on DWI because of the phenomenon of “T2 shine through.” In these situations, ADC quantification can address the T2 shine-through effect and provides a more accurate quantitative method than DWI for breast lesion characterization. The use of optimized ADC cutoff might improve lesion characterization without compromising sensitivity, with the advantage of decreasing the number of negative biopsies. ADC values and optimal cutoffs for benign and malignant differentiation might depend on the b-value associated with the applied gradients. Research is ongoing to determine the potential role of DWI in monitoring tumor response to neoadjuvant chemotherapy. Initial reports have described varying results on the reliability of pretreatment ADC in predicting tumor response to therapy.48,49
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Optical Imaging
Figure 7 Diffusion-weighted MRI. (A) Axial T1-weighted contrastenhanced MRI of left breast shows an irregular enhancing mass (arrow) with post-biopsy clip in situ. (B) Diffusion-weighted image (b ⫽ 1000 s/mm2) shows hyperintense signal in the medial left breast mass (arrow). (C) Corresponding ADC grayscale map (b ⫽ 0,1000 s/mm2) demonstrates reduced diffusion of the mass (arrow). The minimal ADC value in the region of the suspicious lesion was reduced.69 Final histopathology showed invasive ductal cancer. (Image courtesy of Basak Dogan, MD, The University of Texas M.D. Anderson Cancer Center.)
Functional imaging with DOT to discover techniques that can image disease at the biological and molecular level has shown promise. Optical tomography is a new technique that uses diffuse light in the near-infrared (NIR) spectrum to provide functional information of tumors by quantifying the tissue composition of normal and malignant breast tissue. This is facilitated by NIR laser (radiofrequency-modulated, continuous-wave, or pulse) probes that interrogate tissues noninvasively and provide quantitation of tumor hemoglobin content that is directly related to tumor angiogenesis and tumor hypoxia.50-55 Most optical imaging approaches have been based on the intrinsic contrast of major tissue chromophores that include hemoglobin, water, and lipids (Fig. 8A). The concentrations of tissue chromophores can be derived by measuring optical signals at multiple wavelengths that are matched with the known chromophore absorption spectra. Total hemoglobin concentration and tumor hypoxia can be derived from oxyhemoglobin and deoxyhemoglobin distributions, which are highly correlated with malignant status.56 An inherent limitation of DOT is the intense light scattering in tissue that leads to low spatial resolution, location uncertainty, imprecise target qualification and quantitation, and resultant difficulty in interpretation. A flexible light guide comprising optical fibers permits concurrent optical imaging with other imaging modalities to enable identical geometric considerations. The exquisite morphologic and anatomical detail that is provided by conventional imaging modalities can be exploited to assist optical imaging reconstruction, thereby improving the quantitation accuracy of light. Optical tomography with ultrasound and MRI has shown promise in overcoming these problems.57,58 When the breast is illuminated with a short laser pulse with red or NIR color by using laser optoacoustic ultrasound, a malignant lesion will absorb the laser pulse more intensely than surrounding normal tissue because of a higher concentration of blood in the tumor as a result of angiogenesis59 (Fig. 8B). The absorbed light is converted into heat instantly, and thermoacoustic pressure is generated before it is released from the tumor as an ultrasound wave. The optical energy effectively generates an optoacoustic (ultrasound) pulse with a profile that resembles the lesion.60 Positioning the array of ultrasound detectors in the breast allows the detection of optoacoustic signals and permits reconstruction of high-resolution images. The optical absorption coefficient is proportional to the concentration of molecular chromophores, ie, tissue molecules that absorb red or NIR light. The 2 main chromophores abundant in tumors are hemoglobin and oxyhemoglobin as a result of angiogenesis-related microvasculature. The wavelength of 755 nm is preferentially absorbed in hypoxic blood, and 1064 nm is preferentially absorbed in oxygenated blood. By altering the wavelength (color) of laser illumination, one can determine the rate of oxygenation in tumors. Increased hypoxia indicates a higher probability of malignancy. In addition, functional information on hemoglobin and oxyhemoglobin concentrations can help differentiate
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Figure 8 Laser optico-acoustic ultrasound (LOUS). (A) Laser optico-acoustic ultrasound is a real-time imaging modality whereby 760-nm and 1064-nm lasers are interleaved to image regions with predominantly deoxygenated and oxygenated hemoglobin, respectively. (B) The absorption spectra of 4 main tissue chromophores, including water, lipids, oxyhemoglobin, and hemoglobin, are shown in this graph. (C) Co-registered ultrasonic ⫹ optoacoustic images of invasive ductal carcinoma. (D) Co-registered ultrasonic ⫹ optoacoustic images of invasive lobular carcinoma. The wavelength of 755 nm is preferentially absorbed in hypoxic blood, and 1064 nm is preferentially absorbed in oxygenated blood. (Reprinted with permission from Ermilov et al.60) (Color version of figure is available online.)
malignancies on the basis of the biology. Aggressively proliferating tumors have advanced angiogenesis with hypoxic blood.56 Red and NIR spectral range of laser wavelengths allows deeper penetration of light into tissue. The image resolution and maximal imaging depth are scalable with ultrasonic frequency and can be up to several centimeters. Coregistered ultrasound and optoacoustic images of breast carcinomas are shown in Fig. 8C and D. Although DOT has been aggressively investigated in clinical pilot studies,51,53-56 NIR imaging with endogenous contrast depicts benign lesions as well as carcinomas, leading to difficulty in differentiating benign from malignant tissue. Pilot NIR breast imaging studies have been performed by using indocyanine green (ICG), a weak fluorescent dye, and omocianine, an ICG derivative, as contrast agents to facilitate increased absorption and fluorescence of carcinomas.61-63
The role of DOT in monitoring response of tumors to neoadjuvant chemotherapy has also been explored.64,65 Tumors have been shown to demonstrate heterogeneous blood flow. Regions of reduced blood flow in tumors might not receive adequate systemic therapy, leading to poor response to chemotherapy.66,67 Ultrahigh resolution with optical coherence tomography performed in 43 freshly excised breast specimens from 23 patients showed exquisite anatomical detail that might assist in the visualization of early benign and malignant human breast disease.68
Conclusions Conventional mammography remains the standard of care for the early diagnosis of breast cancer with established interpretation criteria, wide availability, and low cost as a
298 screening tool. Nonetheless, a high percentage of breast biopsies yield benign findings. Many biological and molecular processes that impact prognosis and outcome and influence the treatment algorithm for cancer patients cannot be measured and monitored by mammography, ultrasound, MRI, or CT, which are largely anatomical imaging methods. Because normal cellular pathways are either suppressed or enhanced by tumor-specific molecular changes, it is logical that advances in molecular imaging will help provide tumor-specific details that can contribute to (1) early assessment of treatment response, (2) individualization of treatment options, and (3) detection before there is morphologic disease. Significant progress has been made in developing alternate breast imaging modalities and molecular imaging that provide functional information on molecular processes in addition to structural and morphologic information that will help improve cancer diagnosis, research, and treatment paradigms.
References 1. Berg WA, Gutierrez L, NessAiver MS, et al: Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 233:830-849, 2004 2. Mandelson MT, Oestreicher N, Porter PL, et al: Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 92:1081-1087, 2000 3. Kolb TM, Lichy J, Newhouse JH: Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology 225:165-175, 2002 4. Niklason LT, Christian BT, Niklason LE, et al: Digital tomosynthesis in breast imaging. Radiology 205:399-406, 1997 5. Niklason LE, Kopans DB, Hamberg LM: Digital breast imaging: tomosynthesis and digital subtraction mammography. Breast Dis 10:151164, 1998 6. Poplack SP, Tosteson TD, Kogel CA, et al: Digital breast tomosynthesis: initial experience in 98 women with abnormal digital screening mammography. AJR Am J Roentgenol 189:616-623, 2007 7. Good WF, Abrams GS, Catullo VJ, et al: Digital breast tomosynthesis: a pilot observer study. AJR Am J Roentgenol 190:865-869, 2008 8. Helvie MA, Roubidoux M, Zhang Y, et al: Tomosynthesis mammography versus conventional mammography: lesion detection and reader preference—initial experience. Presented at the Radiologic Society of North America 92nd Scientific Assembly and Annual Meeting, Chicago, IL, November 26-December 1, 2006 9. Lo JY, Durham NC, Baker JA: Breast tomosynthesis: assessing patient compression, comfort, and preference. Presented at the Radiologic Society of North America 92nd Scientific Assembly and Annual Meeting, Chicago, IL, 2006 10. Teertstra HJ, Loo CE, van den Bosch MA, et al: Breast tomosynthesis in clinical practice: initial results. Eur Radiol 20:16-24, 2010 11. Helvie MA, Chan HP, Hadjiiski L, et al: Digital breast tomosynthesis mammography: successful assessment of benign and malignant microcalcifications. Presented at the Radiologic Society of North America 95th Scientific Assembly and Annual Meeting, Chicago, IL, November 28-December 4, 2009 12. Jong RA, Yaffe MJ, Skarpathiotakis M, et al: Contrast-enhanced digital mammography: initial clinical experience. Radiology 228:842-850, 2003 13. Lewin JM, Isaacs PK, Vance V, et al: Dual-energy contrast-enhanced digital subtraction mammography: feasibility. Radiology 229:261-268, 2003 14. Diekmann F, Diekmann S, Jeunehomme F, et al: Digital mammography using iodine-based contrast media: initial clinical experience with dynamic contrast medium enhancement. Invest Radiol 40:397-404, 2005
W.T. Yang 15. Dromain C, Balleyguier C, Muller S, et al: Evaluation of tumor angiogenesis of breast carcinoma using contrast-enhanced digital mammography. AJR Am J Roentgenol 187:W528-W537, 2006 16. Chen SC, Carton AK, Albert M, et al: Initial clinical experience with contrast-enhanced digital breast tomosynthesis. Acad Radiol 14:229238, 2007 17. Diekmann F, Bick U: Tomosynthesis and contrast-enhanced digital mammography: recent advances in digital mammography. Eur Radiol 17:3086-3092, 2007 18. Dromain C, Balleyguier C, Adler G, et al: Contrast-enhanced digital mammography. Eur J Radiol 69:34-42, 2009 19. Boone JM, Nelson TR, Lindfors KK, et al: Dedicated breast CT: radiation dose and image quality evaluation. Radiology 221:657-667, 2001 20. Chen Z, Ning R: Why should breast tumour detection go three dimensional? Phys Med Biol 48:2217-2228, 2003 21. Chen B, Ning R: Cone-beam volume CT breast imaging: feasibility study. Med Phys 29:755-770, 2002 22. Lindfors KK, Boone JM, Nelson TR, et al: Dedicated breast CT: initial clinical experience. Radiology 246:725-733, 2008 23. O’Connell A, Conover DL, Zhang Y, et al: Cone-beam CT for breast imaging: radiation dose, breast coverage, and image quality. AJR Am J Roentgenol 195:496-509, 2010 24. Somerville P, Destounis S, Murphy P, et al: A comparison of cone beam breast computed tomography (CBBCT) to MRI of the breast. Presented at the Radiological Society of North America Scientific Assembly and Annual Meeting, Oak Brook, IL, 2010 25. Seifert P, Somerville P, Murphy P, et al: Initial experience of cone beam breast computed tomography (CBBCT) with or without contrast in a community-based practice. Presented at the Radiological Society of North America Scientific Assembly and Annual Meeting, Oak Brook, IL, 2009 26. Berg WA, Weinberg IN, Narayanan D, et al: High-resolution fluorodeoxyglucose positron emission tomography with compression (“positron emission mammography”) is highly accurate in depicting primary breast cancer. Breast J 12:309-323, 2006 27. Berg WA, Madsen KS, Schilling K, et al: Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology 258:59-72, 2011 28. Kalinyak JE, Schilling K, Berg WA, et al: PET-guided breast biopsy. Breast J 17:143-151, 2011 29. Yang WT, Rohren E, Mawlawi O, et al: Functional imaging of triple receptor negative versus HER2 overexpressing breast cancer. Presented in Electronic Exhibit # E018, American Roentgen Ray Society 2011 Annual Meeting, Chicago, IL, May 1-6, 2011 30. Brem RF, Schoonjans JM, Kieper DA, et al: High-resolution scintimammography: a pilot study. J Nucl Med 43:909-915, 2002 31. Brem RF, Rapelyea JA, Zisman G, et al: Occult breast cancer: scintimammography with high-resolution breast-specific gamma camera in women at high risk for breast cancer. Radiology 237:274-280, 2005 32. Brem RF, Fishman M, Rapelyea JA: Detection of ductal carcinoma in situ with mammography, breast specific gamma imaging, and magnetic resonance imaging: a comparative study. Acad Radiol 14:945-950, 2007 33. Brem RF, Floerke AC, Rapelyea JA, et al: Breast-specific gamma imaging as an adjunct imaging modality for the diagnosis of breast cancer. Radiology 247:651-657, 2008 34. O’Connor M, Rhodes D, Hruska C: Molecular breast imaging. Expert Rev Anticancer Ther 9:1073-1080, 2009 35. Raza S, Vallejo M, Chikarmane SA, et al: Pure ductal carcinoma in situ: a range of MRI features. AJR Am J Roentgenol 191:689-699, 2008 36. Hruska CB, Phillips SW, Whaley DH, et al: Molecular breast imaging: use of a dual-head dedicated gamma camera to detect small breast tumors. AJR Am J Roentgenol 191:1805-1815, 2008 37. Rhodes DJ, Hruska CB, Phillips SW, et al: Dedicated dual-head gamma imaging for breast cancer screening in women with mammographically dense breasts. Radiology 258:106-118, 2011
Emerging techniques and molecular imaging in breast cancer 38. Gribbestad IS, Singstad TE, Nilsen G, et al: In vivo 1H MRS of normal breast and breast tumors using a dedicated double breast coil. J Magn Reson Imaging 8:1191-1197, 1998 39. Roebuck JR, Cecil KM, Schnall MD, et al: Human breast lesions: characterization with proton MR spectroscopy. Radiology 209:269-275, 1998 40. Kvistad KA, Bakken IJ, Gribbestad IS, et al:Characterization of neoplastic and normal human breast tissues with in vivo 1H MR spectroscopy. J Magn Reson Imaging 10:159-164, 1999 41. Kim JK, Park SH, Lee HM, et al: In vivo 1H-MRS evaluation of malignant and benign breast diseases. Breast 12:179-182, 2003 42. Jacobs MA, Barker PB, Argani P, et al: Combined dynamic contrast enhanced breast MR and proton spectroscopic imaging: a feasibility study. J Magn Reson Imaging 21:23-28, 2005 43. Baek HM, Yu HJ, Chen JH, et al: Quantitative correlation between (1)H MRS and dynamic contrast-enhanced MRI of human breast cancer. Magn Reson Imaging 26:523-531, 2008 44. Bartella L, Thakur SB, Morris EA, et al: Enhancing nonmass lesions in the breast: evaluation with proton (1H) MR spectroscopy. Radiology 245:80-87, 2007 45. Guo Y, Cai YQ, Cai ZL, et al: Differentiation of clinically benign and malignant breast lesions using diffusion-weighted imaging. J Magn Reson Imaging 16:172-178, 2002 46. Kinoshita T, Yashiro N, Ihara N, et al: Diffusion-weighted half-Fourier single-shot turbo spin echo imaging in breast tumors: differentiation of invasive ductal carcinoma from fibroadenoma. J Comput Assist Tomogr 26:1042-1046, 2002 47. Kuroki Y, Nasu K, Kuroki S, et al: Diffusion-weighted imaging of breast cancer with the sensitivity encoding technique: analysis of the apparent diffusion coefficient value. Magn Reson Med Sci 3:79-85, 2004 48. Woodhams R, Kakita S, Hata H, et al: Identification of residual breast carcinoma following neoadjuvant chemotherapy: diffusion-weighted imaging— comparison with contrast-enhanced MR imaging and pathologic findings. Radiology 254:357-366, 2010 49. Park SH, Moon WK, Cho N, et al: Diffusion-weighted MR imaging: pretreatment prediction of response to neoadjuvant chemotherapy in patients with breast cancer. Radiology 257:56-63, 2010 50. Mahmood U, Tung CH, Bogdanov A Jr, et al: Near-infrared optical imaging of protease activity for tumor detection. Radiology 213:866870, 1999 51. Tromberg BJ, Shah N, Lanning R, et al: Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy. Neoplasia 2:26-40, 2000 52. Poplack SP, Paulsen KD, Hartov A, et al: Electromagnetic breast imaging: average tissue property values in women with negative clinical findings. Radiology 231:571-580, 2004 53. Poplack SP, Tosteson TD, Wells WA, et al: Electromagnetic breast imaging: results of a pilot study in women with abnormal mammograms. Radiology 243:350-359, 2007
299 54. Gibson AP, Hebden JC, Arridge SR: Recent advances in diffuse optical imaging. Phys Med Biol 50:R1-R43, 2005 55. Kukreti S, Cerussi AE, Tanamai W, et al: Characterization of metabolic differences between benign and malignant tumors: high-spectral-resolution diffuse optical spectroscopy. Radiology 254: 277-284, 2010 56. Brown JM: The hypoxic cell. Cancer Res 59:5863-5870, 1999 57. Zhu Q, Cronin EB, Currier AA, et al: Benign versus malignant breast masses: optical differentiation with US-guided optical imaging reconstruction. Radiology 237:57-66, 2005 58. Zhu Q, Hegde PU, Ricci A Jr, et al: Early-stage invasive breast cancers: potential role of optical tomography with US localization in assisting diagnosis. Radiology 256:367-378, 2010 59. Folkman J, Watson K, Ingber D, et al: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58-61, 1989 60. Ermilov SA, Fronheiser MP, Nadvoretsky V, et al: Real-time optoacoustic imaging of breast cancer using an interleaved two-laser imaging system coregistered with ultrasound. Proceedings of SPIE 7564: 75641W1-74641W-7, 2010 61. Intes X, Ripoll J, Chen Y, et al: In vivo continuous-wave optical breast imaging enhanced with indocyanine green. Med Phys 30:1039-1047, 2003 62. Corlu A, Choe R, Durduran T, et al: Three-dimensional in vivo fluorescence diffuse optical tomography of breast cancer in humans. Opt Express 15:6696-6716, 2007 63. Poellinger A, Burock S, Grosenick D, et al: Breast cancer: early- and late-fluorescence near-infrared imaging with indocyanine green—a preliminary study. Radiology 258:409-416, 2011 64. Tromberg BJ, Cerussi A, Shah N, et al: Imaging in breast cancer: diffuse optics in breast cancer— detecting tumors in pre-menopausal women and monitoring neoadjuvant chemotherapy. Breast Cancer Res 7:279285, 2005 65. Jiang S, Pogue BW, Carpenter CM, et al: Evaluation of breast tumor response to neoadjuvant chemotherapy with tomographic diffuse optical spectroscopy: case studies of tumor region-of-interest changes. Radiology 252:551-560, 2009 66. Zhu Q, Kurtzma SH, Hegde P, et al: Utilizing optical tomography with ultrasound localization to image heterogeneous hemoglobin distribution in large breast cancers. Neoplasia 7:263-270, 2005 67. Mankoff DA, Dunnwald LK, Gralow JR, et al: Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy. J Nucl Med 43:500-509, 2002 68. Hsiung PL, Phatak DR, Chen Y, et al: Benign and malignant lesions in the human breast depicted with ultrahigh resolution and three-dimensional optical coherence tomography. Radiology 244:865-874, 2007 69. Tsushima Y, Takahashi-Taketomi A, Endo K: Magnetic resonance (MR) differential diagnosis of breast tumors using apparent diffusion coefficient (ADC) on 1.5T. J Magn Reson Imaging 30:249-255, 2009
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creening mammography is the gold standard for breast cancer screening and is associated with up to 40% mortality reduction rate. Mammographic sensitivity decreases significantly in dense breasts, with sensitivity reported to be as low as 45% in women with extremely dense breasts.1-3 Supplemental imaging with higher sensitivity for cancer detection is necessary for women with dense breasts. Conventional breast imaging methods including mammography, sonography, and dynamic contrast-enhanced magnetic resonance imaging (MRI) are anatomy- and morphology-based imaging techniques that have achieved success in the detection and diagnosis of most but not all small cancers. The inability to detect all early cancers that would be amenable to effective treatment is an impediment to further improvement of patient outcomes. Emerging breast technologies include advanced digital applications in mammography: digital breast tomosynthesis (DBT), dedicated breast computed tomography (DBCT), intravenous and dual energy subtraction mammography; nuclear medicine techniques: positron emission mammography (PEM) and breast-specific gamma imaging (BSGI); MRI techniques: single-voxel MR spectroscopy (MRS) and diffusionweighted imaging (DWI); and diffuse optical tomography
Breast Imaging Section, Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Wei Tse Yang, MD, Breast Imaging Section, Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. E-mail: wyang@ mdanderson.org
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(DOT), an emerging technique that is cheap and portable and provides functional information on normal and malignant tissue of the breast.
Advanced Digital Applications in Mammography An inherent limitation of conventional mammography is the 2-dimensional (2-D) planar approach that creates pseudolesions caused by undercompression of normal glandular tissue and allows superimposed breast tissue to obscure small masses and areas of architectural distortion. Full-field digital mammography has improved dynamic range, tissue contrast, and the ability to post-process digital images. Advanced digital applications with 3-dimensional (3-D) opportunities include DBT and DBCT.
DBT DBT is an emerging digital imaging modality in which tomographic images of the breast are generated from multiple 2-D x-ray projection images. A series of usually 7-9 low-dose projection images are recorded as the mammographic unit moves gradually in a small arc over the compressed breast.4,5 The total dose is similar to single-view breast examination. The digital information is processed by the computer and displayed on a workstation as hundreds of raw images at selected slice thicknesses. Each individual slice presents a planar mammogram in either the craniocaudad or mediolateral oblique view and can be reconstructed at specified slab
Emerging techniques and molecular imaging in breast cancer or slice thicknesses to address spatial resolution issues and signal-to-noise ratio problems. A reader preference study in a screening recall population that evaluated DBT versus conventional mammography reported preference for DBT to be equal in 50%, superior in 37%, and inferior in 11%, when compared with conventional mammography.6 A subjective reader study that involved 9 readers and used 30 mixed diagnostic cases comprising twothirds masses versus one-third calcifications rated DBT better in up to 67% of cases.7 DBT is perceived as providing improved characterization and margin assessment of masses in preliminary studies. A reader study with 4 readers to assess margins of masses scheduled for biopsy reported incremental visible mass margin for all readers.8 Helvie et al8 compared DBT with conventional mammography in analyzing diagnostic image sets of masses scheduled for biopsy and reported 36.5% increase in the number of masses detected by DBT. An incremental detection rate of cancer of 40% was also reported for a small number (n ⫽ 7) of cancers in this same cohort by Helvie et al, whereas an incremental detection rate of 40% was noted by Lo et al9 without increased detection of cancers (n ⫽ 4). A large study from the Netherlands, however, reported no benefit with DBT.10 A total of 513 diagnostic digital mammograms were compared with DBT by a single observer, who reported similar sensitivity of 92.9% for both digital mammography and DBT and similar specificity of 86.1% and 84.4% for DBT and digital mammography, respectively, in the detection of cancer. The literature is scarce regarding the clinical detection and characterization of microcalcifications with DBT.11 Because in-plane versus out-of-plane resolution is different for calcification visualization, the assessment of microcalcifications requires further study. This problem might be addressed by developing maximum intensity projection (MIP) images consisting of thick slices, up to 1 or 2 cm, for calcification review. Advanced digital mammographic technology such as DBT is an exciting new development for breast cancer screening and diagnostic applications. Patient acceptance is expected to be high. Positive preliminary results require validation in larger prospective clinical trials. If DBT is successful in clinical trials, reading thresholds, reading times, recall rates, and biopsy indications will need to be addressed. Development of biopsy capabilities with DBT will be essential to address lesions that are seen only with DBT. Physician and technologist training will be necessary. The significant increase in the number of images for physician review with DBT will have considerable downstream impact on workflow and archiving. Other new digital mammography systems include contrast-enhanced digital mammography that provides information on neovascularity related to tumor angiogenesis. The potential advantages compared with MRI include low cost, simple installation on existing mammography systems, and superior patient acceptance from decreased time on the imaging system. Considerations need to be given to intravenous iodinated contrast requirements and adverse contrast reactions in a screening setting.12-18
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Figure 1 DBCT.(A) Koning Breast CT System including gantry, patient table, and free-standing operator’s console with radiation barrier. The gantry is self-shielded for radiation safety, obviating the need for lead walls. (B) Illustration shows patient lying prone with 1 breast pendant through tabletop opening into the imaging field. High-power mammography-style x-ray tube and flat-panel detector designed for cone-beam imaging are illustrated. (Images courtesy of Koning Corporation.) (Color version of figure is available online.)
DBCT Breast CT has higher contrast resolution than projection radiography (10⫻) and high signal-to-noise ratio, eliminates overlapping structures, demonstrates better x-ray penetration, and uses dose levels comparable to mammography.19,20 A flat-panel detector enabled cone-beam CT scanner of the breast has been studied in the experimental setting (Fig. 1A).21 The patient lies prone with 1 breast in a pendant position through a tabletop opening into the imaging field (Fig. 1B). The x-ray tube and flat-panel detector rotate around the breast in a 360° arc while obtaining data (Fig. 1B). The scanner developed at the University of Rochester uses pulsed
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290 x-ray sources and 10-second acquisition, with the capability of obtaining 300 views at 30 frames per second and at 49 kVp. The University of California Davis scanners use a PaxScan (Varian Medical Systems, Inc, Palo Alto, CA) 4030CB detector system and a continuous (nonpulsed) x-ray source operating at 80 kVp. At 30 frames per second, this system acquires 500 frames or projection images during a 16.6-second acquisition sequence. The short scan time on both scanners is a tremendous advantage in terms of the breath-hold examination. The first prospective comparison of noncontrast DBCT with screen film mammography was reported in 2008.22 Lesion conspicuity in both modalities was subjectively ranked by a single experienced breast imager, who reported equivalent overall conspicuity of benign and malignant breast lesions on DBCT to mammography but noted that masses were significantly more conspicuous on DBCT than microcalcifications22 (Figs. 2-4). Although these preliminary results are interesting, multireader multicenter studies are necessary to establish the true benefit and reproducibility of this new and emerging technique for imaging the breast. A second study published in 2010 reported on radiation dose, breast coverage, and image quality in 23 women aged 40 years and older with Breast Imaging Reporting and Data System (BIRADS) 1 and 2 mammograms.23 The authors concluded that DBCT can be used to image the entire breast from the chest wall to the nipple with spatial and contrast resolution adequate for the detection of masses and calcifications at a radiation dose within the range of conventional mammography. Preliminary results from contrast-enhanced DBCT show promise in the diagnostic evaluation and delineation of disease extent in a study of 50 patients with BIRADS 4 and 5 lesions who underwent both MRI and DBCT (noncontrast and contrastenhanced). Although most cancers were visible on both MRI and DBCT, there were cancers not visible on MRI but visible on contrast-enhanced DBCT and cancers that were visible on MRI but not seen on non– contrast-enhanced DBCT.24 Another study evaluated BIRADS 4 and 5 lesions on both unenhanced and contrast-enhanced CT and showed that intravenous contrast increased the conspicuity of malignant lesions.25 Patient tolerance of the DBCT table is similar to the stereotactic biopsy procedures, with reported discomfort in the neck and the back region. The limitations of breast CT include the identification of calcifications for screening, inadequate coverage of the axillary tail, and a need for dose reduction. This might be a barrier to using DBCT as a screening tool.
Nuclear Medicine Techniques Alternate screening methods for the detection of breast cancer and characterization of breast lesions in women with dense breasts are necessary to address the limitation of mammographically occult cancers (even when palpable) in women with dense breasts. Adjunct imaging techniques to detect, characterize, and monitor response are necessary to improve the performance of breast cancer imaging.
Figure 2 DBCT. A 67-year-old woman presents with a palpable finding in the left breast. (A) Left mediolateral oblique mammogram shows grouped coarse heterogeneous calcifications with segmental distribution (arrows). (B) Breast CT without contrast administration shows coarse heterogeneous calcifications with segmental distribution (arrows) in upper outer quadrant. Four-in-one display of coronal, axial, 3-D reconstruction, and sagittal CT scans starting from top left, clockwise. Final histopathology showed papillary carcinoma. (Images courtesy of Posy Seifert, MD, Elizabeth Wende Breast Care LLC.)
PEM PEM is a Food and Drug Administration (FDA) approved high spatial resolution (2 mm), dedicated breast positron emission tomography device that can provide anatomical and functional information. Dual moving head detectors are
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Figure 3 DBCT. A 51-year-old woman presents for screening. (A) Left craniocaudad mammogram shows a lobular mass with indistinct margins (arrow). (B) 3-D volume rendering of left breast shows lobular mass with circumscribed margins (arrow). Major vessels are visualized without contrast administration. (C) 3-D MIP of section of same breast shows circumscribed margins to this lobular mass (arrow). Vessels down to 1 mm in size are visible without contrast administration and might impact biopsy planning. Final histopathology showed fibroadenoma. (Images courtesy of Avice O’Connell, MD, University of Rochester Medical Center.)
mounted opposite each other on compression paddles attached to a portable compact scanner to obtain tomographic images of the breast. Ten to 15 mCi of fluorine 18 (18F) fluorodeoxyglucose (FDG) is injected intravenously in the arm contralateral to the side of the abnormality after a minimum 4-hour fast and appropriate blood glucose level confirmation. Each breast is gently immobilized and scanned in the craniocaudad and mediolateral oblique positions for between 4 and 10 minutes per view. Preliminary studies with FDGPEM showed 90% sensitivity in the depiction of invasive and in situ ductal carcinoma (10/11 ductal carcinoma in situ [DCIS] [91%], 33/37 invasive breast cancers [89%], 5/8 invasive cancers 1 cm or smaller [62.5%]).26 A recent multicenter study compared the performance of PEM with MRI in evaluating the extent of disease in ipsilateral breasts with cancer and in evaluating the impact on surgical management.27 Four hundred seventy-two women with newly diagnosed breast cancer who were candidates for breast-conserving surgery underwent contrast material– enhanced MRI and 18F FDG-PEM in randomized order. PEM and MRI had comparable breast-level sensitivity, although MRI had greater lesion-level sensitivity and more accurately depicted the need for mastectomy. PEM had greater specificity at the breast and lesion levels (Fig. 5). Integration of PEM and MRI increased cancer detection to 61 of 82 breasts (74%) versus 49 of 82 breasts (60%) identified with MRI alone (P ⬍ 0.001). FDG has been cleared for use in imaging cancers, and a breast biopsy guidance device that has been FDA approved
will be critical in the histologic evaluation of lesions seen only with PEM that are occult on mammography, sonography, and MRI.28 PEM has the capability to measure hypermetabolic tumor cells that can potentially contribute to the analysis and identification of functional differences in breast cancer subtypes, thereby aiding in treatment selection and monitoring of response to therapy.29 PEM will be an important platform for the exploitation of novel radiotracers such as 18-fluorothymidine (FLT), an agent that can potentially measure proliferation and serve as a surrogate biomarker for treatment response and drug discovery.
BSGI Nuclear medicine imaging of the breast requires intravenous administration of a radiotracer (technetium 99m methoxyisobutyl isonitrile [MIBI]) and a camera that detects radiotracer activity. Tc 99m sestamibi, originally used for myocardial perfusion imaging, has found success as a tumor seeking agent because radiotracers preferentially accumulate in tumor cellular mitochondria (Fig. 6), with minimal to no uptake in benign tissue. Tc 99m sestamibi accumulation in cancer cells is dependent on regional blood flow, plasma and mitochondrial membrane potential, angiogenesis, and tissue metabolism. BSGI employs a detector composed of thallium doped sodium iodide crystals [NaI(Tl)], while molecular breast imaging (MBI) is performed using a high-resolution, small field-
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Figure 4 DBCT. A 70-year-old woman presents with a palpable finding in right breast. (A) Spot compression right craniocaudad mammogram shows an irregular high-density mass with indistinct margins (arrow). (B) Sagittal and (C) coronal CT scans of right breast performed without contrast administration demonstrate an irregular mass with indistinct margins (arrow). Final histopathology showed invasive ductal cancer. (Images courtesy of Avice O’Connell, MD, University of Rochester Medical Center.)
of-view device that uses a cadmium zinc telluride solid state detector and addresses the limited tumor visibility (minimum size, 15-20 mm) of large field-of-view sestamibi imaging. This detector provides optimal pixel size for system spatial resolution and sensitivity and is targeted at 95% detectability rate of lesions 5 mm in diameter. For both BSGI and MBI, the breast is positioned and compressed in a manner similar to a mammogram examination after intravenous injection of 20 mCi of technetium sestamibi. Routine craniocaudad and mediolateral oblique images are obtained, with additional images as necessary (Fig. 6). Images are obtained at 100,000 counts per image, which requires between 4 and 10 minutes per view, resulting in an approximate 45-minute total examination time. An early study with a prototype camera recruited 50 patients with 28 cancers (mean size, 11 mm; range, 3-60 mm), 71% of which were nonpalpable.30 This study confirmed that it was feasible to image and detect subcentimeter cancers with higher sensitivity than was previously reported with large field-of-view imaging.30 Another study involved 146 consecutive women who underwent BSGI and had subsequent biopsy of 167 suspicious lesions, with 83 malignant lesions at histopathology. BSGI had overall sensitivity of
96.4% for the detection of cancer, sensitivity of 97% (65 of 67) for the detection of invasive cancers (mean size, 10 mm), and sensitivity of 93.8% (15 of 16) for the detection of DCIS (mean size, 18 mm).31 These single institution studies have provided encouraging data on the role of BSGI in the detection of occult cancer in women with newly diagnosed breast cancer and have demonstrated improved visualization of nonpalpable invasive cancers ⬍1 cm size. BSGI has also demonstrated comparable high sensitivity in the diagnosis of DCIS compared with mammography or MRI. A recent study reported sensitivity of 91%-94% for the detection of DCIS by using BSGI, compared with 77%-96% for MRI.32-35 A recent publication comparing a dual-headed MBI camera versus single-headed camera for the detection of cancer in 88 women reported sensitivity of 90% compared with 80%, respectively.36 For invasive cancers measuring ⬍1 cm, sensitivity was 82% compared with 68% for the single-headed camera. A dedicated dual-head gamma imaging system was compared with mammography in screening 1007 asymptomatic women with mammographically dense breasts and additional risk factors.37 All women underwent mammography and gamma imaging after intravenous injection of 740 mBq (20 mCi) technetium 99m sestamibi. The reference
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Figure 5 PEM versus MRI. (A) Axial postcontrast MIP MRI shows bilateral irregular enhancing masses suspicious for malignancy; one is in the central right breast (arrow), and one is in the medial left breast (short arrow). Right craniocaudad (B) and mediolateral oblique (C) PEM images show a corresponding irregular mass (arrows) with increased FDG uptake. Final histopathology showed invasive ductal cancer, confirming true-positive PEM and MRI. Left craniocaudad (D) and mediolateral oblique (E) PEM images show no corresponding uptake in a normal breast. Final histopathology obtained via MRI-guided biopsy showed fibrocystic change, confirming true-negative PEM and false-positive MRI. (Images courtesy of James Rogers, MD, Swedish Medical Center, Seattle, WA.) (Color version of figure is available online.)
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Figure 6 BSGI. (A) Tile image showing right and left craniocaudad and mediolateral oblique images in 30-year-old woman who presents with dense breasts and thickening. Extensive increased activity is seen throughout the right upper outer quadrant (long arrows), exceeding 12 cm in size. Two axillary nodes demonstrate increased uptake (arrows). (B) Extended craniocaudad views can be performed to image lateral abnormalities (arrow), as with mammography. (C) Right craniocaudad mammogram shows dense breast and smaller area of focal asymmetry and associated pleomorphic microcalcifications that measures 5 cm (arrow). (D) Transverse gray scale ultrasound of the right breast shows a hypoechoic mass that measures 3 cm (arrow) and is significantly less extensive than the BSGI images.
Emerging techniques and molecular imaging in breast cancer standard was cancer diagnosis or 12-month follow-up findings. The diagnostic yield, sensitivity, specificity, and positive predictive values were determined for mammography, gamma imaging, and both combined. Gamma imaging in addition to mammography significantly increased the detection of node-negative breast cancer in dense breasts by 7.5 per 1000 women screened (95% confidence interval, 3.615.4). Women at increased risk for breast cancer may benefit from adjunct gamma imaging, which has a reported negative predictive value of 94%-98%.37 Dose reduction with equivalent performance is critical in the context of high-risk screening that involves serial imaging. Research is ongoing to determine whether detector modification will permit success of molecular imaging with doses as low as 5 mCi. Issues that require consideration include establishing clear guidelines and indications for nuclear medicine imaging of the breast that might be linked to reimbursement, scan time, cost of the unit, and incremental advantage over conventional imaging with mammography, ultrasound, and MRI. Appropriate terminology and a nuclear medicine lexicon for breast imaging are critical for responsible clinical practice. An FDA-approved gamma-guided stereotactic localization device is available that can facilitate biopsy of lesions identified only with BSGI. This application will require clear indications for biopsy. As more data on BSGI and MBI emerge and mature, these new imaging technologies might be considered for imaging women with dense breasts who are unable or unwilling to undergo a breast MRI examination.
MRI Techniques MRS MRS is a technique that is used to suppress water and lipid signals to enhance the weaker signals from hydrogen atoms of metabolites with small molecular weights. Breast MRS is predicated on the detection of the choline peak and its derivatives (total choline [tCho]) at 3.2 ppm. Choline is an essential molecule for fatty acid synthesis during cell membrane production. Detection of the choline peak and an elevated tCho reflect an increase in the concentration of choline that is more frequently observed in malignant lesions,38-42 and a tCho peak greater than twice the adjacent spectral noise level has been proposed as an index of the probability of malignancy.43 Clinical MRS data can in principle be acquired as either single-voxel or multi-voxel modes. In single-voxel MRS, a rectangular volume of interest of variable size is outlined by the radiologist or technologist after the gadolinium-enhanced series. The MR signals outside the region of interest are suppressed, resulting in a single MR spectrum reflecting the metabolite profile of the volume of tissue outlined. In general, minimal voxel sizes of approximately 1 cm cube or more are necessary to produce spectra with adequate signalto-noise ratio in a reasonable time frame. Although multivoxel MRS can theoretically provide higher spatial resolution than single-voxel MRS, multi-voxel MRS has not found success in the breast. This is because breast MRI or MRS is
295 performed with phased array coils, and the product software to date has not been optimized in combining multi-voxel spectral data that are acquired by different channels of a phased array coil. The use of MRS has been suggested as an adjunct to dynamic contrast-enhanced MRI to increase specificity in defining malignant lesions. A 100% sensitivity of tCho depiction by MRS for malignant nonmass enhancements was reported, with an increase in the positive predictive value for suspicious enhancing nonmass lesions from 20% to 63% with the incorporation of MRS criteria into the diagnostic algorithm in several studies.44 Its true impact on clinical imaging and diagnosis remains uncertain at this time.
DWI DWI involves the application of pairs of large magnetic gradients that decrease the relative MR signal intensity of different tissues in proportion to the amount of free diffusion of their water molecules and can be performed via the application of a single set of diffusion gradients in a single orientation. DWI is generally applied with T2-weighted echo-planar imaging (EPI), an extremely rapid imaging technique that allows a short examination time and reduction of patient motion artifacts. However, EPI is complicated by high sensitivity to local magnetic field variations and uncompensated eddy currents, both of which can result in severe image distortion and artifacts.45-47 The amount of signal loss of water molecules in tissue is exponentially proportional to the degree of diffusion for a given diffusion gradient strength. When DWI is performed, 1 or more sets of diffusion-weighted images can be produced and viewed. In addition, an apparent diffusion coefficient (ADC) pixel map can be calculated from the component diffusion-weighted images produced from 2 or more DWI sets. Invasive breast cancers demonstrate restricted diffusion (lower ADC) relative to normal or benign breast tissue (Fig. 7). This reduced diffusivity of water in invasive cancers will render these lesions bright on diffusion-weighted images and can potentially help identify malignant lesions when dynamic contrast-enhanced imaging is equivocal. Benign lesions with high intrinsic T2 signal intensity might also appear bright on DWI because of the phenomenon of “T2 shine through.” In these situations, ADC quantification can address the T2 shine-through effect and provides a more accurate quantitative method than DWI for breast lesion characterization. The use of optimized ADC cutoff might improve lesion characterization without compromising sensitivity, with the advantage of decreasing the number of negative biopsies. ADC values and optimal cutoffs for benign and malignant differentiation might depend on the b-value associated with the applied gradients. Research is ongoing to determine the potential role of DWI in monitoring tumor response to neoadjuvant chemotherapy. Initial reports have described varying results on the reliability of pretreatment ADC in predicting tumor response to therapy.48,49
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Optical Imaging
Figure 7 Diffusion-weighted MRI. (A) Axial T1-weighted contrastenhanced MRI of left breast shows an irregular enhancing mass (arrow) with post-biopsy clip in situ. (B) Diffusion-weighted image (b ⫽ 1000 s/mm2) shows hyperintense signal in the medial left breast mass (arrow). (C) Corresponding ADC grayscale map (b ⫽ 0,1000 s/mm2) demonstrates reduced diffusion of the mass (arrow). The minimal ADC value in the region of the suspicious lesion was reduced.69 Final histopathology showed invasive ductal cancer. (Image courtesy of Basak Dogan, MD, The University of Texas M.D. Anderson Cancer Center.)
Functional imaging with DOT to discover techniques that can image disease at the biological and molecular level has shown promise. Optical tomography is a new technique that uses diffuse light in the near-infrared (NIR) spectrum to provide functional information of tumors by quantifying the tissue composition of normal and malignant breast tissue. This is facilitated by NIR laser (radiofrequency-modulated, continuous-wave, or pulse) probes that interrogate tissues noninvasively and provide quantitation of tumor hemoglobin content that is directly related to tumor angiogenesis and tumor hypoxia.50-55 Most optical imaging approaches have been based on the intrinsic contrast of major tissue chromophores that include hemoglobin, water, and lipids (Fig. 8A). The concentrations of tissue chromophores can be derived by measuring optical signals at multiple wavelengths that are matched with the known chromophore absorption spectra. Total hemoglobin concentration and tumor hypoxia can be derived from oxyhemoglobin and deoxyhemoglobin distributions, which are highly correlated with malignant status.56 An inherent limitation of DOT is the intense light scattering in tissue that leads to low spatial resolution, location uncertainty, imprecise target qualification and quantitation, and resultant difficulty in interpretation. A flexible light guide comprising optical fibers permits concurrent optical imaging with other imaging modalities to enable identical geometric considerations. The exquisite morphologic and anatomical detail that is provided by conventional imaging modalities can be exploited to assist optical imaging reconstruction, thereby improving the quantitation accuracy of light. Optical tomography with ultrasound and MRI has shown promise in overcoming these problems.57,58 When the breast is illuminated with a short laser pulse with red or NIR color by using laser optoacoustic ultrasound, a malignant lesion will absorb the laser pulse more intensely than surrounding normal tissue because of a higher concentration of blood in the tumor as a result of angiogenesis59 (Fig. 8B). The absorbed light is converted into heat instantly, and thermoacoustic pressure is generated before it is released from the tumor as an ultrasound wave. The optical energy effectively generates an optoacoustic (ultrasound) pulse with a profile that resembles the lesion.60 Positioning the array of ultrasound detectors in the breast allows the detection of optoacoustic signals and permits reconstruction of high-resolution images. The optical absorption coefficient is proportional to the concentration of molecular chromophores, ie, tissue molecules that absorb red or NIR light. The 2 main chromophores abundant in tumors are hemoglobin and oxyhemoglobin as a result of angiogenesis-related microvasculature. The wavelength of 755 nm is preferentially absorbed in hypoxic blood, and 1064 nm is preferentially absorbed in oxygenated blood. By altering the wavelength (color) of laser illumination, one can determine the rate of oxygenation in tumors. Increased hypoxia indicates a higher probability of malignancy. In addition, functional information on hemoglobin and oxyhemoglobin concentrations can help differentiate
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Figure 8 Laser optico-acoustic ultrasound (LOUS). (A) Laser optico-acoustic ultrasound is a real-time imaging modality whereby 760-nm and 1064-nm lasers are interleaved to image regions with predominantly deoxygenated and oxygenated hemoglobin, respectively. (B) The absorption spectra of 4 main tissue chromophores, including water, lipids, oxyhemoglobin, and hemoglobin, are shown in this graph. (C) Co-registered ultrasonic ⫹ optoacoustic images of invasive ductal carcinoma. (D) Co-registered ultrasonic ⫹ optoacoustic images of invasive lobular carcinoma. The wavelength of 755 nm is preferentially absorbed in hypoxic blood, and 1064 nm is preferentially absorbed in oxygenated blood. (Reprinted with permission from Ermilov et al.60) (Color version of figure is available online.)
malignancies on the basis of the biology. Aggressively proliferating tumors have advanced angiogenesis with hypoxic blood.56 Red and NIR spectral range of laser wavelengths allows deeper penetration of light into tissue. The image resolution and maximal imaging depth are scalable with ultrasonic frequency and can be up to several centimeters. Coregistered ultrasound and optoacoustic images of breast carcinomas are shown in Fig. 8C and D. Although DOT has been aggressively investigated in clinical pilot studies,51,53-56 NIR imaging with endogenous contrast depicts benign lesions as well as carcinomas, leading to difficulty in differentiating benign from malignant tissue. Pilot NIR breast imaging studies have been performed by using indocyanine green (ICG), a weak fluorescent dye, and omocianine, an ICG derivative, as contrast agents to facilitate increased absorption and fluorescence of carcinomas.61-63
The role of DOT in monitoring response of tumors to neoadjuvant chemotherapy has also been explored.64,65 Tumors have been shown to demonstrate heterogeneous blood flow. Regions of reduced blood flow in tumors might not receive adequate systemic therapy, leading to poor response to chemotherapy.66,67 Ultrahigh resolution with optical coherence tomography performed in 43 freshly excised breast specimens from 23 patients showed exquisite anatomical detail that might assist in the visualization of early benign and malignant human breast disease.68
Conclusions Conventional mammography remains the standard of care for the early diagnosis of breast cancer with established interpretation criteria, wide availability, and low cost as a
298 screening tool. Nonetheless, a high percentage of breast biopsies yield benign findings. Many biological and molecular processes that impact prognosis and outcome and influence the treatment algorithm for cancer patients cannot be measured and monitored by mammography, ultrasound, MRI, or CT, which are largely anatomical imaging methods. Because normal cellular pathways are either suppressed or enhanced by tumor-specific molecular changes, it is logical that advances in molecular imaging will help provide tumor-specific details that can contribute to (1) early assessment of treatment response, (2) individualization of treatment options, and (3) detection before there is morphologic disease. Significant progress has been made in developing alternate breast imaging modalities and molecular imaging that provide functional information on molecular processes in addition to structural and morphologic information that will help improve cancer diagnosis, research, and treatment paradigms.
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