Number: 0584

  1. Aetna considers annual mammography screening a medically necessary preventive service for women aged 40 and older.  Annual mammography is also considered medically necessary for younger women who are judged to be at high-risk including:

    1. BRCA1 or BRCA2 mutation carrier; or
    2. Women who meet criteria for BRCA mutation testing in CPB 227 - BRCA Testing, Prophylactic Mastectomy, and Prophylactic Oophorectomy; or
    3. Women with diagnosis of, or has first-degree relative with, one or more of the following:

      1. Bannayan-Riley-Ruvalcaba syndrome; or
      2. Cowden syndrome; or
      3. Li-Fraumeni syndrome; or
      4. Personal history of radiation to chest between ages 10 and 30 years.

    Screening mammography for other women is considered experimental and investigational because its benefits in these other women are unproven.

  2. Aetna considers screening mammography for men experimental and investigational, as the clinical benefits of such screening in men are unproven.  Current guidelines from the U.S. Preventive Services Task Force and the American College of Radiology recommend such screening only for women.  Aetna considers mammography medically necessary for surveillance of men with a prior history of breast cancer.

  3. Aetna considers diagnostic mammography medically necessary for members with signs or symptoms of breast disease or history of breast cancer.

    Note: Diagnostic mammography is covered regardless of whether the member has preventive services benefits

  4. Aetna considers digital mammography a medically necessary acceptable alternative to film mammography.

  5. Aetna considers digital breast tomosynthesis ("3D mammography") as a medically necessary acceptable alternative to standard (2D) mammography.
  6. Aetna considers computer-aided detection (CAD) a medically necessary adjunct to mammography.

  7. Aetna considers xeroradiography for breast imaging experimental and investigational because this method of radiography is obsolete.

  8. Aetna considers contrast-enhanced spectral mammography experimental and investigational because of insufficient evidence of its effectiveness.

See also CPB 0105 - Magnetic Resonance Imaging (MRI) of the BreastCPB 0269 - Breast Biopsy Procedures and CPB 0386 - Breast Transillumination and Electrical Impedance Scanning (EIS), and Elastography.


A mammogram is an x-ray of the breast.  A screening mammography is one of several tools that are used for early detection of breast cancer in asymptomatic women.  Other screening tools include the clinical breast examination and breast self-examination.  Diagnostic mammography is used to diagnose breast cancer in women who have signs or symptoms of breast disease, or who has a history of breast cancer.

With screen-film mammography, 2D X-ray images of the breasts are recorded onto photographic film. Each breast is positioned and compressed between two clear plates, which are attached to a specialized camera, and pictures are taken from two directions.

With full field digital mammography (FFDM), two-dimensional (2D) X-ray images are recorded onto a computer, rather than directly onto film. The technique is the same as in screen-film mammography. Adjustments can be made during the procedure, thus reducing the need to repeat mammograms and reducing the exposure to radiation. Images of the entire breast can be captured regardless of tissue density.

Screening mammography aims to reduce morbidity and mortality from breast cancer by early detection and treatment of occult malignancies.  There is extensive evidence from a variety of well-conducted, randomized controlled studies that annual or biennial mammography is effective in reducing breast cancer mortality by 30 % in women aged 50 to 69 years.  Data on women under age 50 are less clear.  Results from the Canadian National Breast Screening Study (CNBSS) suggest that the contribution of mammography over good physical examinations to breast cancer mortality reduction may be less than has been assumed.  This observation re-emphasizes a truism of screening -- that it is not necessary to detect cancers as early as possible to obtain a benefit -- it is only necessary to detect them early enough.  What is early enough in any individual case is uncertain because there are insufficient outcomes data.  This has made it difficult for professional societies to develop specific mammography screening recommendations for high-risk women.

The U.S. Preventive Services Task Force (USPSTF) revised their recommendations for mammography screening in 2009.  Whereas they had formerly recommended routine screening every 1 to 2 years starting at age 40, they now recommend against routine screening for women aged 40 to 49 and biennial rather than annual screening for women aged 50 to 74.  In their 2009 recommendations, the USPSTF recommend that women aged 40 to 49 consider their personal risk for developing breast cancer before deciding to participate in regular, biennial screening.  The USPSTF concluded that the current evidence is insufficient to assess the additional benefits and harms of (i) screening mammography in women aged 75 years or older, (ii) clinical breast examination (CBE) beyond screening mammography in women aged 40 years or older, and (iii) either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer.  In addition, the USPSTF recommended against clinicians teaching women how to perform breast self-examination.

The American Medical Association (AMA), the Society of Breast Imaging (SBI), the American College of Radiology (ACR), and the American Cancer Society (ACS), all support screening with mammography and CBE beginning at age 40.  Recent recommendations from the SBI and the ACR (2010) released after the 2009 USPSTF recommendations, which recommended that average-risk women wait until age 50 to undergo screening mammography, continue to support yearly screening mammography beginning at age 40 for women at average-risk for breast cancer.  The American College of Obstetricians and Gynecologists (ACOG, 2000) supports screening with mammography beginning at age 40 and CBE beginning at age 19.  The Canadian Task Force on Preventive Health Care (CTFPHC), the American Academy of Family Physicians (AAFP), and the American College of Preventive Medicine (ACPM) recommend beginning mammography for average-risk women at age 50.  The AAFP and ACPM recommend that mammography in high-risk women begin at age 40, and AAFP recommends that all women aged 40 to 49 be counseled about the risks and benefits of mammography before making decisions about screening.

A 1997 Consensus Development Panel convened by the National Institutes of Health concluded that the evidence was insufficient to determine the benefits of mammography among women aged 40 to 49.  This panel recommended that women aged 40 to 49 should be counseled about potential benefits and harms before making decisions about mammography.  In 2001, the CTFPHC concluded there was insufficient evidence to recommend for or against mammography in women aged 40 to 49.

Organizations differ on their recommendations for the appropriate interval for mammography.  Annual mammography is recommended by AMA, ACR, and ACS.  Mammography every 1 to 2 years is recommended by AAFP, ACPM, and the CTFPHC.  ACOG recommends mammography every 1 to 2 years for women aged 40 to 49 and annually for women aged 50 and older.

On behalf of the USPSTF, Siu (2016) updated the 2009 USPSTF recommendation on screening for breast cancer. The USPSTF reviewed the evidence on the following: effectiveness of breast cancer screening in reducing breast cancer-specific and all-cause mortality, as well as the incidence of advanced breast cancer and treatment-related morbidity; harms of breast cancer screening; test performance characteristics of digital breast tomosynthesis as a primary screening strategy; and adjunctive screening in women with increased breast density.  In addition, the USPSTF reviewed comparative decision models on optimal starting and stopping ages and intervals for screening mammography; how breast density, breast cancer risk, and comorbidity level affect the balance of benefit and harms of screening mammography; and the number of radiation-induced breast cancer cases and deaths associated with different screening mammography strategies over the course of a woman's lifetime.  This recommendation applies to asymptomatic women aged 40 years or older who do not have pre-existing breast cancer or a previously diagnosed high-risk breast lesion and who are not at high risk for breast cancer because of a known underlying genetic mutation (such as a BRCA1 or BRCA2 gene mutation or other familial breast cancer syndrome) or a history of chest radiation at a young age. 

  • The USPSTF recommends biennial screening mammography for women aged 50 to 74 years (B recommendation). The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years (C recommendation).
  • The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older (I statement).
  • The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer (I statement).
  • The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging (MRI), DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement).

Currently, there are no guideline recommendations from leading medical professional organizations to screen men at risk for hereditary breast cancer with mammography.  Robson (2002) explained “There are no established guidelines for screening of men at risk for hereditary breast cancer.  It is reasonable to suggest periodic self-examination and evaluation by a provider experienced in clinical breast examination.  The utility of screening mammography in men is unknown, although it is technically possible in at least some individuals.”  However, diagnostic mammography may be indicated in men with a breast mass on clinical examination (American Cancer Society, 2003).

Berg et al (2008) compared the diagnostic yield, defined as the proportion of women with positive screen test results and positive reference standard, and performance of screening with ultrasound plus mammography versus mammography alone in women at elevated risk of breast cancer.  A total of 2,809 women, with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited from 21 sites to undergo mammographic and physician-performed ultrasonographic examinations in randomized order by a radiologist masked to the other examination results.  Reference standard was defined as a combination of pathology and 12-month follow-up and was available for 2,637 (96.8 %) of the 2,725 eligible participants.  Main outcome measures included diagnostic yield, sensitivity, specificity, and diagnostic accuracy (assessed by the area under the receiver operating characteristic curve) of combined mammography plus ultrasound versus mammography alone and the positive predictive value of biopsy recommendations for mammography plus ultrasound versus mammography alone.  A total of 40 participants (41 breasts) were diagnosed with cancer: 8 suspicious on both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography alone, and 8 participants (9 breasts) on neither.  The diagnostic yield for mammography was 7.6 per 1,000 women screened (20 of 2,637) and increased to 11.8 per 1,000 (31 of 2,637) for combined mammography plus ultrasound; the supplemental yield was 4.2 per 1,000 women screened (95 % confidence interval [CI]: 1.1 to 7.2 per 1,000; p = 0.003 that supplemental yield is 0).  The diagnostic accuracy for mammography was 0.78 (95 % CI: 0.67 to 0.87) and increased to 0.91 (95 % CI: 0.84  to 0.96) for mammography plus ultrasound (p = 0.003 that difference is 0).  Of 12 supplemental cancers detected by ultrasound alone, 11 (92 %) were invasive with a median size of 10 mm (range of 5 to 40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89 %) reported had negative nodes.  The positive predictive value of biopsy recommendation after full diagnostic workup was 19 of 84 for mammography (22.6 %; 95 % CI: 14.2 % to 33 %), 21 of 235 for ultrasound (8.9 %, 95 % CI: 5.6 %  to 13.3 %), and 31 of 276 for combined mammography plus ultrasound (11.2 %; 95 % CI: 7.8 % to 15.6 %).  The authors concluded that adding a single screening ultrasound to mammography will yield an additional 1.1 to 7.2 cancers per 1,000 high-risk women, but it will also substantially increase the number of false positives.

Poller et al (2012) stated that annual ultrasound screening may detect small, node-negative breast cancers that are not seen on mammography; and magnetic resonance imaging (MRI) may reveal additional breast cancers missed by both mammography and ultrasound screening.  These researchers examined supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer.  From April 2004 to February 2006, a total of 2,809 women at 21 sites with elevated cancer risk and dense breasts consented to 3 annual independent screens with mammography and ultrasound in randomized order.  After 3 rounds of both screenings, 612 of 703 women who chose to undergo an MRI had complete data.  The reference standard was defined as a combination of pathology (biopsy results that showed in-situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes) and 12-month follow-up.  Main outcome measures included cancer detection rate (yield), sensitivity, specificity, positive-predictive value (PPV) of biopsies performed and interval cancer rate.  A total of 2,662 women underwent 7,473 mammogram and ultrasound screenings, 110 of whom had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen.  Among 4,814 incidence screens in the 2nd and 3rd years combined, 75 women were diagnosed with cancer.  Supplemental incidence-screening ultrasound identified 3.7 cancers per 1,000 screens (95 % CI: 2.1 to 5.8; p < 0.001).  Sensitivity for mammography plus ultrasound was 0.76 (95 % CI: 0.65 to 0.85); specificity, 0.84 (95 % CI: 0.83 to 0.85); and PPV, 0.16 (95 % CI: 0.12 to 0.21).  For mammography alone, sensitivity was 0.52 (95 % CI: 0.40 to 0.64); specificity, 0.91 (95 % CI: 0.90 to 0.92); and PPV, 0.38 (95 % CI: 0.28 to 0.49; p < 0.001 all comparisons).  Of the MRI participants, 16 women (2.6 %) had breast cancer diagnosed.  The supplemental yield of MRI was 14.7 per 1,000 (95 % CI: 3.5 to 25.9; p = 0.004).  Sensitivity for MRI and mammography plus ultrasound was 1.00 (95 % CI: 0.79 to 1.00); specificity, 0.65 (95 % CI: 0.61 to 0.69); and PPV, 0.19 (95 % CI: 0.11 to 0.29).  For mammography and ultrasound, sensitivity was 0.44 (95 % CI: 0.20 to 0.70, p = 0.004); specificity 0.84 (95 % CI: 0.81 to 0.87; p < 0.001); and PPV, 0.18 (95 % CI: 0.08 to 0.34; p = 0.98).  The number of screens needed to detect 1 cancer was 127 (95 % CI: 99 to 167) for mammography; 234 (95 % CI: 173 to 345) for supplemental ultrasound; and 68 (95 % CI: 39 to 286) for MRI after negative mammography and ultrasound results.  The authors concluded that the addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings.

Digital Mammography:

Although digital mammography has not shown greater accuracy than film mammography, it has become standard of care.  The Food and Drug Administration (FDA)'s initial market approval of digital mammography technology was based, in part, on studies that demonstrated its effectiveness in patients referred for further testing after an initial suspicious mammogram (FDA, 2004).  In that setting, the FDA found the accuracy of digital technology was similar to that of screen film.  Studies are currently underway to evaluate the effectiveness of digital mammography in screening of the general population.

Hendrick and colleagues (2008) retrospectively compared the accuracy for cancer diagnosis of digital mammography with soft-copy interpretation with that of screen-film mammography for each digital equipment manufacturer, by using results of biopsy and follow-up as the reference standard.  The American College of Radiology Imaging Network Digital Mammographic Imaging Screening Trial (DMIST) collected screening mammography studies performed by using both digital and screen-film mammography in 49,528 women (mean age of 54.6 years; range of 19 to 92 years).  Digital mammography systems from 4 manufacturers (Fischer, Fuji, GE, and Hologic) were used.  For each digital manufacturer, a cancer-enriched reader set of women screened with both digital and screen-film mammography in DMIST was constructed.  Each reader set contained all cancer-containing studies known for each digital manufacturer at the time of reader set selection, together with a subset of negative and benign studies.  For each reader set, 6 or 12 experienced radiologists attended 2 randomly ordered reading sessions 6 weeks apart.  Each radiologist identified suspicious findings and rated suspicion of breast cancer in identified lesions by using a 7-point scale.  Results were analyzed according to digital manufacturer by using areas under the receiver operating characteristic curve (AUCs), sensitivity, and specificity for soft-copy digital and screen-film mammography.  Results for Hologic digital are not presented owing to the fact that few cancer cases were available.  The implemented design provided 80 % power to detect average AUC differences of 0.09, 0.08, and 0.06 for Fischer, Fuji, and GE, respectively.  No significant difference in AUC, sensitivity, or specificity was found between Fischer, Fuji, and GE soft-copy digital and screen-film mammography.  Large reader variations occurred with each modality.  The authors concluded that no statistically significant differences were found between soft-copy digital and screen-film mammography for Fischer, Fuji, and GE digital mammography equipment.

Pisano and associates (2008) retrospectively compared the accuracy of digital versus film mammography in population subgroups of the DMIST defined by combinations of age, menopausal status, and breast density, by using either biopsy results or follow-up information as the reference standard.  For analysis, AUCs for each modality were compared within each subgroup evaluated (age less than 50 versus 50 to 64 versus greater than or equal to 65 years; dense versus non-dense breasts at mammography; and pre- or peri-menopausal versus post-menopausal status for the 2 younger age cohorts) while controlling for multiple comparisons (p < 0.002 indicated a significant difference).  All DMIST cancers were evaluated with respect to mammographic detection method (digital versus film versus both versus neither), mammographic lesion type (mass, calcifications, or other), digital machine type, mammographic and pathologic size and diagnosis, existence of prior mammographic study at time of interpretation, months since prior mammographic study, and compressed breast thickness.  A total of 33 centers enrolled 49,528 women.  Breast cancer status was determined for 42,760 women, the group included in this study.  Pre- or peri-menopausal women younger than 50 years who had dense breasts at film mammography comprised the only subgroup for which digital mammography was significantly better than film (AUCs, 0.79 versus 0.54; p = 0.0015).  Breast Imaging Reporting and Data System-based sensitivity in this subgroup was 0.59 for digital and 0.27 for film mammography.  AUCs were not significantly different in any of the other subgroups.  For women aged 65 years or older with fatty breasts, the AUC showed a non-significant tendency toward film being better than digital mammography (AUCs, 0.88 versus 0.70; p = 0.0025).  The authors concluded that digital mammography performed significantly better than film for pre- and peri-menopausal women younger than 50 years with dense breasts, but film tended non-significantly to perform better for women aged 65 years or older with fatty breasts.

Screening film mammography has been shown to reduce the mortality rate from breast cancer; however, conventional mammography does not detect all breast cancers.  A significant factor contributing to the limitations of mammography is the structure overlap that results on a 2-dimensional mammogram.  Structure overlap not only obscures lesions, but can mimic abnormalities, thus contributing to reductions in both the sensitivity and specificity of mammography.  A number of new imaging techniques and enhancements for digital mammography have recently become available or are likely to become available in the near future.

Computer-Aided Detection and Diagnosis (CAD):

Computer-Aided Detection (CAD) involves computer software used by radiologists to assist in the interpretation and identification of suspicious findings on mammogram MRI, or ultrasound of the breast. CAD is not intended to be used in place of a radiologist but as a second set of eyes when examining the images.

Computer-aided detection and diagnosis (CAD) systems consist of computer programs that are designed to recognize patterns in images.  CAD may be applied to digital mammograms or to plain film mammograms that have been digitized.  CAD has been used for 2 different purposes: (i) to improve radiologists' ability to identify suspicious areas that may otherwise be overlooked on screening mammograms (detection), and (ii) to distinguish between benign and malignant lesions (diagnosis).  The radiologist remains the reader and interpreter of the mammogram.  CAD assists the radiologist by identifying areas warranting further review.

The American Cancer Society breast cancer screening guidelines (Smith et al, 2003) indicate that for digital mammography and CAD there is “some clinical evidence for effectiveness or equivalence to screen-film mammography for screening” (Evidence Level B).

Bennett et al (2006) assessed current evidence to ascertain if the accuracy of single reading with CAD compares with that of double reading.  These researchers performed a literature review to identify studies where both protocols had been investigated and compared.  They identified 8 studies that compared single reading with CAD against double reading, of which 6 reported on comparisons of both sensitivity and specificity.  Of the 6 studies identified, 3 showed no differences in either sensitivity or specificity; 1 showed single reading with CAD had a higher sensitivity at the same specificity; 1 showed that single reading with CAD had a higher specificity at the same sensitivity.  However, 1 study, in a real-life setting, showed that single reading with CAD had a higher sensitivity but a lower specificity.  The authors concluded that as the majority of the studies were not in a real-life setting, used test sets, lacked sufficient training in the use of CAD and simulated double reading (using a protocol of recall if one suggests), current evidence is therefore limited as to the accuracy, in terms of sensitivity and specificity, of single reading with CAD in comparison with the most common practice in the United Kingdom of double reading using a protocol of consensus or arbitration.

Fenton and colleagues (2007) stated that CAD identifies suspicious findings on mammograms to assist radiologists.  Since the FDA approved the technology in 1998, it has been disseminated into practice, but its effect on the accuracy of interpretation is unclear.  These investigators determined the association between the use of CAD at mammography facilities and the performance of screening mammography from 1998 through 2002 at 43 facilities in 3 states.  They had complete data for 222,135 women (a total of 429,345 mammograms), including 2,351 women who received a diagnosis of breast cancer within 1 year after screening.  They calculated the specificity, sensitivity, and positive predictive value of screening mammography with and without CAD, as well as the rates of biopsy and breast-cancer detection and the overall accuracy, measured as the area under the receiver-operating-characteristic (ROC) curve.  A total of 7 facilities (16 %) implemented CAD during the study period.  Specificity decreased from 90.2 % before implementation to 87.2 % following implementation (p < 0.001), the positive predictive value decreased from 4.1 % to 3.2 % (p = 0.01), and the rate of biopsy increased by 19.7 % (p < 0.001).  The increase in sensitivity from 80.4 % before implementation of CAD to 84.0 % after implementation was insignificant (p = 0.32).  The change in the cancer-detection rate (including invasive breast cancers and ductal carcinomas in situ) was insignificant (4.15 cases per 1,000 screening mammograms before implementation and 4.20 cases after implementation, p = 0.90).  Analyses of data from all 43 facilities showed that the use of CAD was associated with significantly lower overall accuracy than was non-use (area under the ROC curve, 0.871 versus 0.919; p = 0.005).  The authors concluded that the use of CAD is associated with reduced accuracy of interpretation of screening mammograms.  The increased rate of biopsy with the use of CAD is not clearly associated with improved detection of invasive breast cancer.  This is in agreement with Bazzocchi et al (2007) who noted that there is still considerable variation among different studies in the level of benefit deriving from CAD.  Thus, the role of these systems in clinical practice is still debated, and their real contribution to the overall management of the diagnostic process is still unclear.

An assessment of CAD in mammography screening by the Swedish Council on Health Technology Assessment (SBU, 2011) concluded that the scientific evidence is insufficient to determine whether CAD plus single reading by one breast radiologist would yield results that are at least equivalent to those obtained in standard practice, i.e. double reading where two breast radiologists independently read the x-ray images.


Xeroradiography (Xerox Corporation, Stamford, CT) is an outmoded X-ray imaging method that had been used especially in mammographic screening for breast cancer.  With Xeroradiography, X-rays pass through the body to an X-ray-sensitive metal plate.  The plate is then processed through a unique photocopying-type machine, and the X-ray image transferred to paper rather than X-ray film.  Unlike photographically recorded X-ray images, Xeroradiographs produce a “positive” image in which the denser elements appear darker.  Unlike X-ray films, the Xeroradiographic image is a mirror image of the object.  The primary advantage of Xeroradiography over conventional plain film mammography is that the former produces instant radiographs.  However, Xeroradiography has become outmoded because the radiation exposure required is much higher than with conventional radiographs, and the Xeroradiographic image has a number of defects, such as excessive contrast and edge enhancement.

Breast Tomosynthesis (3D Mammography):

Breast tomosynthesis is a 3-dimensional imaging technique based on FFDM that involves acquiring images of a stationary compressed breast at multiple angles during a short scan.  During an examination, the individual’s breast is positioned and compressed as with a standard mammogram. An X-ray tube moves along an arc around the breast to acquire multiple image slices of approximately one milliliter or less in about 10 seconds. A computer processes the series of slices and displays the data on a workstation. The individual images are then reconstructed into a series of thin, high-resolution slices that can be displayed individually or in a dynamic cine mode.  While holding the breast stationary, images are acquired at a number of different x-ray source angles.  Objects at different heights in the breast project differently for each angle.  The data are then reconstructed to generate images that enhance objects from a given height by appropriate shifting of the projections relative to one another. 

Three important areas in tomosynthesis system requirements are: (i) detector efficiency and dose, (ii) field of view, and (iii) equipment geometry.  While holding the breast stationary, an x-ray tube is rotated over a limited angular range and a series of low-dose exposures are made every few degrees, creating a series of digital images.  The x-ray tube is rotated about +/-15 degrees, and 11 exposures are made every 3 degrees during a total scan of a few seconds.  These individual images are then reconstructed into slices.  There are 2 basic tomosynthesis system designs that differ in the motion of the detector during acquisition.  One method moves the detector in concert with the x-ray tube so as to maintain the shadow of the breast on the detector.  An altenate method is to keep the detector stationary relative to the breast platform. The tomosynthesis reconstruction process consists of computing high-resolution images whose planes are parallel to the breast support plates.  These images are reconstructed with slice separation of 1 mm; thus, a 5-cm compressed breast tomosynthesis study will have 50 reconstructed slices.  The reconstructed tomosynthesis slices can be displayed similarly to computed tomography reconstructed slices.  Proponents of breast tomosynthesis hope it will resolve many of the tissue overlap reading problems that are a major source of recalls and additional imaging in 2-D mammography examinations (Smith, 2005). Studies suggest that breast tomosynthesis has comparable or superior image quality to that of film-screen mammography and has the potential to decrease the recall rate when used adjunctively with digital screening mammography (Good et al, 2008; Chen et al, 2007; Poplack et al, 2007). 

In February 2011, the FDA approved the Selenia Dimensions 3D System (Digital Breast Tomosynthesis), a mammography device that provides digital 2D and 3D images for the screening and diagnosis of breast cancer.

Spangler and colleagues (2011) compared the ability of digital breast tomosynthesis and full field digital mammography (FFDM) to detect and characterize calcifications.  A total of 100 paired examinations were performed utilizing FFDM and digital breast tomosynthesis: 20 biopsy-proven cancers, 40 biopsy-proven benign calcifications, and 40 randomly selected negative screening studies were retrospectively reviewed by 5 radiologists in a crossed multi-reader multi-modal observer performance study.  Data collected included the presence of calcifications and forced Breast Imaging, Reporting and Data System (BI-RADS) scores.  Receiver operator curve analysis using BI-RADS was performed.  Overall calcification detection sensitivity was higher for FFDM (84 % [95 % CI: 79 % to 88 %]) than for digital breast tomosynthesis (75 % [95 % CI: 70 % to 80 %]).  In the cancer cohort, 75 (76 %) of 99 interpretations identified calcification in both modes.  Of those, a BI-RADS score less than or equal to 2 was rendered in 3 (4 %) and 9 (12 %) cases with FFDM and digital breast tomosynthesis, respectively.  In the benign cohort, 123 (62 %) of 200 interpretations identified calcifications in both modes.  Of those, a BI-RADS score greater than or equal to 3 was assigned in 105 (85 %) and 93 (76 %) cases with FFDM and digital breast tomosynthesis, respectively.  There was no significant difference in the non-parametric computed AUC using the BI-RADS scores (FFDM, AUC = 0.76 and SD = 0.03; digital breast tomosynthesis, AUC = 0.72 and SD = 0.04 [p = 0.1277]).  The authors concluded that in this small data set, FFDM appears to be slightly more sensitive than digital breast tomosynthesis for the detection of calcification.  However, diagnostic performance as measured by AUC using BI-RADS was not significantly different. With improvements in processing algorithms and display, digital breast tomosynthesis could potentially be improved for this purpose.

Sahiner et al (2012) designed a computer-aided detection (CADe) system for clustered micro-calcifications in reconstructed DBT volumes and performed a preliminary evaluation of the CADe system.  Institutional review board approval and informed consent were obtained in this study.  A data set of 2-view DBT of 72 breasts containing micro-calcification clusters was collected from 72 subjects who were scheduled to undergo breast biopsy.  Based on tissue sampling results, 17 cases had breast cancer and 55 were benign.  A separate data set of 2-view DBT of 38 breasts free of clustered micro-calcifications from 38 subjects was collected to independently estimate the number of false-positives (FPs) generated by the CADe system.  A radiologist experienced in breast imaging marked the biopsied cluster of micro-calcifications with a 3D bounding box using all available clinical and imaging information.  A CADe system was designed to detect micro-calcification clusters in the reconstructed volume.  The system consisted of pre-screening, clustering, and FP reduction stages.  In the pre-screening stage, the conspicuity of micro-calcification-like objects was increased by an enhancement-modulated 3D calcification response function.  An iterative thresholding and 3D object growing method was used to detect cluster seed objects, which were used as potential centers of micro-calcification clusters.  In the cluster detection stage, micro-calcification candidates were identified using a 2nd iterative thresholding procedure, which was applied to the signal-to-noise ratio (SNR) enhanced image voxels with a positive calcification response.  Starting with each cluster seed object as the initial cluster center, a dynamic clustering algorithm formed a cluster candidate by including micro-calcification candidates within a 3D neighborhood of the cluster seed object that satisfied the clustering criteria.  The number, size, and SNR of the micro-calcifications in a cluster candidate and the cluster shape were used to reduce the number of FPs.  The pre-screening stage detected a cluster seed object in 94 % of the biopsied micro-calcification clusters at a threshold of 100 cluster seed objects per DBT volume.  After clustering, the detection sensitivity was 90 % at 15 marks per DBT volume.  After FP reduction, at 85 % sensitivity, the average number of FPs estimated using the data set containing micro-calcification clusters was 3.8 per DBT volume, and that estimated using the data set free of micro-calcification clusters was 3.4.  The detection performance for malignant micro-calcification clusters was superior to that for benign clusters.  The authors concluded that these findings indicated the feasibility of the 3D approach to the detection of clustered micro-calcifications in DBT and that the newly designed enhancement-modulated 3D calcification response function is promising for pre-screening.  They stated that further work is needed to assess the generalizability of this approach and to improve its performance.

Skaane and colleagues (2012) compared DM and DBT in a side-by-side feature analysis for cancer conspicuity, and examined if there is a potential additional value of DBT to standard state-of-the-art conventional imaging work-up with respect to detection of additional malignancies.  The study had ethics committee approval.  A total of 129 women underwent 2D DM including supplementary cone-down and magnification views and breast ultrasonography if indicated, as well as DBT.  The indication for conventional imaging in the clinical setting included a palpable lump in 30 (23 %), abnormal mammographic screening findings in 54 (42 %), and surveillance in 45 (35 %) of the women.  The women were examined according to present guidelines, including spot-magnification views, ultrasonography, and needle biopsies, if indicated.  The DBT examinations were interpreted several weeks after the conventional imaging without knowledge of the conventional imaging findings.  In a later session, 3 radiologists performed a side-by-side feature analysis for cancer conspicuity in a sample of 50 cases.  State-of-the-art conventional imaging resulted in needle biopsy of 45 breasts, of which 20 lesions were benign and a total of 25 cancers were diagnosed.  The remaining 84 women were dismissed with a normal/definitely benign finding and without indication for needle biopsy.  The subsequent DBT interpretation found suspicious findings in 4 of these 84 women, and these 4 women had to be called back for repeated work-up with knowledge of the tomosynthesis findings.  These delayed work-ups resulted in 2 cancers (increasing the cancer detection by 8 %) and 2 FP findings.  The side-by-side feature analysis showed higher conspicuity scores for tomosynthesis compared to conventional 2D for cancers presenting as spiculated masses and distortions.  The authors concluded that DBT is a promising new technique.  The authors’ preliminary clinical experience showed that there is a potential for increasing the sensitivity using this new technique, especially for cancers manifesting as spiculated masses and distortions.

Bernardi et al (2012a) prospectively evaluated the effect of integrating 3D mammography as a triage to assessment in 158 consecutive recalls to assessment (recalled in standard 2D-mammographic screening) in asymptomatic subjects.  Radiologists provided 3D mammography-based opinion as to whether recall/assessment was warranted or unnecessary, and all subjects proceeded to assessment.  3D triage was positive (confirmed the need for assessment) in all 21 subjects with breast cancer (there were no false-negatives), and would have avoided recall in 102 of 137 (74.4 %) subjects with a negative/benign final outcome in whom 3D triage did not recommend recall.  Proportion of true negative 3D triage (as a proxy for potential reduction in recalls) was slightly higher in dense than non-dense breasts, did not differ across age-groups, but was significantly associated with the type of lesion seen on imaging (being highest for distortions, asymmetric densities, and lesions with ill-defined margins).  While the simulation design may have over-estimated the potential for 3D mammography triage to reduce recalls, this study clearly demonstrates its capability to improve breast screening specificity and to reduce recall rates.  The authors stated that future studies of 3D mammography should further assess its role as a recall-reducing strategy in screening practice and should include formal cost-analysis.

Bernardi et al (2012b) supplemented the information available on logistical aspects of the application of 3D mammography in breast screening.  These investigators prospectively examined the effect on radiographers' and radiologists' workload of implementing 3D mammography in screening by comparing image acquisition time and screen-reading time for 2D mammography with that of combined 2D+3D mammography.  Radiologists' accuracy was also calculated.  Average acquisition time (measured from start of first-view breast positioning to compression release at completion of last view) for 7 radiographers, based on 20 screening examinations, was longer for 2D+3D (4 min 3 s; range of 3 min 53 s to 4 min 18 s) than 2D mammography (3 min 13 s; range of 3 min 0 s to 3 min 26 s; p < 0.01).  Average radiologists' reading time per screening examination (3 radiologists reading case-mix of 100 screens: 10 cancers, 90 controls) was longer for 2D+3D (77 s; range of 60 to 90 s) than for 2D mammography (33 s; range of 25 to 46 s; p < 0.01).  2D+3D screen-reading was associated with detection of more cancers and with substantially fewer recalls than 2D mammography alone.  The authors concluded that relative to standard 2D mammography, combined 2D+3D mammography prolongs image acquisition time and screen-reading time (at initial implementation), and appears to be associated with improved screening accuracy.  They stated that these findings provided relevant information to guide larger trials of integrated 3D mammography (2D+3D) and its potential implementation into screening practice.

Houssami and Skaane (2013) stated that DBT, a 3D derivative of DM, reduces the effect of tissue superimposition and may improve mammographic interpretation.  These investigators examined the evidence on the accuracy of DBT in clinical studies.  Published studies of DBT were relatively small studies, mostly test-set observer (reader) studies or clinical series that included symptomatic and screen-recalled cases, and were generally enriched with cancers.  With these limitations in mind, the evidence showed some consistent findings, summarized as follows: 2-view DBT has at least equal or better accuracy than standard 2-view DM, whereas 1-view DBT does not have better accuracy than standard DM; the addition of DBT to standard mammography (for mammographic interpretation or for assessment or triage of screen-recalled abnormalities) increases accuracy; improved accuracy from using DBT (relative to, or added to, DM) may be due to increased cancer detection or due to reduced false positive recalls, or both; and subjective interpretation of cancer conspicuity consistently found that cancers were equally or more conspicuous on DBT relative to DM.  Preliminary data from population screening trials suggested that the integration of DBT with conventional DM (screen-reading using combined 2D + 3D mammography) may substantially improve breast cancer detection, although final results are not yet available, and many logistical issues need further evaluation to determine the potential implications and cost of combined 2D + 3D mammographic screening.  At present, there is insufficient evidence to justify a change from standard DM to DBT however the available data strongly support investment in new large-scale population screening trials.  These trials need to avoid the 'double' acquisitions required for 2D + 3D mammograms, and should therefore focus on evaluating integrated 2Dsynthetic + 3D mammography (where 2D-images are reconstructed from the DBT acquisition), and should consider using a randomized design.

Friedewald et al (2014) determined if mammography combined with tomosynthesis is associated with better performance of breast screening programs in the United States.  The authors concluded that addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate.  Moreover, they stated that further studies are needed to assess the relationship to clinical outcomes.

Gartner et al (2014) discussed clinical applications of digital breast tomosynthesis (DBT) in both screening and diagnostic settings.  The authors concluded that DBT is a promising new technology that has shown improved accuracy for screening and diagnostic breast imaging.  Their early clinical experience supported these findings.  One year after implementing DBT for all screening patients, these researchers demonstrated a substantial reduction in their overall callback rate and a trend toward increased cancer detection.  They stated that “As with any new technology, several issues must be considered when implementing DBT into daily practice.  Ongoing large-scale prospective trials will help guide the evidence-based utilization of this new technology”.

Garcia-Leon et al (2015) estimated and compared the diagnostic validity of tomosynthesis and digital mammography for screening and diagnosing breast cancer.  These investigators systematically searched MedLine, EMBASE, and Web of Science for the terms breast cancer, screening, tomosynthesis, mammography, sensitivity, and specificity in publications in the period comprising June 2010 through February 2013.  They included studies on diagnostic tests and systematic reviews.  Two reviewers selected and evaluated the articles.  They used QUADAS 2 to evaluate the risk of bias and the NICE criteria to determine the level of evidence.  They compiled a narrative synthesis.  Of the 151 original studies identified, these investigators selected 11 that included a total of 2,475 women.  The overall quality was low, with a risk of bias and follow-up and limitations regarding the applicability of the results.  The level of evidence was not greater than level II.  The sensitivity of tomosynthesis ranged from 69 % to 100 % and the specificity ranged from 54 % to 100 %.  The negative likelihood ratio was good, and this makes tomosynthesis useful as a test to confirm a diagnosis.  One-view tomosynthesis was no better than 2-view digital mammography, and the evidence for the superiority of 2-view tomosynthesis was inconclusive.  The authors concluded that the results for the diagnostic validity of tomosynthesis in the diagnosis of breast cancer were inconclusive and there were no results for its use in screening.

Gilbert et al (2015) stated that digital breast tomosynthesis (DBT) is a 3D mammography technique with the potential to improve accuracy by improving differentiation between malignant and non-malignant lesions.  These researchers compared the diagnostic accuracy of DBT in conjunction with 2D mammography or synthetic 2D mammography, against standard 2D mammography and determined if DBT improves the accuracy of detection of different types of lesions.  Women (aged 47 to 73 years) recalled for further assessment after routine breast screening and women (aged 40 to 49 years) with moderate/high of risk of developing breast cancer attending annual mammography screening were recruited after giving written informed consent.  All participants underwent a 2-view 2D mammography of both breasts and 2-view DBT imaging.  Image-processing software generated a synthetic 2D mammogram from the DBT data sets.  In an independent blinded retrospective study, readers reviewed (i) 2D or (ii) 2D + DBT or (iii) synthetic 2D + DBT images for each case without access to original screening mammograms or prior examinations.  Sensitivities and specificities were calculated for each reading arm and by subgroup analyses.  Data were available for 7,060 subjects comprising 6,020 (1,158 cancers) assessment cases and 1,040 (2 cancers) family history screening cases.  Overall sensitivity was 87 % [95 % confidence interval (CI): 85 % to 89 %] for 2D only, 89 % (95 % CI: 87 % to 91 %) for 2D + DBT and 88 % (95 % CI: 86 % to 90 %) for synthetic 2D + DBT.  The difference in sensitivity between 2D and 2D + DBT was of borderline significance (p = 0.07) and for synthetic 2D + DBT there was no significant difference (p = 0.6).  Specificity was 58 % (95 % CI: 56 % to 60 %) for 2D, 69 % (95 % CI 67 % to 71 %) for 2D + DBT and 71 % (95 % CI: 69 % to 73 %) for synthetic 2D + DBT.  Specificity was significantly higher in both DBT reading arms for all subgroups of age, density and dominant radiological feature (p < 0.001 all cases).  In all reading arms, specificity tended to be lower for micro-calcifications and higher for distortion/asymmetry.  Comparing 2D + DBT to 2D alone, sensitivity was significantly higher: 93 % versus 86 % (p < 0.001) for invasive tumors of size 11 to 20 mm.  Similarly, for breast density 50 % or more, sensitivities were 93 % versus 86 % (p = 0.03); for grade 2 invasive tumors, sensitivities were 91 % versus 87 % (p = 0.01); where the dominant radiological feature was a mass, sensitivities were 92 % and 89 % (p = 0.04).  For synthetic 2D + DBT, there was significantly (p = 0.006) higher sensitivity than 2D alone in invasive cancers of size 11 to 20 mm, with a sensitivity of 91 %.  The authors concluded that the specificity of DBT and 2D was better than 2D alone; but there was only marginal improvement in sensitivity.  The performance of synthetic 2D appeared to be comparable to standard 2D.  If these results were observed with screening cases, DBT and 2D mammography could benefit to the screening program by reducing the number of women recalled unnecessarily, especially if a synthetic 2D mammogram were used to minimize radiation exposure.  They stated that further research is required into the feasibility of implementing DBT in a screening setting, prognostic modeling on outcomes and mortality, and comparison of 2D and synthetic 2D for different lesion types.

Melnikow and colleagues (2016) performed a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. Data sources included  Medline, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015.  Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts were selected for analysis; quality assessment and abstraction of 24 studies from 7 countries were carried out; 6 studies were good-quality.  A total of 3 good-quality studies reported reproducibility of BI-RADS density; 13 % to 19 % of women were re-categorized between "dense" and "non-dense" at subsequent screening; 2 good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80 % to 83 %; specificity, from 86 % to 94 %; and positive predictive value (PPV), from 3 % to 8 %.  The sensitivity of MRI ranged from 75 % to 100 %; specificity, from 78 % to 94 %; and PPV, from 3 % to 33 % (3 studies).  Rates of additional cancer detection with ultrasonography were 4.4 per 1,000 examinations (89 % to 93 % invasive); recall rates were 14 %.  Use of MRI detected 3.5 to 28.6 additional cancer cases per 1,000 examinations (34 % to 86 % invasive); recall rates were 12 % to 24 %.  Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1,000 examinations compared with mammography alone (3 studies).  Recall rates ranged from 7 % to 11 %, compared with 7 % to 17 % with mammography alone.  No studies examined breast cancer outcomes.  The authors concluded that density ratings may be re-categorized on serial screening mammography.  Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results.  They stated that use of DBT may reduce recall rates; effects of supplemental screening on breast cancer outcomes remain unclear.  The main drawbacks of this study were: (i) good-quality evidence was sparse, (ii) studies were small and CIs were wide, and (iii) definitions of recall were absent or inconsistent.

Nelson and associates (2016) stated that in 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. These investigators reviewed studies of screening in average-risk women with mammography, magnetic resonance imaging, or ultrasonography that reported on false-positive results, over-diagnosis, anxiety, pain, and radiation exposure.  Data sources included Medline and Cochrane databases through December 2014.  English-language systematic reviews, randomized trials, and observational studies of screening were selected for analysis.  Investigators extracted and confirmed data from studies and dual-rated study quality.  Discrepancies were resolved through consensus.  Based on 2 studies of U.S. data, 10-year cumulative rates of false-positive mammography results and biopsies were higher with annual than biennial screening (61 % versus 42 % and 7 % versus 5 %, respectively) and for women aged 40 to 49 years, those with dense breasts, and those using combination hormone therapy.  A total of 29 studies using different methods reported over-diagnosis rates of 0 % to 54 %; rates from randomized trials were 11 % to 22 %.  Women with false-positive results reported more anxiety, distress, and breast cancer-specific worry, although results varied across 80 observational studies; 39 observational studies indicated that some women reported pain during mammography (1 % to 77 %); of these, 11 % to 46 % declined future screening.  Models estimated 2 to 11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography, depending on age and screening interval; 5 observational studies of tomosynthesis and mammography indicated increased biopsies but reduced recalls compared with mammography alone.  The authors concluded that false-positive results are common and are higher for annual screening, younger women, and women with dense breasts.  Although over-diagnosis, anxiety, pain, and radiation exposure may cause harm, their effects on individual women are difficult to estimate and vary widely.  The main drawbacks of this study were: (i) studies of over-diagnosis were highly heterogeneous, and estimates varied depending on the analytic approach, (ii) studies of anxiety and pain used different outcome measures, and (iii) radiation exposure was based on models.

Tagliafico et al (2016) noted that debate on adjunct screening in women with dense breasts has followed legislation requiring that women be informed about their mammographic density and related adjunct imaging. Ultrasound or tomosynthesis can detect breast cancer (BC) in mammography-negative dense breasts, but these modalities have not been directly compared in prospective trials.  These researchers conducted a trial of adjunct screening to compare, within the same participants, incremental BC detection by tomosynthesis and ultrasound in mammography-negative dense breasts.  This trial is a prospective multi-center study recruiting asymptomatic women with mammography-negative screens and dense breasts.  Eligible women had tomosynthesis and physician-performed ultrasound with independent interpretation of adjunct imaging.  Outcome measures included cancer detection rate (CDR), number of FP recalls, and incremental CDR for each modality; these were compared using McNemar's test for paired binary data in a pre-planned interim analysis.  Among 3,231 mammography-negative screening participants (median age of 51 years; interquartile range [IQR] of 44 to 78 years) with dense breasts, 24 additional BCs were detected (23 invasive): 13 tomosynthesis-detected BCs (incremental CDR, 4.0 per 1,000 screens; 95 % CI: 1.8 to 6.2) versus 23 ultrasound-detected BCs (incremental CDR, 7.1 per 1,000 screens; 95 % CI: 4.2 to 10.0), p = 0.006.  Incremental FP recall occurred in 107 participants (3.33 %; 95 % CI: 2.72 % to 3.96 %); FP recall (any testing) did not differ between tomosynthesis (FP = 53) and ultrasound (FP = 65), p = 0.26; FP recall (biopsy) also did not differ between tomosynthesis (FP = 22) and ultrasound (FP = 24), p = 0.86.  The authors concluded that the Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts' interim analysis showed that ultrasound has better incremental BC detection than tomosynthesis in mammography-negative dense breasts at a similar FP-recall rate.  However, they stated that future application of adjunct screening should consider that tomosynthesis detected more than 50 % of the additional BCs in these women and could potentially be the primary screening modality.

In an editorial that accompanied the afore-mentioned study by Tagliafico et al, Berg (2016) stated that “Because the primary goal of screening is detection of early breast cancer, US would seem the clear choice compared with tomosynthesis …. On the basis of the results from ASTOUND, tomosynthesis still misses a substantial number of invasive cancers in women with dense breasts: supplemental US after tomosynthesis would still be reasonable, although further study is warranted …. For women with dense breasts given the choice of US or tomosynthesis, US shows more cancers. Further validation of these results is critically needed, as is longer-term follow-up to compare incidence screening results for tomosynthesis and US”.

Houssami and Turner (2016) stated that high breast tissue density increases BC risk, and the risk of an interval BC in mammography screening.  Density-tailored screening has mostly used adjunct imaging to screen women with dense breasts, however, the emergence of DBT provides an opportunity to steer density-tailored screening in new directions potentially obviating the need for adjunct imaging.  These investigators summarized data on DBT screening in women with heterogeneously dense or extremely dense breasts, with the aim of estimating incremental (additional) BC detection attributed to DBT in comparison with standard 2D-mammography.  Meta-analyzed data from prospective trials comparing these mammography modalities in the same women (n = 10,188) in predominantly biennial screening showed significant incremental BC detection of 3.9/1,000 screens attributable to DBT (p < 0.001).  Studies comparing different groups of women screened with DBT (n = 103,230) or with 2D-mammography (n = 177,814) yielded a pooled difference in BC detection of 1.4/1,000 screens representing significantly higher BC detection in DBT-screened women (p < 0.001), and a pooled difference for recall of -23.3/1,000 screens representing significantly lower recall in DBT-screened groups (p < 0.001), than for 2D-mammography.  The authors noted that enhanced BC detection from DBT, in comparison with mammography alone, or indeed from adjunctive screening in dense breasts, has not been examined in studies evaluating screening benefit in terms of mortality reduction; therefore, increased BC detection can only be taken as indicative of the potential to improve screening outcomes and/or to reduce the risk of interval BC.  They stated that although evidence of improved screening benefit is currently lacking for density-tailored screening, what makes the issue of DBT screening for dense breasts immediately relevant in breast imaging and screening practice is the implementation of density-specific legislation in some settings, plus the reality of using DBT alone for primary screening.  Since DBT acquisitions can now also be used to reconstruct high-definition 2D images, yielding similar BC detection as that from DBT plus 2D-mammography acquisitions, it seems reasonable that the next phase of DBT research and practice will increasingly adopt DBT-only acquisitions (with reconstructed 2D images).  Therefore, a new direction in research is needed to evaluate DBT alone as the primary screening modality for women known to have mammography-dense breasts, potentially obviating the need to add other imaging tests to screen dense breasts.  The estimates provided in this review can be used to plan estimates of effect for future studies and trials of DBT for density-tailored BC screening.

In a retrospective study, Aujero and colleagues (2017) compared the clinical performance of synthesized two-dimensional (s2D) mammography combined with DBT with that of FFDM alone and FFDM combined with DBT in a large community-based screening population by analyzing recall rate, PPV, and cancer detection rate.  A total of 78,810 screening mammograms from October 11, 2011, to June 30, 2016, were retrospectively collected.  Of these, 32,076 were FFDM, 30,561 were DBT-FFDM, and 16,173 were DBT-s2D mammograms.  Diagnostic performance of FFDM, DBT-FFDM, and DBT-s2D mammography was compared.  Statistical significance was determined by using the Pearson χ2 test and was expressed as odds ratios (ORs)and related CIs determined by means of logistic regression analysis with pair-wise comparisons.  Recall rates were significantly lower with DBT-s2D mammography (4.3 %, 687 of 16,173) when compared with DBT-FFDM (5.8 %, 1,785 of 30,561; OR, 0.72; 95 % CI: 0.65 to 0.78; p < 0.0001) and when compared with FFDM alone (8.7 %, 2,799 of 32,076; OR, 0.46; 95 % CI: 0.43 to 0.51).  The cancer detection rate was similar among FFDM alone (5.3 of 1,000 screening examinations), DBT-FFDM (6.4 of 1,000 screening examinations), and DBT-s2D mammography (6.1 of 1,000 screening examinations) with no significant difference (FFDM versus DBT-FFDM, p = 0.08; FFDM versus DBT-s2D, p = 0.27).  The percentage of invasive cancers detected was significantly higher with DBT-s2D mammography (76.5 %) than with DBT-FFDM (61.3 %, p = 0.01), and PPVs with DBT-s2D mammography (40.8 %) were significantly higher than those with DBT-FFDM (28.5 %, p < 0.0001).  The authors concluded that screening with DBT-s2D mammography in a large community-based practice improved recall rate and PPVs without loss of cancer detection rate when compared with DBT-FFDM and FFDM alone.

This study had several drawbacks: (i) this was a single-institution, single-vendor study, and PPV varied with BC prevalence, which differs per geographic location and limits the generalizability of these results, (ii) this was a retrospective study, and given the free text dictation system used at the authors’ institution for reporting, complete data regarding availability of prior studies, risk profile, or reason for recall were not available for full analysis, (iii) it is possible that the learning-curve effect influenced the results of our study, because the readers had nearly 3 years of experience with DBT, including a trial period, before s2D mammography was fully implemented, (iv) since this was a retrospective review, intra-patient comparisons could not be avoided.  Thus, women with more than 1 screening examination during the study time-period might have been more or less likely to have obtained screening with the same or different technologies after a previous negative or positive result, and (v) the last accrual date was June 30, 2016, and thus information on true- or false-negative results was not available for complete assessment.  Although the results showed that DBT-s2D mammography detected more invasive cancers without a statistically significant loss of in-situ cancer detection compared with DBT-FFDM, further research with adequate follow-up time and sample size is needed to elucidate the reasons behind this result.  Theoretical considerations include the theory that subtle features of invasive cancers may have been more conspicuous on the DBT-s2D images, and this may have contributed to the increased detection of invasive cancers.  It is also possible that in-situ cancers are being under-diagnosed.  Additional research is necessary to clarify the underlying factors.

Guidelines on breast cancer screening from the American College of Obstetricians and Gynecologists (ACOG, 2011) considered, but did not recommend, breast tomosynthesis. The guidelines concluded that "[c]olor Doppler ultrasonography, computer-aided detection, positron emission tomography, scintimammography, and digital breast tomosynthesis have shown promise in selected clinical situations or as adjuncts to mammography for breast cancer diagnosis. However, these technologies are not considered alternatives to routine mammography."

An American College of Obstetrician and Gynecologist technology assessment on “Digital breast tomosynthesis” (ACOG, 2013) noted that “Clinical data suggest that digital mammography with tomosynthesis produces a better image, improved accuracy, and lower recall rates compared with digital mammography alone.  Further study will be necessary to confirm whether digital mammography with tomosynthesis is a cost-effective approach, capable of replacing digital mammography alone as the first-line screening modality of choice for breast cancer screening”. The ACOG technology assessment on DBT (2013) stated that this strategy of 2D plus 3D mammography would need to be compared to other potential strategies for comparative cost-effectiveness, such as the use of computer aided detection.  Additional studies will be needed to confirm whether digital mammography with tomosynthesis is a cost-effective approach capable of replacing digital mammography alone as the first-line screening modality of choice for breast cancer screening. Furthermore, the ACOG technology assessment also noted the concern with the high-dose of radiation with breast tomosynthesis.

An assessment by the Standing Committee on Screening of the Screening Section of the Australian Department of Health and Ageing (2013) stated that: "Whilst there is some evidence that DBT is at least as sensitive and specific as DM, it is not clear whether the use of DBT in large populations outside of a research setting would deliver the same results or whether the additional cost is justified. The issue of radiation dose also needs to be considered in terms of safety for women being screened".

A BlueCross BlueShield Association TEC Assessment, “Use of digital breast tomosynthesis with mammography for breast cancer screening or diagnosis” (BCNSA, 2014), concluded that “Improved health outcomes following the addition of breast tomosynthesis to screening or diagnostic mammography [has] not been demonstrated in the investigational setting.  Based on the above, the addition of digital breast tomosynthesis to screening or diagnostic mammography does not meet the TEC criteria”. The BCBS Medical Advisory Panel reaffirmed their position on digital breast tomosynthesis in 2015.

The USPSTF’s most recent (2016) review concludes that there is insufficient evidence to assess the benefits and harms of DBT as a primary screening method or adjunctive screening method. The USPSTF found insufficient evidence to assess the balance of benefits and harms of DBT as a primary screening method for breast cancer. The Task Force stated that the evidence for DBT is limited. In support, they cited an  assessment of DBT prepared for the USPSTF by the Federal Agency for Healthcare Research and Quality (AHRQ). The AHRQ review found only a single study on the test characteristics of DBT as a primary screening strategy for breast cancer that met the inclusion criteria of the systematic evidence review.

Digital breast tomosynthesis decreases the recall rate by 15 percent (Friedewald, et al., 2014) and increases the number of cancers detected. The extent to which the increased cancers detected are the consequence of overdiagnosis is unknown. The USPSTF found that, “from the limited data available, DBT seems to reduce recall rates (that is, follow-up for additional imaging or testing) and increase cancer detection rates compared with conventional digital mammography alone. However, current study designs cannot determine whether all of the additional cases of cancer detected would have become clinically significant (that is, the degree of overdiagnosis) or whether there is an incremental clinical benefit to detecting these cancers earlier than with conventional digital mammography. In addition, no studies of DBT looked at clinical outcomes, such as breast cancer morbidity or mortality or quality of life.”

The USPSTF found that, “as currently practiced in most settings, DBT exposes women to approximately twice the amount of radiation as conventional digital mammography.  In 2013, the U.S. Food and Drug Administration approved a method to generate synthetic reconstruction of 2-dimensional images from 3-dimensional views, which reduces the total radiation dose associated with DBT. Although the extent to which this new software technology has been implemented in mammography screening centers is not precisely known, it is currently thought to be low. In women with abnormal findings, DBT may also increase the rate of breast biopsy compared with conventional digital mammography.” 

National Comprehensive Cancer Network (NCCN) guidelines on breast cancer screening (NCCN, 2017) include a recommendation to “consider tomosynthesis.” Although the NCCN guidelines were published in July 2016, the accompanying discussion providing the rationale for their decision was published in May 2017. The NCCN guidelines state that digital breast tomosynthesis “appears to improve cancer detection rates and reduce false-positive call-back rates. . . The use of 2D and DBT results in double the radiation exposure compared with mammography alone… The radiation dose can be minimized by newer tomosynthesis techniques that create a synthetic 3D image … “ 

The ongoing TOMMY trial: (A comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme) will compare the accuracy of digital breast tomosynthesis (DBT) with standard digital full field mammography( FFDM) in the diagnosis of breast cancer. The aim of the trial is to assess whether DBT could improve upon digital mammography as a screening tool, particularly in certain groups of women, e.g. those with a family history of breast cancer, or women with dense breasts. The diagnostic accuracy of DBT, FFDM and DBT+FFDM will be evaluated in an independent retrospective reading study and compared to the final clinical outcome for each case.

Contrast-Enhanced Spectral Mammography (CESM):

With contrast enhanced spectral mammography (CESM), an X-ray contrast agent is used to produce contrast enhanced images to purportedly facilitate localization of a lesion. Two sets of images are produced (pre/post contrast) for comparison purposes. 

Allec et al (2011) noted that the accumulation of injected contrast agents allows the image enhancement of lesions through the use of contrast-enhanced mammography.  In this technique, the combination of 2 acquired images is used to create an enhanced image.  There exist several methods to acquire the images to be combined, which include dual energy subtraction using a single detection layer that suffers from motion artifacts due to patient motion between image acquisition.  To mitigate motion artifacts, a detector composed of 2 layers may be used to simultaneously acquire the low and high energy images.  In this work, these researchers evaluated both of these methods using amorphous selenium as the detection material to find the system parameters (tube voltage, filtration, photoconductor thickness and relative intensity ratio) leading to the optimal performance.  They then compared the performance of the 2 detectors under the variation of contrast agent concentration, tumor size and dose.  The detectability was found to be most comparable at the lower end of the evaluated factors.  The single-layer detector not only led to better contrast, due to its greater spectral separation capabilities, but also had lower quantum noise.  The single-layer detector was found to have a greater detectability by a factor of 2.4 for a 2.5 mm radius tumor having a contrast agent concentration of 1.5 mg ml(-1) in a 4.5 cm thick 50 % glandular breast.  The authors stated that the inclusion of motion artifacts in the comparison is part of ongoing research efforts.

Zhao et al (2012) noted that mammography is the primary imaging tool for screening and diagnosis of human breast cancers, but approximately 10 to 20 % of palpable tumors are not detectable on mammograms and only about 40 % of biopsied lesions are malignant.  These researchers reported a high-resolution, low-dose phase contrast X-ray tomographic method for 3D diagnosis of human breast cancers.  By combining phase contrast X-ray imaging with an image reconstruction method known as equally sloped tomography, these investigators imaged a human breast in 3D and identified a malignant cancer with a pixel size of 92 μm and a radiation dose less than that of dual-view mammography.  According to a blind evaluation by 5 independent radiologists, this method can reduce the radiation dose and acquisition time by approximately 74 % relative to conventional phase contrast X-ray tomography, while maintaining high image resolution and image contrast.  The authors concluded that these results demonstrated that high-resolution 3D diagnostic imaging of human breast cancers can, in principle, be performed at clinical compatible doses.

Furthermore, an UpToDate review on "MRI of the breast and emerging technologies" (Slanetz, 2013) states that "Emerging Imaging Technology for Breasr Cancer Detection -- Recognition of the limitations of mammography, ultrasound, and breast MRI has led to investigation of other breast imaging techniques including contrast-enhanced dual energy digital mammography, high-field strength MRI, magnetic resonance spectroscopy, diffusion weighted imaging, breast specific gamma imaging, and positron emission mammography".  Contrast enhanced spectral mammography is not mentioned in this review.

Luczyiska et al (2015) compared contrast-enhanced spectral mammography (CESM) and breast MRI with histopathological results and to compare the sensitivity, accuracy, and positive and negative predictive values for both imaging modalities.  After ethics approval, CESM and MRI examinations were performed in 102 patients who had suspicious lesions described in conventional mammography.  All visible lesions were evaluated independently by 2 experienced radiologists using BI-RADS classifications (scale 1 to 5).  Dimensions of lesions measured with each modality were compared to post-operative histopathology results.  There were 102 patients entered into CESM/MRI studies and 118 lesions were identified by the combination of CESM and breast MRI.  Histopathology confirmed that 81 of 118 lesions were malignant and 37 were benign.  Of the 81 malignant lesions, 72 were invasive cancers and 9 were in-situ cancers.  Sensitivity was 100 % with CESM and 93 % with breast MRI.  Accuracy was 79 % with CESM and 73 % with breast MRI.  Receiver-operating-characteristic curve areas based on BI-RADS were 0.83 for CESM and 0.84 for breast MRI.  Lesion size estimates on CESM and breast MRI were similar, both slightly larger than those from histopathology.  The authors concluded that these findings indicated that CESM has the potential to be a valuable diagnostic method that enables accurate detection of malignant breast lesions, has high negative predictive value, and a false-positive rate similar to that of breast MRI.

Hobbs et al (2015) stated that CESM may have similar diagnostic performance to contrast-enhanced MRI (CEMRI) in the diagnosis and staging of breast cancer.  To date, research has focused exclusively on diagnostic performance when comparing these 2 techniques.  Patient experience is also an important factor when comparing and deciding on which of these modalities is preferable.  These researchers compared patient experience of CESM against CEMRI during pre-operative breast cancer staging.  A total of 49 participants who underwent both CESM and CEMRI, as part of a larger trial, completed a Likert questionnaire about their preference for each modality according to the following criteria: comfort of breast compression, comfort of intravenous (IV) contrast injection, anxiety and overall preference.  Participants also reported reasons for preferring one modality to the other.  Quantitative data were analyzed using a Wilcoxon sign-rank test and chi-squared test.  Qualitative data were reported descriptively.  A significantly higher overall preference towards CESM was demonstrated (n = 49, p < 0.001), with faster procedure time, greater comfort and lower noise level cited as the commonest reasons.  Participants also reported significantly lower rates of anxiety during CESM compared with CEMRI (n = 36, p = 0.009).  A significantly higher rate of comfort was reported during CEMRI for measures of breast compression (n = 49, p = 0.001) and the sensation of IV contrast injection (n = 49, p = 0.003).  The authors concluded that these data suggested that patients preferred the experience of CESM to CEMRI, adding support for the role of CESM as a possible alternative to CEMRI for breast cancer staging.

Furthermore, an UpToDate review on “Breast imaging for cancer screening: Mammography and ultrasonography” (Venkataraman and Slanetz, 2015) does not mention contrast-enhanced spectral mammography as a management option. 

Fredenberg and colleagues (2010) noted that spectral imaging is a method in medical x-ray imaging to extract information about the object constituents by the material-specific energy dependence of x-ray attenuation.  The authors have investigated a photon-counting spectral imaging system with 2 energy bins for contrast-enhanced mammography.  System optimization and the potential benefit compared to conventional non-energy-resolved absorption imaging were studied.  A framework for system characterization was set up that included quantum and anatomical noise and a theoretical model of the system was benchmarked to phantom measurements.  Optimal combination of the energy-resolved images corresponded approximately to minimization of the anatomical noise, which is commonly referred to as energy subtraction. In that case, an ideal-observer detectability index could be improved close to 50% compared to absorption imaging in the phantom study.  Optimization with respect to the signal-to-quantum-noise ratio, commonly referred to as energy weighting, yielded only a minute improvement.  In a simulation of a clinically more realistic case, spectral imaging was predicted to perform approximately 30 % better than absorption imaging for an average glandularity breast with an average level of anatomical noise.  For dense breast tissue and a high level of anatomical noise, however, a rise in detectability by a factor of 6 was predicted.  Another approximately 70 to 90 % improvement was found to be within reach for an optimized system.  The authors concluded that contrast-enhanced spectral mammography is feasible and beneficial with the current system, and there is room for additional improvements.  Inclusion of anatomical noise is essential for optimizing spectral imaging systems.

Schmitzberger et al (2011) demonstrated the feasibility of low-dose photon-counting tomosynthesis in combination with a contrast agent (contrast material-enhanced tomographic mammography) for the differentiation of breast cancer.  All studies were approved by the institutional review board, and all patients provided written informed consent.  A phantom model with wells of iodinated contrast material (3 mg of iodine per milliliter) 1, 2, 5, 10, and 15 mm in diameter was assessed.  A total of 9 patients with malignant lesions and 1 with a high-risk lesion (atypical papilloma) were included (all women; mean age of 60.7 years).  A multi-slit photon-counting tomosynthesis system was utilized (spectral imaging) to produce both low- and high-energy tomographic data (below and above the k edge of iodine, respectively) in a single scan, which allowed for dual-energy visualization of iodine.  Images were obtained prior to contrast material administration and 120 and 480 seconds after contrast material administration.  Four readers independently assessed the images along with conventional mammograms, ultrasonographic images, and magnetic resonance images. Glandular dose was estimated.  Contrast agent was visible in the phantom model with simulated spherical tumor diameters as small as 5 mm.  The average glandular dose was measured as 0.42 mGy per complete spectral imaging tomosynthesis scan of one breast.  Because there were 3 time-points (prior to contrast medium administration and 120 and 480 seconds after contrast medium administration), this resulted in a total dose of 1.26 mGy for the whole procedure in the breast with the abnormality.  Seven of 10 cases were categorized as Breast Imaging Reporting and Data System score of 4 or higher by all four readers when reviewing spectral images in combination with mammograms.  One lesion near the chest wall was not captured on the spectral image because of a positioning problem.  The authors concluded that the use of contrast-enhanced tomographic mammography has been demonstrated successfully in patients with promising diagnostic benefit.  They stated that further studies are necessary to fully assess diagnostic sensitivity and specificity.

Ambicka and colleagues (2016) noted that CESM is one of the new diagnostic modalities implemented in clinical practice.  In the case of these techniques, there are 2 major issues to be addressed: (i) their diagnostic usefulness, and (ii) the relation between parameters assessed using these techniques and well-known diagnostic/prognostic/predictive markers (histological, clinical, and molecular).  Thus, these researchers studied the relationship between the tumor margin assessed on CESM and (i) tumor borders defined on the basis of macroscopic and microscopic examination, (ii) pT, (ii) pN, and (iv) tumor grade in a group of 82 breast cancer patients.  Based on CESM, the tumor border was defined as sharp, indistinct or spiculated, whereas in the case of lesions showing weak or medium enhancement on CESM the borders were classified as unspecified.  These investigators found a statistically significant relationship between tumor margin on CESM and (i) macroscopic border (a spiculated margin on CESM was found only in carcinomas with an invasive border on histological examination; p = 0.004), (ii) pT (p = 0.016), and (iii) pN (nodal involvement was observed most frequently in carcinomas with a spiculated or indistinct margin on CESM; p = 0.045).  Moreover, in cases with an undefined margin on CESM (cases showing weak or medium enhancement on CESM), both invasive and pushing borders were found on histological examination.  The authors concluded that the findings of this preliminary study suggested that it is possible to assess macroscopic borders of examined lesions on the basis of CESM imaging.  This might be useful in planning the extent of surgical excision.  On the other hand, the assessment of the tumor margin on CESM might not be precise in cases showing weak enhancement.

Kariyappa and colleagues (2016) the role of contrast-enhanced dual-energy spectral mammogram (CEDM) as a problem-solving tool in equivocal cases.  A total of 44 consenting females with equivocal findings on full-field digital mammogram underwent CEDM.  All the images were interpreted by 2 radiologists independently.  Confidence of presence was plotted on a 3-point Likert scale and probability of cancer was assigned on Breast Imaging Reporting and Data System scoring.  Histopathology was taken as the gold standard.  Statistical analyses of all variables were performed.  A total of 44 breast lesions were included in the study, among which 77.3 % lesions were malignant or pre-cancerous and 22.7 % lesions were benign or inconclusive; 20 % of lesions were identified only on CEDM.  True extent of the lesion was made out in 15.9 % of cases, multi-focality was established in 9.1 % of cases and ductal extension was demonstrated in 6.8 % of cases.  Statistical significance for CEDM was p < 0.05; inter-observer kappa value was 0.837.  The authors noted that CEDM has a useful role in identifying occult lesions in dense breasts and in triaging lesions.  In a mammographically visible lesion, CEDM characterizes the lesion, affirmed the finding and better demonstrated response to treatment.  They concluded that CEDM is a useful complementary tool to standard mammogram; it has the potential to be a screening modality with need for further studies and validation.

Phillips and associates (2017) evaluated patient preferences toward screening CESM versus MRI.  As part of a prospective study, high-risk patients had breast MRI and CESM.  Patients completed an anonymous survey to evaluate preferences regarding the 2 modalities; 88 % of participants completed the survey; 79 % preferred CESM over MRI if the exams had equal sensitivity; 89 % would be comfortable receiving contrast as part of an annual screening test.  The authors concluded that high-risk populations may accept CESM as a screening exam and may prefer it over screening MRI if ongoing trials demonstrate screening CESM to be clinically non-inferior MRI.

Li and co-workers (2017) retrospectively compared the diagnostic performance of CESM with that of breast MRI (BMRI) in breast cancer detection using parameters, including sensitivity, PPV, lesion size, morphology, lesion and background enhancement, and examination time.  A total of 48 women (mean age of 56 years ± 10.6 [SD]) with breast lesions detected between October 2012 and March 2014 were included.  Both CESM and BMRI were performed for each patient within 30 days.  The enhancement intensity of lesions and breast background parenchyma was subjectively assessed for both modalities and was quantified for comparison.  Statistical significance was analyzed using paired t-test for mean size of index lesions in all malignant breasts (an index lesion defined as the largest lesion in each breast), and a mean score of enhancement intensity for index lesions and breast background; PPV, sensitivity, and accuracy were calculated for both CESM and BMRI.  The average duration time of CESM and MRI examinations was also compared.  A total of 66 lesions were identified, including 62 malignant and 4 benign lesions.  Both CESM and BMRI demonstrated a sensitivity of 100 % for detection of breast cancer.  There was no statistically significant difference between the mean size of index lesions (p = 0.108).  The enhancement intensity of breast background was significantly lower for CESM than for BMRI (p < 0.01).  The mean score of enhancement intensity of index lesions on CESM was significantly less than that for BMRI (p < 0.01).  The smallest lesion that was detected by both modalities measured 4 mm; CESM had a higher PPV than BMRI (p > 0.05).  The average examination time for CESM was significantly shorter than that of BMRI (p < 0.01).  The authors concluded that CESM had similar sensitivity than BMRI in breast cancer detection, with higher PPV and less background enhancement.  They stated that CESM is associated with significantly shorter examination time thus a more accessible alternative to BMRI, and has the potential to play an important tool in breast cancer detection and staging.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
77061 - 77062 Digital breast tomosynthesis
77063 Screening digital breast tomosynthesis, bilateral (List separately in addition to code for primary procedure)
77065 Diagnostic mammography, including computer-aided detection (CAD) when performed; unilateral
77066 Diagnostic mammography, including computer-aided detection (CAD) when performed; bilateral
77067 Screening mammography, bilateral (2-view study of each breast), including computer-aided detection (CAD) when performed
HCPCS codes covered if selection criteria are met:
G0202 Screening mammography, producing direct digital image, bilateral, all views
G0204 Diagnostic mammography, producing direct 2D digital image, bilateral, all views
G0206 Diagnostic mammography, producing direct 2D digital image, unilateral, all views
G0279 Diagnostic digital breast tomosynthesis, unilateral or bilateral (List separately in addition to G0204 or G0206)
ICD-10 codes covered if selection criteria are met:
C50.011 - C50.929 Malignant neoplasm of breast
C79.81 Secondary malignant neoplasm of breast
D05.00 - D05.92 Carcinoma in situ of breast
D24.1 - D24.9 Benign neoplasm of breast
D48.60 - D48.62 Neoplasm of uncertain behavior of breast
N60.01 - N65.1 Disorders of breast
Q85.8 Other phakomatoses, not elsewhere classified [Cowden syndrome]
Z12.31 Encounter for screening mammogram for malignant neoplasm of breast
Z15.01 Genetic susceptibility to malignant neoplasm of breast [Li-Fraumeni syndrome]
Z80.3 Family history of malignant neoplasm of breast
Z84.81 Family history of carrier of genetic disease
Z85.3 Personal history of malignant neoplasm of breast
Z86.00 Personal history of in-situ neoplasm of breast
Z92.3 Personal history of irradiation

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