1. Aetna considers transillumination (light scanning or diaphanography) of the breast experimental and investigational because this technique has not been established by the peer-reviewed medical literature to be an acceptable alternative to conventional mammography in detecting breast cancer.

2. Aetna considers electrical impedance scanning (EIS) of the breast to be experimental and investigational because there is inadequate evidence in the peer-reviewed published medical literature of the ability of this method to distinguish benign from malignant breast lesions or the effectiveness of EIS of the breast in improving clinical outcomes.

3. Aetna considers breast elastography by any method (i.e., ultrasound or magnetic resonance) experimental and investigational because there is insuffcient evidence of its effectiveness in improving clinical outcomes.

See also CPB 105 - Magnetic Resonance Imaging (MRI) of the Breast; CPB 269 - Breast Biopsy Procedures; CPB 337 - BreastAlert Differential Temperature Sensor; CPB 517 - Breast Ductal Lavage and Fiberoptic Ductoscopy; and CPB 584 - Mammography.

Based on the theory that normal and abnormal tissues reflect different light intensities, transilluminators have been created to screen and diagnose cancers of the breast. One such breast transilluminator, the Lintroscan (Lintronics Technologies) produces video film of breast tissue with visible and infrared light passing through it for detection of breast abnormalities. Breast transilluminators have not been proven to be an acceptable alternative to conventional mammography. An Agency for Healthcare Research and Quality Clinical Practice Guideline (Bassett, et al., 1994) concluded that “[l]ight scanning (diaphanography and transillumination) should not be used for screening or diagnostic evaluation of the breast”. The British Columbia Cancer Agency (2001) has concluded that “[a]t the present state of development, transillumination is not an appropriate imaging device for breast cancer screening.”

Experimental studies have shown that significant changes occur in the electrical properties of breast cancer tissue compared to the surrounding normal tissue. This phenomenon motivated studies on cancer detection using electrical impedance techniques. Some evidence has been found that malignant breast tumors have lower electrical impedance than surrounding normal tissues. This observation has led to the proposal that electrical impedance could be used as an indicator for breast cancer detection. However, the separation of malignant tumors from benign lesions based on impedance measurements needs further investigation. There are no prospective clinical studies demonstrating the clinical utility of electrical impedance scanning (EIS) in distinguishing benign from malignant breast lesions, either in place of or as an adjunct to mammography or magnetic resonance imaging. An assessment of technologies for breast cancer screening and diagnosis conducted by the Institute of Medicine of the National Academy of Sciences (2001) concluded that “[c]linical data suggest the technology [EIS] could play a role in breast cancer detection, but more study is needed to define a role in relation to existing technologies.”

Stojadinovic, et al. (2005) presented preliminary results on the use of EIS for the early detection of breast cancer in young women. They stated that EIS appears promising for early detection of breast cancer, and identification of young women at increased risk for having the disease at time of screening. Positive EIS-associated breast cancer risk compares favorably with relative risks of conditions commonly used to justify early breast cancer screening. The authors also noted that more data are needed to ascertain more accurately the actual sensitivity. These investigators also believe that EIS has promise as a breast cancer screening modality for a group of women for whom no effective screening modality currently exists. EIS seems to identify a population at increased risk for having breast cancer for whom further imaging examinations may be warranted.

On August 29, 2006, the Food and Drug Administration (FDA)'s Obstetrics and Gynecology Devices Panel voted unanimously not to recommend approval of Mirabel Medical Systems' T-Scan 2000 ED bioimpedance device, which is designed to evaluate the risk of breast cancer in asymptomatic women aged 30 to 39 years with no family history of breast cancer and no other known risk factors. The device would be employed in combination with clinical breast examination for this age group whose annual examination does not usually entail mammography.

The FDA panel decided that the data did not provide a reasonable assurance of the effectiveness to support the device's proposed indication. Furthermore, some panel members were concerned with other aspects of the clinical trial: (i) the apparent differences in the characteristics of the two trial populations (1751 women aged 30 to 39 years in the study arm designed to measure specificity and 390 women aged 30 to 45 years in the study arm measuring sensitivity), (ii) a lack of ethnicity data, and (iii) a "high" false positive rate (Taulbee, 2006).

Blackmore, et al. (2007) stated that risk assessment by parenchymal density pattern, a strong physical indicator of future breast cancer risk, is available with the onset of mammographic screening programmes. However, due to the use of ionizing radiation, mammography is not recommended for use in younger women, thereby rendering risk assessment unattainable at an earlier age. These investigators reported on the use of visible and near infra-red light on 292 women with radiologically normal mammograms to determine if transillumination breast spectroscopy (TIBS) can identify women with a high parenchymal density pattern as an intermediate indicator of breast cancer risk. Principal component analysis was used to reduce the spectral data and generate density scores for each woman. To assess the accuracy of TIBS, logistic regression was used to calculate crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for each score. Receiver operator characteristic curves and area under the curve (AUC) were also calculated for the crude and adjusted logistic models. Optical information relating to tissue chromophores, such as water, lipid and haemoglobin content, was sufficient to identify women with high parenchymal density. The resulting AUC for the final and most parsimonious multi-variate logistic model was 0.922 (95% CI 0.878 - 0.967). The authors concluded that TIBS provides information correlating to high parenchymal density and is a promising tool for risk assessment, particularly for younger women. Furthermore, Blackmore and colleagues (2008) also reported that TIBS scores may prove useful as intermediate markers in studies of breast cancer etiology and prevention.

In a prospective, two-cohort trial of pre-menopausal women, Stojadinovic, et al. (2008) estimated the relative probability of breast cancer in T-Scan+ women compared to randomly selected young women. The Specificity (S(p))-Cohort evaluated T-Scan specificity in 1,751 asymptomatic women aged 30 to 39. The Sensitivity)S(n))-Cohort evaluated T-Scan sensitivity in 390 women aged 45 to 30 scheduled for biopsy. Specificity, sensitivity, and conservative estimate of disease prevalence were used to calculate relative probability. In the S(p)-Cohort, 93 of 1,751 women were T-Scan+ (S(p) = 94.7%; 95% CI: 93.7 - 95.7%). In the S(n)-Cohort, 23 of 87 biopsy-proven cancers were T-Scan+ (S(n) = 26.4%; 95% CI: 17.4 - 35.4%). Given S(p) = 94.7%, S(n) = 26.4% and prevalence of 1.5 cancers/1,000 women (aged 30 to 39), the relative probability of a T-Scan+ woman having Br-Ca is 4.95: (95% CI: 3.16 - 7.14). The authors concluded that EIS can identify a subset of young women with a relative probability of breast cancer almost 5 times greater than in the population of young women at-large. The drawbacks of this study were discussed by the afore-mentioned FDA panel.

Elastography refers to the measurement of elastic properties of tissues and is based on the principle that malignant tissue is harder than benign tissue.  Manual palpation in the detection of breast cancer suggests that breast elastography could potentially provide a diagnostic tool for detecting cancerous lesions deeper within the breast.  The technique is typically performed with ultrasound (US), but research with magnetic resonance (MR) is also under way.  Advantages of the US elastography are ubiquitous applicability and cost-effectiveness.  Magnetic resonance elastography (MRE) offers improved reconstruction and the possibility to assess potential anisotropic properties. 

There are 3 main types of US elasticity imaging: (i) elastography that tracks tissue movement during compression to obtain an estimate of strain, (ii) sonoelastography that uses color Doppler to generate an image of tissue movement in response to external vibrations, and (iii) tracking of shear wave propagation through tissue to obtain the elastic modulus.

The SonixTouch Ultrasound Imaging System received 510(k) marketing clearance by the FDA in October, 2008.  The device includes an elastography imaging mode.  Mechanical pressure with the hand on the transducer produces an imaging sequence similar to the B-mode sequence except the system will acquire the radio-frequency signal instead of acquiring B mode data.  The algorithm extracts a strain value information for every point on the image.  The elastography image then color-codes the stiff versus softer structures.

Magnetic resonance elastography is a phase-contrast-based magnetic resonance imaging (MRI) technique that can directly visualize and quantitatively measure propagating acoustic strain waves in tissue subjected to harmonic mechanical excitation.  The data acquired allows the calculation of local quantitative values of shear modulus and the generation of images that depict tissue elasticity or stiffness.

Garra, et al. (1997) examined the feasibility of elastography to determine the appearance of various breast lesions and the potential of elastography to diagnosis breast lesions.  A total of 46 breast lesions were examined with elastography.  Patients underwent biopsy or aspiration of all lesions, revealing 15 fibroadenomas, 12 carcinomas, 6 fibrocystic nodules, and 13 other lesions.  The elastogram was generated from radio-frequency data collected with use of a 5-MHz linear-array transducer.  The elastogram and corresponding sonogram were evaluated by a single observer for lesion visualization, relative brightness, and margin definition and regularity.  The sizes of the lesions at each imaging examination and at biopsy were recorded and compared.  Softer tissues such as fat appeared as bright areas on elastograms.  Firm tissues, including parenchyma, cancers, and other masses, appeared darker.  The cancers were statistically significantly darker than fibroadenomas (p < 0.005) and substantially larger on the elastogram than on the sonogram.  Seventy-three percent of fibroadenomas and 56% of solid benign lesions could be distinguished from cancers by using lesion brightness and size difference.  Some cancers that appeared as areas of shadowing on sonograms appeared as discrete masses on elastograms.  The authors concluded that elastography has the potential to be useful in the evaluation of areas of shadowing on the sonogram and that it may be helpful in the distinction of benign from malignant masses.

Lorenzen, et al. (2002) explored the potential of elasticity as a parameter for the diagnosis of breast lesions using MRE in 15 female patients with malignant tumors of the breast, 5 patients with benign breast tumors, and 15 healthy volunteers.  Malignant invasive breast tumors documented the highest values of elasticity with a median of 15.9 kPa and a wide range of stiffnesses between 8 and 28 kPa.  In contrast, benign breast lesions represented low values of elasticity, which were significantly different from malignant breast tumors (median elasticity: 7.0 kPa; p = 0.0012).  This was comparable to the stiffest tissue areas in healthy volunteers (median elasticity 7.0 kPa), whereas breast parenchyma (median: 2.5 kPa) and fatty breast tissue (median: 1.7 kPa) showed the lowest values of elasticity. Two invasive ductal carcinomas had elasticity values of 8 kPa and two stiff parenchyma areas in healthy volunteers had elasticities of 13 and 15 kPa.  These lesions could not be differentiated by their elasticity.  The authors concluded that MRE is a promising new imaging modality with the capability to assess the viscoelastic properties of breast tumors and the surrounding tissues; however, there is an overlap in the elasticity ranges of soft malignant tumors and stiff benign lesions.

Sinkus, et al. (2005) examined the viscoelastic shear properties of breast lesions measured by MRE applied in the course of standard MR mammography to 15 patients with different pathologies (6 breast cancer cases, 6 fibroadenoma cases and 3 mastopathy cases).  Breast cancer appeared on average 2.2 (p < 0.001) times stiffer.  All breast cancer cases showed a good delineation to the surrounding breast tissue with an average elevation of a factor of 3.3 (p < 1.4 x 10(-6)).  However, the results were not found to be useful for separating benign from malignant lesions.

Giuseppetti, et al. (2005) assessed the diagnostic accuracy of elastography in characterizing nodular breast lesions.  A total of 82 patients who received mammographic, US and elastographic evaluation in a single session at two Italian centers between January and August 2004 according to identical protocols exhibited 91 nodules that were subjected to cytological/histological examination.  Lesions were classified and scored and the sensitivity and specificity of elastography calculated.  Overall sensitivity and specificity were 79% and 89%, respectively.  However, sensitivity was 86% and 65% and specificity 100% and 62% for lesions less than 2 cm and greater than 2 cm in diameter, respectively.  The authors concluded that larger studies are needed to establish semiological patterns.

Itoh, et al. (2006) evaluated the diagnostic performance of real-time elastography (RTE) by using the extended combined autocorrelation method (CAM) to differentiate benign from malignant breast lesions, with pathologic diagnosis as the reference standard.  Conventional US and RTE with CAM were performed in 111 women (mean age, 49.4 years; age range, 27-91 years) who had breast lesions (59 benign, 52 malignant).  Elasticity images were assigned an elasticity score according to the degree and distribution of strain induced by light compression.  The area under the curve and cut-off point, both of which were obtained by using a receiver operating characteristic curve analysis, were used to assess diagnostic performance.  Mean scores were examined by using a Student t test.  Sensitivity, specificity, and accuracy were compared by using the standard proportion difference test or the Delta-equivalent test.  For elasticity score, the mean +/- standard deviation was 4.2 +/-  0.9 for malignant lesions and 2.1 +/- 1.0 for benign lesions (p < 0.001). When a cut-off point of between 3 and 4 was used, elastography had 86.5% sensitivity, 89.8% specificity, and 88.3% accuracy.  When a best cut-off point of between 4 and 5 was used, conventional US had 71.2% sensitivity, 96.6% specificity, and 84.7% accuracy.  Elastography had higher sensitivity than conventional US (p < 0 .05).  By using equivalence bands for non-inferiority or equivalence, it was shown that the specificity of elastography was not inferior to that of conventional US and that the accuracy of elastography was equivalent to that of conventional US.  The authors concluded that US elastography with the proposed imaging classification had almost the same diagnostic performance as conventional US.

Thomas, et al. (2006) compared the sensitivity and specificity of elastography with that of B-mode US and mammography in 300 patients with histologically confirmed breast lesions (168 benign, 132 malignant).  Evaluation was by means of the 3-dimensional (3-D) finite-element method.  The data were color-coded and superimposed on the B-mode US scan.  The images were evaluated by two independent readers.  The results were compared with mammography, histology, and the data obtained by previous US investigations.  Sensitivity and specificity in the differentiation of benign and malignant lesions were 87% and 85%, respectively, for mammography and 94% and 83% for B-mode US.  The two examiners were in very good agreement in their evaluation of the elastograms (kappa: 0.86).  Elastography had a sensitivity of 82% and a specificity of 87%.  Elastography was superior to B-mode US in diagnosing Breast Imaging Reporting and Data System (BI-RADS) 3 lesions (92% versus 82% specificity) and in lipomatous involution (80% versus 69% specificity).

Zhang, et al. (2006) investigated the clinical value of RTE in the diagnosis of breast cancer in 120 patients with breast lumps (135 lesions).  Patients were examined with B-mode imaging, color Doppler flowing imaging (CDFI) and RTE.  The elastogram was graded using a 5-score evaluating method.  The post-operative pathological diagnosis was used as the gold standard, and the sensitivity, specificity and accuracy of RTE and 2-D US combined with RTE in diagnosis of breast cancer were calculated.  When the score greater than 4 was set for cut-off criteria of malignancy, the sensitivity, specificity and accuracy of RTE was 85.45%, 83.75% and 84.4%, respectively.  When 2-D US combined with RTE was used, the sensitivity, specificity and accuracy increased up to 100%, 95% and 97%, respectively.

Thomas, et al. (2006) evaluated whether RTE could improve the differentiation and characterization of benign and malignant breast lesions.  Real-time elastography was carried out in 108 potential breast tumor patients with cytologically/histologically confirmed focal breast lesions (59 benign, 49 malignant; median age, 53.9 years; range, 16-84 years).  Tumor and healthy tissue were differentiated by measurement of elasticity based on the correlation between tissue properties and elasticity modulus.  Evaluation was performed using the 3-D finite element method, in which the information is color-coded and superimposed on the B-mode US image.  A second observer evaluated the elastography images, in order to improve the objectivity of the method.  The results of B-mode scan and elastography were compared with those of histology and previous sonographic findings.  Sensitivities and specificities were calculated, using histology as the gold standard.  B-mode US had a sensitivity of 91.8% and a specificity of 78%, compared with sensitivities of 77.6% and 79.6% and specificities of 91.5% and 84.7%, respectively, for the two observers evaluating elastography.  Agreement between B-mode US and elastography was good, yielding a weighted kappa of 0.67.  The authors concluded that RTE improves the specificity of breast lesion diagnosis and is a promising new approach for the diagnosis of breast cancer. 

Zhi, et al. (2007) compared the use of US elastography with mammography, and sonography in the diagnosis of solid breast lesions.  From September 2004 to May 2005, 296 solid lesions from 232 consecutive patients were diagnosed as benign or malignant by mammography and sonography and further analyzed with US elastography.  The diagnostic results were compared with histopathologic findings.  The sensitivity, specificity, accuracy, positive and negative predictive values, and false-positive and -negative rates were calculated for each modality and the combination of US elastography and sonography.  Of 296 lesions, 87 were histologically malignant, and 209 were benign.  Ultrasound elastography was the most specific (95.7%) and had the lowest false-positive rate (4.3%) of the 3 modalities.  The accuracy (88.2%) and positive predictive value (PPV) (87.1%) of US elastography were higher than those of sonography (72.6% and 52.5%, respectively).  The sensitivity values, negative predictive values (NPV), and false negative rates of the 3 modalities had no differences.  A combination of US elastography and sonography had the best sensitivity (89.7%) and accuracy (93.9%) and the lowest false-negative rate (9.2%).  The specificity (95.7%) and PPV (89.7%) of the combination were better, and the false-positive rate (4.3%) of the combination was lower than those of mammography and sonography.  The authors concluded that US elastography is a promising technique for evaluating breast lesions.

Tardivon, et al. (2007) evaluated elastography in the characterization of breast nodules in 122 lesions.  Elastography (Hitachi, 7.5- to 13-MHz probe; Ueno classification, scores 1-3 = benign, 4-5 = malignant) was evaluated in 125 sub-clinical lesions in 114 patients.  The results were compared to those of the American College of Radiology's BI-RADS sonography categories (benign = 2 and 3, malignant = 4 and 5) and to the results of the percutaneous samples taken and/or surgery (122 lesions evaluated, 59% less than 10 mm, 61 cancers, 61 benign lesions).  There were 3 technical failures (2.4%).  The elastography was in agreement with histology for 101 lesions, with 13 false-negative results and 8 false-positive results (sensitivity, 78.7%; specificity, 86.9%; PPV, 85.7%; NPV, 80.3%); versus agreement with the BI-RADS classification for 98 lesions with one false-negative result and 23 false-positive results (sensitivity, 98.4%; specificity, 47.5%; PPV, 65.2%; NPV, 96.7%).

Cho, et al. (2008) compared the diagnostic performances of conventional US and US elastography for the differentiation of non-palpable breast masses, and to evaluate whether elastography is helpful at reducing the number of benign biopsies, using histological analysis as a reference standard.  Conventional US and RTE images were obtained for 100 women who had been scheduled for a US-guided core biopsy of 100 non-palpable breast masses (83 benign, 17 malignant).  Two experienced radiologists unaware of the biopsy and clinical findings analyzed conventional US and elastographic images by consensus, and classified lesions based on degree of suspicion regarding the probability of malignancy.  Results were evaluated by receiver operating characteristic (ROC) curve analysis.  In addition, the authors investigated whether a subset of lesions were categorized as suspicious by conventional US, but as benign by elastography.  Areas under the ROC curves (Az values) were 0.901 for conventional US and 0.916 for elastography (p = 0.808).  For BI-RADS category 4a lesions, 44% (22 of 50) had an elasticity score of 1 and all were found to be benign.  The authors concluded that elastography had a diagnostic performance comparable to that of conventional US for the differentiation of non-palpable breast masses.

Researchers have tested the feasibility of breast elastography and the results confirm the hypothesis that breast elastography can quantitatively depict the elastic properties of breast tissues and reveal high shear elasticity in known breast tumors.  However, the clinical benefits of elastography imaging are still under evaluation and no clinical diagnosis can be made other than being able to tell whether or not a structure inside the patient is stiffer than another one.  Further research is needed to evaluate the potential clinical applications of breast elastography, such as detecting breast carcinoma and characterizing suspicious breast lesions.