Diagnostic System in Mono Frequency Electrical Impedance Mammography (EIM) in Breast Cancer Screening.

Background Some evidence has been found that malignant breast tumors have lower electrical impedance than surrounding normal tissues. Electrical impedance could be used as an indicator for breast cancer detection. Methods Is a prospective, cross-sectional epidemiological observational study of serial screening. The women were invited to participate and signed their consent letter. The purpose of our study was to analyze the sensitivity and specificity of electrical impedance mammography (EIM) and its implementation for the differential diagnosis of pathological lesions of the breast, either alone or in combination with mammography / ultrasound, in 1200 women between 25 to 70 years old. Results We found a sensitivity of 85 % and a specificity of 96 %, the positive predictive value was 12% and 99% negative predictive value. Seven biopsy confirmed cancers. Significant correlation between electrical conductivity index and Body mass index (BMI) (p<0.05) and patient's age was observed (p=0.01). We also observed that the average of the conductivity distribution is increasing according to the age group (p <0.01). We used chi-squared test to assess for interactions between percent density mammary and BMI (normal <25 kg/m2 (n= 310), overweight 25-29.9 kg/m2 (n= 418) and obese ≥ 30 (n=437) (p<0.05). The patients with a diagnosis of mammary carcinoma had a BMI of 35.51 kg / m2. Conclusions Our study showed that the sensitivity and specificity of Mono Frequency Electrical Impedance Mammography (EIM) has 85% and 96% respectively. These results suggest that breast electroimpedance can be used in women with obesity and dense breasts since these factors generate an effect that leads to a high rate of cancers at intervals, especially in young women.


Introduction 3
Mammography of electrical impedance is a relatively new method for the diagnosis of mammary diseases (1). In a short period of time, diagnostic criteria have been developed for the early detection of breast cancer by means of electrical impedance imaging (2). It is a non-invasive diagnostic technique based on the electrical storage potential different from normal and pathologically altered tissues that allows image differences in the conductivity and permissiveness of inferred tissue from electrical measurements of the body surface. Mammography by electrical impedance belongs to the class of 3D tomography systems (3).
Raneta et.al. reported that electro-impedance mammography showed a sensitivity of 87% with specificity of 85%. The use of electro-impedance mammography in addition to Mammography and Ultrasound (MMG/USG) can improve the sensitivity of these methods and to increase the rate of early detection of breast cancer with minimal economic costs and highly qualified staff time expenditures (3).
The Electric Impedance Mammography Mono-frequency (EIM) apparatus appears in Russia, created by Modern Impedance Medical Equipment (MEIK) and has been used for breast screening without radiation, allowing screening of high-risk groups, as well as the effective monitoring of any treatment in the patient, with a high degree of precision (4).
Its efficiency was estimated to be 87.39%. Of 75 patients with breast cancer, 96% were found to have degree III of risk of disease progression; 4%, degree II of disease progression risk. Additional examination was recommended. Taking into consideration that EIM works without any type of ionizing radiation, it can be recommended to be used in pregnant patients, hospitalized patients, as well as ambulatory, Family Medicine and Obstetrics and Gynecology Units for the screening of women under 40 years of age (5).
The electrical conductivity index (IC) obtained from the electrical impedance exploration is a quantitative variable, which characterizes the structure of the mammary gland. A low 4 index is typical of a gland that contains a large number of cellular elements and, subsequently, a high concentration of ions. A high index of electrical conductivity is typical of a gland that contains a large number of fatty lobes and a large amount of connective tissue and, therefore, a low concentration of ions (6).
Thus the mammary gland structure can be assessed from the perspective of electrical impedance mammography with a view to the electric conductivity index. As it is well known, the mammary gland structure determines its density, so that the different ranges of electrical conductivity correspond to different types of mammary density (7,8). The assessment is done in line with the American College of Radiology (ACR) terms (9).
Wang k, et al, showed that there are significant differences in the properties of electrical impedance between cancerous tissue and healthy tissue. The impedance of the benign tumor is smaller and is at the same level as that of the mammary glandular tissue. The different growth pattern of the mammary lesions determined the different electrical impedance characteristics in the EIS results (10).
The structural types of breast have been defined according to the correlation between the ductal component and the fat lobes, the breast can have a variable appearance in the tomogram. This is why the mammographic scheme of electrical impedance depends on the type of mammary structure, so the structure of the mammary gland is studied from the perspective of mammography by electrical impedance according to the types of mammary density of the ACR classification (11).
A volumetric lesion is an affectation that is detected in several planes of exploration (12).
The analysis of the image involves the evaluation of the shape of the lesion, the contour, the internal electrical structure and the changes in the surrounding tissues were scored between 0 and 2 values for each alteration or pathological finding (13,14). The sum of the 5 scores is stratified into a scale impedance score of 5 degrees BI-EIM, in great agreement with the BI-RADS classification system (15).
The BI-EIM IV and V scores are considered positive and are referred to biopsy (16). The use of the numerical score for the evaluation of the volumetric lesions by electro breast impedance allows comparing this information with the BI-RADS categories.
The cancer cells exhibit altered local dielectric properties compared to normal cells, measurable as different electrical conductance and capacitance by electrical impedance scanning (17). The divergence of the distribution form of the histograms should be

Study design and populations
Is a prospective observational epidemiological study of cross section of screening of breast cancer in series, of the medical unit of high specialty number 1, Guanajuato Delegation of the Mexican Institute of Social Security. The women were invited to participate and signed their consent letter.
To know the sensitivity and specificity of mammography by mono frequency electroimpedance, we screened one thousand one two hundred women from 25 to 70 years of age, underwent EIM examinations as part of this study. This protocol was approved by committee bioethics (R-2017-785-108). Written informed consent was obtained from each volunteer. All women aged ≥40 years were subjected to a screening mammography (asymptomatic) and complementary ultrasound. Doppler ultrasound was performed in those <40 years old, with BIRADS 3 to 5.
In addition to collecting data on results of the EIM examination and other breast examinations, menopausal status and exogenous hormone use were also recorded.

Mono Frequency Electrical Impedance Mammography (EIM).
It was performed in the patient at rest in dorsal decubitus, the electrodes were placed. For the recording of conductivity, two electrodes were placed: on the right arm to analyze the right breast and, later, on the left arm to analyze the left breast. The interpretation of the study consists in the analysis of the image that describes the following: contour 7 (deformation, hyperimpedance), anatomy of the mammary gland (anatomical changes, displacement of internal structures, hyperimpedance of the area around the focus), local changes of the electrical conductivity (hyperimpedance area, hypoimpedance) and area of the galactophore sinus, which can form a dilated image.
Conductivity measurement: average electrical conductivity index (histogram of distribution of electrical conductivity, divergence of electrical conductivity distribution and local changes in electrical conductivity). In order to know the sensitivity and specificity of the mammography study with electroimpedance, it was carried out at the beginning and, later, the concordance with mammography and ultrasound imaging studies was analyzed. The final diagnosis was made by biopsy and histopathological study.

Mammary Gland Structure and Density types.
Percent density was measured with EIM Classification to evaluate the association between percent density, age and BMI subgroup (normal/underweight, < 25kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used wald chi-squared test to assess for interactions between percent density and BMI. family history of breast cancer (categories were no first-degree relatives with breast cancer, one first degree [sister/mother] relative with breast cancer, or two or more firstdegree relatives with breast cancer); palpability of lesion (palpable mass present or not present); and breast tissue density.
The methods included the Breast Imaging Reporting and Data System (BI-RADS) numerical system. Distribution of mammary gland structure and density types from the perspective of EIM execution in accordance with to ACR classification, for the purposes of this analysis, women were classified into one of four categories: Predominantly Fat, Fat whit some fibroglandular tissue, Heterogeneously dense, Extremely dense. All data are presented as mean ± SE, with a P value < 0.05 was considered significant.

Results
The study involved 1,200 female participants. Patient characteristics are shown in Table 1. The body mass index (BMI) was 28.63 ± 5.94 kg / m2. The anthropometric distribution was as follows: percentage of body fat 37. 28

Electrical Conductivity Index.
When analyzing the electrical conductivity in the mammary tissue of the patients, it was observed that the average of the conductivity distribution is increasing according to the age group (r= 0.49, p <0.01) (Fig. 1). Group 4, which corresponds to women from 56 to 70 years, presented the highest conductivity, with a mean of 0.53 ± 0.11, and group 1, of women between 25 and 35 years, had the lowest conductivity, of 0.36 ± 0.11, with a statistically significant difference (p <0.001).
The difference in the distribution of conductivity between mammary glands of the total group was 10.15 ± 5.18, the conductivity in the left breast was 0.48 ± 0.13 and in the right breast, 0.49 ± 0.13, p= >0.05.

Mammography (EIM).
Regarding the distribution of the BIRADS diagnosis with MEIK electroimpedance  Table 3 .
In total 6 biopsy-proven benign and 7 biopsy-proven malignancies. Negative cases were followed for at least 1 year without evidence of cancer. The 7 cases suggestive of malignancy were corroborated by EIM: BI-RADS 3 (n=1), BI-RADS 4 (n=4), B-IRADS 5 (n=2), which were confirmed with a histopathological diagnosis of mammary carcinoma. 44 cases False-negative findings on EIM were identified by other imaging modalities (US, Mammography) and 6 cases confirmed histologically bening. Table ( (Table 5).

Electric conductivity and Body Mass Index.
Electric Conductivity was associated with body mass index, we observed a statistically significant correlation (r=0.28, p<0.05) Figure ( Fuchsjäger et al, found the same increased sensitivities for smaller cancer as we did in our study, the increased sensitivity for small malignant lesions could indicate a potential of this method, our results showed that the use of EIM in addition to Mammography/US can improve the sensitivity of these methods and to increase the rate of early detection of breast cancer with minimal economic costs and highly qualified staff time expenditures (24). We included visible lesions by ultrasound and were located posteriorly to EIM in the suspected area. The high specificity is the result of a low number of false positives.
With a NPV of 99 % of EIM in BI-RADS category 4 breast lesions, a negative result in these lesions could be firm indication to manage them as BI-RADS category 3 and refer patients for a 6 month short interval follow up rather than performing a biopsy (25). Negative cases were followed for at least 1 year without evidence of cancer.
Many investigations have been oriented to establish an association between obesity and breast cancer (26,27). It is necessary to have methods that allow us to select, in those patients with high breast density, those with a high risk of breast cancer to undergo complementary studies and / or breast biopsies in order to diagnose cancers in the early stages. Obesity and high breast density are common risk factors for breast cancer (28). In 13 our study, 7 patients with mammary carcinoma had a BMI of 30.64. Shien Y et al, found a significant correlation between the percentage of mammary density in the BMI (29). We analyzed the distribution of the conductivity and the mammary density we could find its relation with the BM! We found that 40% of postmenopausal women have a high BMI. The average of the conductivity was higher 0.62 ± 0.04 in the category 1 of the ACR The electroimpedance contributes to an evaluation with greater sensitivity in the dense breast tissue (31) and estrogen use in postmenopausal women (32). On the other hand women < 40 years of age are not screened and in their majority have dense breasts, as observed in our study. In addition to biological causal effects, dense breasts also have a masking effect that leads to a high rate of interval cancers due to a lower sensitivity, particularly in young women (33)(34)(35). This population can be analyzed with EIM the best adjunctive diagnostic performance can be achieved by a combination of US and EIM. Costs and patient morbidity could be minimized.

Conclusions
In conclusion, our study showed that the sensitivity and specificity of Mono Frequency Electrical Impedance Mammography (EIM) has 85% and 96% respectively. These results suggest that breast electroimpedance can be used in women with obesity and dense breasts since these factors generate an effect that leads to a high rate of cancers at intervals, especially in young women. Our results showed that the use of EIM in addition to 14 Mammography / US can improve the sensitivity of these methods and increase the rate of early detection of breast cancer with minimal economic costs and shorter time of highly qualified personnel.  MM Histopathology studies of biopsy tissue samples were carried out.

Abbreviations
SM Participated in coordination and helped to draft the manuscript.
AR Contributing with the realization of Electroimpedance Mammography.
RR Participated with data collection and statistical analysis.
XL Participated in coordination of the study, recruiting clinical data.
All authors read and approved the final manuscript.

Figure 2
Correlation of Electric Conductivity and Body Mass Index.

Supplementary Files
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