Screening and Diagnosis Imagery in Breast Cancer: Classical and Emergent Techniques

Abstract

In light of the limitations of mammography, ultrasound, and breast MRI, some other breast imaging techniques have recently been investigated to reduce false positive rates and raise breast cancer detection including (1) digital breast tomosynthesis, (2) bilateral contrast-enhanced dual-energy digital mammography, (3) ultrasound elastography, (4) abbreviated breast MRI, (5) magnetic resonance spectroscopy, and (6) ductoscopy and duct cytology. The purpose of this review was to examine the advantages and disadvantages of these six different breast cancer imaging techniques.

1. Introduction

According to the National Cancer Institute, 297,790 new cases and 43,170 anticipated deaths from breast cancer are expected in 2023, making it one of the most common and deadly malignancies for women in the US [1]. The goal of continuously investigating innovations in screening modalities is to create technology that maximizes sensitivity and specificity while minimizing radiation exposure and patient discomfort. According to most international groups, breast cancer screening is suggested with annual or biennial mammography for average-risk women aged 50–74 years [2, 3]. To maximize the benefits of screening mammography and further reduce breast cancer mortality, breast cancer screening could start from 45 years of age, according to the American Cancer Society and European screening guidelines [3], or 40 years [4, 5]. However, in high-risk patients, imaging could begin as early as 30 years of age. Despite that mammography remains the gold standard for breast cancer screening [2] (Figures 1 and 2), its sensitivity varies from 37% to 71%, while its specificity is approximately 95% [3]. When an abnormality is detected on screening mammography, ultrasonography is frequently utilized for diagnostic follow-up to clarify features of a possible lesion. Although ultrasonography can be used in addition to mammography screening in women with dense breasts (e.g., to spot malignancies not visible on mammography), there is insufficient evidence to support the use of ultrasound alone in screening [3]. With a sensitivity that ranges from 70% to 100%, breast magnetic resonance imaging (MRI) is thought to be the most sensitive method of breast imaging. However, because of its high cost and limited availability, MRI is typically reserved for high-risk patients and may be regarded as somewhat inaccessible [6].

Figure 1.

Early breast cancer (DCIS) in mammography (mediolateral oblique [MLO] view).

Figure 2.

Early breast cancer (DCIS) in mammography (craniocaudal [CC] view).

In light of the limitations of mammography, ultrasound, and breast MRI, some other breast imaging techniques have been investigated including (1) digital breast tomosynthesis, (2) bilateral contrast-enhanced dual-energy spectral mammography, (3) abbreviated breast MRI, (4) magnetic resonance spectroscopy, (5) microwave imaging, (6) ultrasound elastography, (7) PET/CT and PET/MRI, (8) 18F-fluoroestradiol PET, and (9) ductoscopy.

2. Effectiveness of investigated screening techniques

2.1 Digital breast tomosynthesis (DBT)

DBT is an imaging method [7] (Figure 3) that was created to be used with digital mammography in order to improve its sensitivity and specificity while lowering the false positive rate. A digital detector and moving X-ray are used in DBT to create a three-dimensional mammography image. Actually, in DBT, individual images are reconstructed into a series of high-resolution slices displayed individually or in a “ciné” mode. DBT can be obtained independently using a synthetic two-dimensional (2D) mammogram that is artificially produced from the 3D picture collection, or it can be used in conjunction with digital mammography [3]. Compared to mammography, DBT provides a more detailed image of the breast that helps clarify any suspicious areas seen on mammograms because it allows decades of images to be taken of the same point in the breast from various angles along an arc. This is because the superimposed benign tissues from a two-dimensional perspective may appear more clinically questionable [8]. Numerous studies have demonstrated the superiority of DBT over standard full-field digital mammography in the detection of breast cancer [9]. Specifically, some prospective clinical trials and retrospective cohort studies indicate that tomosynthesis, as compared to digital mammography, slightly raises the rates of cancer diagnosis and lowers the recall rates for false-positive mammography readings [10, 11, 12].

Figure 3.

Digital mammography and tomosynthesis.

According to a 2018 meta-analysis, DBT increased the incremental cancer detection rate by 1.6 cases per 1000 screens (95% CI 1.1–2.0) compared to digital mammography screening alone [13]. DBT had a poorer recall rate (pooled absolute decrease: −2.2, 95% CI −3.0 to −1.4) than digital mammography alone. The impact of DBT on breast cancer mortality has not been evaluated by any research.

While the patient experience with DBT is not much different from that of mammography, the concern about increased radiation exposure needs to be considered when making this decision. However, because of its better sensitivity and specificity in cancer detection rates when compared to mammography alone, DBT is advised as a cancer screening method, particularly in patients with dense breasts [14].

2.2 Bilateral contrast-enhanced dual-energy spectral mammography (CESM)

Twenty years ago, it was shown that bilateral CESM was a useful diagnostic technique for breast cancer detection [15] (Figure 4). CESM combines classic mammography with an iodinated contrast agent to improve diagnostic accuracy. Actually, the method consists of high-energy and low-energy (dual-energy) digital mammography after an intravenous injection of an iodinated contrast liquid. This enables the creation of an “anatomical and functional” image of the breast, with the low-energy component indicating calcifications and the subtracted image showing neovascularization, which represents angiogenesis [16].

Figure 4.

Angiomammography CESM.

Studies indicate that, in 2D digital mammography, CESM can reveal calcifications that would otherwise be undetected. Furthermore, there has not been any research to support the theory that this imaging method is effective in identifying invasive lobular carcinoma (ILC), a type of breast cancer that is known to be challenging to diagnose as it may not manifest as a palpably noticeable mass [16].

Additionally, studies have demonstrated that when combined with mammography, CESM is particularly helpful for detecting breast cancer in women with dense breasts [17]. Moreover, this kind of digital mammography may be a useful alternate technique for patients who cannot undergo a full diagnostic MRI study (e.g., patients with a pacemaker). It should be mentioned that the use of contrast is not always the best option for patients and is not always effective, particularly in cases of allergy or pathological or drug-induced renal impairment. Interestingly, it should be emphasized that CESM has shown comparable sensitivity with other imaging modalities, including MRI [18]. However, comparing its specificity to the current gold standard for breast cancer screening, it has been discovered to be quite variable [19].

2.3 Abbreviated breast MRI

In contrast to a full diagnostic MRI study, which takes 15–20 minutes, an abbreviated breast MRI (ultrafast) (Figures 5 and 6) for breast cancer screening involves a shorter imaging protocol (with fewer sequences) that allows patients to spend no more than 5 to 10 minutes within the MRI scanner. Compared to a full MRI, this abbreviated protocol revealed >98% accuracy in the diagnostic setting as well as 100% accuracy in the screening setting [20].

Figure 5.

Breast MRI.

Figure 6.

Breast MRI dynamic study.

Thus, this technology may be a useful adjunct for patients who cannot undergo a full diagnostic MRI evaluation (e.g., claustrophobic patients). Actually, some recent retrospective studies are showing that the abbreviated MRI protocol has comparable sensitivity with the full diagnostic protocol of MRI [21, 22].

Furthermore, as an example of the reliability of abbreviated MRI imaging, a recent study conducted on women who had previously undergone breast surgery revealed that when an abbreviated MRI imaging was compared to screening mammography and ultrasound, the abbreviated MRI imaging identified all cancers. Thus, it should be emphasized that some cancers detected by abbreviated breast MRI were missed by screening mammography and ultrasound [23]. Similarly, in a recent study, abbreviated MRI discovered breast cancers missed by digital breast tomosynthesis [24].

These findings suggest that abbreviated MRI may be used in screening for breast cancer in women who have low, average, or high risk.

2.4 Magnetic resonance spectroscopy (MRS)

MRS is a specialized an MRI imaging technique allowing the assessment of the chemical composition of breast tissue. In fact, it was observed that malignant tumors have elevated choline levels. Thus, MRS of the breast detects choline and its derivatives in breast tumors [25].

Unfortunately, not all breast cancers express choline, and the method remains investigational due to a substantial number of false negative results.

The method could increase the specificity of the classic breast MRI. Increasing the specificity means fewer false positive findings and, thus, fewer biopsies in many women. In the past, the method showed some promising results in therapy response [26] and could have a future role in predicting outcomes after certain therapies for breast cancer.

2.5 Microwave imaging

The method is based on the difference of certain electric parameters between normal breast tissue and cancer within the microwave spectrum. Microwave imaging does not expose the patient to ionizing radiation and avoids breast compression to achieve best imaging. However, the contrast between malignant tissue, normal fatty, and fibroglandular tissue can be as low as 10%, and, at this level, the resolution is noticeably low resulting in blurred images. The method could be proposed in younger women although further research is necessary as the dielectric contrast in MWI varies greatly at different ages and between individuals. Furthermore, additional research is needed to demonstrate the feasibility of certain techniques to improve the method [27].

2.6 Ultrasound elastography

Breast malignant tumors look larger, and benign lesions appear smaller on the strain elastography compared to a B-mode ultrasound (Figures 7 and 8), an imaging characteristic that could differentiate malignant from benign tumors in certain cases. Furthermore, sharewave elastography is displaying relative stiffness in color differences, distinguishing “harder” malignant tumors from the benign ones [28]. However, size differences and color gradients in the above methods do not provide the information required with high sensitivity, compared to MRI, which is necessary for cancer detection methods. Furthermore, data related to mortality, as in mammography, are missing.

Figure 7.

Breast ultrasound and power Doppler.

Figure 8.

Breast ultrasound and elastography.

2.7 PET/CT and PET/MRI

For breast cancer imaging, PET/CT (Figures 9 and 10) and PET/MRI may be utilized for diagnosis, staging, in cases of probable metastasis at the diagnosis of breast cancer, and evaluation of the treatment response. However, the methods are not proposed for breast cancer screening. Compared to PET/MRI, there is significantly increased radiation exposure to the patient with PET/CT. Furthermore, PET/CT seems inferior to PET/MRI for detecting unsuspected regional or distant diseases [29]. However, compared to PET/MRI scanners, PET/CT scanners are more widely available, and there is a greater experience in their use for distant diseases.

Figure 9.

PET/CT multiple metastasis.

Figure 10.

PET/CT and PET/MRI bone metastasis.

2.8 18F-fluoroestradiol PET (FES-PET)

18F-fluoroestradiol (FES) is a PET tracer with high specificity for estrogen receptor breast cancer. However, the method cannot be used in other cases (as in triple-negative breast cancer), and its usefulness was shown mainly in oligometastatic disease [30].

2.9 Ductoscopy

Ductoscopy is an innovative diagnostic method based on the endoscopic examination of the breast ducts (Figures 11 and 12), especially in the case of pathologic nipple discharge. Ductoscopy is performed under local anesthesia or light sedation. The technique is completely painless and takes between 5 and 20 minutes depending on the case. It is a short procedure in which the duct that secretes fluid is dilated, the ductoscope penetrates the duct and the surgeon checks the inside of the duct through the monitor. After the visual examination is completed, saline is injected into the duct, followed by aspiration (duct lavage) for the collection of endothelial cells and cytological examination [31] (Figure 13). Recently some specialists have used an additional diagnostic procedure during ductoscopy, the “duct brushing” (Figure 14). With a very thin brush, which is inserted into the duct through the ductoscope, the duct walls are scraped to collect more cells (brushing). Then, the cytological examination is performed using the liquid phase technique (ThinPrep), while for greater collection of cells for diagnosis, fluid is also taken from the nipple, using a special pump (Zervoudis’s mammary pump) [32] (Figure 13).

Figure 11.

Breast ductoscopy papilloma.

Figure 12.

Breast ductoscopy breast cancer.

Figure 13.

Zervoudis’s mammary pump and duct lavage.

Figure 14.

Duct brushing.

Ductoscopy is an emergent complementary technique of mammography and breast ultrasound used in women with nipple discharge and also to detect breast cancer in patients with very early breast cancer and patients with a heavy family history. Also, if the intraductal tumor needs to be removed, ductoscopy guides the microsurgical procedure of removal (pyramidectomy and microdolicectomy).

Given the diagnostic efficiency of more than 75% and affordable cost, ductoscopy becomes an additional powerful procedure for the surgeon.

The accuracy of the diagnosis is increased when ductoscopy, duct lavage, and duct brushing are combined [33, 34]. According to a recent meta-analysis, although liquid cytology has a modest sensitivity, it is a valuable diagnostic tool for the high-specificity detection of breast cancer in patients with pathological nipple discharge [35].

3. Harms of breast cancer screening

In addition to the discomfort and hazards associated with the screening process, false-positive or false-negative results from breast cancer screening can be harmful. Furthermore, an overdiagnosis of breast cancer could be harmful to women. The term “overdiagnosis” describes the diagnosis of illnesses that, had screening not been used, would not have progressed to a clinically important stage. Overdiagnosis results in unneeded testing and therapy, as well as psychological effects and further repercussions from receiving a cancer diagnosis and treatment [3].

3.1 False-positive tests

While test sensitivity and specificity are both significant, false-positive results are frequently the source of greatest concern for patients and physicians. The advice for further testing and procedures if a woman does not have cancer is the clinical consequence. Because breast cancer is less common and the tests are less specific, false-positive findings are more common in younger women [36].

Consequently, even if fewer tumors are discovered, younger women will undergo more follow-up procedures. Interestingly, in a retrospective cohort study of 2400 women, the calculated cumulative risk of a false-positive result following 10 mammograms was 49.1%, and following 10 clinical breast exams (CBEs), it was 22.3% [37].

In a different study, it was estimated that 61.3% of women starting at age 40 who underwent annual mammography would require recall for at least one scan over 10 years, and 7% percent would undergo biopsy in the event of a false-positive reading. For women having biennial (every other year) mammography, the estimated rate of recall was 41.6%, and the rate of biopsy over 10 years was 4.8% [38].

The risk of a false-positive study at the first, and by the ninth, screening mammogram was 98 and 100% in those women with the highest risk variables (young age, prior breast biopsies, a family history of breast cancer, current hormonal therapy, 3 years between screenings, no comparison to prior mammograms, and the tendency of the radiologist to call mammograms abnormal [radiologist’s random effect]). On the other hand, the predicted risks for the first and ninth mammograms were 0.7 and 4.6%, respectively, for those with the lowest risk characteristics. The scientists hypothesized that women could have less worry when abnormal mammography was reported if they were aware of their relative risk of a false-positive study based on these characteristics [39].

3.2 Anxiety related to false-positive findings

There is no proof that having false-positive findings will have long-term, persistently unpleasant psychological effects. However, there are short-term, detrimental psychological effects that could last days to weeks [40].

3.3 False-negative tests can delay diagnosis and breast cancer treatment

Screening exams and other medical examinations are not infallible. Sometimes screening mammography results are regarded as negative, yet at the time of the test, the breast does indeed contain cancer. The radiologist may have overlooked these malignancies, or the lesions may not have been obvious on a retrospective imaging examination [41]. A combination of these factors results in the missing diagnosis of about one in eight breast cancers during screening mammography [42]. A false-negative test result is more likely to occur in women who are younger, have dense breasts, have hormone-independent cancer, or have cancer that is proliferating. Consequently, even after a recent negative screening imaging scan, women who exhibit worrying signs or symptoms (e.g., palpable breast lump and new nipple retraction) should have a follow-up evaluation, preferably with a breast surgeon or breast cancer expert.

3.4 Overdiagnosis

The identification of an illness that, had it not been discovered, would not have resulted in morbidity or death is known as overdiagnosis [42]. Certain tumors develop slowly, and some may even go into remission. Overdiagnosis can only be estimated using one of the several methods; it cannot be assessed directly. The percentage of women who receive a false positive for breast cancer ranges from 10% to over 50%, depending on the definition used (e.g., whether ductal carcinoma in situ [DCIS] is included and what age women are studied), as well as the methods used for study design, measurement, and estimation. A perfect screening test would differentiate between malignancies with high or low risk, enabling tailored treatment based on tumor biology [43]. There is not any testing like that accessible. As it is impossible to accurately determine which cancers in a given patient will never progress, treatment is almost always advised.

3.5 Radiation

Although ionizing radiation raises the risk of breast cancer, the majority of cohort studies investigating the issue have included women who were exposed to radiation doses significantly higher than the average glandular dosage for a two-view digital mammography performed at facilities authorized by the American College of Radiology [44]. According to a study conducted in 2015, which supported the adjustment of the US Preventive Services Task Force breast cancer screening guidelines, 16 out of 100,000 women will die from radiation-induced cancer as a result of annual mammography screening throughout their lifetimes [45].

3.6 Ductal carcinoma in situ

DCIS (Figures 1 and 2) accounts for about 16% of breast cancer diagnoses in the US. Over 48,000 women in the US received a DCIS diagnosis in 2019 [46]. About 50% of DCIS cases may not progress to aggressive malignancy, and the natural history of the condition is unclear [47]. It is unknown which cases of DCIS may advance to invasive illness; hence, concerns have been expressed that the discovery of DCIS by mammography may result in overdiagnosis and overtreatment. Typically, the diagnosis leads to surgery and systemic therapy. Suboptimal concordance (84% agreement) across pathologists in identifying DCIS in a breast biopsy sample is another cause for worry. Study pathologists misinterpreted DCIS as invasive breast cancer, and overinterpreted it as benign with or without atypia [48].

3.7 Other possible harms

Another potential harm of breast cancer screening is discomfort, especially during mammography. According to a well-conducted study, patient-controlled breast compression improved the image quality and decreased patient pain [49]. There was a stronger intention to return for another screening assessment when there was less discomfort.

Furthermore, there are more possible risks connected to alternative screening methods. For example, women may not be able to tolerate intravenous gadolinium injection (e.g., because of an allergic response or kidney failure) or may experience claustrophobia, which makes breast MRI unfeasible [50].

3.8 Discussion

Mammography is the gold standard for breast cancer screening [2]. However, its sensitivity is relatively low. Thus, if an abnormality is detected on screening mammography, other imaging techniques are necessary to clarify the initial findings. These techniques include ultrasonography, digital breast tomosynthesis, classic or abbreviated breast MRI, bilateral contrast-enhanced dual-energy spectral mammography, magnetic resonance spectroscopy, microwave imaging, ultrasound elastography, PET/CT, PET/MRI, 18F-fluoroestradiol PET, and ductoscopy. However, it should be emphasized that annual mammography proved beneficial for most women in terms of reduced mortality from breast cancer [51], a finding not yet related to other imaging techniques.

4. Conclusion

The primary key to women’s survival from breast cancer is early detection and treatment. As a result, imaging is essential in the diagnosis and management of breast cancer cases. In recent years, DBT, CESM, abbreviated breast MRI, MRS, and breast ductoscopy have become more heavily investigated. Given its potential effects on health and society, research on new breast imaging technologies is crucial. Many patients worry when undergoing breast cancer screening, and any progress made in reducing the financial burden, scan-to-result time, and accuracy will lessen patient anxiety. Although it is clear that no screening technique has yet been created that is more practical or dependable than mammography, advancements in this area are significant enough to warrant further research in the hopes of improving the management of all breast cancer cases.