The potentially large number of unnecessary biopsies resulting from the current recommendation for BI-RADS-US category 4a creates an additional burden for women and impacts clinical resources. Our findings showed that the false-positive rate of category 4a in ABUS was almost 65.81% which was similar to HHUS (67.55%). Meanwhile, clinical and sonographic factors influencing the 4a false-positive lesions were observed differently between HHUS and ABUS which might be associated with radiologists’ experiences and equipment difference. Supplementing MAM in women with BI-RADS-US (HHUS or ABUS) category 4a lesions can improve specificity and PPV. To note, the potential added value of the second-look MAM adjunct to HHUS 4a was identified to reduce unnecessary biopsy procedures, but might with the risk of missing invasive cancer. However, the new strategy combining ABUS category 4a and MAM 3, 4, and 5 as a new biopsy threshold would have the potential to safely reduce false-positive biopsies.
Current criticisms of HHUS include concern about the false positive results and associated unnecessary biopsies [17]. The range of the malignancy rate for BI-RADS-US 4 lesions is wide (2 ~ 95%) [7]. In particular, considerable overlapped image features between benign and malignant lesions in category 4a result in difficulty to distinguish malignancy. The primary reason is lacking objective criteria for the subclassification of category 4 lesions which are largely based on the experience of the sonographers [18]. Our results also reflected the benign biopsy rate of 4a was higher even when performed by highly qualified experts from high-level hospitals which was following the conclusions of previous studies [9–10].
The potential of ABUS in the diagnostic setting of breast cancer has currently become the research focus because of its benefits [19]. Some unique features through multiplanar reconstructions can provide additional information for differentiating benign and malignant masses [20]. For example, the retraction phenomenon, as the specific feature observed in ABUS coronal view, has been suggested to be a predictable characteristic of breast cancer [21]. Our previous studies have suggested that specificity and PPV were significantly higher in ABUS, compared with that of HHUS [22–23]. However, this study showed the unnecessary biopsy rate of ABUS among 4a masses is similar to that of HHUS. This might be explained by the lower ability of radiologists who review the ABUS images to evaluate category 4a even with standardized training before. Additionally, there is not yet a well-established specific criterion in determining lesion characteristics with ABUS images worldwide, primarily based on BI-RADS-US descriptors. Of note, the non-essential biopsy rate was 72.84% in 81 patients assessed with both ABUS and HHUS. Thereby, the technological inherent limitations of US equipment may also be another important reason.
In routine clinical practice, the interpretation criteria of category 4a are that a mass with benign ultrasound appearance but exhibiting any suspicious sign [24]. Of all normal or benign lesions, duct change, nonparallel masses, and architectural distortion increased the level of suspicion for these masses and prefer BI-RADS 3 to 4a for HHUS in our study. Surrounding background tissue change results in the poor demarcation between masses and normal tissue, which may partly be explained by these features impede evaluate accurately the breast lesion [25–27]. Meanwhile, Calcification was observed associated with false-positive cases in lesions of category 4a examined using ABUS. Due to the influence of probe frequency, tissue background echo, and operator technology, ultrasound is not ideal to detect microcalcification in lesions even though it is the key imaging feature for the diagnosis of breast cancer [28]. Notably, we also found that menopausal status and larger masses tended to higher probability of false positives. ABUS separates image acquisition (performed by the technicians) from interpretation. Therefore, sonographers will pay more attention to the clinical characteristics of patients compared with HHUS, such as menopausal status. In addition, a previous study has also revealed that women with larger lesions tend to raise the level of suspicion [29]. Above all, benign possibilities should be taken into account when these features are found which suggests that examiners need to integrate other important image features when interpreting ultrasound images by receiving specific training about BI-RADS descriptors. More importantly, supplemental other screening tools might be effective strategies help to triage populations with lower risk by delaying biopsy interventions and avoiding making unnecessary recommendations.
No other trials of integrated MAM in ultrasound have reported results. Lacking sufficient evidence to reduce breast cancer mortality could be a barrier to implementing the widespread ultrasound as the stand-alone screening modality. Currently, supplemental ultrasound to MAM has become a mainstay of diagnostic breast imaging for women with mammographically dense breasts. Some low- and middle-income countries (LMICs) are exploring HHUS application as a primary screening method for breast cancer because of the advantages of being cheap, having higher access, and being noninvasive [30–32]. A meta-analysis study demonstrated that studies focusing on HHUS applications in LMICs have risen nearly by 60%, which reveals the increasing adoption of HHUS equipment worldwide [33]. However, given the lower specificity and higher false-positive rate of HHUS, it is important to explore ultrasound-based diagnostic strategies in combination with other techniques.
US (HHUS or ABUS) category 4a combined with MAM positive results as the biopsy threshold can significantly improve diagnostic performance and reduce false-positive biopsies when compared to the current scenario, but probably with the risk of missing invasive cancer. The most likely explanation is that more than 70% of participants age 40 and older and almost 50% of them were premenopausal who undergo MAM are found to have dense breasts in our study, which may be associated with the lower sensitivity of MAM [16]. Of note, our findings also revealed that the new biopsy threshold did not affect the invasive cancer yield which is comparative with the current scenario for women with less dense breasts. Furthermore, this study was conducted in hospitals and the conclusions came from the symptomatic population who has a higher risk for breast cancer than the asymptomatic population. In view of these issues, whether an immediate biopsy strategy is needed for this group still depends on clinicians’ perceptions of acceptable risks based on an individual patient basis to balance the pros and cons.
Notably, we found that the added value of the second-look MAM adjunct to HHUS 4a could acquire higher cancer yields when breast masses were palpable which might be related to the probability of malignancy being fairly high in palpable lesions. Pliability is likely to be viewed with more suspicion by these masses, providing information to aid diagnosis for radiologists [29]. A previous study showed the combination of MAM and HHUS could potentially increase the negative predictive value among women with palpable breast abnormality [34].
Most importantly, this study provides a more practical perspective that when the biopsy threshold identified BI-RADS 3 and above for MAM combined with BI-RADS 4a for ABUS has benefited over the current biopsy strategy for reducing false-positive biopsies without affecting the detection performance. Findings from a prospective study indicated that ABUS has a higher ability to detect architectural distortions, one of the risk factors of subsequent breast cancer in mammographic findings [35], on the coronal plane than HHUS [36]. Additionally, ABUS can supplement mammography to detect more non-calcified carcinomas compare with HHUS in women with dense breasts [35]. This might explain the higher diagnostic performance of the biopsy threshold (Scenario #2) for ABUS than that of HHUS. Furthermore, we also acknowledged that the difference between HHUS and ABUS might result from the limited sample size in category 4a.
The reasons for false-positive findings need to be identified through external quality assessment in clinical practice. Some cases without abnormal pathological findings might have image changes that mimic the appearance of precancerous lesions, resulting in misclassification as positive results. This group then needs to be given priority attention, because the image feature abnormalities are more likely to be risk markers of breast cancer [37]. A previous retrospective study performed by Hofvind et al. showed a higher interval breast cancer rate appeared after a false-positive result in a MAM-based screening program [38]. The biological susceptibility maybe contributes to the increased risk for breast cancer [39]. Thereby, risk-based stratification management strategies play a vital role for women with false-positive results. However, because of our cross-sectional study design, future works should be conducted to explore the safe screening intervals for false-positive recalls.
The main strength of this study is the first to evaluate the added value of the second-look MAM adjunct to US (HHUS or ABUS) category 4a. It possibly contributes to understanding that MAM might be a useful additional tool for US in breast cancer diagnostics to better distinguish which patients require a histopathologic confirmation of suspicious lesions on imaging.
This study had several limitations. First, the experience of the radiologists among five research centers could affect the ability of image acquisition and interpretation. However, the variability among radiologists might be avoided to some extent by the standardized training before the research. Another limitation is the absence of follow-up information may affect the accurate evaluation of long-term effectiveness results in patients with false-positive biopsies of US 4a among different biopsy thresholds. In addition, the study participants were recruited from hospital outpatient with a higher risk of breast cancer, which does not reflect the new biopsy thresholds applications for the general population. To address this issue, we now have conducted ongoing real-world research to explore the screening effectiveness for HHUS, ABUS, and MAM in average-risk populations.