Contrast-enhanced ultrasound for differentiating benign from malignant BI-RADS 4a breast lesions: A prospective diagnostic accuracy study

Background: Breast Imaging Reporting and Data System (BI‑RADS) 4a breast lesions are considered low suspicion for malignancy (2‑10%), yet current guidelines recommend biopsy for definitive diagnosis, leading to a high rate of unnecessary invasive procedures. Contrast‑enhanced ultrasound (CEUS) provides real‑time microvascular perfusion information that may improve risk stratification in this indeterminate category. This study aimed to evaluate the diagnostic performance of CEUS in differentiating benign from malignant BI‑RADS 4a lesions, with a focus on its potential to reduce avoidable biopsies.

Methods: In this prospective diagnostic study, consecutive patients with BI‑RADS 4a lesions identified on conventional ultrasound underwent CEUS examination using a sulfur‑hexafluoride microbubble contrast agent. CEUS cine loops were independently reviewed by two blinded readers. Lesions were classified as CEUS‑positive (suspicious for malignancy) if they exhibited ≥2 predefined malignant perfusion features (e.g., heterogeneous hyper‑enhancement, centripetal filling, perfusion defects, fast wash‑in/wash‑out). Histopathology from biopsy or surgery served as the reference standard. Diagnostic accuracy metrics—sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the receiver‑operating‑characteristic curve (AUC)—were calculated.

Results: A total of 149 BI‑RADS 4a lesions were included. Histopathology revealed 129 benign and 20 malignant/high‑risk lesions. CEUS demonstrated a sensitivity of 85.0% (95% confidence interval [CI] 62.1‑96.8%), specificity of 89.9% (95% CI 83.3‑94.6%), PPV of 47.2% (32.9%-62.0%), and NPV of 98.2% (95% CI 93.8‑99.6%). The overall accuracy was 89.3% (95% CI 83.2‑93.7%), with an AUC of 0.88 (95% CI 0.81‑0.94). Malignant lesions showed significantly higher frequencies of heterogeneous hyper‑enhancement, centripetal perfusion, perfusion defects, and fast wash‑in/wash‑out kinetics (all p<0.001). Inter‑observer agreement for CEUS classification was substantial (κ=0.76).

Conclusion: CEUS exhibits high diagnostic performance, especially a high NPV, in the evaluation of BI‑RADS 4a breast lesions. It can reliably identify a subset of lesions with a very low probability of malignancy, suggesting that CEUS may help identify a subset of patients in whom immediate biopsy could be considered for deferral within a shared decision‑making framework, though prospective validation in larger cohorts is needed. These findings support the integration of CEUS as a valuable adjunctive triage tool to reduce unnecessary biopsies in low‑suspicion breast lesions.