Simple SummaryThe widespread use of screening mammography and breast ultrasound has enhanced early diagnosis and reduced breast cancer mortality. At the same time, this practice has led to an increase in breast biopsies for suspicious lesions, some of them ultimately resulting in breast lesions of uncertain malignant potential (B3 lesions). The correct management of B3 lesions is controversial, but surgical excision is generally recommended because of the considerable risk of an upgrade to cancer diagnosis upon final histology. Very little data exist concerning the role of B3 diagnosis as a risk factor for future development of breast cancer. The current study analyzes the largest series of B3 lesions from a single institution, providing new insights on both the risk of immediate upgrade to cancer and the subsequent risk of cancer development during the follow-up. An upgrade to carcinoma was found in 4.8% to 39.8% of B3 lesions depending on histologic subtype and in 22.7% on average. In the subsequent years, a diagnosis of breast carcinoma occurred in 9.2% of the patients. This information has considerable implications for future management of patients with B3 lesions.AbstractBreast lesions of uncertain malignant potential (B3) are frequently diagnosed in the era of breast cancer (BC) screening and their management is controversial. They are generally removed surgically, but some international organizations and guidelines for breast research suggest follow-up care alone or, more recently, propose vacuum-assisted excision (VAE). The risk of upgrade to BC is known, but very little data exist on its role as risk factor for future BC development. We analyzed 966 B3 lesions diagnosed at our institution, 731 of which had long-term follow-up available. Surgical removal was performed in 91%, VAE in 3.8%, and follow-up in 5.2% of cases. The B3 lesions included flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), lobular intraepithelial neoplasia (LIN), atypical papillary lesions (PLs), radial scars (RSs), and others. Overall, immediate upgrade to BC (invasive or in situ) was 22.7%. After long-term follow-up, 9.2% of the patients were diagnosed with BC in the same or contralateral breast. The highest risk was associated with ADH diagnosis, with 39.8% of patients upgraded and 13.6% with a future BC diagnosis (p< 0.0001). These data support the idea that B3 lesions should be removed and provide evidence to suggest annual screening mammography for women after a B3 diagnosis because their BC risk is considerably increased.