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To evaluate imaging and histopathologic differences between screen-detected benign and malignant upgraded lesions initially assessed as BI-RADS 3 at diagnostic evaluation. An IRB approved retrospective review of the mammography data base from January 1, 2004 to December 31, 2008 identified 1,188 (1.07%) of 110,776 screening examinations assessed as BI-RADS 3 following diagnostic evaluation at our academic center (staffed by breast specialists) or our outpatient center (staffed by general radiologists), 1,017 with at least 24 months follow-up or biopsy. Sixty (5.9%) BI-RADS 3 lesions were upgraded to BI-RADS 4 or 5 during imaging surveillance (study population). Prospective reports, patient demographics, and clinical outcomes were abstracted from the longitudinal medical record. Mean patient age was 54.1 years (range 35-85). Lesions consisted of 7 masses, 12 focal asymmetries and 41 calcifications. Fifteen (25%) of 60 lesions upgraded from initial BI-RADS 3 assessment were malignant (1.47% of total; 15/1,017 BI-RADS 3 studies). Malignancy rates by upgraded lesion type showed no significant difference: Thirty-three (73.3%) of 45 benign upgraded lesions were calcifications compared to 8 (53.3%) of 15 malignant upgraded lesions (p = 0.202). Twelve (26.7%) of 45 benign upgraded lesions were masses or focal asymmetries, compared to 7 (46.7%) of 15 upgraded malignant lesions (p = 0.202). Six (85.7%) of 7 malignant upgraded masses/focal asymmetries had no US correlate at initial BI-RADS 3 assessment compared to 7 (58.3%) of 12 benign upgraded masses/focal asymmetries (p = 0.33). Breast-imaging specialists interpreted 21 studies, 3 (14.3%) malignant; general radiologists interpreted 39 studies, 12 (30.8%) malignant (p = 0.218). There was no significant difference in malignancy rate among different types of upgraded mammographic lesions, nor depending on subspecialty interpretation versus nonsubspecialist interpretation. Although calcifications made up a majority of upgraded lesions, most were benign, suggesting that decreased surveillance of calcifications may be appropriate., (© 2016 Wiley Periodicals, Inc.)