Probably benign lesions at screening breast US in a population with elevated risk: prevalence and rate of malignancy in the ACRIN 6666 trial.

PURPOSE: To prospectively validate predefined breast ultrasonographic (US) Breast Imaging Reporting and Data System (BI-RADS) category 3 criteria in a multicenter setting in an elevated-risk population. MATERIALS AND METHODS: The American College of Radiology Imaging Network 6666 database was reviewed for prospectively defined BI-RADS category 3 lesions. Patient characteristics, lesion US features at initial detection, and work-up recommendations were analyzed with descriptive statistics. Exact 95% confidence intervals (CIs) were given, where appropriate. Lesion reference standard was biopsy or a minimum of 1-year follow-up. In addition, malignancy rate for lesions that had at least 2 years of follow-up data or that had biopsy data was calculated. RESULTS: Of 2662 participants, 519 (19.5%) had 745 BI-RADS category 3 lesions (25.5% of 2916 US lesions other than simple cysts), with a median size of 7 mm (range, 2-135 mm). The number of new BI-RADS category 3 lesions decreased with year 2-3 screening, but the percentage of new BI-RADS category 3 lesions was stable at 26.4% (506 of 1920 lesions), 23.6% (142 of 601 lesions), and 24.6% (97 of 395 lesions), respectively. Of 745 BI-RADS category 3 lesions, 124 (16.6%) were ultimately sampled for biopsy. Six malignancies (0.8% of BI-RADS category 3 lesions; 95% confidence interval [CI]: 0.3%, 1.7%) occurred in five (1.0%) of 519 participants: Five malignancies were invasive (median size, 10 mm; size range, 2-18 mm), and one was node positive. When the analysis is limited to lesions with at least 2-year follow-up or biopsy, the malignancy rate among BI-RADS category 3 lesions is 0.9% (95% CI: 0.3%, 2.0%). Three malignant BI-RADS category 3 lesions were sampled for biopsy because of a suspicious change at follow-up (two N0 lesions, one each at 6- and 12-month follow-up; one N1 lesion at 24-month follow-up), one was sampled for biopsy because of an upgrade after additional mammography (NX), one was found at mastectomy for another cancer (N0), and one was found at prophylactic contralateral mastectomy in the same patient (NX). CONCLUSION: As BI-RADS category 3 lesions have a low malignancy rate (0.8%; 95% CI: 0.3%, 1.7%) and only 0.1% of the cancers had suspicious changes at 6-month follow-up and only one (17%; 95% CI: 0.4%, 64%) of six malignancies were node positive at detection (24-month follow-up), a recommendation of 1-year diagnostic follow-up may be appropriate for BI-RADS category 3 lesions detected at screening US. Online supplemental material is available for this article.

Multiple bilateral circumscribed masses at screening breast US: consider annual follow-up.

PURPOSE: To determine prospectively the prevalence and rate of malignancy of multiple bilateral (MB) circumscribed breast masses detected at screening ultrasonography (US) compared with those of other US-depicted masses. MATERIALS AND METHODS: This institutional review board-approved, HIPAA-compliant prospective trial included women at elevated risk for breast cancer, who gave written informed consent to participate in a study evaluating cancer detection rates for three rounds of annual supplemental screening US at 21 international sites. After exclusions, 2662 participants and 7473 screening studies were included. Physician-performed US studies were interpreted, with blinding to mammography results. Simple cysts were noted. Breast Imaging Reporting and Data System features of all other findings were recorded, with addition of the descriptor MB similar-appearing circumscribed masses (minimum of three total and at least one in each breast), with details of the largest such mass recorded. Rates of malignancy were determined after biopsy or mammographic and US follow-up at a minimum of 11 months. For this analysis, 490 women (1370 screenings) with prior mastectomy were excluded. Descriptive statistics and exact 95% confidence intervals (CIs) were generated. RESULTS: Of 2172 evaluable participants (6103 screening studies; median age at study entry, 54.0 years; range, 25-91 years), 1454 had unique findings at US. One hundred thirty-five (6.2%) participants had 153 unique MB circumscribed masses, with no malignancies (0% [95% CI: 0%, 2.4%]; 95% CI: 0%, 2.9% for the 127 masses with at least 2 years of follow-up). There were 1319 (60.7%) participants with 2464 non-MB lesions, including 1038 solitary circumscribed masses with a malignancy rate of 0.8% (eight of 1038). Of 836 solitary circumscribed masses with at least 2 years of follow-up, the malignancy rate was 0.4% (three of 836; 95% CI: 0.1%, 1.0%). Of the 135 women with MB circumscribed masses, 82 (60.7%) also had a solitary lesion. Two of these 82 women (2.4%) had cancer. CONCLUSION: MB similar-appearing circumscribed masses seen at screening US are almost always benign, with no malignancies found among such lesions in this prospective, multicenter experience. These lesions are suitable for diagnostic follow-up in 1 year, with resumption of screening thereafter if they are stable.

Training the ACRIN 6666 Investigators and effects of feedback on breast ultrasound interpretive performance and agreement in BI-RADS ultrasound feature analysis.

OBJECTIVE: Qualification tasks in mammography and breast ultrasound were developed for the American College of Radiology Imaging Network (ACRIN) 6666 Investigators. We sought to assess the effects of feedback on breast ultrasound interpretive performance and agreement in BI-RADS feature analysis among a subset of these experienced observers. MATERIALS AND METHODS: After a 1-hour didactic session on BI-RADS: Ultrasound, an interpretive skills quiz set of 70 orthogonal sets of breast ultrasound images including 25 (36%) malignancies was presented to 100 experienced breast imaging observers. Thirty-five observers reviewed the quiz set twice: first without and then with immediate feedback of consensus feature analysis, management recommendations, and pathologic truth. Observer performance (sensitivity, specificity, area under the curve [AUC]) was calculated without feedback and with feedback. Kappas were determined for agreement on feature analysis and assessments. RESULTS: For 35 observers without feedback, the mean sensitivity was 89% (range, 68-100%); specificity, 62% (range, 42-82%); and AUC, 82% (range, 73-89%). With feedback, the mean sensitivity was 93% (range, 80-100%; mean increase, 4%; range of increase, 0-12%; p < 0.0001), the mean specificity was 61% (range, 45-73%; mean decrease, 1%; range of change, -18% to 11%; p = 0.19), and the mean AUC was 84% (range, 78-90%; mean increase, 2%; range of change, -3% to 9%; p < 0.0001). Three breast imagers in the lowest quartile of initial performance showed the greatest improvement in sensitivity with no change or improvement in AUC. The kappa values for feature analysis did not change, but there was improved agreement about final assessments, with the kappa value increasing from 0.53 (SE, 0.02) without feedback to 0.59 (SE, 0.02) with feedback (p < 0.0001). CONCLUSION: Most experienced breast imagers showed excellent breast ultrasound interpretive skills. Immediate feedback of consensus BI-RADS: Ultrasound features and histopathologic results improved performance in ultrasound interpretation across all experience variables.

Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk.

CONTEXT: Annual ultrasound screening may detect small, node-negative breast cancers that are not seen on mammography. Magnetic resonance imaging (MRI) may reveal additional breast cancers missed by both mammography and ultrasound screening. OBJECTIVE: To determine supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: From April 2004-February 2006, 2809 women at 21 sites with elevated cancer risk and dense breasts consented to 3 annual independent screens with mammography and ultrasound in randomized order. After 3 rounds of both screenings, 612 of 703 women who chose to undergo an MRI had complete data. The reference standard was defined as a combination of pathology (biopsy results that showed in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes) and 12-month follow-up. MAIN OUTCOME MEASURES: Cancer detection rate (yield), sensitivity, specificity, positive predictive value (PPV3) of biopsies performed and interval cancer rate. RESULTS: A total of 2662 women underwent 7473 mammogram and ultrasound screenings, 110 of whom had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Among 4814 incidence screens in the second and third years combined, 75 women were diagnosed with cancer. Supplemental incidence-screening ultrasound identified 3.7 cancers per 1000 screens (95% CI, 2.1-5.8; P < .001). Sensitivity for mammography plus ultrasound was 0.76 (95% CI, 0.65-0.85); specificity, 0.84 (95% CI, 0.83-0.85); and PPV3, 0.16 (95% CI, 0.12-0.21). For mammography alone, sensitivity was 0.52 (95% CI, 0.40-0.64); specificity, 0.91 (95% CI, 0.90-0.92); and PPV3, 0.38 (95% CI, 0.28-0.49; P < .001 all comparisons). Of the MRI participants, 16 women (2.6%) had breast cancer diagnosed. The supplemental yield of MRI was 14.7 per 1000 (95% CI, 3.5-25.9; P = .004). Sensitivity for MRI and mammography plus ultrasound was 1.00 (95% CI, 0.79-1.00); specificity, 0.65 (95% CI, 0.61-0.69); and PPV3, 0.19 (95% CI, 0.11-0.29). For mammography and ultrasound, sensitivity was 0.44 (95% CI, 0.20-0.70, P = .004); specificity 0.84 (95% CI, 0.81-0.87; P < .001); and PPV3, 0.18 (95% CI, 0.08 to 0.34; P = .98). The number of screens needed to detect 1 cancer was 127 (95% CI, 99-167) for mammography; 234 (95% CI, 173-345) for supplemental ultrasound; and 68 (95% CI, 39-286) for MRI after negative mammography and ultrasound results. CONCLUSION: The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00072501.

Prostate cancer: sextant localization at MR imaging and MR spectroscopic imaging before prostatectomy--results of ACRIN prospective multi-institutional clinicopathologic study.

PURPOSE: To determine the incremental benefit of combined endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging, as compared with endorectal MR imaging alone, for sextant localization of peripheral zone (PZ) prostate cancer. MATERIALS AND METHODS: This prospective multicenter study, conducted by the American College of Radiology Imaging Network (ACRIN) from February 2004 to June 2005, was institutional review board approved and HIPAA compliant. Research associates were required to follow consent guidelines approved by the Office for Human Research Protection and established by the institutional review boards. One hundred thirty-four patients with biopsy-proved prostate adenocarcinoma and scheduled to undergo radical prostatectomy were recruited at seven institutions. T1-weighted, T2-weighted, and spectroscopic MR sequences were performed at 1.5 T by using a pelvic phased-array coil in combination with an endorectal coil. Eight readers independently rated the likelihood of the presence of PZ cancer in each sextant by using a five-point scale-first on MR images alone and later on combined MR-MR spectroscopic images. Areas under the receiver operating characteristic curve (AUCs) were calculated with sextant as the unit of analysis. The presence or absence of cancer at centralized histopathologic evaluation of prostate specimens was the reference standard. Reader-specific receiver operating characteristic curves for values obtained with MR imaging alone and with combined MR imaging-MR spectroscopic imaging were developed. The AUCs were estimated by using Mann-Whitney statistics and appropriate 95% confidence intervals. RESULTS: Complete data were available for 110 patients (mean age, 58 years; range, 45-72 years). MR imaging alone and combined MR imaging-MR spectroscopic imaging had similar accuracy in PZ cancer localization (AUC, 0.60 vs 0.58, respectively; P > .05). AUCs for individual readers were 0.57-0.63 for MR imaging alone and 0.54-0.61 for combined MR imaging-MR spectroscopic imaging. CONCLUSION: In patients who undergo radical prostatectomy, the accuracy of combined 1.5-T endorectal MR imaging-MR spectroscopic imaging for sextant localization of PZ prostate cancer is equal to that of MR imaging alone.

Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer.

CONTEXT: Screening ultrasound may depict small, node-negative breast cancers not seen on mammography. OBJECTIVE: To compare the diagnostic yield, defined as the proportion of women with positive screen test results and positive reference standard, and performance of screening with ultrasound plus mammography vs mammography alone in women at elevated risk of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: From April 2004 to February 2006, 2809 women, with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited from 21 sites to undergo mammographic and physician-performed ultrasonographic examinations in randomized order by a radiologist masked to the other examination results. Reference standard was defined as a combination of pathology and 12-month follow-up and was available for 2637 (96.8%) of the 2725 eligible participants. MAIN OUTCOME MEASURES: Diagnostic yield, sensitivity, specificity, and diagnostic accuracy (assessed by the area under the receiver operating characteristic curve) of combined mammography plus ultrasound vs mammography alone and the positive predictive value of biopsy recommendations for mammography plus ultrasound vs mammography alone. RESULTS: Forty participants (41 breasts) were diagnosed with cancer: 8 suspicious on both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography alone, and 8 participants (9 breasts) on neither. The diagnostic yield for mammography was 7.6 per 1000 women screened (20 of 2637) and increased to 11.8 per 1000 (31 of 2637) for combined mammography plus ultrasound; the supplemental yield was 4.2 per 1000 women screened (95% confidence interval [CI], 1.1-7.2 per 1000; P = .003 that supplemental yield is 0). The diagnostic accuracy for mammography was 0.78 (95% CI, 0.67-0.87) and increased to 0.91 (95% CI, 0.84-0.96) for mammography plus ultrasound (P = .003 that difference is 0). Of 12 supplemental cancers detected by ultrasound alone, 11 (92%) were invasive with a median size of 10 mm (range, 5-40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89%) reported had negative nodes. The positive predictive value of biopsy recommendation after full diagnostic workup was 19 of 84 for mammography (22.6%; 95% CI, 14.2%-33%), 21 of 235 for ultrasound (8.9%, 95% CI, 5.6%-13.3%), and 31 of 276 for combined mammography plus ultrasound (11.2%; 95% CI. 7.8%-15.6%). CONCLUSIONS: Adding a single screening ultrasound to mammography will yield an additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially increase the number of false positives. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00072501.

Diagnostic accuracy of digital versus film mammography: exploratory analysis of selected population subgroups in DMIST.

PURPOSE: To retrospectively compare the accuracy of digital versus film mammography in population subgroups of the Digital Mammographic Imaging Screening Trial (DMIST) defined by combinations of age, menopausal status, and breast density, by using either biopsy results or follow-up information as the reference standard. MATERIALS AND METHODS: DMIST included women who underwent both digital and film screening mammography. Institutional review board approval at all participating sites and informed consent from all participating women in compliance with HIPAA was obtained for DMIST and this retrospective analysis. Areas under the receiver operating characteristic curve (AUCs) for each modality were compared within each subgroup evaluated (age < 50 vs 50-64 vs >or= 65 years, dense vs nondense breasts at mammography, and pre- or perimenopausal vs postmenopausal status for the two younger age cohorts [10 new subgroups in toto]) while controlling for multiple comparisons (P < .002 indicated a significant difference). All DMIST cancers were evaluated with respect to mammographic detection method (digital vs film vs both vs neither), mammographic lesion type (mass, calcifications, or other), digital machine type, mammographic and pathologic size and diagnosis, existence of prior mammographic study at time of interpretation, months since prior mammographic study, and compressed breast thickness. RESULTS: Thirty-three centers enrolled 49 528 women. Breast cancer status was determined for 42,760 women, the group included in this study. Pre- or perimenopausal women younger than 50 years who had dense breasts at film mammography comprised the only subgroup for which digital mammography was significantly better than film (AUCs, 0.79 vs 0.54; P = .0015). Breast Imaging Reporting and Data System-based sensitivity in this subgroup was 0.59 for digital and 0.27 for film mammography. AUCs were not significantly different in any of the other subgroups. For women aged 65 years or older with fatty breasts, the AUC showed a nonsignificant tendency toward film being better than digital mammography (AUCs, 0.88 vs 0.70; P = .0025). CONCLUSION: Digital mammography performed significantly better than film for pre- and perimenopausal women younger than 50 years with dense breasts, but film tended nonsignificantly to perform better for women aged 65 years or older with fatty breasts.

Operator dependence of physician-performed whole-breast US: lesion detection and characterization.

PURPOSE: To prospectively examine operator dependence of lesion detection, description, and interpretation when experienced breast radiologists perform whole-breast ultrasonography (US). MATERIALS AND METHODS: Institutional review board approval was obtained for the HIPAA-compliant study. Ten women (aged 19-53 years; mean, 37.4 years; 20 breasts) with numerous known breast lesions consented to participate. Eleven breast radiologists, who passed experience and qualification requirements for a screening breast US trial and consented to participate, scanned both breasts in all participants and documented images of each detected lesion and its size, location, features, palpability, and Breast Imaging Reporting and Data System final assessment. Intraclass correlation coefficients (ICCs) were used to measure agreement on lesion size and location, and kappa statistics were calculated for agreement on features and final assessments compared with consensus. RESULTS: Eighty-eight unique lesions were identified by at least two investigators (five to 13 lesions per participant). Mean diameter was 6.7 mm (standard error, 0.4; range, 2-22 mm), and eight lesions (9%) were palpable. Of 968 potential detections (88 lesions, 11 investigators), 536 (55%) detections were made. Individual investigators detected between 43 (49%) and 58 (66%) lesions. Larger lesions were more consistently detected: Detection rates were six of 33 lesions (18%) at 3 mm or smaller; 164 of 374 (43.9%) at 3.1-5 mm; 145 of 275 (52.7%) at 5.1-7 mm; 119 of 176 (67.6%) at 7.1-9 mm; 38 of 44 (86%) at 9.1-11 mm; and 64 of 66 (97%) lesions larger than 11 mm (P < .001). ICCs for clockface, distance from nipple, and individual lesion diameter all exceeded 0.7, indicating high reliability. For shape, margins, and final assessments of solid lesions, kappa values were 0.62, 0.67 (substantial agreement), and 0.52 (moderate agreement), respectively. Of 110 detections of consensus cysts 8 mm and smaller, 15 (14%) detections were considered to be of solid lesions by at least one reader. CONCLUSION: Larger lesions (>11 mm) are most consistently detected, with fewer than half of lesions 5 mm or smaller in mean diameter identified; substantial agreement was found for description of lesion size, location, and key features, and moderate agreement was found for lesion management.

Lesion detection and characterization in a breast US phantom: results of the ACRIN 6666 Investigators.

PURPOSE: To prospectively evaluate ultrasonographic (US) lesion detection and characterization in a breast phantom by potential investigators in a screening US protocol, American College of Radiology Imaging Network (ACRIN) 6666. MATERIALS AND METHODS: National Cancer Institute Cancer Experimental Therapeutic Protocol review and ACRIN internal institutional review board approved the protocol; potential investigators were informed of the study purpose prior to participation. Six equivalent anthropomorphic phantoms were prepared with 17 masses (2-10 mm in mean diameter) in different locations at different depths. Sixty-six investigators, experienced in breast US, from 23 institutions scanned a phantom with high-frequency linear-array transducers (12-5 MHz). Lesion location, diameters, echogenicity, shape, and posterior features were recorded. Reader-specific phantom maps were generated and compared with known lesion locations and features. Results from 64 observers could be analyzed and were masked to investigator identity. Agreement on US features was measured with kappa statistics. A generalized linear model generated log relative risks for detection rates as a function of lesion diameter, depth, and features. RESULTS: Of 17 lesions, a median of 14 (82%) were detected (range, 9-16), and 86% of observers detected at least 12 lesions. Of 1088 potential detections, 861 (79.1%) were made. Among 5-10-mm lesions, 499 (97.5%) of 512 detections were made (excluding a 6-mm "skin" lesion seen by only seven observers [11%]). One 4-mm mass was seen by 53 observers (83%). Among 3-mm lesions, 274 (71.4%) of 384 detections were made. One 2-mm lesion was seen by 28 (44%) observers. Relative risk of detection decreased to 0.55 (95% confidence interval: 0.51, 0.59) for each centimeter increase in lesion depth. Agreement was slight for lesion shape (kappa=0.14), substantial for echogenicity (kappa=0.61), and moderate for posterior features (kappa=0.45). Feature description errors were common for 2-4-mm lesions; only 33% of 3-mm anechoic masses were so characterized. Among eight 6-10-mm lesions, investigators erred in feature description of a median of 1 lesion (mean, 1.3; range, 0-4). CONCLUSION: US detection and description of lesions in a breast phantom were highly consistent for lesions 5-10 mm in diameter; those smaller than 5 mm were less reliably identified or characterized by experienced investigators.