Accuracy and Value of Breast Ultrasound for Primary Imaging Evaluation of Symptomatic Women Years of Age

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1 Women s Imaging Original Research Lehman et al. Breast Ultrasound for Primary Imaging Evaluation Women s Imaging Original Research Constance D. Lehman 1,2 Christoph I. Lee 1,2 Vilert A. Loving 1,2 Michael S. Portillo 1,2 Sue Peacock 1,2 Wendy B. DeMartini 1,2 Lehman CD, Lee CI, Loving VA, Portillo MS, Peacock S, DeMartini WB Keywords: breast imaging, mammography, ultrasound, young women DOI: /AJR Received March 5, 2012; accepted after revision April 26, Presented at the 2009 annual meeting of the Radiological Society of North America, Chicago, IL. 1 Department of Radiology, University of Washington School of Medicine, Seattle WA. 2 Seattle Cancer Care Alliance, G2-600, 825 Eastlake Ave E, Seattle, WA Address correspondence to C. D. Lehman (lehman@uw.edu). CME This article is available for CME credit. AJR 2012; 199: X/12/ American Roentgen Ray Society Accuracy and Value of Breast Ultrasound for Primary Imaging Evaluation of Symptomatic Women Years of Age OBJECTIVE. The purpose of this study was to determine the accuracy and value of breast ultrasound for primary imaging evaluation of women years of age who present with focal breast signs or symptoms. METHODS. We identified all women years of age who underwent imaging evaluation (ultrasound and mammography) at our institution between January 1, 2002, and August 31, 2006, for focal breast signs or symptoms. Each area of concern was designated a study case. Benign versus malignant outcomes were determined by biopsy or imaging surveillance and through linkage with a tumor registry with a minimum 24-month follow-up. Overall cancer yield, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of ultrasound and mammography were calculated. RESULTS. We identified 1208 cases in 954 patients. Outcomes were benign in 1185 of 1208 (98.1%) and malignant in 23 of 1208 (1.9%) cases. Sensitivities for ultrasound and mammography were 95.7% and 60.9%, respectively. Specificities for ultrasound and mammography were 89.2% and 94.4%, respectively. NPV was 99.9% for ultrasound and 99.2% for mammography. PPV was 13.2% for ultrasound and 18.4% for mammography. Mammography detected one additional malignancy in an asymptomatic area in a 32-year-old woman who was subsequently found to have a BRCA2 gene mutation. CONCLUSION. Breast imaging is warranted in women years of age with focal signs or symptoms because of the small (1.9%) but real risk of malignancy. Ultrasound has high sensitivity (95.7%) and high NPV (99.9%) in this setting and should be the primary imaging modality of choice. The added value of adjunct mammography is low. B reast imaging in women less than 40 years old is typically performed to evaluate focal areas of clinical concern, such as palpable lumps or sites of pain. Imaging plays an important role in the diagnostic evaluation of such localized areas of concern because clinical breast examination alone is unreliable in distinguishing benign from malignant lesions [1, 2]. Because of concerns related to mammographic radiation, the relatively poor performance of mammography, and the low incidence of breast cancer in young women, ultrasound is the primary modality used to evaluate symptomatic young women, with mammography used as the primary modality in older women [3, 4]. In Europe, current guidelines more typically recommend ultrasound as the primary modality in women under 40 years, with mammography as the primary modality in women 40 years and over [5]. However, the current American College of Radiology (ACR) Appropriateness Criteria for the workup of palpable masses recommend mammography as the primary imaging modality in women 30 years and over, with ultrasound reserved as the primary modality for women under 30 years [6]. The rationale for adding mammography to ultrasound is to increase the sensitivity for cancer detection at the area of clinical concern and to screen the remaining asymptomatic portions of the breasts. There are currently sparse data to support adjunct mammography to increase cancer detection in the diagnostic workup of women in the 30- to 39-year age range. For diagnostic performance at the site of clinical concern, one previous study in this age cohort found that adjunct mammography failed to detect even large palpable breast cancers, whereas ultrasound had 100% sensitivity for palpable masses [7]. In screening for occult asymptomatic malignancy, 90% of women years old have extremely dense breasts, making screening mammography in general AJR:199, November

2 Lehman et al. relatively ineffective. This modality is therefore not routinely recommended in the absence of signs or symptoms [8 12]. Because the currently available evidence raises questions about the magnitude of benefit conferred by diagnostic mammography as the primary imaging modality in this specific cohort of symptomatic young women with localized clinical findings, the purpose of this study was to determine the accuracy and value of breast ultrasound compared with mammography in the evaluation of women years of age presenting with focal breast signs or symptoms. Materials and Methods Study Population Institutional review board (IRB) approval was obtained with a waiver of informed consent for this HIPAA-compliant study (Fred Hutchinson Cancer Research Center IRB protocols #6798 and #7339). We reviewed our electronic radiology records to identify all breast ultrasound examinations with corresponding mammography performed between January 1, 2002, and August 31, 2006, in women years of age. We cross-referenced these examinations with electronic clinical records and included all cases for which the imaging evaluation was for focal breast signs or symptoms, including palpable lumps, thickenings, or focal pain. Patients being evaluated for nonfocal signs or symptoms were excluded from the study as were patients undergoing diagnostic imaging for a finding seen on screening mammography. Additionally, patients were excluded if they were being evaluated for nipple inversion or discharge as the sole complaint or if they were undergoing follow-up of a known malignancy. Each focal area of concern was designated a separate study case. If a patient had multiple focal areas of concern (e.g., multiple palpable lumps), each area was counted as an individual case. We recorded the patient s age; presenting signs or symptoms (lump, thickening, pain); imaging findings, including lesion visibility on ultrasound and mammography; and ACR BI-RADS assessments. Imaging and Image Interpretation Diagnostic mammograms were acquired using a Senographe DMR+ ( ) or a Senographe Essential unit ( ) (both, GE Healthcare). All examinations were interpreted by one of seven radiologists subspecialized in breast imaging. Mammographic evaluation consisted of standard mediolateral oblique and craniocaudal views. If deemed necessary by the interpreting radiologist, additional mediolateral and spot-magnification views at the areas of concern were obtained. Ultrasound examinations were acquired using a LOGIQ 7 unit (GE Healthcare) with a 12-MHz linear transducer. All ultrasound examinations were performed by a radiologist. During the ultrasound examinations, patients were asked to identify the site of concern, and the ultrasound transducer was placed directly over this location. Alternatively, if the patient s health care provider originally identified the abnormality, transducer placement was based on the location indicated on the imaging request form. At the time of diagnostic evaluation, the radiologist prospectively described the following regarding any mammographically or sonographically detected lesion: location (clock position and distance from the nipple), size and imaging characteristics on each modality, BI-RADS assessments, and management recommendations. Patient Management If the diagnostic evaluation was negative (BI- RADS category 1) or benign (e.g., simple cyst or involuting fibroadenoma, BI-RADS category 2), no additional imaging or tissue sampling was recommended. Clinical follow-up was recommended for all patients with negative examinations, with the details of clinical follow-up at the discretion of the referring clinician. If an evaluation was not negative or benign, management was based on the imaging characteristics of the identified findings and was at the discretion of the interpreting radiologist. Lesions that were deemed probably benign (less than 2% risk of malignancy) were categorized as BI-RADS category 3. In general, this category included lesions that were mammographically round or oval with circumscribed margins. Sonographically, these lesions were also round or oval with circumscribed margins, parallel in orientation, and uniformly hypoechoic in echotexture. For BI-RADS category 3 lesions, short-interval follow-up ultrasound was recommended in 6, 12, and 24 months. If at least 2 years of imaging stability was established, these lesions were then considered benign. For calcifications, focal asymmetries, or masses with suspicious or highly suggestive characteristics (BI-RADS category 4 or 5), core needle biopsy (CNB) was recommended. The biopsy guidance method depended on the imaging modality that best depicted the abnormality. For abnormalities best seen mammographically, a stereotactic CNB was recommended; sonographically visible abnormalities were biopsied under ultrasound guidance. At our institution, CNB of lesions identified with ultrasound is almost exclusively performed by radiologists using ultrasound guidance, although referring clinicians occasionally perform palpation-guided fine-needle aspiration (FNA) or CNB. Stereotactic CNB was performed using a Suros 9-gauge vacuum-assisted CNB biopsy device (Hologic). Ultrasound-guided CNB was performed using one of three 14-gauge spring-loaded CNB devices (Manan, C.R. Bard [ ]; Achieve, Cardinal Health [ ]; or MaxCore, C.R. Bard [ ]). Outcomes This study used the Consortium Oncology Data Integration (CODI) project (IR #5586, protocol 1833E) as the final data source for case outcomes. CODI is a solid tumor clinical research database developed and maintained by the Fred Hutchinson Cancer Research Center in collaboration with the University of Washington. Data in CODI have been obtained in accordance with applicable human subject laws and regulations, including any requiring informed consent. There are many sources of data for CODI, including the Cancer Surveillance System (CSS) regional tumor registry. CSS is a part of the National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) program and collects population-based data on the incidence, treatment, and follow-up on all newly diagnosed cancers (except nonmelanoma skin cancers) occurring in residents of 13 counties in western Washington State. This registry has achieved case ascertainment of 95% or higher completeness according to the North American Association of Central Cancer Registries [13]. Benign versus malignant outcomes were determined by biopsy, 24 months of follow-up imaging, and at least 24 months of follow-up using data from the regional tumor registry to identify malignancies diagnosed at other medical institutions. Similar tumor registry linkage for outcomes has been validated and used in multiple key breast imaging studies, such as those by the Breast Cancer Surveillance Consortium [7]. Histopathology outcomes were obtained directly from pathology reports and the tumor registry. Final histopathology outcomes for lesions yielding non high-risk benign or malignant s at CNB were based on the CNB s. Final histopathology outcomes for high-risk lesions at CNB (atypical ductal or lobular hyperplasia, lobular carcinoma in situ, radial scar) were based on subsequent benign (no upgrade to malignancy) or malignant (upgrade to malignancy) surgical biopsy s. Any invasive carcinoma or ductal carcinoma in situ (DCIS) histology was categorized as malignant. The percentage of cases in each BI-RADS assessment category was calculated on the basis of the s of the initial evaluation. Overall cancer yield was calculated and was defined as the percentage of cases with pathologically confirmed malignancy. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value 1170 AJR:199, November 2012

3 Breast Ultrasound for Primary Imaging Evaluation Areas of clinical focal concern included in study (n = 1208) No corresponding lesions on either ultrasound or mammography (n = 707) (no malignancies identified in follow-up) True-positive (n = 22) Corresponding lesions on ultrasound only (n = 301) True-negative (n = 1057) (PPV) of ultrasound and mammography were calculated following guidelines from the BI-RADS atlas [14]. A BI-RADS assessment of category 1, 2, or 3 was considered a negative test, and a BI-RADS assessment of category 4 or 5 was considered a positive test. Results A total of 1621 consecutive ultrasound examinations in 1298 patients years old were performed in the study interval. Three hundred sixty-five patients were not eligible because their ultrasound was performed for evaluation of a nonfocal sign or symptom, an abnormality had been detected on a recent screening mammography, a previously identified known mass or cancer was present, the patient had nipple inversion or discharge alone, or mammography was not performed with the ultrasound. The study cohort consisted of 1208 cases in 954 patients (mean age, 35 years; age range, years) (Fig. 1). Of these 1208 cases, the corresponding focal sign or symptom being evaluated was a palpable lump in 1050 (87%), pain in 135 (11%), palpable lump with associated pain in 15 (1%), and focal skin changes in eight (1%). Most (82.3%) cases were assessed as negative or benign. The BI-RADS assessment was category 1 for 708 (58.6%) cases (Table 1). None of these were found to be malignant with 2-year follow-up in the tumor registry. The BI-RADS assessment was category 2 for 286 (23.7%) cases. One of these, assessed Total corresponding lesions on ultrasound (n = 486) False-positive (n = 128) Corresponding lesions on both ultrasound and mammography (n = 185) False-negative (n = 1) True-positive (n = 14) by mammography and ultrasound as an oval well-circumscribed mass and described as anechoic on ultrasound, was reported as a simple cyst with clinical follow-up recommended. On the basis of increase in size and clinical suspicion on follow-up clinical examination, a palpation-guided FNA was attempted by the referring clinician but was unsuccessful. Repeat ultrasound the same day showed a complex mass at the site. Given the recent attempted FNA, short-interval follow-up to document resolution was recommended. However, by patient request, surgical excision rather than imaging follow-up was performed and revealed an infiltrating ductal carcinoma. The BI-RADS assessment was category 3 for 64 (5.3%) lesions. Ten (15.6%) of these lesions underwent biopsy because of patient or ordering clinician preference or morphology or size change during surveillance, and all True-negative (n = 1119) Corresponding lesions on mammography only (n = 15) Total corresponding lesions on mammography (n = 200) False-positive (n = 66) False-negative (n = 9) Fig. 1 Flowchart shows diagnostic evaluation and outcomes of study population. Positive indicates case with corresponding lesion identified on imaging and assessed as BI-RADS 4 or 5. Negative indicates case with corresponding lesion identified on imaging and assessed as BI-RADS 2 or 3, as well as examinations assessed as BI-RADS 1 (without a corresponding lesion identified). Status of true and false outcomes was determined by presence or absence of cancer. 10 were benign. For the majority of BI-RADS 3 cases (68.9%), patients did not complete 24 months of imaging follow-up or undergo biopsy at our institution. Review of the tumor registry, however, confirmed none of the patients with BI-RADS 3 assessments were diagnosed with breast cancer on long-term follow-up. The BI-RADS assessment was category 4 for 139 (11.5%) cases (Fig. 2). Of these, 135 (97.1%) underwent biopsy, and 12 (8.6%) were found to be malignant. The remaining four lesions did not undergo biopsy at our institution, but no corresponding malignancies were recorded in the tumor registry. All of the 12 malignancies identified at our institution were detected by ultrasound. However, only one half (6/12) were also detected by mammography. The BI-RADS assessment was category 5 for 11 (0.9%) cases (Fig. 3). All of these lesions TABLE 1: Final Outcome of 1208 Cases in Women Years Old at Site of Focal Clinical Concern Outcome BI-RADS Assessment Benign Malignant Total (100) 0 (0) 708 (58.6) (99.7) 1 (0.3) 286 (23.7) 3 64 (100) 0 (0) 64 (5.3) (91.4) 12 (8.6) 139 (11.5) 5 1 (9.1) 10 (90.9) 11 (0.9) Total 1185 (98.1) 23 (1.9) 1208 Note Data in parentheses are percentages. AJR:199, November

4 Lehman et al. A C B D Fig year-old woman who presented with palpable left breast lump. A D, Whole-breast craniocaudal (A) and mediolateral oblique (B) and spot-magnification craniocaudal (C) and mediolateral (D) mammographic images show oval mass with circumscribed margins corresponding to area of clinical concern, marked by BB. E, Targeted ultrasound image reveals solid mass with oval shape and partially circumscribed partially indistinct margins. BI-RADS 4 assessment was made. Histopathology from ultrasound-guided core needle biopsy showed benign fibroadenoma. were subsequently biopsied at our institution, and 10 (90.9%) were malignant. Of the 10 malignancies, all were detected by ultrasound. However, mammography failed to detect two of 10 malignancies. Pathology from the one benign lesion revealed infection, and the corresponding palpable mass resolved clinically after antibiotic treatment. In total, 23 malignancies were diagnosed in the 1208 study cases at the areas of clinical concern, for a cancer yield of 1.9%. Twentytwo of the 23 cancers were assessed as positive on ultrasound, for sensitivity of 95.7% and NPV of 99.9% (Table 2). No malignancies were detected by mammography alone at the site of clinical concern. Thus, the cancer yield of imaging at the sites of clinical concern was 1.8%, with 22 malignancies detected in 1208 cases. Mammography failed to detect nine of 23 malignancies, for sensitivity of 60.9% and NPV of 99.2%. Ultrasound falsely identified 128 cases as suspicious, for a specificity of 89.2%. Mammography falsely identified 66 cases as suspicious, for a specificity of 94.4%. The PPV was 18.4% for mammography and 13.2% for ultrasound. In one patient, bilateral diagnostic mammography yielded an additional malignancy separate from the area of clinical concern. This was a 32-year-old woman who had a palpable right breast lump (Fig. 4). Diagnostic mammography and ultrasound were negative at the site of clinical concern, and there E 1172 AJR:199, November 2012

5 Breast Ultrasound for Primary Imaging Evaluation was no malignancy at follow-up. However, there was an incidental group of calcifications in a separate quadrant of the right breast that was deemed suspicious. Subsequent stereotactic CNB revealed infiltrating ductal carcinoma. The patient was later identified as a BRCA2 gene mutation carrier. A C Discussion To our knowledge, this study represents the largest analysis to date of breast ultrasound and adjunct mammography for the evaluation of women years old who present with focal breast signs or symptoms. Moreover, this study is the first to examine B D Fig year-old woman who presented with palpable left breast lump. A D, Whole-breast craniocaudal (A) and mediolateral oblique (B) and spot-magnification craniocaudal (C) and mediolateral (D) mammographic images show no abnormality at area of clinical concern, marked by BB. E, Targeted ultrasound image reveals solid mass with irregular shape and indistinct and angular margins. BI-RADS 5 assessment was made. Histopathology from ultrasound-guided core needle biopsy showed invasive ductal carcinoma. the most effective use of imaging for the diagnostic workup of this patient population and the only study to investigate this imaging application within the past decade. Current imaging recommendations for this cohort are based on expert opinion and prior reports published when ultrasound was in its E AJR:199, November

6 Lehman et al. TABLE 2: Performance of Mammography and Ultrasound in Women Years Old at Site of Focal Clinical Concern Performance Statistic Mammography Ultrasound Biopsy recommended 80/1208 (6.6) 150/1208 (12.4) Cancer yield 14/1208 (1.2) 22/1208 (1.8) PPV of biopsy performed (PPV 3 ) 14/76 (18.4) 22/146 (15.1) NPV 1119/1128 (99.2) 1057/1058 (99.9) Sensitivity 14/23 (60.9) 22/23 (95.7) Specificity 1119/1185 (94) 1057/1185 (89) True-positive 14/1208 (1.2) 22/1208 (1.8) True-negative 1119/1208 (92.6) 1057/1208 (87.5) False-positive 66/1208 (5.5) 128/1208 (10.6) False-negative 9/1208 (0.7) 1/1208 (> 0.01) Note Data are number/total with percentage in parentheses. PPV = positive predictive value, NPV = negative predictive value. clinical nascency and could often only reliably differentiate cysts from solid masses [12, 15 17]. In the intervening decade, technical advances, including high-mhz linear array transducers with excellent near-field resolution, compound imaging, and harmonics, have made breast ultrasound the primary breast imaging modality for younger women, with vastly improved characterization of the shape, margins, and internal matrix of solid masses [18]. Despite the widely accepted practice of ultrasound as an important imaging modality for focal breast concerns in women years of age, there have been few studies validating this practice [19]. Our s show that breast ultrasound has 95.7% sensitivity for cancer detection at the site of focal breast concerns and 99.9% NPV, substantiating its use as a primary imaging modality for this patient cohort. Our extremely high sensitivity is corroborated by prior reports of breast ultrasound sensitivity approaching 100% for detecting malignancy among women under 40 years of age [7, 20 23]. For example, in our recent study evaluating women under 30 years of age with focal signs and symptoms, we found ultrasound to be 100% sensitive with a 100% NPV [23]. The high sensitivity and NPV of ultrasound validate its use as an accurate diagnostic tool in younger women. Importantly, we found that adjunct mammography adds little value to ultrasound evaluation in this clinical scenario. In our study, mammography had lower sensitivity (60.9%) compared with ultrasound at the focal site of concern, a figure similar to that of prior reports [19, 21 24]. The 99.9% NPV of ultrasound implies that there are virtually no false-negative ultrasound studies for which adjunct mammography would have added diagnostic value. In addition, both the specificity and PPV of biopsied lesions in our study did not significantly differ between mammography and ultrasound. Although an additional theoretic added value of mammography is to screen for ipsilateral and contralateral malignancy separate from the primary area of concern, we found that mammography yielded additional malignancy in only one of our 954 patients. In this patient, a small group of microcalcifications away from the site of clinical concern was identified by mammography and subsequently found to be malignant at biopsy. However, this patient was also determined to carry the BRCA2 gene mutation and would likely have benefited from screening mammography at an earlier age given her highrisk status. No other patient in our study had a malignancy for which mammography added diagnostic value over ultrasound during the initial evaluation. Our study also confirms the very low incidence rate of malignancy (1.9%) among women years of age at the site of focal breast signs or symptoms. This finding is consistent with prior reports that estimate the incidence of breast cancer to be as low as 1% for this age group [3, 4]. Furthermore, we found that the vast majority of young women presenting with focal breast concerns in our study had a negative examination or benign finding at the time of imaging workup (82.3%), confirming prior reports of similar patient populations [4, 25]. The ACR Appropriateness Criteria for women 30 years of age or older with a palpable breast mass recommends mammography as the primary imaging modality followed by ultrasound [6]. In contrast, ultrasound is the recommended initial modality of choice for women younger than 30 years of age, with mammography used only for patients with known high risk or as an adjunct study in clinically or sonographically suspicious cases [6]. This arbitrary age cutoff of 30 years for recommending different imaging protocols is largely because the few studies evaluating mammography versus ultrasound in young women with focal breast symptoms were conducted in patients younger than 30 years and did not specifically include women years of age [15, 26 29]. In fact, little evidence exists as to the appropriate age that delineates the choice of initial diagnostic imaging for this specific clinical scenario. Overall, our findings in women years of age of a high likelihood of negative or benign cause combined with a low malignancy rate and low sensitivity of mammography compared with ultrasound suggest that the current recommendations for mammography in this patient population should be reconsidered. Our findings, focused specifically on the largely unstudied 30- to 39-year age group, suggest that ultrasound should be the primary imaging modality over mammography for initial evaluation in this age cohort, as is currently recommended by the ACR for women younger than 30 years of age. Given the very high sensitivity and NPV of ultrasound for identifying malignancy at the site of focal concern and that only one of 954 patients had an additional malignancy identified by adjunct mammography, a strong argument can be made that ultrasound should take priority over mammography. The only patient who benefited from adjunct mammography carried a BRCA2 mutation, suggesting that adjunct mammography is appropriate for highrisk patients. However, the same argument is difficult to make for average-risk women on the basis of our study s. These s have important implications to decrease the costs, potential anxiety, and radiation exposure associated with mammography in women years old presenting for diagnostic breast imaging. Since its foundation in 1924, the ACR has been a clear leader in establishing appropriateness of imaging examinations for specific patient populations and eliminating unnecessary radiation exposure. This commitment to the highest quality patient care includes support of accreditation programs; practice guidelines and technical standards; ACR Appropriateness 1174 AJR:199, November 2012

7 Breast Ultrasound for Primary Imaging Evaluation A B Fig year-old woman who presented with palpable right breast lump at 3-o clock position. A D, Whole-breast craniocaudal (A) and, mediolateral oblique (B) and spot-magnification craniocaudal (C) and mediolateral (D) mammographic images show no abnormality at area of clinical concern at 3-o clock position, marked by BB. E, Targeted ultrasound image reveals no abnormality at area of clinical concern. BI-RADS 1 assessment was made for this location, and no malignancy occurred at this site in follow-up interval. However, mammograms (A D) showed group of asymptomatic pleomorphic calcifications in 9- to 10-o clock position of breast. BI-RADS 4 assessment was made for this area. Histopathology from stereotactic core needle biopsy showed invasive ductal carcinoma and highgrade ductal carcinoma in situ. C D E AJR:199, November

8 Lehman et al. Criteria; educational programs; and research programs, such as the ACR Imaging Network [30 32]. Although the impact of radiation from mammography on cancer risk is widely debated, it is clear that patients should be exposed to radiation only if the benefits of the imaging test outweigh the potential and real risks. The added years of unnecessary mammography may put women years old at a small, but not insignificant, increased lifetime risk of radiation-induced breast cancer. Although our findings support limiting the routine use of adjunct mammography in average-risk women presenting with focal signs and symptoms, they also highlight the central importance of breast imaging for this patient population. The added value of ultrasound in the diagnostic evaluation of focal breast abnormalities over physical examination alone has been well documented [33, 34]. In our study, nearly all BI-RADS category 1, 2, and 3 masses were found to be benign on imaging or tumor registry follow-up. Assuming appropriate use of BI-RADS criteria, our s suggest that clinical follow-up for category 1 and 2 and short-interval imaging follow-up for category 3 lesions are safe practices. Furthermore, the use of ultrasound as a primary diagnostic tool obviates tissue biopsy and imaging follow-up, thus preventing downstream economic costs and patient morbidity [20, 35 38]. Our s should not diminish the need for an imaging evaluation to identify the few breast cancers that do present in women years of age. Rather, our study suggests that adjunct mammography be used in appropriate situations of high clinical suspicion of malignancy, including for patients with highly suspicious lesions according to ultrasound or those at higher risk due to known genetic mutation or family history. There are several limitations to our study. This is a retrospective analysis from a single institution. However, ours is a regional tertiary care referral center with robust adoption of an electronic medical record and serving a large diverse geographic area. Furthermore, our ultrasound examinations were performed by radiologists, which may not be possible in the community setting. In addition, a large proportion of patients with BI- RADS category 3 lesions did not complete the recommended 24 months of imaging follow-up or undergo biopsy at our institution. However, these patients may have undergone follow-up imaging at other institutions, and the cancer status outcomes of these patients were captured by tumor registry linkage. In conclusion, to our knowledge, our study is the largest to date involving women between 30 and 39 years of age presenting with focal breast signs and symptoms in the United States. 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