Risk of Malignancy in Palpable Solid Breast Masses Considered Probably Benign or Low Suspicion

ORIGINAL RESEARCH Risk of Malignancy in Palpable Solid Breast Masses Considered Probably Benign or Low Suspicion Implications for Management Catherine S. Giess, MD, Lisa Zorn Smeglin, MD, Jack E. Meyer, MD, Julie A. Ritner, MD, Robyn L. Birdwell, MD Received April 13, 2012, from the Department of Radiology, Brigham and Women s Hospital, Boston, Massachusetts USA. Revision requested May 8, 2012. Revised manuscript accepted for publication May 31, 2012. We thank Nora McCarthy for assistance with the audit of the breast ultrasound database and preparation of the images and Dorothy A. Sippo, MD, for assistance with statistical analysis. Address correspondence to Catherine S. Giess, MD, Department of Radiology, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115 USA. E-mail: cgiess@partners.org Abbreviations BI-RADS, Breast Imaging Reporting and Data System Objectives To determine whether solid palpable breast masses with benign sonographic features have less than 2% incidence of malignancy, allowing management by surveillance instead of biopsy. Methods With Institutional Review Board approval, sonography reports of palpable solid breast masses from January 1, 2006, to December 31, 2009, prospectively classified as probably benign (American College of Radiology Breast Imaging Reporting and Data System [BI-RADS] 3) or low suspicion (BI-RADS 4A) were reviewed. Category 4A lesions were included because many palpable benign-appearing masses at our institution are classified as 4A for palpability. The BI-RADS categories were correlated with outcome data, comprising tissue diagnosis, imaging stability for at least 24 months, or decrease/resolution during imaging surveillance. Results The study population included 440 lesions in 381 patients (mean age, 31.0 years; range, 15 68 years). A total of 161 lesions were prospectively classified as BI-RADS 3 and 279 as BI-RADS 4A. A total of 295 lesions (67%) had biopsy within 4.5 months of presentation, with 3 invasive malignancies; 145 of 440 lesions (33%) underwent surveillance. Forty-one lesions were considered benign for the following reasons: stability for at least 24 months (n = 28), benign tissue diagnosis during surveillance (n = 5), and decrease/resolution during follow-up (n = 8). The malignancy rate in lesions with adequate follow-up or biopsy was 3 of 336 (0.9%). All 3 malignancies occurred in women older than 40 years. Conclusions The incidence of malignancy in palpable solid breast masses classified as BI-RADS 3 or 4A in this study was less than 2%. In young women, surveillance rather than biopsy is appropriate for BI-RADS 3 palpable lesions. Palpability does not merit a BI-RADS 4A classification in solid masses with otherwise benign-appearing morphologic features, particularly in young women. Key Words breast; breast cancer; palpable mass; sonography The mammographic Breast Imaging Reporting and Data Systems (BI-RADS) lexicon 1 of the American College of Radiology has enabled more consistent assessment and management of nonpalpable breast imaging abnormalities. The high negative predictive value of probably benign (BI-RADS 3) mammographic lesions has been validated by several studies. 2 4 Such studies have traditionally excluded palpable breast abnormalities from categorization. 2 5 2012 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2012; 31:1943 1949 0278-4297 www.aium.org

Initially, breast sonography was used predominantly to distinguish cystic from solid breast masses. Substantial improvements in equipment and in clinical experience have resulted in higher sensitivity and specificity in assessing breast lesions. In 2003, the BI-RADS lexicon was expanded to include a breast ultrasound lexicon. 6 A number of studies have validated the application of sonographic features to assess and manage breast lesions. 7 15 Although the 2003 BI-RADS ultrasound lexicon did not include palpable lesions in the application of the BI-RADS 3 category, 6 some published studies did include both palpable and impalpable breast masses in their analyses. 7 12,15 Nevertheless, the BI-RADS ultrasound lexicon is a younger addition to breast imaging management than the BI-RADS mammographic lexicon, and data are considered somewhat less robust. 6 Solid palpable breast masses have traditionally undergone biopsy, in large part because of palpability. 5,16 19 More recently in the literature, the long-standing practice of performing biopsy for any solid palpable breast finding, despite benign-appearing sonographic features, has been challenged. 20 23 These authors have specifically examined the malignancy rate for palpable masses with benign-appearing morphologic features, concluding that the malignancy rate is low enough, ranging from 0% 20 to 3.2%, 22 that surveillance rather than biopsy of such lesions could reasonably be elected. Within our breast imaging section, the management of palpable benign-appearing solid masses varies. Some radiologists prefer to obtain a tissue diagnosis, whereas others are comfortable placing these lesions into imaging surveillance. Thus, some lesions may be described as having benign sonographic features by the diagnostic radiologist but may be classified as BI-RADS 4A because of palpability; other radiologists may give similar lesions with benign sonographic features a BI-RADS 3 assessment. The purpose of this study was to determine the malignancy rate for our patient population with palpable solid breast lesions with benign sonographic features to determine whether biopsy of such lesions may be safely deferred. Materials and Methods Institutional Review Board (IRB) approval for retrospective review of patient medical records and images was given. All consecutive solid palpable breast lesions originally reported and assessed as probably benign (BI-RADS 3) or low suspicion but needing tissue diagnosis (BI-RADS 4A) over a 4-year period (January 1, 2006 December 31, 2009) were identified by an audit of the breast ultrasound database. Before 2008, BI-RADS 4 subcategories (4A 4C) were not consistently applied; only lesions prospectively subcategorized as 4A were included in this study. Category 4A lesions were included in this retrospective study because palpability alone leads some radiologists at our institution to refer solid masses otherwise described with benign sonographic features for biopsy. Lesions prospectively considered probable complicated or complex cysts, fat necrosis, lipomas, and lymph nodes were excluded because of their characteristic clinical and imaging features. A total of 440 lesions in 381 patients constituted the study population. Five staff radiologists reviewed diagnostic sonography reports and any available mammography reports and extracted patient demographics and BI-RADS categories for analysis. Follow-up surveillance data were tracked from the first sonographic study available to the prospective diagnostic radiologist during the study period; most studies were from our own institution. For patients presenting for follow-up at our institution after prior studies had been performed elsewhere, follow-up was tracked from the outside studies if the images themselves were available to the original diagnostic radiologist. Original prospective BI-RADS classifications were assigned according to sonographic features and, where applicable, in conjunction with mammographic features, according to the BI-RADS ultrasound lexicon 6 and BI-RADS mammography lexicon. 1 At our institution, the standard imaging protocol for women presenting with a palpable breast mass is a targeted sonographic examination for patients younger than 30 years, with mammography added at the interpreting radiologist s discretion. For patients older than 30 years, diagnostic mammography is performed first, followed by sonography. Pathologic results, whether by image-guided needle biopsy or excisional biopsy, were considered definitive. Lesions placed into imaging surveillance were considered benign if they were stable for at least 24 months, were decreased or resolved on follow-up imaging, or had a benign tissue diagnosis obtained during the surveillance period. Sonographic examinations were performed on iu22 ultrasound machines (Philips Healthcare, Bothell, WA) with 7- to 15-MHz linear array transducers. All sonographic examinations were performed by radiologists in training and or attending radiologists. Digital mammography, when performed, was done on Senographe DS and Senographe Essential equipment (GE Healthcare, Milwaukee, WI). Diagnostic evaluations were done by staff radiologists at an academic medical center. The standard imaging surveillance protocol for probably benign lesions on sonography at our institution includes 6-, 12-, and 24-month 1944 J Ultrasound Med 2012; 31:1943 1949

targeted sonographic studies; some radiologists also recommend an 18-month follow-up examination. Statistical analysis was performed with SAS version 9.2 software (SAS Institute Inc, Cary, NC). The Fisher exact test with α=.05 was used to compare the malignancy rates of women younger than 40 years to those of women 40 years or older. Ninety-five percent confidence intervals were calculated. P <.05 was considered statistically significant. Results A total of 440 lesions in 381 patients constituted the study population. The mean patient age was 31.0 years (range, 15 68 years). By decade, 49 lesions occurred in patients younger than 20 years; 180 lesions occurred in patients 20 to 29 years old; 115 lesions occurred in patients 30 to 39 years old, 75 lesions occurred in patients 40 to 49 years old; and 21 lesions occurred in patients 50 years or older. The mean lesion size was 1.7 cm (range, 0.4 7 cm). Seventytwo percent of lesions were smaller than 2 cm, and 28% were equal to or larger than 2 cm in their maximal dimension. Only 171 of the 440 solid palpable lesions (45%) were evaluated with diagnostic mammography, and 67% of the mammograms were negative. The most common mammographic finding was a circumscribed or partially obscured mass. Prospective BI-RADS assessments of these 440 lesions included 161 BI-RADS 3 and 279 BI-RADS 4A. Overall, 295 of 440 lesions (67%) had tissue diagnosis within 4.5 months of diagnostic evaluation, with 3 malignancies found. All 3 malignancies were invasive breast cancers. One hundred forty-five of 440 lesions (33%) were placed into surveillance. Forty-one lesions were considered benign for the following reasons: stability for at least 24 months (n = 28), a benign tissue diagnosis during the 24- month surveillance period (n = 5), and decrease/resolution during follow-up (n = 8). Therefore, overall malignancy rate in patients with adequate follow-up or biopsy was 3 of 336 lesions (0.9%). The remaining 104 lesions had no clinical or imaging follow-up nor any known breast cancer diagnosis documented in the longitudinal medical record (n = 76), or they underwent surveillance for less than 24 months (n = 28). The most common pathologic diagnosis for benign lesions was fibroadenoma or another adenomatous lesion. Pathologic results are detailed in Table 1. BI-RADS 3 Lesions A total of 161 lesions were prospectively classified as BI- RADS 3: probably benign. The mean patient age in this subgroup was 30.5 years (range, 16 66 years). The mean lesion size was 1.6 cm (range, 0.4 5.5 cm). A representative lesion classified as probably benign is illustrated in Figure 1. Despite a BI-RADS 3 assessment, 46 of these 161 lesions (29%) underwent tissue diagnosis (25 sonographically guided core biopsy, 20 excisional biopsy, and 1 fineneedle aspiration cytologic examination) within 4.5 months of evaluation, with 1 invasive breast cancer. The invasive malignancy (Figure 2), in a 53-year old woman, was initially placed into short-term surveillance and was upgraded to BI-RADS 4A by a different radiologist at a 3- month follow-up study. Of the 115 lesions placed into follow-up surveillance, 3 increased on imaging and underwent biopsy, revealing a benign fibroepithelial lesion, a hamartoma, and a papilloma. Three lesions disappeared on follow-up imaging and therefore were considered benign. Twenty-three lesions were stable for 24 or more months and were considered benign. Twenty-six lesions had follow-up surveillance for less than 24 months; 1 of these lesions was excised (benign fibroadenoma) at a 6- month follow-up. Sixty lesions had no clinical or imaging follow-up nor any known breast cancer diagnosis documented in the longitudinal medical record. In summary, 1 of 76 (1.3%; 95% confidence interval, 0.0% 7.1%) of BI- RADS 3 lesions with a tissue diagnosis, stability for 24 or more months, or imaging resolution during follow-up surveillance was malignant. This malignancy (Figure 2) represented a 5.5-cm invasive cancer with lobular and ductal features and 4 positive nodes; the lesion was described as infiltrative and non mass forming on pathologic analysis. The subcentimeter palpable finding in this patient was much smaller than the pathologic tumor size. Table 1. Pathologic Results for BI-RADS 3 and 4A Masses That Underwent Biopsy Pathologic Result Fibroadenoma 205 Lactating adenoma/lactational change/galactocele 19 Fat-containing lesion a 5 Fibroepithelial lesion 12 Tubular adenoma 1 Papilloma 4 Pseudoangiomatous stromal hyperplasia 3 Phyllodes 2 Miscellaneous b 46 Invasive cancer 3 Total 300 a Fat-containing lesions included hamartoma, lipoma, and angiolipoma. b Miscellaneous findings included focal fibrocystic changes, stromal fibrosis, vascular lesions, complex sclerosing lesions, inflammation, epidermal inclusion cysts, lymph nodes, and lymphocytic mastopathy. n J Ultrasound Med 2012; 31:1943 1949 1945

BI-RADS 4A Lesions A total of 279 lesions were prospectively classified as BI- RADS 4A: low suspicion. The mean patient age was 31.2 years (range, 15 68 years). The mean lesion size was 1.7 cm (range, 0.5 7 cm). A total of 249 lesions had prompt tissue diagnosis (199 sonographically guided core biopsy, 47 excisional biopsy, and 3 fine-needle aspiration cytologic examination) with 2 malignancies. Both malignancies were invasive ductal cancer. One 49-year-old patient had a 2.3- cm poorly differentiated breast cancer with a positive sentinel node (Figure 3); the other 42-year-old patient had a 0.8-cm moderately differentiated invasive ductal cancer with negative nodes (Figure 4). Thirty lesions underwent imaging follow-up despite a 4A assessment. Five were stable on imaging follow-up for 24 or more months; 3 were stable for less than 24 months; 5 resolved or decreased on follow-up imaging; 1 underwent delayed biopsy during surveillance (benign); and 16 were lost to follow-up. Therefore, 2 of 260 (0.8%; 95% confidence interval, 0.1% 2.8%) lesions with follow-up for at least 24 months, biopsy, or decrease/resolution during surveillance were malignant. BI-RADS 3 and 4A Lesions by Age Overall, 263 BI-RADS 3 and 4A lesions with a tissue diagnosis or adequate follow-up occurred in women younger than 40 years, and 73 lesions were in women 40 years or older. All 3 malignancies occurred in women 40 years or older. There was a significant difference in the malignancy rate of BI-RADS 3 and 4A lesions in women younger than 40 Figure 1. Palpable mass in the right axis at the 3-o clock position (black arrows) in a 27-year-old woman. The sonographic appearance was described as an oval circumscribed 1.5-cm mass parallel to the skin surface, prospectively assessed as BI-RADS 3. Despite the BI-RADS 3 assessment, tissue diagnosis was suggested in the radiology report. Excisional biopsy showed a fibroadenoma. years of age compared to that in women 40 years or older (P =.01). Discussion Traditionally, palpable solid masses have undergone biopsy. 16 19 In this retrospective review, many diagnostic reports described palpable masses as likely a fibro adenoma with benign-appearing sonographic features but classified them as BI-RADS 4A. In palpable masses assessed as BI-RADS 3, biopsy was sometimes mentioned as an alternative to surveillance, perhaps reflecting unease with observing palpable solid masses. Raza et al 24 reported that 14% of BI-RADS 3 palpable and nonpalpable lesions had recommendations by the radiologist that biopsy be considered, and 29.2% of BI-RADS 3 lesions actually underwent biopsy or aspiration. In this study, 29% of palpable solid lesions prospectively classified as probably benign underwent biopsy. The assessment of sonographic features to manage breast masses has been validated by a number of studies. 7 15 High negative predictive values for malignancy when benign sonographic features are present have ranged from 96% to 100%. 7,8,10,12,13,15 Although some studies included palpable masses, others included only nonpalpable masses. More recently, it has been suggested that the BI-RADS ultrasound lexicon 6 can also be accurately applied to palpable solid breast masses. 20 23 Our results add to the body of literature supporting noninvasive man- Figure 2. Palpable mass (thick white arrows) adjacent to the left areolar margin in a 53-year-old woman. The sonographic appearance was described as a 5-mm hypoechoic round mass in the dermis, prospectively assessed as BI-RADS 3. The lesion actually lies in the hypodermis, below the dermal layer (black arrow). On follow-up imaging at 3 months, a different radiologist upgraded the lesion to BI-RADS 4A despite stability. On excision, the lesion represented invasive breast cancer with ductal and lobular features. The pathologic tumor size was much larger than the mass depicted on sonography. Thin white arrows indicate nipple and central subareolar hypoechoic ducts. (The initial recommendation for 3-month follow-up sonography was not a standard follow-up interval.) 1946 J Ultrasound Med 2012; 31:1943 1949

agement of probably benign palpable solid breast masses. Palpability may be due to the lesion size relative to the breast size or the depth of the lesion within the breast. Patients sometimes note a palpable mass when initiating breast self-examination, when seeing a new physician, or with weight fluctuations. Palpability may not necessarily imply recent development or growth of a lesion. 23 We found a less than 2% incidence of malignancy in palpable solid breast masses assessed as low suspicion, or BI-RADS 4A. The BI-RADS 4 subdivisions are intended to indicate the radiologist s estimation of the likelihood of malignancy (3% 94% for BI-RADS 4) to the referring clinician and the patient. However, the imaging criteria used to distinguish among 4A, 4B, and 4C categories are not specifically delineated. 6 In this retrospective review, the reason for prospective BI-RADS 4A assessment rather than BI-RADS 3 assessment could not be determined, although many reports indicated that palpability influenced the BI-RADS assessment. The low positive predictive value for BI-RADS 4A lesions in this retrospective study supports the idea that palpability alone should not generate a BI-RADS 4A assessment for an otherwise benign-appearing solid mass. The positive predictive value of the BI-RADS 4 subdivisions has been evaluated by several authors. Lazarus et al, 14 assessing mammograms and sonograms, found malignancy rates of 6% in 4A lesions, 15% in 4B lesions, and 53% in 4C lesions. Sanders et al 25 assessed BI-RADS 4 subcategories for mammographically detected microcalcifications, finding ductal carcinoma in situ in 10% of 4A lesions, 21% of 4B lesions, and 70% of 4C lesions. Vincenti et al 26 Figure 3. Palpable mass (white arrows) in the right breast of a 49- year-old woman. The sonographic appearance was described as a hypoechoic and lobulated mass, prospectively assessed as BI-RADS 4A. The heterogeneous background echo texture might have made the palpable finding less visually conspicuous. Pathologically, the lesion represented a 2.3-cm poorly differentiated invasive ductal cancer with a positive sentinel node. reported malignancy rates of 13% in 4A, 29% in 4B, and 82% in 4C BI-RADS categories for mammographic lesions at their institution. Further work needs to be done to clarify the sonographic features distinguishing among the BI- RADS 4 subdivisions because some sonographic features are more suspicious than others. Increasing age is a risk factor for developing breast cancer. In our series, as in that of Harvey et al, 23 most patients were young. Fifty-two percent of palpable solid lesions occurred in women younger than 30 years, and 78% of palpable solid lesions occurred in women younger than 40 years, with no cancers. All 3 patients with cancer in this series were older than 40 years (53, 42, and 49 years, respectively). In the study by Harvey et al, 23 the single patient with cancer who had a BI-RADS 3 finding was 59 years old, and in the study by Park et al, 21 2 patients with cancer had BI-RADS 3 findings, who were 50 and 37 years old, respectively. Sickles 27 found no statistically significant difference in malignancy rates among larger masses or older women for nonpalpable solid mammographically benign masses. In that study, sonograms were used to exclude cysts and lymph nodes, but sonographic features of solid masses were not described. Our series contained only 73 BI-RADS 3 and 4A lesions with adequate follow-up or tissue diagnosis in women 40 years or older. However, 3 of 73 palpable lesions (4.1%) in this age group proved malignant, including 1 of 18 BI-RADS 3 lesions (5.6%) and 2 of 55 BI-RADS 4A lesions (3.6%). These numbers, although small, suggest that our results may not be applicable to older age groups, particularly given the preponderance of young women in this study. It would valuable to compare the malignancy rates in larger numbers of BI- RADS 3 and 4A palpable and impalpable lesions in women Figure 4. Palpable mass (black arrows) in the right axillary tail in a 42-year-old woman. The sonographic appearance was described as a hypoechoic round partially circumscribed mass, prospectively assessed as BI-RADS 4A. Pathologic examination showed a 0.8-cm moderately differentiated invasive ductal cancer with negative nodes. J Ultrasound Med 2012; 31:1943 1949 1947

younger than 40 years compared to women older than 40 years; that comparison is a topic for future study. Because of the increasing incidence of breast cancer with age, we recommend caution in evaluating and managing palpable solid masses in women of appropriate screening age. We found patient compliance with imaging surveillance to be moderate for BI-RADS 3 lesions. Helvie et al 28 reported that 12% patients with probably benign mammographic findings had no follow-up, and only 47% completed 3 years of surveillance. Moderate compliance with imaging follow-up after breast needle biopsy has also been reported. 29,30 It is possible that some lesions in our study were monitored clinically rather than by imaging. Young women may have more geographic mobility in our city, which has many universities, and they may have been followed elsewhere. Additionally, patients may have been reassured by the low likelihood of malignancy during the initial imaging evaluation or by their primary care provider and felt little need for surveillance. One could argue that if compliance with imaging surveillance is only moderate for probably benign lesions, then core needle biopsy may be preferable. However, core needle biopsy is more expensive than imaging surveillance. 23,31,32 Core biopsy generates patient stress and anxiety; in fact, Lindfors et al 33 found that self-reported stress was higher for women who underwent core biopsy than for women who underwent mammographic surveillance. In their study, younger women had significantly more stress than older women, regardless of the management option. Although it may sometimes be preferable to perform biopsy for a benign-appearing solid mass, imaging surveillance is a reasonable and safe alternative. However, it should be emphasized that any palpable breast mass with suspicious clinical features should undergo biopsy regardless of imaging findings. Our study had several limitations. Our radiologists have a variable approach to palpable solid benign-appearing masses, some preferring tissue diagnosis over surveillance. Many diagnostic reports referenced palpability as a factor influencing the biopsy recommendation. Therefore, this high negative predictive value for palpable BI-RADS 4A lesions may not be applicable to nonpalpable BI-RADS 4A lesions in our population. These results do suggest that the presence of palpability alone in an otherwise benignappearing solid mass should not generate a BI-RADS 4A assessment. Given our young demographic, these results may not be applicable to older age groups for whom the rate of malignancy increases. Although there were no known cancers among those patients lost to follow-up, the patients have not been linked to a tumor registry. In summary, the malignancy rate in palpable solid breast masses considered BI-RADS 3 based on sonographic features was less than 2%, and surveillance rather than biopsy is appropriate. Palpability alone should not result in a BI-RADS 4A assessment in a solid mass with otherwise benign-appearing sonographic features, particularly in young women. Further work needs to be done to delineate sonographic criteria for 4A, 4B, and 4C subdivisions and to determine their applicability in women older than 40 years, a demographic with an increasing incidence of breast cancer. Although noncompliance with surveillance is a potential problem for probably benign lesions, biopsy remains more costly than observation, with a minimal increase in cancer diagnosis. References 1. D Orsi CJ, Bassett LW, Berg WA, et al. Mammography. In: Breast Imaging Reporting and Data System (BI-RADS). 4th ed. Reston, VA: American College of Radiology; 2003:1 259. 2. Sickles EA. 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