Comparison of Sonographically Guided Core Needle Biopsy and Excision in Breast Papillomas

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1 ORIGINAL RESEARCH Comparison of Sonographically Guided Core Needle Biopsy and Excision in Breast Papillomas Clinical and Sonographic Features Predictive of Malignancy Yu-Mee Sohn, MD, PhD, So Hyun Park, MD Received June 27, 2012, from the Department of Radiology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea. Revision requested July 16, Revised manuscript accepted for publication July 19, This work was supported by a grant from Kyung Hee University (KHU , 2012). Address correspondence to Yu-Mee Sohn, MD, PhD, Department of Radiology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul , Korea. sonyumee@naver.com Abbreviations BI-RADS, Breast Imaging and Reporting and Data System Objectives The aim of this study was to evaluate the clinical factors and sonographic features of benign papillomas of the breast proven by sonographically guided 14-gauge core needle biopsy and their upgrade or malignancy rate after sonographically guided vacuum-assisted excision or surgical excision. Methods We reviewed the medical records of patients who underwent core needle biopsy from July 2005 to December We evaluated 39 benign papillomas without atypia in 34 patients. The papillomas were diagnosed by core needle biopsy and underwent surgical or vacuum-assisted excision. After core needle biopsy, imaging-histologic correlation was performed to determine concordance. The upgrade and malignancy rates were assessed after surgical or vacuum-assisted excision, and associated clinical and radiologic factors, including patient age, lesion size, distance from the nipple, sonographic features, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) category were evaluated. Results Three lesions (7.7 %) among 39 papillomas were upgraded to papilloma with atypia after surgical excision. There was no malignancy after excision. The upgrade rates for BI-RADS categories 3, 4a, 4b, and 4c were 0%, 6.9%, 0%, and 20%, respectively. There were no significant differences in the upgrade to papilloma with atypia in terms of the presence of symptoms, lesion size, distance from the nipple, BI-RADS category, or imaging-histologic correlation. Conclusions Prediction of papilloma with atypia, not malignancy, was challenging because there were no associated clinical or radiologic factors to predict papilloma with atypia before excision. However, there was no malignancy after excision. Therefore, intensive surveillance is preferable to immediate surgical excision for benign papillomas diagnosed on core needle biopsy. Key Words core needle biopsy; excision; papilloma; sonography B reast papillomas have a wide spectrum of pathologic types, ranging from benign papilloma to papilloma with atypical ductal hyperplasia or atypical lobular hyperplasia, carcinoma in situ, and invasive or noninvasive papillary carcinoma. 1 Although image-guided core needle biopsy has replaced the old methods of fine-needle aspiration and excisional biopsy, sampling errors, limited material, and underestimation may cause a falsenegative result or delay the exact diagnosis of malignancy in the papilloma, and the distinction between a benign and malignant lesion is reportedly difficult for this disease entity. 2 Therefore, sur by the American Institute of Ultrasound in Medicine J Ultrasound Med 2013; 32:

2 gical excision has been recommended for management after percutaneous biopsy of papillary lesions because of the potential for an upgrade to malignancy. 3 However, there have been a number of controversies regarding management with subsequent surgical excision in benign papillomas without atypia after core needle biopsy. 1,2,4 12 Some recent investigators have suggested the use of selective surgical excision for benign papillomas without atypia after considering clinical and radiologic factors or supported conservative management. 4,7,13 18 Prediction of clinical and radiologic factors associated with an upgrade to atypia or malignancy will be very helpful for both clinicians and radiologists. Therefore, the purpose of this study was to evaluate the clinical and sonographic features of papillomas proven to be benign by 14-gauge core needle biopsy and to investigate their upgrade and malignancy rates after sonographically guided vacuum-assisted excision or surgical excision. We also sought to validate the clinical and radiologic predictors of malignancy and to suggest guidelines for management of these lesions. Materials and Methods Study Population The Institutional Review Board approved this retrospective study and required neither patient approval nor informed consent for review of patient images and records. From July 2005 to December 2011, 58 patients with 67 lesions underwent 14-gauge core needle biopsy to confirm breast papillomas without atypia. Among them, 24 patients with 28 lesions did not undergo subsequent surgery or vacuum-assisted excision after percutaneous biopsy. Therefore, these patients were excluded, and 34 patients with 39 lesions constituted the final study population. The mean age of the included patients was 46.3 years (range, years). The choice of removal method (surgery or vacuum-assisted excision) was determined according to the physician s or patient s preferences. Imaging Evaluation and Biopsy Mammograms were obtained with dedicated equipment (Senographe 2000D; GE Healthcare, Milwaukee, WI). Standard craniocaudal and mediolateral oblique views were routinely obtained with additional views as needed. Sonographic examinations were performed with highresolution ultrasound units and or 5 12-MHz linear array transducers (HDI 5000; Philips Healthcare, Bothell, WA; and LOGIQ 9; GE Healthcare) by full-time board-certified radiologists dedicated to breast imaging with 5 years of experience. Sonographically guided core biopsy was performed by a freehand technique, and each procedure was performed with a 14-gauge dual-action semiautomatic core biopsy needle (Stericut coaxial; TSK Laboratory, Tochigi, Japan). The throw of the biopsy needle was 2.2 cm. Biopsy was performed by a specially trained radiologist who was dedicated to breast imaging with 5 years of experience. Four or 5 core samples per lesion were obtained. Surgical or Vacuum-Assisted Excision Management For exact localization before surgery, nonpalpable lesions (n = 30) were localized by sonographically guided marking or localization with a 21-gauge Kopans spring-hook needle to excise the biopsy-proven papillomas. Palpation-guided excision was performed for palpable lesions (n = 9). The surgery was performed by a breast surgeon with 25 years of experience. The surgical pathologic results were compared with sonographically guided core needle biopsy results. Vacuum-assisted excision was performed with a vacuumassisted device (Mammotome; Ethicon Endosurgery, Cincinnati, OH) and an 8-gauge probe for lesions of 1.5 to 3.0 cm and an 11-gauge probe for lesions smaller than 1.5 cm. After the administration of local anesthesia, the probe was inserted into the breast through a small skin incision and was guided into the biopsy position directly under the guidance of the ultrasound units mentioned above. Multiple core samples were taken until the mass was completely removed, as determined by real-time sonography of the biopsy site. 19 Forced scan pressure was used to disperse air artifacts, and multidirectional sonograms, such as views perpendicular to the biopsy needle, were acquired to visualize the residual mass. In our practice, to ensure complete mass removal during vacuum-assisted excision, we remove breast tissue surrounding the lesion at 4 sampling sites (12, 3, 6, and 9-o clock directions). The vacuum-assisted excision procedure was performed by a board-certified radiologist with 5 years of experience in breast imaging and biopsy with sonographic guidance. Data and Statistical Analysis Medical records were reviewed for clinical variables such as patient age and symptoms (palpable masses, bloody nipple discharge, and pain). Sonograms were reviewed to collect sonographic variables such as lesion size, distance from the nipple, multiplicity, and number of specimens. Other sonographic features were based on the American College of Radiology Breast Imaging and Reporting and Data System (BI-RADS) lexicon 20 and included shape, margin, orientation, lesion boundary, echo pattern, posterior acoustic features, and duct changes. We used the BI-RADS final 304 J Ultrasound Med 2013; 32:

3 assessment of imaging studies for categorical classification of the original radiology reports instead of having the reviewing radiologists reread the images. Reviewers compared the imaging findings and biopsy results to determine the imaging-histologic concordance. The findings were considered concordant if pathologic results provided an acceptable explanation for imaging features (imaging features and core needle biopsy results were benign), and the findings were considered discordant when they did not (imaging features were suspicious, but core needle biopsy results were benign). 21 A histologic upgrade was defined when lesions were diagnosed as benign papillomas by core needle biopsy but later diagnosed as atypical papilloma, ductal carcinoma in situ, or invasive carcinoma at surgical excision. 22 The upgrade rate was determined by dividing the number of upgraded cases by the total number of core needle biopsies performed. Statistical analyses were performed using the χ 2 test or Fisher exact test for categorical variables and the Mann-Whitney U test for continuous variables. P <.05 indicated statistical significance. All statistical analyses were performed with SAS version software (SAS Institute Inc, Cary, NC). Results Thirty-four lesions were excised by surgical excision, and 5 were removed by vacuum-assisted excision. Among the 39 lesions that were diagnosed as benign papillomas by 14-gauge core needle biopsy, 3 (7.7 %) were upgraded to atypical papillomas or papillomas with atypical ductal hyperplasia (papillomas with atypia). All 3 lesions were excised surgically. There was no malignancy after surgical or vacuum-assisted excision. Clinical characteristics of the patients with benign papillomas are shown in Table 1. There was no significant difference in the frequency of the upgrade to papilloma with atypia. Sixteen patients had symptoms, including a palpable mass (n = 4), nipple discharge (n = 10), and pain (n = 2). The presence of symptoms was not related to the upgrade to papilloma with atypia. Representative images are shown in Figures 1 and 2. Table 2 shows the mammographic and histologic findings after surgical excision. The mammographic findings showed masses, microcalcification, masses with microcalcification, and negative findings; however, the mammographic findings did not affect the differentiation between papillomas with and without atypia. In terms of lesion size, papillomas with atypia were larger than benign papillomas (Table 3). However, there were also no significant differences in the upgrade rates in terms of lesion size and distance from the nipple. Among BI-RADS descriptors and multiplicity, there was no significant difference in the upgrade rates (Table 3). With regard to concordant and discordant imaginghistologic correlations, the upgrade rate was higher in the discordant group than in the concordant group, but there was no significant difference between them (Table 3). Discussion Management of papillomas after core needle biopsy has been reported variably in published reports. There has been considerable debate regarding management of papillary lesions. Some investigators have suggested that surgical excision should be performed in all papillomas regardless of the presence of atypia, 5,6,9 12,23 28 because of associated malignancy or histologic heterogeneity, including small malignant foci. On the other hand, other researchers have supported selective excision in cases of atypia or in the presence of risk factors. 2 4,9,13 16,18,29 33 Table 4 shows the published data on papillomas confirmed by core needle biopsy and subsequent surgical excision and their upgrade rates to malignancy. These studies reported their rates of upgrade from benignity on core needle biopsy to malignancy and papilloma with atypia after surgical excision. 1,5,7 9,11,15,16,25,28,29,31 36 Our finding was within the range of the reported upgrade rate to papilloma with atypia. Table 1. Clinical Characteristics of the Patients With Benign Papillomas Without Atypia Diagnosed by Sonographically Guided 14-Gauge Core Needle Biopsy Histologic Findings After Surgical Excision Characteristic Without Atypia With Atypia P Patient age, y 46.1 ± 6.8 (46, 31 67) 48.3 ± 16.5 (53, 30 62).542 Associated symptoms Yes No 22 1 Age data are reported as mean ± SD (median, range). J Ultrasound Med 2013; 32:

4 The published studies also reported risk factors or associated factors for predicting an upgrade to malignancy after surgical excision. Reported clinical factors included older age (>50 or 65 years), 4,16,25,30,36 palpability, 15 presence of nipple discharge, 16 family history of breast cancer, 8 and atypia on core needle biopsy. 30,33 Radiologic factors included a lesion size greater than 1 cm 36 or 1.5 cm, 1,7 peripheral location, 1 distance from the nipple greater than 3 cm, 36 multiple lesions, 8 a mass 15 or microcalcification 16 on mammography, and an uncircumscribed margin and mixed hyperechoic or complex cystic echogenicity on sonography. 11 Figure 1. Images from a 31-year-old woman with a screening-detected breast lesion. Transverse (A) and longitudinal (B) breast sonograms show an 8-mm oval microlobulated hypoechoic mass (arrows) with a connection to the duct that was located in the subareolar area. This lesion was assigned to BI-RADS category 4a. Sonographically guided core needle biopsy was performed, and an intraductal papilloma was diagnosed. This lesion was classified as a concordant benign lesion after imaging-pathologic correlation. At the patient s request, surgical excision was performed, and the lesion was confirmed to be an intraductal papilloma. A B Figure 2. Images from a 53-year-old woman with a palpable mass and bloody nipple discharge in the right breast. The diagnosis after surgical excision was papilloma with atypical ductal hyperplasia. Transverse (A) and longitudinal (B) breast sonograms show a 17-mm oval microlobulated isoechoic mass (arrows) located in the subareolar area within the dilated duct. This lesion was assigned to BI-RADS category 4b. Sonographically guided core needle biopsy was performed, and an intraductal papilloma was diagnosed. This lesion was classified as a discordant benign lesion after imaging-pathologic correlation. A B 306 J Ultrasound Med 2013; 32:

5 In this study, age showed no significant difference between patients whose lesions were upgraded to papilloma with atypia after surgical excision and patients whose lesions were not. Symptoms such as palpability and nipple discharge were reported to be associated with malignancy after excision, as mentioned above. 15,16 However, although Table 2. Summary of Mammographic and Histologic Findings in the 39 Benign Papillomas Without Atypia Diagnosed by Sonographically Guided 14-Gauge Core Needle Biopsy Histologic Findings After Surgical Excision Mammographic Findings Without Atypia With Atypia Total P Mass Calcification Mass with calcification Negative finding Total Table 3. Sonographic Features of the 39 Benign Papillomas Without Atypia Diagnosed by Sonographically Guided 14-Gauge Core Needle Biopsy Histologic Findings After Surgical Excision Upgraded Characteristic Without Atypia With Atypia to Atypia, % P Lesion size, mm 10.6 ± 5.7 (10, 4 34) 12.3 ± 6.4 (15, 5 17).578 Distance from nipple, mm 1.5 ± 1.6 (1, 0 7) 1.0 ± 1.0 (1, 0 2).660 Multiplicity.570 Yes No Shape.990 Oval Round Irregular Margin.403 Circumscribed Noncircumscribed Orientation.557 Parallel Nonparallel Lesion boundary.990 Abrupt interface Echogenic halo Echo pattern.269 Hypoechoic Isoechoic Complex Posterior acoustic features.990 None Shadowing Duct change.990 Present Absent BI-RADS category a b c Imaging-pathologic correlation.101 Concordant Discordant Size and distance data are reported as mean ± SD (median, range). J Ultrasound Med 2013; 32:

6 there were palpable masses (n = 4) and nipple discharge (n = 10) in this study, the presence of these symptoms was not significantly associated with the upgrade to papilloma with atypia. In terms of mammographic findings, some studies reported that a mass or microcalcification could predict an upgrade to malignancy after surgical excision 15,16 ; however, another study suggested that there was no difference between papillomas with and without atypia according to mammographic findings such as a mass or calcification. 4 With regard to sonographic findings, an upgrade to malignancy was reported to be associated with a lesion size greater than 1 cm 36 or 1.5 cm, 1,7 a distance from the nipple greater than 3 cm, 36 multiple lesions, 8 an uncircumscribed margin, and mixed hyperechoic or complex cystic echogenicity on sonography. 11 However, we were unable to detect the above-mentioned differences between papillomas with and without atypia in our study, possibly because no malignancies were detected after surgical excision. Furthermore, the results from the previous studies might be applicable to an upgrade to malignancy rather than papilloma with atypia. In terms of the imaging-pathologic correlation, Youk et al 36 reported that the upgrade rate of the discordant group was significantly higher than that of the concordant group. In our study, the upgrade rate to papilloma with atypia was higher in the discordant group than in the concordant group (Table 3), but the difference was not significant. Table 4. Summary of Published Literature on Benign Papillomas Diagnosed With Sonographically Guided Core Needle Biopsy Papillary Benign Upgrades to Upgrades to Study Lesions, n a Papillomas, n Malignancy, n (%) b Atypia, n (%) b Predictive Factors Kil et al (5) NA Lesion size (>15 mm), peripheral location Sohn et al (1.1) 0 (0) NA Ahmadiyeh et al (3.4) NA Age c Bernik et al (8.5) 13 (27.7) NA Chang et al 7 NA (4) 13 (13) Lesion size (>15 mm) Liberman et al 8 NA 35 5 (14.3) 3 (8.6) Multiple, family history of breast cancer Mercado et al (4.7) 8 (18.6) NA Rizzo et al (8.9) NA NA Shin et al (14.8) 6 (7.3) Noncircumscribed margin, mixed hyper-hypoechoic, complex cystic echogenicity Jung et al (6.3) 9 (5.6) Palpability, mass on mammography Sakr et al (8.3) 3 (6.3) Age (>50 y), presence of nipple discharge, microcalcification Rizzo et al (8.9) 42 (17.9) Older age Skandarajah et al 28 NA (18.8) 11 (13.8) NA Agoff and Lawton (0) 0 (0) NA Arora et al (0) NA Age (>65 y), atypia on core needle biopsy Philpotts et al (6.3) 0 (0) NA Rosen et al (0) 1 (3.0) NA Sydnor et al (2.6) 0 (0) Atypia on core needle biopsy Liberman et al (0) 0 (0) NA Mercado et al (8.3) 0 (0) NA Youk et al (5) 0 (0) Age (>50 y), lesion size (>1 cm), distance from nipple (>3 cm) This study (0) 3 (7.7) NA NA indicates not applicable. a Including benign papillomas without atypia and benign papillomas with atypia. b Including papillomas with foci of atypical ductal hyperplasia and atypical papillomas. c Those in the atypia group were older than those in the no-atypia group, and the atypia group showed a higher rate of upgrade to malignancy in this study. 308 J Ultrasound Med 2013; 32:

7 In this study, we attempted to identify the associative factors of papillomas diagnosed at core needle biopsy for predicting malignancy and to suggest management guidelines for these lesions. However, no carcinomas were found after surgical or vacuum-assisted excision, and we did not identify any significant predictive factors associated with the upgrade to papilloma with atypia instead of malignancy. Some investigators support surgical excision of benign papillomas diagnosed by core needle biopsy because of their histologic heterogeneity. Actually, a benign papillary lesion can be differentiated from papillary carcinoma in situ on the basis of the presence of atypical epithelial proliferation resembling low-grade ductal carcinoma, in which a normal myoepithelial cell layer is typically absent. In addition, the classification of atypical papillomas depends on the percentage (>33%) 37 or size (>3mm) 38 of the lesion, atypical epithelial proliferation, and the presence or absence of an intact myoepithelial cell layer; usually, the area of atypia is limited to a small area. Bernik et al 5 asserted that there is a strong likelihood of discovering atypia or malignancy in the index lesion or in close proximity to it after surgical excision of a papillary lesion by core needle biopsy; therefore, surgical excision should be performed to avoid missing a malignancy and to ensure an accurate diagnosis. Moreover, prior studies have shown that papillomas with atypia diagnosed at core needle biopsy were more often upgraded histologically to malignancy than benign papillomas after surgical excision. 2 6,10 13,25,33,34,38 Some studies reported atypical papilloma as a generalized risk factor for the development of breast cancer Therefore, surgical excision has been recommended as a management strategy for atypical papillomas at core needle biopsy. 4,13,17,30,32 34 In contrast, other reports have indicated that when lesions have no atypical or malignant features, the incidence of a more serious lesion after removal is extremely low, and excision may not be needed. 29,31,34,35 In this study, there was no papilloma with atypia detected by core needle biopsy. Moreover, a lesion confirmed as papilloma with atypia at surgical excision was deemed to be consistent with a benign result, just like atypical ductal hyperplasia, rather than a false-negative result. 42 Prediction of atypia before core needle biopsy is very important because atypical papilloma has been regarded as a generalized risk factor for development of breast cancer, and a papilloma with atypia at core needle biopsy usually ends up being classified as a more serious lesion after excision. However, papillomas with atypia after excision do not require more procedures. Intensive surveillance will be mandatory to ascertain the recurrence or a residual lesion after removal. In this study, we used a 14-gauge automated gun for biopsy; many researchers have reported the excellent diagnostic accuracy of vacuum-assisted biopsy and its usefulness as an alternative method to surgery for management of papillary lesions. 18,22,24,27,43 45 Previous studies have reported that surgical excision is not necessary after vacuumassisted removal of papillomas diagnosed as benign by vacuum-assisted excision. 18,43 45 Kim et al 43 suggested that there is a higher false-negative rate and increased upgrade rates associated with diagnosis via core needle biopsy compared to vacuum-assisted excision. A sampling error can occur with core needle biopsy; however, there was no malignancy after surgical excision in this study, even though 3 papillomas with atypia were diagnosed. Our study had several limitations. First, our study population was so small because the inclusion criteria were confined to benign papillomas diagnosed at core needle biopsy that were excised surgically or removed by vacuum assistance, and only 3 papillomas with atypia, not malignancy, were diagnosed after surgical excision. Therefore, it was difficult to identify predictive factors associated with a diagnosis of malignancy after surgical excision in our study. A prospective study with a large number of patients is needed to conclude this inference. Second, it was a retrospective study; thus, there was the potential for a selection bias because we only included papillomas subjected to surgical excision, and the decision to proceed with surgical excision depends on the clinician s or patient s preferences. Immunohistochemical methods are currently used to differentiate benign papilloma from papilloma with atypical ductal hyperplasia or ductal carcinoma in situ using CD44 46 and high-molecular-weight cytokeratin. 47 This method could be used in a future prospective study. Third, Doppler sonographic features were not evaluated. In conclusion, 7.7% of benign papillomas were upgraded to papillomas with atypia. The prediction of papilloma with atypia, not malignancy, was challenging because we were unable to identify any clinical or radiologic features associated with an upgrade to papilloma with atypia. However, there were no cases of malignancy diagnosed after surgical excision, suggesting that intensive surveillance is more appropriate than immediate surgical excision for benign papillomas diagnosed on core needle biopsy. References 1. Kil WH, Cho EY, Kim JH, Nam SJ, Yang JH. Is surgical excision necessary in benign papillary lesions initially diagnosed at core biopsy? 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