Michael J. Wagoner, MD, 1 Christine Laronga, MD, 2 and Geza Acs, MD, PhD 1-3. Abstract

Anatomic Pathology / ADH in Breast Core Needle Biopsy Specimens Extent and Histologic Pattern of Atypical Ductal Hyperplasia Present on Core Needle Biopsy Specimens of the Breast Can Predict Ductal Carcinoma In Situ in Subsequent Excision Michael J. Wagoner, MD, 1 Christine Laronga, MD, 2 and Geza Acs, MD, PhD 1-3 Key Words: Atypical ductal hyperplasia; Core needle biopsy; Ductal carcinoma in situ DOI: 1.139/AJCPGHEJ2R8UYFGP Abstract Atypical ductal hyperplasia (ADH) diagnosed by core needle biopsy (CNB) is regarded as an indication for surgical excision. We investigated whether histologic subtype and extent of ADH in a series of 123 CNB specimens can predict the presence of carcinoma on surgical excision. We found that ADH present in more than 2 foci in CNB specimens was a strong predictor of ductal carcinoma in situ (DCIS) on excision (>2 foci, 16/41 vs 6/82 for 1 or 2 foci; P <.1). The micropapillary subtype of ADH also predicted the presence of DCIS (P =.6). Our study suggests that micropapillary histologic subtype and extent of ADH in CNB specimens can be applied to predict the presence of DCIS on surgical excision. By using the combination of the extent of ADH in CNB specimens (1 or 2 foci), the presence of microcalcifications within the lesion, and the lack of residual mammographic calcifications after CNB, we identified a low-risk group of patients (n = 25), none of whom had carcinoma on surgical excision. Patients with ADH restricted to fewer than 3 foci may not need surgical excision, especially when the mammographic abnormality is completely removed by CNB. Image-guided core needle biopsy (CNB) has become the procedure of choice to investigate mammographically suspicious lesions of the breast and has been shown to be an effective means to rule out cancer, alleviating the cost and discomfort of surgery. Overall, CNB histologic findings are in agreement with surgical biopsy in more than 95% of the cases. 1-3 The sensitivity and accuracy of CNB in identifying cancer was further confirmed in a recent study of more than 4, CNB specimens by using different core gauge sizes and guidance methods and for identifying different imagedetected or clinical lesions. 4 However, significant discordance has been reported in the CNB diagnosis of atypical ductal hyperplasia (ADH), with 7% to 87% of cases proving to be ductal carcinoma in situ (DCIS) or invasive carcinoma on subsequent surgical excision. 1,5-11 This finding is not surprising given the fact that CNB techniques sample only a portion of the mammographic target lesion in most cases and, thus, will inevitably have less sensitivity compared with excisional biopsies. Diagnostic criteria for ADH were originally defined based on excisional biopsy material using mainly exclusion criteria (lesions that have some but not all features of low-grade DCIS) in addition to the extent of the lesions. 12-14 It is well known that distinction between ADH and low-grade DCIS can be problematic on excisional biopsy material and even more difficult on the limited tissue samples obtained by CNB. In addition, foci of ADH may be present at the periphery of areas of DCIS, 15 and, thus, even an unequivocal diagnosis of ADH does not preclude the presence of an adjacent, more advanced lesion. Owing to the danger of false-negative biopsy results, it is currently recommended that lesions diagnosed as ADH by CNB should be surgically excised. 16,17 112 Am J Clin Pathol 29;131:112-121 112 DOI: 1.139/AJCPGHEJ2R8UYFGP

Anatomic Pathology / Original Article The identification of patients with ADH diagnosed by CNB who can be spared surgical excision is an area of active investigation. However, at present, clinical, radiologic, and pathologic factors on which to base this decision have not been consistently identified. There are only a handful of published studies that examine in detail the histologic features and extent of ADH in CNB specimens and correlate them with subsequent diagnosis on surgical excision. 7-9,11,18,19 Some of these studies suggested that the extent and histologic pattern of ADH present in CNB specimens can be used to predict the likelihood of the presence of a more advanced lesion (DCIS or invasive carcinoma). 7,8 The purpose of the present study was to predict, based on histologic details, which cases of ADH diagnosed by CNB would be more likely to be associated with a more advanced lesion on subsequent surgical excision. Materials and Methods The surgical pathology files at the Moffitt Cancer Center, Tampa, FL, were searched between January 2 and April 28 for CNB cases with a diagnosis of ADH. Cases with a diagnosis of DCIS or invasive carcinoma present in the same breast in addition to ADH were excluded, leaving 21 CNB cases with ADH as the most significant lesion diagnosed. Of the 21 identified cases, 137 had subsequent surgical excision. Among patients with no follow-up surgical excision, some refused further surgery, and others had excisional biopsy at other institutions and their slides were not available for review; these cases were excluded from the study. All H&E-stained slides of the CNB specimens of these cases were reviewed by two of us (M.J.W. and G.A.) to confirm the diagnosis of ADH, without knowledge of the subsequent excisional biopsy results, using established criteria as defined by Page et al, 12 Page and Rogers, 13 and Tavassoli and Norris. 14 Four cases demonstrated ADH within a partially sclerosed papilloma and were excluded from the study. On review, 7 and 3 additional cases were reclassified as usual hyperplasia and columnar cell change with atypia (flat epithelial atypia), respectively, and were excluded. The remaining 123 cases of ADH diagnosed by CNB with available subsequent open surgical biopsy specimens formed the basis of the study. Following verification of the presence of ADH in the CNB specimens, the extent of involvement was determined by evaluating the number of large ducts and/or terminal duct lobular units affected by ADH, as described by Ely et al. 7 When multiple foci of ADH were present, the size of the largest focus was determined. Additional data recorded at the time of review were the predominant histologic pattern of ADH (cribriform, micropapillary, or solid), presence of calcifications within ADH (determinant calcifications), presence of unrelated calcifications, needle gauge (11 vs 14), number of tissue cores obtained, and number of tissue cores involved by ADH. Additional clinical parameters, such as patient age, race, side affected, family history of breast cancer, menopausal status, use of hormone replacement therapy, clinical manifestations, mammographic findings, presence of residual calcifications following CNB, and follow-up information, were obtained from the patients medical records. All H&E-stained slides of the subsequent surgical excisions were also reviewed by two of us (M.J.W. and G.A.) to confirm the final diagnosis, without knowledge of the CNB findings. The surgical excision specimens were evaluated for the presence of invasive carcinoma, DCIS, lobular carcinoma in situ, atypical lobular hyperplasia (ALH), and residual ADH, using established criteria. 13,2 The presence of a prior biopsy site was confirmed in all cases. Results were compared with the extent and histologic type of ADH present in the CNB specimens. Study protocols were approved by the Moffitt Cancer Center Scientific Review Committee and the University of South Florida Institutional Review Board. The median number of ADH foci and number of cores involved by ADH were compared between various follow-up groups by using the Kruskal-Wallis 1-way analysis of variance by ranks followed by the Dunn multiple comparison test, when appropriate. The histologic type of ADH and presence of microcalcifications were compared between various follow-up groups by using the χ 2 test. The correlation between the number of ADH foci and number of cores involved by ADH or total number of cores was estimated by using the Spearman test. Statistical significance was determined if the 2-sided P value of a test was less than.5. Computations were performed using the GraphPad Prizm software (version 4, GraphPad Software, San Diego, CA). Results The clinical data for the patients are summarized in ztable 1z. CNB was performed for mammographically detected microcalcifications, architectural distortion and/or suspicious asymmetric density, and palpable mass lesion in 11, 12, and 1 of the cases, respectively. Of the CNBs, 116 (94.3%) were stereotactic biopsies performed with an 11-gauge needle, and 7 (5.7%) were ultrasound-guided using a 14-gauge needle. The number of cores obtained from each lesion ranged from 2 to 26 (median, 1), and the median number of cores involved by ADH was 2 (mean ± SEM, 2.18 ±.16). The predominant histologic pattern of ADH in CNB specimens was cribriform in 79 (64.2%) zimage 1Az and zimage 1Bz, micropapillary in 35 (28.5%) zimage 1Cz, and solid in 9 (7.3%) cases, respectively. The median number of ADH foci Am J Clin Pathol 29;131:112-121 113 113 DOI: 1.139/AJCPGHEJ2R8UYFGP 113

Wagoner et al / ADH in Breast Co r e Needle Bi o p s y Specimens was 1 (mean ± SEM, 2.2 ±.17), and the median size of ADH foci was 1 mm (mean ± SEM, 1.61 ±.1 mm). The extent of ADH was limited to 1 or 2 foci in 82 cases (66.7%), confined to 3 foci in 23 cases (18.7%), and involved 4 or more foci in 18 cases (14.6%). No statistically significant differences were found between these groups on the basis of patient age, indication for biopsy, or the number of tissue cores obtained at CNB. The presence of microcalcifications was confirmed histologically in all 11 CNBs performed for mammographic microcalcifications. Microcalcifications were present within areas of ADH (determinant calcifications) in 74 cases (67.3%), while unrelated calcifications were seen in 62 cases (56.4%). Both determinant and unrelated calcifications were present in 26 (23.6%) cases. Residual calcifications were seen on post-biopsy mammograms in 58 (52.7%) cases. The median time between CNB diagnosis of ADH and subsequent surgical excision was 35 days (range, 3-13 days). The subsequent surgical excision consisted of needlelocalized excisional biopsy in 117 cases (95.1%) and simple mastectomy in 6 cases (4.9%). Simple mastectomy was chosen by 5 women because of concurrent or previous contralateral breast cancer treated by mastectomy. One additional high-risk patient was already taking tamoxifen for a history of ADH in the contralateral breast and opted for bilateral mastectomy as treatment for the ADH newly diagnosed by CNB. Sentinel lymph node biopsy was performed in 9 cases (7.3%). Two patients had a needle-localized excisional ztable 1z Summary of Clinical Features in 123 Cases of Atypical Ductal Hyperplasia Feature Result Age (y) Median 56 Range 33-82 Menopausal status Premenopausal 47 (38.2) Postmenopausal 76 (61.8) Side of lesion Left 62 (5.4) Right 61 (49.6) Race/ethnicity White 1 (81.3) Hispanic 16 (13.) Black 5 (4.1) Asian 2 (1.6) Positive family history First-degree relative 21 (17.1) Other relative 23 (18.7) None 79 (64.2) HRT use by postmenopausal women Never 4 (53) Previously 11 (14) Current 25 (33) HRT, hormone replacement therapy. Data are given as number (percentage) unless otherwise indicated. biopsy for ADH resulting in a diagnosis of DCIS and went back for partial mastectomy and sentinel lymph node biopsy. The median number of lymph nodes excised was 2 (mean ± SEM, 2.73 ±.43); no metastatic disease was identified in any of these cases. A B C D zimage 1z A and B, Atypical ductal hyperplasia (ADH) diagnosed on core needle biopsy specimen showing proliferations with cribriform architecture composed of a monotonous population of neoplastic cells forming rigid bars and crisp spaces (H&E, 2). C, Micropapillary ADH showing nonattenuating fronds and detached cell clusters within an enlarged terminal duct lobular unit. Note that most spaces are only partially involved (H&E, 1). D, Open surgical biopsy shows extensive involvement of ducts and lobular units by micropapillary ductal carcinoma in situ (H&E, 5). Previous biopsy site. 114 Am J Clin Pathol 29;131:112-121 114 DOI: 1.139/AJCPGHEJ2R8UYFGP

Anatomic Pathology / Original Article Histologic evaluation of the surgically excised specimens demonstrated benign breast tissue without evidence of atypia in 57 cases (46.3%), residual ADH in 33 cases (26.8%), residual ADH and foci of ALH in 9 cases (7.3%), ALH in 2 cases (1.6%), and DCIS in 22 cases (17.9%) zimage 1Dz. No cases of invasive carcinoma were identified. The foci of residual ADH were focal and usually located adjacent to the previous biopsy site. The median size of DCIS lesions identified was.9 cm (mean ± SEM, 1.6 ±.18 cm; range,.3-3. cm). The DCIS was low grade in 18 cases and intermediate grade in 4 cases. Of the DCIS cases, 8 were cribriform, 13 cases were micropapillary, and 1 case was solid histologic type. Among cases with a final diagnosis of DCIS, the indication for CNB was mammographic calcifications in 2 cases and architectural distortion in 2 cases. The single case manifesting as a palpable mass represented a fibroadenoma with adjacent breast tissue involved by ADH. Residual calcifications after CNB were present in 17 (85%) of 2 DCIS cases with an indication of calcifications for CNB. The correlation between the extent and type of ADH lesions and other features of the CNB specimen with the results of the surgical biopsy specimens are summarized in ztable 2z, ztable 3z, and zfigure 1z. No statistically significant differences were found according to race or ethnicity, menopausal status, use of hormone replacement therapy, and family history of breast cancer. We found a significant positive correlation between the number of ADH foci and the number of cores involved by ADH (r =.658; P <.1; Spearman test) but not between the number of ADH foci and total number of cores obtained (r =.1477; P =.1687; Spearman test). The number of foci of ADH and the number of cores involved by ADH were significantly higher in cases with a follow-up excisional diagnosis of DCIS compared with cases with a benign or an ADH/ALH diagnosis by excisional biopsy (Figures 1A and 1B). In contrast, no difference was seen in the number of total cores obtained between groups according to diagnosis on excisional biopsy (Figure 1C). Among 82 cases of ADH limited to 1 or 2 foci in CNB specimens, 6 (7%) resulted in DCIS, 33 (4%) in residual ztable 2z Correlation of Clinicopathologic Features of ADH in Core Needle Biopsy Specimens With Diagnosis on Surgical Excision Benign (n = 58) ADH/ALH (n = 43) DCIS (n = 22) P Age (y).434 Median 52.5 57 55 Mean ± SEM 54.1 ± 1.3 59.1 ± 1.6 54.5 ± 1.6 ADH type.6 Cribriform 44 (76) 29 (67) 6 (27) Micropapillary 9 (16) 12 (28) 14 (64) Solid 5 (9) 2 (5) 2 (9) ADH size (mm).61 Median 1 1 2 Mean ± SEM 1.5 ±.2 1.4 ±.1 2.2 ±.2 No. of ADH foci <.1 Median 1 1 4 Mean ± SEM 1.7 ±.1 1.7 ±.2 4.5 ±.6 No. of cores obtained.1911 Median 1 8 1 Mean ± SEM 1.1 ±.6 9.2 ±.7 1.9 ±.8 No. of cores involved by ADH <.1 Median 1 1 3.5 Mean ± SEM 1.6 ±.1 2. ±.2 4.3 ±.6 Determinant calcifications.86 Present 35/52 (67) 24/38 (63) 15/2 (75) Absent 17/52 (33) 14/38 (37) 5/2 (25) Unrelated calcifications.4 Present 24/52 (46) 31/38 (82) 7/2 (35) Absent 28/52 (54) 7/38 (18) 13/2 (65) Residual determinant calcifications <.1 Present 8/35 (23) 18/24 (75) 14/15 (93) Absent 27/35 (77) 6/24 (25) 1/15 (7) Residual unrelated calcifications.4 Present 9/24 (38) 25/31 (81) 5/7 (71) Absent 15/24 (63) 6/31 (19) 2/7 (29) ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ. Data are given as number (percentage) or number/total (percentage) unless otherwise indicated. Kruskal-Wallis test. χ 2 test. Am J Clin Pathol 29;131:112-121 115 115 DOI: 1.139/AJCPGHEJ2R8UYFGP 115

Wagoner et al / ADH in Breast Co r e Needle Bi o p s y Specimens ADH and/or ALH, and 43 (52%) in benign histologic features without atypia ztable 4z (Figure 1D). Among ADH confined to 3 foci (n = 23) in CNB specimens, 3 (13%) resulted in a final diagnosis of DCIS; ADH and/or ALH and benign findings were found in 6 cases (26%) and 14 cases (61%), respectively. In contrast, in 18 cases of ADH affecting 4 or more foci in CNB specimens, 13 (72%), 4 (22%), and 1 (6%) resulted in DCIS, ADH and/or ALH, and benign findings without atypia, respectively. The sensitivity and specificity of ADH involving 3 or more foci and 4 or more foci to predict the presence of a worse lesion (DCIS) were.73 and.75 and.59 and.95, respectively. When the number of cores involved by ADH was considered, we obtained similar results (Table 4). The sensitivity and specificity of ADH involving 3 or more cores and 4 or more cores to predict the presence of a worse lesion (DCIS) were.77 and.77 and.5 and.92, respectively. When the predominant histologic pattern of ADH seen in CNB specimens was correlated with the corresponding findings on subsequent surgical excision, a significant association between micropapillary ADH and subsequent DCIS was found (Table 4 and Figure 1E). The number of ADH foci was significantly higher in cases showing a micropapillary pattern (median, 2.; mean ± SEM, 3. ±.4) compared with the cribriform type (median, 1; mean ± SEM, 1.8 ±.1). Micropapillary ADH involved at least 3 foci in 17 (49%) of 35 cases, whereas cribriform ADH was present in more than 2 foci in only 2 (25%) of 79 cases (P =.18; Fisher exact test). The type of DCIS on surgical excision was micropapillary ADH in 13 of 14 cases after a diagnosis of micropapillary ADH by CNB. Among CNB cases with an indication of mammographic calcifications, determinant calcifications were present in 19 (66%) of 29 micropapillary, 52 (71%) of 73 cribriform, and 3 (38%) of 8 solid pattern ADH lesions. Neither determinant nor unrelated calcifications in the CNB specimen were useful for predicting the presence of a more significant lesion at the time of surgical excision. In contrast, the presence of residual mammographic calcifications after CNB in cases associated with determinant calcifications was significantly ztable 3z Correlation of Clinicopathologic Features of ADH in Core Needle Biopsy Specimens With the Presence of Carcinoma on Surgical Excision No DCIS (n = 11) DCIS (n = 22) P Age (y).786 Median 54 55 Mean ± SEM 55.9 ± 1.1 54.5 ± 1.6 ADH type.2 Cribriform 73 (72.3) 6 (27) Micropapillary 21 (2.8) 14 (64) Solid 7 (6.9) 2 (9) ADH size (mm).15 Median 1 2 Mean ± SEM 1.5 ±.1 2.2 ±.2 No. of ADH foci <.1 Median 1 4 Mean ± SEM 1.7 ±.1 4.5 ±.6 No. of cores obtained.1486 Median 9. 1 Mean ± SEM 9.7 ±.5 1.9 ±.8 No. of cores involved by ADH <.1 Median 1 3.5 Mean ± SEM 1.7 ±.1 4.3 ±.6 Determinant calcifications.599 Present 59/9 (66) 15/2 (75) Absent 31/9 (34) 5/2 (25) Unrelated calcifications.458 Present 55/9 (61) 7/2 (35) Absent 35/9 (39) 13/2 (65) Residual determinant calcifications.9 Present 26/59 (44) 14/15 (93) Absent 33/59 (56) 1/15 (7) Residual unrelated calcifications 1. Present 34/55 (62) 5/7 (71) Absent 21/55 (38) 2/7 (29) ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ. Data are given as number (percentage) or number/total (percentage) unless otherwise indicated. Mann-Whitney test. Fisher exact test. 116 Am J Clin Pathol 29;131:112-121 116 DOI: 1.139/AJCPGHEJ2R8UYFGP

Anatomic Pathology / Original Article associated with the diagnosis of a more significant lesion on surgical excision (Tables 2 and 3 and Figure 1F). The sensitivity and specificity of the presence of residual determinant calcifications after CNB to predict the presence of a more significant lesion (DCIS) at surgical excision were.93 and.56, respectively. ADH lesions with determinant calcifications involving at least 3 foci and residual microcalcifications seen after CNB resulted in a diagnosis of DCIS on surgical excision in 9 (5%) of 18 cases, in contrast with of 25 cases of ADH lesions with determinant calcifications involving 1 or 2 foci and no residual calcifications after CNB (P <.1; Fisher exact test). The sensitivity and specificity of ADH confined to 1 or 2 foci associated with determinant calcifications and no residual calcifications present after CNB (low-risk group) to predict a benign result on excision among all cases with an indication of mammographic calcification for CNB were.28 and 1., respectively. The sensitivity and specificity of this low-risk group compared with ADH cases involving more than 2 foci associated with determinant calcifications and residual calcifications seen after CNB (high-risk group) to predict a more significant lesion were.74 and 1., respectively. No. of ADH Foci on CNB No. of Cases A B C 1 5 DCIS ADH/ALH Benign Final Diagnosis No. of Cores With ADH 12 1 8 6 4 2 DCIS ADH/ALH Benign Final Diagnosis D E F 15 DCIS No DCIS 1 5 >2 2 >3 3 No. of Foci of ADH on CNB No. of Cases No. of Cores 8 DCIS ADH/ALH 6 Benign 4 2 Cribriform Micropapillary Solid Type of ADH on CNB 3 2 1 No. of Cases 6 4 2 DCIS ADH/ALH Benign Present Final Diagnosis DCIS No DCIS NS Absent Present Absent Residual Calcifications After CNB Determinant Unrelated zfigure 1z A and B, The extent of atypical ductal hyperplasia (ADH) determined as the number of ADH foci (A) or the number of cores involved (B) in the core needle biopsy (CNB) specimen correlates highly significantly with the presence of ductal carcinoma in situ (DCIS) at the time of surgical excision. C, The number of total tissue cores obtained showed no correlation with the presence of a more advanced lesion at excision. D, The presence of ADH in >2 or >3 foci in the CNB specimen predicts the presence of DCIS on surgical excision. E, Evaluation of the predominant histologic subtype of ADH in the CNB specimen indicates that the micropapillary subtype of ADH significantly predicts the presence of DCIS on excision, which represents micropapillary DCIS in most cases (P =.6). F, The presence of residual mammographic calcifications after CNB in cases associated with determinant calcifications in ADH foci in CNB specimens is significantly associated with the presence of a more advanced lesion on excision. In contrast, the presence of residual microcalcifications in cases with only unrelated calcifications in the CNB specimens cannot predict the presence of a more advanced lesion on excision. P <.1. ALH, atypical lobular hyperplasia; NS, not significant (A-C, Kruskal-Wallis test; D-F, χ 2 test). Am J Clin Pathol 29;131:112-121 117 117 DOI: 1.139/AJCPGHEJ2R8UYFGP 117

Wagoner et al / ADH in Breast Co r e Needle Bi o p s y Specimens ztable 4z Correlation of the Extent and Histologic Type of ADH in Core Needle Biopsy Specimens With Diagnosis on Surgical Excision Discussion ADH/ DCIS ALH Benign P No. of ADH foci <.1 1-2 6 33 43 3 3 6 14 4 13 4 1 No. of cores involved by ADH <.1 1-2 5 3 48 3 6 7 8 4 11 6 2 Histologic type of ADH.6 Cribriform 6 29 44 Micropapillary 14 12 9 Solid 2 2 5 ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; DCIS, ductal carcinoma in situ. χ 2 test. Image-guided CNB, initially described by Parker et al, 21 has revolutionized the diagnosis and treatment of radiographically detected suspicious breast lesions. CNB has become a widely used alternative to open surgical biopsy in patients with radiographically suspicious, nonpalpable breast lesions and has reduced the number of surgical biopsies performed for benign lesions. The accuracy of CNB in the diagnosis of benign and malignant disease is well established, with histologic agreement to excision in more than 95% of cases. 1,3,4 Despite these advantages, CNB seems to be less reliable with the diagnosis of ADH because in situ or invasive carcinoma is found in a variable but significant number of cases on surgical excision. 1,5-11,18,22-25 To avoid false-negative results, it is currently recommended that patients with a CNB diagnosis of ADH undergo surgical excision. 16,17 Several studies have examined various mammographic, clinical, and pathologic factors that may predict the presence of a more significant lesion on surgical excision after a CNB diagnosis of ADH. 5,22,26 It is believed that the variability of cancer rates depends on the size and features of the mammographic lesion, the size of the biopsy needle, the extent and completeness of sampling of the mammographic target lesion, histologic criteria used to diagnose ADH vs DCIS and/ or usual hyperplasia, and the threshold for surgical excision. The highest percentage of malignancies was mostly found in earlier studies using 14-gauge automatic biopsy devices, studies with lower numbers of cores obtained, and studies with small numbers of cases. Although there is no universal agreement about the number of cores necessary to achieve an accurate histologic diagnosis, previous studies have demonstrated that underestimation of malignancy decreases as the average number of cores obtained per lesion increases. 2,27 Jackman et al 23,24 found that the underestimation at CNB diminished as the mean number of cores per lesion increased from 6.3 to 9.5 and later demonstrated a further reduction in the underestimation rate when more than 1 cores were acquired per lesion. Zografos et al 27,28 found no underestimation of malignancy in 25 cases using an extended CNB protocol with removal of 96 cores per lesion. Others, while acknowledging that a certain number of tissue cores is needed for accurate lesion categorization, found that the underestimation rate is not related to the number of cores obtained, suggesting that numbers might not accurately reflect how thoroughly the lesion is sampled by CNB. 6,29-31 We also found no correlation between the number of tissue cores removed and final diagnosis on surgical excision. It was suggested that this lack of correlation may be related to the size of the mammographic or pathologic lesion biopsied, 31 a variable not addressed in the present study. Jackman et al 24 also recognized that as the maximum diameter of the mammographic lesion increased, so did the rate of ADH underestimation. In contrast with earlier studies using 14-gauge needles, more recent data from series using a vacuum-assisted device with 11-gauge needles have shown a lower rate of underdiagnosis of carcinoma among patients with a diagnosis of ADH determined by CNB, presumably resulting from more extensive tissue sampling and the greater likelihood of complete removal of the target lesions. 3,32,33 The literature indicates that with the use of vacuum assistance and more extensive sampling, the underestimation of carcinoma on surgical biopsy after a diagnosis of ADH on CNB has improved from 33% to 48% 2,25 to 7% to 35%. 8,29,32,34,35 The 17.9% underestimation rate found in our study using an 11-gauge needle in the vast majority of the cases is consistent with the literature. However, it must be emphasized that, as also shown by the present study, even with the use of vacuum assistance with an 11-gauge needle and complete removal of the mammographic lesion, there is still a finite underestimation rate for the diagnosis of ADH. Recently, several investigators attempted to use histologic features to identify a subset of lesions diagnosed as ADH by CNB with lower risk of being associated with a more significant lesion, 7,9,36 with the goal to identify patients who can be safely followed up without surgical excision. Diagnostic criteria for ADH are defined in terms of low-grade DCIS and usual hyperplasia without atypia and are based on cytologic features and histologic patterns of growth. 12,13 In 199, Tavassoli and Norris 14 suggested the addition of an overall size criterion to help resolve difficult cases. Although interobserver reproducibility is known to be a problem in the diagnosis of proliferative breast lesions, 37,38 Schnitt et al 39 have shown that when standardized, strict criteria are used, interobserver variability is markedly reduced. Histopathologic 118 Am J Clin Pathol 29;131:112-121 118 DOI: 1.139/AJCPGHEJ2R8UYFGP

Anatomic Pathology / Original Article criteria for the diagnosis of ADH by CNB are exactly the same, although the limited sampling provided by CNB may make the evaluation of the extent of the lesion more difficult. In addition, because ADH is often present at the periphery of low-grade DCIS, 15 sampling of the lesion is critical for proper interpretation of CNB specimens. Therefore, it is not surprising that the distinction between ADH and low-grade DCIS may be difficult if not impossible for CNB specimens, despite strict adherence to established criteria. The study by Ely et al 7 provided the first evidence that histologic variables of extent and pattern can be applied to adequately sampled CNB specimens of ADH to help predict excisional outcomes. These authors found that all patients in whom ADH was limited to 1 or 2 foci had no worse lesion on open biopsy. In contrast, when ADH involved 4 or more foci, there was a high probability of an underlying, more advanced lesion on excision, with DCIS or invasive carcinoma seen in 86.6% of the cases. Outcomes for the ADH lesions restricted to 3 foci (n = 8) were less predictable with equal numbers containing ADH/ALH (n = 4) on open biopsy as DCIS (n = 3) and invasive carcinoma (n = 1). These findings suggest that ADH confined to 1 or 2 foci in adequately sampled CNB specimens is predictive of a good outcome and that a greater number of foci of involvement strongly correlates with concomitant malignancy. Sneige et al 8 studied 42 patients diagnosed with ADH by CNB and evaluated mammographic and histopathologic factors for predicting the underestimation of carcinoma. By using vacuum-assisted biopsy with 11-gauge needles, these authors had an underestimation rate of only 7%, among the lowest reported. These authors also found that the extent of ADH in CNB specimens correlated with the findings of excisional biopsy. If ADH involved 3 or more lobules or ducts, a higher risk lesion was identified at the time of excision. The authors suggested that excision may not be necessary following vacuum-assisted 11-gauge needle biopsy diagnosis of ADH when the lesion is confined to fewer than 3 lobular units, provided that most of the mammographic microcalcifications have been removed. Our results, obtained in one of the largest series of patients studied, are in agreement with the findings of Ely et al 7 and Sneige et al. 8 We found that ADH involving 3 or more foci in CNB is a strong predictor of a more significant lesion on excision, with DCIS diagnosed in 16 (39%) of 41 such cases, in contrast with 6 (7%) of 82 cases with ADH confined to 1 or 2 foci. In contrast, Doren et al 4 found no correlation between the number of ADH foci and risk of carcinoma on excision in their series of 51 cases. Bonnett et al 11 analyzed the extent of ADH in CNB specimens, but reported cases of ADH admixed with ALH and other types of borderline lesions (papillary lesions, columnar cell lesions), making it difficult to draw conclusions from their study. Renshaw et al 9 studied 95 patients with a CNB diagnosis of ADH and found no correlation between the risk of carcinoma and the size of the ADH lesion in the CNB specimen. Although these results seem to differ from the former studies, these authors did not examine the number of ADH foci in the biopsy specimens. Yeh et al 19 also reviewed histologic features of ADH in CNB specimens that predicted DCIS or invasive carcinoma on surgical excision in 33 cases and found that cytologic atypia and individual cell necrosis predicted carcinoma. Similarly, Adrales et al 32 identified marked atypia as a predictor of carcinoma after a CNB diagnosis of ADH. Unfortunately, the histologic criteria for marked atypia were not defined in their report, and no representative images were provided, making it difficult to draw conclusions from their study because marked atypia is not usually considered consistent with a diagnosis of ADH. O Hea and Tornos 36 and Doren et al 4 also found that severe atypia in CNB specimens predicted cancer on excision; however, they also included cases with less severe atypia (not fulfilling diagnostic criteria for ADH) in their series, making interpretation difficult. The study by Ely et al 7 suggested that the histologic pattern of ADH may also provide clues to the likelihood of underestimation of carcinoma. These authors found a strong association between micropapillary ADH and subsequent DCIS. In their series, all cases of micropapillary ADH resulted in micropapillary DCIS at open biopsy and all lesions involved at least 4 foci. They pointed out that this tendency for more diffuse disease in the breast is similar to that described for micropapillary DCIS, 15,41,42 which is more likely than other patterns to affect multiple quadrants of the breast. Although the small number of cases limited their data, it seemed that the finding of micropapillary ADH is indicative of extensive disease and should prompt surgical excision, regardless of extent in the CNB specimen. In contrast, Doren et al 4 found no association between increased risk of carcinoma on excision and a micropapillary pattern of ADH. We found a strong association between micropapillary ADH and subsequent cancer on excision with 14 (4%) of 35 such cases resulting in a diagnosis of DCIS. In addition, we also found that micropapillary ADH tends to involve more foci in CNB specimens compared with cribriform patterns. Our current findings are, thus, in agreement with those of Ely et al 7 and suggest that the micropapillary pattern of ADH can predict the presence of DCIS on subsequent excision. Besides the extent and histologic pattern of ADH, the extent to which the mammographic lesion has been removed was also suggested to be related to the likelihood of underdiagnosis of malignancy. Although clustered microcalcifications are thought to be the most common mammographic findings associated with ADH, 22,25,33,43 no specific patterns were identified that would indicate a higher risk of coexisting carcinoma. Am J Clin Pathol 29;131:112-121 119 119 DOI: 1.139/AJCPGHEJ2R8UYFGP 119

Wagoner et al / ADH in Breast Co r e Needle Bi o p s y Specimens Several authors have observed that among cases manifesting as microcalcifications, underestimation of carcinoma is more often encountered when the mammographic lesion is not completely removed. 9,29,33 Furthermore, several studies suggested that complete removal of calcifications at the time of CNB ensures that the excisional biopsy will not contain a clinically more significant lesion. 8,9,29,33 In the study by Bonnett et al, 11 residual calcifications were present in all cases showing carcinoma at open excision. However, residual calcifications had low specificity because they were present in 71% of cases having negative surgical excisions. Other studies, in contrast, suggested that even complete removal of the imaging target does not substantially reduce ADH underestimates. 18,44 Jackman et al 5 reported that after total removal of the mammographic target with vacuumassisted CNB, there was still an 8% underestimation of malignancy from lesions that were considered ADH in the CNB specimen. However, these studies did not distinguish between microcalcifications associated with the ADH lesions (determinant calcifications) and those present only in benign tissue. This distinction is important because our results indicate that although removal of all calcifications at the time of CNB does not ensure complete removal of the pathologic lesion, the presence of residual calcifications in cases associated with determinant calcifications is a strong predictor of a worse lesion on excision. In fact, the sensitivity of the presence of residual determinant calcifications to predict DCIS was.93 in our series. It is important to note that all 6 of our patients with ADH confined to 1 or 2 foci in CNB specimens and diagnosed with DCIS on excision had determinant calcifications, and residual mammographic microcalcifications were present after CNB. By combining the extent of ADH in CNB specimens, the presence of determinant calcifications within the lesion, and completeness of removal of the mammographic abnormality, we were able to identify a subgroup of patients patients with ADH associated with determinant calcifications restricted to 1 or 2 foci and no residual mammographic calcifications after CNB who seem to be at low risk of having a more significant lesion. In fact, none of 25 low-risk patients had carcinoma at excision in this study. Although these findings need to be confirmed in independent cohorts of patients by other investigators, to further investigate the significance of limited ADH in CNB specimens, we are planning a prospective randomized clinical trial in our institution for patients with low-risk disease with excisional biopsy vs no further surgery, while continuing to offer all patients with ADH found on CNB chemoprevention and high-risk surveillance. Conclusions Our study in a series of 123 cases of ADH diagnosed by CNB indicates that determination of the extent and micropapillary histologic type of ADH can be applied to predict the presence of carcinoma found by surgical excision. Including the number of ADH foci, histologic type, and presence or absence of determinant and/or unrelated calcifications in the pathology report may help in clinical decision making about surgical excision. 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