MRI to Predict Nipple Involvement in Breast Cancer Patients

Women s Imaging Original Research Piato et al. MRI of Breast Cancer Patients Women s Imaging Original Research José Roberto Morales Piato 1 Roberta Dantas Jales Alves de Andrade 1 Luciano Fernandes Chala 2 Nestor de Barros 2 Max Senna Mano 3 Alexandre Santos Melitto 1 Rodrigo Goncalves 1 José Maria Soares Junior 1 Edmund Chada Baracat 1 José Roberto Filassi 1 Piato JRM, Jales Alves de Andrade, RD, Chala LF, et al. Keywords: breast cancer, MRI, nile involvement rediction DOI:10.2214/AJR.15.15187 Received June 6, 2015; acceted after revision December 31, 2015. Based on a resentation at the 2014 Jornada Paulista de Mastologia, São Paulo, Brazil. 1 Deartment of Gynecology and Obstetrics, Universidade de São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, 10 Andar Cerqueira César, Sao Paulo 05403900, Brazil. Address corresondence to R. D. Jales Alves de Andrade (robertajales@gmail.com). 2 Deartment of Radiology, Universidade de São Paulo, São Paulo, Brazil. 3 Division of Medical Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil. AJR 2016; 206:1124 1130 0361 803X/16/2065 1124 American Roentgen Ray Society MRI to Predict Nile in Breast Cancer Patients OBJECTIVE. The selection of breast cancer atients as candidates for nile-saring mastectomy (NSM) is deendent on the reoerative detection of neolastic involvement of the nile-areola comlex (NAC). This cross-sectional study was designed to evaluate the accuracy of reoerative breast MRI as a noninvasive method to redict neolastic involvement of the nile. MATERIALS AND METHODS. We included 165 female breast cancer atients with a surgical lan that included total mastectomy or breast conservation surgery with the removal of the NAC. All atients underwent MRI before surgery on a 1.5-T unit with a 4-channel in vivo dedicated surface breast coil. One radiologist who was blinded to the results of the histologic evaluations of the secimens evaluated the MRI studies. RESULTS. Of the 170 mastectomy secimens evaluated, 37 (21.8%) had neolastic involvement of the NAC. The MRI findings of enhancement between the index lesion and the NAC and of nile retraction were considered statistically significant redictors of nile involvement in breast cancer atients ( < 0.01 and = 0.01, resectively). The negative redictive value of the combination of these MRI findings was 83.3%. CONCLUSION. Breast MRI is a safe noninvasive method to reoeratively evaluate breast cancer atients eligible for NSM with a high secificity and a high negative redictive value when enhancement between the index lesion and the nile and nile retraction are analyzed. N ile-saring mastectomy (NSM) as a treatment otion for selected cases of breast cancer is of great interest to breast surgeons. The reservation of the nile-areola comlex (NAC) can lead to favorable sychologic effects in breast cancer atients treated with this tye of rocedure. To evaluate the oncologic safety of, aesthetic results of, comlication rates of, and atients satisfaction indexes related to NSM, several studies with significant samle sizes were conducted in the ast decade [1 6]. Regarding oncologic safety, the main concern when considering NSM is the ossibility of occult carcinoma foci in the NAC. This concern is due to the fact that the rates of nile involvement are significant even in atients with early stage disease [7 10]. The incidence of occult neolastic involvement of the nile ranges from 9% to 50% [11 19]. The most commonly used method to assess neolastic involvement of the nile is the subareolar frozen-section examination, but the falsenegative rates of this method are reorted to be between 1.3% and 9.3% [1, 20 22] and the adotion of this technique is limited because of the comlexity of the method involved. The crucial question for surgeons who select breast cancer atients to undergo NSM is whether there is a reoerative method to safely redict neolastic involvement of the NAC [7]. For that reason, we designed a cross-sectional study to evaluate the accuracy of reoerative breast MRI as a noninvasive method to redict neolastic involvement of the NAC. Materials and Methods Patients We included female breast cancer atients with a surgical lan that included total mastectomy or breast conservation surgery with the removal of the NAC. The inclusion criteria were ductal carcinoma in situ (DCIS) and stage I, II, or IIIA breast cancer. The exclusion criteria were clinical evidence of neolastic involvement of the NAC, stage IV breast cancer, revious incisional biosy of the breast, and contraindication for breast MRI. The institutional review board aroved this cross-sectional study rotocol, and all study subjects signed informed consent forms. 1124 AJR:206, May 2016

MRI of Breast Cancer Patients Breast MRI Every atient underwent MRI before surgery. The MRI examinations were erformed using a 1.5-T unit (Signa, GE Healthcare) with a 4-channel in vivo dedicated surface breast coil. The standard imaging rotocol included a localizing sequence followed by axial T2-weighted images with fat saturation. Fat-suressed T1-weighted images were obtained before and after IV administration of aramagnetic contrast material. Dynamic axial contrast-enhanced sequences were obtained 0, 2, 4, 6, and 8 minutes after contrast administration to evaluate the dynamic criteria of enhancement. A dose of 0.1 nmol er kilogram of body weight of contrast material (gadoentetate dimeglumine [Magnevist, Bayer HealthCare]) was infused via an IV catheter and was followed by IV infusion of 10 ml of saline solution. Pathologic Examination of the Nile The retroareolar area and nile, reviously embedded in araffin, were evaluated in histologic sections of 4 μm. After H and E staining, the sections were evaluated with regular otical microscoy. Breast MR Image Interretation The reoerative breast MR images were evaluated by one radiologist who was blinded to the results of the histoathologic evaluation of the mastectomy secimens. The reviewer evaluated the following MRI arameters: tye of enhancement of the index lesion (mass or nonmass), size of the index lesion, resence of enhancement between the index lesion and the nile, distance between the index lesion and the nile, enhancement of the nile, thickening of the areola, nile retraction, and enhancement of the nile in comarison with the contralateral nile. Fig. 1 63-year-old woman with breast cancer and neolastic involvement of nile. MR image shows enhancement between index lesion and nile. Statistical Analysis Under the assumtions of 90% sensitivity of MRI, tye I error of 5%, 95% statistical ower and allowing for a loss to follow-u of 10% of subjects, we calculated a samle size of 138 atients. We erformed a descritive analysis of the MRI arameters. To estimate the association between neolastic involvement of the NAC (outcome) and the MRI arameters, we calculated odds ratios (ORs) and resective 95% CIs and values using chi-square tests. We then constructed a logistic regression model to verify which MRI arameters remained associated with neolastic involvement of the NAC after adjusting for all variables that had a < 0.2 in the first ste of the analysis. Indeendent variables that remained associated with the outcome after adjusting for all the included variables were ket in our model. The results of our logistic regression model are resented as adjusted ORs and as robabilities of the occurrence of the outcome. TABLE 1: Clinical and Pathologic Characteristics of the Study Cohort Characteristic Mastectomy Secimens No. % Clinical stage (n = 170) 0 19 11.2 I 39 22.9 II 75 44.1 III 35 20.6 IV 2 1.2 Tumor size (cm) (n = 170) 2 65 38.2 > 2 105 61.8 Nile retraction (n = 170) No 152 89.4 Yes 18 10.6 Multicentricity (n = 170) No 140 82.4 Yes 30 17.6 Histologic grade (n = 169) 1 28 16.6 2 92 54.4 3 49 29.0 Lymhovascular invasion (n = 170) No 114 67.1 Yes 56 32.9 Intraductal comonent (n = 170) Absent 30 17.6 Present 140 82.4 Lymh node status (n = 170) Negative 90 52.9 Positive 80 47.1 Estrogen recetor (n = 170) Negative 35 20.6 Positive 133 78.2 Not available 2 1.2 (Table 1 continues on next age) Fig. 2 66-year-old woman with breast cancer involving ailla. MR image shows nile retraction. AJR:206, May 2016 1125

Piato et al. TABLE 1: Clinical and Pathologic Characteristics of the Study Cohort (continued) Characteristic Mastectomy Secimens No. % Progesterone recetor (n = 170) Negative 58 34.1 Positive 103 60.6 Inconclusive 4 2.4 Not available 5 2.9 ErbB-2 a (n = 170) Negative 128 75.3 Positive 35 20.6 Inconclusive 1 0.6 Not available 6 3.5 Pathologic involvement of NAC (n = 170) Negative 133 78.2 Positive 37 21.8 Diagnosis (n = 37) Low-grade DCIS 3 8.1 High-grade DCIS 19 51.4 Invasive carcinoma 13 35.1 Atyical lesion 2 5.4 Note NAC = nile-areola comlex, DCIS = ductal carcinoma in situ. a Also known as HER2/neu. We calculated the sensitivity, secificity, ositive redictive value, and negative redictive value of the model. We made the assumtion that 0.05 is statistically significant. The statistical analysis was erformed using statistics software (Stata, version 11.1, StataCor). Results One hundred seventy-two atients with stage 0 to IIIA breast cancer were enrolled from October 2012 to July 2014. Five atients had bilateral cancer, and seven atients were considered ineligible for the following reasons: One had a final athologic diagnosis of hyllodes tumor, two had undergone rior surgery for diagnosis, and four did not undergo MRI before surgery. A total of 170 mastectomy secimens were included in this analysis. The clinical and athologic characteristics of the study grou are summarized in Table 1. The mean age was 51 years (age range, 25 97 years). The majority of atients had stage I or II breast cancer (67%), and disease in two atients (1.2%) was considered metastatic after surgery and was classified as stage IV. More than 80% of the atients had an intraductal comonent at final athologic analysis, and 32.9% had lymhovascular invasion. Of the 170 mastectomy secimens evaluated, 37 (21.8%) had neolastic involvement of the NAC. The majority of those were affected by DCIS (59.5%), followed by invasive carcinoma (35.1%). Two secimens were involved by atyical lesions (5.4%). The results of the univariate analysis correlating clinicoathologic characteristics and neolastic involvement of the NAC are shown in Table 2. Eighteen atients had retraction of the NAC at hysical examination. However, only seven of these 18 atients (38.9%) had athologic NAC involvement (OR, 2.6; 95% CI, 0.78 8.01; = 0.06). Several MRI findings were analyzed and correlated with neolastic involvement of the NAC (Table 3). The tye of enhancement of the index lesion (mass or nonmass enhancement), resence of enhancement between the tumor and the NAC, distance between the index lesion and the NAC of 2 cm or less, enhancement of the NAC, and nile retraction had statistically significant correlations with neolastic involvement of the NAC. Nonmass enhancement was seen in 50 cases. In 20 of those 50 cases (40%), that feature was associated with malignant athology findings (OR, 4.00; 95% CI, 1.11 17.97; < 0.01). In the majority of these cases (16/20), nonmass enhancement was associated with DCIS in the athology secimen. In three cases, the athology evaluation showed neolastic involvement of the NAC by invasive carcinoma, and in the remaining case an atyical lesion was diagnosed. Enhancement between the index lesion and the nile was resent in 35 cases, and in 20 (57.1%) there was an association with malignant athology findings (OR, 9.25; 95% CI, 3.67 23.32; < 0.01). The distance between the index lesion and the nile was 2 cm or less in 63 cases, and 25 (39.7%) of those cases had neolastic involvement of the NAC. Enhancement of the nile was described in 17 cases, and in 11 (64.7%) there was an association with malignant athology findings (OR, 8.96; 95% CI, 2.70 31.72; < 0.01). Nile retraction was described in 35 cases, and in 16 (45.7%) there was an association with involvement of the NAC (OR, 4.57; 95% CI, 1.86 11.06; < 0.01). After multivariate analysis of the MRI features, only two radiologic findings remained statistically associated with neolastic involvement of the NAC (Table 4): enhancement between the index lesion and the nile (OR, 9.25; 95% CI, 3.67 23.32; < 0.01) (Fig. 1) and nile retraction (OR, 4.57; 95% CI, 1.86 11.06; = 0.01) (Fig. 2). We constructed a model correlating these two variables to redict the neolastic involvement of the NAC. When both characteristics were resent, the robability of neolastic involvement of the NAC was 67.5%. Otherwise, in the absence of these two variables, only 11.8% of the atients would be affected by neolastic involvement of the NAC. Discrimination of the model was estimated using the AUC under the ROC curve, which was 0.7569 (Fig. 3). The sensitivity of this model was 29.7% (95% CI, 15.9 47.0%), secificity was 97.7% (95% CI, 93.5 99.5%), ositive redictive value was 78.6% (95% CI, 49.2 95.3%), and negative redictive value was 83.3% (95% CI, 76.5 88.8%). TABLE 2: Association of Clinicoathologic Features and Nile-Areola Comlex (NAC) Characteristics No. (%) of Mastectomy Secimens Negative Findings Positive Findings Clinical stage (n = 170) 0.11 0 11 (8.3) 8 (21.6) 1 I 33 (24.8) 6 (16.2) 0.25 (0.06 1.05) II 61 (45.9) 14 (37.8) 0.32 (0.10 1.10) III and IV 28 (21.1) 9 (24.3) 0.44 (0.12 1.71) Tumor size (cm) (n = 170) 0.66 2 52 (39.1) 13 (35.1) 1 > 2 81 (60.9) 24 (64.9) 1.19 (0.52 2.77) (Table 2 continues on next age) 1126 AJR:206, May 2016

TABLE 2: Association of Clinicoathologic Features and Nile-Areola MRI of Breast Cancer Patients Comlex (NAC) (continued) Characteristics Nile retraction (n = 170) 0.06 No 122 (91.7) 30 (81.1) 1 Yes 11 (8.3) 7 (18.9) 2.6 (0.78 8.01) Multicentricity (n = 176) 0.80 No 109 (78.4) 31 (83.8) 1 Yes 30 (21.6) 6 (16.2) 0.88 (0.27 2.47) Total 139 (100) 37 (100) Histologic grade (n = 169) 0.35 1 23 (17.4) 5 (13.5) 1 2 68 (51.5) 24 (64.9) 1.6 (0.52 6.06) 3 41 (31.1) 8 (21.6) 0.9 (0.23 3.92) Total 132 (100) 37 (100) Lymhovascular invasion (n = 170) 0.87 No 89 (66.9) 25 (67.6) 1 Yes 44 (33.1) 12 (32.4) 0.9 (0.39 2.16) Intraductal comonent (n = 170) 0.03 Absent 28 (21.1) 2 (5.4) 1 Present 105 (78.9) 35 (94.6) 4.67 (1.07 42.17) Lymh node status (n = 170) 0.21 Negative 74 (55.6) 16 (43.2) 1 Positive 59 (44.4) 21 (56.8) 1.6 (0.72 3.58) Estrogen recetor (n = 168) 0.82 Negative 27 (20.5) 8 (22.2) 1 Positive 105 (79.5) 28 (77.8) 0.9 (0.35 2.55) Total 132 (100) 36 (100) Progesterone recetor (n = 173) 0.81 Negative 58 (42.0) 12 (34.3) 1 Positive 80 (58.0) 23 (65.7) 1.1 (0.47 2.67) Total 138 (100) 35 (100) ErbB-2 a (n = 163) 0.08 Negative 105 (81.4) 23 (67.6) 1 Positive 24 (18.6) 11 (32.4) 2.09 (0.8 5.2) Total 129 (100) 34 (100) Note OR = odds ratio. Also known as HER2/neu. Discussion The results of this study indicate that breast MRI is an excellent noninvasive method to reoeratively evaluate breast cancer atients otentially eligible for NSM. The No. (%) of Mastectomy Secimens Negative Findings Positive Findings resence of the two combined MRI findings enhancement between the index lesion and the nile and nile retraction as an MRI finding was associated with a secificity of 97.7%. We designed a cross-sectional study, different than the existing studies in the literature, in which breast MR images were evaluated by one radiologist blinded to the histoathologic results of the mastectomy secimens. Before starting our study, we determined the necessary samle size. We believe that the careful lanning of the study design confers to it a higher level of reliability. From a clinical oint of view, the evaluation of the accuracy of the association of multile MRI findings with the risk of neolastic involvement of the NAC rovides breast surgeons with a broader and more comlete reoerative evaluation of atients. Recently, the most commonly used method to redict neolastic involvement of the nile has been the subareolar frozen-section examination. Studies involving exressive cohorts showed that the subareolar frozen-section examination could yield false-negative rates between 1.3% and 9.3% [1, 20 22]. Even with the very favorable results shown with this technique, its use is limited because of the comlexity of the method involved. Using a different aroach, Govindarajulu et al. [23] assessed vacuum-assisted needle biosy (Mammotome, Devicor Medical Products) for the reoerative evaluation of the NAC in a small cohort of 33 atients and found 100% correlation between the mastectomy histoathology secimen and the Mammotome secimen. We tried to relicate that study in 2012 but stoed the trial because the high rate of adverse events, mainly ain, led to the withdrawal of consent from the recruited atients. For those reasons, we have been conducting studies to evaluate the accuracy of MRI to reoeratively redict neolastic involvement of the nile. In the ast years, the relevance of MRI has been roved in different fields of medicine, esecially breast surgery. However, there is a aucity of studies investigating the use of breast MRI to redict neolastic involvement of the NAC. Sakamoto et al. [24] reorted in a cohort of 81 breast cancer atients that enhancement of the nile in continuity with the index lesion on MRI was a statistically significant redictor of neolastic involvement of the NAC. They also found that diffuse enhancement of the breast, skin enhancement, enhancement of the ductal area, and rim enhancement are atterns that may suggest a higher risk of neolastic involvement of the nile. Moon et al. [25] evaluated the accuracy of breast MRI to redict neolastic involvement of the nile in 51 breast cancer atients. A statistically significant correlation was found AJR:206, May 2016 1127

Piato et al. TABLE 3: Correlation of MRI Findings and Nile-Areola Comlex (NAC) No. (%) of Mastectomy Secimens Characteristics Negative Findings for Pathologic NAC between neolastic involvement of the nile and NAC enhancement, eriareolar skin thickening, and nile inversion or retraction on the reoerative MRI study. In concordance with the findings reorted by Moon et al., our results also showed that enhancement between the index lesion and the nile was associated with neolastic involvement of the NAC. Furthermore, we also found that nonmass enhancement was more revalent in our cohort and was highly associated with DCIS (16/20 cases). The median tumor-to-nile distance was 0.96 cm for invasion-negative cases and 0.27 cm for invasion-ositive cases ( = 0.02). In the Moon et al. cohort, breast MRI showed a sensitivity of Positive Findings for Pathologic NAC Tye of enhancement (n = 170) < 0.01 No enhancement 24 (18.0) 4 (10.8) 1 Mass enhancement 79 (59.4) 13 (35.1) 0.99 (0.27 4.55) Nonmass enhancement 30 (22.6) 20 (54.1) 4.00 (1.11 17.97) Lesion size (n = 170) 0.44 No enhancement 24 (18.0) 4 (10.8) 1 2 cm 19 (14.3) 4 (10.8) 1.26 (0.21 7.71) > 2 cm 90 (67.7) 29 (78.4) 1.93 (0.59 8.27) Enhancement between lesion and NAC (n = 170) < 0.01 Absent 118 (88.7) 17 (45.9) 1 Present 15 (11.3) 20 (54.1) 9.25 (3.67 23.32) Distance between lesion and NAC (n = 145) < 0.01 2 cm 38 (33.9) 25 (75.8) 1 > 2 cm 74 (66.1) 8 (24.2) 0.16 (0.06 0.42) Total 112 (100) 33 (100) Enhancement of nile (n = 170) < 0.01 Absent 127 (95.5) 26 (70.3) 1 Present 6 (4.5) 11 (29.7) 8.96 (2.70 31.72) Thickening of areola (n = 175) 0.25 Absent 123 (89.1) 32 (86.5) 1 Present 15 (10.9) 5 (13.5) 1.92 (0.48 6.69) Total 138 (100) 37 (100) Nile retraction (n = 170) < 0.01 Absent 114 (85.7) 21 (56.8) 1 Present 19 (14.3) 16 (43.2) 4.57 (1.86 11.06) Enhancement of the nile in comarison with the contralateral 0.54 nile (n = 161) Equal 120 (96.8) 35 (94.6) 1 Different 4 (3.2) 2 (5.4) 1.70 (0.15 12.49) Total 124 (100) 37 (100) Note OR = odds ratio. 93.8% and secificity of 85.7% in detecting neolastic involvement of the NAC. The results of our study corroborate data ublished to date regarding enhancement between the index lesion and the nile (OR, 9.25; 95% CI, 3.67 23.32; < 0.01) and nile retraction (OR, 4.57; 95% CI, 1.86 11.06; = 0.01) as being MRI findings suggestive of neo- 1128 AJR:206, May 2016

MRI of Breast Cancer Patients TABLE 4: Multivariate Analysis of MRI Findings and Nile-Areola Comlex (NAC) MRI Findings lastic involvement of the NAC. The distance between the tumor and the NAC, however, was not statistically associated with neolastic involvement of the NAC in our cohort, contradicting the studies in the literature that indicate that the ideal distance between the tumor and the NAC is 2 cm [19, 26, 27]. We hyothesize that considering distance between the lesion and the NAC as a categoric variable revented us from reaching a conclusion regarding the ideal distance. That decision, however, was made to rovide the necessary samle size and statistical ower to test our hyothesis. Our data showed that the most imortant MRI characteristics to exclude the ossibility of neolastic involvement of the NAC in breast cancer atients were the absence of enhancement between the index lesion and the nile associated with the absence of retraction of the nile. The negative redictive value of the combination of the absence of these two characteristics was 83.3% (95% CI, 76.5 88.8%). The wide CIs yielded by our statistical analysis are the main weakness of our study. These results could suggest heterogeneity of Gross OR a Adjusted OR b Enhancement between lesion and NAC < 0.01 Absent 1 1 Present 9.25 (3.67 23.32) 7.69 (3.23 18.35) Nile retraction 0.01 Absent 1 1 Present 4.57 (1.86 11.06) 3.33 (1.35 8.21) Note OR = odds ratio. Univariate analysis. Multivariate analysis. Sensitivity 1.00 0.75 0.50 0.25 0 AUC under ROC curve = 0.7569 0 0.25 0.50 0.75 1.00 1 Secificity our samle or a small, yet sufficient, number of atients with neolastic involvement of the NAC to assess the association of all breast MRI variables studied. With that in mind, we acknowledge that studies with larger samle sizes might be necessary to relicate our results with narrower CIs. 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