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Value of Hand-held Ultrasound in the Differential Diagnosis and Accurate Breast Imaging Reporting and Data System Subclassification of Complex Cystic and Solid Breast Lesions
ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 18, 2020 Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter
https://doi.org/10.1016/j.ultrasmedbio.2020.01.006
Original Contribution VALUE OF HAND-HELD ULTRASOUND IN THE DIFFERENTIAL DIAGNOSIS AND ACCURATE BREAST IMAGING REPORTING AND DATA SYSTEM SUBCLASSIFICATION OF COMPLEX CYSTIC AND SOLID BREAST LESIONS AGEDPH T UILING
XIANG,* GUOXUE TANG,y,z YIN LI,x YING LIU,* LIXIAN LIU,* and XI LIN*TAGEDEN
* Department of Ultrasound, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China; y Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; z Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; and x Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China (Received 5 July 2019; revised 5 December 2019; in final from 8 January 2020)
Abstract—To explore the value of hand-held ultrasound (HHUS) for diagnosing complex cystic and solid breast lesions, 472 pathologically proven lesions were analyzed. The lesions were divided into four types based on ultrasound features. Positive predictive values (PPVs) for lesion types and risk factor performances were assessed. Furthermore, HHUS and mammography (MAM) performances were compared: 27 lesions missed in MAM were detected in HHUS. Ultrasound feature analysis revealed higher PPVs for type III and IV lesions than for type I and II lesions. In patients older than 51 y, a type III or IV lesion with a diameter greater than 18 mm, an irregular shape, a non-parallel orientation, an uncircumscribed margin, calcification, vascularity and abnormal axillary lymph nodes were suggestive of malignancy; the area under the curve reached 0.869. Thus, ultrasound is useful in diagnosing complex cystic and solid breast lesions, which should be categorized as Breast Imaging Reporting and Data System (BI-RADS) 4B or 4C. (E-mail: [email protected]) © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Complex cystic and solid breast lesions, Hand-held ultrasound, Mammography, BI-RADS, Differential diagnosis.
of 22%40% have been reported in previous studies (Berg et al. 2010; Hsu et al. 2011; Chen et al. 2014; Yao et al. 2017). As a result, these complex cystic and solid breast lesions are suggested to be classified as category 4, and a biopsy or excision is recommended for these lesions. A wide range of benign and malignant pathologic results has been detected, including fibrocystic changes, abscess, mastitis, fat necrosis, hematoma, fibroadenoma, galactocele, intraductal papilloma (IDP), phyllodes tumor, intraductal carcinoma in situ, invasive intraductal carcinoma (IDC), invasive lobular carcinoma (ILC), mucinous carcinoma and metaplastic carcinoma (Chang et al. 2007; Doshi et al. 2007; Kim et al. 2011; Choi and Shu 2012; Zhang et al. 2017). Therefore, a BI-RADS subclassification of category 4 is necessary. However, there is no definite criterion for the subclassification, which is subjective and depends on doctors’ individual experience. Additionally, there is
INTRODUCTION Cystic lesions, comprising simple, complicated and complex cystic lesions, are common in women aged 3050 y (Mendelson et al. 2001; Hines et al. 2010; Mendelson et al. 2013). A simple cyst is an oval or round lesion with anechogenicity, a circumscribed margin and posterior enhancement. A complicated cystic lesion fulfills all the criteria of a simple cyst, except that it contains debris with low echo levels. Both simple and complicated cysts are considered benign, and a follow-up for 6 mo or continued surveillance is recommended according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) (Mendelson et al. 2013). Complex cystic and solid breast lesions contain both cystic and solid components, and malignancy rates Address correspondence to: Xi Lin, Department of Ultrasound, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, PR China. E-mail: [email protected]
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little literature combining related risk factors together for the evaluation of the diagnostic efficacy of hand-held ultrasound (HHUS) for complex cystic and solid breast lesions. As a result, this retrospective study, based on a large number of cases and pathologic types, aimed to evaluate the diagnostic performance of HHUS for complex cystic and solid breast lesions and suggest a more accurate approach for BI-RADS subclassification in clinical practice. MATERIAL AND METHODS This retrospective analysis was approved by the institutional research ethics committee of Sun Yat-sen University Cancer Center in Guangzhou, China, and the informed consent requirement was waived. From January 2000 to December 2018, 453 patients with 472 complex cystic and solid breast lesions were included in this study. Clinicopathologic information and ultrasonographic and mammographic findings of these cases were obtained from the password-protected database of our hospital with permission. Ultrasound examinations were performed for all 472 lesions with a high-frequency (712 MHz) linear array transducer (GE Logiq 9, GE Logiq S8, GE Logiq 700 [GE Healthcare, Milwaukee, WI, USA], Philips iU 22 [Philips Healthcare, Bothell, WA,
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USA], or Siemens S2000 [Siemens Medical Solutions, Mountain View, CA, USA]) by 1 of 20 eligible radiologists with 330 y of experience in breast imaging. Ultrasound features of each lesion based on BI-RADS lexicon and axillary lymph node (ALN) status were recorded by two doctors in consensus who did not know the final pathologic results. ALN was considered to be suspicious with one or more of the following features: diffuse (>3 mm) or eccentric cortical thickening, oval shape, focal cortical bulge and loss of fatty hilum and nonhilar cortical blood flow on color Doppler imaging (Cools-Lartigue and Meterissian 2012; Ecanow et al. 2013). These lesions were divided into four types according to the ultrasound features: type I, with a thick wall and/or septations (>0.5 mm) (Fig. 1); type II, with one or multiple mural or papillary nodules (Fig. 2); type III, mixed cystic and solid lesion (cystic component, >50%) (Fig. 3); or type IV, predominantly solid lesion with cystic spaces (solid part, >50%) (Fig. 4), which has been mentioned in previous work (Doshi et al. 2007; Hsu et al. 2011). Pathologic results were standard reference. Craniocaudal and mediolateral oblique views for mammography (MAM) were obtained using a full-field digital MAM system (Senographe DS, GE Healthcare, Milwaukee, WI, USA). Another pathologist with 6 y of experience in MAM interpretation rechecked the
Fig. 1. Type I lesion: Intraductal papilloma (IDP) in the right breast of a 71-y-old woman. Ultrasound image shows a complex cystic and solid lesion with an irregular thick wall and septation (>0.5 mm) and distribution of vessels within the thick septation.
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results with a p value less than 0.05 (2-sided) were considered statistically significant in this study. RESULTS The mean age of the 453 patients involved in this retrospective study was 46.4 y (range 1585 y), and the average lesion diameter was 28.6 mm.
Fig. 2. Type II lesion: Fibrocystic change in the right breast of a 29-y-old woman. Ultrasound image shows a complex cystic and solid lesion with one papillary nodule and blood signals within the papillary nodule.
Fig. 3. Type III lesion: Invasive intraductal (IDC) grade II in the left breast of a 61-y-old woman. Ultrasound image shows a complex cystic and solid lesion with a cystic component of more than 50% and hypervascularity within the solid portion.
negative cases, made the final diagnosis and evaluated the reasons for missed diagnosis. STATISTICAL ANALYSIS MedCalc (version 11.2; 2011 MedCalc Software bvba, Mariakerke, Belgium) and SPSS software (SPSS, version 19.0, Chicago, IL, USA) were used for statistical analysis. X2 tests were applied in categorical variables. Associations between benign and malignant group features were reassessed by binary logistic regression. To explore the diagnostic value of the combined diagnostic method, a series of prediction rates obtained from the multivariate analysis was subject to receiver operating characteristic curve analysis. The area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and 95% confidence interval for each risk factor were calculated. Furthermore, the PPVs for all types were determined. All
Pathology and follow-up information Tumor histology and ultrasound classifications are shown in Table 1. There were 262 (55.5%, 262/472) benign and 210 (44.5%, 210/472) malignant lesions confirmed by core needle biopsy (CNB) (28.0%) or surgery (72.0%). The follow-up information for benign lesions evaluated with only CNB was recorded. Thirty-eight (28.8%, 38/132) lesions of 36 patients were reexamined at least one time with ultrasound, MAM or magnetic resonance imaging. Follow-up time varied as follows: less than 6 mo, seven patients; less than 1 y, three patients; less than 2 y, 15 patients; and more than 2 y, 11 patients with 13 lesions. No malignancy was found during the follow-up period. Ultrasonographic findings and feature analysis Based on ultrasonic features, 62 (13.1%, 62 of 472) lesions were classified as type I, 49 (10.4%, 49 of 472) as type II and 101 (21.4%, 101 of 472) and 260 (55.1%, 260 of 472) as type III and IV, respectively (Table 1). PPVs of type III and IV lesions were higher compared with those of type I and II (p < 0.001, I vs. II, p = 0.081; I vs. III, p = 0.001; I vs. IV, p = 0.015; II vs. III or IV, p < 0.001). Patients’ age and the ultrasonic features of lesions and ALN status are listed in Table 2. Univariate analysis suggested that posterior features were not associated with malignancy. Age older than 51 y, a type III or IV lesion, diameter of more than 18 mm, the presence of an irregular shape, absence of parallel orientation, uncircumscribed margin, calcification, vascularity in the tumor as well as abnormal ALN were identified to be independent factors for malignancy in a multivariate analysis. Lesion type and size showed the highest sensitivity of 87.1% and NPV of 82.2%, respectively. Abnormal ALN had the highest specificity of 93.9% and PPV of 83.2% (Table 3). Performance and AUC of each risk factor and the combined approach are shown in Figure 5. Lesion detection and feature analysis of MAM A total of 262 patients with 271 lesions detected on ultrasound also underwent MAM examinations, with a detection rate of 90.0%. Mammographic findings suggested 68 benign and 72 malignant lesions presenting as masses, 16 benign and six malignant lesions as calcifications, 17 benign and 57 malignant lesions presenting as
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Fig. 4. Type IV lesion: Encapsulated papillary carcinoma in the right breast of a 54-y-old woman. Ultrasound presents a complex cystic and solid lesion with a solid part more than 50% and internal vascularity. Table 1. Pathologic distribution of the complex cystic and solid breast lesions involved Finding Benign Fibrocystic change IDP Mastitis Fibroadenoma IDP +ADH Benign phyllodes tumor UDH Boundary phyllodes tumor Abscess ADH Galactocele Lactating adenoma Fat necrosis Total Malignant IDC DCIS Mucinous CA Metaplastic CA Encapsulated papillary CA Malignant phyllodes tumor Solid papillary CA Intraductal papillary CA ILC Fibrosarcoma CA with apocrine differentiation Invasive cribriform CA Neuroendocrine CA Lymphoma Total
Type I
Type II
Type III
Type IV
Total
24 5 10 2 0 0 0 0 2 0 0 0 0 43
7 25 2 2 2 0 2 0 0 0 0 0 1 41
21 8 11 0 0 2 0 0 0 0 0 0 0 42
40 34 9 28 7 5 4 4 2 1 1 1 0 136
92 72 32 32 9 7 6 4 4 1 1 1 1 262
16 1 0 1 0 1 0 0 0 0 0 0 0 0 19
3 1 1 1 2 0 0 0 0 0 0 0 0 0 8
41 7 1 1 4 0 1 2 0 1 1 0 0 0 59
76 15 8 7 3 5 3 1 3 0 0 1 1 1 124
136 24 10 10 9 6 4 3 3 1 1 1 1 1 210
IDP = intraductal papilloma; ADH = atypical ductal hyperplasia; UDH = usual ductal hyperplasia; CA = carcinoma; IDC = invasive ductal carcinoma; DCIS = ductal carcinoma in situ; ILC = invasive lobular carcinoma.
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Table 2. Univariate and multivariate analysis of factors associated with malignancy Univariate
Age 51 >51 Lesion size 18 mm >18 mm Lesion type I II III IV Shape Regular Irregular Orientation Parallel Not parallel Margin Circumscribed Not circumscribed Posterior features None Enhancement Shadowing Combined Calcification Absent Present Structure distortion Absent Present Duct changes Absent Present Skin changes Absent Present Edema Absent Present Vascularity Absent Present Abnormal ALN Absent Present Echo of solid portion Hypoechoic Isoechoic Hyperechoic Heterogenous
Multivariate
Benign
Malignant
Total
227 35
113 97
340 132
134 128
29 181
163 309
43 41 42 136
19 8 59 124
62 49 101 260
158 104
47 163
205 267
228 34
149 61
377 95
172 90
51 159
223 249
45 192 6 19
24 156 4 26
69 348 10 45
231 31
147 63
378 94
218 44
94 116
312 160
219 43
192 18
411 61
259 3
195 15
454 18
257 5
199 11
456 16
83 179
35 175
118 354
246 16
131 79
377 95
211 6 4 41
133 3 2 72
344 9 6 113
p value
OR
95% CI
p value
<0.001
4.707
2.638
8.399
<0.001
<0.001
3.843
2.196
6.725
<0.001
<0.001
1.292
1.019
1.639
0.034
<0.001
1.909
1.074
3.393
0.028
<0.001
2.109
1.089
4.085
0.027
<0.001
2.534
1.441
4.456
0.001
2.269
1.185
4.346
0.013
0.114
<0.001 <0.001
0.120
0.012
0.059
0.001
0.177
0.047
0.167
<0.001
1.801
1.008
3.219
0.047
<0.001
4.752
2.380
9.490
<0.001
<0.001
0.388
ALN = axillary lymph node; CI = confidence interval; OR = odds ratio.
masses with calcifications and six benign and one malignant lesion presenting as focal asymmetry. Additionally, one lesion showed adjacent skin thickening and was assessed as mastitis, consistent with the pathologic diagnosis. Twenty-five benign and two malignant lesions were missed. A summary of the mammographic outcomes is presented in Table 4.
DISCUSSION In addition to identifying whether a lesion is cystic or solid, HHUS is widely applied to tumor diagnosis, biopsy guidance and even further treatment. However, studies related to the diagnostic yield of HHUS in distinguishing benign from malignant complex cystic and solid breast lesions are limited.
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Table 3. The diagnostic performance of factors associated with malignancy and combined method Factors
AUC (95% CI)
Sensitivity (95% CI) (%)
Specificity (95% CI) (%)
PPV (95% CI) (%)
NPV (95% CI) (%)
Age Size Shape Margin Orientation Calcification Vascularity Abnormal ALN Lesion type Combined
0.664 (0.6140.715) 0.687 (0.6390.735) 0.690 (0.6410.738) 0.707 (0.6590.754) 0.580 (0.5280.633) 0.591 (0.5390.643) 0.575 (0.5240.626) 0.658 (0.6070.708) 0.566 (0.5150.618) 0.869 (0.8370.900)
46.2 (39.353.2) 86.2 (80.690.4) 77.6 (71.382.9) 75.7 (69.281.2) 29.1 (23.135.8) 30.0 (24.036.8) 83.3 (77.488.0) 37.6 (31.144.6) 87.1 (81.791.2) 76.7 (70.282.1)
86.6 (81.890.4) 51.1 (44.957.3) 60.3 (54.166.2) 65.6 (59.571.3) 87.0 (82.291.7) 88.2 (83.591.7) 31.7 (26.237.7) 93.9 (90.196.4) 32.1 (26.538.1) 82.1 (76.886.4)
73.5 (65.080.6) 58.6 (52.864.1) 61.0 (54.966.9) 63.4 (57.569.8) 64.2 (53.773.6) 67.0 (56.576.2) 49.4 (44.154.8) 83.2 (73.889.8) 50.7 (45.456.0) 77.4 (71.082.8)
66.8 (61.471.7) 82.2 (75.387.6) 77.1 (70.682.5) 77.1 (70.982.4) 60.4 (55.365.4) 61.1 (56.066.0) 70.3 (61.178.2) 65.3 (60.270.0) 75.7 (66.483.1) 81.4 (76.185.8)
ALN = axillary lymph node; AUC = area under the curve; CI = confidence interval; NPV = negative predictive value; PPV = positive predictive value.
Fig. 5. Area under the ROC curve of associated risk factors in multivariate analysis. ROC curve = receiver operating characteristic curve.
We enrolled 262 (55.5%) benign and 210 (44.5%) malignant lesions in 453 patients with various pathologic types and a relatively large sample size. Most lesions in our study were benign, which is consistent with the findings of previous studies (Berg et al. 2003; Chang et al. 2007). In comparison with those studies, we observed a relatively higher malignancy rate (44.5%), which may
be attributed to the nature of the specialized tumor hospital and selection bias in this retrospective study. Posterior features were not statistically different between benign and malignant complex cystic and solid breast lesions in univariate analysis (p = 0.114). However, according to Stavros et al. (Stavros et al. 1995), shadowing was usually associated with low-grade IDCs
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Table 4. A summary of mammographic findings Pathology
Mass Calcification Mass with calcification Focal asymmetry Skin thickening Normal Total
Benign
Malignant
68 16 17 6 1 25 133
72 6 57 1 0 2 138
Total
140 22 74 7 1 27 271
and ILCs, while no posterior features or posterior enhancement were evaluated as indeterminate findings and warranted further evaluation. As for edema, Hong et al. (2005) found only five cases showing edema among 403 lesions and no correlation between edema and benign and malignant status, which was inconsistent with the findings of our study (p = 0.047). These differences in findings may be associated with a small sample size for edema. In multivariate analysis, nine features, namely age, size, lesion type, shape, orientation, margin, calcification, vascularity and ALN status, displayed significant differences between the benign and malignant groups (Table 2). For a combination of the nine factors in the multivariate analysis, the AUC, sensitivity, specificity, PPV and NPV values were 0.869, 76.7%, 82.1%, 77.4% and 81.4%, respectively. Mammographic assessments of complex cystic and solid lesions revealed masses (51.7%, 140 of 271), calcifications (8.0%, 22 of 271), masses with calcifications (27.3%, 74 of 271), focal asymmetry (2.6%, 7 of 271) and skin thickening (0.4%, 1 of 271). Additionally, 27 occult lesions (10.0%, 27 of 271) in MAM, including 25 benign (10 fibrocystic change, eight IDP, four usual ductal hyperplasia, two fibroadenoma and one mastitis) and two malignant lesions, were all detected in ultrasound. Fifteen lesions were obscured by overlapping breast tissues in heterogeneous or extremely dense breasts, including one malignant phyllodes tumor, which was in accordance with the findings of previous studies, indicating that overlapping breast tissues were strongly associated with non-detection in MAM (Boyd et al. 2007; Nelson et al. 2016). Five lesions in the central region, four lesions in the posterior part of the breast and two lesions in the upper outer quadrant (UOQ) showed no mammographic abnormality, including one encapsulated papillary carcinoma in the posterior breast. In previous studies, difficult anatomic locations, including central region, pre-pectoral region and UOQ were suggested to affect lesion detection in MAM (Murphy et al. 2007; Bae et al. 2014). One fibrocystic lesion was obscured by a postoperative scar caused by a benign tumor resection 3 y ago. Yeom et al. (2019) reported 12 second breast cancers were missed because of a post-operative scar in a study of 188
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cases. Therefore, we may safely conclude that the HHUS is a useful modality in differential diagnosis of benign and malignant complex cystic and solid breast lesions and a tool complementing MAM in lesion detection. A detailed classification method of complex cystic and solid lesions was used in this study (Doshi et al. 2007; Hsu et al. 2011). In our study, PPVs of each lesion type were calculated: type I (30.6%, 19 of 62), II (16.3%, 8 of 49), III (58.4%, 59 of 101) and IV (47.7%, 124 of 260). In accordance with the findings of previous studies (Berg et al. 2003; Chang et al. 2007; Doshi et al. 2007; Hsu et al. 2011; Chen et al. 2014; Yao et al. 2017), all complex cystic and solid breast lesions should be assigned to BI-RADS 4 (>2% likelihood of malignancy). Lesions type III and IV are more likely to be malignant than those of types I and II, which was similar to the findings reported by Hsu et al. (2011). Lesion types I, II and IV were deemed to be moderately suspicious (2%50%) and could be categorized into 4B, while type III lesions were highly suspicious (50%95%), even into 4C. Our study had several limitations, including a selection bias, the potential for false-negative CNB results and a lack of reproducibility evaluation. First, selection bias was induced in this retrospective study by enrolling only those patients who had undergone HHUS examinations and had pathologic results. Other cystic lesions, including simple and complicated cystic lesions without solid components, and lesions with low malignant potential were thus excluded (Doshi et al. 2007; Daly et al. 2008). Second, ultrasound-guided CNB is reported to have a false-negative rate of 1.4%2.23% (Schueller et al. 2008; Boba et al. 2011; Zhou et al. 2014; Jung et al. 2018), whereas only a small portion of benign lesions that underwent CNB assessments had follow-up information. Collecting long-term follow-up data in future studies will be important to exclude false-negative cases. Third, the reproducibility of imaging acquisition and interpretation were not assessed, despite the operatordependent nature of HHUS examinations as well as the static images used for analysis. In conclusion, HHUS is a helpful modality in the detection and differential diagnosis between benign and malignant complex cystic and solid breast lesions, with a wide range of pathology types. Type I, II and IV lesions can be assessed as BI-RADS 4B, while type III lesions can directly go into BI-RADS 4C, which allows a more accurate subclassification of complex cystic and solid breast lesions in clinical practice. Acknowledgments—We are grateful to Jiao Li of the medical imaging department in Sun Yat-sen University Cancer Center for interpreting and analyzing the negative mammography. Conflict of interest disclosure—The authors declare no competing interests.
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https://doi.org/10.1016/j.ultrasmedbio.2020.01.006
Original Contribution VALUE OF HAND-HELD ULTRASOUND IN THE DIFFERENTIAL DIAGNOSIS AND ACCURATE BREAST IMAGING REPORTING AND DATA SYSTEM SUBCLASSIFICATION OF COMPLEX CYSTIC AND SOLID BREAST LESIONS AGEDPH T UILING
XIANG,* GUOXUE TANG,y,z YIN LI,x YING LIU,* LIXIAN LIU,* and XI LIN*TAGEDEN
* Department of Ultrasound, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China; y Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; z Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; and x Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China (Received 5 July 2019; revised 5 December 2019; in final from 8 January 2020)
Abstract—To explore the value of hand-held ultrasound (HHUS) for diagnosing complex cystic and solid breast lesions, 472 pathologically proven lesions were analyzed. The lesions were divided into four types based on ultrasound features. Positive predictive values (PPVs) for lesion types and risk factor performances were assessed. Furthermore, HHUS and mammography (MAM) performances were compared: 27 lesions missed in MAM were detected in HHUS. Ultrasound feature analysis revealed higher PPVs for type III and IV lesions than for type I and II lesions. In patients older than 51 y, a type III or IV lesion with a diameter greater than 18 mm, an irregular shape, a non-parallel orientation, an uncircumscribed margin, calcification, vascularity and abnormal axillary lymph nodes were suggestive of malignancy; the area under the curve reached 0.869. Thus, ultrasound is useful in diagnosing complex cystic and solid breast lesions, which should be categorized as Breast Imaging Reporting and Data System (BI-RADS) 4B or 4C. (E-mail: [email protected]) © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Complex cystic and solid breast lesions, Hand-held ultrasound, Mammography, BI-RADS, Differential diagnosis.
of 22%40% have been reported in previous studies (Berg et al. 2010; Hsu et al. 2011; Chen et al. 2014; Yao et al. 2017). As a result, these complex cystic and solid breast lesions are suggested to be classified as category 4, and a biopsy or excision is recommended for these lesions. A wide range of benign and malignant pathologic results has been detected, including fibrocystic changes, abscess, mastitis, fat necrosis, hematoma, fibroadenoma, galactocele, intraductal papilloma (IDP), phyllodes tumor, intraductal carcinoma in situ, invasive intraductal carcinoma (IDC), invasive lobular carcinoma (ILC), mucinous carcinoma and metaplastic carcinoma (Chang et al. 2007; Doshi et al. 2007; Kim et al. 2011; Choi and Shu 2012; Zhang et al. 2017). Therefore, a BI-RADS subclassification of category 4 is necessary. However, there is no definite criterion for the subclassification, which is subjective and depends on doctors’ individual experience. Additionally, there is
INTRODUCTION Cystic lesions, comprising simple, complicated and complex cystic lesions, are common in women aged 3050 y (Mendelson et al. 2001; Hines et al. 2010; Mendelson et al. 2013). A simple cyst is an oval or round lesion with anechogenicity, a circumscribed margin and posterior enhancement. A complicated cystic lesion fulfills all the criteria of a simple cyst, except that it contains debris with low echo levels. Both simple and complicated cysts are considered benign, and a follow-up for 6 mo or continued surveillance is recommended according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) (Mendelson et al. 2013). Complex cystic and solid breast lesions contain both cystic and solid components, and malignancy rates Address correspondence to: Xi Lin, Department of Ultrasound, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, PR China. E-mail: [email protected]
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little literature combining related risk factors together for the evaluation of the diagnostic efficacy of hand-held ultrasound (HHUS) for complex cystic and solid breast lesions. As a result, this retrospective study, based on a large number of cases and pathologic types, aimed to evaluate the diagnostic performance of HHUS for complex cystic and solid breast lesions and suggest a more accurate approach for BI-RADS subclassification in clinical practice. MATERIAL AND METHODS This retrospective analysis was approved by the institutional research ethics committee of Sun Yat-sen University Cancer Center in Guangzhou, China, and the informed consent requirement was waived. From January 2000 to December 2018, 453 patients with 472 complex cystic and solid breast lesions were included in this study. Clinicopathologic information and ultrasonographic and mammographic findings of these cases were obtained from the password-protected database of our hospital with permission. Ultrasound examinations were performed for all 472 lesions with a high-frequency (712 MHz) linear array transducer (GE Logiq 9, GE Logiq S8, GE Logiq 700 [GE Healthcare, Milwaukee, WI, USA], Philips iU 22 [Philips Healthcare, Bothell, WA,
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USA], or Siemens S2000 [Siemens Medical Solutions, Mountain View, CA, USA]) by 1 of 20 eligible radiologists with 330 y of experience in breast imaging. Ultrasound features of each lesion based on BI-RADS lexicon and axillary lymph node (ALN) status were recorded by two doctors in consensus who did not know the final pathologic results. ALN was considered to be suspicious with one or more of the following features: diffuse (>3 mm) or eccentric cortical thickening, oval shape, focal cortical bulge and loss of fatty hilum and nonhilar cortical blood flow on color Doppler imaging (Cools-Lartigue and Meterissian 2012; Ecanow et al. 2013). These lesions were divided into four types according to the ultrasound features: type I, with a thick wall and/or septations (>0.5 mm) (Fig. 1); type II, with one or multiple mural or papillary nodules (Fig. 2); type III, mixed cystic and solid lesion (cystic component, >50%) (Fig. 3); or type IV, predominantly solid lesion with cystic spaces (solid part, >50%) (Fig. 4), which has been mentioned in previous work (Doshi et al. 2007; Hsu et al. 2011). Pathologic results were standard reference. Craniocaudal and mediolateral oblique views for mammography (MAM) were obtained using a full-field digital MAM system (Senographe DS, GE Healthcare, Milwaukee, WI, USA). Another pathologist with 6 y of experience in MAM interpretation rechecked the
Fig. 1. Type I lesion: Intraductal papilloma (IDP) in the right breast of a 71-y-old woman. Ultrasound image shows a complex cystic and solid lesion with an irregular thick wall and septation (>0.5 mm) and distribution of vessels within the thick septation.
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results with a p value less than 0.05 (2-sided) were considered statistically significant in this study. RESULTS The mean age of the 453 patients involved in this retrospective study was 46.4 y (range 1585 y), and the average lesion diameter was 28.6 mm.
Fig. 2. Type II lesion: Fibrocystic change in the right breast of a 29-y-old woman. Ultrasound image shows a complex cystic and solid lesion with one papillary nodule and blood signals within the papillary nodule.
Fig. 3. Type III lesion: Invasive intraductal (IDC) grade II in the left breast of a 61-y-old woman. Ultrasound image shows a complex cystic and solid lesion with a cystic component of more than 50% and hypervascularity within the solid portion.
negative cases, made the final diagnosis and evaluated the reasons for missed diagnosis. STATISTICAL ANALYSIS MedCalc (version 11.2; 2011 MedCalc Software bvba, Mariakerke, Belgium) and SPSS software (SPSS, version 19.0, Chicago, IL, USA) were used for statistical analysis. X2 tests were applied in categorical variables. Associations between benign and malignant group features were reassessed by binary logistic regression. To explore the diagnostic value of the combined diagnostic method, a series of prediction rates obtained from the multivariate analysis was subject to receiver operating characteristic curve analysis. The area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and 95% confidence interval for each risk factor were calculated. Furthermore, the PPVs for all types were determined. All
Pathology and follow-up information Tumor histology and ultrasound classifications are shown in Table 1. There were 262 (55.5%, 262/472) benign and 210 (44.5%, 210/472) malignant lesions confirmed by core needle biopsy (CNB) (28.0%) or surgery (72.0%). The follow-up information for benign lesions evaluated with only CNB was recorded. Thirty-eight (28.8%, 38/132) lesions of 36 patients were reexamined at least one time with ultrasound, MAM or magnetic resonance imaging. Follow-up time varied as follows: less than 6 mo, seven patients; less than 1 y, three patients; less than 2 y, 15 patients; and more than 2 y, 11 patients with 13 lesions. No malignancy was found during the follow-up period. Ultrasonographic findings and feature analysis Based on ultrasonic features, 62 (13.1%, 62 of 472) lesions were classified as type I, 49 (10.4%, 49 of 472) as type II and 101 (21.4%, 101 of 472) and 260 (55.1%, 260 of 472) as type III and IV, respectively (Table 1). PPVs of type III and IV lesions were higher compared with those of type I and II (p < 0.001, I vs. II, p = 0.081; I vs. III, p = 0.001; I vs. IV, p = 0.015; II vs. III or IV, p < 0.001). Patients’ age and the ultrasonic features of lesions and ALN status are listed in Table 2. Univariate analysis suggested that posterior features were not associated with malignancy. Age older than 51 y, a type III or IV lesion, diameter of more than 18 mm, the presence of an irregular shape, absence of parallel orientation, uncircumscribed margin, calcification, vascularity in the tumor as well as abnormal ALN were identified to be independent factors for malignancy in a multivariate analysis. Lesion type and size showed the highest sensitivity of 87.1% and NPV of 82.2%, respectively. Abnormal ALN had the highest specificity of 93.9% and PPV of 83.2% (Table 3). Performance and AUC of each risk factor and the combined approach are shown in Figure 5. Lesion detection and feature analysis of MAM A total of 262 patients with 271 lesions detected on ultrasound also underwent MAM examinations, with a detection rate of 90.0%. Mammographic findings suggested 68 benign and 72 malignant lesions presenting as masses, 16 benign and six malignant lesions as calcifications, 17 benign and 57 malignant lesions presenting as
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Fig. 4. Type IV lesion: Encapsulated papillary carcinoma in the right breast of a 54-y-old woman. Ultrasound presents a complex cystic and solid lesion with a solid part more than 50% and internal vascularity. Table 1. Pathologic distribution of the complex cystic and solid breast lesions involved Finding Benign Fibrocystic change IDP Mastitis Fibroadenoma IDP +ADH Benign phyllodes tumor UDH Boundary phyllodes tumor Abscess ADH Galactocele Lactating adenoma Fat necrosis Total Malignant IDC DCIS Mucinous CA Metaplastic CA Encapsulated papillary CA Malignant phyllodes tumor Solid papillary CA Intraductal papillary CA ILC Fibrosarcoma CA with apocrine differentiation Invasive cribriform CA Neuroendocrine CA Lymphoma Total
Type I
Type II
Type III
Type IV
Total
24 5 10 2 0 0 0 0 2 0 0 0 0 43
7 25 2 2 2 0 2 0 0 0 0 0 1 41
21 8 11 0 0 2 0 0 0 0 0 0 0 42
40 34 9 28 7 5 4 4 2 1 1 1 0 136
92 72 32 32 9 7 6 4 4 1 1 1 1 262
16 1 0 1 0 1 0 0 0 0 0 0 0 0 19
3 1 1 1 2 0 0 0 0 0 0 0 0 0 8
41 7 1 1 4 0 1 2 0 1 1 0 0 0 59
76 15 8 7 3 5 3 1 3 0 0 1 1 1 124
136 24 10 10 9 6 4 3 3 1 1 1 1 1 210
IDP = intraductal papilloma; ADH = atypical ductal hyperplasia; UDH = usual ductal hyperplasia; CA = carcinoma; IDC = invasive ductal carcinoma; DCIS = ductal carcinoma in situ; ILC = invasive lobular carcinoma.
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Table 2. Univariate and multivariate analysis of factors associated with malignancy Univariate
Age 51 >51 Lesion size 18 mm >18 mm Lesion type I II III IV Shape Regular Irregular Orientation Parallel Not parallel Margin Circumscribed Not circumscribed Posterior features None Enhancement Shadowing Combined Calcification Absent Present Structure distortion Absent Present Duct changes Absent Present Skin changes Absent Present Edema Absent Present Vascularity Absent Present Abnormal ALN Absent Present Echo of solid portion Hypoechoic Isoechoic Hyperechoic Heterogenous
Multivariate
Benign
Malignant
Total
227 35
113 97
340 132
134 128
29 181
163 309
43 41 42 136
19 8 59 124
62 49 101 260
158 104
47 163
205 267
228 34
149 61
377 95
172 90
51 159
223 249
45 192 6 19
24 156 4 26
69 348 10 45
231 31
147 63
378 94
218 44
94 116
312 160
219 43
192 18
411 61
259 3
195 15
454 18
257 5
199 11
456 16
83 179
35 175
118 354
246 16
131 79
377 95
211 6 4 41
133 3 2 72
344 9 6 113
p value
OR
95% CI
p value
<0.001
4.707
2.638
8.399
<0.001
<0.001
3.843
2.196
6.725
<0.001
<0.001
1.292
1.019
1.639
0.034
<0.001
1.909
1.074
3.393
0.028
<0.001
2.109
1.089
4.085
0.027
<0.001
2.534
1.441
4.456
0.001
2.269
1.185
4.346
0.013
0.114
<0.001 <0.001
0.120
0.012
0.059
0.001
0.177
0.047
0.167
<0.001
1.801
1.008
3.219
0.047
<0.001
4.752
2.380
9.490
<0.001
<0.001
0.388
ALN = axillary lymph node; CI = confidence interval; OR = odds ratio.
masses with calcifications and six benign and one malignant lesion presenting as focal asymmetry. Additionally, one lesion showed adjacent skin thickening and was assessed as mastitis, consistent with the pathologic diagnosis. Twenty-five benign and two malignant lesions were missed. A summary of the mammographic outcomes is presented in Table 4.
DISCUSSION In addition to identifying whether a lesion is cystic or solid, HHUS is widely applied to tumor diagnosis, biopsy guidance and even further treatment. However, studies related to the diagnostic yield of HHUS in distinguishing benign from malignant complex cystic and solid breast lesions are limited.
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Table 3. The diagnostic performance of factors associated with malignancy and combined method Factors
AUC (95% CI)
Sensitivity (95% CI) (%)
Specificity (95% CI) (%)
PPV (95% CI) (%)
NPV (95% CI) (%)
Age Size Shape Margin Orientation Calcification Vascularity Abnormal ALN Lesion type Combined
0.664 (0.6140.715) 0.687 (0.6390.735) 0.690 (0.6410.738) 0.707 (0.6590.754) 0.580 (0.5280.633) 0.591 (0.5390.643) 0.575 (0.5240.626) 0.658 (0.6070.708) 0.566 (0.5150.618) 0.869 (0.8370.900)
46.2 (39.353.2) 86.2 (80.690.4) 77.6 (71.382.9) 75.7 (69.281.2) 29.1 (23.135.8) 30.0 (24.036.8) 83.3 (77.488.0) 37.6 (31.144.6) 87.1 (81.791.2) 76.7 (70.282.1)
86.6 (81.890.4) 51.1 (44.957.3) 60.3 (54.166.2) 65.6 (59.571.3) 87.0 (82.291.7) 88.2 (83.591.7) 31.7 (26.237.7) 93.9 (90.196.4) 32.1 (26.538.1) 82.1 (76.886.4)
73.5 (65.080.6) 58.6 (52.864.1) 61.0 (54.966.9) 63.4 (57.569.8) 64.2 (53.773.6) 67.0 (56.576.2) 49.4 (44.154.8) 83.2 (73.889.8) 50.7 (45.456.0) 77.4 (71.082.8)
66.8 (61.471.7) 82.2 (75.387.6) 77.1 (70.682.5) 77.1 (70.982.4) 60.4 (55.365.4) 61.1 (56.066.0) 70.3 (61.178.2) 65.3 (60.270.0) 75.7 (66.483.1) 81.4 (76.185.8)
ALN = axillary lymph node; AUC = area under the curve; CI = confidence interval; NPV = negative predictive value; PPV = positive predictive value.
Fig. 5. Area under the ROC curve of associated risk factors in multivariate analysis. ROC curve = receiver operating characteristic curve.
We enrolled 262 (55.5%) benign and 210 (44.5%) malignant lesions in 453 patients with various pathologic types and a relatively large sample size. Most lesions in our study were benign, which is consistent with the findings of previous studies (Berg et al. 2003; Chang et al. 2007). In comparison with those studies, we observed a relatively higher malignancy rate (44.5%), which may
be attributed to the nature of the specialized tumor hospital and selection bias in this retrospective study. Posterior features were not statistically different between benign and malignant complex cystic and solid breast lesions in univariate analysis (p = 0.114). However, according to Stavros et al. (Stavros et al. 1995), shadowing was usually associated with low-grade IDCs
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Table 4. A summary of mammographic findings Pathology
Mass Calcification Mass with calcification Focal asymmetry Skin thickening Normal Total
Benign
Malignant
68 16 17 6 1 25 133
72 6 57 1 0 2 138
Total
140 22 74 7 1 27 271
and ILCs, while no posterior features or posterior enhancement were evaluated as indeterminate findings and warranted further evaluation. As for edema, Hong et al. (2005) found only five cases showing edema among 403 lesions and no correlation between edema and benign and malignant status, which was inconsistent with the findings of our study (p = 0.047). These differences in findings may be associated with a small sample size for edema. In multivariate analysis, nine features, namely age, size, lesion type, shape, orientation, margin, calcification, vascularity and ALN status, displayed significant differences between the benign and malignant groups (Table 2). For a combination of the nine factors in the multivariate analysis, the AUC, sensitivity, specificity, PPV and NPV values were 0.869, 76.7%, 82.1%, 77.4% and 81.4%, respectively. Mammographic assessments of complex cystic and solid lesions revealed masses (51.7%, 140 of 271), calcifications (8.0%, 22 of 271), masses with calcifications (27.3%, 74 of 271), focal asymmetry (2.6%, 7 of 271) and skin thickening (0.4%, 1 of 271). Additionally, 27 occult lesions (10.0%, 27 of 271) in MAM, including 25 benign (10 fibrocystic change, eight IDP, four usual ductal hyperplasia, two fibroadenoma and one mastitis) and two malignant lesions, were all detected in ultrasound. Fifteen lesions were obscured by overlapping breast tissues in heterogeneous or extremely dense breasts, including one malignant phyllodes tumor, which was in accordance with the findings of previous studies, indicating that overlapping breast tissues were strongly associated with non-detection in MAM (Boyd et al. 2007; Nelson et al. 2016). Five lesions in the central region, four lesions in the posterior part of the breast and two lesions in the upper outer quadrant (UOQ) showed no mammographic abnormality, including one encapsulated papillary carcinoma in the posterior breast. In previous studies, difficult anatomic locations, including central region, pre-pectoral region and UOQ were suggested to affect lesion detection in MAM (Murphy et al. 2007; Bae et al. 2014). One fibrocystic lesion was obscured by a postoperative scar caused by a benign tumor resection 3 y ago. Yeom et al. (2019) reported 12 second breast cancers were missed because of a post-operative scar in a study of 188
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cases. Therefore, we may safely conclude that the HHUS is a useful modality in differential diagnosis of benign and malignant complex cystic and solid breast lesions and a tool complementing MAM in lesion detection. A detailed classification method of complex cystic and solid lesions was used in this study (Doshi et al. 2007; Hsu et al. 2011). In our study, PPVs of each lesion type were calculated: type I (30.6%, 19 of 62), II (16.3%, 8 of 49), III (58.4%, 59 of 101) and IV (47.7%, 124 of 260). In accordance with the findings of previous studies (Berg et al. 2003; Chang et al. 2007; Doshi et al. 2007; Hsu et al. 2011; Chen et al. 2014; Yao et al. 2017), all complex cystic and solid breast lesions should be assigned to BI-RADS 4 (>2% likelihood of malignancy). Lesions type III and IV are more likely to be malignant than those of types I and II, which was similar to the findings reported by Hsu et al. (2011). Lesion types I, II and IV were deemed to be moderately suspicious (2%50%) and could be categorized into 4B, while type III lesions were highly suspicious (50%95%), even into 4C. Our study had several limitations, including a selection bias, the potential for false-negative CNB results and a lack of reproducibility evaluation. First, selection bias was induced in this retrospective study by enrolling only those patients who had undergone HHUS examinations and had pathologic results. Other cystic lesions, including simple and complicated cystic lesions without solid components, and lesions with low malignant potential were thus excluded (Doshi et al. 2007; Daly et al. 2008). Second, ultrasound-guided CNB is reported to have a false-negative rate of 1.4%2.23% (Schueller et al. 2008; Boba et al. 2011; Zhou et al. 2014; Jung et al. 2018), whereas only a small portion of benign lesions that underwent CNB assessments had follow-up information. Collecting long-term follow-up data in future studies will be important to exclude false-negative cases. Third, the reproducibility of imaging acquisition and interpretation were not assessed, despite the operatordependent nature of HHUS examinations as well as the static images used for analysis. In conclusion, HHUS is a helpful modality in the detection and differential diagnosis between benign and malignant complex cystic and solid breast lesions, with a wide range of pathology types. Type I, II and IV lesions can be assessed as BI-RADS 4B, while type III lesions can directly go into BI-RADS 4C, which allows a more accurate subclassification of complex cystic and solid breast lesions in clinical practice. Acknowledgments—We are grateful to Jiao Li of the medical imaging department in Sun Yat-sen University Cancer Center for interpreting and analyzing the negative mammography. Conflict of interest disclosure—The authors declare no competing interests.
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