Risk of Malignancy in Solid Breast Nodules According to Their Sonographic Features

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1 Article Risk of Malignancy in Solid Breast Nodules According to Their Sonographic Features Régis Resende Paulinelli, MD, Ruffo Freitas-Júnior, MD, PhD, Marise Amaral Rebouças Moreira, PhD, Vardeli Alves de Moraes, MD, PhD, Júlio Roberto M. Bernardes-Júnior, MD, PhD, Célio da Silva Rocha Vidal, MD, Alessandro Naldi Ruiz, MD, Miliana Tostes Lucato, MD Objective. The purpose of this study was to assess the risk of malignancy for each type of sonographic feature in solid breast nodules. Methods. The study included 304 patients from the Department of Gynecology and Obstetrics of the Federal University of Goiás who had solid breast nodules. A medical trainee, working under the supervision of a preceptor, obtained the sonographic images of the breast, and the features were recorded in a questionnaire. Each sonographic feature was analyzed and compared with the anatomic and pathologic findings after the lesion was excised. Results. Of the 304 patients included in the study, 292 (96%) had a conclusive diagnosis. Among these women, 216 (74%) had benign tumors and 76 (26%) had malignant tumors. The odds ratio of malignancy in breast nodules, as calculated by multivariate analysis, was as follows: lesions without circumscribed margins, (95% confidence interval, ); lesions with heterogeneous echo texture, 7.70 ( ); lesions with thickened Cooper ligaments, ( ); nodules whose anteroposterior dimension was larger than their width, 3.29 ( ); those with an anterior echogenic rim, 2.59 ( ); and those with posterior shadowing, 1.57 ( ). Among the 133 cases that had all the sonographic features of a benign lesion, 3 nodules (2.3%) had a histologic diagnosis of malignant. Conclusions. Sonography is a diagnostic method that can help establish the differentiation between benign and malignant solid tumors. A lack of circumscribed margins, heterogeneous echo patterns, thickened Cooper ligaments, and an increased anteroposterior dimension can indicate a higher probability of malignancy in solid breast nodules. Key words: breast; breast neoplasms; diagnosis; sonography. Abbreviations BI-RADS, Breast Imaging Reporting and Data System Received August 20, 2004, from the Departments of Gynecology and Obstetrics (R.R.P., R.F.-J., V.A.d.M., J.R.M.B.-J, C.d.S.R.V., A.N.R., M.T.L.) and Pathology and Imaging (M.A.R.M.), School of Medicine, Federal University of Goiás, Goiás, Brazil. Revision requested October 4, Revised manuscript accepted for publication December 16, Address correspondence to Ruffo Freitas-Júnior, MD, PhD, Alameda das Rosas, 533 Setor Oeste, CEP: Goiânia, Goiás, Brazil. ruffojr@terra.com.br Diagnosing malignant tumors of the breast by sonography has been a long-standing concern. The first organ to be investigated with this objective in mind was the breast. Since the 1950s, several authors have pointed out the sonographic features that could help establish a differential diagnosis for malignant and benign tumors. 1,2 We can cite the following examples: lack of circumscribed margins on the nodule walls, heterogeneous echo patterns, and posterior shadowing. 2 At a later date, other features were put forth as characteristic: high contrast between a hypoechoic nodule and the breast parenchyma, a more echogenic anterior region, and an anteroposterior 2005 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2005; 24: /05/$3.50

2 Risk of Malignancy in Solid Breast Nodules dimension larger than the width. 3 9 Other features that might be considered suggestive include thickened Cooper ligaments, thickened skin, and changes in the texture of the adjacent parenchyma. 10,11 Despite technological advances, there is still no consensus as to what characteristics can be considered more important when separating benign and malignant solid tumors. 12 Aiming at assessing the meaning of sonography for differentiating benign and malignant solid breast lesions and deciding which features, among the several cited by various authors, are important for the diagnosis of a malignancy, we sought to carry out this prospective study. Materials and Methods The prospective study included 304 patients, of any age, from the Breast Clinic of the Department of Gynecology and Obstetrics of the School of Medicine of the Federal University of Goiás who were being investigated for solid breast nodules, either palpable or not, between May 1998 and May Solid lesions with associated skin ulcerations and cystic lesions were not included in this study. The Research Ethics Committee of the Teaching Hospital of the Federal University of Goiás approved this research proposal before it was started. The patients identities were not revealed. The patients were briefed on the nature of the research and agreed to participate in the study by reading and signing an informed consent form. Breast sonographic imaging was used as a routine procedure as part of the workup for solid breast nodules, and it was included in the study in a prospective way, before histologic specimens were obtained. A Tokimec CS 2020 sonography system (Tokimec Inc, Tokyo, Japan), coupled to a 7.5-MHz linear transducer was used. A medical trainee in the last year of specialization in sonology obtained the sonographic images of the breast under the supervision of a preceptor, properly trained in breast sonography, with more than 2 years of experience in the method. The sonographic features studied for each tumor were the margins, the internal echo texture, the posterior echo patterns, the anterior echo patterns, the Cooper ligaments, and the relationship between the larger dimensions of the nodule, that is, the tumor orientation. The margins were considered not circumscribed when at least 25% of the circumference had some degree of irregularity, such as indistinct, angular, microlobulated, or spiculated margins. If that was not the case, the margins were considered regular or smooth. The internal echo texture was considered heterogeneous when hyperechoic areas inside a hypoechoic area were found. If that feature was absent, the nodules were then considered homogeneous. With regard to the posterior acoustic features, the sonologist reported the presence or absence of posterior shadowing. Lateral shadowing was not considered in this case because it sometimes appears in benign nodules. As far as the anterior echo patterns are concerned, the presence or absence of an echogenic rim, defined as an area of hyperechogenicity in the anterior region of the nodule, was the feature to watch for. The Cooper ligaments were considered thickened when there were hyperechoic lines near the nodule, coursing toward the skin. The Cooper ligaments were considered normal if that feature was absent. The nodule orientation and its dimensions were also differentiating features. When the anteroposterior dimension was larger than the width, the nodule was considered suggestive of malignancy. Two hundred ninety-two patients (96%) of the 304 included in the study had a definitive diagnosis. Twelve patients (4%) were excluded from the analysis because they did not undergo surgery, were lost to follow-up, or both. Among the 292 valid cases, 275 (94%) were referred to surgery by their assisting physicians and had their lesions excised. These lesions were surgically removed, and the specimens were analyzed by pathologists at the Department of Pathology of the School of Medicine of the Federal University of Goiás. Seventeen patients (6%) from the group of 292 women opted for biannual clinical sonographic follow-up; in all of them, the nodules did not undergo any changes for more than 2 years and were, therefore, considered benign. Results from histologic or clinical follow-up for at least 2 years were considered the criterion standards and were compared with the reports from the sonographic work-up. The size of the sample was defined on the basis of the result of a pilot study done at the Senology Program of the Teaching Hospital of the Federal University of Goiás. A 25% prevalence rate of malignant tumors in the sample was expected. We also hoped to see a 10% increase, at least, in prevalence of malignancy in each group of nodules when a sonographic feature was shown to be altered. 13, J Ultrasound Med 2005; 24:

3 Paulinelli et al On the basis of the criteria mentioned above, the size of the sample was then set to a minimum of 240 patients. However, to allow us to carry out a more sound analysis, a larger number of cases was included in this study (304 women). In the statistical analysis, the power of test and the level of significance were set at 80% and 5%, respectively. Each sonographic feature (independent variable) was compared with the definite diagnosis (dependent variable) after the lesion was excised. A univariate analysis was done with the χ 2 test and calculation of the odds ratio with the confidence interval set at 95%. A multivariate analysis was done with the Wald test, with logistic regression, to calculate the odds ratio with a confidence interval of 95%. To compare the age between the groups, we used the mean, the SD, and the Student t test. To compare the size of the tumor, we used the median and the Mann- Whitney U test because the distribution of this feature differed significantly from the normal distribution, as verified after the Kolmogorov- Smirnov test was performed. For the statistical analysis, SPSS version software (SPSS Inc, Chicago, IL) was used. Results Among the 292 patients who had a definite diagnosis, 216 (74%) had benign tumors and 76 (26%) had malignant tumors. Table 1 illustrates how the resected lesions were distributed by histologic diagnosis. The mean overall age of the patients ± SD was 38 ± 14 years, and the median overall tumor size was 20 mm (range mm). The mean ages were 51 ± 12 years for patients with malignant tumors and 34 ± 13 for those with benign tumors (P <.01). The median tumor sizes were 25 mm for malignant tumors and 20 mm for benign tumors (P <.01). The sonographic features of the lesion were studied with the objective of relating them to a diagnosis of malignancy or benign lesions. The comparison between the sonographic features of the nodules with the definite diagnosis, done through univariate analysis, can be seen in Table 2, where the odds ratios and 95% confidence intervals are also presented. It is possible to see in this table that all 6 sonographic features considered for this study, when present, were related to a greater probability of nodule malignancy. The odds ratio was also calculated by multivariate analysis (Table 3). The features that were significantly related to a diagnosis of malignancy, in decreasing order of risk, were the absence of circumscribed margins, thickened Cooper ligaments, a heterogeneous echo texture, and an anteroposterior dimension larger than the width. The presence of an anterior echogenic rim and posterior shadowing were not independently related to a higher risk for malignancy in the multivariate analyses. When all 6 sonographic features considered in this study were included in the analysis, the malignant tumors had a greater number of altered features (median, 3) relative to the benign tumors (median, 0) (P <.01). Among the 133 nodules without any suggestive feature, as observed on the sonographic images, 3 (2.3%) malignant tumors were found: a 25-mm intracystic carcinoma in a 40-year-old woman; a 26-mm infiltrating ductal carcinoma in a 45-year-old woman, and a 13-mm lobular carcinoma in a 90-year-old woman. We also evaluated the relationship between the sonographic features noted in the benign and the malignant tumors and the patients ages and the sizes of the tumors. The median tumor sizes were 80 mm for malignant nodules with thickened Cooper ligaments and 21 mm for those in which the ligaments were found to be normal (P <.01), 29 mm for malignant nodules with heterogeneous internal echoes and 16 mm when the echoes were homogeneous (P =.01), and Table 1. Histologic Diagnosis of Solid Nodules Included in This Study Histologic Diagnosis No. of Cases % Fibroadenoma Fibroadenosis Lipoma Benign phyllodes tumor Typical ductal hyperplasia Adenoma Other benign lesions* Invasive ductal carcinoma Ductal carcinoma in situ Lobular carcinoma Medullary carcinoma Malignant phyllodes tumor Total In 17 lesions, it was not possible to get a histologic diagnosis, and they were considered benign after a clinical follow-up of at least 2 years. Another 12 patients were excluded from the analysis because they were lost to follow-up. *Atypical hyperplasia, lactating adenoma, radial scar, papilloma, fat necrosis (2), reactions to foreign material, fibromatosis, and chronic mastitis. J Ultrasound Med 2005; 24:

4 Risk of Malignancy in Solid Breast Nodules Table 2. Odds Ratio of Malignancy of the Sonographic Features After Univariate Analysis Malignant, Benign, 95% CI Feature n (%) n (%) χ 2 P OR Lower Upper No circumscribed margins 71 (93) 43 (20) < Heterogeneous echo texture 67 (88) 41 (19) < Anterior echogenic rim 22 (29) 16 (7) < Thickened Cooper ligaments 7 (9) 1 (0.5) < Posterior shadowing 34 (45) 25 (12) < AP > W 25 (33) 9 (4) < AP > W indicates anteroposterior dimension larger than width; CI, confidence interval; and OR, odds ratio. Table 3. Odds Ratio of Malignancy of the Sonographic Features After Multivariate Analysis Wald 95% CI Feature B SE Statistic P OR Lower Upper No circumscribed margins < Heterogeneous echo texture < Anterior echogenic rim Thickened Cooper ligaments Posterior shadowing AP > W AP > W indicates anteroposterior dimension larger than width; B, estimated coefficient; CI, confidence interval; and OR, odds ratio. Constant: B = 4.53; SE = 0.58; Wald = 61.80; P <.01; and OR = mm for malignant nodules with an anterior echogenic rim and 20.5 mm for those without this finding (P =.04). No difference was observed in the median tumor size or in the mean age of the patients for the other sonographic features analyzed in this study. For the following analysis, we considered the lesion suggestive if any of the features were present. With inclusion of all 6 descriptors in the logistic model, the overall sensitivity, specificity, positive predictive value, and negative predictive value were 96.1%, 60.2%, 45.9%, and 97.7%, respectively. There were 3 (2.3%) false-negative results. When posterior shadowing and an anterior echogenic rim were excluded from the analysis, because they did not have statistically significant contribution in the logistic model, the overall sensitivity, specificity, positive predictive value, and negative predictive value were 96.1%, 69.4%, 52.5%, and 98.0%, respectively. As a result, the overall accuracy of breast sonography was increased from 69.5% to 76.4% without an increase in the number of false-negative results. Discussion Several features have been singled out as important for differentiating between benign and malignant lesions. The problem, however, lies in the importance that each author ascribes to these features because they are far from being uniform. In this study, we chose to analyze the most wellknown features because they are the easiest to observe by the sonography specialist during a breast workup. The second objective was to rate the importance of each of these features for the diagnosis. Among the elements included in the study, assessed by univariate analysis, it was found that there was a greater chance for malignancy when any 1 of the following features was present: lack of circumscribed margins, heterogeneous echo texture, anteroposterior dimension larger than the width, anterior echogenic rim, posterior shadowing, and thickening of the Cooper ligaments. Sonographic examples of probable benign and suggestive lesions are shown in Figures 1 3. In the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon, there is the term complex echo pattern, but it is described as a mass that contains both anechoic and echogenic components, which is seen in solid-cystic lesions. 15 The term heterogeneous echo pattern does not exist in the lexicon, but in our experience and in some other research, it was one of the most important features. 12,16 We suggest that the American College of Radiology add this term to its classification form. 638 J Ultrasound Med 2005; 24:

5 Paulinelli et al Figure 1. Benign-looking oval solid nodule with circumscribed margins, hypoechoic homogeneous content, width larger than the anteroposterior dimension, and discrete posterior enhancement in a 22-year-old woman. The BI-RADS classification was category 3. Pathologic examination revealed evidence of a fibroadenoma. In the multivariate analysis, both posterior shadowing and an anterior echogenic rim lost their statistical significance. Despite the fact that these 2 features are frequently observed in malignant tumors, according to our results, their presence is not significant if they are not associated with other features. Although these 2 features did not reach statistical significance, there is a tendency toward it, and it may be related to our sample size. The shadowing and the echogenic rim have been related to a diagnosis A of malignancy for many years, although more recent studies have shown that they are less important than previously thought for the diagnosis of breast cancer with sonography. 1,2,7,12 In the malignant nodules, which had heterogeneous echo patterns with anterior echogenic rims or thickening of the Cooper ligaments, the tumors were larger than those in which these features were not noted. This fact leads us to think that these features are better observed in larger tumors. In spite of their statistical significance, thickened Cooper ligaments were only seen in larger tumors and seem to be of little importance for the early diagnosis of breast cancer. Of the 7 malignant tumors in which we were able to note the thickened Cooper ligaments, only 1 was smaller than 50 mm. Among the nodules resected during the interval of the study, we found a representative sample of the most frequent breast lesions, with a predominance of fibroadenomas and fibroadenosis among the benign lesions and invasive ductal carcinomas among the malignant lesions. 17 As expected, there were few cases of more uncommon neoplasias, such as phyllodes tumor, lobular carcinoma, and medullary carcinoma, and no cases of other types of rare carcinomas, such as Figure 2. A, Suggestive lobulated solid nodule with indistinct margins, hypoechoic homogeneous content, and marked posterior shadowing in a 53-year-old woman with a previous breast biopsy. It was not possible to measure the anteroposterior dimension because of the shadow. The BI-RADS classification was category 4. Pathologic examination revealed evidence of fibroadenosis. B, Palpable suggestive irregular nodule with microlobulated margins, hypoechoic heterogeneous content, and horizontal long axis orientation but without posterior acoustic features in a 38-year-old woman. The BI-RADS classification was category 4. Pathologic examination revealed evidence of an infiltrating ductal carcinoma. B J Ultrasound Med 2005; 24:

6 Risk of Malignancy in Solid Breast Nodules Figure 3. Nonpalpable solid nodule, highly suggestive of malignancy, with indistinct and microlobulated margins, hypoechoic heterogeneous content, anteroposterior dimension larger than width, and posterior shadowing in a 47-year-old patient. The BI- RADS classification was category 5. Pathologic examination revealed evidence of an infiltrating ductal carcinoma. mucinous carcinoma, tubular carcinoma, papillary carcinoma, and adenoid cystic carcinoma. We know from the literature that certain tumors can be wrongly diagnosed as benign on sonography because their margins are usually smoother than those of ductal carcinomas. 7,18 It is important to point out that, in this study, 3 cases of cancer (2.3%) did not have any of the features thought to suggest malignancy on sonography. This frequency of false-negative results was similar to what was expected for a BI-RADS category 3 mammographic classification, probably benign, for which biannual mammography is advocated to avoid more invasive biopsy procedures. 19 It is important to note that false-negative results occurred only in patients 40 years of age and older. Some elements are still waiting for a better definition; the patient s age, size of the lesion, and associated factors can be decisive for estimating the risk of breast cancer, thus decreasing the number of false-negative results. Several types of indices for sonographic assessment have been tested with the objective of improving the accuracy of the sonographic method for the diagnosis in solid breast lesions. The Michelin and Levy score, the Roche score, and the BI-RADS system are some examples. 12,15,20 22 These different scores may help improve the accuracy of sonographic imaging. However, more discussion is needed as a first step toward a consensus on the relevant, less subjective, and more reproducible features. Regarding this research, some conclusions can be derived. Sonographic imaging can help in the diagnosis of solid breast nodules. The risk of malignancy in solid breast nodules increases with age and tumor size. That risk is increased in those solid nodules that have at least 1 of these features: a lack of circumscribed margins, heterogeneous echo patterns, thickened Cooper ligaments, and an increased anteroposterior dimension. We think that when any of these features is observed in a breast nodule, the physician must consider referring the patient for a biopsy. The risk is also increased for older patients and for larger tumors. The presence of an anterior echogenic rim and posterior shadowing in solid breast nodules are frequently associated with malignancy; however, the multivariate analysis did not show any statistical significance. The larger the malignant tumor, the easier it is to note thickening of the Cooper ligaments, the presence of heterogeneous internal echo patterns, and the presence of an anterior echogenic rim. References 1. Marussi EF. Análise da morfologia ultra-sonográfica aliada à colordopplervelocimetria na previsão do diagnóstico histológico dos nódulos sólidos da mama. In: Faculdade de Ciências Médicas. Campinas, Brazil: Universidade Estadual de Campinas; 2001: Kobayashi T, Takatani O, Hattori N, Kimura K. Differential diagnosis of breast tumors: the sensitivity graded method ultrasonotomography and clinical evaluation of its diagnostic accuracy. Cancer 1974; 33: Kossoff G. Causes of shadowing in breast sonography. Ultrasound Med Biol 1988; 14(suppl 1): Leucht WJ, Rabe DR, Humbert KD. Diagnostic value of different interpretative criteria in real-time sonography of the breast. Ultrasound Med Biol 1988; 14(suppl 1): Guyer PB, Dewbury KC, Rubin CM, Butcher C, Royle GT, Theaker J. Ultrasonic attenuation in fibroadenoma of the breast. Clin Radiol 1992; 45: Skaane P, Engedal K. Analysis of sonographic features in the differentiation of fibroadenoma and invasive ductal carcinoma. AJR Am J Roentgenol 1998; 170: J Ultrasound Med 2005; 24:

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