Ultrasound Assessment of Breast Development: Distinction Between Premature Thelarche and Precocious Puberty

Transcription

1 Pediatric Imaging Original Research Youn et al. Ultrasound Assessment of Breast Development Pediatric Imaging Original Research Inyoung Youn 1 Sung Hee Park 2 In Seok Lim 3 Soo Jin Kim 2 Youn I, Park SH, Lim IS, Kim SJ Keywords: breast growth and development, hormones, precocious puberty, ultrasound DOI: /AJR Received January 17, 2014; accepted after revision May 25, Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea. 2 Department of Radiology, Chung-Ang University Hospital, Heukseok-dong, Dongjak-gu, Seoul, Korea. Address correspondence to S. J. Kim (ksj1567@hanmail.net). 3 Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea. AJR 2015; 204: X/15/ American Roentgen Ray Society Ultrasound Assessment of Breast Development: Distinction Between Premature Thelarche and Precocious Puberty OBJECTIVE. We analyzed the correlation between breast development and ultrasoundmeasured breast bud diameter. We also evaluated different breast ultrasound findings in pediatric subjects with precocious puberty and premature thelarche while comparing bone age and hormone levels. MATERIALS AND METHODS. We performed a retrospective study with a sample of 90 girls (mean age, 7.8 years) who underwent breast ultrasound for evaluation of early breast development between March 2011 and February We evaluated breast ultrasound grade, bud diameter, and clinical characteristics including bone age and hormone levels. Among the 90 girls, 69 were up to 8 years old (mean age, 7.3 years). We divided them into healthy, precocious puberty, and premature thelarche groups and evaluated the clinicoradiologic findings for each group. RESULTS. Breast ultrasound grade was correlated with age, bone age, bud diameter, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E 2 ). Bud diameter was correlated with age, bone age, LH, FSH, and E 2. However, the difference between bone age and chronological age was not correlated with ultrasound grade or bud diameter. Among 69 girls up to 8 years old, including 11 healthy girls (15.9%), 26 girls with precocious puberty (37.7%) (mean [SD] age, 7.3 years), and 32 girls with premature thelarche (46.4%) (mean age, 7.2 years), there were no significant differences in other variables except values for bone age (p 0.001) and difference between bone age and chronological age (p < 0.001). CONCLUSION. Breast ultrasound might be useful for evaluating sexual development with respect to bud diameter or ultrasound grade. However, its ability to distinguish precocious puberty from premature thelarche is limited. U ltrasound is an easy, valuable modality to evaluate breast condition, but it is rarely used in children because pathologic conditions are unusual during this period [1]. However, physicians are using ultrasound more often than they have in the past to diagnose breast development in young girls. The Tanner scale divides breast development into 5 stages based on physical description [2, 3]. If ultrasound could be used for quantitative evaluation of breast parenchyma, including visual assessment and degree, then we could classify breast development by ultrasound Tanner stage, which would be more objective, simple, and reproducible than the conventional Tanner scale. Premature thelarche is defined as isolated early breast development without bone maturation in girls up to 8 years old and does not require therapy [4, 5]. In contrast, precocious puberty is defined as the development of secondary sex characteristics including growth acceleration or bone maturation in girls up to 8 years old, and early initiation of treatment is required [4, 5]. It is important to distinguish precocious puberty from premature thelarche to make early decisions about treatment; however, it is very difficult to distinguish them at initial presentation because both are characterized by breast budding. If breast ultrasound could distinguish between precocious puberty and premature thelarche, it would provide valuable assistance in making treatment decisions in patients with precocious puberty. However, to our knowledge, there have been only two English publications regarding ultrasound findings of normal breast development [3, 6]. Another report found that breast ultrasound findings were correlated with bone age and hormonal status in premature thelarche and precocious puberty [7]. 620 AJR:204, March 2015

2 Ultrasound Assessment of Breast Development TABLE 1: Breast Ultrasound Grades With Detailed Characteristic Findings Compared With Clinical Tanner Stages Grade Tanner Stage Ultrasound Grade I Elevation of papilla only Prepubertal stage; ill-defined hyperechoic retroareolar tissue II Elevation of breast and papilla as a small mound; enlargement of Palpable subareolar bud before elevation; hyperechoic retroareolar nodule with areola diameter central star-shaped or linear hypoechoic area III IV V Further enlargement of breast and areola with no separation of their contours Projection of areola and papilla to form a secondary mound above the level of the breast Projection of papilla only, due to recession of the areola to the general contour of the breast The purpose of the present study was to analyze the correlation between breast development and ultrasound-measured breast bud diameter. We also evaluated breast ultrasound findings in pediatric subjects with precocious puberty and premature thelarche while comparing bone age and hormone levels. Materials and Methods Between March 2011 and February 2013, 107 girls who had undergone breast ultrasound for evaluation of early breast development at our institution were recruited for this study. Seventeen patients were excluded because they had no record of bone age or laboratory data such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E 2 ). Thus, we included 90 girls (mean age, 7.8 years; range, 2 12 years) in the final sample. Our institutional review board approved this retrospective study, and informed consent was waived for the review of images and records. Real-time gray-scale ultrasound was performed using a 5 12-MHz linear-array transducer (iu22, Philips Healthcare), and all ultrasound scans were retrospectively reviewed by two breast radiologists. We categorized breast ultrasound grades into the 5 Tanner stages according to characteristic ultrasound findings, as summarized in Table 1, using the larger of the two breasts (Fig. 1) [6]. Obvious enlargement and elevation; extending hyperechoic glandular tissue away from the retroareolar areas with central spider-shaped hypoechoic region Transient areolar mounding; hyperechoic periareolar fibroglandular tissue with prominent central hypoechoic nodule and sometimes subcutaneous adipose tissue Mature breast contour; hyperechoic glandular tissue with increased subcutaneous fat tissue and without hypoechoic central nodule Bud diameter was defined as the longest diameter (in centimeters) of fibroglandular echogenic area in the larger of the two breasts on ultrasound images, including the nipple, as determined by two radiologists. Bone age was measured according to the Greulich and Pyle scale [8], and the difference between bone age and chronological age was also calculated. Hormonal evaluations were obtained via outpatient blood tests. Basal LH levels were assessed using a MiniVIDAS apparatus (VIDAS 12, 1992, BioMérieux) and an enzyme immunoassay technique, and the basal levels of FSH and serum E 2 were measured using direct chemiluminescence and the ADVIA Centaur CP Immunoassay System (Siemens Healthcare). From the 90 subjects, we excluded 21 girls over 8 years old and reclassified the remaining 69 girls (mean age, 7.3 years; range, 2 8 years) up to 8 years old into precocious puberty, premature thelarche, and healthy groups. Precocious puberty was diagnosed in girls with advanced bone age greater than 2 SDs of chronologic age. We diagnosed premature thelarche in girls with breast development greater than Tanner stage II but within the normal range in bone age. The healthy group was defined as belonging to Tanner stage I by breast ultrasound and within the normal range in bone age. All statistical analyses were performed using PASW Statistics (version 18.0, IBM). Categoric TABLE 2: Clinical and Hormonal Characteristics of Subjects in Each Ultrasound Grade data were summarized as frequencies and percentages. Spearman correlation or Pearson correlation analysis was used to evaluate the relationships among breast ultrasound grades, bud diameter, difference between bone age and chronological age, and laboratory results for FSH, LH, and E 2 levels. In girls up to 8 years old, Mann- Whitney U tests were used to analyze precocious puberty and premature thelarche group differences in variables after excluding patients in the healthy group. Statistical significance was established as a two-sided p value of less than Results The clinical data for each ultrasound grade are summarized in Table 2. Among the total sample of 90 girls, the distribution of breast ultrasound grade was as follows: grade I, 18 girls (20.0%); grade II, 30 girls (33.3%); grade III, 26 girls (28.9%); grade IV, 15 girls (16.7%); and grade V, one girl (1.1%). The mean bud diameter of each group is presented in Table 2, and the median values were 0.5 cm in grade I, 2.0 cm in grade II, 2.9 cm in grade III, 3.6 cm in grade IV, and 12 cm in grade V. Breast ultrasound grade was positively correlated with age (p 0.003, r s 0.307); bone age (p 0.009, r s 0.275); bud diameter (p < 0.001, r s 0.891); Parameter Grade I (n 18) Grade II (n 30) Grade III (n 26) Grade IV (n 15) Grade V (n 1) p Age (mo) 97.8 ± ± ± ± Bone age (mo) ± ± ± ± BD (cm) 0.5 ± ± ± ± < BA-CA (mo) 2.6 ± ± ± ± LH (miu/ml) 0.1 ± ± ± ± < FSH (miu/ml) 1.6 ± ± ± ± < E 2 (pg/ml) 16.5 ± ± ± ± Note Continuous variables are expressed as mean ± SD. Spearman correlation was used to evaluate associations of breast ultrasound grade with variables. BD breast bud diameter (as measured on ultrasound), BA-CA difference between bone age and chronological age, LH luteinizing hormone, FSH follicle-stimulating hormone, E 2 estradiol. AJR:204, March

3 Youn et al. and levels of LH (p < 0.001, r s 0.469), FSH (p < 0.001, r s 0.531), and E 2 (p 0.012, r s 0.265). Bud diameter was also positively correlated with age (p 0.047, r s 0.210); bone age (p 0.016, r s 0.253); and levels of LH (p < 0.001, r s 0.537), FSH (p 0.001, r s 0.348), and E 2 (p 0.001, r s 0.397). However, there were no significant differences in either ultrasound grade (p 0.679) or bud diameter (p 0.788) with respect to difference between bone age and chronological age. Among the 69 subjects up to 8 years old, we excluded 11 healthy girls (15.9%), and 26 girls (37.7%) (mean age, 7.3 ± 1.0 years; range, 5 8 years) received diagnosis of precocious puberty; 32 girls (46.4%) (mean age, 7.2 ± 1.4 years; range, 2 8 years) retrospectively received diagnosis of premature thelarche. The differences between the groups in the values for bone age (p 0.001) and difference between bone age and chronological age (p < 0.001) were statistically significant; however, there were no significant differences between the groups in terms of the other variables (Table 3). Discussion In women, breast buds enlarge and glandular formation occurs under the influence TABLE 3: Clinical, Hormonal, and Ultrasound Data in Girls With Precocious Puberty and Premature Thelarche Parameter Precocious Puberty Group (n 26) of hormones during sexual maturation. Physiologic changes include increased volume of subcutaneous fat and connective tissues, ductal proliferation and elongation, and development of terminal duct lobular units [3, 6]. Puberty is defined as the transition from child to adult, which is a dynamic, complex period in development with somatic growth and sexual maturation, under the influence Premature Thelarche Group (n 32) Age (mo) 93.4 ± ± Bone age (mo) ± ± Ultrasound grade 2.4 ± ± BD (cm) 2.6 ± ± BA-CA (mo) 17.0 ± ± 8.0 < LH (miu/ml) 0.3 ± ± FSH (miu/ml) 2.5 ± ± E 2 (pg/ml) 19.7 ± ± Note Continuous variables are expressed as mean ± SD. Mann-Whitney U tests were used to evaluate associations of breast ultrasound grade with variables. BD breast bud diameter (as measured on ultrasound), BA-CA difference between bone age and chronological age, LH luteinizing hormone, FSH follicle-stimulating hormone, E 2 estradiol. A of multiple genetic and endocrine controls such as increased gonadal hormone levels [2]. The Tanner scale is widely used to grade normal breast development into five stages in pubertal girls [2, 3]. However, this classification is based on physical descriptions without consideration of other factors such as ultrasound findings. Areas of fat deposition could be mistaken for true breast budding owing C D Fig. 1 Breast ultrasound grades with characteristic findings [6]. A, Grade I. Gray-scale ultrasound image of 7-year-old girl shows ill-defined hyperechoic area in retroareolar region and ultrasound-measured breast bud diameter of 0.5 cm. B, Grade II. Gray-scale ultrasound image of 7-year-old girl shows hypoechoic core within hyperemic parenchyma confined within subareolar area and bud diameter of 2 cm. C, Grade III. Gray-scale ultrasound image of 7-year-old girl shows hypoechoic area with first branching pattern surrounding hyperechoic area beyond subareolar region and bud diameter of 2.9 cm. D, Grade IV. Gray-scale ultrasound image of 8-year-old girl shows secondary branching hypoechoic area surrounding large amount of hyperechoic parenchyma and bud diameter of 5.2 cm. (Fig. 1 continues on next page) p B 622 AJR:204, March 2015

4 Ultrasound Assessment of Breast Development to current trends in dietary changes in modern children, and that can lead to suspected breast enlargement. Therefore, the accuracy of Tanner staging is in some cases doubtful. Breast ultrasound is a simple, objective method that can be used to assess the presence or absence and extent of fibroglandular tissue. Visualization of developing stages by breast ultrasound is a more accurate and quantitative method than traditional Tanner staging that is also practical in daily contexts. Recently breast ultrasound has been used more frequently, and its ability to diagnose masses otherwise mistaken for breast buds, as well as to enhance understanding of changes at follow-up, has benefits for clinical practice. García et al. [6] reported the ultrasound characteristics of each Tanner stage in normally developing breasts, but it was only a descriptive report without statistical analysis. In our study, we used García et al. s breast ultrasound grades and found that they positively correlated with bud diameter, age, bone age, and levels of hormones. Recently, Calcaterra et al. [7] reported that breast volume increases with progressive breast ultrasound stage, and they presented the first quantified data using ultrasound in developing breasts. However, measuring breast volume is more complicated than measuring bud diameter. Observing the longest diameter in the fibroglandular echogenic area via ultrasound is simpler than other methods because it is not necessary to understand morphologic changes. Therefore, bud diameter could replace Tanner staging or breast ultrasound grading as a parameter describing breast development. The results would be more reliable because all hormonal levels positively correlated with ultrasound grade and bud diameter. Our results are meaningful because few studies of breast development show correlations between ultrasound quantification and hormonal status [7]. Disorders of premature secondary sexual maturation range across the spectrum from premature thelarche to precocious puberty, and distinguishing between these conditions is important for both prognostic and therapeutic reasons [9, 10]. Precocious puberty is caused by early activation of the hypothalamic-pituitary-gonadal axis, as in normal physiologic puberty, and results in the early progression of secondary sexual maturation and rapid somatic growth [5, 9, 10]. Precocious puberty is also characterized by a difference of either more than 2 SD or 1 year between bone age and chronological age [10, Fig. 1 (continued) Breast ultrasound grades with characteristic findings [6]. E, Grade V. Gray-scale ultrasound image of 8-year-old girl shows normal mature breast composition with subcutaneous fat layer and bud diameter of more than 15 cm. 11]. Measuring hormone levels, including LH, FSH, and E 2, is still the most important diagnostic test, along with gonadotropin-releasing hormone (GnRH) stimulation tests, to diagnose precocious puberty, but it is very difficult. Neely et al. [12] reported that spontaneous FSH and LH levels are also useful screening tools for precocious puberty, and Houk et al. [13] reported that a single basal LH measurement is adequate to evaluate the hypothalamic-pituitary-gonadal axis in most cases. We evaluated basal gonadotropin levels without GnRH stimulation tests because these data were not available for all patients; however, there was no significant difference between the precocious puberty and premature thelarche groups. Regarding the parameter of difference between bone age and chronological age, ultrasound grade and bud diameter were not correlated, but the values for difference between bone age and chronological age were significantly different between the precocious puberty and premature thelarche groups; this result suggests that our overall study results are reliable. Longitudinal studies monitoring the progression of bone age, including anthropometric investigations and assessments of breast development, would be helpful to distinguish precocious puberty and premature thelarche as accelerated somatic growth and sexual development are characteristic of precocious puberty. This study has several limitations. First, it was a retrospective study and included only patients who had received ultrasound, left hand and wrist radiographs for bone age, and blood hormone level measurements, leaving open the possibility of selection bias. Second, the number of patients included was small, because breast ultrasound was performed selectively depending on clinician preference and not routinely to diagnose precocious puberty or premature thelarche; in the future, larger-scale clinical studies should be performed. Third, we used only baseline gonadal hormone measurements without GnRH stimulation tests, but we have already explained why this caveat is acceptable. Fourth, this study included only Korean patients, and our results may not be generalizable to other populations. Finally, two radiologists performed ultrasound examinations; therefore, interobserver variability may be an issue both in this study and in clinical practice. In conclusion, breast ultrasound might be useful for evaluating sexual development in pediatric patients with respect to bud diameter or ultrasound grade, but its utility is limited in distinguishing precocious puberty from premature thelarche. A better understanding of the relationship between objective hormonal values and ultrasound findings might allow clinicians to predict hormonal status according to breast ultrasound grade. References 1. West KW, Rescorla FJ, Scherer LR 3rd, Grosfeld JL. Diagnosis and treatment of symptomatic breast masses in the pediatric population. J Pediatr Surg 1995; 30: ; discussion, Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44: Bock K, Duda VF, Hadji P, et al. Pathologic breast conditions in childhood and adolescence: evaluation by sonographic diagnosis. J Ultrasound Med 2005; 24: ; quiz, Salardi S, Cacciari E, Mainetti B, Mazzanti L, Pirazzoli P. Outcome of premature thelarche: relation to puberty and final height. Arch Dis Child E AJR:204, March

5 Youn et al. 1998; 79: Della Manna T, Setian N, Damiani D, Kuperman H, Dichtchekenian V. Premature thelarche: identification of clinical and laboratory data for the diagnosis of precocious puberty. Rev Hosp Clin Fac Med Sao Paulo 2002; 57: García CJ, Espinoza A, Dinamarca V, et al. Breast US in children and adolescents. RadioGraphics 2000; 20: Calcaterra V, Sampaolo P, Klersy C, et al. Utility of breast ultrasonography in the diagnostic workup of precocious puberty and proposal of a prognostic index for identifying girls with rapidly progressive central precocious puberty. Ultrasound Obstet Gynecol 2009; 33: Pyle SI, Waterhouse AM, Greulich WW. Attributes of the radiographic standard of reference for the National Health Examination Survey. Am J Phys Anthropol 1971; 35: Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler GB Jr. Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinizing hormone-releasing hormone. J Clin Endocrinol Metab 1988; 67: Berberoğlu M. Precocious puberty and normal variant puberty: definition, etiology, diagnosis and current management. J Clin Res Pediatr Endocrinol 2009; 1: de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. Eur J Endocrinol 2006; 154: Neely EK, Wilson DM, Lee PA, Stene M, Hintz RL. Spontaneous serum gonadotropin concentrations in the evaluation of precocious puberty. J Pediatr 1995; 127: Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics 2009; 123:e1059 e1063 FOR YOUR INFORMATION The AJR has made getting the articles you really want really easy with an online tool, Really Simple Syndication, available at It s simple. Click the RSS button located in the menu on the right side of the page. You ll be on your way to syndicating your AJR content in no time. 624 AJR:204, March 2015