Clinicopathologic characteristics of early-onset Becker s nevus in Korean children and adolescents

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1 Report Clinicopathologic characteristics of early-onset Becker s nevus in Korean children and adolescents Young J. Kim 1, *, MD, Mi R. Roh 2, *, MD, PhD, Ji H. Lee 2, MD, Jung I. Na 3, MD, PhD, Joo Y. Ko 4, MD, PhD, Joon M. Jung 1, MD, Jong H. Lee 5, MD, PhD, and Sung E. Chang 1, MD, PhD 1 Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, 2 Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, 3 Department of Dermatology, Seoul National University Bundang Hospital, Gyeonggi-do, Korea, 4 Department of Dermatology, Hanyang University College of Medicine, Seoul, Korea, and 5 Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence Sung Eun Chang, MD, PHD Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43- gil, Songpa-gu, Seoul, 05505, Korea changse2016@gmail.com * These two authors contributed equally as first authors. Abstract Background Becker s nevus (BN) presents as a hairy patch or plaque with or without proliferation of the dermal smooth muscles. BN has been described as acquired as found in a similar entity, congenital smooth muscle hamartoma (CSMH). This study was aimed at evaluating the clinicopathological aspects of BN in Korean cases in differential diagnosis with CSMH. Methods We performed a retrospective study of 103 patients histopathologically diagnosed as having BN or CSMH. The cases included 40 cases diagnosed with BN or CSMH before the age of 10 years who had clinical monitoring and a second skin biopsy after puberty to determine the disease course. Results Among cases of children to adolescents (<18 years), we observed a slight male predominance. Among children aged <14 years, sex ratio converged at 1:1. Early-onset BN showed a female predominance and hyperpigmented skin lesions. All BN cases showed hyperpigmentation, and face and neck involvement tended to make severe cosmetic concerns. In contrast, hypertrichosis was more frequent in CSMH. Either skin-colored lesion or pseudo-darier s sign was not seen in early-onset BN. BN showed less dermal smooth muscle than CSMH. Conclusions Androgens themselves do not seem to be related to the development of BN but play only an aggravating role especially in male patients. Considering high occurrence in exposed areas, BN may distress patients severely. As early laser treatment may be helpful in some patients with BN, early-onset BN in comparison to CSMH should be diagnosed appropriately. Funding Source: The authors consent for publication. Conflict of interest: The authors declare no conflicts of interest. Introduction Becker s nevus (BN) typically presents as an acquired hairy patch or plaque with somewhat increased smooth muscle, most likely the arrector pili muscles. Although BN is encountered commonly after puberty, considering its hamartomatous nature of BN, it is more rational that BN might develop at early childhood or even at birth. 1,2 In the pathogenesis of BN, androgens may play a role, as evidenced by its peripubertal development, male preponderance, hypertrichosis, occasional development of acneiform lesions within the patches, and increase in the number of androgen receptors in BN lesional skin. 3,4 BN becomes hairy and darker under the influence of androgens, and thus more visible, during and after puberty. There is another entity of hamartoma composed of smooth muscles, smooth muscle hamartoma. Congenital smooth muscle hamartoma (CSMH) is a cutaneous plaque or nodule characterized histologically by smooth muscle hyperplasia of the deep dermis. 5,6 Hypermelanosis of the basal layer and hypertrichosis, which are the features of BN, may also be encountered in CSMH. 5 7 Owing to these similar clinicopathological features, some authors suggested that BN and CSMH be included in the same spectrum of cutaneous hamartomas. 8,9 Others have characterized these two conditions as separate clinicopathological 55

2 56 Report Characteristics of early-onset Becker s nevus Kim et al. entities. 1,5,10 Hence, we evaluated the clinical characteristics of 103 patients who were diagnosed as having BN or CSMH in order to rediagnose for differential diagnosis. Among patients, 40 who were diagnosed with BN or CSMH before the age of 10 years were prospectively monitored to determine the nature of the disease course with increasing age. Becker s nevus (n = 93) Total (n = 103) Congenital smooth muscle hamartoma (n = 10) Materials and Methods Patients We retrospectively identified 103 patients from five hospitals in Korea (Asan Medical Center, Gangnam Severance Hospital, Hanyang University Hospital, Seoul National University Bundang Hospital, Samsung Medical Center) who were diagnosed as having either BN or CSMH between January 2006 and February Their medical records and photographs were reviewed. Data noted from reviewing the medical records, including age, sex, age at onset, signs and symptoms of disease, location and morphology of the lesions, associations with cutaneous alterations, and histopathological findings, were analyzed for each patient. Diagnosis of BN or CSMH was based on clinicopathological findings. Histopathological evidence of dermal smooth muscle bundles was the main criteria for the diagnosis of CSMH. Patients with no pathological data were excluded. The patients were divided into the BN and CSMH groups. The BN group was divided according to age at onset before or after 10 years. We defined childhood as before the age of 10, considering the mean beginning age of puberty in Korean children. The institutional review boards of the hospitals approved this retrospective study. Follow-up assessments Among the patients, 30 and 10 had BN and CSMH, respectively, before the age of 10 years. The medical records, photographs, and skin biopsy slides of 40 patients were reviewed retrospectively for clinical follow-up. The follow-up duration ranged from 1 to 15 years. To evaluate the nature of the lesion, skin biopsies were performed prospectively in 12 patients after age 18 years. Results Patients with BN Of the 93 patients with BN (Fig. 1), 60 (64.5%) were male and 33 (35.5%) were female. The ages at initial diagnosis ranged from 0 to 75 years (mean standard deviation [SD], years), and the ages at onset ranged from 0 to 59 years ( years). In 18 patients (19.3%), the BN or CSMH was regarded as congenital. Focusing on the children (age 18 years), of 42 cases, 25 (59.5%) were male and 17 (40.5%) were female. In the female patients, the mean age at onset was years, which is significantly earlier than that in male patients ( years, P = 0.006). Based on our Onset at birth (n = 18) Onset age 10 (n = 30) The other (n = 12) Onset age > 10 (n = 63) Figure 1 Flowchart of the patients included in the study. Classification of the patients according to clinicopathological diagnosis and age at onset review of the skin biopsy slides of 35,770 patients, we found that the estimated prevalence of BN was 0.26%. The most common site for BN was the trunk (39.8%), followed by the face (22.1%; Table 1). Multiple lesions were observed in 17 patients (18.2%), of who 2 showed separate lesions without anatomical continuum. Patients with early-onset BN before 10 years of age Of the 30 patients identified as patients with BN before age 10, females were predominant (17/30, 56.6%). Patient ages at initial diagnosis ranged 0 25 years ( years). Patient ages at first onset ranged 0 10 years ( years). All lesions were identified at birth (60.0%) or before the age of 10 (40.0%). At initial presentation, the lesion clinically showed hyperpigmentation in 30 cases (100.0%), hypertrichosis in 20 cases (66.7%), and grouped follicular papules in 10 cases (33.3%) (Fig. 2A). Skin biopsy revealed epidermal changes such as acanthosis in 25 cases (83.3%), melanocytic proliferation in 18 cases (60.0%), vellus hair in 9 cases (30.0%), and the presence of dermal smooth muscles in 13 cases (43.3%) (Fig. 2B). To characterize the natural course of BN, all patients data were followed up until the last visit. The age at final follow-up ranged ( years). In all patients, the clinical features of the lesions showed prominent changes after puberty. Increased hyperpigmentation was seen in 20 cases (66.7%) and hypertrichosis in 21 cases (70.0%) (Fig. 3). In addition, nine patients showed aggravation of other epidermal changes, such as accentuation of grouped follicles or thickening. In the 12 patients who underwent follow-up biopsy, increased epidermal changes such as acanthosis, papillomatosis, and fusion of adjacent rete ridges were revealed (Fig. 4). The features of the disease at final followup were compatible with a diagnosis of BN in all patients. Patients with CSMH Of the 10 patients included as patients with CSMH, 7 (70.0%) were males and 3 (30.0%) females. Patient ages at initial International Journal of Dermatology 2018, 57, ª 2017 The International Society of Dermatology

3 Kim et al. Characteristics of early-onset Becker s nevus Report 57 Table 1 Locations of clinicohistopathologically diagnosed Becker s nevus according to disease onset Site Lesion a Early childhood (0 10 years) Late childhood (11 18 years) Early adulthood (19 39 years) Late adulthood (40 75 years) Face 25 (22.1) 1 (8.3) 12 (22.2) 8 (20.5) 4 (50.0) Neck 11 (9.7) 2 (3.7) 7 (17.9) 2 (25.0) Trunk 45 (39.8) 7 (58.3) 21 (38.9) 15 (38.5) 2 (25.0) Nonspecified area 27 (23.8) 6 (50.0) 12 (22.2) 8 (20.5) 1 (12.5) Mammary region 11 (9.7) 1 (8.3) 3 (5.6) 6 (15.3) 1 (12.5) Scapular region 7 (6.2) 6 (11.1) 1 (2.6) Buttocks 6 (5.3) 1 (8.3) 3 (5.5) 2 (5.1) Arms 13 (11.5) 1 (8.3) 8 (14.8) 4 (10.2) Legs 13 (11.5) 2 (16.7) 8 (14.8) 3 (7.7) Total 113 a (100) 12 (100) 54 (100) 39 (100) 8 (100) a Multiple skin lesions were, respectively, counted. (A) Figure 2 (A) Clinical presentation of Becker s nevus. A hyperpigmented large brownish patch with prominent hypertrichosis located on the right thigh. (B) Histopathological findings of Becker s nevus. A few to minimally increased number of smooth muscle cells can be observed in the dermis. The overlying epidermis shows slightly elongated rete ridges and diffuse basal layer hyperpigmentation (a: hematoxylin-eosin [H&E] stain, original magnification 940; b: H&E stain, original magnification 9100) (B) a b diagnosis ranged 0 16 years ( years). Patient ages at first onset ranged 0 4 years ( years). Nine patients were identified as congenital cases. The most common site for CSMH was the back (40.0%), followed by the arm (20.0%) (Table 3). As 10 cases were identified from 35,770 reviewed patients slides, the prevalence of CSMH was estimated as 0.028%. All lesions were identified at birth (90.0%) except one case identified at the age of 14. At initial presentation, the lesion clinically showed hyperpigmentation in five cases (50.0%), hypertrichosis in nine cases (90.0%), and accentuation of grouped follicles in one case (10.0%) (Table 3; Fig. 5A). Skin biopsy revealed epidermal changes such as acanthosis in nine cases (90.0%), melanocytic proliferation in one case (10.0%), vellus hair in seven cases (70.0%), and the presence of dermal smooth muscles in all

4 58 Report Characteristics of early-onset Becker s nevus Kim et al. (a) (b) Figure 3 Clinical features of the neck showing (a) mild hyperpigmented patches at the time of clinicopathological diagnosis at age 8 years and (b) dark brownish pigmented hairy patches at age 15 years (a) (b) Figure 4 Histopathological features of the neck showing (a) hair follicles and smooth muscle fiber in the dermis at the time of diagnosis at age 8 years and (b) showing increase in epidermal changes, including acanthosis, papillomatosis, and fusion of adjacent rete ridges, at age 15 years (a: hematoxylin-eosin [H&E] stain, original magnification 9100 [inset, 9400], b: H&E stain, original magnification 9100) cases (100.0%) (Fig. 5B). Dermal smooth muscle was found through papillary dermis to deep reticular dermis in CSMH, unlike BN, which was merely found in papillary dermis. The age at final follow-up ranged 2 26 ( years). Two patients were adults (ages 19 and 26), whose clinical lesions had not been aggravated after puberty. Comparison of clinical aspects between BN and CSMH before age of 10 In order to find a clue for the differential diagnosis between BN and CSMH, we compared both patients with BN and CSMH. All patients were diagnosed with skin biopsy and under age of 10. Of the 35,770 patient slides reviewed, BN was more frequently observed, three times more than CSMH. Among 30 patients with BN whose ages at onset were before the age of 10, 9 patients were excluded in the analysis because we could not re-review the clinical photos. All clinical data were summarized on Table 3. BN patients showed female predominance in contrast to CSMH patients. Hyperpigmentation was more frequent in BN patients than CSMH patients (100%, 50.0%, respectively). Hypertrichosis was predominantly observed in CSMH patients (90.0%), which was almost half as frequent in BN patients (57.1%). Pseudo-Darier s sign was observed in 80% of CSMH patients. Due to the small sample size, statistical analysis was impossible. Discussion Becker s nevus (BN) was first described as acquired melanosis and hypertrichosis in unilateral distribution. 11 BN has been classically described as an acquired, between the first and second decade of life, hyperpigmented and hypertrichotic patch, usually appearing on the shoulders, anterior chest, or scapular region of male patients in the peripubertal period or early adulthood. 5,12 On the other hand, congenital smooth muscle hamartoma (CSMH) is typically observed at birth or early infancy and characterized by a localized skin-colored or mildly hyperpigmented patch, plaque, or nodule with prominent vellus hairs. 5 CSMH may also present with hypermelanosis of the basal layer and hypertrichosis, 7 which are common features of BN. The similarity of clinicopathological features of the two diseases and the lack of specific diagnostic criteria for CSMH and BN makes the differential diagnosis challenging. Our multicenter study of patients diagnosed with BN or CSMH was designed to identify characteristics of these patients. CSMH presents as hairy patches with increased dermal smooth muscle fibers at birth, but congenital cases of BN were under-recognized perhaps due to misdiagnosis. Unlike its reported rarity, 13,14 we found that 26.5% of BN cases onset was congenital or early infancy among patients aged <18 years in our study (Table 2). Similarly, a recent Italian study of 118 children with BN found that the peak incidence of BN onset was observed at birth (26.3% of cases) rather than at puberty. 2 As BN often shows only basal hyperpigmentation with minimal smooth muscle hyperplasia, it is clinicopathologically confused with cafe au lait (CAL) spot. In fact, four (13.3%, all female) of our cases of early-onset or congenital BN were misdiagnosed as CAL, although they were diagnosed as BN after International Journal of Dermatology 2018, 57, ª 2017 The International Society of Dermatology

5 Kim et al. Characteristics of early-onset Becker s nevus Report 59 (A) (B) a b Figure 5 (A) Clinical presentation of congenital smooth muscle hamartoma. Hypertrichosis with vellus hair and a slightly hyperpigmented patch on the right thigh. (B) Histopathological findings of congenital smooth muscle hamartoma. Numerous dermal smooth muscle bundles are oriented in haphazard directions. The hyperkeratosis, papillomatosis, and acanthosis are found in the epidermis (a: hematoxylin-eosin [H&E] stain, original magnification 940; b: H&E stain, original magnification 9100) Table 2 Clinical aspects of Becker s nevus diagnosed before age 18 years Characteristics Korean Italian 2 France 23a Brazilian 24 Chinese 25b Prevalence 1.11% 0.25% 0.52% 4.19% Sex ratio 1.4 : : 1.1 c c 4.5 : 1.0 Location Trunk (38.7%) Trunk (59.3%) Trunk (32.0%) Shoulder (69.5%) Shoulder (31.7%) Face (22.5%) Face (0.8%) Face (1.1%) Face (6.7%) Neck (3.8%) Neck (2.5%) Neck (2.1%) Neck (3.3%) Multiple lesions 6.25% 5.08% 3.16% 6.6% Hyperpigmentation 100% 100% 75.0% Hypertrichosis 57.8% 31.3% About 50% 23.2% 68.3% Male 64.8% (n = 60) 67.3% (n = 33/49) Female 48.1% (n = 33) 72.2% (n = 8/11) Associated factor Sun exposure, darker skin Sun exposure Sun exposure Darker skin Onset 26.5% congenital, 43.7% before age 10 years 26.3% congenital 50% before age 10 years 6.7% congenital, 20% before age 10 years a The study population consisted of male patients aged years. b The study population consisted of patients aged years. c The survey was performed only for male patients. puberty. As BNs in female patients are less likely to be hypertrichotic, early-onset BN tends to be misdiagnosed as CAL. Remarkably, our data showed that all of the cases that were indefinitely diagnosed as BN before age 10 years were diagnosed as BN at follow-up after the age of 18 years. We found that all the patients had aggravated skin lesions after puberty, which shows the typical clinicopathological features of BN. Increased hyperpigmentation and hypertrichosis were

6 60 Report Characteristics of early-onset Becker s nevus Kim et al. Table 3 Clinical features of Becker s nevus and congenital smooth muscle hamartoma that developed and was clinicopathologically diagnosed before age 10 years Characteristics BN CSMH Total patients, n Age, years (mean SD) Sex ratio (male : female) 1 : : 1 Location Thigh (7), face (4), flank (3), chest (2), arm (2), buttock (2), back (1) Back (4), arm (2), chest (1), thigh (1), flank (1), buttock (1) Hyperpigmentation 21 (100%) 5 (50.0%) Hypertrichosis 12 (57.1%) 9 (90.0%) Accentuation of 3 (14.3%) 1 (10.0%) grouped follicles Pseudo-Darier s sign 0 8 (80.0%) observed in 20 (66.7%) and 21 cases (70.0%), respectively, in a skin biopsy performed after puberty. For the role of androgens in BN, our data would support the androgen-related hypothesis because hypertrichosis is more frequently observed in male patients (64.8%) than in female patients (48.1%) as shown in Table 2. Conversely, unlike BN, hypertrichosis and hyperpigmentation often decrease with age in CSMH. 15,16 The key features of CSMH include smooth muscle hyperplasia of the reticular dermis with variably oriented, well-defined bundles of smooth muscle. 1,5,6,17,18 BN also frequently exhibits dermal smooth muscle proliferation on histological examination but does not appear as a mass or bundle-like structure. Considering the clinicopathological differences between BN and CSMH, as shown in our study, several aspects may provide additional information for differential diagnosis (Table 3). First, early-onset BN has a female predominance in contrast to CSMH, which has a male predominance. Second, CSMH may manifest as a hyperpigmented or skin-colored lesion, but earlyonset BN shows hyperpigmentation in all patients. Third, hypertrichosis is more frequently found in CSMH than in early-onset BN. Finally, a pseudo-darier s sign that rubbing over the CSMH lesion induces transient erythema or induration, 19 is never observed in early-onset BN. Lastly, BN is not uncommonly seen in Asians, but estimated prevalence of CSMH is as rare as 1 : 2600 to 1 : 2700 live births. 17 Therefore, we suggest that an early-onset pigmented patch with few vellus hairs and with a sparse smooth muscle hyperplasia in Asians is better to be diagnosed as BN rather than CSMH. The importance of differentiation between BN and CSMH is mainly derived from the different treatment strategies. The early proper diagnosis of BN may facilitate laser treatments such as Qs-Nd:YAG laser and Alexandrite laser before puberty, and this could prevent progression of BN, which is a disfiguring condition. By contrast, CSMH usually does not require surgical or aggressive laser therapy. Recently, a case of facial CSMH was well treated with 595-nm-pulsed dye laser. 20 An interesting observation from our study is the clinical characteristics of Korean BN. Among children to adolescent (<18 years) aged subjects, we observed a slight male predominance (Table 2). However, when we analyzed the data of patients aged <14 years, we found that 10 patients (55.5%) were female and 8 (45.5%) were male, so the sex ratio converged at 1 : 1. This fact would also support the androgenrelated hypothesis. In the literature, the reported male-to-female ratios vary from 4 : 1 to 6 : 1. 4 Alfadley et al. 21 reported that the true sex ratio may be 1 : 1, while other studies reported higher numbers of female patients with BN. 2,22 Female BN cases show less hypertrichosis, resulting in lower clinic visit after puberty (Table 2). In our Korean cases, the relatively higher face and neck involvement is also noticeable (Table 2). As all patients would show hyperpigmentation, BN on the exposed area such as the face and neck would be cosmetically sensitive, which may lead many patients to visit dermatology departments for cosmetic problems. Moreover, in Korean patients, BN was not accompanied by other systemic diseases, causing only cosmetic problems and not functional problems. In conclusion, considering high occurrence of BN in females and exposed areas, BN may distress patients severely. As early laser treatment may be helpful in some patients with BN, earlyonset BN in comparison to CSMH should be diagnosed appropriately. The main limitations of this study include retrospective design, multicenter study, and potent bias in data collections. Although more patients are needed to clarify whether BN and CSMH are two distinct entities, hopefully our analysis of the clinical aspects of Korean BN and comparison between earlyonset BN and CSMH would help clinicians to establish the proper diagnosis and treatment plan. 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