Juvenile Fibroadenoma with Features of Phyllodes Tumor

Human Pathology: Case Reports (2015) xx, xxx–xxx

http://www.humanpathologycasereports.com

Juvenile fibroadenoma with features of phyllodes tumor showing intraductal growth and prominent epithelial hyperplasia in an 11-year-old girl☆ Jun Miyauchi MD a,b,⁎, Fumiko Yoshida MD c, Seiya Akatsuka MD b, Miwako Nakano MD c aDepartment of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Chiba-ken, Japan 272-8513 bDepartment of Clinical Laboratory, Saitama City Hospital, Saitama, Saitama-ken, Japan 336-8522 cDepartment of Pediatric Surgery, Saitama City Hospital, Saitama, Saitama-ken, Japan 336-8522

Received 3 March 2015; revised 26 June 2015; accepted 7 July 2015

Keywords: Abstract Breast tumors in children are uncommon, with the majority of them being adult-type fibroadenoma Juvenile fibroadenoma; (FA). We report a case of juvenile FA (JFA) with features of a benign phyllodes tumor (PT) in an 11-year-old Phyllodes tumor; girl, showing very unusual intraductal/intracystic growth. The tumor was located at the outer peripheral Intraductal papilloma; portion of the right breast apart from the nipple. Histologically, the tumor showed extensive leaf-like Intraductal growth; papillary structures with a broad fibrous stroma, protruding into multiple contiguous cystic spaces lined by Pediatric breast tumor flat ductal epithelium, and closely resembled PT but the stroma of the tumor was only slightly cellular, showing no nuclear atypia and very few mitotic figures. In contrast, epithelial cells covering the fronds exhibited marked hyperplasia, forming a thick multilayered epithelium. The histology of the tumor with intracystic papillary structures and epithelial hyperplasia showed some similarities with intraductal papilloma (IDP). The mechanism of such unusual intraductal growth of fibroepithelial tumors, including FA/ JFA and PT, and their possible common histogenesis with IDP are discussed. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction (FA), which comprises 44–70% of all breast lesions [1,2]. Although adult-type FA accounts for the large majority (93% Breast tumors are uncommon in children and adolescents. [3]) of FA cases in childhood, a small proportion of The tumor most often seen in these ages is fibroadenoma fibroepithelial tumors clinically show rapid growth, often giving rise to large-sized mass lesions, and pathologically ☆ Conflict of interest: None. exhibit somewhat different histology, including cellular ⁎ Corresponding author at: Department of Pathology and Laboratory stroma and epithelial hyperplasia, which is often florid. Medicine, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba-ken, Japan 272-8513. Tel.: +81 47 322 0151; fax: These tumors are called juvenile fibroadenoma (JFA) [3]. +81 47 325 4456. Phyllodes tumor (PT) is another fibroepithelial tumor, E-mail address: [email protected] (J. Miyauchi). rarely seen (about 1% [1,2,4]) in children. PT is distinguished http://dx.doi.org/10.1016/j.ehpc.2015.07.001 2214-3300/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). 2 J. Miyauchi et al. from FA by higher degree of stromal cell growth and peculiar and her general health condition was good. Physical intracanalicular growth pattern, producing characteristic examination confirmed a well-defined movable mass at the leaf-like structures with very broad cellular fibrous stroma. boundary portion between upper and lower outer quadrants PT is classified into three categories, namely, benign, of her right breast, apart from the nipple. Ultrasonography borderline and malignant, depending on the degree of stromal revealed a slightly lobulated oval tumor with sharply hypercellularity, cytological atypia and mitoses, stromal demarcated smooth margins, measuring 19 × 15 × 10 mm overgrowth, and nature of tumor borders/margins [5]. in diameter (Fig. 1). The tumor showed slightly hypoechoic Although JFA typically lacks an intracanalicular growth homogeneous internal structure with slight posterior echo pattern and leaf-like structures, which characterize PT, JFA may enhancement. No signs of echogenic spots indicative of exhibit such a growth pattern and show considerable overlap- calcification were present. FA was clinically suspected and ping features with benign PT, both clinically as well as the tumor was surgically enucleated. The resected tumor was pathologically [2,4]. Some authors have included benign PT in pathologically diagnosed as JFA with features of benign PT childhood and adolescents into the entity and concept of JFA [4]. as described below and the patient underwent postoperative Here, we report a case of JFA with an extensive phyllodes follow-up with physical examination and ultrasonography at pattern in an 11-year-old girl, which showed extremely unusual 3- to 6-month intervals. She has been well without any signs intraductal growth in multiple contiguous cystic spaces along of recurrence for 3 years since the surgery. with coincident, prominent epithelial hyperplasia, showing some similarities with intraductal papilloma (IDP). Only a limited number of cases of fibroepithelial tumors, including FA 3. Results and PT, showing intraductal/intracystic growth have been reported in the literature, with some of them described as having foci of IDP. These cases may indicate a possible causative link On gross examination, the surgically resected specimen and common histogenesis between intraductal fibroepithelial was a fairly circumscribed tumor, the cut surface of which was tumors and IDP. solid, yellowish white in color, and 17 × 14 mm in diameter. Histologically, the tumor consisted of fibroepithelial cells forming large leaf-like structures with a broad fibrous stroma covered by thick columnar epithelial layers, protruding into 2. Case report multiple contiguous cystic cavities (Fig. 2A and B). This phyllodes pattern was extensively present throughout the An 11-year-old girl visited the hospital since she had tumor, with only a small part showing an intracanalicular FA noticed a palpable lump in her right breast for 5 months, pattern. The inner surface of the cyst wall was covered with a during which it gradually increased the size. She had no thin monolayer of flat ductal epithelium (Fig. 2CandD).The particular past history and family history for breast cancer tumor contained a mildly cellular stroma, with some

Fig. 1 Ultrasonography. The tumor exhibits a slightly lobulated oval mass lesion with smooth margins (arrow heads), slightly hypoechoic homogeneous internal structure and slight enhancement of posterior echoes. 3

A B

C D

E F

Fig. 2 Histology of the tumor. (A) and (B) Low-power view of the tumor. Leaf-like structures with a broad fibrous stroma are present in multiple cystic cavities (A). The tumor is connected to the cyst wall through a stalk-like structure (arrowhead) (B). H-E stain. (C) and (D) Higher magnification shows mildly cellular fibrous stroma covered by thick epithelial layers. Inner surface of the cyst wall is covered by flat epithelium (arrowhead) (D). H-E stain. (E) High-power micrograph depicts bland-looking, plump stromal cells and prominent hyperplasia of multilayered epithelial cells with frequent mitotic figures (arrowheads). H-E stain. (F) Immunohistochemistry (p63). Myoepithelial cells positively stained for p63 are orderly arranged at the basal portion of the epithelium. Scale bars: 1 mm (A and B), 500 μm(C),200μm (D and F) and 100 μm (E). fibroblasts being plump but showing no nuclear atypia and papillary carcinoma. Immunostaining for p63 clearly very few mitotic figures (b1 per 10 high-power fields demonstrated the presence of myoepithelial cells orderly [HPF]), and loose or dense collagenous matrix (Fig. 2C–E). arranged at the basal layer of the epithelium (Fig. 2F). Based In contrast, hyperplasia of epithelial cells covering the upon these findings, a pathological diagnosis of “JFA with stromal projections was striking, constituting a thick, features of PT” was made. pseudostratified epithelium with slit-like structures and frequent mitotic figures (7 per 10 HPF) (Fig. 2C–E). On Ki-67 immunostaining, approximately 20% of epithelial 4. Discussion cells were positive. However, the epithelial cells were bland-looking with variable nuclear configurations and no Cellular FA, including JFA, and benign PT, which fall increase of chromatin, being inconsistent with the features of into the same spectrum of benign fibroepithelial lesions, 4 J. Miyauchi et al.

Table 1 Summary of patients with intraductal PT or FA reported in the literature. Case Ref. no. Age Location of Pathology Therapy Follow-up Recurrence no. (year) (year/sex) tumor and period nipple discharge 1 [6] (1998) 62/F Rt. U/O Borderline PT Wide excision 2 y None 2 [7] (2001) 13/F Rt. subareolar, bloody Benign PT Excision through 15 mo None discharge (+) circumareolar incision 3 [8] (2007) 45/F Lt., behind the nipple, Benign PT + ADH (2 Microdochectomy + wide 12 mo None clear discharge (+) lesions) local excision 4 [9] (2008) 33/F Lt., L/O Intraductal Excision through ND ND fibroadenomatosis with circumareolar incision overlapping features of FA, benign PT, IDP and ductal adenoma 5 [10] (2009) 13/F Rt. FA + IDP + areas Wide local excision ND ND resembling PT 6 [10] (2009) 60/F Rt., U/O FA + IDP + low-grade Wide local excision ND ND PT features 7 [11] (2013) 12/F Rt. L/O, bloody Benign PT Wide local excision 14 mo None discharge (+) 8 [12] (2014) 11/F Lt., under the nipple, FA (with benign PT Simple excision 6 mo None bloody discharge (+) features) + focal IDP present 11/F Rt., O/U-L Juvenile FA with Simple excision 3 y None case features of benign PT and IDP Abbreviations: FA, fibroadenoma; PT, phyllodes tumor; ADH, atypical ductal hyperplasia; IDP, intraductal papilloma. O, L and U represent outer, lower and upper quadrant of the breast, respectively. ND, not described. sometimes show a very similar histology, and distinction region, indicating that intraductal growth can occur at a site between the two could be difficult and arguably arbitrary apart from the nipple. It has been reported that PT arises from [5]. In intracanalicular FA, leaf-like structures are the stroma around the interlobular ducts rather than basically absent or, even if present, few in number, intralobular stroma [7,11], which may explain the histogen- localized in only a minor part of the tumor and incomplete esis of intraductal PT. It is plausible that periductal and, therefore, well-developed fronds along with stromal overgrowth of the fibrous stroma involving an interlobular hypercellularity are an indication of benign PT. In our duct causes stenosis or obstruction of the duct lumen, leading patient, the tumor had a cellular stroma and was to ductal fluid retention and dilation of the distal portion of exaggerated with a disproportionally expanded stromal the duct, and that the tumor protrudes into these dilated component and a wide-spread phyllodes pattern, thus ducts. Although FA is thought to arise from the terminal duct closely resembling PT. However, the tumor stroma was lobular unit [5], FAs exhibiting such unusual intraductal only slightly cellular, which was not diagnostic for PT. growth may arise around interlobular ducts as in the case of From these findings along with florid epithelial hyperpla- PT, and the above mechanism seems to be applicable to sia, which is also a characteristic of JFA, and the age of intraductal FAs as well. The tumor in our case was located in the patient (11 years), we diagnosed the tumor as “JFA multiple contiguous cystic cavities rather than in a single with features of PT”. cyst, a finding similar to that described by Lian et al. [8]. This In fibroepithelial tumors, including FA and PT, cyst growth pattern also appears to be explained by the above formation within a tumor may be occasionally seen, but mechanism: the tumor might have caused bending and intraductal/intracystic tumor growth is extremely rare, with twisting of a single interlobular duct or, alternatively, might only a small number of such cases having been described in have arisen near the branching ducts, where the tumor could the literature [6–12] (Table 1), and its mechanism is have caused the cystic dilatation of multiple ducts and unknown. The tumor in a 13-year-old girl reported by protruded simultaneously into multiple cystic lumens. Martino et al. [7] was present in the subareolar region and In addition to the unusual intraductal/intracystic growth, protruded from the nipple, indicating that it arose near the marked epithelial proliferation was seen in the present case. large subareolar duct and grew toward the duct lumen. The Due to both of these features, namely, papillary protrusions tumors reported by Lian et al. [8] and Hayano et al. [12] were into the cystic space and hyperplastic, pseudostratified, thick also located adjacent to the nipple, showing discharge, but epithelial layers, both of which are also the characteristics of the other cases seem to be present outside the subareolar IDP, the histology of the tumor showed some similarities to 5

IDP. Although broad leaf-like fibrous stroma in our case is that simple excision could be sufficient therapy for not consistent with the diagnosis of IDP, which typically has intraductal fibroepithelial tumors, including PT and those a delicate branching fibrovascular stromal core, stromal with features of PT. However, the number of patients fibrosis is not uncommon and can be extensive in IDP, reported is too small, and so additional cases need to be leading to a diagnosis of sclerosing papilloma. In fact, in a analyzed before any conclusion is made. case of intraductal benign PT, the preoperative biopsy specimen led to a suspected diagnosis of sclerosing papilloma [7]. Furthermore, Chung et al. [9] described a References very unusual ill-defined breast lesion comprised of admixed fibroadenomatous polypoid structures and IDP-like compo- [1] Pettinato G, Manivel JC, Kelly DR, et al. Lesions of the breast in nents within multiple dilated ducts. Cummings et al. [10] children exclusive of typical fibroadenoma and gynecomastia. A described two cases of breast tumors with overlapping clinicopathologic study of 113 cases. Pathol Annu 1989;24(Pt 2): features of IDP and FA or low-grade PT concomitant within 296-328. [2] Dehner LP, Hill DA, Deschryver K. Pathology of the breast in the same ducts. They found intermediate or transitional children, adolescents, and young adults. Semin Diagn Pathol 1999;16: features between the two and suggested that these different 235-47. types of lesion, namely, intraductal FA/PT and IDP, develop [3] Pike AM, Oberman HA. Juvenile (cellular) adenofibromas. A along a common/similar pathway. The findings of our case, clinicopathologic study. Am J Surg Pathol 1985;9:730-6. sharing features of intraductal JFA and IDP, are consistent [4] Mueller J, Wilcox R, Taxy JB. The breast. In: Stocker TJ, Dehner LP, Husain AN, editors. Pediatric pathology. Philadelphia, USA: Lippincott with the above hypothesis. Williams & Wilkins; 2011. p. 897-910. The wide local excision of tumors with adequate normal [5] Tan PH, Tse G, Lee A, et al. Fibroepithelial tumours. In: Lakhani SRE, marginal tissues is generally recommended as the initial Ian O, Schnitt SJ, Tan PH, van de Vijver MJ, editors. WHO therapy for PT. Although the tumor in the present case classification of tumours of the breast. Geneva, Switzerland: WHO extensively showed features of PT, the patient underwent Press; 2011. p. 142-7. [6] Horiguchi J, Iino Y, Aiba S, et al. Phyllodes tumor showing intracystic follow-up without the additional surgical excision of growth: a case report. Jpn J Clin Oncol 1998;28:705-8. marginal tissues since the tumor was diagnosed as JFA, [7] Martino A, Zamparelli M, Santinelli A, et al. Unusual clinical and there have been no signs of recurrence for 3 years. The presentation of a rare case of phyllodes tumor of the breast in an previously reported cases of intraductal/intracystic fibroe- adolescent girl. J Pediatr Surg 2001;36:941-3. pithelial tumors, including PT, were mostly benign [7–12] [8] Lian D, Cheah E, Tan PH, et al. Phyllodes tumour with intraductal growth: a rare cause of nipple discharge. Histopathology 2007;50:666-9. with some borderline tumors [6,10], and no patient showed [9] Chung A, Scharre K, Wilson M. Intraductal fibroadenomatosis: an recurrence during the 6-month to 2-year follow-up period unusual variant of fibroadenoma. Breast J 2008;14:193-5. (Table 1). Although wide local excision was performed for [10] Cummings MC, da Silva L, Papadimos DJ, et al. Fibroadenoma and the majority of patients, the favorable outcome of these intraduct papilloma—a common pathogenesis? Virchows Arch 2009; patients, including our case, may be due to the mostly benign 455:271-5. [11] Makidono A, Tsunoda H, Mori M, et al. Phyllodes tumor showing histology of the tumors, localized growth pattern confined to intraductal growth. Breast Cancer 2013;20:275-8. intraductal spaces, and/or generally young age (5 out of 9 [12] Hayano F, Yamada S, Nakano S, et al. Intraductal fibroadenoma under patients were between 11 and 13 years of age), indicating the nipple in an 11-year-old female. Diagn Pathol 2014;9:32.