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Pathology – Research and Practice 201 (2005) 333–339

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TEACHING CASE

Pleomorphic adenoma (benign mixed tumor) of the breast:

A case report and review of the literature

Katsuaki Satoa, Yoshimichi Uedaa,�, Miyako Shimasakia, Mamoru Ozakib,Naoki Nittac, Kiran Chadad, Yoshimaro Ishikawaa, Shogo Katsudaa

aDepartment of Pathophysiological and Experimental Pathology, Kanazawa Medical University, 1-1 Daigaku,

Uchinada, Kahoku-gun, Ishikawa, 920-0293, JapanbDivision of Human Genetics, Clinical Genetics, Kanazawa Medical University, Ishikawa, JapancSuzuki Lady’s Hospital, Kanazawa, JapandDepartment of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, NJ, USA

Received 13 August 2004; accepted 7 March 2005

Abstract

We report a case of pleomorphic adenoma (benign mixed tumor) of the breast, which is an extremely rare locationfor this tumor. Examination of a 55-year-old woman unexpectedly revealed a mass measuring 0.8 cm in diameter in thesubareolar region of the right breast. Excisional biopsy was performed, and the tumor histologically showedpleomorphic adenoma composed of duct epithelial cells, myoepithelial cells, and a myxochondroid matrix.Immunohistochemically, duct epithelial cells were positive for the estrogen receptor, but negative for the progesteronereceptor. The nuclei of the spindle and myoepithelial cells were immunoreactive for HMGI-C and HMGI(Y) proteins,indicating a histogenesis similar to pleomorphic adenoma of the salivary glands. Interphase fluorescence in situhybridization performed on paraffin-embedded tissue sections with 12q15 probes and a 6p21 probe demonstrated nochromosomal rearrangement. Sixty-nine cases of this type of tumor arising in the breast have been describedpreviously. Using imaging procedures, the tumor has occasionally been misdiagnosed as malignant clinically and evenpathologically in frozen section diagnosis. Careful diagnosis based on paraffin sections is required to avoidunnecessary aggressive surgery, and pathologists should include pleomorphic adenoma in the differential diagnosis ofa demarcated, juxtaareolar, small hard mass.r 2005 Elsevier GmbH. All rights reserved.

Keywords: Pleomorphic adenoma; Breast; HMGA2 (HMGI-C); HMGIY; FISH

Introduction

Pleomorphic adenoma (benign mixed tumor) is anuncommon benign type of tumor occurring in thebreast, although it is the most common tumor type in

e front matter r 2005 Elsevier GmbH. All rights reserved.

p.2005.03.004

ng author. Tel.: +8176 218 8119;

2484.

ss: z-ueda@kanazawa-med.ac.jp (Y. Ueda).

the salivary gland. Only 69 cases have been previouslydescribed in the literature [20]. The tumor is character-istically composed of epithelial cells, myoepithelial cells,and mesenchymal stroma. Diagnosis rendered byclinical examination and imaging studies is difficult,and frozen sections of restricted areas are potentiallymisdiagnosed as malignant.Chromosomal translocations have been demonstrated

in 50–80% of pleomorphic adenoma of the salivary

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glands [3]. The frequent rearrangements involve chro-mosomes 12 (12q15), leading to activation of the highmobility group protein gene HMGA2 (HMGI-C), whichis a key event in the histogenesis of pleomorphicadenoma of the salivary glands [9]. Few cases of salivarygland pleomorphic adenoma have affected chromo-some 6 (6p21), and the breakpoint of translocation ismapped distal to HMGIY [21]. However, the rearrange-ments involving 12q15 or 6p21 in the pleomorphicadenoma of the mammary glands have not yet beenanalyzed [8].We report an additional case of pleomorphic adeno-

ma of the breast for which we carried out animmunohistochemical study, conducted interphasefluorescence in situ hybridization (FISH) analysis todetect chromosome rearrangement, and reviewed theEnglish literature.

Case report

Medical examination of a 55-year-old woman un-expectedly revealed a small bean-sized mass in thesubareola of the right breast. There was no pain ornipple discharge. The patient had no distinctive past orfamily history. The tumor was located below the rightmargin of the areola and did not adhere to thesurrounding tissue. An excisional biopsy was performed.

Materials and methods

The biopsy specimen was fixed in formalin andembedded in paraffin, and 5-mm-thick tissue sectionswere used for staining with hematoxylin and eosin,immunohistochemical study, and interphase FISHanalysis.Immunohistochemical studies were carried out using

the avidin-biotin-peroxidase complex method of Hsuand co-workers [11]. The deparaffinized sections werestained with primary antibodies against cytokeratin(monoclonal CAM5.2, Becton Dickinson, San Jose,CA, prediluted), EMA (monoclonal E29, DakoCytoma-tion, Glostrup, Denmark, 1/50), a-smooth muscle actin(monoclonal 1A4, Sigma, St. Louis, MO, USA, 1/50),vimentin (monoclonal V9, DakoCytomation, 1/30),S-100 protein (polyclonal, DakoCytomation, 1/800),glial fibrillary acidic protein (polyclonal, DakoCyto-mation, 1/200), estrogen receptor (monoclonal 1D5,DakoCytomation, 1/50), progesterone receptor (mono-clonal PgR636, DakoCytomation, 1/50), HMGI-Cprotein (polyclonal, 1/1000) [32], and HMGI(Y) protein(polyclonal, 1/4000) [32].Interphase FISH was performed on the paraffin-

embedded tissue sections. Bacterial artificial chromo-

some probes were purchased from Invitrogen Corp.(Carlsbad, CA, USA). To detect chromosomal rearran-gement, RP11-18B8 labeled with digoxigenin and RP11-184C7 labeled with biotin were used for the 12q15probes, and RP11-513I15 labeled with biotin was usedfor the 6p21 probe. The RP11-18B8 was on about600 kb distantly 50 (centromeric), and the RP11-184C7was on about 800 kb distantly 30 (telomeric) of theHMGA2 gene. The RP11-513I15 fully covered theHMGIY gene. The slides were deparaffinized in xylenefor 10� 3min and then dehydrated in 100% ethanol for5� 3min, followed by washes in 1� phosphate-bufferedsaline (PBS). The slides were pretreated by microwavingin 10mmol/L citrate buffer (pH 6.0) for 15min and werethen put in 2� saline sodium citrate (SSC) at roomtemperature. The extracellular matrix in the tissuesection was digested using 0.8% type II collagenase(Sigma, St. Louis, MO, USA) for 20min at 37 1C. Theslides were rinsed in 1�PBS, dehydrated in a70%–80%–100% ethanol series, and then dried. TheDNA in the tissue sections and the probes weredenatured for 10min at 90 1C and then incubatedovernight at 37 1C. Washings were done at 37 1C for20min in 50% formamide, 2�SSC, then for 15min in1�SSC while shaken, followed by putting in 4� SSCfor 5min. Biotinylated probes were detected withfluorescein-isothiocyanate (FITC) conjugated to avidin(Roche Diagnostic, Basel, Switzerland). Digoxigenin-labeled probes were detected with rhodamine-conju-gated antidigoxigenin antibody (Roche). The washingswere done in 0.1% Tween 20 in 4� SSC for 10� 2minand in 4� SSC for 10min using a shaker, followed byputting in 2�SSC for 5min. The nuclei were counter-stained with a mounting medium with 40,6-diamidino-2-phenylindole (DAPI) (Vector, Burlingame, CA,USA). The probe signals were detected using afluorescence microscope with a digital camera, withFITC as green and rhodamine as red. For eachslide, more than 30 nuclei of tumor cells were analyzed.The composed images were reconstructed by computersoftware, Adobe Photoshop 6.0 (Adobe, San Jose,CA, USA).

Results

Macroscopically, the specimen showed a well-circum-scribed tumor measuring 0.8 cm in diameter. Micro-scopically, the tumor had a cohesive multi-nodularappearance without a fibrous capsule, and each nodulewas composed of proliferated ductal epithelial cells,myoepithelial cells, and myxochondroid stroma (Fig. 1).The ductal epithelial cells and myoepithelial cellsconsisted mainly of a double-layered tubular formationand the former focally trabecular arrangement (Fig. 2).

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Fig. 1. Low power view showing that the tumor is composed

of proliferated ductal epithelial cells, myoepithelial cells, and

myxochondroid stroma. � 40, H&E.

Fig. 2. Medium-power view showing that the ductal epithelial

cells and myoepithelial cells have a double-layered tubular

formation. � 100, H&E.

Fig. 3. High power view showing that spindle cells are merged

with the myxochondroid matrix. � 200, H&E.

Table 1. Immunohistochemical findings

Duct

epithelial

cells

Myoepithelial

cells

Spindle

cells

Cytokeratin

(CAM5.2)

+ � �

EMA + � �

a-SMA � + +

Vimentin � + W+

S-100 protein + + +

GFAP � W+ W+

Estrogen receptor + � �

Progesterone

receptor

� � �

HMGI-C protein � + +

HMGI(Y)

protein

� + +

EMA, epithelial membrane antigen; SMA, smooth muscle actin;

GFAP, glial fibrillary acidic protein; HMG, high-mobility group; +,

positive; �, negative; W, weak.

K. Sato et al. / Pathology – Research and Practice 201 (2005) 333–339 335

Apocrine metaplasia was partially seen. The myxochon-droid area was situated in the central portion of thenodule intermingled with spindle cells (Fig. 3). Cytolo-gical atypia was not evident in any of the components.Table 1 summarizes the immunohistochemical find-

ings of the present case. Duct epithelial cells wereimmunoreactive for the estrogen receptor (Fig. 4). Thenuclei of the myoepithelial and spindle cells werepositive for HMGI-C protein (Fig. 5) and HMGI(Y)protein (Fig. 6).Interphase FISH analysis of paraffin-embedded tissue

revealed no split with the 12q15 probes or the 6p21probe. The nuclei exhibited two green and two redsignals as paired spots with the former probe (Fig. 7)and two green spots with the latter (Fig. 8).

Discussion

Pleomorphic adenoma is the most common benigntumor type of the salivary glands. An analogous tumoroccurring in the sweat glands of the subcutaneous tissueis termed chondroid syringoma. Tumors that occur atrare sites such as the palate, maxillary sinus, nasalseptum, larynx, tracheobronchus, lungs, and lacrimalglands have also been reported [15].Pleomorphic adenoma of the breast is extremely rare.

The first case of breast pleomorphic adenoma wasdescribed in French by Lecene in 1906 [12]. Smith andTaylor [25] reported nine cases in English, and they

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Fig. 5. Immunohistochemistry for the HMGI-C protein. The

nuclei of the myoepithelial and spindle cells were positive.

� 100, HMGI-C.

Fig. 4. Immunohistochemistry for the estrogen receptor. Duct

epithelial cells were positive. � 200, Estrogen receptor.

Fig. 6. Immunohistochemistry for the HMGI(Y) protein. The

nuclei of the myoepithelial and spindle cells were positive.

� 100, HMGI(Y).

Fig. 7. Interphase FISH analysis with the 12q15 probes. The

paired two green and two red spots in a nucleus show no split.

Fig. 8. Interphase FISH analysis with the 6p21 probe. Two

green spots in a nucleus show no split.

K. Sato et al. / Pathology – Research and Practice 201 (2005) 333–339336

believed that the tumors were intraductal papillomaswith areas of chondroid and osseous metaplasia of thestroma rather than a separate neoplastic entity. Othersregarded these cases as separate entities or pleomorphicadenoma. Nevertheless, it was also believed that the ninecases were similar, but not identical, to pleomorphicadenoma of the salivary gland type [5]. Intraductalpapilloma extremely rarely contains a cartilage or bonecomponent [20,27]; therefore, the cases are likely to bepleomorphic adenoma. Only 69 cases of pleomorphicadenoma of the breast have been described in theliterature so far [20].Table 2 lists the clinicopathological features of cases

reported in the English literature. A few Oriental caseshave been reported, and Narita et al. [17] point outdifferences in lifestyle such as lactation between Oriental

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and Western women. This type of tumor has beenreported almost entirely in women except for three casesaffecting men [6,14,24], and it occurs between 23 and 85years of age. Tumor size ranged between 0.6 and 17 cm,which was the maximum diameter, and most werearound 2 cm. One patient had a 17-cm-diameter tumorthat lasted, unusually, for 30 years [31]. There was aslight tendency for the tumors to occur on the right side(R:L ¼ 3:2). There was a strong tendency for the tumorsto be located in the juxtaareolar area, suggesting that thetumor originates from the large duct [29].Pleomorphic adenoma is characteristically composed

of epithelial cells, myoepithelial cells, and myxochon-droid and/or osseous matrices. There are many reportsin the literature that describe myoepithelial cell pro-liferation as a key factor in tumorigenesis [2,5,12,23].Narita et al. [17] suggest the essential role of ductal cellsthat have the multipotentiality to differentiate intomyoepithelial cells. Myxoid stroma was present in 32cases, chondroid stroma in 26 cases and osteoid stromain 13 of 33 described cases. The differential diagnosis ofmyxochondroid and/or osseous stroma containingtumors of the breast includes fibroadenoma, phyllodestumor, stromal sarcoma, and adenocarcinoma withcartilaginous and/or osseous metaplasia [25,27]. Mostof these tumors can be clearly distinguished frompleomorphic adenoma on paraffin sections. Neverthe-less, frozen section of restricted areas may lead to a

Table 2. Clinicopathological features of pleomorphic adenoma of

Case Author [Reference] Age/Sex Size (cm

1–9 Smith and Taylor (1969) [25] 23–77/F 0.8–4.5

10 Williams et al. (1975) [31] 72/F 17

11 Sheth et al. (1978) [23] 74/F 1.5

12–14 Makek et al. (1980) [14] 35–78/F,2; M,1 1.5–4

15 McClure et al. (1982) [13] 46/F 2

16 Van der Walt et al. (1982) [29] 67/F 2.5

17 Spagnolo et al. (1983) [27] 46/F 1.5

18 Segen et al. (1986) [22] 75/F 1

19 Willen et al. (1986) [30] 76/F 2.5 and

20 Cuadros et al. (1987) [5] 65/F 2

21 Søreide et al. (1988) [26] 61/F 1.8

22 Ballance et al. (1990) [2] 77/F 2

23–28 Moran et al. (1990) [16] 37–85/F 1.0–4.0

29, 30 Chen et al. (1990) [4] 58, 75/F 0.7–1.3

31 Nevado et al. (1991) [18] 84/F 0.8

32–41 Diaz et al. (1991) [6] 50–68/F, 9; M, 1 0.6–5.0

42 Simha et al. (1992) [24] 65/M 2.5

43 Agnantis et al. (1992) [1] 62/F 3.2

44 Narita et al. (1995) [17] 70/F 1

45 Mochinaga et al. (1997) [15] 74/F 3

46 Ficks (1999) [7] 43/F 1.2

47 Reid-Nicholson et al. (2003) [20] 59/F 0.9

48 Present case (2005) 55/F 0.8

F, female; M, male; R, right; L, left; SA, subareolar; M, myxoid matrix; C,

misdiagnosis of malignant tumor, because epithelial cellspartially show a scirrhous-like pseudoinvasive patternand are associated with microcalcification in the centralor peripheral portion of the tumor [2,14]. It is essentialfor pathologists to include pleomorphic adenoma in thedifferential diagnosis of tumors forming chondroid orosteoid matrices.The immunohistochemical findings are analogous to

those of salivary gland pleomorphic adenoma. As forhormone receptors, the estrogen receptor was positive,but the progesterone receptor was negative for thenuclei of ductal epithelial cells in our study. Diaz et al.[6] and Fiks [7] reported the same results. Fibro-cystic disease formed the background of the tumor insix of 13 cases [5,13,16,22]. These findings suggest thattumor growth is influenced by the hormonal environ-ment [22].The overexpression of the HMGI-C and HMGI(Y)

protein in immunohistochemistry usually correlates withchromosomal rearrangement [28]. The detection ofaberrantly expressed protein by immunohistochemistrymay be more sensitive than by cytogenetics such askaryotyping or FISH study [28]. The immunohisto-chemically positive staining of the HMGI-C andHMGI(Y) protein in the tumor cells of the present casesuggests that breast pleomorphic adenoma may alsoshow an abnormal expression of HMGI-C or HMGI(Y)protein.

the breast in the English-language literature

) Location Stroma Treatment

C, 9; O, 6 Excision, 7; Mastectomy, 2

R M, C, O Mastectomy

R, SA M, C, O Excision

R,2; L,1 M,2; C, 2; O, 1 Excision, 2; Mastectomy, 1

R, SA M Excision

L, SA M, C, O Excision

R, SA M, C, O Excision

L, SA M, C Excision

1.7 R, SA M, C Mastectomy

R, SA M, C Excision

L, SA M, C Excision

R, SA M, C, O Excision

L, 2; R, 3 Excision, 5; Mastectomy, 1

L, SA M,2; C, 2 Excision, 1; Mastectomy, 1

L, SA M, C Excision

M, 10; C, 6; O, 4 Excision, 8; Mastectomy, 2

R M, C Excision

L, SA M, C, O Mastectomy

R, SA M, C, O Excision

L, SA M, C Excision

R M, C, O Excision

R M Excision

R, SA M, C Excision

chondroid matrix; O, osteoid matrix.

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The interphase FISH in our study revealed no splitwith the 12q15 or 6p21 probe. Although the majority ofbreakpoints in HMGA2 occur within the third intron,the breakpoints in HMGA2 in cases of uterine leiomyo-ma could be mapped 4100 kb 50 upstream of the gene[19]. As the 12q15 probes used in our study were locatedat about 600 kb 50 (centromeric) of HMGA2 and atabout 800 kb 30 (telomeric) of HMGA2, it would bereasonable to assume that most of the presumedrearrangements around HMGA2 could be detected assplits. The preferential breakpoint in mesenchymaltumors of HMGIY is 30 (centromeric) outside the gene.The 6p21 probe used in our study was about 180 kb,fully covering HMGIY. Although the 30 (centromeric)end of the probe was 70 kb downstream of the gene, thepossibility of the breakpoint being located outside theregion covered with this probe cannot be excluded.Further studies are required to elucidate the exactactivation mechanisms of HMGA2 and HMGI(Y).The therapeutic procedures performed on the tumor

in the reported cases were mastectomy in eight cases(coincident invasive ductal carcinoma in one case) andexcision in 31 cases. There was local recurrence in twocases [6,26]. Multiple occurrence was also proposed bySheth et al. [23], Willen et al. [30], and Moran et al. [16].A few rare cases of carcinoma ex-pleomorphic adenomaof the breast have recently been reported [10]. However,a case with metastasis has not yet been described.Pleomorphic adenoma of the breast is a demarcatedbenign tumor, and local excision with clear margins is anappropriate treatment [16]. Careful diagnosis based onparaffin sections is necessary to prevent unnecessarysurgical overresection. It is essential that pathologistsconsider the diagnosis of pleomorphic adenoma for awell-circumscribed, juxtaareolar small hard mass.

Acknowledgements

The authors thank Ms. Keiko Okazaki for theimmunohistochemistry. This work was partially sup-ported by a Grant for Collaborative Research ofKanazawa Medical University (C2003-2), and aGrant-in-Aid for Scientific Research (15590322) fromMinistry of Education, Science, and Culture, Japan.

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